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Revisiting Preclinical Observations of Several Histamine H3 Receptor AntagonistsInverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep-Wake Cycle Disorder.

A relationship appears to exist between dysfunction of brain histamine (HA) and various neuropsychiatric brain disorders. The possible involvement of brain HA in neuropathology has gained attention recently, and its role in many (patho)physiological brain functions including memory, cognition, and sleep-wake cycle paved the way for further research on the etiology of several brain disorders. Histamine H3 receptor (H3R) evidenced in the brains of rodents and humans remains of special interest, given its unique position as a pre- and postsynaptic receptor, controlling the synthesis and release of HA as well as different other neurotransmitters in different brain regions, respectively. Despite several disappointing outcomes for several H3R antagonistsinverse agonists in clinical studies addressing their effectiveness in Alzheimers disease (AD), Parkinsons disease (PD), and schizophrenia (SCH), numerous H3R antagonistsinverse agonists showed great potentials in modulating memory and cognition, mood, and sleep-wake cycle, thus suggesting its potential role in neurocognitive and neurodegenerative diseases such as AD, PD, SCH, narcolepsy, and major depression in preclinical rodent models. In this review, we present preclinical applications of selected H3R antagonistsinverse agonists and their pharmacological effects on cognitive impairment, anxiety, depression, and sleep-wake cycle disorders. Collectively, the current review highlights the behavioral impact of developments of H3R antagonistsinverse agonists, aiming to further encourage researchers in the preclinical drug development field to profile the potential therapeutic role of novel antagonistsinverse agonists targeting histamine H3Rs.

Traditional Chinese Medicine as a Promising Strategy for the Treatment of Alzheimers Disease Complicated With Osteoporosis.

Alzheimers disease (AD) and osteoporosis (OP) are progressive degenerative diseases caused by multiple factors, placing a huge burden on the world. Much evidence indicates that OP is a common complication in AD patients. In addition, there is also evidence to show that patients with OP have a higher risk of AD than those without OP. This suggests that the association between the two diseases may be due to a pathophysiological link rather than one disease causing the other. Several

Low-Dose Anti-HIV Drug Efavirenz Mitigates Retinal Vascular Lesions in a Mouse Model of Alzheimers Disease.

A small dose of the anti-HIV drug efavirenz (EFV) was previously discovered to activate CYP46A1, a cholesterol-eliminating enzyme in the brain, and mitigate some of the manifestation of Alzheimers disease in 5XFAD mice. Herein, we investigated the retina of these animals, which were found to have genetically determined retinal vascular lesions associated with deposits within the retinal pigment epithelium and subretinal space. We established that EFV treatment activated CYP46A1 in the retina, enhanced retinal cholesterol turnover, and diminished the lesion frequency >5-fold. In addition, the treatment mitigated fluorescein leakage from the aberrant blood vessels, deposit size, activation of retinal macrophagesmicroglia, and focal accumulations of amyloid β plaques, unesterified cholesterol, and Oil Red O-positive lipids. Studies of retinal transcriptomics and proteomics identified biological processes enriched with differentially expressed genes and proteins. We discuss the mechanisms of the beneficial EFV effects on the retinal phenotype of 5XFAD mice. As EFV is an FDA-approved drug, and we already tested the safety of small-dose EFV in patients with Alzheimers disease, our data support further clinical investigation of this drug in subjects with retinal vascular lesions or neovascular age-related macular degeneration.

Association of Alzheimers disease and periodontitis - a systematic review and meta-analysis of evidence from observational studies.

The relationship between periodontitis (or periodontal disease) with Alzheimers disease has been reported by various primary sources in the past decade, but not with a solid secondary research statement. A systematic review and meta-analysis was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and registered (Reference number CRD42020185264) with PROSPERO (International prospective register for systematic reviews). A literature search was conducted on specific databases for suitable articles in English language. Out of 612 studies selected, 41 underwent full-text analysis five studies were eligible for systematic review, and 3 for meta-analysis. Meta-analysis was performed with tests for sensitivity and statistical heterogeneity followed by calculation of summary effect measures in terms of odds ratio (OR) and 95% confidence interval (CI). The results of this review showed a significant association between periodontitis and Alzheimers disease in the meta-analysis OR 1.67 (1.21-2.32).

Combined Multi-Atlas and Multi-Layer Perception for Alzheimers Disease Classification.

Alzheimers disease (AD) is a progressive and irreversible neurodegenerative disease. To distinguish the stage of the disease, AD classification technology challenge has been proposed in Pattern Recognition and Computer Vision 2021 (PRCV 2021) which provides the gray volume and average cortical thickness data extracted in multiple atlases from magnetic resonance imaging (MRI). Traditional methods either train with convolutional neural network (CNN) by MRI data to adapt the spatial features of images or train with recurrent neural network (RNN) by temporal features to predict the next stage. However, the morphological features from the challenge have been extracted into discrete values. We present a multi-atlases multi-layer perceptron (MAMLP) approach to deal with the relationship between morphological features and the stage of the disease. The model consists of multiple multi-layer perceptron (MLP) modules, and morphological features extracted from different atlases will be classified by different MLP modules. The final vote of all classification results obtains the predicted disease stage. Firstly, to preserve the diversity of brain features, the most representative atlases are chosen from groups of similar atlases, and one atlas is selected in each group. Secondly, each atlas is fed into one MLP to fetch the score of the classification. Thirdly, to obtain more stable results, scores from different atlases are combined to vote the result of the classification. Based on this approach, we rank 10th among 373 teams in the challenge. The results of the experiment indicate as follows (1) Group selection of atlas reduces the number of features required without reducing the accuracy of the model (2) The MLP architecture achieves better performance than CNN and RNN networks in morphological features and (3) Compared with other networks, the combination of multiple MLP networks has faster convergence of about 40% and makes the classification more stable.

Different Profiles of Spatial Navigation Deficits In Alzheimers Disease Biomarker-Positive Versus Biomarker-Negative Older Adults With Amnestic Mild Cognitive Impairment.

Spatial navigation impairment is a promising cognitive marker of Alzheimers disease (AD) that can reflect the underlying pathology. We assessed spatial navigation performance in AD biomarker positive older adults with amnestic mild cognitive impairment (AD aMCI) vs. those AD biomarker negative (non-AD aMCI), and examined associations between navigation performance, MRI measures of brain atrophy, and cerebrospinal fluid (CSF) biomarkers. A total of 122 participants with AD aMCI ( In route learning, AD aMCI performed worse than non-AD aMCI ( AD biomarker positive and negative older adults with aMCI had different profiles of spatial navigation deficits that were associated with posterior MTL and parietal atrophy and reflected AD pathology.

Deep Learning Model for Prediction of Progressive Mild Cognitive Impairment to Alzheimers Disease Using Structural MRI.

Alzheimers disease (AD) is an irreversible neurological disorder that affects the vast majority of dementia cases, leading patients to experience gradual memory loss and cognitive function decline. Despite the lack of a cure, early detection of Alzheimers disease permits the provision of preventive medication to slow the diseases progression. The objective of this project is to develop a computer-aided method based on a deep learning model to distinguish Alzheimers disease (AD) from cognitively normal and its early stage, mild cognitive impairment (MCI), by just using structural MRI (sMRI). To attain this purpose, we proposed a multiclass classification method based on 3D T1-weight brain sMRI images from the ADNI database. Axial brain images were extracted from 3D MRI and fed into the convolutional neural network (CNN) for multiclass classification. Three separate models were tested a CNN built from scratch, VGG-16, and ResNet-50. As a feature extractor, the VGG-16 and ResNet-50 convolutional bases trained on the ImageNet dataset were employed. To achieve classification, a new densely connected classifier was implemented on top of the convolutional bases.

A Reparametrized CNN Model to Distinguish Alzheimers Disease Applying Multiple Morphological Metrics and Deep Semantic Features From Structural MRI.

It is of potential clinical value to improve the accuracy of Alzheimers disease (AD) recognition using structural MRI. We proposed a reparametrized convolutional neural network (Re-CNN) to discriminate AD from NC by applying morphological metrics and deep semantic features. The deep semantic features were extracted through Re-CNN on structural MRI. Considering the high redundancy in deep semantic features, we constrained the similarity of the features and retained the most distinguishing features utilizing the reparametrized module. The Re-CNN model was trained in an end-to-end manner on structural MRI from the ADNI dataset and tested on structural MRI from the AIBL dataset. Our proposed model achieves better performance over some existing structural MRI-based AD recognition models. The experimental results show that morphological metrics along with the constrained deep semantic features can relatively improve AD recognition performance. Our code is available at httpsgithub.comczp19940707Re-CNN.

Decreased Cerebral Amyloid-β Depositions in Patients With a Lifetime History of Major Depression With Suspected Non-Alzheimer Pathophysiology.

Cerebral amyloid-β (Aβ) depositions in depression in old age are controversial. A substantial proportion of individuals with late-life major depressive disorder (MDD) could be classified as having suspected non-Alzheimers disease pathophysiology (SNAP) by a negative test for the biomarker amyloid-β (Aβ-) but positive neurodegeneration (ND). This study aimed to evaluate subthreshold Aβ loads in amyloid-negative MDD, particularly in SNAP MDD patients. This study included 46 amyloid-negative MDD patients 23 SNAP (Aβ-ND) MDD and 23 Aβ-ND- MDD, and 22 Aβ-ND- control subjects. All subjects underwent

Physical Exercise-Induced Astrocytic Neuroprotection and Cognitive Improvement Through Primary Cilia and Mitogen-Activated Protein Kinases Pathway in Rats With Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is closely related to vascular cognitive impairment and dementia (VCID) and Alzheimers disease (AD). The neuroinflammation involving astrocytes is an important pathogenic mechanism. Along with the advancement of the concept and technology of astrocytic biology, the astrocytes have been increasingly regarded as the key contributors to neurological diseases. It is well known that physical exercise can improve cognitive function. As a safe and effective non-drug treatment, physical exercise has attracted continuous interests in neurological research. In this study, we explored the effects of physical exercise on the response of reactive astrocytes, and its role and mechanism in CCH-induced cognitive impairment. A rat CCH model was established by 2 vessel occlusion (2VO) and the wheel running exercise was used as the intervention. The cognitive function of rats was evaluated by morris water maze and novel object recognition test. The phenotypic polarization and the primary cilia expression of astrocytes were detected by immunofluorescence staining. The activation of MAPKs cascades, including ERK, JNK, and P38 signaling pathways, were detected by western blot. The results showed that physical exercise improved cognitive function of rats 2 months after 2VO, reduced the number of C3GFAP-positive neurotoxic astrocytes, promoted the expression of S100A10GFAP-positive neuroprotective astrocytes, and enhanced primary ciliogenesis. Additionally, physical exercise also alleviated the phosphorylation of ERK and JNK proteins induced by CCH. These results indicate that physical exercise can improve the cognitive function of rats with CCH possible by promoting primary ciliogenesis and neuroprotective function of astrocytes. The MAPKs signaling cascade, especially ERK and JNK signaling pathways may be involved in this process.

Age-Related Midbrain Inflammation and Senescence in Parkinsons Disease.

Immune responses are arising as a common feature of several neurodegenerative diseases, such as Parkinsons disease (PD), Alzheimers disease (AD), and Amyotrophic Lateral Sclerosis (ALS), but their role as either causative or consequential remains debated. It is evident that there is local inflammation in the midbrain in PD patients even before symptom onset, but the underlying mechanisms remain elusive. In this mini-review, we discuss this midbrain inflammation in the context of PD and argue that cellular senescence may be the cause for this immune response. We postulate that to unravel the relationship between inflammation and senescence in PD, it is crucial to first understand the potential causative roles of various cell types of the midbrain and determine how the possible paracrine spreading of senescence between them may lead to observed local immune responses. We hypothesize that secretion of pro-inflammatory factors by senescent cells in the midbrain triggers neuroinflammation resulting in immune cell-mediated killing of midbrain dopaminergic (DA) neurons in PD.

Novel Stilbene-Nitroxyl Hybrid Compounds Display Discrete Modulation of Amyloid Beta Toxicity and Structure.

Several neurodegenerative diseases are driven by misfolded proteins that assemble into soluble aggregates. These toxic oligomers have been associated with a plethora of cellular dysfunction and dysregulation, however the structural features underlying their toxicity are poorly understood. A major impediment to answering this question relates to the heterogeneous nature of the oligomers, both in terms of structural disorder and oligomer size. This not only complicates elucidating the molecular etiology of these disorders, but also the druggability of these targets as well. We have synthesized a class of bifunctional stilbenes to modulate both the conformational toxicity within amyloid beta oligomers (AβO) and the oxidative stress elicited by AβO. Using a neuronal culture model, we demonstrate this bifunctional approach has the potential to counter the molecular pathogenesis of Alzheimers disease in a powerful, synergistic manner. Examination of AβO structure by various biophysical tools shows that each stilbene candidate uniquely alters AβO conformation and toxicity, providing insight towards the future development of structural correctors for AβO. Correlations of AβO structural modulation and bioactivity displayed by each provides insights for future testing

Changes in Adiposity and Cerebrospinal Fluid Biomarkers Following a Modified Mediterranean Ketogenic Diet in Older Adults at Risk for Alzheimers Disease.

Ketogenic diets have been used to treat both obesity and neurological disorders, including epilepsy and more recently Alzheimers disease (AD), likely due to favorable effects on both central and peripheral metabolism. Improvements in body composition have also been reported however, it is unclear if diet-induced changes in adiposity are related to improvements in AD and related neuropathology. We examined the effects of a Modified Mediterranean Ketogenic (MMK) diet vs. an American Heart Association (AHA) diet on body weight, body composition, and body fat distribution and their association with cerebrospinal fluid (CSF) biomarkers in older adults at risk for AD. Twenty adults (mean age 64.3 ± 6.3 years, 35% Black, 75% female) were randomly assigned to a crossover trial starting with either the MMK or AHA diet for 6 weeks, followed by a 6-week washout and then the opposite diet for 6 weeks. At baseline and after each diet adiposity was assessed by dual-energy x-ray absorptiometry and CSF biomarkers were measured. Linear mixed effect models were used to examine the effect of diet on adiposity. Spearman correlations were examined to assess associations between adiposity and CSF biomarkers. At baseline there was a high prevalence of overweightobesity and central adiposity, and higher visceral fat and lower peripheral fat were associated with an adverse CSF biomarker profile. The MMK and AHA diets led to similar improvements in body composition and body fat distribution. Significant correlations were found between changes in adiposity and changes in CSF biomarkers (rs 0.63-0.92, ps < 0.05), with notable differences by diet. Decreases in body fat on the MMK diet were related to changes in Aβ biomarkers, whereas decreases in body fat on the AHA diet were related to changes in tau biomarkers and cholinesterase activity. Interestingly, increases in CSF Aβ on the MMK diet occurred in those with less fat loss. An MMK diet leads to favorable changes in body composition, body fat distribution, and CSF biomarkers. Our data suggest that modest weight loss that maximizes visceral fat loss and preserves peripheral fat, may have the greatest impact on brain health. www.ClinicalTrials.gov, identifier NCT02984540.

The Coupled Representation of Hierarchical Features for Mild Cognitive Impairment and Alzheimers Disease Classification.

Structural magnetic resonance imaging (MRI) features have played an increasingly crucial role in discriminating patients with Alzheimers disease (AD) and mild cognitive impairment (MCI) from normal controls (NC). However, the large number of structural MRI studies only extracted low-level neuroimaging features or simply concatenated multitudinous features while ignoring the interregional covariate information. The appropriate representation and integration of multilevel features will be preferable for the precise discrimination in the progression of AD. In this study, we proposed a novel inter-coupled feature representation method and built an integration model considering the two-level (the regions of interest (ROI) level and the network level) coupled features based on structural MRI data. For the intra-coupled interactions about the network-level features, we performed the ROI-level (intra- and inter-) coupled interaction within each network by feature expansion and coupling learning. For the inter-coupled interaction of the network-level features, we measured the coupled relationships among different networks

Mapping the Spatial Distribution of Fibrillar Polymorphs in Human Brain Tissue.

Alzheimers disease (AD) is a neurodegenerative disorder defined by the progressive formation and spread of fibrillar aggregates of Aβ peptide and tau protein. Polymorphic forms of these aggregates may contribute to disease in varying ways since different neuropathologies appear to be associated with different sets of fibrillar structures and follow distinct pathological trajectories that elicit characteristic clinical phenotypes. The molecular mechanisms underlying the spread of these aggregates in disease may include nucleation, replication, and migration all of which could vary with polymorphic form, stage of disease, and region of brain. Given the linkage between mechanisms of progression and distribution of polymorphs, mapping the distribution of fibrillar structures

Previous reports on To investigate demographic distribution of A total of 632 participants were recruited (NC 243, SCDs 298, OCI 91). Total This study demonstrated that the distribution of

Alzheimers Disease, Hearing Loss, and Deviance Detection.

Age-related hearing loss is a widespread condition among the elderly, affecting communication and social participation. Given its high incidence, it is not unusual that individuals suffering from age-related hearing loss also suffer from other age-related neurodegenerative diseases, a scenario which severely impacts their quality of life. Furthermore, recent studies have identified hearing loss as a relevant risk factor for the development of dementia due to Alzheimers disease, although the underlying associations are still unclear. In order to cope with the continuous flow of auditory information, the brain needs to separate repetitive sounds from rare, unexpected sounds, which may be relevant. This process, known as deviance detection, is a key component of the sensory perception theory of predictive coding. According to this framework, the brain would use the available incoming information to make predictions about the environment and signal the unexpected stimuli that break those predictions. Such a system can be easily impaired by the distortion of auditory information processing that accompanies hearing loss. Changes in cholinergic neuromodulation have been found to alter auditory deviance detection both in humans and animal models. Interestingly, some theories propose a role for acetylcholine in the development of Alzheimers disease, the most common type of dementia. Acetylcholine is involved in multiple neurobiological processes such as attention, learning, memory, arousal, sleep andor cognitive reinforcement, and has direct influence on the auditory system at the levels of the inferior colliculus and auditory cortex. Here we comment on the possible links between acetylcholine, hearing loss, and Alzheimers disease, and association that is worth further investigation.

Changes in personality traits in patients with Alzheimers Disease.

Changes in personality traits in patients with Alzheimers disease (AD) are extremely common throughout the course of the pathology, and these behavioral changes present themselves as challenges in clinical management and as a significant cause of caregivers burden. Using a personality inventory based on the five-factor model of personality, this study aimed to assesses the change in these factors by comparing the premorbid and current personality of individuals recently diagnosed with AD. A total of 30 AD patients were recruited, and their respective family members responded to the personality inventory at home through a hosted site. The patients were also divided into two groups according to the Clinical Dementia Rating (CDR) mild dementia (CDR 1) and moderate dementia (CDR 2). Among all patients, there was a significant increase in neuroticism factor levels and a significant decrease in the extraversion, conscientiousness, openness, and socialization factors. When comparing the groups, only the extraversion factor showed a difference, with CDR 1 group accusing a higher change in scores. Higher scores in the factor neuroticism in the premorbid personality correlated with the current severity of the disease. This research draws the attention of family members and health professionals to changes in personality traits or behavior of relatives or patients, because it can reflect an underlying neurodegenerative process. Mudanças em traços de personalidade em pacientes com doença de Alzheimer (DA) são extremamente comuns ao longo do curso da referida patologia, e essas alterações comportamentais apresentam-se como desafios no manejo clínico e como causa significativa de esgotamento dos cuidadores. Por meio de um inventário de personalidade baseado nos cinco fatores de personalidade, este estudo avalia a mudança nos escores desses fatores comparando a personalidade pré-mórbida e a atual dos indivíduos com DA. O total de 30 pacientes com DA foi recrutado, e seus familiares responderam ao inventário de personalidade. Os pacientes também foram divididos em dois grupos conforme a avaliação clínica da demência demência leve (CDR1) e demência moderada (CDR2). Em todos os pacientes, houve aumento significativo nos escores do fator neuroticismo e decréscimos significativos nos fatores extroversão, realização, abertura e socialização. Quando feita a comparação entre grupos, apenas o fator extroversão apresentou diferença, com o grupo CDR 1 mostrando maiores mudanças nos escores. Os níveis do fator neuroticismo da personalidade pré-mórbida correlacionaram-se com a gravidade da doença no momento do diagnóstico. Este estudo procura esclarecer aos familiares e profissionais de saúde que mudanças em traços de personalidade de seus parentes ou pacientes podem refletir processos neurodegenerativos subjacentes.

Lithium Intoxication as a cause of reversible dementia mimicking FDG PET features of Alzheimers disease.

Rapidly progressive dementia (RPD) is a rare neurological disorder. Drug toxicity is among the differential diagnoses, including the use of lithium, in which an overdosage might cause cognitive dysfunction. Clinical suspicion, laboratory confirmation, and drug interruption are key points in the management of lithium intoxication. We described a 66-year-old female patient under treatment with lithium who developed an RPD associated with parkinsonian symptoms. Demência rapidamente progressiva é uma condição rara, cujos diagnósticos diferenciais incluem intoxicação por drogas como lítio, podendo causar importante disfunção cognitiva. A suspeita clínica, a confirmação laboratorial e a interrupção do uso medicamentoso são elementos fundamentais em seu diagnóstico e manejo. Trata-se de paciente feminina, de 66 anos de idade, que apresentou quadro demencial após intoxicação por lítio. Tal quadro foi acompanhado de sintomas parkinsonianos, além de Tomografia por Emissão de Pósitrons com 18F-Fluodeoxiglicose (

Effects of concert music on cognitive, physiological, and psychological parameters in the elderly with dementia a quasi-experimental study.

Non-pharmacological interventions, such as the use of music, have been shown to be important potential means of controlling adverse symptoms and signs resulting from chronic diseases already present in elderly patients with dementia. The objective of this study was to analyze the effects of concert music on cognitive and physiological parameters, and behavioral and psychological symptoms in institutionalized elderly people with dementia. A descriptive-exploratory, quantitative, quasi-experimental study was conducted with 14 elderly people. They were allocated in intervention group (IG) (n7) with eight sessions of music listening, once a week, for 2 months, and control group (CG) (n7) with the same procedure but without listening to the music. All participants were assessed by Neuropsychiatric Inventory Questionnaire (NPI-Q) and Addenbrookes Cognitive Examination - Revised (ACE-R) before and after the intervention. Blood pressure (BP) data were obtained heart rate (HR) and coherence were obtained through Cardioemotion during sessions. The data were analyzed using Fishers exact test and Students There was a predominance of female participants, who were widowed and diagnosed with Alzheimers disease (AD) in both groups. A statistically significant reduction was found in the mean of apathy reduction (p0.038) and the total mean of NPI-Q severity (p0.033) (paired Students Concert music had a positive effect on the behavior of institutionalized elderly. Stimuli and possibilities of improving the current behavioral conditions are observed. Intervenções não farmacológicas, como o uso da música, têm-se mostrado importantes meios potenciais de controlar os sintomas e sinais adversos decorrentes das enfermidades crônicas já instaladas em idosos com demência. Analisar o efeito da música de concerto sobre a cognição, parâmetros fisiológicos e sintomas comportamentais e psicológicos em idosos com demência institucionalizados. Estudo descritivo-exploratório, quantitativo, quase experimental, realizado com 14 idosos. Eles foram alocados em Grupo Intervenção (GI) (n7), com oito sessões de audição musical, uma vez por semana, durante dois meses e Grupo Controle (GC) (n7), com o mesmo procedimento, porém sem a audição da música. Todos os participantes foram avaliados pelo Neuropsychiatric Inventory Questionnaire (NPI-Q) e Addenbrooke’s Cognitive Examination – Revised (ACE-R) antes e depois do período da intervenção. Foram obtidos dados de pressão arterial, frequência e coerência cardíaca por meio do Em ambos os grupos houve predominância de participantes do sexo feminino, estado civil de viuvez e com diagnóstico de Alzheimer. Foi encontrada redução estatisticamente significativa na média do desgaste na apatia (p0,038) e média total do NPI-Q gravidade (p0,033) (teste A música de concerto teve efeitos positivos no comportamento dos idosos institucionalizados. Nota-se que, em geral, ela trouxe estímulos e possibilidades de melhoria das condições comportamentais atuais.

Effect of providing purple sweet potato water extract on tumor necrosis factor-α levels, protein 53 expression, glial fibrillary acidic protein expression, brain-derived neurotrophic factor levels, and spatial working memory in rats with d-galactose induction.

Alzheimers dementia (AD) is a neurodegenerative disease. The mechanism of oxidative stress in AD is due to amyloid beta (Aβ) protein that aggregates to form plaques, which further triggers chronic inflammation and neuronal apoptosis. Purple sweet potato extract with the main content of anthocyanins is a potential antioxidant with a direct target on the amyloid cascade hypothesis. The research objective was to determine the role of purple sweet potato water extract as an antioxidant and anti-inflammatory in preventing apoptosis in order to provide a neuroprotective effect in d-galactose-induced rats. A total of 100 male Wistar rats with randomized posttest-only control group design that met the eligibility criteria were included in this study. The treatment group was given 200 mgkg BWday of purple sweet potato water extract on days 1-70. d-galactose induction was administered in the treatment and control groups on days 15-70. The independent t-test showed that the mean tumor necrosis factor-α (TNF-α) levels in the treatment group (735.36±139.74) was significantly lower than that in the control group (896.77±152.52). The p53 and glial fibrillary acidic protein (GFAP) expressions of astrocyte cells in the treatment group were significantly lower than that in the control group. The brain-derived neurotrophic factor (BDNF) levels in the treatment group (498.13±121.47) were higher than that in the control (391.93±140.28), and there was a significant increase in spatial working memory in the treatment group (72.01±10.22) than the control (59.77±11.87). The neuroprotective effect of purple sweet potato extract is due to d-galactose induction resulting from decrease in TNF-α levels, p53 expression, and GFAP expression and increase in BDNF levels and spatial working memory. A doença de Alzheimer (DA) é uma doença neurodegenerativa. O mecanismo de estresse oxidativo na DA ocorre devido à proteína beta amilóide que se agrega para formar placas que desencadeiam inflamação crônica e apoptose neuronal. O extrato de batata-doce roxa composto principalmente por antocianinas é um potencial antioxidante com efeito direto sobre a hipótese da cascata amilóide. O objetivo da pesquisa foi determinar o papel do extrato aquoso de batata-doce roxa como antioxidante e anti-inflamatório na prevenção da apoptose, para proporcionar um efeito neuroprotetor em ratos induzidos por D-galactose. Grupo controle randomizado pós-teste com 100 ratos Wistar machos que preencheram os critérios de elegibilidade. O grupo de tratamento recebeu 200mgkg de peso corporaldia de extrato aquoso de batata-doce roxa nos dias 1-70. A indução de D-galactose foi testada nos grupos de tratamento e controle nos dias 15-70. O teste t independente mostrou que a média dos níveis de TNF-α no grupo de tratamento (735,36±139,74) foi significativamente menor do que no grupo controle (896,77±152,52). A expressão de p53 e a expressão de GFAP de células de astrócitos foram significativamente menores no grupo de tratamento do que no grupo controle. Os níveis de BDNF no grupo de tratamento (498,13±121,47) foram maiores que no grupo controle (391,93±140,28) e houve um aumento significativo da memória de trabalho espacial no grupo de tratamento (72,01±10,22) em relação ao controle (59,77±11,87). O efeito neuroprotetor do extrato de batata-doce roxa é devido à indução de D-galactose pela diminuição dos níveis de TNF-α, expressão de p53 e expressão de GFAP, aumentando assim os níveis de BDNF e memória espacial.

12-item version of Boston Naming Test usefulness in the diagnosis of primary progressive aphasia, frontotemporal dementia, and Alzheimers disease.

The 12-item version of the Boston Naming Test (BNT) was adapted to Argentina for the detection of dementia due to Alzheimers disease (AD), with scores similar to the original 60-item version (sensitivity and specificity of 85 and 94%, respectively) without demographic influence (age and educational level). To date, no publications on the use of abbreviated BNT in other degenerative pathologies with language impairment have been reported. The objective of this study was to evaluate the usefulness of 12-item BNT in primary progressive aphasia (PPA), the behavioral variant of frontotemporal dementia (FTDbv), and AD. Notably, 47 patients with probable AD (NIA-AA 2011) - clinical dementia rating (CDR) 0.5-1, 55 with FTDbv, 17 with PPA, and 46 controls were evaluated and matched for age and education. Exclusion criteria were as follows alcoholism, other previous neurological or psychiatric illnesses, and education <4 years. All were assessed with a full neuropsychological battery and a 12-item version of BNT. Median scores of 12-item BNT were as follows PPA 3.87 (SD2.99), AD 6.13 (SD3.03) FTDbv 8.41 (SD2.53) and controls 10.22 (SD1.82). Receiver Operating Characteristic (ROC) curves were plotted. The 12-item version of BNT can be useful, simple, and fast to identify and differentiate PPA, FTDbv, and AD from controls while retaining the discriminative ability of the original version. A versão de 12 itens do Teste de Nomeação de Boston (TNB) foi adaptada para a Argentina para a detecção de demência por doença de Alzheimer (DA), com escores semelhantes à versão original de 60 itens (sensibilidade e especificidade de 85 e 94%, respectivamente) sem influência demográfica (idade e escolaridade). Até o momento, não foram relatadas publicações sobre o uso do TNB abreviado em outras patologias degenerativas com comprometimento da linguagem. avaliar a utilidade do TNB de 12 itens na afasia progressiva primária (APP), na variante comportamental da demência frontotemporal (DFT) e na doença de Alzheimer (DA). 47 prováveis DA (NIA-AA 2011) — CDR 0,5–1, 55 DFT, 17 APP e 46 controles foram avaliados e pareados por idade e escolaridade. Critérios de exclusão alcoolismo, outras doenças neurológicas ou psiquiátricas prévias e escolaridade <4 anos. Todos foram avaliados com uma bateria neuropsicológica completa e versão de 12 itens do TNB. medianas das pontuações de 12 itens TNB APP 3,87 (DP2,99), DA 6,13 (DP3,03) DFT 8,41 (DP2,53) e Controles 10,22 (DP1,82). As curvas ROC foram traçadas. O TNB de 12 itens pode ser útil, simples e rápido para identificar e diferenciar APP, DFT e DA nos controles, mantendo a capacidade discriminativa da versão original.

Applicability of an immersive virtual reality system for assessing route learning in older adults.

Spatial orientation is defined as the ability to find ones way around an environment, follow familiar routes, recognize places, and learn new routes. Spatial disorientation is one of the early symptoms of Alzheimers disease (AD), and traditional cognitive evaluation lacks ecological validity. Therefore, new assessment methods are needed for the early identification of this cognitive impairment. This study aimed to compare the applicability and stability of an immersive virtual reality (VR) system developed to assess route learning between older adults with and without mild cognitive impairment (MCI). The study sample included 43 older adults 22 without MCI and 23 with MCI. Applicability was assessed based on the recording of adverse events and the sense of presence reported through questionnaires. The Mann-Whitney U test was applied to compare the applicability of the Spatial Orientation in Immersive Virtual Environment Test (SOIVET)-Route task between older adults with and without MCI. Both short- and long-term stabilities of the task were evaluated using the intraclass correlation coefficient (ICC). The mean age of participants was 71.4 years (SD5.5). A minimum number of adverse events (mean1.46 SD2.11) and high levels of presence (mean138.04 SD14.80) were reported, and there was no difference between groups with and without MCI. A good to excellent correlation was found for short-term stability (CCI 0.78) and a reasonable correlation was found for long-term stability (CCI 0.58). The VR system was applicable for older adults and showed a good to excellent correlation for short-term stability. Orientação espacial é a capacidade de encontrar um caminho em um ambiente, seguir rotas familiares, reconhecer lugares e aprender novas rotas. A desorientação espacial é um dos primeiros sintomas da doença de Alzheimer, e a avaliação cognitiva tradicional carece de validade ecológica. Diante disso, novos métodos de avaliação são necessários para a identificação precoce desse comprometimento cognitivo. Este estudo teve como objetivo comparar a aplicabilidade e a estabilidade de um sistema de realidade virtual imersivo desenvolvido para avaliar a aprendizagem de rotas entre idosos com e sem comprometimento cognitivo leve (CCL). Participaram do estudo 43 idosos 22 sem CCL e 23 com CCL. A aplicabilidade foi avaliada por meio do registro de eventos adversos e pela sensação de presença relatados. O teste de Mann-Whitney foi aplicado para comparar a aplicabilidade da tarefa SOIVET- A idade média dos participantes foi de 71,4 anos (desvio padrão — DP5,5). Em relação à aplicabilidade, encontramos mínimo relato de sintomas adversos (média1,46 DP2,11) e altos níveis de sensação de presença (média 138,04 DP14,80), e não houve diferença entre os grupos com e sem CCL. Ao analisarmos a estabilidade, encontramos de boa a excelente correlação em curto prazo (CCI0,78) e uma correlação razoável em longo prazo (CCI0,58). O sistema de realidade virtual foi aplicável em idosos e mostrou boa correlação na estabilidade de curto prazo.

DSNN A DenseNet-Based SNN for Explainable Brain Disease Classification.

Non-Coding RNAs as Novel Regulators of Neuroinflammation in Alzheimers Disease.

Alzheimers disease (AD) is one of the most common causes of dementia. Although significant breakthroughs have been made in understanding the progression and pathogenesis of AD, it remains a worldwide problem and a significant public health burden. Thus, more efficient diagnostic and therapeutic strategies are urgently required. The latest research studies have revealed that neuroinflammation is crucial in the pathogenesis of AD. Non-coding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), microRNAs (miRNAs), circular RNAs (circRNAs), PIWI-interacting RNAs (piRNAs), and transfer RNA-derived small RNAs (tsRNAs), have been strongly associated with AD-induced neuroinflammation. Furthermore, several ongoing pre-clinical studies are currently investigating ncRNA as disease biomarkers and therapeutic interventions to provide new perspectives for AD diagnosis and treatment. In this review, the role of different types of ncRNAs in neuroinflammation during AD are summarized in order to improve our understanding of AD etiology and aid in the translation of basic research into clinical practice.

Supplementation of Carvacrol Attenuates Hippocampal Tumor Necrosis Factor-Alpha Level, Oxidative Stress, and Learning and Memory Dysfunction in Lipopolysaccharide-Exposed Rats.

Carvacrol is a natural phenolic monoterpene with anti-inflammatory and antioxidant bioactivities. Neuroinflammatory and oxidative stress responses play a crucial role in the pathogenesis of Alzheimers disease. The present study examined the effect of carvacrol on brain tumor necrosis factor-alpha (TNF-α) level and oxidative stress as well as spatial learning and memory performances in lipopolysaccharide (LPS)-exposed rats. The rats were treated with either carvacrol (25 and 50 mgkg) or Tween 80 for 2 weeks. Thereafter, LPS (1 mgkg) or saline was intraperitoneally administered on days 15-19, 2 h before Morris water maze task, and treatments with carvacrol or Tween 80 were performed 30 min prior to behavioral testing. The level of TNF-α, lipid peroxidation, and total thiol concentration were measured in the hippocampus and cerebral cortex at the end of the experiment. It was found that LPS-exposed rats exhibited spatial learning and memory dysfunction, which was accompanied by increased TNF-α level and lipid peroxidation, and decreased total thiol concentration in the hippocampus andor cortex. Moreover, treatment with carvacrol at a dose of 25 mgkg attenuated learning and memory impairments, decreased TNF-α and lipid peroxidation level in the hippocampus and cortex, and increased total thiol concentration in the cortex. Carvacrol exerts neuroprotective effects against LPS-induced spatial memory deficits through attenuating hippocampal TNF-α level and oxidative stress in rats.

Casein Kinase 1 and Human Disease Insights From the Circadian Phosphoswitch.

Biological systems operate in constant communication through shared components and feedback from changes in the environment. Casein kinase 1 (CK1) is a family of protein kinases that functions in diverse biological pathways and its regulation is beginning to be understood. The several isoforms of CK1 take part in key steps of processes including protein translation, cell-cell interactions, synaptic dopaminergic signaling and circadian rhythms. While CK1 mutations are rarely the primary drivers of disease, the kinases are often found to play an accessory role in metabolic disorders and cancers. In these settings, the dysregulation of CK1 coincides with increased disease severity. Among kinases, CK1 is unique in that its substrate specificity changes dramatically with its own phosphorylation state. Understanding the process that governs CK1 substrate selection is thus useful in identifying its role in various ailments. An illustrative example is the PERIOD2 (PER2) phosphoswitch, where CK1δε kinase activity can be varied between three different substrate motifs to regulate the circadian clock.

Heightened Tameness and Accelerated Handling-Habituation in 3×Tg-AD Mice on a B6129 Genetic Background.

The triple transgenic mouse model of Alzheimers disease (3×Tg-AD) has gained popularity in Alzheimers research owing to the progressive development of both amyloid- We sought to determine whether 3×Tg-AD mice differ from B6129 genetic control mice in terms of tameness and prior habituation to handling. We devised hand-staying and hand-boarding assays to evaluate tameness in 3×Tg-AD and B6129 genetic control mice at 2.5, 7, and 11.5 months of age, representing cognitively pre-symptomatic, early symptomatic and advanced symptomatic stages of the disease, respectively. We monitored the progress of handling-habituation across 8-15 daily handling sessions and assessed the animal behaviors in elevated plus maze. We found that 3×Tg-AD mice were markedly tamer than age-matched control mice at the baseline. Whereas it took 2-3 days for 3×Tg-AD mice to reach the criteria for full tameness, it took an average of 7-9 days for young genetic control mice to do so. Prior handling-habituation enhanced risk assessment and coping strategy in mice in elevated plus maze. Completely handling-habituated mice exhibited comparable anxiety indices in the maze regardless of genotype and age. These findings collectively point to inherently heightened tameness and accelerated handling-habituation in 3×Tg-AD mice on a B6129 genetic background. These traits should be carefully considered when behaviors are compared between 3×Tg-AD and the genetic control mice.

Usability of the Virtual Supermarket Test for Older Adults with and without Cognitive Impairment.

This study conducted a preliminary usability assessment of the Virtual Supermarket Test (VST), a serious game-based self-administered cognitive screening test for mild cognitive impairment (MCI). Twenty-four healthy older adults with subjective cognitive decline and 33 patients with MCI self-administered the VST and then completed the System Usability Scale (SUS). The average SUS score was 83.11 (SD 14.6). The SUS score was unaffected by age, education, touch device familiarity, and diagnosis of MCI. SUS score correlated with VST performance (

Association Between the Cholinesterase Inhibitor Donepezil and the Cholinergic Precursor Choline Alphoscerate in the Treatment of Depression in Patients with Alzheimers Disease.

Depressive symptoms are common in Alzheimers disease (AD) patients and are associated with an increased functional decline. Selective serotonin reuptake inhibitor antidepressants showed a limited efficacy. The purpose of this work was to evaluate if a higher brain cholinergic stimulation induced by the association between the acetylcholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate has any effect on depression in AD patients. Patients were selected among those recruited in the ASCOMALVA (association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in AD) trial. Depressive symptoms were investigated in 90 AD patients through the neuropsychiatric inventory at baseline and after 3, 6, 9, 12, 18, and 24 months of treatment. Patients were randomized in a group association therapy (45 subjects) receiving donepezil 10 mg plus choline alphoscerate 1,200 mgday, and a group monotherapy (45 subjects) receiving donepezil 10 mgday plus placebo. Based on the results of the MMSE at the recruitment patients were divided into 3 groups severely impaired (score < 15) moderately impaired (score 19-16) mild-moderately impaired (score 24-20). Depression symptoms were significantly lower ( Depression symptoms of AD patients in the mild to moderate stage probably could to benefit of a stronger cholinergic stimulation induced by associating donepezil with the cholinergic precursor choline alphoscerate.

Progress Toward a Multiomic Understanding of Traumatic Brain Injury A Review.

Traumatic brain injury (TBI) is not a single disease state but describes an array of conditions associated with insult or injury to the brain. While some individuals with TBI recover within a few days or months, others present with persistent symptoms that can cause disability, neuropsychological trauma, and even death. Understanding, diagnosing, and treating TBI is extremely complex for many reasons, including the variable biomechanics of head impact, differences in severity and location of injury, and individual patient characteristics. Because of these confounding factors, the development of reliable diagnostics and targeted treatments for brain injury remains elusive. We argue that the development of effective diagnostic and therapeutic strategies for TBI requires a deep understanding of human neurophysiology at the molecular level and that the framework of multiomics may provide some effective solutions for the diagnosis and treatment of this challenging condition. To this end, we present here a comprehensive review of TBI biomarker candidates from across the multiomic disciplines and compare them with known signatures associated with other neuropsychological conditions, including Alzheimers disease and Parkinsons disease. We believe that this integrated view will facilitate a deeper understanding of the pathophysiology of TBI and its potential links to other neurological diseases.

Targeted Screening for Alzheimers Disease Clinical Trials Using Data-Driven Disease Progression Models.

Heterogeneity in Alzheimers disease progression contributes to the ongoing failure to demonstrate efficacy of putative disease-modifying therapeutics that have been trialed over the past two decades. Any treatment effect present in a subgroup of trial participants (responders) can be diluted by non-responders who ideally should have been screened out of the trial. How to identify (screen-in) the most likely potential responders is an important question that is still without an answer. Here, we pilot a computational screening tool that leverages recent advances in data-driven disease progression modeling to improve stratification. This aims to increase the sensitivity to treatment effect by screening out non-responders, which will ultimately reduce the size, duration, and cost of a clinical trial. We demonstrate the concept of such a computational screening tool by retrospectively analyzing a completed double-blind clinical trial of donepezil in people with amnestic mild cognitive impairment (clinicaltrials.gov NCT00000173), identifying a data-driven subgroup having more severe cognitive impairment who showed clearer treatment response than observed for the full cohort.

Aesthetic Preference for Negatively-Valenced Artworks Remains Stable in Pathological Aging A Comparison Between Cognitively Impaired Patients With Alzheimers Disease and Healthy Controls.

Despite severe cognitive dysfunction in Alzheimers disease (AD), aesthetic preferences in AD patients seem to retain some stability over time, similarly to healthy controls. However, the underlying mechanisms of aesthetic preference stability in AD remain unclear. We therefore aimed to study the role of emotional valence of stimuli for stability of aesthetic preferences in patients with AD compared to cognitively unimpaired elderly adults. Fifteen AD patients (Mini-Mental State Examination (MMSE) score 12-26) without visual impairment andor psychiatric disorder, as well as 15 healthy controls without cognitive impairment (MMSE ≥ 27) matched in age, sex, art interest and highest level of education were included in this study. All participants were asked to rank-order eight artworks per stimulus category (positive, negative, neutral in emotional valence) according to their preference twice with a 2-week span in-between. Based on these two rankings a preference change score was calculated. In order to assess explicit recognition memory of the artworks in the second testing session, four artworks of each stimulus category used in the preference ranking task were presented together with a content-matched distractor artwork painted by the same artist. Participants had to indicate which of the stimuli they had seen 2 weeks previously. AD patients MMSE ( Even in cognitively impaired AD patients, aesthetic preference for negatively-valenced artworks remains relatively stable. Our study provides novel evidence that AD patients may have a somewhat preserved implicit valence system for negative compared to neutral or positive visual information, especially in the domain of aesthetics. However, more studies need to further uncover the details of the underlying neurocognitive mechanisms of preference stability in pathological aging.

Translation, cross-cultural adaptation, and validity of the Brazilian version of the Cognitive Function Instrument.

Subjective cognitive decline (SCD) is defined as a self-perception of a progressive cognitive impairment, which is not detected objectively through neuropsychological tests. The Alzheimers Disease Cooperative Study developed the Cognitive Function Instrument (CFI) to evaluate individuals with SCD. The CFI consists of two versions, namely, a self-report and a partner report. This study aimed to translate CFI into Brazilian Portuguese, perform a cross-cultural adaptation, and validate the Brazilian version. The translation and transcultural adaptation process consisted of six stages, and the preliminary version was answered by a sample of individuals recruited among the patients caregivers from a cognitive neurology outpatient clinic. Finally, the final Brazilian version of the CFI was applied to a sample of nondemented older adults to validate the instrument, which was divided into with and without SCD, according to the answer The final version of CFI showed a high level of acceptability as an assessment tool in nondemented older adults. Participants with SCD had higher scores in the CFI self-report compared with those without complaints. In the receiver operating characteristic curve analysis, the area under the curve of the CFI self-report was 0.865 (95% confidence interval 0.779-0.951), and the cutoff score of 2.0 was the one that best distinguished the SCD group from the control group, with a sensitivity of 73.3% and a specificity of 81.5%. CFI proved to be an instrument with good accuracy and easy applicability to identify older adults with SCD. O declínio cognitivo subjetivo (DCS) é definido como uma autopercepção de um comprometimento cognitivo progressivo, não detectado objetivamente por meio de testes neuropsicológicos. O O objetivo deste estudo foi traduzir para o português brasileiro, fazer uma adaptação transcultural e validar a versão brasileira do IFC. O processo de tradução e adaptação transcultural consistiu em seis etapas, e a versão preliminar foi respondida por uma amostra de voluntários recrutados entre os cuidadores de pacientes de um ambulatório de Neurologia Cognitiva. Por fim, a versão brasileira final do IFC foi aplicada a idosos sem demência, que foram divididos naqueles com e sem DCS de acordo com a resposta “sim” à questão “Você sente que a sua memória está piorando”. A versão final do IFC mostrou alto nível de aceitabilidade como ferramenta de avaliação em idosos sem demência. Os participantes com DCS tiveram pontuações mais altas na versão do paciente em comparação com aqueles sem queixas. Nas análises da curva característica de operação do receptor (ROC), a área sobre a curva da versão do paciente foi de 0,865 (intervalo de confiança IC95% 0,779–0,951) e a pontuação de corte de 2,0 foi a que melhor distinguiu o grupo com DCS dos controles, com sensibilidade de 73,3% e especificidade de 81,5%. O IFC mostrou-se um instrumento de boa acurácia e de fácil aplicabilidade para identificar idosos com DCS.

Cortisol Reactivity to a physical stressor in Patients with Depression and Alzheimers disease.

Some prevalent mental disorders in the elderly, such as Alzheimers disease (AD) and major depression disorder (MDD), are associated with chronic stress and consequently with possible dysregulation of hypothalamic-pituitary-adrenal (HPA) axis and cortisol levels in basal conditions or in the reactivity of an acute stressor. However, evidence of cortisol behavior after a physical stressor in patients with AD and MDD is scarce. This study aimed to investigate the cortisol reactivity to a single session of physical exercise in patients with MDD and AD and compare it to healthy control (HC) older individuals. HC individuals (n10) and elderly with clinical diagnostic of MDD (n08) and AD (n13) were submitted to a single bout of aerobic exercise in a treadmill during 30 minutes of moderate intensity. Salivary cortisol was collected before and after acute stressor. A repeated-measure analysis of variance (ANOVA), spearman correlation, and linear regression were performed. The repeated-measure ANOVA revealed no interaction for cortisol on the moment×group F(2.000, 28.000)1.285 p0.293 and no effect for group (F0.323 p0.727). However, a significant effect for moment F(1.000, 28.000)4.930 p0.035 was found, with a decreased cortisol levels in postexercise for all groups. The effect size (ES) of cortisol reduction was small for patients with MDD (d0.402) and trivial for patients with AD (d0.166) and HC group (d0.090). All participants show a decreased cortisol reactivity to a physical stressor, which can be associated with an impairment in coping with an acute stressor. A doença de Alzheimer (DA) e o transtorno depressivo maior (TDM) são transtornos que acometem idosos e estão associadas ao estresse crônico e à desregulação do eixo hipotálamo-hipófise-adrenal (HPA), que repercute em alterações nos níveis de cortisol (basal e reatividade). Investigar a reatividade do cortisol em uma única sessão de exercício físico em pacientes com TDM e com DA e compará-la com a de idosos saudáveis. Indivíduos controle saudáveis (n10) e idosos com diagnóstico clínico de TDM (n08) e DA (n13) foram submetidos a uma única sessão de exercício aeróbio em esteira rolante, durante 30 minutos, em intensidade moderada. O cortisol salivar foi coletado antes e depois do estressor agudo. Na estatística, foram realizadas as análises de variância (ANOVA) de medidas repetidas, correlação de spearman e regressão linear. Não foi encontrada interação para momento x grupo F (2.000, 28.000)1.285 p0,293 e tampouco efeito para o grupo (F0,323 p0,727). Todavia, foi observado efeito significativo para o momento F(1,000, 28,000)4,930 p0,035, mostrando diminuição dos níveis de cortisol no pós-exercício para todos os grupos. O tamanho do efeito (TE) foi considerado pequeno para o grupo TDM (d0,402) e trivial para o DA (d0,166) e o saudável (d0,090). Todos os participantes apresentaram diminuição da reatividade do cortisol a um estressor físico, o que pode estar associado a um comprometimento no enfrentamento de um estressor agudo.

Introduction of Induction Heating is too late for older residents with difficulty in handling fire.

Handling errors with household flammables, for example pan burning, may result in serious accidents, which may be caused by decreased attention or executive function. The manuals by several cities simply suggest the use of induction heating (IH) cookers. However, it requires complicated operation of buttons. Furthermore, no previous studies have examined the difficulty of IH operation in older adults. We examined 166 residents aged 75 years in Wakuya, consisting 66 Clinical Dementia Rating (CDR) 0 (healthy), 79 CDR 0.5 (very mild dementia), and 21 CDR 1 (dementia) participants. Based on fire accident, they were classified into high-risk, low-risk, and safety groups. They were asked to actually use an IH as an examination. The participants who passed all procedures were classified as good users, and the remaining who failed were classified as poor users. Their overall cognitive and executive functions were assessed using the Mini-Mental State Examination (MMSE) and Trail Making Test A and Digit Symbol (DS), respectively. The proportions of good users in the CDR 0, CDR 0.5, and CDR 1 groups were 7 (10.6%), 6 (7.3%), and 0 (0%), respectively. For the CDR 0 and CDR 0.5 group, the good users had higher scores on the MMSE and DS than do the poor users. The introduction of IH is too late for high-risk group. Since the IH cooker requires complicated operation of buttons, they may be difficult for older residents to handle. Executive function may be examined for early detection of handling errors with household flammables. Erros no manuseio de artigos domésticos muito aquecidos, por exemplo, panelas, podem resultar em acidentes graves, que podem ser causados por diminuição da atenção ou de funções executivas. Manuais de várias cidades sugerem simplesmente o uso de fogões de aquecimento por indução (FAI), mas esses aparelhos requerem uma operação complexa, com necessidade de uso de diversos botões. No entanto, nenhum estudo anterior examinou a dificuldade de operação de FAI em adultos mais velhos. Foram examinados 166 residentes de Wakuya, Japão, com mais de 75 anos, entre os quais 66 participantes com classificação clínica de demência (CDR) 0 (saudável), 79 CDR 0,5 (demência muito leve) e 21 CDR 1 (demência). Em função do risco de queimadura, eles foram classificados nos grupos “alto,“ “baixo risco” e “sem risco”. Solicitou-se que realmente utilizassem o FAI como parte do exame. Os participantes que passaram em todos os procedimentos foram classificados como “bons usuários”, enquanto os demais foram classificados como “usuários fracos”. As funções cognitivas e executivas globais foram avaliadas por meio do Miniexame do Estado Mental (MEEM), do Teste de Trilha A e do Teste Dígito-Símbolo (DS), respectivamente. As proporções de “bons usuários” nos grupos CDR 0, CDR 0,5 e CDR 1 foram 7 (10,6%), 6 (7,3%) e 0 (0%), respectivamente. Para os grupos CDR 0 e CDR 0,5, os “bons usuários” tiveram pontuações mais altas no MEEM e no DS em comparação com os “usuários fracos”. A introdução de FAI é muito tardia para o grupo de “alto risco”. Uma vez que o FAI requer uma operação complicada com o uso de botões, o seu manuseio pode ser difícil para os residentes mais velhos. A função executiva pode ser examinada para a detecção precoce de erros de manuseio de aparelhos domésticos que podem causar acidentes.

Association between cognitive performance and sarcopenic obesity in older adults with Alzheimers disease.

Sarcopenic obesity (SO), the co-occurrence of sarcopenia and obesity, is associated with functional loss, frailty, and incapacity in older adults. Recently, SO was associated with reduced cognitive performance in adults. However, no SO studies have been done with older adults with Alzheimers disease (AD). The objective of this study was to verify the occurrence of SO and associated factors in 43 older adults with AD. We applied the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). SO was verified by using dual-emission X-ray absorptiometry. We found five women with SO. Women had higher body fat and lower muscle mass compared with men. There was a significant relationship between body fat and cognitive performance only in men (r0.65 p<0.01) adjusted by age and education. Men with obesity and aged >75 years had better cognitive performance compared with non-obese men aged <75 years (p0.010) and women with obesity aged >75 years (p0.033). Women with AD had higher body fat and lower muscle mass than men. SO occurs in older women with AD. Men with higher body fat showed better cognitive performance, independent of age and education. A obesidade sarcopênica (SO), coocorrência de sarcopenia e obesidade, está associada à perda funcional, à fragilidade e à incapacidade em idosos. Recentemente, verificou-se que a SO está associada ao desempenho cognitivo reduzido em adultos. No entanto, não foram feitos estudos de SO em idosos com doença de Alzheimer (AD). Verificar a ocorrência de obesidade sarcopênica e fatores associados em 43 adultos idosos com doença de Alzheimer. Aplicamos o miniexame do estado mental (MEEM) e a avaliação clínica da demência (CDR). A SO foi verificada utilizando a absorciometria de dupla emissão de raios X. Foram classificadas cinco idosas com SO. As mulheres idosas tinham maior gordura corporal e menor massa muscular em comparação com os homens. Houve relação significativa, ajustada por idade e educação, entre gordura corporal e desempenho cognitivo apenas nos homens (r0,65 p<0,01). Os homens com obesidade e com mais de 75 anos tiveram melhor desempenho cognitivo em comparação com os homens não obesos <75 anos (p0,010) e com as mulheres com obesidade >75 anos (p0,033). As mulheres com AD tinham maior gordura corporal e menor massa muscular do que os homens. A SO ocorreu em mulheres mais velhas com AD. Os homens com maior gordura corporal apresentaram melhor desempenho cognitivo, independentemente da idade e da educação.

A new diagnostic approach in Alzheimers disease The critical flicker fusion threshold.

Alzheimers disease (AD) is the most common cause of dementia in the elderly. Although AD treatment is still insufficient despite all the recent developments, detection and treatment in the early stage of disease have provided more clinical benefits. In this study, we aimed to use the critical flicker fusion (CFF) threshold test to diagnose AD in the early stage. In this study, 120 patients (above 65 years of age) and 50 control groups who were admitted to geriatrics outpatient clinic and diagnosed in early- and middle-stage AD were included. The remaining 58 patients and 25 healthy volunteers underwent comprehensive geriatric assessment and CFF testing. The mean CFF value of AD group was significantly lower than the control group (36.44±7.00 vs. 44.24±3.82, p<0.001, respectively). There was a significant difference in standardized mini-mental state examination (MMSE) score in both groups (18.05±5.25 vs. 25.96±2.85, p<0.001, respectively). There was also a positive correlation between CFF value and MMSE score (p<0.001, r0.459). Thirty-four patients were in the early-stage AD group and 24 patients were in the middle-stage AD group. There was a significant difference in CFF values between the three groups when we compared the patients in early- and middle-stage AD and control groups (p<0.001). The mean CFF values in patients with early- and middle-stage AD were 37.93±7.33 and 34.97±7.43, respectively. The mean age, gender, education level, and the number of drugs used did not show a statistically significant difference in both groups (p>0.05). The cutoff value for the CFF variable was determined as 39 Hz p<0.001 area under the curve (AUC)0.852 sensitivity70.69% (95% confidence interval 95%CI 57.3-81.9) specificity92.00% (95%CI 74.00-99.00). There is a significant difference in mean CFF values between AD and healthy groups. CFF testing may play an important role in diagnosing AD in the early stage. A doença de Alzheimer (DA) é a causa mais comum de demência em idosos. Embora o tratamento da DA ainda seja insuficiente mesmo com todos os desenvolvimentos recentes, a detecção precoce e o tratamento no estágio inicial da doença têm demonstrado maior benefício clínico. Neste estudo, nosso objetivo foi usar o teste Foram incluídos 120 pacientes e 50 controles em ambulatório de geriatria, com diagnóstico de DA inicial e moderada e acima de 65 anos. Os 58 pacientes restantes e 25 voluntários saudáveis foram submetidos a avaliação geriátrica abrangente e ao CFF. A média de CFF do grupo AD foi significativamente menor do que a do grupo controle (36,44±7,00 Há diferença significativa entre os valores médios de CFF do grupo de DA e do grupo saudável. O CFF pode desempenhar um papel importante no diagnóstico de DA no estágio inicial.

Segmental Bioimpedance Variables in Association With Mild Cognitive Impairment.

To examine the changes in body composition, water compartment, and bioimpedance in mild cognitive impairment (MCI) individuals. We obtained seven whole-body composition variables and seven pairs of segmental body composition, water compartment, and impedance variables for the upper and lower extremities from the segmental multi-frequency bioelectrical impedance analysis (BIA) of 939 elderly participants, including 673 cognitively normal (CN) people and 266 individuals with MCI. Participants characteristics, anthropometric information, and the selected BIA variables were described and statistically compared between the CN participants and those with MCI. The correlations between the selected BIA variables and neuropsychological tests such as the Korean version of the Mini-Mental State Examination and Seoul Neuropsychological Screening Battery - Second Edition were also examined before and after controlling for age and sex. Univariate and multivariate logistic regression analyses with estimated odds ratios (ORs) were conducted to investigate the associations between these BIA variables and MCI prevalence for different sexes. Participants with MCI were slightly older, more depressive, and had significantly poorer cognitive abilities when compared with the CN individuals. The partial correlations between the selected BIA variables and neuropsychological tests upon controlling for age and sex were not greatly significant. However, after accounting for age, sex, and the significant comorbidities, segmental lean mass, water volume, resistance, and reactance in the lower extremities were positively associated with MCI, with ORs 95% confidence interval (CI) of 1.33 (1.02-1.71), 1.33 (1.03-1.72), 0.76 (0.62-0.92), and 0.79 (0.67-0.93), respectively with presumably a shift of water from the intracellular area to extracellular space. After stratifying by sex, resistance and reactance in lower extremities remained significant only in the women group. An increase in segmental water along with segmental lean mass and a decrease in body cell strength due to an abnormal cellular water distribution demonstrated by reductions in resistance and reactance are associated with MCI prevalence, which are more pronounced in the lower extremities and in women. These characteristic changes in BIA variables may be considered as an early sign of cognitive impairment in the elderly population.

Digital biomarkers and sex impacts in Alzheimers disease management - potential utility for innovative 3P medicine approach.

Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimers disease (AD) to dementia due to AD in individuals aged 55 . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimers, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoidas digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoidas application, achieved a 75% ROC-AUC (receiver operating characteristic - area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline. The online version contains supplementary material available at 10.1007s13167-022-00284-3.

Mass spectrometry methods for analysis of extracellular matrix components in neurological diseases.

The brain extracellular matrix (ECM) is a highly glycosylated environment and plays important roles in many processes including cell communication, growth factor binding, and scaffolding. The formation of structures such as perineuronal nets (PNNs) is critical in neuroprotection and neural plasticity, and the formation of molecular networks is dependent in part on glycans. The ECM is also implicated in the neuropathophysiology of disorders such as Alzheimers disease (AD), Parkinsons disease (PD), and Schizophrenia (SZ). As such, it is of interest to understand both the proteomic and glycomic makeup of healthy and diseased brain ECM. Further, there is a growing need for site-specific glycoproteomic information. Over the past decade, sample preparation, mass spectrometry, and bioinformatic methods have been developed and refined to provide comprehensive information about the glycoproteome. Core ECM molecules including versican, hyaluronan and proteoglycan link proteins, and tenascin are dysregulated in AD, PD, and SZ. Glycomic changes such as differential sialylation, sulfation, and branching are also associated with neurodegeneration. A more thorough understanding of the ECM and its proteomic, glycomic, and glycoproteomic changes in brain diseases may provide pathways to new therapeutic options.

Gastrointestinal Changes and Alzheimers Disease.

There is a well-described mechanism of communication between the brain and gastrointestinal system in which both organs influence the function of the other. This bi-directional communication suggests that disease in either organ may affect function in the other. To assess whether the evidence supports gastrointestinal system inflammatory or degenerative pathophysiology as a characteristic of Alzheimers disease (AD). A review of both rodent and human studies implicating gastrointestinal changes in AD was performed. Numerous studies indicate that AD changes are not unique to the brain but also occur at various levels of the gastrointestinal tract involving both immune and neuronal changes. In addition, it appears that numerous conditions and diseases affecting regions of the tract may communicate to the brain to influence disease. Gastrointestinal changes represent an overlooked aspect of AD, representing a more system influence of this disease.

Adipose tissue-derived stem cells as a potential candidate in treatment of Alzheimers disease A systematic review on preclinical studies.

In recent years, numerous investigations have evaluated the efficacy of adipose tissue-derived stem cells (ADSCs) and their exosome transplantation in managing Alzheimers disease (AD) in different animal models. However, there are still many contradictions among the studies that hinder reaching a reliable conclusion. Therefore, we aimed to systematically review the existing evidence regarding the efficacy of ADSCs administration in treatment of AD. The systematic search was conducted in the databases of Medline (via PubMed), Embase, Scopus, and Web of Science, in addition to the manual search in Google and Google scholar, to find articles published until March 13, 2021. Preclinical studies were included and two independent reviewers summarized the eligible papers. Ten articles were included in our review. The treatment strategies varied between isolated ADSC, ADSCs exosomes, ADSCs conditioned medium, and combination therapy (ADSCs plus conditioned medium in one study, and ADSCs plus melatonin in another study). Overview of the included articles showed promising results of ADSCs and its conditioned mediumexosome administration in animal models of AD. These studies showed significant learning and memory improvements through ADSCs and their conditioned mediumexosome administration in animal models of AD. In addition, the application of ADSCs reduced the amyloid-beta plaque deposits in the hippocampus and neocortex of these animals. Based on the aforementioned evidence, studies have suggested potential beneficial effects of ADSCs in the treatment of AD, particularly through decreasing the size of Aβ plaques and improvement of cognitive deficits. Further investigations regarding the subject are encouraged to achieve more accurate conclusions.

The Ketogenic Diet and Alzheimers Disease.

Alzheimers disease (AD) is a progressive neurodegenerative disease that is the most common form of dementia. There are currently FDA-approved symptomatic therapies for AD and a recently approved, potentially disease-modifying drug, Aducanumab however, there are no curative or preventative therapies. Research suggests that diet may play a role in AD, but it is inconclusive relative to which dietary approach provides the most neuroprotective effects. There are other life-style approaches that have been found to possibly play a role in AD preventiontreatment. These include exercise, brain training, and social interaction. A combined approach may be more effective than any one modality alone. The ketogenic diet (KD) is one specific diet that has been studied vis a vis neurodegenerative diseases. Similar benefits to those of a KD can also be achieved through consuming a normal diet and supplementing with ketogenic agents. The purpose of this review is to compare the methods of inducing hyperketonemia and their impact on AD preventiontreatment, as well as to explore the possible benefits of a combined approach. The PubMed database was searched for clinical trials and randomized, controlled trials involving the KD or exogenous ketone administration and AD. Key search terms used included ketogenic diet and Alzheimers disease, ketosis and Alzheimers disease, MCT and Alzheimers disease, and exercise and diet and Alzheimers disease. Only studies involving patients diagnosed with AD were included in this paper, but for the combined approach section, studies included patients diagnosed with MCI due to a paucity of combined approach studies involving AD patients alone. There is evidence that the KD and exogenous ketone supplementation may provide treatment benefits in AD patients. It is unclear whether one method is better than the other. The specific food composition of the KD should be considered, because certain types of fat sources are healthier than others. Many forms of the KD require strict monitoring of carbohydrate intake, which would often fall under the responsibility of the caregiver. Future studies may be more feasible in an institutional setting, where it would be easier to administer and to monitor a dietary protocol. Exogenous supplementation may be more likely to be adhered to as a long-term treatment, because the dietary changes are not as drastic. A multidomain approach may be the most effective in possibly preventingdelaying AD and in improvingstabilizing and possibly slowing disease progression in those with AD. Most current studies are small, often uncontrolled, and only look at the short-term effects of ketosis on cognition. Large, long-term, randomized, controlled trials relative to the impact of the KD in patients with cognitive impairment and AD are lacking and thus needed. Combined approaches may prove to be more beneficial in possibly preventingdelaying AD and in improvingstabilizing and possibly slowing disease progression in those with MCI or AD. Future research should investigate the effect of additional combined approaches relative to neurocognitive decline in AD patients.

Circulating Levels of Apelin, GDF-15 and Sarcopenia Lack of Association in the MAPT Study.

Apelin and GDF-15 have been proposed as biomarkers of age-related sarcopenia but evidence in human models is scarce. This study aimed to explore the associations between blood apelin and GDF-15 with sarcopenia incidence and the evolution of sarcopenia components over two years in older adults >70 years. Secondary longitudinal analysis of the Multidomain Alzheimer Preventive Trial. Older adults (>70 years) attending primary care centers in France and Monaco. Community. Serum Apelin (pgmL) and plasma GDF-15 (pgmL) were measured. Outcomes included sarcopenia defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and its determinants (appendicular lean mass ALM evaluated through a Dual-energy X-ray Absorptiometry (DXA) scan, handgrip strength (HGS) and the 4-meter gait speed) measured over 2 years. Linear mixed models and logistic regression were used to explore the longitudinal associations. We included 168 subjects from MAPT (median age76y, IQR73-79 78% women). Serum apelin was not significantly associated with sarcopenia incidence (OR1.00195%CI1.000,1.001p-value>0.05 in full-adjusted models) nor with ALM (β-5.8E-0595%CI-1.0E-04,2.12E-04p>0.05), HGS (β-1.1E-0495%CI-5.0E-04,2.8E-04p>0.05), and GS (β-5.1E-0695%CI-1.0E-05,2.0E-05p>0.05) in fully adjusted models. Similarly, plasma GDF-15 was not associated with both the incidence of sarcopenia (OR1.001,95%CI1.000,1.002,p>0.05) and the evolution of its determinants (ALM, β2.1E-0595%CI-2.6E-04,3.03E-04p>0.05, HGS β-5.9E-0495%CI-1.26E-03,8.1E-05 p>0.05 nor GS β-2.6E-0695%CI-3.0E-05, 2.3E-05p>0.05) in fully adjusted models. Blood apelin and GDF-15 were not associated with sarcopenia incidence or with the evolution of sarcopenia components over a 2-year follow-up in community-dwelling older adults. Well-powered longitudinal studies are needed to confirm or refute our findings.

Biomarkers of Age-Related Frailty and Frailty Related to Diseases An Exploratory, Cross-Sectional Analysis from the MAPT Study.

Frailty may in most cases result from two main causes the aging process (age-related frailty) and diseases (evolving chronic conditions or acute medical illnesses - disease-related frailty). The biological determinants characterizing these two main causes of frailty may be different. The aim of this study is to compare the biological and neuroimaging profile of people without frailty, those with age-related frailty, and subjects with disease-related frailty in community-dwelling older adults. We performed a secondary, cross-sectional analysis from the Multidomain Alzheimer Preventive Trial (MAPT). We included 1199 subjects without frailty throughout the 5-year follow-up, 82 subjects with incident age-related frailty, and 53 with incident disease-related frailty. Available blood biomarkers involved nutritional (eg, vitamin D, omega-3 fatty acids), inflammatory-related (IL-6, TNFR1, GDF15), neurodegenerative (eg, beta-amyloid, neurofilament light chain) and neuroimaging markers (MRI, Amyloid-PET). Although not statistically significant, the results of the unadjusted model showed increasing gradients for inflammatory markers (GDF15, TNFR1) and decreasing gradients for nutritional and neuroimaging markers (omega 3 index, hippocampal volume) from age-related frailty participants to individuals with disease-related frailty. Considering the linear models we observed higher GDF15 values in disease-related frailty group compared to age-related frailty individuals β 242.8 (49.5, 436.2). We did not find any significant difference between subjects without frailty and those with age-related frailty. Subjects with disease-related frailty compared to subjects without frailty had lower values of DHA β -2.42 (-4.76, -0.08), Omega 3 Index β -0.50 (-0.95, -0.06) and hippocampal volume β -0.22 (-0.42,-0.02). They also had higher values of GDF15 β 246.1 (88.9, 403.4) and TNFR1 β 157.5 (7.8, 307.2). Age-related frailty and disease-related frailty may represent different degrees of frailty severity on a biological level. Further research is needed to identify biomarkers potentially able to distinguish these classifications of frailty.

The Potential Economic Value of Lecanemab in Patients with Early Alzheimers Disease Using Simulation Modeling.

Alzheimers disease (AD) is a progressive, neurodegenerative disease that affects memory, thinking, and behavior and places a substantial economic burden on caregivers and healthcare systems. This early-phase study aimed to model lecanemab, a humanized monoclonal antibody targeting amyloid protofibrils, for patients with early AD, and estimate the potential value-based price (VBP) of lecanemab standard of care (SoC) compared to SoC alone given an expected product profile of lecanemab informed by data from a phase II trial from payer and societal perspectives using a broad range of willingness-to-pay (WTP) thresholds in the USA. A disease simulation model was used to capture how key AD pathology components relate to the clinical and economic presentation of AD. The effects of disease modification and early intervention on disease progression were simulated on the basis of BAN2401-G000-201 trial data as well as published literature. Model outcomes included patient and caregiver quality-adjusted life years (QALYs), total life years, and total care costs including direct medical and non-medical costs for healthcare resource use and indirect costs for caregiving over a lifetime horizon. Lecanemab SoC was predicted to result in a gain of 0.61 QALYs (societal, 0.64) and a $8707 decrease in total non-treatment costs (societal, $11,214) vs. SoC alone for patients with early AD. For a WTP threshold range of $50,000 to $200,000 per QALY gained, the potential annual VBP of lecanemab was estimated at $9249 (societal, $10,400) to $35,605 (societal, $38,053), respectively. Other patient subsets, treatment stopping rules, and dosing regimens were used to assess the sensitivity of the VBP estimates. The early model predicted that lecanemab would potentially improve long-term health outcomes and reduce formal and informal care costs, resulting in a range of VBPs that reflect the value of lecanemab to society.

Depressive symptoms mediate the relationship between diabetes and cognitive performance in a community-based sample of older adults.

To evaluate whether diabetes and prediabetes are associated with impaired cognitive performance among older adults and examine depressive symptoms as a mediator. We used cross-sectional data from the Einstein Aging Study, a systematically recruited, community-based cohort study of diverse older adults (N 794 Age Mean (SD) 78.9 (5.3) 64.4% Non-Hispanic White, 28.7% Non-Hispanic Black, 5.7% Hispanic). Diabetes status was established via self-reported diagnosis, prescribed medications, and fasting blood glucose. Depressive symptoms were assessed using the Geriatric Depression Scale. Cognitive tests included Digit Symbol, Trails-B, Free Recall, Category Fluency, Boston Naming, and Block Design. Linear regression and mediation analyses were applied. Compared to those without diabetes, diabetes was associated with worse performance on all cognitive tests (ps < 0.05), except Trails-B (p 0.53), and increased depressive symptoms (p < 0.01). For diabetes, mediation via increased depressive symptoms was observed for Free Recall (p 0.044), Category Fluency (p 0.033), and Boston Naming (p 0.048). Diabetes was consistently associated with worse cognitive performance and increased depressive symptoms among this older cohort, while prediabetes was not. Mediation findings suggest depressive symptoms may be a biobehavioral pathway linking diabetes and cognition, though the temporal sequence is unclear. If causal, addressing both diabetes and depressive symptoms among older adults may protect cognitive function.

Breaking barriers in postoperative delirium.

Systemic perturbations such as peripheral surgical trauma induce neurovascular, inflammatory, and cognitive changes. The blood-brain barrier is a key interface between the periphery and the central nervous system, and is critically involved in regulating neuroimmune interactions to maintain overall homeostasis. Mounting evidence suggests that blood-brain barrier dysfunction is a hallmark of ageing and multiple neurological conditions including Alzheimers disease. We discuss a recent study published in the British Journal of Anaesthesia that describes blood-brain barrier changes and neuroinflammation in patients with postoperative delirium after non-intracranial surgery.

Galangin alleviates learning and memory impairments in APPPS1 double- transgenic mice by regulating AktMEF2DBeclin-1 signaling pathway.

The study aimed to investigate the effects of galangin on learning and memory impairments and AktMEF2 DBeclin-1 signaling pathway in APPPS1 double-transgenic mice. The mice in this experiment were divided into the normal group, model group, low-(25 mg·kg(-1)), medium-(50 mg·kg(-1)), and high-dose(100 mg·kg(-1)) galangin groups, donepezil(3 mg·kg(-1)) group, Akt inhibitor(25 mg·kg(-1)) group, and autophagy inhibitor(30 mg·kg(-1)) group, with ten in each group, and administered with the corresponding drugs for 30 successive days. On the 24 th day of medication, the water maze and dark avoidance tests were performed. The levels of p-tau, β-amyloid peptide 1-42(Aβ(42)), acetylcholinesterase(AChE), β-site amyloid precursor protein cleaving enzyme 1(BACE1), and amyloid precursor protein(APP) in hippocampus were detected by ELISA, the Beclin-1 mRNA expression by RT-PCR, the expression of Aβ(42) and glial fibrillary acidic protein(GFAP) by immunohistochemistry, and the expression of myocyte enhancer factor 2 D(MEF2 D) by immunofluorescence assay. The pathological changes in hippocampus were observed after HE staining, and the expression of Akt, MEF2 D, and Beclin-1 in hippocampus were assayed by Western blot. These results showed that compared with the normal group, the model group exhibited prolonged swimming time, increased number of errors and electric shocks, up-regulated p-tau, Aβ(42), APP, AChE, BACE1, GFAP, and Beclin-1, shortened incubation period, decreased p-Akt and MEF2 D, and obvious hippocampal injury. Compared with the model group, donepezil and galangin shortened the swimming time, reduced the number of errors and electric shocks, down-regulated the expression of p-tau, Aβ(42), APP, AChE, BACE1, GFAP, and Beclin-1, prolonged the incubation period, up-regulated p-Akt and MEF2 D, and improved the pathological changes in hippocampus. Compared with the autophagy inhibitor group, galangin prolonged the swimming time, elevated the number of errors and electric shocks, enhanced the expression of p-tau, Aβ(42), APP, AChE, BACE1, GFAP, and Beclin-1, shortened the incubation period, and diminished the expression of p-Akt and MEF2 D. In conclusion, galangin improves the learning and memory impairments and hippocampal neuron injury of APPPS1 mice, which may be related to its regulation of AktMEF2 DBeclin-1 signaling pathway.

Serum Neurogranin Measurement as a Biomarker of Central Nervous System Infections A Preliminary Study.

The early diagnosis of central nervous system infections is of great importance to minimize morbidity and mortality. Neurogranin is a postsynaptic neural protein, and when the blood-brain barrier is damaged, neurogranin levels increase in both the cerebrospinal fluid and serum. The aim of this study was to evaluate the level of serum neurogranin and to investigate its utility in the diagnosis of central nervous system infections. This study was conducted as a prospective case-control study of patients diagnosed with meningitis. The study initially included 55 patients, and 15 patients with proven central nervous system infection were ultimately included in the patient group. The results in the patient group were compared with those of the control group of 15 healthy subjects. The 15 patients comprised 4 women and 11 men with a mean cerebrospinal fluid neurogranin level of 432.4 ± 123.5 ngml. Correlation analysis revealed a moderate positive correlation between cerebrospinal fluid neurogranin levels and serum neurogranin levels. The mean serum neurogranin level was 198.6 ± 51.7 ngml in the control group but was significantly higher at 429.2 ± 104.3 ngml in the patient group. In conclusion, it may be useful to measure blood neurogranin levels in patients suspected of having central nervous system infections, especially in those for whom computed tomography, magnetic resonance imaging, or lumbar puncture cannot be performed.

Effects of thymoquinone on scopolamine-induced spatial and echoic memory changes through regulation of lipid peroxidation and cholinergic impairment.

Thymoquinone (TMQ), one of the main components active of Nigella sativa, shows very useful biomedical properties. Evidence suggests that cholinergic dysfunction and oxidative stress play role in the pathogenesis of neurodegenerative disorders such as Alzheimers disease (AD). In the present study, we investigated the anti-amnestic effect of TMQ in scopolamine-induced animal model of AD. Wistar rats were randomly divided into four groups Sham(SH), TMQ-treated(TMQ), scopolamine-treated(SCO) and scopolamineTMQ-treated(SCOTMQ) groups. TMQ (20 mgkg) prepared in corn oil was administered intraperitoneally (i.p.) 1-h before experiments. Scopolamine (1 mgkg) dissolved in 0.9% physiological saline was administered intraperitoneally (i.p.). We recorded mismatch negativity (MMN) response as an electrophysiological correlate of echoic memory. Object location memory (OLM) and Y-maze alternation tests were carried out to assess spatial memory. Then, the brain homogenates content of thiobarbituric-acid-reactive-substances (TBARS), 4-Hydroxy-2-nonenal (4-HNE) and acetylcholine (ACh)acetylcholine (AChE) activity were biochemically determined. In the scopolamine-treated rats, TMQ was found to significantly improve the discrimination and spontaneous alteration levels in the OLM and Y-maze tests, respectively. Furthermore, TMQ significantly mitigated the scopolamine-induced attenuation of MMN and related theta responses. Moreover, scopolamine treatment increased TBARS4-HNE level and decreased ACh level in the brain, and TMQ was able to significantly prevent these effects. AChE activity was increased in the SCO group this effect was significantly attenuated by TMQ. TMQ diminished the lipid peroxidation and cholinergic dysfunction in the scopolamine-induced AD rat model which all reflected in improving the MMNtheta response and spatial memory. This may implement TMQ as an adjuvant therapeutic strategy in ameliorating AD.

Mice expressing P301S mutant human tau have deficits in interval timing.

Interval timing is a key executive process that involves estimating the duration of an interval over several seconds or minutes. Patients with Alzheimers disease (AD) have deficits in interval timing. Since temporal control of action is highly conserved across mammalian species, studying interval timing tasks in animal AD models may be relevant to human disease. Amyloid plaques and tau neurofibrillary tangles are hallmark features of AD. While rodent models of amyloid pathology are known to have interval timing impairments, to our knowledge, interval timing has not been studied in models of tauopathy. Here, we evaluate interval timing performance of P301S transgenic mice, a widely studied model of tauopathy that overexpresses human tau with the P301S mutation. We employed an interval timing task and found that P301S mice consistently underestimated temporal intervals compared to wild-type controls, responding early in anticipation of the target interval. Our study indicating timing deficits in a mouse tauopathy model could have relevance to human tauopathies such as AD.

Low-rank sparse feature selection with incomplete labels for Alzheimers disease progression prediction.

How to predict the cognitive performance of Alzheimers disease (AD) and identify the informative neuroimaging markers is essential for timely treatment and possible delay of the disease. However, incomplete labeled samples and noises in neuroimaging data pose challenges to building reliable and robust prediction models. In this paper, we present a model named Low-rank Sparse Feature Selection with Incomplete Labels (LSFSIL) for predicting cognitive performance and identifying informative neuroimaging markers with MRI data and incomplete cognitive scores. We propose a sparse matrix decomposition method to decompose the incomplete cognitive score matrix into two parts for recovering missing scores and utilizing incomplete labeled data. The former is the recovered cognitive score matrix without missing values. To make the recovered scores close to the real ones, a manifold regularizer is devised to fit the label distribution for capturing the label correlations locally. The latter is a ℓ Experimental results demonstrate that LSFSIL achieves higher performance and outperforms several state-of-the-art feature selection approaches. Moreover, the neuroimaging markers selected by LSFSIL are consistent with the previous AD studies. LSFSIL is effective in informative neuroimaging marker identification for cognitive performance prediction with incomplete labeled data.

Sensitivity of the S1 neuronal calcium network to insulin and Bay-K 8644 in vivo Relationship to gait, motivation, and aging processes.

Neuronal hippocampal Ca

Computational investigation of the dynamic control of cAMP signaling by PDE4 isoform types.

Cyclic adenosine monophosphate (cAMP) is a generic signaling molecule that, through precise control of its signaling dynamics, exerts distinct cellular effects. Consequently, aberrant cAMP signaling can have detrimental effects. Phosphodiesterase 4 (PDE4) enzymes profoundly control cAMP signaling and comprise different isoform types wherein enzymatic activity is modulated by differential feedback mechanisms. Because these feedback dynamics are non-linear and occur coincidentally, their effects are difficult to examine experimentally but can be well simulated computationally. Through understanding the role of PDE4 isoform types in regulating cAMP signaling, PDE4-targeted therapeutic strategies can be better specified. Here, we established a computational model to study how feedback mechanisms on different PDE4 isoform types lead to dynamic, isoform-specific control of cAMP signaling. Ordinary differential equations describing cAMP dynamics were implemented in the VirtualCell environment. Simulations indicated that long PDE4 isoforms exert the most profound control on oscillatory cAMP signaling, as opposed to the PDE4-mediated control of single cAMP input pulses. Moreover, elevating cAMP levels or decreasing PDE4 levels revealed different effects on downstream signaling. Together these results underline that cAMP signaling is distinctly regulated by different PDE4 isoform types and that this isoform specificity should be considered in both computational and experimental follow-up studies to better define PDE4 enzymes as therapeutic targets in diseases in which cAMP signaling is aberrant.

Staging of Alzheimers disease past, present, and future perspectives.

For many years Alzheimers disease (AD) was associated with the dementia stage of the disease, the tail end of a pathophysiological process that lasts approximately two decades. Whereas early disease staging assessments focused on progressive deterioration of clinical functioning, brain imaging with positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarker studies highlighted the long preclinical phase of AD in which a cascade of detectable biological abnormalities precede cognitive decline. The recent proliferation of imaging and fluid biomarkers of AD pathophysiology provide an opportunity for the identification of several biological stages in the preclinical phase of AD. We discuss the use of clinical and biomarker information in past, present, and future staging of AD. We highlight potential applications of PET, CSF, and plasma biomarkers for staging AD severity in vivo.

Near-infrared light reduces β-amyloid-stimulated microglial toxicity and enhances survival of neurons mechanisms of light therapy for Alzheimers disease.

Low-intensity light can decelerate neurodegenerative disease progression and reduce amyloid β (Aβ) levels in the cortex, though the cellular and molecular mechanisms by which photobiomodulation (PBM) protects against neurodegeneration are still in the early stages. Microglia cells play a key role in the pathology of Alzheimers disease by causing chronic inflammation. We present new results concerning the PBM of both oxidative stress and microglia metabolism associated with the activation of metabolic processes by 808 nm near-infrared light. The studies were carried out using healthy male mice to obtain the microglial cell suspension from the hippocampus. Oligomeric β-amyloid (1-42) was prepared and used to treat microglia cells. Light irradiation of cells was performed using diode lasers emitting at 808 nm (30 mWcm The light induces a metabolic shift from glycolysis to mitochondrial activity in pro-inflammatory microglia affected by oligomeric Aβ. Thereby, the level of anti-inflammatory microglia increases. This process is accompanied by a decrease in pro-inflammatory cytokines and an activation of phagocytosis. Light exposure decreases the Aβ-induced activity of glucose-6-phosphate dehydrogenase, an enzyme that regulates the rate of the pentose phosphate pathway, which activates nicotinamide adenine dinucleotide phosphate oxidases to further produce ROS. During co-cultivation of neurons with microglia, light prevents the death of neurons, which is caused by ROS produced by Aβ-altered microglia. These original data clarify reasons for how PBM protects against neurodegeneration and support the use of light for therapeutic research in the treatment of Alzheimers disease.

LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions.

Microglia plays crucial roles in Alzheimers disease (AD) development. Triggering receptor expressed on myeloid cells 2 (TREM2) in association with DAP12 mediates signaling affecting microglia function. Here we study the negative regulation of TREM2 functions by leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), an inhibitory receptor bearing ITIM motifs. To specifically interrogate LILRB2-ligand (oAβ and PS) interactions and microglia functions, we generated potent antagonistic LILRB2 antibodies with sub-nanomolar level activities. The biological effects of LILRB2 antagonist antibody (Ab29) were studied in human induced pluripotent stem cell (iPSC)-derived microglia (hMGLs) for migration, oAβ phagocytosis, and upregulation of inflammatory cytokines. Effects of the LILRB2 antagonist antibody on microglial responses to amyloid plaques were further studied in vivo using stereotaxic grafted microglia in 5XFAD mice. We confirmed the expression of both LILRB2 and TREM2 in human brain microglia using immunofluorescence. Upon co-ligation of the LILRB2 and TREM2 by shared ligands oAβ or PS, TREM2 signaling was significantly inhibited. We identified a monoclonal antibody (Ab29) that blocks LILRB2ligand interactions and prevents TREM2 signaling inhibition mediated by LILRB2. Further, Ab29 enhanced microglia phagocytosis, TREM2 signaling, migration, and cytokine responses to the oAβ-lipoprotein complex in hMGL and microglia cell line HMC3. In vivo studies showed significantly enhanced clustering of microglia around plaques with a prominent increase in microglial amyloid plaque phagocytosis when 5XFAD mice were treated with Ab29. This study revealed for the first time the molecular mechanisms of LILRB2-mediated inhibition of TREM2 signaling in microglia and demonstrated a novel approach of enhancing TREM2-mediated microglia functions by blocking LILRB2-ligand interactions. Translationally, a LILRB2 antagonist antibody completely rescued the inhibition of TREM2 signaling by LILRB2, suggesting a novel therapeutic strategy for improving microglial functions.

Positron Emission Tomography-Based Assessment of Cognitive Impairment and Dementias, Critical Role of Fluorodeoxyglucose in such Settings.

Positron emission tomography (PET) has been a key component in the diagnostic armamentarium for assessing neurodegenerative diseases such as Alzheimer or Parkinson disease. PET imaging has been useful for diagnosing these disorders, identifying their pathophysiology, and following their treatment. Further, PET imaging has been extensively used for both clinical and research purposes, particularly for helping with potential therapeutic approaches for managing neurodegenerative diseases. This article will review the current literature regarding PET imaging in patients with neurodegenerative disorders. This includes an evaluation of the most commonly used tracer fluorodeoxyglucose that measures cerebral glucose metabolism, tracers that assess neurotransmitter systems, and tracers designed to reveal disease-specific pathophysiological processes. With the continuing development of an expanding variety of radiopharmaceuticals, PET imaging will likely play a prominent role in future research and clinical applications for neurodegenerative diseases.

An integrative analysis of miRNA and mRNA expression in the brains of Alzheimers disease transgenic mice after real-world PM

Fine particulate matter (PM

Δ133p53α Protects Human Astrocytes from Amyloid-beta Induced Senescence and Neurotoxicity.

Cellular senescence is an important contributor to aging and age-related diseases such as Alzheimers disease (AD). Senescent cells are characterized by a durable cell proliferation arrest and the acquisition of a proinflammatory senescence-associated secretory phenotype (SASP), which participates in the progression of neurodegenerative disorders. Clearance of senescent glial cells in an AD mouse model prevented cognitive decline suggesting pharmacological agents targeting cellular senescence might provide novel therapeutic approaches for AD. Δ133p53α, a natural protein isoform of p53, was previously shown to be a negative regulator of cellular senescence in primary human astrocytes, with clinical implications from its diminished expression in brain tissues from AD patients. Here we show that treatment of proliferating human astrocytes in culture with amyloid-beta oligomers (Aβ), an endogenous pathogenic agent of AD, results in reduced expression of Δ133p53α, as well as induces the cells to become senescent and express proinflammatory SASP cytokines such as IL-6, IL-1β and TNFα. Our data suggest that Aβ-induced astrocyte cellular senescence is associated with accelerated DNA damage, and upregulation of full-length p53 and its senescence-inducing target gene p21

Potential disease-modifying therapies for Huntingtons disease lessons learned and future opportunities.

Huntingtons disease is the most frequent autosomal dominant neurodegenerative disorder however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntingtons disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis aberrant intron-1 splicing of the HTT gene and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntingtons disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.

A biological classification of Huntingtons disease the Integrated Staging System.

The current research paradigm for Huntingtons disease is based on participants with overt clinical phenotypes and does not address its pathophysiology nor the biomarker changes that can precede by decades the functional decline. We have generated a new research framework to standardise clinical research and enable interventional studies earlier in the disease course. The Huntingtons Disease Integrated Staging System (HD-ISS) comprises a biological research definition and evidence-based staging centred on biological, clinical, and functional assessments. We used a formal consensus method that involved representatives from academia, industry, and non-profit organisations. The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntingtons disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntingtons disease. Huntingtons disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3). Individuals can be precisely classified into stages based on thresholds of stage-specific landmark assessments. We also demonstrated the internal validity of this system. The adoption of the HD-ISS could facilitate the design of clinical trials targeting populations before clinical motor diagnosis and enable data standardisation across ongoing and future studies.

Mass spectrometry-based ganglioside profiling provides potential insights into Alzheimers disease development.

Gangliosides are a family of glycosphingolipids which are particularly enriched in the nervous system. They play crucial roles in neuroprotection and neurological diseases. Alzheimers disease (AD) is a neurodegenerative disease with cognitive, judgment and memory dysfunction. In this study, a mass spectrometry-based data-dependent acquisition method assisted with fragmentation characteristics screening by computer algorithm was developed for qualitative and quantitative analysis of gangliosides at low concentration. The developed method was applied to obtain detailed ganglioside species content in hippocampus of model mice (APPswePS1dE9 transgenic mice) with AD at 3- to 8-month-old. Up-regulated acetylated and N-acetylgalactosaminylated ganglioside species, and the down-regulated major gangliosides were observed with the development of AD from early to late stage. We speculated that deterioration of AD may be related to the acetylationN-acetylgalactosaminylation transformation of complex gangliosides due to the inhibition of GD3 synthase activity. Moreover, the ganglioside species di-O-Ac-GT1a (d361), O-Ac-GD1b (d361) and O-Ac-GD1b (d360) were considered as the time-coursed biomarkers, and O-Ac-GT1a (d362) could be a candidate for early diagnosis of AD.

Subjective Memory Decline Predicts Incident Cognitive Impairment among White-but Not Black or Hispanic-Older Adults.

This study investigates whether subjective memory decline in a racially diverse sample of older adults without cognitive impairment at baseline is associated with incident cognitive impairment during a 12-year follow-up period. With panel data from a national sample (N9,244) of cognitively-intact Black, White, and Hispanic Americans 65 years or older in 2004, we examine if subjective memory decline is associated with the loss of normal cognition by 2016. Cognitive status was assessed every two years with a modified version of the Telephone Interview for Cognitive Status to identify the transition from normal cognition to cognitive impairment. Estimates from Weibull accelerated failure-time models reveal that subjective memory decline is associated with earlier incident cognitive impairment (time ratio 0.96, p<.05). In subsequent models stratified by race-ethnicity, this association was evident among White respondents (time ratio 0.95, p<.01) but not among Black, US-born Hispanic, or foreign-born Hispanic respondents. Given that the prognostic validity of subjective memory decline differs by race and ethnicity, caution is warranted when using it as a screening or clinical tool in diverse populations.

Validation of Plasma and CSF Neurofilament Light Chain as an Early Marker for Sporadic Creutzfeldt-Jakob Disease.

Biomarkers are becoming increasingly important for the differential diagnosis of neurodegenerative diseases. Previous observations indicated neurofilament light chain (NfL) as a potential blood-based biomarker for sporadic Creutzfeldt-Jakob disease (sCJD). Here, we investigated the stability, inter-assayintra-assay variation and the regulation of NfL levels in CSF and plasma in a large cohort of sCJD patients by using a single-molecule array (SIMOA). We defined cutoffs for an accurate diagnosis and measured plasma NfL level in prion-infected mice models at different time points to identify the potential dynamics throughout the disease. Our analyses confirmed CSF and plasma NfL as stable and consistent marker for sCJD. Receiver operating characteristic (ROC) curve analysis showed an AUC of 0.92-0.93 to distinguish sCJD from control groups. Newly defined cutoffs revealed good diagnostic accuracies of CSF and plasma NfL, indicated by a sensitivity of 80-83.5% and a specificity of 87.4-91%. Studies on two humanized prion-infected mice lines (Tg340-PRNP 129MM and Tg361-PRNP 129VV) revealed increased plasma NfL levels in a late pre-clinical or very early clinical stage between 120-150 days post-inoculation. In conclusion, our work supports the potential use of CSF and plasma NfL as a very early biomarker in sCJD diagnostic with good diagnostic accuracies.

Old age amyotrophic lateral sclerosis and limbic TDP-43 pathology.

This study aimed to assess and compare the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate-to-severe Alzheimers disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death 75 years or older (old-ALS, n 8), 64-74 years (middle-ALS, n 23), and 63 years or younger (young-ALS, n 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS-CBS), were summarized. Sections of paraffin-embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho-TDP-43 immunohistochemistry. The burden of TDP-43 pathology was analyzed using digital image analysis. The TDP-43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old-ALS than in young-ALS and middle-ALS. TDP-43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS-CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP-43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic-predominant, age-related TDP-43 encephalopathy neuropathologic change.

Global incidence of young-onset dementia A systematic review and meta-analysis.

Reliable data on the incidence rates for young-onset dementia (YOD) are lacking, but are necessary for research on disease etiology and to raise awareness among health care professionals. We performed a systematic review and meta-analysis on population-based studies on the incidence of YOD, published between January 1, 1990 and February 1, 2022, according to Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Data were analyzed using random-effects meta-analyses. Results were age-standardized, and heterogeneity was assessed by subgroup analyses and meta-regression. Sixty-one articles were included. Global age-standardized incidence rates increased from 0.17100,000 in age 30 to 34 years, to 5.14100,000 in age 60 to 64 years, giving a global total age-standardized incidence rate of 11 per 100,000 in age 30 to 64. This corresponds to 370,000 new YOD cases annually worldwide. Heterogeneity was high and meta-regression showed geographic location significantly influenced this heterogeneity. This meta-analysis shows the current best estimate of YOD incidence. New prospective cohort studies are needed.

Autologous skin-derived neural precursor cell therapy reverses canine Alzheimer dementia-like syndrome in a proof of concept veterinary trial.

Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis. A Phase 12A veterinary trial was conducted in N 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses these were compared to a brain bank (N 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation. Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits. With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.

Identification of characteristic metabolic panels for different stages of prostate cancer by

Prostate cancer (PCa) is the second most prevalent cancer in males worldwide, yet detecting PCa and its metastases remains a major challenging task in clinical research setups. The present study aimed to characterize the metabolic changes underlying the PCa progression and investigate the efficacy of related metabolic panels for an accurate PCa assessment. In the present study, 75 PCa subjects, 62 PCa patients with bone metastasis (PCaB), and 50 benign prostatic hyperplasia (BPH) patients were enrolled, and we performed a cross-sectional metabolomics analysis of serum samples collected from these subjects using a Multivariate analysis revealed that BPH, PCa, and PCaB groups showed distinct metabolic divisions, while univariate statistics integrated with variable importance in the projection (VIP) scores identified a differential metabolite series, which included energy, amino acid, and ketone body metabolism. Herein, we identified a series of characteristic serum metabolic changes, including decreased trends of 3-HB and acetone as well as elevated trends of alanine in PCa patients compared with BPH subjects, while increased levels of 3-HB and acetone as well as decreased levels of alanine in PCaB patients compared with PCa. Additionally, our results also revealed the metabolic panels of discriminant metabolites coupled with the clinical parameters (age and body mass index) for discrimination between PCa and BPH, PCaB and BPH, PCaB and PCa achieved the AUC values of 0.828, 0.917, and 0.872, respectively. Overall, our study gave successful discrimination of BPH, PCa and PCaB, and we characterized the potential metabolic alterations involved in the PCa progression and its metastases, including 3-HB, acetone and alanine. The defined biomarker panels could be employed to aid in the diagnosis and classification of PCa in clinical practice.

Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia.

A consequence of our progressively ageing global population is the increasing prevalence of worldwide age-related cognitive decline and dementia. In the absence of effective therapeutic interventions, identifying risk factors associated with cognitive decline becomes increasingly vital. Novel perspectives suggest that a dynamic bidirectional communication system between the gut, its microbiome, and the central nervous system, commonly referred to as the microbiota-gut-brain axis, may be a contributing factor for cognitive health and disease. However, the exact mechanisms remain undefined. Microbial-derived metabolites produced in the gut can cross the intestinal epithelial barrier, enter systemic circulation and trigger physiological responses both directly and indirectly affecting the central nervous system and its functions. Dysregulation of this system (i.e., dysbiosis) can modulate cytotoxic metabolite production, promote neuroinflammation and negatively impact cognition. In this review, we explore critical connections between microbial-derived metabolites (secondary bile acids, trimethylamine-N-oxide (TMAO), tryptophan derivatives and others) and their influence upon cognitive function and neurodegenerative disorders, with a particular interest in their less-explored role as risk factors of cognitive decline.

An integrated genome and phenome-wide association study approach to understanding Alzheimers disease predisposition.

Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs) that increase late-onset Alzheimers disease (LOAD) risk. To identify additional LOAD-associated variants and provide insight into underlying disease biology, we performed a phenome-wide association study on 23 known LOAD-associated SNPs and 41 matched control SNPs using UK Biobank data. LOAD-associated SNPs were significantly enriched for associations with 8778 queried traits, including 3 platelet traits. The strongest enrichment was for platelet distribution width (PDW) (p 1.2 × 10

γ-Glutamylcysteine attenuates amyloid-β oligomers-induced neuroinflammation in microglia via blocking NF-κB signaling pathway.

Alzheimers disease (AD) is the most prevalent neurogenerative disease, characterized by progressive memory loss and cognitive deficits. Intracellular neurofibrillary tangles (NFTs) and amyloid-β (Aβ)-formed neuritic plaques are major pathological features of AD. Aβ evokes activation of microglia to release inflammatory mediators and ROS to induce neurotoxicity, leading to neurodegeneration. γ-Glutamylcysteine (γ-GC), an intermediate dipeptide of the GSH-synthesis pathway with anti-inflammatory and anti-oxidative properties, represents a relatively unexplored option for AD treatment. In the present study, we investigated the anti-inflammatory effect of γ-GC on Aβ oligomer (AβO)-induced neuroinflammation and the associated molecular mechanism in microglia. The results showed that γ-GC reduced AβO-induced release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO), and the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2). γ-GC decreased ROS and MDA production and increased the GSH level, GSHGSSG ratio, and SOD activity in AβO-treated microglia. Mechanistically, γ-GC inhibited activation of nuclear factor kappa B (NF-κB), and upregulated the nuclear receptor-related 1 (Nurr1) protein expression to suppress the transcriptional effect of NF-κB on the inflammatory genes. Besides, γ-GC suppressed the AβO-induced neuroinflammation in mice. These findings suggested that γ-GC might represent a potential therapeutic agent for anti-neuroinflammation.

Vesicles of yeast cell wall-sitagliptin to alleviate neuroinflammation in Alzheimers disease.

A cell-based drug delivery system based on yeast-cell wall loaded with sitagliptin, a drug with an anti-inflammatory effect, was developed to control neuroinflammation associated with Alzheimers disease. The optimized nanoparticles had a spherical shape with a negative surface charge, and were shown to be less toxic than the carrier and sitagliptin. Moreover, the nanoparticles caused anti-inflammatory effects against tumor necrosis factor-alpha in mice model of neuroinflammation. The pharmacokinetics study showed the brain concentration of drug in the nanoparticles group was much higher than in the control group. To evaluate the effect of P-glycoprotein on brain entry of sitagliptin, the experiment was repeated with verapamil, as a P-glycoprotein inhibitor. Brain concentration of the nanoparticles group remained approximately unchanged, proving the Trojan Horse effect of the developed nanocarriers. The results are promising for using yeast-cell wall as a carrier for targeted delivery to immune cells for the management of inflammation.

Anti-Alzheimers disease active components screened out and identified from Hedyotis diffusa combining bioaffinity ultrafiltration LC-MS with acetylcholinesterase.

Hedyotis diffusa is a traditional ethnomedicinal plant in local communities in northeastern Asia and used to treat inflammation, nervous breakdown, among others. In recent years, it has been applied in the treatment of Alzheimers disease (AD), while the specific chemical components responsible for the activity remain need to be explored. To prepare, screen and identify the potential anti-AD active components from Hedyotis diffusa. The acetylcholinesterase (AChE) inhibitory activity of four different extracts of Hedyotis diffusa were initially assessed using a spectrophotometric Ellmans method. A more accurate LC-MSMS screening method combining functional enzyme assay and affinity ultrafiltration (AU) screening assay was developed and applied for the screening of natural compound inhibitors of AChE from Hedyotis diffusa. The binding mode was further investigated between protein and ligands via molecular docking. Subsequently, CL4176, a transgenic nematode model for AD, was used for activity validation of one of these components. N-butanol extract of Hedyotis diffusa (NHD) appeared significant inhibitory activities on AChE, were chosen to delve deeper. Five bioactive components targeting AChE were screened out and identified using AU coupled to liquid chromatography-mass spectrometry. Molecular docking technique further confirmed the results of the screening assay. Finally, quercetin-3-O-sophoroside (QS) was confirmed as a potent anti-AD agent by in vivo experiments in C. elegans. This study explores a new idea for screening anti-AD active components from traditional medicine. The findings provide a molecular structure and bioactivity basis for future potential applications of Hedyotis diffusa in medical industries.

Longitudinal associations of mid-life employment status with impaired physical function in the Study of Womens Health Across the Nation.

This study examined whether employment status during mid-life and older adulthood is associated with physical function impairment. Participants were 2700 women in the multiracialmultiethnic Study of Womens Health Across the Nation. Time-varying, lagged, and cumulative exposure analyses modeled associations between self-reported employment status and the likelihood of severe physical function impairment across 19 years of follow-up. Independent of demographic variables, women who were not working (OR 1.58, 95% CI 1.22, 2.04) or employed part-time (OR 1.29, 95% CI 1.04, 1.61) were more likely to report severe physical function impairments than women employed full-time. This same pattern was seen in lagged analyses predicting risk of physical function impairment from employment status at the prior assessment (not working vs. full-time OR 1.53, 95% CI 1.08, 2.18 part-time vs. full-time OR 1.53, 95% CI 1.17, 2.00). The likelihood of severe physical function impairment increased by 20% for every additional 10% of follow-up spent not working (OR 1.02, 95% CI 1.01, 1.03). Associations were robust to adjustment for health-related variables, body mass index, and physical activity. Women with lower levels of employment from mid-life to older adulthood were more likely to experience severe impairment in physical function. However, the underlying mechanisms, and the timescales over which associations unfold, require further study.

Microglia Friend and foe in tauopathy.

Aggregation of misfolded microtubule associated protein tau into abnormal intracellular inclusions defines a class of neurodegenerative diseases known as tauopathies. The consistent spatiotemporal progression of tau pathology in Alzheimers disease (AD) led to the hypothesis that tau aggregates spread in the brain via bioactive tau seeds underlying advancing disease course. Recent studies implicate microglia, the resident immune cells of the central nervous system, in both negative and positive regulation of tau pathology. Polymorphisms in genes that alter microglial function are associated with the development of AD and other tauopathies. Experimental manipulation of microglia function can alter tau pathology and microglia-mediated neuroinflammatory cascades can exacerbate tau pathology. Microglia also exert protective functions by mitigating tau spread microglia internalize tau seeds and have the capacity to degrade them. However, when microglia fail to degrade these tau seeds there are deleterious consequences, including secretion of exosomes containing tau that can spread to neurons. This review explores the intersection of microglia and tau from the perspective of neuropathology, neuroimaging, genetics, transcriptomics, and molecular biology. As tau-targeted therapies such as anti-tau antibodies advance through clinical trials, it is critical to understand the interaction between tau and microglia.

Risk factors for apathy in Alzheimers disease A systematic review of longitudinal evidence.

Apathy is frequent and persistent in Alzheimers disease (AD), associated with poor prognosis and carer distress yet our knowledge of risk factors remains limited. To identify risk factors associated with apathy incidence and progression in AD over time. We systematically reviewed evidence based on longitudinal studies assessing risk factors for apathy in AD up to June 2021. Two authors independently assessed article eligibility and rated quality. 13,280 articles were screened, of which 13 met inclusion criteria. Studies had a mean follow-up of 2.7 years reporting on a total of 2012 participants. Most findings were based on single studies of moderate quality evidence. Risk factors increasing apathy onset were being a carrier of the T allele of the PRND gene polymorphism, and having high levels of the IL-6 and TNFα cytokines at baseline. Risk factors for apathy worsening were reduced inferior-temporal cortical thickness, taking antidepressants, being an ApoE ε4 carrier, living longer with AD, lower cognitive test scores, higher baseline apathy, premorbid personality traits (lower agreeableness, higher neuroticism), and higher midlife motivational abilities. Although results are limited by the small number of studies, this review identified specific genetic, neurobiological, AD specific, and dispositional factors that may increase risk of apathy onset and worsening in AD.

Z-Guggulsterone attenuates cognitive defects and decreases neuroinflammation in APPswePS1dE9 mice through inhibiting the TLR4 signaling pathway.

Growing evidence indicates that inflammatory damage is implicated in the pathogenesis of Alzheimers disease (AD). Z-Guggulsterone (Z-GS) is a natural steroid, which is extracted from Commiphora mukul and has anti-inflammatory effects in vivo and in vitro. In the present study, we investigated the disease-modifying effects of chronic Z-GS administration on the cognitive and neuropathological impairments in the transgenic mouse models of AD. We found that chronic Z-GS administration prevented learning and memory deficits in the APPswePS1dE9 mice. In addition, Z-GS treatment significantly decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswePS1dE9 mice. We also found that Z-GS treatment markedly alleviated neuroinflammation and reduced synaptic defects in the APPswePS1dE9 mice. Furthermore, the activated TLR4NF-κB signaling pathways in APPswePS1dE9 mice were remarkably inhibited by Z-GS treatment, which was achieved via suppressing the phosphorylation of JNK. Collectively, our data demonstrate that chronic Z-GS treatment restores cognitive defects and reverses multiple neuropathological impairments in the APPswePS1dE9 mice. This study provides novel insights into the neuroprotective effects and neurobiological mechanisms of Z-GS on AD, indicating that Z-GS is a promising disease-modifying agent for the treatment of AD.

The role of mixed B vitamin intakes on cognitive performance Modeling, genes and miRNAs involved.

To assess the relationships between mixed B vitamin intakes (B1, B2, B3, B6, B9, B12) and cognitive performance, as well as their molecular mechanisms. The associations of mixed B vitamin intakes with cognitive function were assessed using multivariate regression models, weighted quantile sum (WQS), quantile g-computation (qgcomp), and Bayesian kernel machine regression (BKMR). GeneMANIA, Comparative Toxicogenomics Database, MIENTURNET, miRNAsong were employed as the main data-mining methods. Overall effects of the B vitamin intake mixture were significantly associated with global cognition in the WQS, qgcomp, and BKMR models. A mixture of B vitamins (B1, B2, B3, B9) interacted with the five genes (IL1B, BCL2, CASP3, BAX, PTGS2) and was associated with better cognitive function, especially CASP3 and BAX. Physical interactions (77.6%) were observed to be the most important interactions in gene networks. The IL-18 signaling pathway, apoptosis, and Alzheimers disease were annotated as the key molecular mechanisms involved in mixed B vitamins improving cognitive function. NFKB1, ATF3, and NR3C1 were the key significant transcription factors associated with cognitive function targeted by a mixture of B vitamins. The strong interaction and expression of hsa-miR-34a-5p, hsa-miR-128-3p, hsa-miR-181a-5p, and hsa-miR-204-5p are involved in mixed B vitamins better cognitive performance. We also created and evaluated miRNA sponge sequences for these miRNAs, which might be used to alleviate cognitive decline. The cutoff thresholds for B vitamin intake levels that are associated with cognition performance were reported. Given the increased incidence of dementia across the world, increasing daily mixed B vitamin intake via regular meals may contribute to minimizing dementia risk. Further studies are warranted to identify these links in well-characterized cohorts of diverse populations, either independently or together.

Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents.

Alzheimers disease (AD) is a neurological disorder that leads to dementia i.e., progressive memory loss accompanied with worsening of thinking ability of an individual. The cause of AD is not fully understood but it progresses with age where brain cells gradually die over time. According to the World Health Organization (WHO), currently 50 million people worldwide are affected by dementia and 60-70% of the cases belong to AD. Cumulative research over the past few decades have shown that molecules that act at a single target possess limited efficacy since these investigational drugs are not able to act against complex pathologies and thus do not provide permanent cure. Designing of multi-target directed ligands (MTDLs) appears to be more beneficial and a rational approach to treat chronic complex diseases including neurodegenerative diseases. Recently, MTDLs are being extensively researched by the medicinal chemists for the development of drugs for the treatment of various multifactorial diseases. Indole is one of the privileged scaffolds which is considered as an essential mediator between the gut-brain axis because of its neuroprotective, anti-inflammatory, β-amyloid anti-aggregation and antioxidant activities. Herein, we have reviewed the potential of some indole-hybrids acting at multiple targets in the pathogenesis of AD. We have reviewed research articles from the year 2014-2021 from various scientific databases and highlighted the synthetic strategies, mechanisms of neuroprotection, toxicity, structure activity relationships and molecular docking studies of various indole-hybrid derivatives. This literature review of published data on indole derivatives indicated that developing indole hybrids have improved the pharmacokinetic profile with lower toxicity, provided synergistic effect, helped to develop more potent compounds and prevented drug-drug interactions. It is evident that this class of compounds have potential to inhibit multiple enzymes targets involved in the pathogenesis of AD and therefore indole hybrids as MTDLs may play an important role in the development of anti-AD molecules.

BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1.

BACE-1 is required for generating β-amyloid (Aβ) peptides in Alzheimers disease (AD). Here, we report that microglial BACE-1 regulates the transition of homeostatic to stage 1 disease-associated microglia (DAM-1) signature. BACE-1 deficiency elevated levels of transcription factors including

Artificial Intelligence on FDG PET Images Identifies Mild Cognitive Impairment Patients with Neurodegenerative Disease.

The purpose of this project is to develop and validate a Deep Learning (DL) FDG PET imaging algorithm able to identify patients with any neurodegenerative diseases (Alzheimers Disease (AD), Frontotemporal Degeneration (FTD) or Dementia with Lewy Bodies (DLB)) among patients with Mild Cognitive Impairment (MCI). A 3D Convolutional neural network was trained using images from the Alzheimers Disease Neuroimaging Initiative (ADNI) database. The ADNI dataset used for the model training and testing consisted of 822 subjects (472 AD and 350 MCI). The validation was performed on an independent dataset from La Fe University and Polytechnic Hospital. This dataset contained 90 subjects with MCI, 71 of them developed a neurodegenerative disease (64 AD, 4 FTD and 3 DLB) while 19 did not associate any neurodegenerative disease. The model had 79% accuracy, 88% sensitivity and 71% specificity in the identification of patients with neurodegenerative diseases tested on the 10% ADNI dataset, achieving an area under the receiver operating characteristic curve (AUC) of 0.90. On the external validation, the model preserved 80% balanced accuracy, 75% sensitivity, 84% specificity and 0.86 AUC. This binary classifier model based on FDG PET images allows the early prediction of neurodegenerative diseases in MCI patients in standard clinical settings with an overall 80% classification balanced accuracy.

Promising application of polyoxometalates in the treatment of cancer, infectious diseases and Alzheimers disease.

As shown in studies conducted in recent decades, polyoxometalates (POMs), as inorganic metal oxides, have promising biological activities, including antitumor, anti-infectious and anti-Alzheimers activities, due to their special structures and properties. However, some side effects impede their clinical applications to a certain extent. Compared with unmodified POMs, POM-based inorganic-organic hybrids and POM-based nanocomposite structures show significantly enhanced bioactivity and reduced side effects. In this review, we introduce the biological activities of POMs and their derivatives and highlight the side effects of POMs on normal cells and organisms and their possible mechanisms of action. We then propose a development direction for overcoming their side effects. POMs are expected to constitute a new generation of inorganic metal drugs for the treatment of cancer, infectious diseases, and Alzheimers disease.Graphical abstract.

TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury.

Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimers disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aβ formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.

Monosialotetrahexosylganglioside Promotes Early Aβ42 Oligomer Formation and Maintenance.

The aggregation of the amyloid beta (Aβ) peptide is associated with Alzheimers disease (AD) pathogenesis. Cell membrane composition, especially monosialotetrahexosylganglioside (GM1), is known to promote the formation of Aβ fibrils, yet little is known about the roles of GM1 in the early steps of Aβ oligomer formation. Here, by using GM1-contained liposomes as a mimic of the neuronal cell membrane, we demonstrate that GM1 is a critical trigger of Aβ oligomerization and aggregation. We find that GM1 not only promotes the formation of Aβ fibrils but also facilitates the maintenance of Aβ42 oligomers on liposome membranes. We structurally characterize the Aβ42 oligomers formed on the membrane and find that GM1 captures Aβ by binding to its arginine-5 residue. To interrogate the mechanism of Aβ42 oligomer toxicity, we design a new liposome-based Ca

Decreased Frontal Gamma Activity in Alzheimer Disease Patients.

In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients. Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks. Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 202292464-475.

Amyloid Beta Peptide-Mediated Alterations in Mitochondrial Dynamics and its Implications for Alzheimers Disease.

Alzheimers disease (AD) is considered the most frequent neurodegenerative disorder worldwide, compromising cognitive function in patients, with an average incidence of 1-3% in the open population. Protein aggregation into amyloidogenic plaques and neurofibrillary tangles, as well as neurodegeneration in the hippocampal and cortical areas represent the neuropathological hallmarks of this disorder. Mechanisms involved in neurodegeneration include protein misfolding, augmented apoptosis, disrupted molecular signaling pathways and axonal transport, oxidative stress, inflammation, and mitochondrial dysfunction, among others. It is precisely through a disrupted energy metabolism that neural cells trigger toxic mechanisms leading to cell death. In this regard, the study of mitochondrial dynamics constitutes a relevant topic to decipher the role of mitochondrial dysfunction in neurological disorders, especially when considering that amyloid beta peptides can target mitochondria. Specifically, amyloid beta (Aβ) peptide, which is known to accumulate in the brain of AD patients, has been shown to disrupt overall mitochondrial metabolism by impairing energy production, mitochondrial redox activity, and calcium homeostasis, thus highlighting its key role for the AD pathogenesis. In this work, we review and discuss recent evidence supporting the concept that mitochondrial dysfunction mediated by amyloid peptides contributes to the development of AD.

Community services for older people a cross-sectional study to explore awareness and the degree of need for long-term care resources.

Day service use and improved Serial 7 and Verbal fluency scores in patients with Alzheimers disease.

Day services (DS) are provided as part of the Japanese public nursing care system. Recent studies have suggested a possible relationship between DS use and limited progression of Alzheimers disease (AD). This study examined in detail the relationship between improvements in cognitive function and DS use in people with AD. We retrospectively analysed Revised Hasegawa Dementia Scale (HDS-R) scores of 208 patients with AD at five memory clinics over a 6-month period. The patients were divided into a group that started using DS (n 132) and a group that did not (n 76) during the study period. We then compared each participants total and item scores on the HDS-R between the first clinic visit and 6 months later also compared scores between DS users and non-users. DS non-users were younger, predominantly male, had longer school education, and better total HDS-R score at the first visit. After 6 months, DS users showed significantly improved total HDS-R score and individual Serial 7 and Verbal fluency scores. Immediate memory scores were comparable between the first visit and after 6 months. Among the DS users, more frequent participation in DS was significantly associated with improved total HDS-R score. DS use was significantly associated with improved HDS-R scores, especially for the Serial 7 and Verbal fluency tasks, and there was no deterioration in Immediate memory score. These results suggest the usefulness of DS participation as a non-pharmacological therapy.

Focusing on Formononetin Recent Perspectives for its Neuroprotective Potentials.

Nervous system is the most complex system of the human body, hence, the neurological diseases often lack effective treatment strategies. Natural products have the potential to yield unique molecules and produce integrative and synergic effects compared to standard therapy. Mounting evidence has shown that isoflavonoids contained in traditional medicinal plant or dietary supplementation may play a crucial role in the prevention and treatment of neurological diseases due to their pronounced biological activities correlating to nervous system. Formononetin, a non-steroidal isoflavonoid, is a bioactive constituent of numerous medicinal plants such as red clover (

Basal Forebrain Impairment Understanding the Mnemonic Function of the Septal Region Translates in Therapeutic Advances.

The basal forebrain is one of the three major brain circuits involved in episodic memory formation together with the hippocampus and the diencephalon. The dysfunction of each of these regions is known to cause anterograde amnesia. While the hippocampal pyramidal neurons are known to encode episodic information and the diencephalic structures are known to provide idiothetic information, the contribution of the basal forebrain to memory formation has been exclusively associated with septo-hippocampal cholinergic signaling. Research data from the last decade broadened our understanding about the role of septal region in memory formation. Animal studies revealed that septal neurons process locomotor, rewarding and attentional stimuli. The integration of these signals results in a systems model for the mnemonic function of the medial septum that could guide new therapeutic strategies for basal forebrain impairment (BFI). BFI includes the disorders characterized with basal forebrain amnesia and neurodegenerative disorders that affect the basal forebrain. Here, we demonstrate how the updated model of septal mnemonic function can lead to innovative translational treatment approaches that include pharmacological, instrumental and behavioral techniques.

Training-Specific Changes in Regional Spontaneous Neural Activity Among Professional Chinese Chess Players.

Our previous reports reflected some aspects of neuroplastic changes from long-term Chinese chess training but were mainly based on large-scale intrinsic connectivity. In contrast to functional connectivity among remote brain areas, synchronization of local intrinsic activity demonstrates functional connectivity among regional areas. Until now, local connectivity changes in professional Chinese chess players (PCCPs) have been reported only at specific hubs whole-brain-based local connectivity and its relation to training profiles has not been revealed. To investigate whole-brain local connectivity changes and their relation to training profiles in PCCPs. Regional homogeneity (ReHo) analysis of rs-fMRI data from 22 PCCPs versus 21 novices was performed to determine local connectivity changes and their relation to training profiles. Compared to novices, PCCPs showed increased regional spontaneous activity in the posterior lobe of the left cerebellum, the left temporal pole, the right amygdala, and the brainstem but decreased ReHo in the right precentral gyrus. From a whole-brain perspective, local activity in areas such as the posterior lobe of the right cerebellum and the caudate correlated with training profiles. Regional homogeneity changes in PCCPs were consistent with the classical view of automaticity in motor control and learning. Related areas in the pattern indicated an enhanced capacity for emotion regulation, supporting cool and focused attention during gameplay. The possible participation of the basal ganglia-cerebellar-cerebral networks, as suggested by these correlation results, expands our present knowledge of the neural substrates of professional chess players. Meanwhile, ReHo change occurred in an area responsible for the pronunciation and reading of Chinese characters. Additionally, professional Chinese chess training was associated with change in a region that is affected by Alzheimers disease (AD).

Alzheimers Disease and Stroke A Tangled Neurological Conundrum.

A neurodegenerative disorder, Alzheimers disease (AD), is characterized by dementia in which there is an age-related decline in cognition and higher functions. Stroke is a cerebrovascular disorder that frequently presents in old age and is a known risk factor for AD development. However, the association that AD can be a risk factor for stroke is not well-studied. This review article compiled various studies that pointed out the association between stroke development in patients with dementia, particularly AD-related dementia. The pathophysiological progression of stroke in AD cases and the genetic makeup possibly affecting the interrelation between these disorders were analyzed in detail using currently available data and studies. Therapeutic and management modalities already in use for AD were put together, and the possibility of early intervention in such patients benefitting cerebrovascular pathologies, particularly stroke-related, was explored. Prognostic differences between patients of stroke with and without AD were also reviewed, and how appropriate management can reduce the burden on health care settings when both present simultaneously was emphasized.

Tau Acts in Concert With KinasePhosphatase Underlying Synaptic Dysfunction.

Alzheimers disease (AD) is characterized by two pathological features neurofibrillary tangles (NFTs), formed by microtubule-associated protein tau, and abnormal accumulation of amyloid-β (Aβ). Multiple evidence placed synaptic tau as the vital fact of AD pathology, especially at the very early stage of AD. In the present review, we discuss tau phosphorylation, which is critical for the dendritic localization of tau and synaptic plasticity. We review the related kinases and phosphatases implicated in the synaptic function of tau. We also review the synergistic effects of these kinases and phosphatases on tau-associated synaptic deficits. We aim to open a new perspective on the treatment of AD.

Machine Learning Analysis Reveals Biomarkers for the Detection of Neurological Diseases.

It is critical to identify biomarkers for neurological diseases (NLDs) to accelerate drug discovery for effective treatment of patients of diseases that currently lack such treatments. In this work, we retrieved genotyping and clinical data from 1,223 UK Biobank participants to identify genetic and clinical biomarkers for NLDs, including Alzheimers disease (AD), Parkinsons disease (PD), motor neuron disease (MND), and myasthenia gravis (MG). Using a machine learning modeling approach with Monte Carlo randomization, we identified a panel of informative diagnostic biomarkers for predicting AD, PD, MND, and MG, including classical liver disease markers such as alanine aminotransferase, alkaline phosphatase, and bilirubin. A multinomial model trained on accessible clinical markers could correctly predict an NLD diagnosis with an accuracy of 88.3%. We also explored genetic biomarkers. In a genome-wide association study of AD, PD, MND, and MG patients, we identified single nucleotide polymorphisms (SNPs) implicated in several craniofacial disorders such as apnoea and branchiootic syndrome. We found evidence for shared genetic risk loci among NLDs, including SNPs in cancer-related genes and SNPs known to be associated with non-brain cancers such as Wilms tumor, leukemia, and colon cancer. This indicates overlapping genetic characterizations among NLDs which challenges current clinical definitions of the neurological disorders. Taken together, this work demonstrates the value of data-driven approaches to identify novel biomarkers in the absence of any known or promising biomarkers.

Association of Cardiovascular Health Metrics with Dementia in Rural Chinese Older Adults A Population-Based Study.

We explore the associations of individual and composite cardiovascular health metrics with all-cause dementia, Alzheimers disease, and vascular dementia among rural-dwelling older adults and the potential age variations in their associations. This community-based cross-sectional study included 4980 older adults (age ≥65 years 57.23% women) from the baseline examination of MIND-China. In March-September 2018, data were collected via face-to-face interviews, clinical examinations, and laboratory test. We defined six cardiovascular health metrics according to the modified American Heart Associations recommendations. We diagnosed dementia and its subtypes following the international criteria. Data were analyzed using logistic regression models. Of all the participants, 250 were diagnosed with dementia, including 165 with Alzheimers disease and 75 with vascular dementia. Ideal composite global cardiovascular health metrics (vs poor composite metrics) were associated with a multi-adjusted odds ratio (95% confidence interval) of 0.62 (0.42-0.93) for dementia, 0.88 (0.52-1.48) for Alzheimers disease, and 0.31 (0.16-0.60) for vascular dementia. Moreover, ideal biological cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.52 (0.28-0.95) for dementia and 0.21 (0.06-0.77) for vascular dementia in young-old adults (65-74 years), whereas ideal behavioral cardiovascular health metrics were associated with multi-adjusted odds ratio of 0.48 (0.26-0.89) for dementia and 0.16 (0.06-0.43) for vascular dementia in old-old adults (≥75 years). Our results suggest that ideal cardiovascular health metrics are cross-sectionally associated with a low likelihood of dementia and vascular dementia among rural-dwelling older Chinese adults. The associations vary with age, components of cardiovascular health metrics, and dementia subtypes.

Exploring the zinc-related transcriptional landscape in Alzheimers disease.

Alzheimers disease (AD) is a progressive neurological disorder, and increasing evidence suggests AD pathology is driven by metabolic dysfunction in the brain. Zinc is the second most abundant trace element found in the human body and is required by all living organisms. Zinc is used extensively in many biological processes, and alterations in zinc levels are implicated in the pathogenesis of numerous diseases, including AD. Since small fluctuations in brain zinc levels appear to effect AD progression, we investigated the zinc-related transcriptional responses in an AD versus non-AD state using microarray and RNA-sequencing (RNA-seq) datasets from cultured cells, mice, and humans. We identified 582 zinc-related differentially expressed genes (DEG) in human dorsolateral prefrontal cortex samples of late-onset AD (LOAD) versus non-AD controls, 146 zinc-related DEG in 5XFAD versus wild-type mice, and 95 zinc-related DEG in lipopolysaccharide (LPS)-stimulated N9 microglia versus unstimulated control cells, with 19 zinc-related DEG common to all three datasets. Of the 19 common DEG, functional enrichment and network analyses identified several biological processes and molecular functions, such as mRNA destabilization and nucleic acid binding, which may be important in neuroinflammation and AD development. Furthermore, therapeutic drugs targeting zinc-related DEG in the human dataset were identified. Taken together, these data provide insights into zinc utilization for gene transcription during AD progression which may further our understanding of AD pathogenesis and could identify new targets for therapeutic strategies targeted towards AD.

Pure word deafness a case report of an atypical manifestation of Alzheimers disease.

Auditory agnosia refers to the impairments in sound recognition despite intact hearing and written language abilities. When auditory agnosia is specific to spoken language, it can be indicated as pure word deafness (PWD), which is characterized by the isolated difficulty in understanding spoken language, despite preserved reading comprehension, recognition of nonverbal sounds, and production of written and spoken language. A middle-aged man with a high level of education developed a progressive speech disorder initially characterized by isolated phonemic errors during spontaneous speech and later enriched by difficulties in comprehending long sentences. The patients past medical history was unremarkable except for hypertension. The neuropsychological picture was suggestive of PWD, while cerebrospinal fluid (CSF) analyses lead to a biomarker-based diagnosis of Alzheimers disease (AD). PWD remained the prevalent cognitive deficit over the subsequent 4 years. This case report shows that the presence of isolated auditory agnosia or PWD should prompt consideration of a diagnosis of AD. It also suggests that the spectrum of atypical presentations of early-onset AD may be larger than what we currently think.