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Western diet associated with increased post-stroke depressive symptoms.

The present study examines the association of diet with depressive symptoms among stroke survivors from a community cohort of older adults. Depression is common after stroke. A healthy diet has previously been associated with fewer depressive symptoms in older individuals, but it is unknown if this effect is also seen in stroke survivors. Eighty-six participants from the Memory and Aging Project with a history of stroke at their study baseline enrolment, complete dietary data and two or more assessments for depression were included in this observational prospective cohort analysis. Depressive symptoms were assessed annually with a 10-item version of the Center for Epidemiologic Studies Depression scale. Diet was assessed using a validated food-frequency questionnaire administered at baseline. Diet scores were based on analysis of participants reported intakes of 144 food items. A generalised estimating equation (GEE) model was applied to examine the association of diet score with depressive symptoms. The study participants had a mean age of 82 ± 7⋅17 years and 14⋅42 ± 2⋅61 years of education, and 82⋅56 % were female. Western diet score was positively associated with depressive symptoms over time (diet score tertile 3

Methodology and preliminary data on feasibility of a neurofeedback protocol to improve visual attention to letters in mild Alzheimers disease.

Brain-computer interface (BCI) systems are controlled by users through neurophysiological input for a variety of applications, including communication, environmental control, and motor rehabilitation. Although individuals with severe speech and physical impairment are the primary users of this technology, BCIs have emerged as a potential tool for broader populations, including delivering cognitive traininginterventions with neurofeedback (NFB). This paper describes the development and preliminary testing of a protocol for use of a BCI system with NFB as an intervention for people with mild Alzheimers disease (AD). The intervention focused on training visual attention and language skills, as AD is often associated with functional impairments in both. This funded pilot study called for enrolling five participants with mild AD in a six-week BCI EEG-based NFB intervention that followed a four-to-seven-week baseline phase. While two participants completed the study, the remaining three participants could not complete the intervention phase because of COVID-19 restrictions. Preliminary pilot results suggested (1) participants with mild AD were able to participate in a study with multiple assessments per week and complete all outcome measures, (2) most outcome measures were reliable during the baseline phase, and (3) all participants with mild AD learned to operate a BCI spelling system with training. Although preliminary results demonstrate practical feasibility to deliver NFB intervention using a BCI to adults with AD, completion of the protocol in its entirety with more participants is needed to further assess whether implementing NFB-based cognitive intervention is justified by functional treatment outcomes. This study was registered with ClinicalTrials.gov (NCT03790774).

Coenzyme A-Dependent Tricarboxylic Acid Cycle Enzymes Are Decreased in Alzheimers Disease Consistent With Cerebral Pantothenate Deficiency.

Sporadic Alzheimers disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβtau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology. We tested the hypothesis that the recently identified, pervasive cerebral deficiency of pantothenate (vitamin B5) in sAD, might undermine brain energy metabolism by impairing levels of tricarboxylic acid (TCA)-cycle enzymes and enzyme complexes, some of which require the pantothenate-derived cofactor, coenzyme A (CoA) for their normal functioning. We applied proteomics to measure levels of the multi-subunit TCA-cycle enzymes and their cytoplasmic homologues. We analysed six functionally distinct brain regions from nine sAD cases and nine controls, measuring 33 cerebral proteins that comprise the nine enzymes of the mitochondrial-TCA cycle. Remarkably, we found widespread perturbations affecting only two multi-subunit enzymes and two enzyme complexes, whose function is modulated, directly or indirectly by CoA pyruvate dehydrogenase complex, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and succinyl-CoA synthetase. The sAD cases we studied here displayed widespread deficiency of pantothenate, the obligatory precursor of CoA. Therefore, deficient cerebral pantothenate can damage brain-energy metabolism in sAD, at least in part through impairing levels of these four mitochondrial-TCA-cycle enzymes.

Alteration of Visuospatial System as an Early Marker of Cognitive Decline A Double-Center Neuroimaging Study.

Amnestic-type mild cognitive impairment (a-MCI) represents the prodromal phase of Alzheimers disease associated with a high conversion rate to dementia and serves as a potential golden period for interventions. In our study, we analyzed the role of visuospatial (VS) functions and networks in the recognition of a-MCI. We examined 78 participants (32 patients and 46 controls) in a double-center arrangement using neuropsychology, structural, and resting-state functional MRI. We found that imaging of the lateral temporal areas showed strong discriminating power since in patients only the temporal pole (

MPC-STANet Alzheimers Disease Recognition Method Based on Multiple Phantom Convolution and Spatial Transformation Attention Mechanism.

Alzheimers disease (AD) is a progressive neurodegenerative disease with insidious and irreversible onset. The recognition of the disease stage of AD and the administration of effective interventional treatment are important to slow down and control the progression of the disease. However, due to the unbalanced distribution of the acquired data volume, the problem that the features change inconspicuously in different disease stages of AD, and the scattered and narrow areas of the feature areas (hippocampal region, medial temporal lobe, etc.), the effective recognition of AD remains a critical unmet need. Therefore, we first employ class-balancing operation using data expansion and Synthetic Minority Oversampling Technique (SMOTE) to avoid the AD MRI dataset being affected by classification imbalance in the training. Subsequently, a recognition network based on Multi-Phantom Convolution (MPC) and Space Conversion Attention Mechanism (MPC-STANet) with ResNet50 as the backbone network is proposed for the recognition of the disease stages of AD. In this study, we propose a Multi-Phantom Convolution in the way of convolution according to the channel direction and integrate it with the average pooling layer into two basic blocks of ResNet50 Conv Block and Identity Block to propose the Multi-Phantom Residual Block (MPRB) including Multi-Conv Block and Multi-Identity Block to better recognize the scattered and tiny disease features of Alzheimers disease. Meanwhile, the weight coefficients are extracted from both vertical and horizontal directions using the Space Conversion Attention Mechanism (SCAM) to better recognize subtle structural changes in the AD MRI images. The experimental results show that our proposed method achieves an average recognition accuracy of 96.25%, F1 score of 95%, and mAP of 93%, and the number of parameters is only 1.69 M more than ResNet50.

Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration.

Aging is an intricate process characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. Whereas each of these traits is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1-associated protein essential for neurogenesis, results in persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). These defects extend to cellular senescence and proteasome-mediated histone H2A proteolysis with alterations in cells proteomic and epigenetic states. Brap deletion in the mouse brain causes neuroinflammation, impaired proteostasis, accelerated neurodegeneration, and substantially shortened the lifespan. We further show the elevation of H2Aub also occurs in human brain tissues with Alzheimers disease. These data together suggest that chromatin aberrations mediated by H2Aub may act as a nexus of multiple aging hallmarks and promote tissue-wide degeneration.

Bulk and Single-Nucleus Transcriptomics Highlight Intra-Telencephalic and Somatostatin Neurons in Alzheimers Disease.

Cortical neuron loss is a pathological hallmark of late-onset Alzheimers disease (AD). However, it remains unclear which neuronal subtypes beyond broad excitatory and inhibitory classes are most vulnerable. Here, we analyzed cell subtype proportion differences in AD compared to non-AD controls using 1037 post-mortem brain samples from six neocortical regions. We identified the strongest associations of AD with fewer somatostatin (SST) inhibitory neurons (β -0.48,

Alzheimers disease (AD) is the most prevalent neural disorder. However, the therapeutic agents for AD are limited.

Endosomal-Lysosomal and Autophagy Pathway in Alzheimers Disease A Systematic Review and Meta-Analysis.

The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimers disease (AD) however, findings thus far have been inconsistent. To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1 NADNHC 348381, SMD 95% CI 0.599 0.268, 0.930, I2 72.8% LAMP-2 NADNHC 401510, SMD 95% CI 0.480 0.134, 0.826, I2 78.7%) and intra-lysosomal proteins (GM2A NADNHC 390420, SMD 95% CI 0.496 0.039, 0.954, I2 87.7% CTSB NADNHC 485443, SMD 95% CI 0.201 0.029, 0.374, I2 28.5% CTSZ NADNHC 535820, SMD 95% CI -0.160 -0.305, -0.015, I2 24.0%) and in proteins involved in endocytosis (AP2B1NADNHC 171205, SMD 95% CI 0.513 0.259, 0.768, I2 27.4% FLOT1 NADNHC 4145, SMD 95% CI -0.489 -0.919, -0.058, I2 <0.01). LC3B, an autophagy marker, also showed a difference (NADNHC 7059, SMD 95% CI 0.648 0.180, 1.116, I2 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy. Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD.

Noninvasive Antemortem Detection of Retinal Prions by a Fluorescent Tracer.

Neurodegenerative diseases are widespread yet challenging to diagnose and stage antemortem. As an extension of the central nervous system, the eye harbors retina ganglion cells vulnerable to degeneration, and visual symptoms are often an early manifestation of neurodegenerative disease. Here we test whether prion protein aggregates could be detected in the eyes of live mice using an amyloid-binding fluorescent probe and high-resolution retinal microscopy. We performed retinal imaging on an experimental mouse model of prion-associated cerebral amyloid angiopathy in a longitudinal study. An amyloid-binding fluorophore was intravenously administered, and retinal imaging was performed at timepoints corresponding to early, mid-, and terminal prion disease. Retinal amyloid deposits were quantified and compared to the amyloid load in the brain. We report that by early prion disease (50% timepoint), discrete fluorescent foci appeared adjacent to the optic disc. By later timepoints, the fluorescent foci surrounded the optic disc and tracked along retinal vasculature. The progression of perivascular amyloid can be directly monitored in the eye by live imaging, illustrating the utility of this technology for diagnosing and monitoring the progression of cerebral amyloid angiopathy.

Natural Pattern of Cognitive Aging.

Considering the worlds rapidly increasing life expectancy, with people working and maintaining active lifestyles longer than ever before, addressing the effects of aging on cognition is of utmost importance. A greater understanding of cognitive aging may also be critical in distinguishing natural cognitive aging from pre-clinical stages of Alzheimers disease and related cognitive disorders. To systematically examine the association between aging and cognitive performance in a cognitively and otherwise healthy probability population-based sample using a computer-based method. This cross-sectional study enrolled 673 cognitively and otherwise healthy participants aged 25-89 years (mean age 52.3±14.2 years, 52.5% of whom were female) from the Kardiovize study cohort. Mild cognitive impairment and dementia cases were excluded, followed by measurement of cognitive performance with the computer-administered Cogstate Brief Battery. We used ANCOVA and Modified Signed-Likelihood Ratio tests to examine patterns of cognition across age groups. We found a gradual decrease in cognitive performance across the lifespan, which required two decades to demonstrate significant changes. In contrast to attention and learning, psychomotor speed and working memory showed the most significant age-related decrease and variability in performance. The established pattern of cognitive aging was not altered by sex or education. These findings corroborate, validate, and extend the current understanding of natural cognitive aging and pinpoint specific cognitive domains with the most extensive age-related interindividual differences. This will contribute to the development of strategies to preserve cognition with aging and may also serve to improve early diagnostics of cognitive disorders using computer-based methods.

Amyloid-PET Levels in the Precuneus and Posterior Cingulate Cortices Are Associated with Executive Function Scores in Preclinical Alzheimers Disease Prior to Overt Global Amyloid Positivity.

Global amyloid-β (Aβ) deposition in the brain can be quantified by Aβ-PET scans to support or refute a diagnosis of preclinical Alzheimers disease (pAD). Yet, Aβ-PET scans enable quantitative evaluation of regional Aβ elevations in pAD, potentially allowing even earlier detection of pAD, long before global positivity is achieved. It remains unclear as to whether such regional changes are clinically meaningful. Test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in pAD. Global and regional standardized uptake value ratios (SUVr) from 18F-florbetapir PETCT scanning were determined using the Siemens Syngo.via® Neurology software package across a sample of 99 clinically normal participants with Montreal Cognitive Assessment (MoCA) scores≥23. Relationships between regional SUVr and cognitive test scores were analyzed using linear regression models adjusted for age, sex, and education. Participants were divided into two groups based on SUVr in the posterior cingulate and precuneus gyri (SUVR≥1.17). Between group differences in cognitive test scores were analyzed using ANCOVA models. Executive function performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p < 0.05). There were no significant associations between memory and Aβ-PET SUVr in any regions of the brain. These data demonstrate that increased Aβ deposition in the precuneus and posterior cingulate (the earliest brain regions affected with Aβ pathology) is associated with changes in executive function that may precede memory decline in pAD.

Potential Involvement of Varicella Zoster Virus in Alzheimers Disease via Reactivation of Quiescent Herpes Simplex Virus Type 1.

Varicella zoster virus (VZV) has been implicated in Alzheimers disease (AD), and vaccination against shingles, caused by VZV, has been found to decrease the risk of ADdementia. VZV might reside latently in brain, and on reactivation might cause direct damage leading to AD, as proposed for herpes simplex virus type 1 (HSV-1), a virus strongly implicated in AD. Alternatively, shingles could induce neuroinflammation and thence, reactivation of HSV-1 in brain. To investigate these possibilities by comparing the effects of VZV and HSV-1 infection of cultured cells, and the action of VZV infection on cells quiescently infected with HSV-1. We infected human-induced neural stem cell (hiNSC) cultures with HSV-1 andor VZV and sought the presence of AD-related phenotypes such as amyloid-β (Aβ) and P-tau accumulation, gliosis, and neuroinflammation. Cells infected with VZV did not show the main AD characteristics, Aβ and P-tau accumulation, which HSV-1 does cause, but did show gliosis and increased levels of pro-inflammatory cytokines, suggesting that VZVs action relating to ADdementia is indirect. Strikingly, we found that VZV infection of cells quiescently infected with HSV-1 causes reactivation of HSV-1 and consequent AD-like changes, including Aβ and P-tau accumulation. Our results are consistent with the suggestion that shingles causes reactivation of HSV1 in brain and with the protective effects against AD of various vaccines, as well as the decrease in herpes labialis reported after certain types of vaccination. They support an indirect role for VZV in ADdementia via reactivation of HSV-1 in brain.

B Lymphocytes in Alzheimers Disease-A Comprehensive Review.

Alzheimers disease (AD) represents the most common type of neurodegenerative dementia and is characterized by extracellular amyloid-β (Aβ) deposition, pathologic intracellular tau protein tangles, and neuronal loss. Increasing evidence has been accumulating over the past years, supporting a pivotal role of inflammation in the pathogenesis of AD. Microglia, monocytes, astrocytes, and neurons have been shown to play a major role in AD-associated inflammation. However recent studies showed that the role of both T and B lymphocytes may be important. In particular, B lymphocytes are the cornerstone of humoral immunity, they constitute a heterogenous population of immune cells, being their mature subsets significantly impacted by the inflammatory milieu. The role of B lymphocytes on AD pathogenesis is gaining interest for several reasons. Indeed, the majority of elderly people develop the process of inflammaging, which is characterized by increased blood levels of proinflammatory molecules associated with an elevated susceptibility to chronic diseases. Epitope-specific alteration pattern of naturally occurring antibodies targeting the amino-terminus and the mid-domain of Aβ in both plasma and cerebrospinal fluid has been described in AD patients. Moreover, a possible therapeutic role of B lymphocytes depletion was recently demonstrated in murine AD models. Interestingly, active immunization against Aβ and tau, one of the main therapeutic strategies under investigation, depend on B lymphocytes. Finally. several molecules being tested in AD clinical trials can modify the homeostasis of B cells. This review summarizes the evidence supporting the role of B lymphocytes in AD from the pathogenesis to the possible therapeutic implications.

Alteration of Gut Microbiota in Alzheimers Disease and Their Relation to the Cognitive Impairment.

Dysbiosis of gut microbiota has been reported to be enrolled in the pathogenesis of Alzheimers disease (AD). However, there is a lack of relevant studies on this topic in Egyptian patients with AD. To investigate different species of gut microbiota in Egyptian patients with AD and correlate microbiota bacterial abundance with clinical data. The study included 25 patients with AD and 25 healthy volunteers as age and sex-matched controls. Clinical data was taken for each patient, including medical history and examination Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were assessed for each participant. Bacterial DNA was extracted from stool, and abundance quantified via qPCR using 16S rRNA group-specific primers. Akkermansia, Enterobacteria, Bacteroidetes, Bacillus cereus, Prevotella, and Clostridium cluster IV were more abundant in the AD group than in the control group, although there was significantly less abundance of Bifidobacterium spp., Firmicutes, and Actinobacteria in patients with AD than in controls, whereas no such significance was found for lactic acid bacteria between both groups. Lactic acid bacteria and Prevotella abundance was negatively correlated with cognitive impairment (p 0.03 with MMSE, and p 0.03 with MoCA). Prevotella abundance was positively correlated with age of onset and duration of illness and negatively correlated with smoking and coronary heart disease (p 0.007, p 0.03, p 0.035, and p 0.047, respectively). The current work highlighted a significant relationship between AD and gut microbiota dysbiosis. A higher abundance of Prevotella species and lactic acid bacteria was correlated with cognition.

Prevalence of Depressive Symptoms in a Memory Clinic Cohort A Retrospective Study.

Depression has been suggested to be a cause of reversible cognitive impairment but also a risk factor for neurodegenerative disease. Studies suggest that depression prevalence may be high in early onset dementia, particularly Alzheimers disease, but this has not been systematically assessed in a biomarker-validated clinical dementia cohort to date. To examine the prevalence, features, and association with amyloid pathology of lifetime depressive symptoms in a memory clinic cohort meeting appropriate use criteria for amyloid PET imaging. We included 300 patients from a single-center memory clinic cohort that received diagnostic biomarker evaluation with amyloid PET imaging according to appropriate use criteria. History of lifetime depressive symptoms was retrospectively assessed through structured review of clinical correspondence. One hundred forty-two (47%) patients had a history of significant depressive symptoms (D). Of these, 89% had ongoing symptoms and 60% were on antidepressants at the time of presentation to our Clinic. Depressive symptoms were equally highly prevalent in the amyloid-positive and the heterogeneous group of amyloid-negative patients. Approximately half of patients who meet appropriate use criteria for amyloid PET have a history of depressive symptoms. We suggest that depression is an important feature of both neurodegenerative and non-neurodegenerative cognitive impairment and may contribute to the diagnostic uncertainty behind referral to amyloid PET.

DAPI (4,6-diamidino-2-phenylindole) Stains Compact Amyloid Plaques.

DAPI is conventionally used as a nuclear stain for cells in culture or tissue. Here we demonstrate that it binds specifically to the β-sheet core of amyloid-β plaques but not diffuse amyloid-β at the plaque periphery. The specific DAPI induced blue fluorescence is much stronger than amyloid plaque autofluorescence. DAPI staining of fibrillar amyloid deposit may yield a misleading impression of damaged or dying cells. On the other hand, it provides a handy and low-cost means of staining compact amyloid plaques together with cell nuclei in double or triple immunofluorescent studies.

The Associations of Cerebrospinal Fluid Ferritin with Neurodegeneration and Neuroinflammation Along the Alzheimers Disease Continuum.

Increasing evidence has suggested that iron accumulation plays an important role in the onset and development of Alzheimers disease (AD). However, the potential mechanism remains unclear. The present study investigated the associations of cerebrospinal fluid (CSF) ferritin, an indicator for brain iron load, with neurodegenerative and inflammatory changes in AD. The study involved 302 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). They were classified as normal controls (A-T-N-, n 48), AD continuum (ATN-, n 46 ATN, n 166), and suspected non-AD pathology (A-TN, n 42), according to the amyloidtauneurodegeneration (ATN) system. Group comparisons of CSF ferritin among groups were performed using one-way ANOVA. Linear regression models were used to test the relationships between CSF ferritin and cognitive assessments, and the associations between CSF ferritin and other biomarkers, respectively. We found that CSF ferritin showed significant differences among the ATN groups, with higher concentration in more advanced categories (ATN). Furthermore, CSF ferritin level was independently related to cognitive performance (MMSE, ADAS-Cog13, and ADNI-mem). Linear regression analysis indicated positive relationships between CSF ferritin and phosphorylated tau and total tau, rather than Aβ42. Significant associations were revealed between CSF ferritin and inflammatory proteins, including TNF-α, TNFR1, TNFR2, ICAM1, VCAM1, TGF-β1, IL-9, and IP-10, respectively. Our results provide new insight into iron dysfunction in AD pathology and highlight elevated brain iron as a possible mechanism of neurodegeneration and neuroinflammation along AD continuum.

Genotypic effects of APOE-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation.

The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimers disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-ε4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the ε4 allele. Yet, no study has assessed APOE-ε4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-ε4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of ε4 homozygotes (n 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-ε4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the ε4-homozygotes. Our data indicate that APOE-ε4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.

Impact of spill-in counts from off-target regions on

309 amyloid-beta (Aβ) negative cognitively normal subjects were included in the study. Additionally, 510 realistic FTP images with different levels of OFF were generated using Monte Carlo simulation (MC). Images were corrected for PVC using both a simple two-compartment and a multi-region method including OFF regions. FTP standardized uptake value ratio (SUVR) was quantified in Braak Areas (BA), the hippocampus (which was not included in Braak III) and different OFF regions (caudate, putamen, pallidum, thalamus, choroid plexus (ChPlex), cerebellar white matter (cerebWM), hemispheric white matter (hemisWM) and cerebrospinal fluid (CSF)) using the lower portion of the cerebellum as a reference region. The correlations between OFF and cortical SUVRs were studied both in real and in simulated PET images, with and without PVC. In-vivo, we found correlations between all OFF and target regions, especially strong for the hemisWM (slope>0.63, R HemisWM is the main driver of spill-in effects in FTP PET, affecting both target regions and the rest of OFF regions. PVC successfully reduces PVE, even when using a simple two-compartment method. Despite PVC, non-zero correlations were still observed between target and OFF regions in vivo, which suggests the existence of biological or tracer-related contributions to these correlations.

Deep learning based low-activity PET reconstruction of

Positron Emission Tomography (PET) can support a diagnosis of neurodegenerative disorder by identifying disease-specific pathologies. Our aim was to investigate the feasibility of using activity reduction in clinical A total of 162 patients with clinically uncertain Alzheimers disease underwent amyloid Noise reduction of low-activity PET images was successful for both cohorts using 5% of the original activity with improvement in visual quality and all similarity metrics with respect to the ground-truth images. Clinically relevant metrics extracted from the low-activity images deviated < 2% compared to ground-truth values, which were not significantly changed when extracting the metrics from the denoised images. The presented models were based on the same network architecture and proved to be a robust tool for denoising brain PET images with two widely different tracer distributions (delocalized, (

Clathrin adaptor AP-1-mediated Golgi export of amyloid precursor protein is crucial for the production of neurotoxic amyloid fragments.

One of the hallmarks of Alzheimers disease is the accumulation of toxic amyloid-β (Aβ) peptides in extracellular plaques. The direct precursor of Aβ is the carboxyl-terminal fragment β (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimers disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aβ. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aβ release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.

Association between obstructive sleep apnea and Alzheimers disease-related blood and cerebrospinal fluid biomarkers A meta-analysis.

Recent studies indicate that Alzheimers disease- (AD) related biomarkers, including amyloid β (Aβ40 and Aβ42) and tau proteins (P-tau and T-tau), in blood and cerebrospinal fluid (CSF) are associated with obstructive sleep apnea (OSA). However, the results have been inconsistent. Therefore, the primary purpose of this meta-analysis was to determine the relationship between blood and CSF AD-related biomarkers and OSA. We searched the Embase, PubMed, Scopus, and Cochrane Library databases for relevant articles till February 2022. Eight articles were finally included after the literature screening, including 446 patients with OSA and 286 controls. Pooled analysis showed that CSF Aβ42 (SMD -0.220, P 0.136), T-tau (SMD 0.012, P 0.89), and P-tau (SMD 0.099, P 0.274) levels were not different between patients with OSA and controls. In patients with moderate to severe OSA, CSF Aβ42 (SMD -0.482, P 0.031) were significantly lower than in controls. Blood T-tau (SMD 0.560, P 0.026), P-tau (SMD 0.621, P < 0.001), and Aβ40 (SMD 0.656, P < 0.001) levels were significantly higher in patients with OSA than in controls. Blood Aβ42 (SMD 0.241, P 0.232) were not different between patients with OSA and controls. OSA is associated with changes in AD-related markers. Higher OSA severity may be associated with the development of AD. AD-related biomarkers, especially in the blood, are clinically efficient, less invasively assessed and monitored, and may be useful for detecting OSA and related cognitive impairments. Further studies are needed to confirm these results.

Secular trends in the prevalence of dementia based on a community-based complete enumeration in Japan the Nakayama Study.

The number of dementia patients is increasing worldwide, especially in Japan, which has the worlds highest ageing population. The increase in the number of older people with dementia is a medical and socioeconomic problem that needs to be prevented, but the actual situation is still not fully understood. Four cross-sectional studies on dementia were conducted in 1997, 2004, 2012, and 2016 for complete enumeration of all residents aged 65 years and older. We examined the secular trends in the prevalence of all-cause dementia, Alzheimers disease (AD), vascular dementia (VaD), and otherunclassified dementia. The age-standardised prevalence of all-cause dementia significantly increased (4.5% in 1997, 5.7% in 2004, 5.3% in 2012, 9.5% in 2016 P for trend <0.05). Similar trends were observed for AD (1.7%, 3.0%, 2.5% and 4.9%, respectively P for trend <0.05) and otherunclassified dementia (0.8%, 1.0%, 1.0% and 2.2%, respectively P for trend <0.05), whereas no significant change in VaD was seen (2.1%, 1.8%, 1.8%, 2.4%, respectively P for trend 0.77). The crude prevalence of all-cause dementia and AD increased from 1997 to 2016 among participants aged 75-79 years and ≥85 years (all P for trend <0.05). Similar trends were observed for otherunclassified dementia among participants aged ≥80 years (all P for trend <0.05), but not in VaD. The prevalence of dementia has increased beyond the ageing of the population, suggesting that factors in addition to ageing are involved in the increase in the number of older people with dementia. To control the increase in the number of older people with dementia, elucidation of secular trends in the incidence, mortality, and prognosis of dementia as well as the factors that promote and protect against dementia, and development of preventive strategies are necessary.

Progress in Modeling Neural Tube Development and Defects by Organoid Reconstruction.

It is clear that organoids are useful for studying the structure as well as the functions of organs and tissues they are able to simulate cell-to-cell interactions, symmetrical and asymmetric division, proliferation, and migration of different cell groups. Some progress has been made using brain organoids to elucidate the genetic basis of certain neurodevelopmental disorders. Such as Parkinsons disease and Alzheimers disease. However, research on organoids in early neural development has received insufficient attention, especially that focusing on neural tube precursors. In this review, we focus on the recent research progress on neural tube organoids and discuss both their challenges and potential solutions.

Prescribing Alzheimers Disease treatments by provider type and geographic region a comparison among physicians, nurse practitioners, and physician assistants.

The estimated increase in Alzheimers Disease (AD) caseload may present a logistical challenge to the US healthcare system. While nurse practitioners (NPs) and physician assistants (PAs) are increasingly delivering primary care to patients with chronic diseases, the nature of their prescribing of AD medications is largely unknown. The primary objective of this study was to compare the prescribing of AD medications across provider types (physician, NP, and PA) and geographic regions. We conducted a retrospective cohort study using IBM MarketScan® commercial and Medicare supplemental claims to examine unique AD prescriptions prescribed between January 1, 2016, and December 31, 2019. Parallel analysis of prescriptions for another geriatric condition, osteoporosis (OP), was also conducted for comparison. A total of 103,067 AD prescriptions and 131,773 OP prescriptions were included in analyses. Physicians prescribed most AD prescriptions (95.65%), followed by NPs (3.37%) and PAs (0.98%). Small differences were identified among individual AD medications prescribed by physicians compared to NPPAs. NPsPAs prescribed a significantly higher proportion of AD prescriptions in rural as compared to urban areas (z 0.023, 95%CI 0.018, 0.028). Minimal variation exists in AD prescribing among physicians, NPs, and PAs, but NPsPAs prescribe more AD prescriptions in rural areas. NPsPAs, especially in rural areas, may play critical roles in alleviating projected workforce constraints. Further research assessing AD care, health outcomes, and costs by provider type and region is necessary to better guide healthcare workforce planning for AD care.

Genetic landscape of early-onset dementia in Hungary.

Early-onset dementias (EOD) are predominantly genetically determined, but the underlying disease-causing alterations are often unknown. The most frequent forms of EODs are early-onset Alzheimers disease (EOAD) and frontotemporal dementia (FTD). This study included 120 Hungarian patients with EOD (48 familial and 72 sporadic) which had a diagnosis of EOAD (n 49), FTD (n 49), or atypical dementia (n 22). Monogenic dementia was detected in 15.8% of the patients. A pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was present in 6.7% of cases and disease-causing variants were detected in other known AD or FTD genes in 6.7% of cases (APP, PSEN1, PSEN2, GRN). A compound heterozygous alteration of the TREM2 gene was identified in one patient and heterozygous damaging variants in the CSF1R and PRNP genes were detected in two other cases. In two patients, the coexistence of several heterozygous damaging rare variants associated with neurodegeneration was detected (1.7%). The APOE genotype had a high odds ratio for both the APOE ɛ43 and the ɛ44 genotype (OR 2.7 (95%CI 1.3-5.9) and OR 6.5 (95%CI 1.4-29.2), respectively). In TREM2, SORL1, and ABCA7 genes, 5 different rare damaging variants were detected as genetic risk factors. These alterations were not present in the control group. Based on our observations, a comprehensive, targeted panel of next-generation sequencing (NGS) testing investigating several neurodegeneration-associated genes may accelerate the path to achieve the proper genetic diagnosis since phenotypes are present on a spectrum. This can also reveal hidden correlations and overlaps in neurodegenerative diseases that would remain concealed in separated genetic testing.

Dissociable contribution of plasma NfL and p-tau181 to cognitive impairment in Parkinsons disease.

Cognitive dysfunction is a disabling complication in Parkinsons disease (PD). Accuracy of diagnosis of mild cognitive impairment in PD (PD-MCI) depends on the tests performed, which limits results generalization. Blood-based biomarkers could provide additional objective information for PD-MCI diagnosis and progression. Blood neurofilament light chain (NfL), a marker of neuronal injury, has shown good performance for PD disease stratification and progression. While NfL is not disease-specific, phosphorylated-tau at threonine-181 (p-tau181) in blood is a highly specific marker of concomitant brain amyloid-β and tau pathology. We investigated the potential of plasma NfL and p-tau181 levels as markers of cognitive impairment in a prospective cohort of 109 PD patients with and without PD-MCI (age 68.1 ± 7 years, education 12.2± 5 years), and 40 comparable healthy controls. After a follow-up of 4 years, we evaluated their predictive value for progression to dementia. Although NfL and p-tau181 levels were significantly increased in PD compared with healthy controls, only NfL levels were significantly higher in PD-MCI compared with PD with normal cognition (PD-NC) at baseline. After a follow-up of 4 years, only NfL predicted progression to dementia (HR 1.23, 95% CI 1.02-1.53 p 0.038). Significant correlations between fluid biomarkers and neuropsychological examination were only found with NfL levels. Plasma NfL levels objectively differentiates PD-MCI from PD-NC patients, and may serve as a plasma biomarker for predicting progression to dementia in PD. Plasma levels of p-tau181 does not seem to help in differentiating PD-MCI or to predict future cognitive deterioration.

MicroRNA-29c-3p in dual-labeled exosome is a potential diagnostic marker of subjective cognitive decline.

The present study aimed to determine whether peripheral blood neural cell adhesion molecule (NCAM)amphiphysin 1 dual-labeled exosomal proteins and microRNAs (miRs) might serve as a marker for the early diagnosis of Alzheimers disease (AD). This observational, retrospective, multicenter study used a two-stage design conducted in Beijing and Shanghai, China. The subjects included 76 patients with subjective cognitive decline (SCD), 80 with amnestic mild cognitive impairment (aMCI), 76 with dementia of Alzheimers type (AD), 40 with vascular dementia (VaD), and 40 controls in the discovery stage. These results were confirmed in the verification stage. The levels of Aβ42, Aβ In the discovery stage, the levels of Aβ42 and miR-29c-3p in peripheral blood NCAMamphiphysin 1 dual-labeled exosome of the SCD group were significantly higher than those in control and VaD groups (all P < 0.05). The verification stage further confirmed the results of the discovery stage. Plasma NCAMamphiphysin 1 dual-labeled exosomal miR-29c-3p showed a good diagnostic performance. The NCAMamphiphysin 1 dual-labeled exosomal miR-29c-3p had the highest AUC for diagnosis of SCD. The levels of Aβ42, Aβ The plasma NCAMamphiphysin 1 dual-labeled exosomal miR-29c-3p had potential advantages in the diagnosis of SCD.

TNF inhibitors have a protective role in the risk of dementia in patients with ankylosing spondylitis Results from a nationwide study.

Ankylosing spondylitis (AS) is a chronic progressive and debilitating form of arthritis with associated extra-articular features including uveitis, intestinal and lung apical inflammation and psoriasis. Putative associations between AS and neurologic disorders has been relatively overlooked. The purpose of this study is to assess the link between AS and major neurologic disorders and whether treatment with Tumor-Necrosis-Factor inhibitors (TNFi) has an impact on that association. A retrospective cross-sectional study was carried out based on the Clalit Health Services (CHS) computerized database. AS patients were compared to age- and gender-matched controls with respect to the proportion of Alzheimers disease (AD), Parkinsons disease (PD), epilepsy, and multiple sclerosis (MS). The impact of AS therapy (biologic vs conventional therapy) was assessed as well. 4082 AS patients and 20,397 age- and gender-matched controls were identified. AS was associated with a higher prevalence of AD (odds-ratio(OR) 1.46 95%Confidence-interval(CI) 1.13-1.87, p 0.003), epilepsy (OR 2.33 95%CI 1.75-3.09 p < 0.0001) and PD (OR 2.75 95%CI 2.04-3.72, p < 0.0001), whereas no statistically significant association was found for MS. Association with PD remained significant in the multivariate analysis (OR 1.49 95%CI 1.05-2.13,p 0.027). Within AS patients, the use of TNFi (OR 0.10 95%CI 0.01-0.74, p 0.024) were associated with a lowered risk of developing AD. AS is positively associated with AD, PD, and epilepsy but not MS. AS patients treated with TNFi have lower rates of AD.

Chitosan mediated layer-by-layer assembly based graphene oxide decorated surface plasmon resonance biosensor for highly sensitive detection of β-amyloid.

Alzheimers disease (AD), and its consequent effect primarily clinical dementia, Parkinsons disease dementia, etc. currently bring potential avenues for diagnosis centered on identification of beta-amyloid

The role of triggering receptor expressed on myeloid cells 2 in Parkinsons disease and other neurodegenerative disorders.

Parkinsons disease (PD) is a progressive neurological disorder marked by cardinal clinical symptoms such as rigor, tremor, and akinesia. Albeit a loss of dopaminergic neurons from the substantia nigra pars compacta is causative for the movement impairments found in patients, molecular reasoning for this loss is still incomplete. In recent years, triggering factor expressed on myeloid cells (TREM2) gained attention in the field of neurodegeneration as it could be associated with different neurodegenerative disorders. Primarily identified as a risk factor in Alzheimers disease, variants in TREM2 were linked to PD and multiple sclerosis, too. Expressed on phagocytic cells, such as macrophages and microglia, TREM2 puts the focus on inflammation associated conditions in PD and provides a molecular target that could at least partly explain the role of immune cells in PD. Here, we summarize expression patterns and molecular functions of TREM2, recapitulate on its role in inflammation, phagocytosis and cell survival, before turning to neurodegenerative disorders with an emphasis on PD.

LiuweiDihuang improved cognitive functions in SAMP8 mice by inhibiting COX-2 expression and subsequent neuroinflammation.

LiuweiDihuang (LW) pills was mainly used to treatment of childrens fontanelle incomplete closure, enuresis and nervous system development delays and other diseases.Following the deepening of pharmacological research, LW has a good effect on neurological diseases include senile dementia. However, the neuroprotection mechanism of LW on Alzheimers disease (AD) through regulation of inflammation remains unclear. Here, we aimed to explore the effects and mechanism of LW on learning and memory deficits in SAMP8 mice. Mice aged 6 months were treated with LW for 2 months and BV2, C6 and HT22 cells were treated with LW pharmaceutic serum and Lipopolysaccharide (LPS) continuously. Then, cognitive tests were performed, including the Morris water maze and Y maze tests. The mRNA level of cyclooxygenase 2 (COX-2) and pro-inflammatory factors (IL-1β, IL-6 and TNF-α) were examined in cells and the cortex and hippocampus by quantitative RT-PCR. The expression of postsynaptic density protein 95, synaptophysin and various inflammatory factors were detected in the cortex and hippocampus by Western blot. Furthermore, Ionized calcium binding adapter molecule 1, glial fibrillary acidic protein and Aβ were examined in the brain of AD mice by immunofluorescence staining and immunohistochemistry. And synaptic loss and neuronal ultrastructure were observed by transmission electron microscope. We found that LW suppressed LPS-induced COX-2 expression in vitro. Importantly, LW dramatically improved spatial learning and memory in SAMP8 mice through inhibiting Aβ accumulation and restoring structural synaptic integrity. Furthermore, LW inhibited the glial activation and neuroinflammation (COX-2, IL-1β, IL-6 and TNF-α) in the cortex and hippocampus of SAMP8 mice. Taken together, the present data not only indicated that LW is an effective agent on improving the learning and memory deficits through mitigating neuroinflammation but highlighted the LW can be a potential therapeutic drug for AD therapy.

Motor features associated with cognition in non-demented individuals with essential tremor.

Essential tremor (ET) is a clinically heterogeneous disease characterized by motor and non-motor features, including cognitive impairment. In a cross-sectional analysis, we determined whether the presence and severity of motor features of ET are associated with cognitive performance. Participants enrolled in a study that used motor and neuropsychological measures to characterize a cohort of ET subjects. Action tremor severity and additional motor features (rest tremor, intention tremor, cranial tremor, dystonia, tandem gait missteps) were assessed in non-demented participants. Participants completed a cognitive test protocol assessing domains of memory, executive function, attention, visuospatial ability, and language. An average z-score was calculated to represent global cognition. There were 204 ET participants (mean age 78.6, range 55-95). Participants with 10 missteps were more likely to have MCI than those with 0 or 1 misstep (p < 0.001). In unadjusted linear regression models, action tremor severity (p 0.010), rest tremor (p < 0.001), and tandem gait missteps (p < 0.001) were negatively associated with global cognition. In adjusted models, only tandem gait missteps were negatively associated with global cognition (p < 0.001). Missteps were also negatively associated with memory (p < 0.001), executive function (p < 0.001), attention (p 0.011), and visuospatial function (p 0.043). No other motor features were associated with global cognition in adjusted models (p > 0.05). Among non-demented participants with ET, there is an association between cognitive performance and tandem gait missteps, but no other motor features of ET. This is a first step in establishing impaired tandem gait as a possible indicator of cognitive impairment in patients with ET.

Effects of Assistive Technology Application in Dementia Intervention for People with Mild Cognitive Impairment Mild Alzheimer Type Dementia and Caregiver.

Dementia, a degenerative disease, requires alternative treatment to maintain function, but previous studies suggest only the therapeutic effect of a temporary program. The current study aimed to examine the effects of assistive technologies on cognitive function, daily living ability, and psychosocial symptoms in elderlies with mild cognitive impairment, elderlies with mild dementia and their caregivers. The research team designed an experimental study that used application as the intervention. To recruit participants living in the local community, research participation was supported through local public health centers, welfare centers, and social welfare organizations. Evaluation and intervention were conducted by visiting the participants home. The study participants were 29 Mild Cognitive Impairment (MCI) and 16 mild Alzheimer type dementia (AD) patients over the age of 75 with a total of 45 patients, 10 MCI caregivers and 11 AD caregivers with a total of 21 caregivers. The assistive technologies used for intervention are 3 area (8 daily living assistive devices, 7 safety assistive technologies, and 7 cognitive assistive technologies). Up to 5 assistive technologies were provided to one subject, and they were instructed to use them every day for 8 weeks. Participants were evaluated at baseline and postintervention using specific scales appropriate to an area cognitive function, activities of daily living, depression, anxiety, quality of life, satisfaction. Cognitive function showed statistically significant changes in the MCI group. Basic activities of daily living, depression, anxiety, quality of life, satisfaction showed statistically significant positive effects in both MCI and AD groups. Instrumental activities of daily living did not show any statistically significant differences. As an alternative to dementia care in the future, the application and management of assistive technologies for each area should be provided at the government level.

Transcorneal electrical stimulation enhances cognitive functions in aged and 5XFAD mouse models.

Dementia is a major burden on global health for which there are no effective treatments. The use of noninvasive visual stimulation to ameliorate cognitive deficits is a novel concept that may be applicable for treating dementia. In this study, we investigated the effects of transcorneal electrical stimulation (TES) on memory enhancement using two mouse models, in aged mice and in the 5XFAD model of Alzheimers disease. After 3 weeks of TES treatment, mice were subjected to Y-maze and Morris water maze tests to assess hippocampal-dependent learning and memory. Immunostaining of the hippocampus of 5XFAD mice was also performed to examine the effects of TES on amyloid plaque pathology. The results showed that TES improved the performance of both aged and 5XFAD mice in memory tests. TES also reduced hippocampal plaque deposition in male, but not female, 5XFAD mice. Moreover, TES significantly reversed the downregulated level of postsynaptic protein 95 in the hippocampus of male 5XFAD mice, suggesting the effects of TES involve a postsynaptic mechanism. Overall, these findings support further investigation of TES as a potential treatment for cognitive dysfunction and mechanistic studies of TES effects in other dementia models.

Spatial-temporal graph convolutional network for Alzheimer classification based on brain functional connectivity imaging of electroencephalogram.

Functional connectivity of the human brain, representing statistical dependence of information flow between cortical regions, significantly contributes to the study of the intrinsic brain network and its functional mechanism. To fully explore its potential in the early diagnosis of Alzheimers disease (AD) using electroencephalogram (EEG) recordings, this article introduces a novel dynamical spatial-temporal graph convolutional neural network (ST-GCN) for better classification performance. Different from existing studies that are based on either topological brain function characteristics or temporal features of EEG, the proposed ST-GCN considers both the adjacency matrix of functional connectivity from multiple EEG channels and corresponding dynamics of signal EEG channel simultaneously. Different from the traditional graph convolutional neural networks, the proposed ST-GCN makes full use of the constrained spatial topology of functional connectivity and the discriminative dynamic temporal information represented by the 1D convolution. We conducted extensive experiments on the clinical EEG data set of AD patients and Healthy Controls. The results demonstrate that the proposed method achieves better classification performance (92.3%) than the state-of-the-art methods. This approach can not only help diagnose AD but also better understand the effect of normal ageing on brain network characteristics before we can accurately diagnose the condition based on resting-state EEG.

Increased levels of insulin-degrading enzyme in patients with type 2 diabetes mellitus.

Decreasing levels of serum insulin-degrading enzyme (IDE) have been associated with an increased risk for Alzheimer´s disease (AD) in patients with type 2 diabetes mellitus (T2DM). Research on serum IDE levels in patients with T2DM is sparse and the aim of this study was to explore serum levels of IDE in patients with T2DM. Blood serum samples were obtained from a biobank. Samples from subjects with T2DM and without metabolic disease were divided into subgroups lifestyle treatment (n 10), oral antidiabetic treatment (n 17), insulin treatment (n 20) and metabolically healthy controls (n 18). Serum levels of IDE were analysed using specific ELISA assays. Serum levels of IDE were elevated in subjects with T2DM compared to metabolically healthy individuals (p 0.033). No significant differences were detected between treatment subgroups. The present study indicates that patients with T2DM have increased serum IDE levels, compared to metabolically healthy individuals. However, for IDE to be clinically useful as a biomarker, its full function and possible use needs to be further elucidated in larger studies showing reproducible outcomes.

Investigating the use of plasma pTau181 in retired contact sports athletes.

Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration. Fifty-four retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181 were included. A portion (N 21) of retired athletes had a 2-years follow-up visit. All participants had completed a neuropsychological battery and MRI imaging. Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.94 ± 5.08 pgmL vs. 6.00 ± 2.53 pgmL, respectively 95% BCa CI 1.38-4.62 p 0.02) and was significantly associated with fornix fractional anisotropy values only in the athletes group (β - 0.002 95% BCa CI - 0.003 to - 0.001 p 0.002). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) volume and white-matter integrity was significantly lower in high pTau181 compared to older healthy controls (CC volume 1.57 ± 0.19 vs. 2.02 ± 0.32, p 0.002 CC medial diffusivity 0.96 ± 0.04 × 10 Although high plasma pTau181 levels were associated with abnormalities in CC and fornix, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white-matter integrity in the athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.

Use of α1-adrenoceptor antagonists tamsulosin and alfuzosin and the risk of Alzheimers disease.

Tamsulosin has been associated with dementia, but the results have been inconsistent. Concerns have been raised about using exposure assessment time too close to the outcome. We investigated the association between use of α1-adrenoceptor antagonists indicated for benign prostate hyperplasia and risk of Alzheimers disease (AD) using different exposure windows. The study (24 602 cases and 98 397 matched controls) included men from the Finnish nationwide nested case-control study on Medication and Alzheimers disease (MEDALZ). Cases received clinically verified AD diagnosis during 2005-2011 and were community-dwelling at the time of diagnosis. Use of tamsulosin and alfuzosin in 1995-2011 was identified from the Prescription Register and categorized based on whether it had occurred within 3 years before AD diagnosis (lag time) or before that. Dose-response analysis using defined daily doses of drug (DDDs) was conducted. Associations were investigated with conditional logistic regression, adjusted for confounders and mediators. The use of α1-adrenoceptor antagonists before lag time associated with an increased risk of AD (OR 1.24 1.20-1.27). After adjustment for comorbidities and concomitant drug use throughout the assessment time (confounders) and healthcare contacts within the lag period (mediators), the association weakened (aOR 1.10 1.06-1.14). We found no evidence of dose-response-relationship when comparing the users of higher than median DDDs to the users of lower than median DDDs. Our findings, especially the lack of dose-response-relationship and attenuation after mediator adjustment, do not provide strong support for the previous hypothesis on α1-adrenoceptor antagonists as a risk factor for dementia.

Olfactory Bulb Amyloid-β Correlates With Brain Thal Amyloid Phase and Severity of Cognitive Impairment.

The Alzheimer disease (AD) neuropathological hallmarks amyloid β (Aβ) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aβ throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aβ and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aβ was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aβ and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aβ pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology.

Heterogeneity and developmental dynamics of LYVE-1 perivascular macrophages distribution in the mouse brain.

Brain perivascular macrophages (PVMs) are border-associated macrophages situated along blood vessels in the Virchow-Robin space and are thus found at a unique anatomical position between the endothelium and the parenchyma. Owing to their location and phagocytic capabilities, PVMs are regarded as important components that regulate various aspects of brain physiology in health and pathophysiological states. Here, we used LYVE-1 to identify PVMs in the mouse brain using brain-tissue sections and cleared whole-brains to learn about how they are distributed within the brain and across different developmental postnatal stages. We find that LYVE-1

The relationship between fatigue severity and mild cognitive impairment in Saudi patients with type 2 diabetes mellitus.

Type 2 Diabetes Mellitus (T2DM) is a major health issue in Saudi Arabia, with a prevalence of 23.7% in 2015. Several factors contribute to the occurrence of Mild Cognitive Impairment (MCI) and its progression to Alzheimers disease in patients with T2DM. This study assesses MCI and fatigue severity and their relationship in patients with T2DM. Out of the 160 Saudi adults interviewed at the King Khalid University Hospital in Riyadh from October 2019 till March 2020, 80 were known cases of T2DM while the rest were non-diabetic individuals. The Montreal Cognitive Assessment (MoCA) test, Mini Mental State Exam (MMSE) and Fatigue Severity Score (FSS) were used to evaluate MCI and fatigue severity, respectively. According to the MoCA scale, 68.7% diabetic individuals as against 42.5% from the non-diabetic group had MCI. While the FSS showed that 40% of the diabetic group vs 26.3% of the non-diabetic were fatigued. In conclusion, patients with T2DM are at a higher risk of developing MCI.

Early detection of Alzheimers disease using single nucleotide polymorphisms analysis based on gradient boosting tree.

Alzheimers disease (AD) is a degenerative disorder that attacks nerve cells in the brain. AD leads to memory loss and cognitive intellectual impairments that can influence social activities and decision-making. The most common type of human genetic variation is single nucleotide polymorphisms (SNPs). SNPs are beneficial markers of complex gene-disease. Many common and serious diseases, such as AD, have associated SNPs. Detection of SNP biomarkers linked with AD could help in the early prediction and diagnosis of this disease. The main objective of this paper is to predict and diagnose AD based on SNPs biomarkers with high classification accuracy in the early stages. One of the most concerning problems is the high number of features. Thus, the paper proposes a comprehensive framework for early AD detection and detecting the most significant genes based on SNPs analysis. Usage of machine learning (ML) techniques to identify new biomarkers of AD is also suggested. In the proposed system, two feature selection techniques are separately checked the information gain filter and Boruta wrapper. The two feature selection techniques were used to select the most significant genes related to AD in this system. Filter methods measure the relevance of features by their correlation with dependent variables, while wrapper methods measure the usefulness of a subset of features by training a model on it. Gradient boosting tree (GBT) has been applied on all AD genetic data of neuroimaging initiative phase 1 (ADNI-1) and Whole-Genome Sequencing (WGS) datasets by using two feature selection techniques. In the whole-genome approach ADNI-1, results revealed that the GBT learning algorithm scored an overall accuracy of 99.06% in the case of using Boruta feature selection. Using information gain feature selection, the proposed system achieved an average accuracy of 94.87%. The results show that the proposed system is preferable for the early detection of AD. Also, the results revealed that the Boruta wrapper feature selection is superior to the information gain filter technique.

Exploring the possible molecular targeting mechanism of Saussurea involucrata in the treatment of COVID-19 based on bioinformatics and network pharmacology.

Based on bioinformatics and network pharmacology, the treatment of Saussurea involucrata (SAIN) on novel coronavirus (COVID-19) was evaluated by the GEO clinical sample gene difference analysis, compound-target molecular docking, and molecular dynamics simulation. role in the discovery of new targets for the prevention or treatment of COVID-19, to better serve the discovery and clinical application of new drugs. Taking the Traditional Chinese Medicine System Pharmacology Database (TCMSP) as the starting point for the preliminary selection of compounds and targets, we used tools such as Cytoscape 3.8.0, TBtools 1.098, AutoDock vina, R 4.0.2, PyMol, and GROMACS to analyze the compounds of SAIN and targets were initially screened. To further screen the active ingredients and targets, we carried out genetic difference analysis (n 72) through clinical samples of COVID-19 derived from GEO and carried out biological process (BP) analysis on these screened targets (P ≤ 0.05)., gene 9), KEGG pathway analysis (FDR≤0.05, gene 9), protein interaction network (PPI) analysis (gene 9), and compounds-target-pathway network analysis (gene 9), to obtain the target Point-regulated biological processes, disease pathways, and compounds-target-pathway relationships. Through the precise molecular docking between the compounds and the targets, we further screened SAINs active ingredients (Affinity ≤ -7.2 kcalmol) targets and visualized the data. After that, we performed molecular dynamics simulations and consulted a large number of related Validation of the results in the literature. Through the screening, analysis, and verification of the data, it was finally confirmed that there are five main active ingredients in SAIN, which are Quercitrin, Rutin, Caffeic acid, Jaceosidin, and Beta-sitosterol, and mainly act on five targets. These targets mainly regulate Tuberculosis, TNF signaling pathway, Alzheimers disease, Pertussis, Toll-like receptor signaling pathway, Influenza A, Non-alcoholic fatty liver disease (NAFLD), Neuroactive ligand-receptor interaction, Complement and coagulation cascades, Fructose and mannose metabolism, and Metabolic pathways, play a role in preventing or treating COVID-19. Molecular dynamics simulation results show that the four active ingredients of SAIN, Quercitrin, Rutin, Caffeic acid, and Jaceosidin, act on the four target proteins of COVID-19, AKR1B1, C5AR1, GSK3B, and IL1B to form complexes that can be very stable in the human environment. Tertiary structure exists. Our study successfully explained the effective mechanism of SAIN in improving COVID-19, and at the same time predicted the potential targets of SAIN in the treatment of COVID-19, AKR1B1, IL1B, and GSK3B. It provides a new basis and provides great support for subsequent research on COVID-19.

PITRM1 interaction studies with amyloidogenic nonapeptide mutants of familial Alzheimers disease.

Amyloid β-protein (ABP) is found to be the major cause for the development of neurodegeneration which leads to Alzheimers. The Aβ nonapeptide segment, QKLVFFAED (amino acids 15-23) is the highly amyloidogenic central region of Aβ. Familial mutation in Aβ increases the aggregation property of the peptide compared to the Native (Wild) amyloid-beta (Aβ) and these mutations fall on the Aβ nonapeptide segment. The catalytic activity of pitrilysin metallopeptidase 1(PITRM1) with familial mutant Aβ (Flemish, Arctic, Dutch, Italian and Iowa) during interaction is examined using molecular dynamic simulation. The molecular dynamics simulation of PITRM1 and the Aβ nonapeptide segment showed similar RMSD with respect to stability. The active site amino acid (AA) H108, hydrophobic pocket AA residues L111, F123, F124, and L127 and the basic pocket AA residues R888 and H896 showed similar interactions with both wild and familial Aβ. The molecular level interaction between amyloid beta and PITRM1 were similar in the wild and familial mutants except for the Arctic mutant. The hydrophobic interaction was commonly observed between the S1 hydrophobic pocket and the LVFF region, the Arctic mutant showed less hydrogen bond formation consistently when compared to other complexes. This molecular information on catalytic activity suggests that modulating inactive PITRM1 or an increase in expression of PITRM1 can help in eliminating different kinds of familial mutant Aβ in neurodegenerative cells.Communicated by Ramaswamy H. Sarma.

Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys.

Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimers disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-β peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans. CS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models. Following CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aβ4240 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aβ42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDLLDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids. Treatment with the ABCA1 agonist CS-6253 appears to favor Aβ clearance from the brain.

The functional connectivity of basal forebrain is associated with superior memory performance in older adults a case-control study.

Aging is related with memory deterioration. However, some older adults demonstrate superior performance compared to age- and education-matched adults, who are referred to as superagers. To explore the neural mechanisms that mediate their unusually successful memory is important not only for the ameliorate the effects of aging in brain, but also for the prevention of neurodegenerative diseases, including Alzheimers disease. This case-control study is aimed to investigate the effects of volume and function of basal forebrain cholinergic neurons on the cognition of superagers. The morphometric and resting-state functional MRI analysis, including 34 superagers and 48 typical older adults, were conducted. We compared the basal forebrain gray matter density and related resting-state functional connectivity (FC) in the two groups. To investigate the relationship of FC with cognition, we measure the correlation of significant altered FC and individual cognitive domain. No significant differences of gray matter density was observed between superagers and typical older adults. The superagers had stronger cortical FC of Ch1-3 with left putamen and insular cortex. The strength of FC positively correlated with global cognition, memory and executive function. These findings demonstrated that the stronger FC of basal forebrain correlated with specific cognitive difference in global cognition and domains of memory and executive function in superagers.

Can the administration of platelet lysates to the brain help treat neurological disorders

Neurodegenerative disorders of the central nervous system (CNS) and brain traumatic insults are characterized by complex overlapping pathophysiological alterations encompassing neuroinflammation, alterations of synaptic functions, oxidative stress, and progressive neurodegeneration that eventually lead to irreversible motor and cognitive dysfunctions. A single pharmacological approach is unlikely to provide a complementary set of molecular therapeutic actions suitable to resolve these complex pathologies. Recent preclinical data are providing evidence-based scientific rationales to support biotherapies based on administering neurotrophic factors and extracellular vesicles present in the lysates of human platelets collected from healthy donors to the brain. Here, we present the most recent findings on the composition of the platelet proteome that can activate complementary signaling pathways in vivo to trigger neuroprotection, synapse protection, anti-inflammation, antioxidation, and neurorestoration. We also report experimental data where the administration of human platelet lysates (HPL) was safe and resulted in beneficial neuroprotective effects in established rodent models of neurodegenerative diseases such as Parkinsons disease, Alzheimers disease, traumatic brain injury, and stroke. Platelet-based biotherapies, prepared from collected platelet concentrates (PC), are emerging as a novel pragmatic and accessible translational therapeutic strategy for treating neurological diseases. Based on this assumption, we further elaborated on various clinical, manufacturing, and regulatory issues that need to be addressed to ensure the ethical supply, quality, and safety of HPL preparations for treating neurodegenerative and traumatic pathologies of the CNS. HPL made from PC may become a unique approach for scientifically based treatments of neurological disorders readily accessible in low-, middle-, and high-income countries.

Associations between Homelessness and Alzheimers Disease and Related Dementia A Systematic Review.

The homeless population in the United States is rapidly aging, with a parallel increase in Alzheimers disease and related dementia (ADRD). During an evolving pandemic that jeopardizes employment and housing, assessing the relationship between ADRD and homelessness is critical since the latter is potentially intervenable. The objective of this study is to review the literature and determine whether there is an association between homelessness and dementia risk. A systematic review of existing studies was conducted through PubMED, SCOPUS, and EMBASE among others. Of the 228 results found, nine met inclusion criteria. Homeless studies mainly centered on veteran populations (

Does essential tremor increase the risk of dementia No.

Essential tremor (ET) is the most common neurological cause of tremor affecting adult humans affecting about 6% of those over age 65 years. In the United States, dementia has a prevalence of 15% in those age 68 and older. Overlap of the two conditions is therefore not surprising. Several studies report mild subclinical cognitive dysfunction in non-demented people with ET, likely related to overactivity of fronto-cerebellar circuitry involved in tremor pathophysiology. Frontalexecutive dysfunction is often though not exclusively noted, and some studies have even shown areas of cognitive strengths. Mild cognitive impairment (MCI) is impairment which a person is aware of but does not interfere significantly with daily activities. While MCI has been considered to presage dementia this is not necessarily the case, as some persons with MCI revert to normal cognition in follow-up. Dementia is a clinical syndrome with cognitive impairment interfering with daily activities. Population-based and clinic-based studies have shown mixed results regarding rates of MCI in ET. A handful of studies have looked at development of dementia in ET with differing results. Brain pathology studies in ET and dementia or investigating Alzheimer-type pathology have thus far been unrevealing. There is evidence by some investigators supporting a greater risk of dementia for those having older onset tremor, while those having ET at a younger age faring at least as well as controls regarding risk of cognitive impairment and dementia. At present the evidence is inconclusive that ET as a group are at a greater risk of developing dementia.

Does essential tremor increase risk of cognitive impairment and dementia Yes.

Essential Tremor (ET), by definition, is a disorder of movement. Yet over the years, epidemiologic, clinical, pathologic, and neuroimaging studies have converged to reveal a cognitive side of ET. The cognitive symptoms in ET are heterogeneous and are likely to reflect heterogeneous underlying mechanisms. In this chapter, we review and synthesize a diverse set of studies from both population-based settings to cohorts with more detailed investigations into cognition to consider the various mechanisms by which cognitive symptoms may emerge in a subset of individuals with ET. As part of our analysis, we consider questions surrounding ET diagnosis and the possibility of comorbid disease as potential factors that, upon closer examination, appear to strengthen the argument in favor of ET as a risk factor for dementia. Importantly, we also consider the clinical relevance of cognitive impairment in ET. While ET is not universally characterized by significant cognitive deficits, the data from epidemiological, cognitive, neuroimaging, and postmortem neuropathologic studies converge to reveal an increased risk for cognitive impairment and dementia among individuals with ET. We conclude by offering directions for future research, and a neurocognitive framework with which to consider existing findings and to use in the design of novel studies dedicated to clarifying the basis, nature, and course of cognitive impairments in ET.

Is inferior olive central to the pathophysiology of essential tremor No.

Essential tremor (ET) represents one of the commonest movement disorder worldwide and is the most common tremor disorder. ET manifests with various combinations of motor and nonmotor symptoms. The clinical hallmark is a kinetic tremor of upper limbs. Historically, the pathogenesis of ET has been based on the hypothesis of an overactivity of the inferior olive (inferior olive hypothesis IOH) where the inferior olive would act as the central pace-maker of ET, resulting in impaired electrophysiological discharges of the olivo-cerebellar tract. The absence of structural alterations in post-mortem studies of the inferior olive is a striking argument against the IOH. Furthermore, neuroimaging studies point towards the implication of the cerebello-thalamo-cerebral pathway rather than the IO, and the harmaline model which has been considered as an animal model of ET presents important weaknesses. By contrast, a series of experiments by Louis et al. have provided convincing evidence of impaired wiring of the Purkinje cell microcircuitry and progressive neurodegeneration of the cerebellar cortex. The Purkinje neuron appears as the primary culprit (Purkinjopathy). The cerebellar cortex hypothesis (CCH) has solid neuropathological signatures, unlike the purely physiological IOH. Rather than a dysregulatory electrophysiological disorder suggested by IOH, ET is a clinical-pathological entity similar to late onset neurodegenerative disorders such as Parkinsons disease or Alzheimers disease. The CCH emphasizes the need to develop novel therapeutic strategies in order to maintain or promote the cerebellar reserve. The modern reconceptualization of ET in a genuine cerebellar disorder is cleaning the IOH to the light of histopathological studies. ET falls in the large basket of the neurodegenerative diseases and we have entered into a novel formulation of the disease pathogenesis with direct impacts on future therapies.

Seed-competent tau monomer initiates pathology in a tauopathy mouse model.

Tau aggregation into ordered assemblies causes neurodegenerative tauopathies. We previously reported that tau monomer exists in either inert (M

Microglial polarization differentially affects neuronal vulnerability to the β-amyloid protein Modulation by melatonin.

Microglial cells play a central but yet debated role in neuroinflammatory events occurring in Alzheimers disease (AD). We here explored how microglial features are modulated by melatonin following β-amyloid (Aβ42)-induced activation and examined the cross-talk with Aβ-challenged neuronal cells. Human microglial HMC3 cells were exposed to Aβ42 (200 nM) in the presence of melatonin (MEL 1 μM) added since the beginning (MELco) or after a 72 h-exposure to Aβ42 (MELpost). In both conditions, MEL favored an anti-inflammatory activation and rescued SIRT1 and BDNF expressionrelease. Caspase-1 up-regulation and phospho-ERK induction following a prolonged exposure to Aβ42 were prevented by MEL. In addition, MEL partially restored proteasome functionality that was altered by long-term Aβ42 treatment, re-establishing both 20S and 26S chymotrypsin-like activity. Differentiated neuronal-like SH-SY5Y cells were exposed to Aβ42 (200 nM for 24 h) in basal medium or in the presence of conditioned medium (CM) collected from microglia exposed for different times to Aβ42 alone or in combination with MELco or MELpost. Aβ42 significantly reduced pre-synaptic proteins synaptophysin and VAMP2 and mean neuritic length. These effects were prevented by CM from anti-inflammatory microglia (Aβ42 for 6 h), or from MELco and MELpost microglia, but the reduction of neuritic length was not rescued when the SIRT1 inhibitor EX527 was added. In conclusion, our data add to the concept that melatonin shows a promising anti-inflammatory action on microglia that is retained even after pro-inflammatory activation, involving modulation of proteasome function and translating into neuroprotective microglial effects.

Alzheimers disease is associated with disruption in thiamin transport physiology A potential role for neuroinflammation.

Alzheimers disease (AD) is a neurodegenerative disease characterized by Amyloid-β peptide (Aβ) containing plaques and cognitive deficits. The pathophysiology of AD also involves neuroinflammation. Vitamin B1 (thiamin) is indispensable for normal cellular energy metabolism. Thiamin homeostasis is altered in AD, and its deficiency is known to aggravate AD pathology. Little, however, is known about possible alterations in level of expression of thiamin transporters-1 and -2 (THTR-1 and -2) in the brain of AD, and whether pro-inflammatory cytokines affect thiamin uptake by brain cells. We addressed these issues using brain tissue samples prefrontal cortex (PFC) and hippocampus (HIP) from AD patients and from 5XFAD mouse model of AD, together with cultured human neuroblastoma SH-SY5Y cells as model. Our results revealed a significantly lower expression of both THTR-1 and THTR-2 in the PFC and HIP of AD patients and 5XFAD mouse model of AD compared to appropriate normal controls. Further, we found that exposure of the SH-SY5Y cells to pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) led to a significant inhibition in thiamin uptake. Focusing on IL-1β, we found the inhibition in thiamin uptake to be time-dependent and reversible it was also associated with a substantial reduction in expression of THTR-1 (but not THTR-2) protein and mRNA as well as a decrease in promoter activity of the SLC19A2 gene (which encodes THTR-1). Finally, using transcriptomic analysis, we found that thiamin availability in SH-SY5Y cells caused changes in the expression of genes relevant to AD pathways. These studies demonstrate, for the first time, that thiamin transport physiologymolecular biology parameters are negatively impacted in AD brain and that pro-inflammatory cytokines inhibit thiamin uptake by neuroblastoma cells. The results also support a possible role for thiamin in the pathophysiology of AD.

Cholesterol and matrisome pathways dysregulated in astrocytes and microglia.

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimers disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.

APOE told me put my fat in the bag and nobody gets hurt.

The ε4 variant in the APOE gene is the strongest genetic risk factor for Alzheimers disease. How does this gene impact different cell types in the brain to increase disease risk In this issue of Cell, TCW and colleagues report APOE-driven cell-type-specific changes that may contribute to Alzheimers disease risk.

Estimating the longitudinal trajectory of cognitive function measurement using short-term data with different disease stages Application in Alzheimers disease.

Alzheimers disease (AD) is a chronic neurodegenerative disease characterized by a gradual decline in cognitive function over a few decades. The Mini-Mental State Examination (MMSE) is a widely used measure for evaluating global cognitive functioning. Characterizing the longitudinal trajectory of the MMSE in the population of interest is important to detect AD onset for preventive intervention. In this study, we formulate a new class of longitudinal trajectory modeling for MMSE from short-term individual data based on an ordinary differential equation. The proposed method models the relationship between individual decline speed of MMSE and the average MMSE using the fractional polynomial function model and subsequently estimates the longitudinal trajectory of MMSE by solving the ordinary differential equation for the estimated model. The appropriate model for trajectory estimation is selected based on the proposed criterion for quantifying the goodness of trajectory fit. The accuracy of the trajectory estimation of the proposed method was demonstrated via simulation studies. The proposed method was successfully applied to MMSE data from the Japanese Alzheimers Disease Neuroimaging Initiative study.

Aβ

Currently Alzheimers Disease (AD) pathological pathways, which lead to cell death and dementia, are not completely well-defined in particular, the lipid changes in brain tissues that begin years before AD symptoms. Due to the central role of the amyloid aggregation process in the early phase of AD pathogenesis, we aimed at developing a lipidomic approach to evaluate the amyloid toxic effects on differentiated human neuroblastoma derived SH-SY5Y cells. First of all, this work was performed to highlight qualitative and relative quantitative lipid variations in connection with amyloid toxicity. Then, with an open outcome, the study was focused to find out some new lipid-based biomarkers that could result from the interaction of amyloid peptide with cell membrane and could justify neuroblastoma cells neurotoxicity. Hence, cells were treated with increasing concentration of Aβ

Design, synthesis, and biological evaluation of thienopyrimidine and thienotriazine derivatives as multitarget anti-Alzheimer agents.

A series of tetrahydrobenzothienopyrimidines and tetrahydrobenzothienotriazines incorporating a pharmacophore from donepezil molecule were designed and synthesized. The 12 newly synthesized compounds were screened for their inhibition activity against acetylcholinesterase enzyme (AChE). Compounds that exerted the most potent AChE inhibitory action were further evaluated for their BChE inhibitory activity. In addition, the inhibitory effects of all newly synthesized compounds on Aβ and reactive oxygen species were assessed. Compounds 4d, 10b, and 10c showed potent inhibitory activity on AChE comparable to donepezil. Compound 10b (IC

Pocahemiketone A, a Sesquiterpenoid Possessing a Spirocyclic Skeleton with a Hemiketal Endoperoxide Unit, Alleviates Aβ

Pocahemiketone A, a novel sesquiterpenoid possessing a unique spirocyclic skeleton with a hemiketal endoperoxide unit, was isolated from the essential oil of

Procedural learning, declarative learning, and working memory as predictors of learning the use of a memory compensation tool in persons with amnestic mild cognitive impairment.

Persons with amnestic Mild Cognitive Impairment (aMCI) are at risk for experiencing changes in their daily functioning due to their memory impairment. The Memory Support System (MSS), a compensatory calendaring system, was developed to support functional independence in persons with aMCI (pwaMCI). This cross-sectional study examined procedural learning, declarative learning, and working memory as predictors of MSS learning efficiency in pwaMCI. Sixty pwaMCI participated in MSS training. The Serial Reaction Time Test and Mirror Tracing Test were used to assess procedural learning. The Rey Auditory Verbal Learning Test and CogState One Card Learning were used to assess declarative learning and the CogState One Back task was used to assess working memory. Multiple regression analyses were conducted to assess if procedural learning, declarative learning, and working memory predicted MSS learning efficiency. This study showed that declarative learning predicted MSS learning efficiency in pwaMCI, with less consistent results for procedural learning and non-significant results for working memory. Findings suggest that success in teaching compensatory tools is greater when training is offered in early aMCI before declarative learning skill is fully lost. Future studies should assess additional strategies to facilitate MSS learning in advanced aMCI.

Data Augmentation in High Dimensional Low Sample Size Setting Using a Geometry-Based Variational Autoencoder.

In this paper, we propose a new method to perform data augmentation in a reliable way in the High Dimensional Low Sample Size (HDLSS) setting using a geometry-based variational autoencoder (VAE). Our approach combines the proposal of 1) a new VAE model, the latent space of which is modeled as a Riemannian manifold and which combines both Riemannian metric learning and normalizing flows and 2) a new generation scheme which produces more meaningful samples especially in the context of small data sets. The method is tested through a wide experimental study where its robustness to data sets, classifiers and training samples size is stressed. It is also validated on a medical imaging classification task on the challenging ADNI database where a small number of 3D brain magnetic resonance images (MRIs) are considered and augmented using the proposed VAE framework. In each case, the proposed method allows for a significant and reliable gain in the classification metrics. For instance, balanced accuracy jumps from 66.3% to 74.3% for a state-of-the-art convolutional neural network classifier trained with 50 MRIs of cognitively normal (CN) and 50 Alzheimer disease (AD) patients and from 77.7% to 86.3% when trained with 243 CN and 210 AD while improving greatly sensitivity and specificity metrics.

Disease Modeling of Neurodegenerative Disorders Using Direct Neural Reprogramming.

Understanding the pathophysiology of CNS-associated neurological diseases has been hampered by the inaccessibility of patient brain tissue to perform live analyses at the molecular level. To this end, neural cells obtained by differentiation of patient-derived induced pluripotent stem cells (iPSCs) are considerably helpful, especially in the context of monogenic-based disorders. More recently, the use of direct reprogramming to convert somatic cells to neural cells has emerged as an alternative to iPSCs to generate neurons, astrocytes, and oligodendrocytes. This review focuses on the different studies that used direct neural reprogramming to study disease-associated phenotypes in the context of neurodegenerative diseases, including Alzheimers disease, Parkinsons disease, and amyotrophic lateral sclerosis.

Mitochondrial SIRT3 Deficiency Results in Neuronal Network Hyperexcitability, Accelerates Age-Related Aβ Pathology, and Renders Neurons Vulnerable to Aβ Toxicity.

Aging is the major risk factor for Alzheimers disease (AD). Mitochondrial dysfunction and neuronal network hyperexcitability are two age-related alterations implicated in AD pathogenesis. We found that levels of the mitochondrial protein deacetylase sirtuin-3 (SIRT3) are significantly reduced, and consequently mitochondria protein acetylation is increased in brain cells during aging. SIRT3-deficient mice exhibit robust mitochondrial protein hyperacetylation and reduced mitochondrial mass during aging. Moreover, SIRT3-deficient mice exhibit epileptiform and burst-firing electroencephalogram activity indicating neuronal network hyperexcitability. Both aging and SIRT3 deficiency result in increased sensitivity to kainic acid-induced seizures. Exposure of cultured cerebral cortical neurons to amyloid β-peptide (Aβ) results in a reduction in SIRT3 levels and SIRT3-deficient neurons exhibit heightened sensitivity to Aβ toxicity. Finally, SIRT3 haploinsufficiency in middle-aged AppPs1 double mutant transgenic mice results in a significant increase in Aβ load compared with AppPs1 double mutant mice with normal SIRT3 levels. Collectively, our findings suggest that SIRT3 plays an important role in protecting neurons against Aβ pathology and excitotoxicity.

Bias correction via outcome reassignment for cross-sectional data with binary disease outcome.

Cross-sectionally sampled data with binary disease outcome are commonly analyzed in observational studies to identify the relationship between covariates and disease outcome. A cross-sectional population is defined as a population of living individuals at the sampling or observational time. It is generally understood that binary disease outcome from cross-sectional data contains less information than longitudinally collected time-to-event data, but there is insufficient understanding as to whether bias can possibly exist in cross-sectional data and how the bias is related to the population risk of interest. Wang and Yang (2021) presented the complexity and bias in cross-sectional data with binary disease outcome with detailed analytical explorations into the data structure. As the distribution of the cross-sectional binary outcome is quite different from the population risk distribution, bias can arise when using cross-sectional data analysis to draw inference for population risk. In this paper we argue that the commonly adopted age-specific risk probability is biased for the estimation of population risk and propose an outcome reassignment approach which reassigns a portion of the observed binary outcome, 0 or 1, to the other disease category. A sign test and a semiparametric pseudo-likelihood method are developed for analyzing cross-sectional data using the OR approach. Simulations and an analysis based on Alzheimers Disease data are presented to illustrate the proposed methods.

Impact of fish consumption on all-cause mortality in older people with and without dementia a community-based cohort study.

Increased fish consumption reduces the risk of dementia. However, it is unknown whether fish consumption reduced all-cause mortality in people with dementia. The purpose of the study is to investigate the association of fish consumption with all-cause mortality in older people with dementia versus those without dementia. Using a standard method of the Geriatric Mental State, we interviewed 4165 participants aged ≥ 60 years who were randomly recruited from five provinces in China during 2007-2009 to collect the baseline data of socio-demography, disease risk factors, histories of disease, and details of dietary intakes, and diagnosed dementia (n 406). They were followed up for vital status until 2012. The cohort follow-up documented 329 deaths 61 were in participants with dementia (55.3 per 1000 person-years) and 224 were those without dementia (22.3). In all participants, the risk of all-cause mortality was reduced with fish intake at ≥ twice a week (multivariate-adjusted hazard ratio 0.58, 95% CI 0.34-0.96) and at once a week or less (0.79, 0.53-1.18) compared to never eat over the past two years. In participants without baseline dementia, the corresponding HRs for all-cause mortality were 0.57 (0.33-0.98) and 0.85 (0.55-1.31), while in participants with dementia were 1.36 (0.28-6.60) and 1.05 (0.30-3.66), respectively. This study reveals that consumption of fish in older age reduced all-cause mortality in older people without dementia, but not in people with dementia. Fish intake should be increased in older people in general, prior to the development of dementia in the hope of preventing dementia and prolonging life.

Multimethod Process Evaluation of a Community Paramedic Delivered Care Transitions Intervention for Older Emergency Department Patients.

We assessed fidelity of delivery and participant engagement in the implementation of a community paramedic coach-led Care Transitions Intervention (CTI) program adapted for use following emergency department (ED) visits. The adapted CTI for ED-to-home transitions was implemented at three university-affiliated hospitals in two cities from 2016 to 2019. Participants were aged ≥60 years old and discharged from the ED within 24 hours of arrival. In the current analysis, participants had to have received the CTI. Community paramedic coaches collected data on program delivery and participant characteristics at each transition contact via inventories and assessments. Participants provided commentary on the acceptability of the adapted CTI. Using a multimethod approach, the CTI implementation was assessed quantitatively for site- and coach-level differences. Qualitatively, barriers to implementation and participant satisfaction with the CTI were thematically analyzed. Of the 863 patient participants, 726 (84.1%) completed their home visits. Cancellations were usually patient-generated (94.9%). Most planned follow-up visits were successfully completed (94.6%). Content on the planning for red flags and post-discharge goal setting was discussed with high rates of fidelity overall (95% and greater), while content on outpatient follow-up was lower overall (75%). Differences in service delivery between the two sites existed for the in-person visit and the first phone follow-up, but the differences narrowed as the study progressed. Participants showed a 24.6% increase in patient activation (i.e., behavioral adoption) over the 30-day study period ( Community paramedic coaches delivered the adapted CTI with high fidelity across geographically distant sites and successfully facilitated participant engagement, highlighting community paramedics as an effective resource for implementing such patient-centered interventions.

The link between cutaneous inflammation and cognitive impairment.

Cognitive impairment is a symptom of neurological disorders, including dementia and Alzheimers disease and mild cognitive impairment can be a precursor of both disorders. Aged humans and animal models with other systemic disorders, such as cardiovascular diseases and diabetes, display a higher incidence of cognitive decline. Epidemiological studies have shown that the incidence of cognitive impairment also is higher in subjects with certain inflammatory skin disorders, including psoriasis and chronic eczematous dermatitis. Chronologically aged individuals exhibit increased cutaneous inflammation and elevated circulating cytokine levels, linked to alterations in epidermal function, which itself can induce cutaneous inflammation. Conversely, strategies that improve epidermal function can lower cytokine levels in both the skin and circulation. Thus, it seems likely that epidermal dysfunction could contribute, at least in part, to the development of chronic low-grade inflammation, also termed inflammaging, in the elderly. The evidence of cognitive impairment in patients with inflammatory dermatoses suggests a link between cutaneous inflammation and cognitive impairment. Because of the pathogenic role of epidermal dysfunction in ageing-associated cutaneous inflammation, improvements in epidermal function could be an alternative approach for mitigation of the ageing-associated decline in cognitive function.

Tau-aggregation inhibition promising role of nanoencapsulated dietary molecules in the management of Alzheimers disease.

Alzheimers disease (AD) is a cumulative form of dementia associated with memory loss, cognition impairment, and finally leading to death. AD is characterized by abnormal deposits of extracellular beta-amyloid and intracellular Tau-protein tangles throughout the brain. During pathological conditions of AD, Tau protein undergoes various modifications and aggregates over time. A number of clinical trials on patients with AD symptoms have indicated the effectiveness of Tau-based therapies over anti-Aβ treatments. Thus, there is a huge paradigm shift toward Tau aggregation inhibitors. Several bioactives of plants and microbes have been suggested to cross the neuronal cell membrane and play a crucial role in managing neurodegenerative disorders. Bioactives mainly act as active modulators of AD pathology besides having antioxidant and anti-inflammatory potential. Studies also demonstrated the potential role of dietary molecules in inhibiting the formation of Tau aggregates and removing toxic Tau. Further, these molecules in nonencapsulated form exert enhanced Tau aggregation inhibition activity both in

A comparison of cerebral amyloid angiopathy in the cerebellum and CAA-positive occipital lobe of 60 brains from routine autopsies.

We semiquantitatively compared the frequency and severity of cerebral amyloid angiopathy (CAA) in the cerebellum and CAA-positive occipital lobe of 60 subjects from routine autopsies. In the 60 subjects with a CAA-positive occipital lobe, cerebellar CAA was observed in 29 subjects (48.3%), and the severity of cerebellar CAA was relatively mild compared with occipital lobe CAA. Capillary CAA was observed in the occipital lobe of 12 subjects and the cerebellum of three subjects. CAA-related vasculopathies were observed in the occipital lobe of 15 subjects and the cerebellum of two subjects. The severity of CAA-related vasculopathy was mild in both of these subjects. Amyloid-β plaques were observed in the occipital lobe of 54 subjects (90%) and the cerebellum of 16 subjects (26.7%). The severity of amyloid-β plaques in the cerebellum was mild compared with the occipital lobe. In summary, we confirmed that cerebellar CAA is frequently observed in the cerebellum but with a lower severity than CAA in the occipital lobe.

Association of Performance on the Financial Capacity Instrument-Short Form With Brain Amyloid Load and Cortical Thickness in Older Adults.

To investigate the association of the Financial Capacity Instrument-Short Form (FCI-SF) performance and timing total scores with brain β-amyloid and cortical thickness in cognitively unimpaired (CU) (at baseline) older adults. A total of 309 participants (aged 70 years or older) of the Mayo Clinic Study of Aging underwent Participants mean age (SD) was 80.2 (4.8) years (56.3% male individuals). In cross-sectional analysis, abnormal amyloid PET (vs normal) was associated with a lower FCI-SF total score and slower total composite time. In longitudinal analysis, FCI-SF total score declined faster (difference in annualized rate of change, beta coefficient β 95% confidence interval (CI) -1.123 -2.086 to -0.161) and FCI-SF total composite time increased faster (difference in annualized rate of change, β 95% CI 16.274 5.951 to 26.597) for participants with neurodegeneration at baseline (vs those without). Participants who exhibited both abnormal amyloid PET and neurodegeneration at baseline had a greater increase in total composite time when compared with the group without abnormal amyloid and without neurodegeneration (difference in annualized rate of change, β 95% CI 16.750 3.193 to 30.307). Performance and processing speed on the FCI-SF were associated with imaging biomarkers of AD pathophysiology in CU (at baseline) older adults. Higher burdens of imaging biomarkers were associated with longitudinal worsening on FCI-SF performance. Additional research is needed to delineate further these associations and their predictive utility at the individual person level.

Genome Sequencing in the Parkinson Disease Clinic.

Genetic variants affect both Parkinson disease (PD) risk and manifestations. Although genetic information is of potential interest to patients and clinicians, genetic testing is rarely performed during routine PD clinical care. The goal of this study was to examine interest in comprehensive genetic testing among patients with PD and document reactions to possible findings from genome sequencing in 2 academic movement disorder clinics. In 203 subjects with PD (age 63 years, 67% male), genome sequencing was performed and filtered using a custom panel, including 49 genes associated with PD, parkinsonism, or related disorders, as well as a 90-variant PD genetic risk score. Based on the results, 231 patients (age 67 years, 63% male) were surveyed on interest in genetic testing and responses to vignettes covering (1) familial risk of PD ( Genome sequencing revealed a Our results highlight broad interest in comprehensive genetic testing among patients with PD and may facilitate integration of genome sequencing in clinical practice.

Plasma Levels of Tissue-Type Plasminogen Activator (tPA) in Normal Aging and Alzheimers Disease Links With Cognition, Brain Structure, Brain Function and Amyloid Burden.

Tissue-type plasminogen activator (tPA) is a protease known for its fibrinolytic action but is also involved in physiological and pathophysiological aging processes including amyloid elimination and synaptic plasticity. The aim of the study was to investigate the role of tPA in cognitive and brain aging. Therefore, we assessed the links between tPA plasma concentration and cognition, structural MRI, FDG-PET and Flobetapir-PET neuroimaging in 155 cognitively unimpaired adults (CUA, aged 20-85 years old) and 32 patients with Alzheimers disease (ALZ). A positive correlation was found between tPA and age in CUA (

Investigation of Underlying Association Between Whole Brain Regions and Alzheimers Disease A Research Based on an Artificial Intelligence Model.

Alzheimers disease (AD) is the most common form of dementia, causing progressive cognitive decline. Radiomic features obtained from structural magnetic resonance imaging (sMRI) have shown a great potential in predicting this disease. However, radiomic features based on the whole brain segmented regions have not been explored yet. In our study, we collected sMRI data that include 80 patients with AD and 80 healthy controls (HCs). For each patient, the T1 weighted image (T1WI) images were segmented into 106 subregions, and radiomic features were extracted from each subregion. Then, we analyzed the radiomic features of specific brain subregions that were most related to AD. Based on the selective radiomic features from specific brain subregions, we built an integrated model using the best machine learning algorithms, and the diagnostic accuracy was evaluated. The subregions most relevant to AD included the hippocampus, the inferior parietal lobe, the precuneus, and the lateral occipital gyrus. These subregions exhibited several important radiomic features that include shape, gray level size zone matrix (GLSZM), and gray level dependence matrix (GLDM), among others. Based on the comparison among different algorithms, we constructed the best model using the Logistic regression (LR) algorithm, which reached an accuracy of 0.962. Conclusively, we constructed an excellent model based on radiomic features from several specific AD-related subregions, which could give a potential biomarker for predicting AD.

Automated High-Definition MRI Processing Routine Robustly Detects Longitudinal Morphometry Changes in Alzheimers Disease Patients.

Longitudinal MRI studies are of increasing importance to document the time course of neurodegenerative diseases as well as neuroprotective effects of a drug candidate in clinical trials. However, manual longitudinal image assessments are time consuming and conventional assessment routines often deliver unsatisfying study outcomes. Here, we propose a profound analysis pipeline that consists of the following coordinated steps (1) an automated and highly precise image processing stream including voxel and surface based morphometry using latest highly detailed brain atlases such as the HCP MMP 1.0 atlas with 360 cortical ROIs (2) a profound statistical assessment using a multiplicative model of annual percent change (APC) and (3) a multiple testing correction adopted from genome-wide association studies that is optimally suited for longitudinal neuroimaging studies. We tested this analysis pipeline with 25 Alzheimers disease patients against 25 age-matched cognitively normal subjects with a baseline and a 1-year follow-up conventional MRI scan from the ADNI-3 study. Even in this small cohort, we were able to report 22 significant measurements after multiple testing correction from SBM (including cortical volume, area and thickness) complementing only three statistically significant volume changes (leftright hippocampus and left amygdala) found by VBM. A 1-year decrease in brain morphometry coincided with an increasing clinical disability and cognitive decline in patients measured by MMSE, CDR GLOBAL, FAQ TOTAL and NPI TOTAL scores. This work shows that highly precise image assessments, APC computation and an adequate multiple testing correction can produce a significant study outcome even for small study sizes. With this, automated MRI processing is now available and reliable for routine use and clinical trials.

Model scenarios for cell cycle re-entry in Alzheimers disease.

Alzheimers disease (AD) is the most prevalent neurodegenerative disease. Aberrant production and aggregation of amyloid beta (Aβ) peptide into plaques is a frequent feature of AD, but therapeutic approaches targeting Aβ accumulation fail to inhibit disease progression. The approved cholinesterase inhibitor drugs are symptomatic treatments. During human brain development, the progenitor cells differentiate into neurons and switch to a postmitotic state. However, cell cycle re-entry often precedes loss of neurons. We developed mathematical models of multiple routes leading to cell cycle re-entry in neurons that incorporate the crosstalk between cell cycle, neuronal, and apoptotic signaling mechanisms. We show that the integration of multiple feedback loops influences disease severity making the switch to pathological state irreversible. We observe that the transcriptional changes associated with this transition are also characteristics of the AD brain. We propose that targeting multiple arms of the feedback loop may bring about disease-modifying effects in AD.

Extracellular Adenosine Triphosphate Binding to P2Y1 Receptors Prevents Glutamate-Induced Excitotoxicity Involvement of Erk12 Signaling Pathway to Suppress Autophagy.

Glutamate-induced neuroexcitotoxicity could be related to the pathophysiology of some neurodegenerative diseases including Parkinsons disease and Alzheimers disease. Extracellular ATP exerts a wide variety of functions, such as attenuating Aβ-mediated toxicity, inhibiting

Rodent Modeling of Alzheimers Disease in Down Syndrome

There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimers disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is 55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene

SUMO-modifying Huntingtons disease.

Small ubiquitin-like modifiers, SUMOs, are proteins that are conjugated to target substrates and regulate their functions in a post-translational modification called SUMOylation. In addition to its physiological roles, SUMOylation has been implicated in several neurodegenerative diseases, such as Alzheimers, Parkinsons, and Huntingtons diseases (HD). HD is a neurodegenerative monogenetic autosomal dominant disorder caused by a mutation in the CAG repeat of the huntingtin (

Extract of

Cognitive dysfunction, presenting as learning and memory impairment, is a common manifestation in many chronic diseases of the nervous system. Some of these diseases include depression, epilepsy, and Alzheimers disease. To date, few drugs or medicinal products have shown ability to improve learning and memory deficits. Neuroprotection is one of the mechanisms by which memory could be improved. The extract of Unripe In the NOR test, XAE (30, 100 and 300 mgkg) and XA (30, 100 and 300 mgkg) increased the percentage exploration and recognition index (p 0.0005 and p < 0.0001, respectively) when compared to both vehicle and ketamine groups. Similarly, doses of XAE and XA as used in the NOR test increased the percentage alternation in the Y-maze test. Although XAE and XA treatments decreased the latencies to find hidden platform in the MWM test, it was not significantly different from the vehicle group. However, this decrease in latency differed significantly when compared to the ketamine group. Interestingly, both XAE and XA treatments increased the percentage frequency to the target quadrant in the probe trial of the MWM. It is noteworthy that in all the three models used, both the extract and xylopic acid performed better than piracetam and citicoline, the reference drugs. The ethanolic extract of

Effects of amyloid-β on protein SUMOylation and levels of mitochondrial proteins in primary cortical neurons.

Defining the molecular changes that underlie Alzheimers disease (AD) is an important question in neuroscience. Here, we examined changes in protein SUMOylation, and proteins involved in mitochondrial dynamics, in an in vitro model of AD induced by application of amyloid-β 1-42 (Aβ

Current Progress on Neuroprotection Induced by Artemisia, Ginseng, Astragalus, and Ginkgo Traditional Chinese Medicines for the Therapy of Alzheimers Disease.

Aging is associated with the occurrence of diverse degenerative changes in various tissues and organs and with an increased incidence of neurological disorders, especially neurodegenerative diseases such as Alzheimers disease (AD). In recent years, the search for effective components derived from medicinal plants in delaying aging and preventing and treating neurodegenerative diseases has been increasing and the number of related publications shows a rising trend. Here, we present a concise, updated review on the preclinical and clinical research progress in the assessment of the therapeutic potential of different traditional Chinese medicines and derived active ingredients and their effect on the signaling pathways involved in AD neuroprotection. Recognized by their multitargeting ability, these natural compounds hold great potential in developing novel drugs for AD.

Review of Current Strategies for Delivering Alzheimers Disease Drugs Across the Blood-Brain Barrier.

(Appeared originally in the International Journal of Molecular Sciences 2019 20381) Reprinted under Creative Commons CC-BY license.

Intraneuronal β-Amyloid Accumulation Aging HIV-1 Human and HIV-1 Transgenic Rat Brain.

The prevalence of HIV-1 associated neurocognitive disorders (HAND) is significantly greater in older, relative to younger, HIV-1 seropositive individuals the neural pathogenesis of HAND in older HIV-1 seropositive individuals, however, remains elusive. To address this knowledge gap, abnormal protein aggregates (i.e., β-amyloid) were investigated in the brains of aging (gt12 months of age) HIV-1 transgenic (Tg) rats. In aging HIV-1 Tg rats, double immunohistochemistry staining revealed abnormal intraneuronal β-amyloid accumulation in the prefrontal cortex (PFC) and hippocampus, relative to F344N control rats. Notably, in HIV-1 Tg animals, increased β-amyloid accumulation occurred in the absence of any genotypic changes in amyloid precursor protein (APP). Furthermore, no clear amyloid plaque deposition was observed in HIV-1 Tg animals. Critically, β-amyloid was co-localized with neurons in the cortex and hippocampus, supporting a potential mechanism underlying synaptic dysfunction in the HIV-1 Tg rat. Consistent with these neuropathological findings, HIV-1 Tg rats exhibited prominent alterations in the progression of temporal processing relative to control animals temporal processing relies, at least in part, on the integrity of the PFC and hippocampus. In addition, in post-mortem HIV-1 seropositive individuals with HAND, intraneuronal β-amyloid accumulation was observed in the dorsolateral PFC and hippocampal dentate gyrus. Consistent with observations in the HIV-1 Tg rat, no amyloid plaques were found in these post-mortem HIV-1 seropositive individuals with HAND. Collectively, intraneuronal β-amyloid aggregation observed in the PFC and hippocampus of HIV-1 Tg rats supports a potential factor underlying HIV-1 associated synaptodendritic damage. Further, the HIV-1 Tg rat provides a biological system to model HAND in older HIV-1 seropositive individuals.

FDG-PET to T1 Weighted MRI Translation with 3D Elicit Generative Adversarial Network (E-GAN).

With the strengths of deep learning, computer-aided diagnosis (CAD) is a hot topic for researchers in medical image analysis. One of the main requirements for training a deep learning model is providing enough data for the network. However, in medical images, due to the difficulties of data collection and data privacy, finding an appropriate dataset (balanced, enough samples, etc.) is quite a challenge. Although image synthesis could be beneficial to overcome this issue, synthesizing 3D images is a hard task. The main objective of this paper is to generate 3D T1 weighted MRI corresponding to FDG-PET. In this study, we propose a separable convolution-based Elicit generative adversarial network (E-GAN). The proposed architecture can reconstruct 3D T1 weighted MRI from 2D high-level features and geometrical information retrieved from a Sobel filter. Experimental results on the ADNI datasets for healthy subjects show that the proposed model improves the quality of images compared with the state of the art. In addition, the evaluation of E-GAN and the state of art methods gives a better result on the structural information (13.73% improvement for PSNR and 22.95% for SSIM compared to Pix2Pix GAN) and textural information (6.9% improvements for homogeneity error in Haralick features compared to Pix2Pix GAN).

Early-Stage Alzheimers Disease Categorization Using PET Neuroimaging Modality and Convolutional Neural Networks in the 2D and 3D Domains.

Alzheimers Disease (AD) is a health apprehension of significant proportions that is negatively impacting the ageing population globally. It is characterized by neuronal loss and the formation of structures such as neurofibrillary tangles and amyloid plaques in the early as well as later stages of the disease. Neuroimaging modalities are routinely used in clinical practice to capture brain alterations associated with AD. On the other hand, deep learning methods are routinely used to recognize patterns in underlying data distributions effectively. This work uses Convolutional Neural Network (CNN) architectures in both 2D and 3D domains to classify the initial stages of AD into AD, Mild Cognitive Impairment (MCI) and Normal Control (NC) classes using the positron emission tomography neuroimaging modality deploying data augmentation in a random zoomed inout scheme. We used novel concepts such as the blurring before subsampling principle and distant domain transfer learning to build 2D CNN architectures. We performed three binaries, that is, ADNC, ADMCI, MCINC and one multiclass classification task ADNCMCI. The statistical comparison revealed that 3D-CNN architecture performed the best achieving an accuracy of 89.21% on ADNC, 71.70% on ADMCI, 62.25% on NCMCI and 59.73% on ADNCMCI classification tasks using a five-fold cross-validation hyperparameter selection approach. Data augmentation helps in achieving superior performance on the multiclass classification task. The obtained results support the application of deep learning models towards early recognition of AD.

4-Aminoquinoline-Based Adamantanes as Potential Anticholinesterase Agents in Symptomatic Treatment of Alzheimers Disease.

Considering that acetylcholinesterase (AChE) inhibition is the most important mode of action expected of a potential drug used for the treatment of symptoms of Alzheimers disease (AD), our previous pilot study of 4-aminoquinolines as potential human cholinesterase inhibitors was extended to twenty-two new structurally distinct 4-aminoquinolines bearing an adamantane moiety. Inhibition studies revealed that all of the compounds were very potent inhibitors of AChE and butyrylcholinesterase (BChE), with inhibition constants (

Exploring the Involvement of the Amyloid Precursor Protein A673T Mutation against Amyloid Pathology and Alzheimers Disease in Relation to Therapeutic Editing Tools.

Alzheimers disease (AD) is biologically defined as a complex neurodegenerative condition with a multilayered nature that leads to a progressive decline in cognitive function and irreversible neuronal loss. It is one of the primary diseases among elderly individuals. With an increasing incidence and a high failure rate for pharmaceutical options that are merely symptom-targeting and supportive with many side effects, there is an urgent need for alternative strategies. Despite extensive knowledge on the molecular basis of AD, progress concerning effective disease-modifying therapies has proven to be a challenge. The ability of the CRISPR-Cas9 gene editing system to help identify target molecules or to generate new preclinical disease models could shed light on the pathogenesis of AD and provide promising therapeutic possibilities. Here, we sought to highlight the current understanding of the involvement of the A673T mutation in amyloid pathology, focusing on its roles in protective mechanisms against AD, in relation to the recent status of available therapeutic editing tools.

A Mathematical Model of In Vitro Cellular Uptake of Zoledronic Acid and Isopentenyl Pyrophosphate Accumulation.

The mevalonate pathway is an attractive target for many areas of research, such as autoimmune disorders, atherosclerosis, Alzheimers disease and cancer. Indeed, manipulating this pathway results in the alteration of malignant cell growth with promising therapeutic potential. There are several pharmacological options to block the mevalonate pathway in cancer cells, one of which is zoledronic acid (ZA) (an N-bisphosphonate (N-BP)), which inhibits the farnesyl pyrophosphate (FPP) synthase enzyme, inducing cell cycle arrest, apoptosis, inhibition of protein prenylation, and cholesterol reduction, as well as leading to the accumulation of isopentenyl pyrophosphate (IPP). We extrapolated the data based on two independently published papers that provide numerical data on the uptake of zoledronic acid (ZA) and the accumulation of IPP (Ag) and its isomer over time by using in vitro human cell line models. Two different mathematical models for IPP kinetics are proposed. The first model (Model 1) is a simpler ordinary differential equation (ODE) compartmental system composed of 3 equations with 10 parameters the second model (Model 2) is a differential algebraic equation (DAE) system with 4 differential equations, 1 algebraic equation and 13 parameters incorporating the formation of the ZAenzymeAg complex. Each of the two models aims to describe two different experimental situations (continuous and pulse experiments) with the same ZA kinetics. Both models fit the collected data very well. With Model 1, we obtained a prevision accumulation of IPP after 24 h of 169.6 pmolmgproth with an IPP decreasing rate per (pmolmgprot) of ZA (kXGZ) equal to 13.24h. With Model 2, we have comprehensive kinetics of IPP upon ZA treatment. We calculate that the IPP concentration was equal to 141.6 pmolmgproth with a decreasing ratepercentage of 0.051 (kXGU). The present study is the first to quantify the influence of ZA on the pharmacodynamics of IPP. While still incorporating a small number of parameters, Model 2 better represents the complexity of the biological behaviour for calculating the IPP produced in different situations, such as studies on γδ T cell-based immunotherapy. In the future, additional clinical studies are warranted to further evaluate and fine-tune dosing approaches.

Evaluation of Topical and Subconjunctival Injection of Hyaluronic Acid-Coated Nanoparticles for Drug Delivery to Posterior Eye.

Posterior eye diseases, such as age-related macular degeneration and diabetic retinopathy, are difficult to treat due to ineffective drug delivery to affected areas. Intravitreal injection is the primary method for posterior eye drug delivery however, it is usually accompanied by complications. Therefore, an effective and non-invasive method is required. Self-assembling nanoparticles (NPs) made from gelatin-epigallocatechin gallate (EGCG) were synthesized (GE) and surface-decorated with hyaluronic acid (HA) for drug delivery to the retinalchoroidal area. Different HA concentrations were used to prepare NPs with negative (GEH-) or positive (GEH) surface charges. The sizezeta potential and morphology of the NPs were characterized by a dynamic light scattering (DLS) system and transmission electron microscope (TEM). The sizezeta potential of GEH NPs was 253.4 nm and 9.2 mV. The GEH- NPs were 390.0 nm and -35.9 mV, respectively. The cytotoxicity was tested by adult human retinal pigment epithelial cells (ARPE-19), with the results revealing that variant NPs were non-toxicity at 0.2-50 µgmL of EGCG, and that the highest amount of GEH NPs was accumulated in cells examined by flowcytometry. Topical delivery (eye drops) and subconjunctival injection (SCI) methods were used to evaluate the efficiency of NP delivery to the posterior eyes in a mouse model. Whole eyeball cryosections were used to trace the location of fluorescent NPs in the eyes. The area of fluorescent signal obtained in the posterior eyes treated with GEH NPs in both methods (eye drops 6.89% and SCI 14.55%) was the greatest when compared with other groups, especially higher than free dye solution (2.79%). In summary, GEH NPs can be transported to the retina by eye drops and SCI in particular, eye drops are a noninvasive method. Furthermore, GEH NPs, characterized by a positive surface and HA decoration, could facilitate drug delivery to the posterior eye as a useful drug carrier.

Therapeutic Approach to Alzheimers Disease Current Treatments and New Perspectives.

Alzheimers disease (AD) is the most common cause of dementia. The pathophysiology of this disease is characterized by the accumulation of amyloid-β, leading to the formation of senile plaques, and by the intracellular presence of neurofibrillary tangles based on hyperphosphorylated tau protein. In the therapeutic approach to AD, we can identify three important fronts the approved drugs currently available for the treatment of the disease, which include aducanumab, donepezil, galantamine, rivastigmine, memantine, and a combination of memantine and donepezil therapies under investigation that work mainly on Aβ pathology and tau pathology, and which include γ-secretase inhibitors, β-secretase inhibitors, α-secretase modulators, aggregation inhibitors, metal interfering drugs, drugs that enhance Aβ clearance, inhibitors of tau protein hyperphosphorylation, tau protein aggregation inhibitors, and drugs that promote the clearance of tau, and finally, other alternative therapies designed to improve lifestyle, thus contributing to the prevention of the disease. Therefore, the aim of this review was to analyze and describe current treatments and possible future alternatives in the therapeutic approach to AD.

Longitudinal Consumption of Ergothioneine Reduces Oxidative Stress and Amyloid Plaques and Restores Glucose Metabolism in the 5XFAD Mouse Model of Alzheimers Disease.

A Pivotal Role of Nrf2 in Neurodegenerative Disorders A New Way for Therapeutic Strategies.

Clinical and preclinical research indicates that neurodegenerative diseases are characterized by excess levels of oxidative stress (OS) biomarkers and by lower levels of antioxidant protection in the brain and peripheral tissues. Dysregulations in the oxidantantioxidant balance are known to be a major factor in the pathogenesis of neurodegenerative diseases and involve mitochondrial dysfunction, protein misfolding, and neuroinflammation, all events that lead to the proteostatic collapse of neuronal cells and their loss. Nuclear factor-E2-related factor 2 (Nrf2) is a short-lived protein that works as a transcription factor and is related to the expression of many cytoprotective genes involved in xenobiotic metabolism and antioxidant responses. A major emerging function of Nrf2 from studies over the past decade is its role in resistance to OS. Nrf2 is a key regulator of OS defense and research supports a protective and defending role of Nrf2 against neurodegenerative conditions. This review describes the influence of Nrf2 on OS and in what way Nrf2 regulates antioxidant defense for neurodegenerative conditions. Furthermore, we evaluate recent research and evidence for a beneficial and potential role of specific Nrf2 activator compounds as therapeutic agents.

Design, Synthesis, and In Vitro, In Silico and In Cellulo Evaluation of New Pyrimidine and Pyridine Amide and Carbamate Derivatives as Multi-Functional Cholinesterase Inhibitors.

Alzheimer disease is an age-linked neurodegenerative disorder representing one of the greatest medical care challenges of our century. Several drugs are useful in ameliorating the symptoms, even if none could stop or reverse disease progression. The standard approach is represented by the cholinesterase inhibitors (ChEIs) that restore the levels of acetylcholine (ACh) by inhibiting the acetylcholinesterase (AChE). Still, their limited efficacy has prompted researchers to develop new ChEIs that could also reduce the oxidative stress by exhibiting antioxidant properties and by chelating the main metals involved in the disease. Recently, we developed some derivatives constituted by a 2-amino-pyrimidine or a 2-amino-pyridine moiety connected to various aromatic groups by a flexible amino-alkyl linker as new dual inhibitors of AChE and butyrylcholinesterase (BChE). Following our previous studies, in this work we explored the role of the flexible linker by replacing the amino group with an amide or a carbamic group. The most potent compounds showed higher selectivity against BChE in respect to AChE, proving also to possess a weak anti-aggregating activity toward Aβ

Probiotic

Probiotics improve brain function, including memory and cognition, via the microbiome-gut-brain axis. Oral administration of

Dietary Glycemic Load and Plasma Amyloid-β Biomarkers of Alzheimers Disease.

Previous studies have highlighted links between a high-glycemic-load (GL) diet and Alzheimers disease in apolipoprotein E ε4 (APOE4) carriers. However, the impact of high-GL diet on plasma amyloid-β (Aβ), an Alzheimers disease hallmark that can be detected decades before clinical symptomatology, is unknown. This study examined the association between plasma Aβ peptides (Aβ

Hydroxybenzoic Acids as Acetylcholinesterase Inhibitors Calorimetric and Docking Simulation Studies.

One of the symptoms of Alzheimers disease (AD) is low acetylcholine level due to high acetylcholinesterase (AChE) activity. For this reason, AChE inhibitors are used in the treatment of AD, the prolonged use of which may cause a cholinergic crisis. There is a need to search for safe natural AChE inhibitors. The study analyzed 16 hydroxybenzoic acids using calorimetry and docking simulation as AChE inhibitors. All tested compounds were shown to inhibit the hydrolysis of ACh. The best properties were shown by methyl syringinate, which acted as competitive inhibitor at a catalytic site. The tested compounds also interacted with the anionic or peripheral binding site known to block β-amyloid plaques formation. The activity of the tested hydroxybenzoic acids IC50 ranged from 5.50 to 34.19 µmolµmol of AChE, and the binding constant Ka from 20.53 to 253.16 Lmol, which proves their reversible, non-toxic effect, and activity at physiological concentrations.

Effects of Diastolic Blood Pressure on Brain Structures and Cognitive Functions in Middle and Old Ages Longitudinal Analyses.

Hypertension is a pervasive public health concern due to strong associations with cardiovascular diseases and stroke. Alternatively, the associations between hypertension and the risk of Alzheimers disease are complex and recent large sample studies reported positive associations. In this paper, we examine the associations between diastolic blood pressure (BP) and subsequent changes in brain structure and cognitive function over several years by multiple regression analyses (with adjustment for a wide range of potential confounding variables) among a large cohort from the UK Biobank. Higher baseline diastolic BP was associated with a slightly smaller relative increase (relative improvements) in reaction time and a slightly greater reduction in depression scores. Higher baseline diastolic BP was also associated with a greater total gray matter volume (GMV) retention, while aging alone was associated with GMV reduction. White matter microstructural analyses revealed that a greater diastolic BP was associated with reduced longitudinal mean and regional fractional anisotropy, greater increases in mean and regional mean diffusivity, radial diffusivity, and axial diffusivity, a greater decline in mean intracellular volume fraction, and greater increases in mean and regional isotropic volume fraction. These white matter microstructural changes were consistent with those seen in the aging process. Additional analyses revealed a greater cheese intake level at baseline, which is associated with a subsequent decline in diastolic BP and a relative subsequent increase in depressive tendency together with a relative increase in fluid intelligence and visuospatial memory performance. These results are congruent with the view that a higher BP in the aging brain has a complex role.