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FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells.

Although tissue-resident memory T (T

Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinsons disease in Chinese population.

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinsons disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P

Chronic traumatic encephalopathy (CTE) criteria for neuropathological diagnosis and relationship to repetitive head impacts.

Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS-NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimers disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose-response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS-NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose-response relationship between RHI and CTE.

Assembled Photonic CrystalGold Nanoparticle Interface A Dual Amplifying Electrochemiluminescent Aptasensor for the Ultrasensitive Detection of an Amyloid-β Monomer.

Amyloid-β (Aβ) protein is considered to be a key biomarker that is closely associated with Alzheimers disease (AD). The level of Aβ, particularly its subtle fluctuation, indicates early neuropathological changes, which poses a considerable challenge in predicting AD, considering the detection limit of sensing technologies. Herein, a new label-free sensor based on luminol electrochemiluminescence (ECL) was proposed by developing a close-packed monolayered-SiO

Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood.

Neurodegenerative diseases are among the most prevalent and devastating neurological disorders, with few effective prevention and treatment strategies. We aimed to integrate genetic and proteomic data to prioritize drug targets for neurodegenerative diseases. We screened human proteomes through Mendelian randomization to identify causal mediators of Alzheimers disease, Parkinsons disease, amyotrophic lateral sclerosis, multiple sclerosis, frontotemporal dementia, and Lewy body dementia. For instruments, we used brain and blood protein quantitative trait loci identified from one genome-wide association study with 376 participants and another with 3301 participants, respectively. Causal associations were subsequently validated by sensitivity analyses and colocalization. The safety and druggability of identified targets were also evaluated. Our analyses showed targeting BIN1, GRN, and RET levels in blood as well as ACE, ICA1L, MAP1S, SLC20A2, and TOM1L2 levels in brain might reduce Alzheimers disease risk, while ICA1L, SLC20A2, and TOM1L2 were not recommended as prioritized drugs due to the identified potential side effects. Brain CD38, DGKQ, GPNMB, and SEC23IP were candidate targets for Parkinsons disease. Among them, GPNMB was the most promising target for Parkinsons disease with their causal relationship evidenced by studies on both brain and blood tissues. Interventions targeting FCRL3, LMAN2, and MAPK3 in blood and DHRS11, FAM120B, SHMT1, and TSFM in brain might affect multiple sclerosis risk. The risk of amyotrophic lateral sclerosis might be reduced by medications targeting DHRS11, PSMB3, SARM1, and SCFD1 in brain. Our study prioritized 22 proteins as targets for neurodegenerative diseases and provided preliminary evidence for drug development. Further studies are warranted to validate these targets.

Pathogenic Role of RAGE in Tau Transmission and Memory Deficits.

In tauopathies, brain regions with tau accumulation strongly correlate with clinical symptoms, and spreading of misfolded tau along neural network leads to disease progression. However, the underlying mechanisms by which tau proteins enter neurons during pathological propagation remain unclear. To identify membrane receptors responsible for neuronal propagation of tau oligomers, we established a cell-based tau uptake assay and screened complementary DNA expression library. Tau uptake and propagation were analyzed in vitro and in vivo using a microfluidic device and stereotactic injection. The cognitive function of mice was assessed using behavioral tests. From a genome-wide cell-based functional screening, RAGE (receptor for advanced glycation end products) was isolated to stimulate the cellular uptake of tau oligomers. Rage deficiency reduced neuronal uptake of pathological tau prepared from rTg4510 mouse brains or cerebrospinal fluid from patients with Alzheimers disease and slowed tau propagation between neurons cultured in a 3-chamber microfluidic device. RAGE levels were increased in the brains of rTg4510 mice and tau oligomer-treated neurons. Rage knockout decreased tau transmission in the brains of nontransgenic mice after injection with Alzheimers disease patient-derived tau and ameliorated memory loss after injection with GFP-P301L-tau-AAV. Treatment of RAGE antagonist FPS-ZM1 blocked transsynaptic tau propagation and inflammatory responses and alleviated cognitive impairment in rTg4510 mice. These results suggest that in neurons and microglia, RAGE binds to pathological tau and facilitates neuronal tau pathology progression and behavioral deficits in tauopathies.

Neuronal SIRT3 deletion predisposes to female-specific alterations in cellular metabolism, memory, and network excitability.

Mitochondrial dysfunction is an early event in the pathogenesis of neurological disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass-spectrometry based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons in the cortex and hippocampus produces altered neuronal excitability and metabolic dysfunction in female mice. Targeted deletion of SIRT3 from neuronal helix-loop-helix 1 (NEX)-expressing neurons resulted in mitochondrial hyperacetylation, female-specific superoxide dismutase-2 (SOD2) modification, increased steady-state superoxide levels, metabolic reprogramming, altered neuronal excitability and working spatial memory deficits. Inducible neuronal deletion of SIRT3 likewise produced female-specific deficits in spatial working memory. Together, the data demonstrate that deletion of SIRT3 from forebrain neurons selectively predisposes female mice to deficits in mitochondrial and cognitive function.

Revisiting the intersection of microglial activation and neuroinflammation in Alzheimers disease from the perspective of ferroptosis.

Alzheimers disease (AD) is a neurodegenerative disorder characterized by chronic neuroinflammation with amyloid beta-protein deposition and hyperphosphorylated tau protein. The typical clinical manifestation of AD is progressive memory impairment, and AD is considered a multifactorial disease with various etiologies (genetic factors, aging, lifestyle, etc.) and complicated pathophysiological processes. Previous research identified that neuroinflammation and typical microglial activation are significant mechanisms underlying AD, resulting in dysfunction of the nervous system and progression of the disease. Ferroptosis is a novel modality involved in this process. As an iron-dependent form of cell death, ferroptosis, characterized by iron accumulation, lipid peroxidation, and irreversible plasma membrane disruption, promotes AD by accelerating neuronal dysfunction and abnormal microglial activation. In this case, disturbances in brain iron homeostasis and neuronal ferroptosis aggravate neuroinflammation and lead to the abnormal activation of microglia. Abnormally activated microglia release various pro-inflammatory factors that aggravate the dysregulation of iron homeostasis and neuroinflammation, forming a vicious cycle. In this review, we first introduce ferroptosis, microglia, AD, and their relationship. Second, we discuss the nonnegligible role of ferroptosis in the abnormal microglial activation involved in the chronic neuroinflammation of AD to provide new ideas for the identification of potential therapeutic targets for AD.

Genetic Predisposition to Alzheimers Disease Alters Inflammasome Activity After Traumatic Brain Injury.

Traumatic Brain Injury (TBI) is a major cause of death and disability in the United States and a recognized risk factor for the development of Alzheimers disease (AD). The relationship between these conditions is not completely understood, but the conditions may share additive or synergistic pathological hallmarks that may serve as novel therapeutic targets. Heightened inflammasome signaling plays a critical role in the pathogenesis of central nervous system injury (CNS) and the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck from neurons and activated microglia contribute significantly to TBI and AD pathology. This study investigated whether inflammasome signaling after TBI was augmented in AD and whether this signaling pathway impacted biochemical and neuropathological outcomes and overall cognitive function. Five-month-old, 3xTg mice and respective wild type controls were randomized and underwent moderate controlled cortical impact (CCI) injury or served as shamuninjured controls. Animals were sacrificed at 1 hour, 1 day, or 1 week after TBI (n5-8group) to assess acute pathology or at 12 weeks (n9-10group) after assessing cognitive function. The ipsilateral cerebral cortex was processed for inflammasome protein expression by immunoblotting. Mice were evaluated for behavior by open field (3 days), novel object recognition (2 weeks), and Morris water maze (6 weeks) testing after TBI. There was a statistically significant increase in the expression of inflammasome signaling proteins Caspase-1, Caspase-8, ASC, and interleukin (IL)-1β after TBI in both wild type and 3xTg animals. At 1-day post injury, significant increases in ASC and IL-1β protein expression were measured in AD TBI mice compared to WT TBI. Behavioral testing showed that injured AD mice had altered cognitive function when compared to injured WT mice. Elevated Aβ was seen in the ipsilateral cortex and hippocampus of sham and injured AD when compared to respective groups at 12 weeks post injury. Moreover, treatment of injured AD mice with IC100, an anti-ASC monoclonal antibody, inhibited the inflammasome, as evidenced by IL-1β reduction in the injured cortex at 1-week post injury. These findings show that the inflammasome response is heightened in mice genetically predisposed to AD and suggests that AD may exacerbate TBI pathology. Thus, dampening inflammasome signaling may offer a novel approach for the treatment of AD and TBI.

The impact of loneliness and social isolation on the development of cognitive decline and Alzheimers Disease.

Alzheimers Disease (AD) is the leading cause of dementia, observed at a higher incidence in women compared with men. Treatments aimed at improving pathology in AD remain ineffective to stop disease progression. This makes the detection of the early intervention strategies to reduce future disease risk extremely important. Isolation and loneliness have been identified among the major risk factors for AD. The increasing prevalence of both loneliness and AD emphasizes the urgent need to understand this association to inform treatment. Here we present a comprehensive review of both clinical and preclinical studies that investigated loneliness and social isolation as risk factors for AD. We discuss that understanding the mechanisms of how loneliness exacerbates cognitive impairment and AD with a focus on sex differences will shed the light for the underlying mechanisms regarding loneliness as a risk factor for AD and to develop effective prevention or treatment strategies.

Examining the Validity and Utility of Montreal Cognitive Assessment Domain Scores for Early Neurocognitive Disorders.

Montreal Cognitive Assessment (MoCA) total scores have been widely used to identify individuals with neurocognitive disorders (NCDs), but the utility of its domain-specific scores have yet to be thoroughly interrogated. This study aimed to validate MoCAs 6 domain-specific scores (ie, Memory, Language, Attention, Executive, Visuospatial, and Orientation) with conventional neuropsychological tests and explore whether MoCA domain scores could discriminate between different etiologies in early NCDs. Baseline data of a cohort study. Study included 14,571 participants recruited from Alzheimers Disease Centers across United States, aged ≥50 years, with global Clinical Dementia Rating of ≤1, and mean age of 71.8 ± 8.9 years. Participants completed MoCA, conventional neuropsychological tests, and underwent standardized assessments to diagnose various etiologies of NCDs. Partial correlation coefficient was used to examine construct validity between Z scores of neuropsychological tests and MoCA domain scores, whereas multinomial logistic regression examined utility of domain scores to differentiate between etiologies of early NCDs. MoCA domain scores correlated stronger with equivalent constructs (r 0.15-0.43, P < .001), and showed divergence from dissimilar constructs on neuropsychological tests. Participants with Alzheimers disease were associated with greater impairment in Memory, Attention, Visuospatial, and Orientation domains (RRR 1.13-1.55, P < .001). Participants with Lewy body disease were impaired in Attention and Visuospatial domains (RRR 1.21-1.47, P < .001) participants with frontotemporal lobar degeneration were impaired in Language, Executive, and Orientation domains (RRR 1.25-1.75, P < .01) and participants with Vascular disease were impaired in Attention domain (RRR 1.14, P < .001). MoCA domain scores approximate well-established neuropsychological tests and can be valuable in discriminating different etiologies of early NCDs. Although MoCA domain scores may not fully substitute neuropsychological tests, especially in the context of diagnostic uncertainties, they can complement MoCA total scores as part of systematic evaluation of early NCDs and conserve the use of neuropsychological tests to patients who are more likely to require further assessments.

Altered global signal topography in Alzheimers disease.

Alzheimers disease (AD) is a neurodegenerative disease associated with widespread disruptions in intrinsic local specialization and global integration in the functional system of the brain. These changes in integration may further disrupt the global signal (GS) distribution, which might represent the local relative contribution to global activity in functional magnetic resonance imaging (fMRI). fMRI scans from a discovery dataset (n 809) and a validated dataset (n 542) were used in the analysis. We investigated the alteration of GS topography using the GS correlation (GSCORR) in patients with mild cognitive impairment (MCI) and AD. The association between GS alterations and functional network properties was also investigated based on network theory. The underlying mechanism of GSCORR alterations was elucidated using imaging-transcriptomics. Significantly increased GS topography in the frontal lobe and decreased GS topography in the hippocampus, cingulate gyrus, caudate, and middle temporal gyrus were observed in patients with AD (P Our findings revealed significant changes in GS topography and its molecular basis, confirming the informative role of GS in AD and further contributing to the understanding of the relationship between global and local neuronal activities in patients with AD. Beijing Natural Science Funds for Distinguished Young Scholars, China Fundamental Research Funds for the Central Universities, China National Natural Science Foundation, China.

Orexin-A aggravates cognitive deficits in 3xTg-AD mice by exacerbating synaptic plasticity impairment and affecting amyloid β metabolism.

Dementia is the main clinical feature of Alzheimers disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APPPS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid β (Aβ) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aβ levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aβ and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aβ production and decreasing Aβ clearance through disruption of the circadian rhythm and sleep-wake cycle.

Prevalence of sleep-related breathing disorders and associated risk factors among people with dementia A meta-analysis.

Sleep-related breathing disorders (SRBD) have shown to cause worsened cognitive impairment among people with dementia. Therefore, we conducted the first meta-analysis to estimate the prevalence of SRBD among people with dementia. Comprehensive searches were conducted in Embase, Ovid-MEDLINE, PubMed, PsycINFO, Scopus, Web of Science, and CINAHL. The generalized linear mixed model (GLMM) was used for the pooled prevalence analysis and heterogeneity using I The pooled prevalence of SRBD among dementia was 59% (95%CI 44%-73%) with 55% (95%CI 34%-74%) for obstructive sleep apnea (OSA), 49% (95%CI 25%-73%) for unspecified SRBD, and 11% (95%CI 5%-21%) for central sleep apnea (CSA). Regarding dementia subtypes, the prevalence of SRBD was 89% (95%CI 61%-97%) for Alzheimers dementia, 56% (95%CI 48%-63%) for Parkinsons and Idiopathic Parkinsons dementia, and 16% (95%CI 8%-30%) for Huntingtons dementia. Significant moderator variables were male, body mass index, larger waist and hip circumference, waist-hip ratio, and comorbidities including hypertension, dyslipidemia, renal disease, diabetes, heart disease, and stroke. There is considerable high prevalence of SRBD among dementia people, with OSA and unspecified SRBD being fivefold higher than CSA. Regarding dementia subtypes, Parkinsons and Idiopathic Parkinsons, and Alzheimers dementia had four to sixfold increased risk of presenting with SRBD than Huntingtons dementia. Therefore, assessment and management of SRBD in Alzheimers, and Parkinsons and Idiopathic Parkinsons dementia deserves more attention in future research.

An S-Shaped Aβ42 Cross-β Hexamer Embedded into a Lipid Bilayer Reveals Membrane Disruption and Permeability.

The interactions of amyloid oligomers with membranes are known to contribute to cellular toxicity. Numerous

Local and Systemic Hypoxia as Inductors of Increased Aluminum and Iron Brain Accumulation Promoting the Onset of Alzheimers Disease.

Human environment is highly contaminated with aluminum, and aluminum is toxic to majority of tissues, particularly to neurons. In previous decades, aluminum exposure was frequently linked with the onset of Alzheimers disease (AD), and increased levels of Al were detected in the brains of individuals with AD. People who live in a certain area are exposed to aluminum in a similar way (they eat the same vegetable and other foodstuffs, use similar cosmetics, and buy medications from the same manufacturer), nevertheless not all of them develop Alzheimers disease. Majority of known risk factors for AD promote atherosclerosis and consequently reduce brain blood supply. In this review, we highlighted the significance of local (carotid disease and atherosclerosis of intracranial blood vessels) and systemic hypoxia (chronic obstructive pulmonary disease and anemia) in the development of AD. Nerve tissue is very sophisticated and sensitive to hypoxia and aluminum toxicity. As a side effect of compensatory mechanisms in case of hypoxia, neurons start to uptake aluminum and iron to a greater extent. This makes perfect a background for the gradual onset and development of AD.

Morphological, cariological, and phytochemical studies of diploid and autotetraploid Hippeastrum papilio plants.

The polyploidization of Hippeastrum papilio influences its primary and secondary metabolism including the biosynthesis of bioactive alkaloids. Hippeastrum papilio is an ornamental plant that has advantages in comparison to the currently used plants for the extraction of galanthamine, a natural compound used for the cognitive treatment of Alzheimers disease. In the present study, an autotetraploid line of H. papilio was induced for the first time, after treatment with 0.05% colchicine for 48 h. The chromosome number in diploids was found to be 2n 2x 22 and for autotetraploids 2n 4x 44. The flow cytometric analyses detected a DNA C-value of 14.88 ± 0.03 pg (1C) in diploids and 26.57 ± 0.12 pg in autotetraploids. The morphological, cytological, and phytochemical studies showed significant differences between diploids and autotetraploids. The length and width of stomata in autotetraploids were 22.47% and 17.94%, respectively, larger than those observed in the diploid leaves. The biomass of one-year-old autotetraploid H. papilio plants was reduced by 53.99% for plants fresh weight, 56.53% for leaves fresh weight, and 21.70% for bulb diameter. The GC-MS analysis of methanol extracts from one-year-old diploid and autotetraploid H. papilio plants revealed over 60 primary and secondary metabolites including alkaloids, phenolic acids, sterols, saccharides, and alcohols, among others. Principal component analysis of the metabolite profiles indicates a divergence of the metabolism between diploid and autotetraploid plants. The content of galanthamine and haemanthamine was found to be 49.73% and 80.10%, respectively, higher in the leaves of autotetraploids, compared to the diploid ones. The biosynthesis of the saccharides shows a tendency to be upregulated in tetraploid plants, while that of phenolic acids was downregulated. Polyploidization of H. papilio creates possibilities for further crop improvement aimed at high-galanthamine-producing genotypes.

Activation of aryl hydrocarbon receptor (AhR) in Alzheimers disease role of tryptophan metabolites generated by gut host-microbiota.

Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as neuropsychiatric conditions and Alzheimers disease (AD). L-tryptophan metabolites and short-chained fatty acids (SCFA) are major messengers in the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) are main targets of tryptophan metabolites in brain microvessels which possess an enriched expression of AhR protein. The Ah receptor is an evolutionarily conserved, ligand-activated transcription factor which is not only a sensor of xenobiotic toxins but also a pleiotropic regulator of both developmental processes and age-related tissue degeneration. Major microbiota-produced tryptophan metabolites involve indole derivatives, e.g., indole 3-pyruvic acid, indole 3-acetaldehyde, and indoxyl sulfate, whereas indoleamine and tryptophan 2,3-dioxygenases (IDOTDO) of intestine host cells activate the kynurenine (KYN) pathway generating KYN metabolites, many of which are activators of AhR signaling. Chronic kidney disease (CKD) increases the serum level of indoxyl sulfate which promotes AD pathogenesis, e.g., it disrupts integrity of blood-brain barrier (BBB) and impairs cognitive functions. Activation of AhR signaling disturbs vascular homeostasis in brain (i) it controls blood flow via the renin-angiotensin system, (ii) it inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production and vasodilatation, and (iii) it induces oxidative stress, stimulates inflammation, promotes cellular senescence, and enhances calcification of vascular walls. All these alterations are evident in cerebral amyloid angiopathy (CAA) in AD pathology. Moreover, AhR signaling can disturb circadian regulation and probably affect glymphatic flow. It seems plausible that dysbiosis of gut microbiota impairs the integrity of BBB via the activation of AhR signaling and thus aggravates AD pathology. KEY MESSAGES Dysbiosis of gut microbiota is associated with dementia and Alzheimers disease. Tryptophan metabolites are major messengers from the gut host-microbiota to brain. Tryptophan metabolites activate aryl hydrocarbon receptor (AhR) signaling in brain. The expression of AhR protein is enriched in brain microvessels and blood-brain barrier. Tryptophan metabolites disturb brain vascular integrity via AhR signaling. Dysbiosis of gut microbiota promotes inflammation and AD pathology via AhR signaling.

Targeting the gut-microbiota-brain axis in irritable bowel disease to improve cognitive function - recent knowledge and emerging therapeutic opportunities.

The brain-gut axis forms a bidirectional communication system between the gastrointestinal (GI) tract and cognitive brain areas. Disturbances to this system in disease states such as inflammatory bowel disease have consequences for neuronal activity and subsequent cognitive function. The gut-microbiota-brain axis refers to the communication between gut-resident bacteria and the brain. This circuits exists to detect gut microorganisms and relay information to specific areas of the central nervous system (CNS) that in turn, regulate gut physiology. Changes in both the stability and diversity of the gut microbiota have been implicated in several neuronal disorders, including depression, autism spectrum disorder Parkinsons disease, Alzheimers disease and multiple sclerosis. Correcting this imbalance with medicinal herbs, the metabolic products of dysregulated bacteria and probiotics have shown hope for the treatment of these neuronal disorders. In this review, we focus on recent advances in our understanding of the intricate connections between the gut-microbiota and the brain. We discuss the contribution of gut microbiota to neuronal disorders and the tangible links between diseases of the GI tract with cognitive function and behaviour. In this regard, we focus on irritable bowel syndrome (IBS) given its strong links to brain function and anxiety disorders. This adds to the growing body of evidence supporting targeted therapeutic strategies to modulate the gut microbiota for the treatment of brainmental-health-related disease.

Direct Effect of Life Course Socioeconomic Status on Late Life Cognition and Cognitive Decline in the Rush Memory and Aging Project.

The role of socioeconomic status (SES) across the life course in late-life cognition is unclear. We tested the hypotheses that 1) high SES in childhood, young adulthood, mid-life, and late-life have independent causal effects on higher cognition level and slower cognitive decline 2) Compared to stable low SES (referent), stable high SES has the largest estimated effect for higher cognition level and slower decline among life course SES combinations. The Rush Memory and Aging Project enrolled 1,940 dementia-free older adults in 1997-2018. We utilized inverse probability weighted marginal structural models to estimate the joint and independent effect of each life course SES on global and domain-specific cognition. A total of 1,746 participants had 6 years average follow-up. High SES at each life course stage starting in young adulthood had a protective estimated effect on global and domain-specific cognition intercepts. Compared to consistently low SES, consistently high SES (β 0.64, 95% CI 0.48, 0.93), and high SES beyond childhood (β 0.64, 95% CI 0.47, 0.83) had the largest benefit for global cognition intercepts. None of the life course SES measures influenced rate of global or domain specific decline. Additional understanding of life course SES components influencing cognitive level is warranted.

Biopsychosocial frailty and mild cognitive impairment subtypes Findings from the Italian project on the epidemiology of Alzheimers disease (IPREA).

Frailty is a critical intermediate status of the aging process including physical, cognitive, and psychosocial phenotypes. We operationalized a biopsychosocial frailty construct, estimating its association with mild cognitive impairment (MCI) and its subtypes. In 1980, older individuals from the population-based Italian PRoject on the Epidemiology of Alzheimers disease (IPREA), we investigated cross-sectional associations among biopsychosocial frailty, MCI, and its subtypes. Participants with biopsychosocial frailty showed an increased odds ratio (OR) of MCI OR 4.36 95% confidence interval (CI) 2.60-7.29 Fishers exact p < 0.01, particularly for nonamnestic MCI single domain (naMCI-SD, OR3.28 95% CI 1.35-7.97 Fishers exact p 0.02) and for nonamnestic MCI multiple domain (naMCI-MD, OR6.92 95% CI 3.37-14.21 Fishers exact p < 0.01). No statistically significant associations between amnestic MCI single or multiple domain and biopsychosocial frailty were observed. In a large, older Italian cohort, a biopsychosocial frailty phenotype was associated with MCI, in particular, could be associated with some of its subtypes, that is, naMCI-SD, and naMCI-MD.

Procyanidins extracted from the lotus seedpod ameliorate cognitive impairment through CREB-BDNF pathway mediated LTP in APPPS1 transgenic mice.

Alzheimers disease (AD) is an age-related neurodegenerative disease and featured by cognitive impairment. Procyanidins have been shown to have a potential protective effect against neurodegenerative diseases, but the underlying mechanism is not comprehensive enough. To further investigate the effects of procyanidins from lotus seedpod (LSPC) on cognition in AD. The APPPS1 transgenic mice were administered with LSPC (100 mgkg body weight) for five months. The Morris water maze test was used to assess learning and memory function, the long-term potentiation (LTP) was measured and the expression of Aβ, pCREBCREB and BDNF were quantified by western blot. LSPC significantly ameliorated cognitive dysfunction, reduced Aβ deposition and reversed remarkable reduction of the phosphorylation of CREB and the expression of BDNF, and then enhanced the effect of LTP in APPPS1 mice. These results revealed that LSPC could ameliorate cognitive impairment through CREB-BDNF pathway mediated the enhancement of LTP in APPPS1 transgenic mice.

Carer burden and behavioral disturbance is similar between younger-onset Alzheimers disease and behavioral variant frontotemporal dementia.

Carer burden is common in younger-onset dementia (YOD), often due to the difficulty of navigating services often designed for older people with dementia. Compared to Alzheimers disease (AD), the burden is reported to be higher in behavioral variant frontotemporal dementia (bvFTD). However, there is little literature comparing carer burden specifically in YOD. This study hypothesized that carer burden in bvFTD would be higher than in AD. Retrospective cross-sectional study. Tertiary neuropsychiatry service in Victoria, Australia. Patient-carer dyads with YOD. We collected patient data, including behaviors using the Cambridge Behavioral Inventory-Revised (CBI-R). Carer burden was rated using the Zarit Burden Inventory-short version (ZBI-12). Descriptive statistics and Mann-Whitney U tests were used to analyze the data. Carers reported high burden (ZBI-12 mean score 17.2, SD 10.5), with no significant difference in burden between younger-onset AD and bvFTD. CBI-R stereotypic and motor behaviors, CBI-R everyday skills, and total NUCOG scores differed between the two groups. There was no significant difference in the rest of the CBI-R subcategories, including the behavior-related domains. Carers of YOD face high burden and are managing significant challenging behaviors. We found no difference in carer burden between younger-onset AD and bvFTD. This could be due to similarities in the two subtypes in terms of abnormal behavior, motivation, and self-care as measured on CBI-R, contrary to previous literature. Clinicians should screen for carer burden and associated factors including behavioral symptoms in YOD syndromes, as they may contribute to carer burden regardless of the type.

Impact of Alzheimers disease and related dementias (ADRD) on the quality of room cleaning in nursing homes.

Persons with Alzheimers disease and related dementias (ADRD) are prone to receiving reduced quality of care. We compared the quality of room cleaning of rooms with ADRD residents and rooms with non-ADRD residents in nursing homes using an ultraviolet (UV) marker. ADRD status was associated with greater failure of UV marker removal (odds ratio, 1.68 95% confidence interval, 1.04-2.71

Genetic architecture of hippocampus subfields volumes in Alzheimers disease.

The hippocampus is a heterogeneous structure, comprising histologically and functionally distinguishable hippocampal subfields. The volume reductions in hippocampal subfields have been demonstrated to be linked with Alzheimers disease (AD). The aim of our study is to investigate the hippocampal subfields genetic architecture based on the Alzheimers Disease Neuroimaging Initiative (ADNI) data set. After preprocessing the downloaded genetic variants and imaging data from the ADNI database, a co-sparse reduced rank regression model was applied to analyze the genetic architecture of hippocampal subfields volumes. Homology modeling, docking, molecular dynamics simulations, and Co-IP experiments for protein-protein interactions were used to verify the function of target protein on hippocampal subfields successively. After that, the association analysis between the candidated genes on the hippocampal subfields volume and clinical scales were performed. The results of the association analysis revealed five unique genetic variants (e.g., ubiquitin-specific protease 10 USP10) changed in nine hippocampal subfields (e.g., the granule cell and molecular layer of the dentate gyrus GC-ML-DG). Among five genetic variants, USP10 had the strongest interaction effect with BACE1, which affected hippocampal subfields verified by MD and Co-IP experiments. The results of association analysis between the candidated genes on the hippocampal subfields volume and clinical scales showed that candidated genes influenced the volume and function of hippocampal subfields. Current evidence suggests that hippocampal subfields have partly distinct genetic architecture and may improve the sensitivity of the detection of AD.

Lower cognitive function attenuates the convergence between self-ratings and observer ratings of depressive symptoms in late-life cognitive impairment.

Assessment of depressive symptoms in older adults is challenging especially in the presence of risks in cognitive impairment. We aimed to examine whether the convergence between two measures of depressive symptoms (self-report and observer ratings) is affected by varying levels of cognitive function in older adults. Self-reported scale of depression, informant-based rating of affective symptoms, and global cognitive function were assessed in 2533 older adults with no impairment, mild cognitive impairment, and Alzheimers disease. The strength of rank-order correlation between the Geriatric Depression Scale (GDS) and behavioral ratings of the Neuropsychiatric Inventory (NPI) was examined as the metric of convergent validity. The results showed that the strength of convergence between the two measurements gradually decreased as a function of lowered cognitive function. Overall tendency showed that diagnoses of cognitive impairment and lower levels of cognitive function were associated with lower correspondence between the two depression measurements. The loss of convergent validity is especially evident in the behavioral symptom of apathy. Utilizing self-report scales of depression in older adults requires a cautious approach even with minimal or mild levels of cognitive impairment.

Click-designed vanilloid-triazole conjugates as dual inhibitors of AChE and Aβ aggregation.

Based on their reported neuroprotective properties, vanilloids provide a good starting point for the synthesis of anti-Alzheimers disease (AD) agents. In this context, nine new 1,2,3-triazole conjugates of vanilloids were synthesized

Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains.

The speed and scope of cognitive deterioration in Alzheimers disease is highly associated with the advancement of tau neurofibrillary lesions across brain networks. We tested whether the rate of tau propagation is a heritable disease trait in a large, well-characterized cohort of genetically divergent mouse strains. Using an AAV-based model system, P301L-mutant human tau (hTau) was introduced into the entorhinal cortex of mice derived from 18 distinct lines. The extent of tau propagation was measured by distinguishing hTau-producing cells from neurons that were recipients of tau transfer. Heritability calculation revealed that 43% of the variability in tau spread was due to genetic variants segregating across background strains. Strain differences in glial markers were also observed, but did not correlate with tau propagation. Identifying unique genetic variants that influence the progression of pathological tau may uncover novel molecular targets to prevent or slow the pace of tau spread and cognitive decline.

Pathogenic tau decreases nuclear tension in cultured neurons.

Neurodegenerative tauopathies, including Alzheimers disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimers disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders.

Mini-review Angiotensin- converting enzyme 1 (ACE1) and the impact for diseases such as Alzheimers disease, sarcopenia, cancer, and COVID-19.

Ageing has been associated with comorbidities, systemic low-grade of inflammation, and immunosenescence. Hypertension is the most common morbidity and anti-hypertensives are used for more than 50%. Angiotensin-converting enzyme 1 inhibitors (ACEi) and angiotensin II receptor blockers (ARB) control blood pressure but also seem to play a role in comorbidities such as Alzheimers disease, sarcopenia and cancer. The impact of anti-hypertensives in comorbidities is due to the expression of renin-angiotensin system (RAS) in several tissues and body fluids. Angiotensin-converting enzyme 1 (ACE1) has been linked to oxidative stress, metabolism, and inflammation. The levels and activity of ACE1 are under genetic control and polymorphisms have been correlated with susceptibility to Alzheimers disease. In addition, some results found that ACEi and ARB users present delayed cognitive decline and reduced risk of dementia. Regarding to sarcopenia, RAS has been linked to the catabolic and anabolic pathways for muscle mass maintenance. In some studies, older adults using ACEi were highly benefited by exercise training. In cancer, RAS and its products have been shown to play a role since their inhibition in animal models modulates tumor microenvironment and improves the delivery of chemotherapy drugs. Clinically, the incidence of colorectal cancer is reduced in patients using ACEi and ARB. During the pandemic COVID-19 it was found that ACE2 receptor plays a role in the entry of SARS-CoV-2 into the host cell. ACE1 genotypes have been linked to an increased risk for COVID-19 and severe disease. In some studies COVID-19 patients taking ARB or ACEi presented better outcome.

Multi-task deep autoencoder to predict Alzheimers disease progression using temporal DNA methylation data in peripheral blood.

Traditional approaches for diagnosing Alzheimers disease (AD) such as brain imaging and cerebrospinal fluid are invasive and expensive. It is desirable to develop a useful diagnostic tool by exploiting biomarkers obtained from peripheral tissues due to their noninvasive and easily accessible characteristics. However, the capacity of using DNA methylation data in peripheral blood for predicting AD progression is rarely known. It is also challenging to develop an efficient prediction model considering the complex and high-dimensional DNA methylation data in a longitudinal study. Here, we develop two multi-task deep autoencoders, which are based on the convolutional autoencoder and long short-term memory autoencoder to learn the compressed feature representation by jointly minimizing the reconstruction error and maximizing the prediction accuracy. By benchmarking on longitudinal DNA methylation data collected from the peripheral blood in Alzheimers Disease Neuroimaging Initiative, we demonstrate that the proposed multi-task deep autoencoders outperform state-of-the-art machine learning approaches for both predicting AD progression and reconstructing the temporal DNA methylation profiles. In addition, the proposed multi-task deep autoencoders can predict AD progression accurately using only the historical DNA methylation data and the performance is further improved by including all temporal DNA methylation data.

Efficacy of Kami Guibi-tang as an Add-On Therapy to Acetylcholinesterase Inhibitor for Cognitive Function in Mild Alzheimers Disease A Pilot Study.

Kami Guibi-tang (KGT), a traditional Korean herbal medicine is mainly used to treat insomnia and nervousness. Acetylcholinesterase inhibitors (AChEIs) are the main treatments for mild Alzheimers disease (AD), a degenerative brain disease. However, currently no drug can fundamentally treat AD or reverse the advanced cognitive decline. This clinical study explored the efficacy and safety of adding KGT to AChEI for cognitive function in mild AD. This was a pilot study for a larger randomized, double-blind, placebo-controlled trial. Participants between 55-90 years diagnosed with mild AD were recruited from Kyung Hee University Hospital at Gangdong, Seoul, Korea. They were randomized to receive either KGT or placebo for 24 weeks, in addition to their regular AChEI. The primary outcome was treatment efficacy, as assessed by the relative amount of change over the study period in total scores on the Dementia version of the Seoul Neuropsychological Screening Battery (SNSB-D). Changes in SNSB subscores were assessed as secondary outcomes. Safety parameters, including adverse events and abnormalities in blood tests, electrocardiograms, and brain magnetic resonance imaging were also monitored. Between March 2018 and November 2020, seven participants each in the KGT group and the placebo group completed the 24-week trial. There were no significant changes in SNSB-D total or subindex scores for either group ( Compared to placebo, adding KGT to AChEI did not significantly improve cognitive function in SNSB in patients with mild AD. We suggest that KGT would have a positive effect on patients with early stages of cognitive impairment such as aMCI. The findings could assist design larger, longer-term clinical trials of KGT use in elderly patients with mild AD. This study was registered in the Korean Clinical Trial Registry on December 26, 2017, with the CRIS approval number KCT0002904.

AVE 0991 Suppresses Astrocyte-Mediated Neuroinflammation of Alzheimers Disease by Enhancing Autophagy.

Our previous study has shown that AVE 0991, a nonpeptide analogue of Ang-(1-7), ameliorates cognitive decline and inhibits NLRP3 inflammasome of astrocytes in Alzheimers disease model mice. Additionally, several studies have suggested that activation of autophagy appears to effectively inhibit the progression of neuroinflammation. However, it is unclear whether AVE 0991 can modulate astrocyte autophagy to suppress neuroinflammation in Alzheimers disease. APPPS1 mice and Aβ-treated primary astrocytes were used as the research objects in vivo and in vitro, respectively. Water maze test was used to evaluate cognitive function of mice, Nissl staining and immunofluorescence staining was used to assess neuronal damage. ELISA kits were used to detect the levels of Ang-(1-7) and Aβ in the cortex, and qRT-PCR was used to detect the expression of cortical inflammation-related mediators. The expression of autophagy-related proteins in cortex were detected by Western blot. The upstream molecular responses involved in inflammation inhibition by AVE 0991 were validated by means of using the Mas1 antagonist and autophagy inhibitor. We found that 30 days of intraperitoneal administration of AVE 0991 improved. Aβ deposition, neuronal death, and cognitive deficits in APPPS1 Alzheimers disease model mice. Moreover, AVE 0991 treatment greatly suppressed astrocyte-mediated inflammation and up-regulated the expression of autophagy. Furthermore, the inhibitory effect of AVE 0991 on the expression of inflammatory factors was reversed by 3-MA, an autophagy inhibitor. These findings suggest that regulation of autophagy is critical for inhibiting astrocyte neuroinflammatory responses and demonstrate a potential neuroprotective mechanism by which AVE 0991 could suppress neuroinflammatory responses by enhancing autophagy.

Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis.

Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimers disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GHIGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults.

Genetic models of cleavage-reduced and soluble TREM2 reveal distinct effects on myelination and microglia function in the cuprizone model.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a cell-surface immunoreceptor expressed on microglia, osteoclasts, dendritic cells and macrophages. Heterozygous loss-of-function mutations in TREM2, including mutations enhancing shedding form the cell surface, have been associated with myelinneuronal loss and neuroinflammation in neurodegenerative diseases, such as Alzheimers disease and Frontotemporal Dementia. Using the cuprizone model, we investigated the involvement of soluble and cleavage-reduced TREM2 on central myelination processes in cleavage-reduced (TREM2-IPD), soluble-only (TREM2-sol), knockout (TREM2-KO) and wild-type (WT) mice. The TREM2-sol mouse is a new model with selective elimination of plasma membrane TREM2 and a reduced expression of soluble TREM2. In the acute cuprizone model demyelination and remyelination events were reflected by a T2-weighted signal intensity change in magnetic resonance imaging (MRI), most prominently in the external capsule (EC). In contrast to WT and TREM2-IPD, TREM2-sol and TREM2-KO showed an additional increase in MRI signal during the recovery phase. Histological analyses of TREM2-IPD animals revealed no recovery of neuroinflammation as well as of the lysosomal marker LAMP-1 and displayed enhanced cytokinechemokine levels in the brain. TREM2-sol and, to a much lesser extent, TREM2-KO, however, despite presenting reduced levels of some cytokineschemokines, showed persistent microgliosis and astrocytosis during recovery, with both homeostatic (TMEM119) as well as activated (LAMP-1) microglia markers increased. This was accompanied, specifically in the EC, by no myelin recovery, with appearance of myelin debris and axonal pathology, while oligodendrocytes recovered. In the chronic model consisting of 12-week cuprizone administration followed by 3-week recovery TREM2-IPD displayed sustained microgliosis and enhanced remyelination in the recovery phase. Taken together, our data suggest that sustained microglia activation led to increased remyelination, whereas microglia without plasma membrane TREM2 and only soluble TREM2 had reduced phagocytic activity despite efficient lysosomal function, as observed in bone marrow-derived macrophages, leading to a dysfunctional phenotype with improper myelin debris removal, lack of remyelination and axonal pathology following cuprizone intoxication.

Sex-divergent effects on the NAD-dependent deacetylase sirtuin signaling across the olfactory-entorhinal-amygdaloid axis in Alzheimers and Parkinsons diseases.

Smell impairment is one of the earliest features in Alzheimers (AD) and Parkinsons diseases (PD). Due to sex differences exist in terms of smell and olfactory structures as well as in the prevalence and manifestation of both neurological syndromes, we have applied olfactory proteomics to favor the discovery of novel sex-biased physio-pathological mechanisms and potential therapeutic targets associated with olfactory dysfunction. SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) and bioinformatic workflows were applied in 57 post-mortem olfactory tracts (OT) derived from controls with no known neurological history (n 6F11M), AD (n 4F13M) and PD (n 7F16M) subjects. Complementary molecular analyses by Western-blotting were performed in the olfactory bulb (OB), entorhinal cortex (EC) and amygdala areas. 327 and 151 OT differentially expressed proteins (DEPs) were observed in AD women and AD men, respectively (35 DEPs in common). With respect to PD, 198 DEPs were identified in PD women, whereas 95 DEPs were detected in PD men (20 DEPs in common). This proteome dyshomeostasis induced a disruption in OT protein interaction networks and widespread sex-dependent pathway perturbations in a disease-specific manner, among them Sirtuin (SIRT) signaling. SIRT1, SIRT2, SIRT3 and SIRT5 protein levels unveiled a tangled expression profile across the olfactory-entorhinal-amygdaloid axis, evidencing disease-, sex- and brain structure-dependent changes in olfactory protein acetylation. Alteration in the OT proteostasis was more severe in AD than in PD. Moreover, protein expression changes were more abundant in women than men independent of the neurological syndrome. Mechanistically, the tangled SIRT profile observed across the olfactory pathway-associated brain regions in AD and PD indicates differential NAD ()-dependent deacetylase mechanisms between women and men. All these data shed new light on differential olfactory mechanisms across AD and PD, pointing out that the evaluation of the feasibility of emerging sirtuin-based therapies against neurodegenerative diseases should be considered with caution, including further sex dimension analyses in vivo and in clinical studies.

Pyroptosis and degenerative diseases of the elderly.

Pyroptosis is a recently described mechanism of programmed cell death mediated by proteins of the gasdermin family. Widely recognized signaling cascades include the classical, non-classical, caspase-3-dependent gasdermin E and caspase-8-dependent gasdermin D pathways. Additional pyroptotic pathways have been subsequently reported. With the rising prevalence of advanced age, the role of pyroptosis in the degenerative diseases of the elderly has attracted increased research attention. This article reviews the primary mechanisms of pyroptosis and summarizes progress in the research of degenerative diseases of the elderly such as presbycusis, age-related macular degeneration, Alzheimers disease, intervertebral disc degeneration, and osteoarthritis.

Comorbidity among inpatients with dementia a preliminary cross-sectional study in West China.

To investigate comorbidities among hospitalized patients with dementia. Data were extracted from the discharge records in our hospital. Comorbidities based on ICD-10 were selected from the Charlson Comorbidity Index (CCI) and Elixhauser Comorbidity Index (ECI). The distributions of these comorbidities were described in dementia inpatients and age- and sex-matched nondementia controls, as well as in inpatients with Alzheimers disease and vascular dementia. A logistic regression model was applied to identify dementia-specific morbid conditions. A total of 3355 patients with dementia were included, with a majority of 1503 (44.8%) having Alzheimers disease, 395 (11.8%) with vascular dementia, and 441 (13.1%) with mixed dementia. The mean number of comorbidities was 3.8 in dementia patients (vs. 2.9 in controls). The most prevalent comorbidities in inpatients with dementia compared with those without dementia were cerebral vascular disease (73.0% vs. 35.9%), hypertension (62.8% vs. 56.2%), and peripheral vascular disease (53.7% vs. 31.2%). Comorbidities associated with dementia included epilepsy (OR 4.8, 95% CI 3.5-6.8), cerebral vascular disease (OR 4.1, 95% CI 3.7-4.5), depression (OR 4.0, 95% CI 3.2-5.0), uncomplicated diabetes (OR 1.5, 95% CI 1.4-1.7), peripheral vascular disease (OR 1.8, 95% CI 1.6-2.0), rheumatoid arthritis collagen vascular disease (OR 1.7, 95% CI 1.3-2.3), and anemia (OR 1.2, 95% CI 1.04-1.3). Some comorbidities suggested a protective effect against dementia. They were hypertension (OR 0.8, 95% CI 0.7-0.9), COPD (OR 0.6, 95% CI 0.5-0.6), and solid tumor without metastasis (OR 0.4, 95% CI 0.3-0.4). Vascular dementia has more cardiovascular and cerebrovascular comorbidities than Alzheimers disease. Patients with dementia coexisted with more comorbidities than those without dementia. Comorbidities (esp. cardio-cerebral vascular risks) in patients with vascular dementia were more than those in patients with AD. Specifically, vascular and circulatory diseases, epilepsy, diabetes and depression increased the risk of dementia.

The Study of Muscle, Mobility and Aging (SOMMA). A Unique Cohort Study about the Cellular Biology of Aging and Age-related Loss of Mobility.

The Study of Muscle, Mobility and Aging (SOMMA) aims to understand the biological basis of many facets of human aging, with a focus on mobility decline, by creating a unique platform of data, tissues, and images. The multidisciplinary SOMMA team includes two clinical centers (University of Pittsburgh and Wake Forest University), a biorepository (Translational Research Institute at Advent Health), and the San Francisco Coordinating Center (California Pacific Medical Center Research Institute). Enrollees were age ≥70 years, able to walk ≥0.6 ms (4 meters) able to complete 400m walk, free of life-threatening disease, and had no contraindications to magnetic resonance or tissue collection. Participants are followed with 6-month phone contacts and annual in-person exams. At baseline, SOMMA collected biospecimens (muscle and adipose tissue, blood, urine, fecal samples) a variety of questionnaires physical and cognitive assessments whole-body imaging (magnetic resonance and computed tomography) accelerometry and cardiopulmonary exercise testing. Primary outcomes include change in walking speed, change in fitness, and objective mobility disability (able to walk 400m in 15 min and change in 400m speed). Incident events, including hospitalizations, cancer diagnoses, fractures, and mortality are collected and centrally adjudicated by study physicians. SOMMA exceeded its goals by enrolling 879 participants, despite being slowed by the COVID-19 pandemic 59.2% women mean age 76.3±5.0 years (range 70-94) mean walking speed 1.04±0.20 ms 15.8% identify as other than Non-Hispanic White. Over 97% had data for key measurements. SOMMA will provide the foundation for discoveries in the biology of human aging and mobility.

Associations of height loss with cognitive decline and incident dementia in adults aged 50 years and older.

Associations of the rate of height loss (RHL) with cognitive decline and dementia in middle-aged and older adults have not been examined. This study included 3610 participants aged 50 years and older from the English Longitudinal Study of Ageing. Standing height was measured with standardized protocols. RHL was estimated as annualized percentage of height loss (% per year) during waves 0-4, and was categorized into slow (< 0.1%), medium (≥ 0.1% and < 0.2%), and fast (≥ 0.2%). Associations between RHL and cognitive decline and incident dementia were analyzed using mixed-effects models and Cox regression models, respectively (waves 5-9). There were 283 individuals identified with incident dementia over a mean follow-up of 7.21 years. Compared with participants in slow group, those in medium coefficient (β) -0.016, 95% confidence interval (CI) -0.023 to -0.009 and fast groups (β -0.030, 95% CI -0.039 to -0.021) had faster declines in cognition. Faster height loss was also associated with increased risks of incident dementia medium vs. slow, hazard ratio (HR) 1.37, 95% CI 1.03 to 1.81 fast vs. slow, HR 1.75, 95% CI 1.29 to 2.37. Besides, associations of RHL with cognitive decline were stronger in females than in males. Our findings indicated that rapid RHL was associated with faster declines in cognition and elevated risks of dementia. RHL may serve as an early marker of progressed neurodegeneration in middle-aged and older adults.

Nicotinic acetylcholine receptors Key targets for attenuating neurodegenerative diseases.

Nicotinic acetylcholine receptors (nAChRs) are master regulators of immune functions via the cholinergic anti-inflammatory pathway and are expressed in microglia, the brains resident immune cells. There is an extensive dialogue between the neurons and the glial cells around them from which microglia are tasked with monitoring, nurturing, and defending their microenvironment. Dysregulation of any of these processes can have devastating and long-lasting consequences involving microglia-mediated neuroinflammation associated with neurodegenerative diseases such as Alzheimers disease, Parkinsons disease, and Huntingtons disease, amongst others. Disease-associated microglia acquire a distinguishing phenotype that emphasizes scavenging and defence functions while nurturing and repairing functions become muted. Attempts to resolve this critical imbalance remain a key focus of research. Furthermore, cholinergic modulation of neuroinflammation represents a promising avenue for treatment.

The kynurenine pathway in Alzheimers Disease A meta-analysis of central and peripheral levels.

Alterations in the kynurenine pathway are recognized in psychiatric disorders, but their role in Alzheimers Disease (AD) is less clear. We aimed to conduct a systematic review and meta-analysis to verify if tryptophan and the metabolites of the kynurenine pathway are altered in AD. We performed a systematic review and random-effects meta-analyses. Inclusion criteria were studies having subjects with AD compared to cognitively normal (CN) subjects and assessing tryptophan or metabolites of the kynurenine pathway in cerebrospinal fluid (CSF) or peripheral blood. Twenty-two studies with 1,356 participants (664 with AD and 692 CN individuals) were included. Tryptophan was decreased only in peripheral blood. The kynurenine to tryptophan ratio was increased in AD in peripheral blood only. 3-hydroxykynurenine was decreased only in CSF and showed higher variability in CN individuals than in those with AD. Kynurenic acid was increased in CSF and decreased in peripheral blood. Finally, there were no alterations in kynurenine and quinolinic acid between individuals with AD and those CN. Our results hinted a shift toward the kynurenine pathway in both the brain and in the periphery, and also a shift towards the production of kynurenic acid in the brain and a decrease in peripheral blood. In addition, our analysis indicated a dissociation between the central and peripheral levels, as well as between plasma and serum of some of these metabolites. Finally, alterations in the kynurenine pathway appear to be a core component in AD. More studies are warranted to verify and consolidate our results.

Thioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimers disease.

A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid β (Aβ

Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimers disease.

Apolipoprotein (apo) E4 sets the stage for neuropathology in Alzheimers disease (AD) by causing mitochondrial dysfunction and altering mitochondria-associated membranes. Contact and apposition of mitochondrial-endoplasmic reticulum membranes are enhanced in brain cells in AD and associated with increases in tethering and spacing proteins that modulate many cellular processes. Contact site protein levels are higher in apoE4 cells. In apoE4 neurons, the NAD

Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality.

Microtubule-associated protein tau is essential for microtubule assembly and stabilization. Hyperphosphorylation of the microtubule-associated protein tau plays an important pathological role in the development of Alzheimers disease and other tauopathies.

Risk of Discharge to Lower-Quality Nursing Homes Among Hospitalized Older Adults With Alzheimer Disease and Related Dementias.

Individuals with Alzheimer disease and related dementias (ADRD) frequently require skilled nursing facility (SNF) care following hospitalization. Despite lower SNF incentives to care for the ADRD population, knowledge on how the quality of SNF care differs for those with vs without ADRD is limited. To examine whether persons with ADRD are systematically admitted to lower-quality SNFs. Cross-sectional analysis of Medicare beneficiaries hospitalized between January 1, 2017, and December 31, 2019, was conducted. Data analysis was performed from January 15 to May 30, 2022. Participants were discharged to a Medicare-certified SNF from a general acute hospital. Patients younger than 65 years, enrolled in Medicare Advantage, and with prior SNF or long-term nursing home use within 1 year of hospitalization were excluded. The quality level of all SNFs available at the patients discharge, measured using publicly reported 5-star staffing ratings. The 5-star ratings were grouped into 3 levels (1-2 stars reference category, low-quality, 3 stars average-quality, and 4-5 stars high-quality). The outcome was the SNF a patient entered among the possible SNF destinations available at discharge. Differences in the association between SNF quality and SNF entry for patients with and without ADRD were assessed using a conditional logit model, which simultaneously controls for differences in discharging hospital, residential neighborhood, and the other characteristics (eg, postacute care specialization) of all SNFs available at discharge. The sample included 2 619 464 patients (mean SD age, 81.3 8.6 years 61% women 87% were White 8% were Black 22% with ADRD). The probability of discharge to higher quality SNFs was lower for patients with ADRD. If the star rating of an SNF was high instead of low, the log-odds of being discharged to it increased by 0.31 for patients with ADRD and by 0.47 for those without ADRD (difference, -0.16 P < .001). The weaker association between quality and entry for patients with ADRD indicates that they are less likely to be discharged to high-quality SNFs. The findings of this study suggest that patients with ADRD are more likely to be discharged to lower-quality SNFs. Targeted reforms, such as ADRD-specific compensation adjustments, may be needed to improve access to better SNFs for patients with ADRD.

Particulate matter and ultrafine particles in urban air pollution and their effect on the nervous system.

According to the World Health Organization, both indoor and urban air pollution are responsible for the deaths of around 3.5 million people annually. During the last few decades, the interest in understanding the composition and health consequences of the complex mixture of polluted air has steadily increased. Today, after decades of detailed research, it is well-recognized that polluted air is a complex mixture containing not only gases (CO, NO

AD-Syn-Net systematic identification of Alzheimers disease-associated mutation and co-mutation vulnerabilities via deep learning.

Alzheimers disease (AD) is one of the most challenging neurodegenerative diseases because of its complicated and progressive mechanisms, and multiple risk factors. Increasing research evidence demonstrates that genetics may be a key factor responsible for the occurrence of the disease. Although previous reports identified quite a few AD-associated genes, they were mostly limited owing to patient sample size and selection bias. There is a lack of comprehensive research aimed to identify AD-associated risk mutations systematically. To address this challenge, we hereby construct a large-scale AD mutation and co-mutation framework (AD-Syn-Net), and propose deep learning models named Deep-SMCI and Deep-CMCI configured with fully connected layers that are capable of predicting cognitive impairment of subjects effectively based on genetic mutation and co-mutation profiles. Next, we apply the customized frameworks to data sets to evaluate the importance scores of the mutations and identified mutation effectors and co-mutation combination vulnerabilities contributing to cognitive impairment. Furthermore, we evaluate the influence of mutation pairs on the network architecture to dissect the genetic organization of AD and identify novel co-mutations that could be responsible for dementia, laying a solid foundation for proposing future targeted therapy for AD precision medicine. Our deep learning model codes are available open access here httpsgithub.comPan-BioAD-mutation-effectors.

Remembering a life an examination of open-ended life stories and the reminiscence bump in patients with Alzheimers disease.

Autobiographical memory impairments are prominent in Alzheimers disease (AD). Yet, life narratives of AD patients are scarcely examined. Here, twenty-one older adults diagnosed with probably AD and 22 age-matched healthy controls told their life story, and dated the events mentioned in these narratives. AD patients provided significantly fewer life story memories overall, but the proportion of memories with reference to specific events did not differ between groups. Patients included fewer negative events in their life story, while the emotional tone of narratives was similar across groups. Impairments were found on most structural aspects, with patients narratives being less coherent and ending somewhere in the past, while no differences were seen for life story beginnings. Both groups showed a peak in remembered events dated to young adulthood, consistent with a reminiscence bump. However, in contrast to controls, patients displayed a steep drop in life story memories after the age of 30. For both groups, a high proportion of memories within the bump period were of life script events, consistent with the idea that the life script helps to structure the recall of personal life story memories, thus suggesting that AD patients still benefit from the retrieval support of this semantic structure.

Four-dimensional proteomics analysis of human cerebrospinal fluid with trapped ion mobility spectrometry using PASEF.

A quadrupole time-of-flight mass spectrometer coupled with a trapped ion mobility spectrometry (timsTOF) operated in parallel accumulation-serial fragmentation (PASEF) mode has recently emerged as a platform capable of providing four dimensional (4D) features comprising of elution time, collision cross section (CCS), mass-to-charge ratio and intensity of peptides. The PASEF mode provides ∼100% ion sampling efficiency both in data-dependent acquisition (DDA) and data-independent acquisition (DIA) modes without sacrificing sensitivity. In addition, targeted measurements using PASEF integrated parallel reaction monitoring (PRM) mode have also been described. However, only limited number of studies have used timsTOF for analysis of clinical samples. Although Orbitrap mass spectrometers have been used for biomarker discovery from cerebrospinal fluid (CSF) in a variety of neurological diseases, these Orbitrap-derived datasets cannot readily be applied for driving experiments on timsTOF mass spectrometers. We generated a catalog of peptides and proteins in human CSF in DDA mode on a timsTOF mass spectrometer and used these data to build a spectral library. This strategy allowed us to use elution times and ion mobility values from the spectral library to design PRM experiments for quantifying previously discovered biomarkers from CSF samples in Alzheimers disease. When the same samples were analyzed using a DIA approach combined with a spectral library search, a higher number of proteins were identified than in a library-free approach. Overall, we have established a spectral library of CSF as a resource and demonstrated its utility for PRM and DIA studies, which should facilitate studies of neurological disorders. This article is protected by copyright. All rights reserved.

The Role of Ketogenic Diet in the Treatment of Neuroblastoma.

The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimers disease, Parkinsons disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumor in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.

Inhibiting tau protein improves the recovery of spinal cord injury in rats by alleviating neuroinflammation and oxidative stress.

After spinal cord injury, the concentrations of total and hyperphosphorylated tau in cerebrospinal fluid increase, and levels of both correlate with injury severity. Tau inhibition is considered effective therapy for many central nervous system diseases, including traumatic brain injury and Alzheimers disease. However, whether it can play a role in the treatment of spinal cord injury remains unclear. In this study, the therapeutic effects of tau inhibition were investigated in a rat model of transection spinal cord injury by injecting the rats with a lentivirus encoding tau siRNA that inhibits tau expression. We found that tau inhibition after spinal cord injury down-regulated the levels of inflammatory mediators, including tumor necrosis factor-α, interleukin-6 and interleukin-1β. It also led to a shift of activated microglial polarization from the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype, and reduced the amount of reactive oxygen species in the acute phase. Furthermore, the survival of residual neural cells around the injury epicenter, and neuronal and axonal regeneration were also markedly enhanced, which promoted locomotor recovery in the model rats. Collectively, our findings support the conclusion that tau inhibition can attenuate neuroinflammation, alleviate oxidative stress, protect residual cells, facilitate neurogenesis, and improve the functional recovery after spinal cord injury, and thus suggest that tau could be a good molecular target for spinal cord injury therapy.

Death-associated protein kinase 1 is associated with cognitive dysfunction in major depressive disorder.

We previously showed that death-associated protein kinase 1 (DAPK1) expression is increased in hippocampal tissue in a mouse model of major depressive disorde and is related to cognitive dysfunction in Alzheimers disease. In addition, depression is a risk factor for developing Alzheimers disease, as well as an early clinical manifestation of Alzheimers disease. Meanwhile, cognitive dysfunction is a distinctive feature of major depressive disorder. Therefore, DAPK1 may be related to cognitive dysfunction in major depressive disorder. In this study, we established a mouse model of major depressive disorder by housing mice individually and exposing them to chronic, mild, unpredictable stressors. We found that DAPK1 and tau protein levels were increased in the hippocampal CA3 area, and tau was hyperphosphorylated at Thr231, Ser262, and Ser396 in these mice. Furthermore, DAPK1 shifted from axonal expression to overexpression on the cell membrane. Exercise and treatment with the antidepressant drug citalopram decreased DAPK1 expression and tau protein phosphorylation in hippocampal tissue and improved both depressive symptoms and cognitive dysfunction. These results indicate that DAPK1 may be a potential reason and therapeutic target of cognitive dysfunction in major depressive disorder.

Alzheimers disease with sleep insufficiency a cross-sectional study on correlations among clinical characteristics, orexin, its receptors, and the blood-brain barrier.

Previous studies have shown that reduced sleep duration, sleep fragmentation, and decreased sleep quality in patients with Alzheimers disease are related to dysfunction in orexin signaling. At the same time, blood-brain barrier disruption is considered an early biomarker of Alzheimers disease. However, currently no report has examined how changes in orexin signaling relate to changes in the blood-brain barrier of patients who have Alzheimers disease with sleep insufficiency. This cross-sectional study included 50 patients with Alzheimers disease who received treatment in 2019 at Beijing Tiantan Hospital. Patients were divided into two groups those with insufficient sleep (sleep duration ≤ 6 hours, n 19, age 61.58 ± 8.54 years, 10 men) and those with normal sleep durations (sleep duration > 6 hours, n 31, age 63.19 ± 10.09 years, 18 men). Demographic variables were collected to evaluate cognitive function, neuropsychiatric symptoms, and activities of daily living. The levels of orexin, its receptor proteins, and several blood-brain barrier factors were measured in cerebrospinal fluid. Sleep insufficiency was associated with impaired overall cognitive function that spanned multiple cognitive domains. Furthermore, levels of orexin and its receptors were upregulated in the cerebrospinal fluid, and the blood-brain barrier was destroyed. Both these events precipitated each other and accelerated the progression of Alzheimers disease. These findings describe the clinical characteristics and potential mechanism underlying Alzheimers disease accompanied by sleep deprivation. Inhibiting the upregulation of elements within the orexin system or preventing the breakdown of the blood-brain barrier could thus be targets for treating Alzheimers disease.

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations lessons from recent clinical trials.

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimers disease, Huntingtons disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinsons disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review. Two long-term, controlled trials on three anti-β-amyloid monoclonal antibodies (solanezumab, gantenerumab and crenezumab) in subjects carrying Alzheimers disease-linked mutated genes encoding for amyloid precursor protein or presenilin 1 or presenilin 2 failed to show cognitive or functional benefits. A major trial on tominersen, an antisense oligonucleotide designed to reduce the production of the huntingtin protein in subjects with Huntingtons disease, was prematurely interrupted because the drug failed to show higher efficacy than placebo and, at highest doses, led to worsened outcomes. A 28-week trial of tofersen, an antisense oligonucleotide for superoxide dismutase 1 in patients with amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutations failed to show significant beneficial effects but the 1-year open label extension of this study indicated better clinical and functional outcomes in the group with early tofersen therapy. A trial of venglustat, a potent and brain-penetrant glucosylceramide synthase inhibitor, in Parkinsons disease subjects with heterozygous glucocerebrosidase gene mutations revealed worsened clinical and cognitive performance of patients on the enzyme inhibitor compared to placebo. We concluded that clinical trials in neurodegenerative diseases with a genetic basis should test monoclonal antibodies, antisense oligonucleotides or gene editing directed against the mutated enzyme or the mutated substrate without dramatically affecting physiological wild-type variants.

Immortalized hippocampal astrocytes from 3xTg-AD mice, a new model to study disease-related astrocytic dysfunction a comparative review.

Alzheimers disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD, emphasizing the urgent need for a comprehensive understanding of cell-specific pathology. Astrocytes, principal homeostatic cells of the central nervous system, are key players in the pathogenesis of neurodegenerative diseases, including AD. Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways. Tumor-derived and immortalized astrocytic cell lines, alongside the emerging technology of adult induced pluripotent stem cells, are widely used to study cellular dysfunction in AD. Surprisingly, no stable cell lines were available from genetic mouse AD models. Recently, we established immortalized hippocampal astroglial cell lines from amyloid-β precursor proteinpresenilin-1Tau triple-transgenic (3xTg)-AD mice (denominated as wild type (WT)- and 3Tg-iAstro cells) using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection, thereby maintaining natural heterogeneity of primary cultures. Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling, mitochondrial dysfunctions, disproteostasis, altered homeostatic and signaling support to neurons, and blood-brain barrier models. Here we provide a comparative overview of the most used models to study astrocytes in vitro, such as primary culture, tumor-derived cell lines, immortalized astroglial cell lines, and induced pluripotent stem cell-derived astrocytes. We conclude that immortalized WT- and 3Tg-iAstro cells provide a non-competitive but complementary, low-cost, easy-to-handle, and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery.

The transient receptor potential melastatin 2 a new therapeutical target for Parkinsons disease

The transient receptor potential melastatin 2 is a calcium-permeable cation channel member of the TRP family. Also known as an oxidative stress-activated channel, the transient receptor potential melastatin 2 gating mechanism is dependent on reactive oxygen species. In pathological conditions, transient receptor potential melastatin 2 is overactivated, leading to a Ca

Mesenchymal stem cell- and extracellular vesicle-based therapies for Alzheimers disease progress, advantages, and challenges.

Alzheimers disease is a severe, highly disabling neurodegenerative disease, clinically characterized by a progressive decline in cognitive functions, and is the most common form of dementia in the elderly. For decades, the search for disease-modifying therapies has focused on the two main Alzheimers disease histopathological hallmarks, seeking to prevent, mitigate, or clear the formation of extracellular aggregates of β-amyloid peptide and intracellular neurofibrillary tangles of tau protein, although without clinical success. Mesenchymal stem cell-based therapy has emerged as a promising alternative for the treatment of Alzheimers disease, especially because it also targets other crucial players in the pathogenesis of the disease, such as neuroinflammation, synaptic dysfunctionloss, oxidative stress, and impaired neurogenesis. Herein, we review current knowledge of the therapeutic potential of mesenchymal stem cells and their extracellular vesicles for Alzheimers disease, discussing the most recent findings in both preclinical and clinical trials as well as how advanced technologies have helped to overcome some limitations and contributed to stimulate the development of more effective treatments.

The effects of endurance exercise and metformin on memory impairment caused by diabetes.

Diabetes has a negative effect on learning and memory performance, and it is a risk factor for Alzheimers disease and dementia development. The present study aims to investigate the effects of two kinds of endurance exercise including high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) as well as metformin on impaired memory and learning related to streptozotocin (STZ) induced diabetes in rats. Forty adult male rats (250 ± 20 g weight) were divided into five groups (n8), including control, diabetic, as well as diabetic rats treated with metformin (300 mgkg), and HIIT (20 mmin), and MICT (15 mmin) exercises. Diabetes was induced by STZ (60 mgkg, i.p.). Serum glucose concentration and oxidative stress markers (SOD, CAT, thiol, and MDA) in the cortex and hippocampus were determined by colorimetric assay. Behavioral tests were performed with a passive avoidance test. The diabetic groups treated with metformin and both HIIT, and MICT exercises improved the latency and the staying time in the darkroom and lightroom. The entrance frequency into the darkroom also was restored (p<0.01-p<0.001). In both HIIT and MICT exercises as well as metformin groups the oxidative stress induced by diabetes has been reversed and attenuation of the serum glucose level has been observed compared to non-treated diabetic ones (p<0.05-p<0.001). The results of the present study revealed both HIIT and MICT exercises had protective effects against oxidative stress and behavioral impairments induced by diabetes and these effects were comparable to the effects of metformin.

Maintaining Continuity of Self as Perceived by People in the Early Stages of Dementia A Qualitative Study.

The purpose of this study is to shed light on the sense of self that occurs among those who have been diagnosed with the early stages of dementia, where the individual attempts to maintain continuity within their world. The research was conducted using qualitative induction research methods and data were collected using semi-structured interview methods. The data were reported according to COnsolidated criteria for REporting Qualitative research (COREQ). The diagnosis was Alzheimers disease for all participants. Of the 15 participants, 6 were male and 9 female. The average age was 69.9 years. For those with the early stages of dementia, a sense of self that attempts to maintain continuity for the world in which they live is made up of the following living in the present while connecting to the past, relying on those that help to connect and fill in the gaps between the past, present, and very near future, and living daily life in ones own world where past and present are connected. By understanding the sense of self that those who are diagnosed with the early stages of dementia experience while trying to maintain continuity within their world, one is able to get closer to their world and it is hoped that this may provide hints as to how to offer support in the future.

Idiopathic normal pressure hydrocephalus and frontotemporal dementia an unexpected association.

Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimers disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (

Myeloid Cells As a Promising Target for Brain-Bone Degenerative Diseases from a Metabolic Point of View.

Brain and bone degenerative diseases such as Alzheimers disease and osteoporosis are common in the aging population and lack efficient pharmacotherapies. Myeloid cells are a diverse group of mononuclear cells that plays important roles in development, immune defense, and tissue homeostasis. Aging drastically alters the expansion and function of myeloid cells, which might be a common pathogenesis of the brain-bone degenerative diseases. From this perspective, the role of myeloid cells in brain-bone degenerative diseases is discussed, with a particular focus on metabolic alterations in myeloid cells. Furthermore, targeting myeloid cells through metabolic regulation via drugs such as metformin and melatonin is proposed as a potential therapy for the clinical treatment of brain-bone diseases.

Initial levels of β-amyloid and tau deposition have distinct effects on longitudinal tau accumulation in Alzheimers disease.

To better assist with the design of future clinical trials for Alzheimers disease (AD) and aid in our understanding of the diseases symptomatology, it is essential to clarify what roles β-amyloid (Aβ) plaques and tau tangles play in longitudinal tau accumulation inside and outside the medial temporal lobe (MTL) as well as how age, sex, apolipoprotein E (APOE) ε4 (APOE-ε4), and Klotho-VS heterozygosity (KL-VS We divided the 325 Aβ PET-positive (A) participants into two groups, AT- (N 143) and AT (N 182), based on the threshold (1.25) of the temporal meta-ROI 18F-flortaucipir (FTP) standardized uptake value ratio (SUVR). We then compared the baseline and slopes of AT- and AT individuals Aβ plaques and temporal meta-ROI tau tangles with those of A-T- cognitively unimpaired individuals (N 162) without neurodegeneration. In addition, we looked into how baseline Aβ and tau may predict longitudinal tau increases and how age, sex, APOE-ε4, and KL-VS In entorhinal, amygdala, and parahippocampal (early tau-deposited regions of temporal meta-ROI), we found that baseline Aβ and tau deposition were positively linked to more rapid tau increases in AT- participants. However, in AT individuals, the longitudinal tau accumulation in fusiform, inferior temporal, and middle temporal cortices (late tau-deposited regions of temporal meta-ROI) was primarily predicted by the level of tau tangles. Furthermore, compared to older participants (age ≥ 65), younger individuals (age < 65) exhibited faster Aβ-dependent but slower tau-related tau accumulations. Additionally, compared to the KL-VS These findings offer novel perspectives to the design of AD clinical trials and aid in understanding the tau accumulation inside and outside MTL in AD. In particular, decreasing Aβ plaques might be adequate for AT- persons but may not be sufficient for AT individuals in preventing tau propagation and subsequent downstream pathological changes associated with tau.

The dynamics of plasma biomarkers across the Alzheimers continuum.

Failures in drug trials strengthen the necessity to further determine the neuropathological events during the development of Alzheimers disease (AD). We sought to investigate the dynamic changes and performance of plasma biomarkers across the entire Alzheimers continuum in the Chinese population. Plasma amyloid-β (Αβ)42, Aβ40, Aβ42Aβ40, phosphorylated tau (p-tau)181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured utilizing the ultrasensitive single-molecule array technology across the AD continuum (n206), wherein Aβ status was defined by the values of cerebrospinal fluid (CSF) Aβ42 or Aβ positron emission tomography (PET). Their trajectories were compared with those of putative CSF biomarkers. Plasma GFAP and p-tau181 increased only in Aβ-positive individuals throughout aging, whereas NfL increased with aging regardless of Aβ status. Among the plasma biomarkers studied, GFAP was the one that changed first. It had a prominent elevation early in the cognitively unimpaired (CU) AT- phase (CU AT- phase 97.10±41.29 pgml CU A-T- phase 49.18±14.39 pgml p<0.001). From preclinical to symptomatic stages of AD, plasma GFAP started to rise sharply as soon as CSF Aβ became abnormal and continued to increase until reaching its highest level during the AD dementia phase. The greatest slope of change was seen in plasma GFAP. This is followed by CSF p-tau181 and total-tau, and, to a lesser extent, then plasma p-tau181. In contrast, the changes in plasma NfL, Aβ42Aβ40, Aβ42, and Aβ40 were less pronounced. Of note, these plasma biomarkers exhibited smaller dynamic ranges than their CSF counterparts, except for GFAP which was the opposite. Plasma GFAP and p-tau181 were tightly associated with AD pathologies and amyloid tracer uptake in widespread brain areas. Plasma GFAP could accurately identify CSF Aβ42 (area under the curve (AUC)0.911) and Aβ PET (AUC0.971) positivity. Plasma p-tau181 also performed well in discriminating Aβ PET status (AUC0.916), whereas the discriminative accuracy was relatively low for other plasma biomarkers. This study is the first to delineate the trajectories of plasma biomarkers throughout the Alzheimers continuum in the Chinese population, providing important implications for future trials targeting plasma GFAP to facilitate AD prevention and treatment.

Development and validation of care stress management scale in family caregivers for people with Alzheimer a sequential-exploratory mixed-method study.

Caring for a person with Alzheimers disease is stressful for caregivers. So that, considering all the emotional and financial costs imposed on the families of Alzheimers patients, stress from caring is an issue that cannot be ignored and plans need to be developed to help these caregivers to manage the care properly. The current study was designed to develop a valid and reliable care stress management scale for family caregivers of patients with Alzheimers. This study is a methodological study with a sequential-exploratory mixed-method approach that was performed in two-phase develop the caring stress management scale and evaluate the psychometric properties of the scale. In the first phase, 14 semi-structured face-to-face interviews were performed with family caregivers of patients with Alzheimers. The interviews were transcribed immediately and an item pool with 275 items was prepared. After removing the duplicate or overlapping code, the initial format of the caring stress management scale (CSMS) was designed. In the second step, the items of the CSMS were evaluated using face and content validity. After that, the construct validity was evaluated using exploratory factor analysis, confirmatory factor analysis, and convergent and divergent validity respectively. Finally, the reliability was assessed by stability and internal consistency. The sample size was 435 and data was gathered via an online form questionnaire. This study designed the CSMS with two factors including emotional-focused coping (4 items) and problem-focused coping (4 items) that explained 51.00% of the total variance. The results of the confirmatory factor analysis showed a good model fit. Furthermore, the internal consistency and stability of this scale were acceptable. The results showed that the care stress management scale has two factors in Iranian family caregivers and it is valid and reliable and can be used by therapists and researchers.

Recent development in tau-sensitive tracers has sparkled significant interest in tracking tauopathies using positron emission tomography (PET) biomarkers. However, the ability of To analyze the topographical patterns of tau pathology in the living brains of patients with CBS using Of the 20 patients with CBS, 19 (95%) were negative for CSF biomarkers of amyloid pathology of them, three had negative In vivo

Rare variant aggregation in 148,508 exomes identifies genes associated with proxy dementia.

Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimers disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimers disease through rare variants. Here we show that a proxy Alzheimers diseasedementia phenotype can capture known Alzheimers disease risk genes through rare variant aggregation. We generated a proxy Alzheimers diseasedementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimers diseasedementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimers diseasedementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimers disease (SORL1, TREM2, and TOMM40APOE). We show that proxy Alzheimers diseasedementia can be used to identify genes associated with Alzheimers disease through rare variant aggregation.

Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis.

The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its amyloidogenic activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an amyloidolytic activity, whereby it degrades longer Aβ peptides into a non‑toxic Aβ34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and Aβ34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased Aβ34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Aβ34 levels. To align the role of γ-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-γ-secretase as the main γ-secretase that generates Aβ40 and Aβ42 peptides serving as substrates for BACE1s amyloidolytic cleavage to generate Aβ34.

Complement in the Brain Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation.

The complement system is an ancient collection of proteolytic cascades with well-described roles in regulation of innate and adaptive immunity. With the convergence of a revolution in complement-directed clinical therapeutics, the discovery of specific complement-associated targetable pathways in the central nervous system, and the development of integrated multi-omic technologies that have all emerged over the last 15 years, precision therapeutic targeting in Alzheimer disease and other neurodegenerative diseases and processes appears to be within reach. As a sensor of tissue distress, the complement system protects the brain from microbial challenge as well as the accumulation of dead andor damaged molecules and cells. Additional more recently discovered diverse functions of complement make it of paramount importance to design complement-directed neurotherapeutics such that the beneficial roles in neurodevelopment, adult neural plasticity, and neuroprotective functions of the complement system are retained. Expected final online publication date for the

A shared decision-making model about care for people with severe dementia A qualitative study based on nutrition and hydration decisions in acute hospitals.

To understand the decision-making processes regarding eating and drinking for hospital patients with severe dementia and use this data to modify a decision-making model about care for people with severe dementia. From January to May 2021, qualitative semi-structured interviews were conducted with 29 family carers and hospital staff in England who cared for people with severe dementia during hospital admissions. Interviews were transcribed verbatim and analysed using codebook thematic analysis. We demonstrated a modified decision-making model consisting of six stages of the decision-making process (i) identify a decision to be made (ii) exchange information and recognise emotions (iii) clarify values and preferences of all involved (iv) consider feasibility of each choice (v) share preferred choice and make a final decision and (vi) deliver the decision, monitor outcomes and renegotiation. From this study, decision-making needed to be shared among all people involved and address holistic needs and personal values of people with dementia and family carers. However, hospital staff often made assumptions about the persons ability to eat and drink without adequate consultation with family carers. The process was impacted by ward culture, professional practice, and legal framework, which might overlook cultural and personal beliefs of the persons and families. Treatment escalation plans could help inform stepwise treatments, create realistic expectations, and guide future decisions. Our decision-making model provides clear stages of decision-making processes and can be used to guide clinical practice and policy around care decisions for eating and drinking, which is often poorly supported.

The human islet amyloid polypeptide reduces hippocampal tauopathy and behavioral impairments in P301S mice without inducing neurotoxicity or seeding amyloid aggregation.

Recent evidence suggests that human islet amyloid polypeptide (h-IAPP) accumulates in the brains of Alzheimers disease (AD) patients and may interact with Aβ or microtubule associated protein tau to associate with the neurodegenerative process. Increasing evidence indicates a potential protective effect of h-IAPP against Aβ-induced neurotoxicity in AD mouse models. However, a direct therapeutic effect of h-IAPP supplementation on tauopathy has not been established. Here, we found that long-term h-IAPP treatment attenuated tau hyperphosphorylation levels and induced neuroinflammation and oxidative damage, prevented synaptic loss and neuronal degeneration in the hippocampus, and alleviated behavioral deficits in P301S transgenic mice (a mouse model of tauopathy). Restoration of insulin sensitization, glucoseenergy metabolism, and activated BDNF signaling also contributed to the underlying mechanisms. These findings suggest that seemly h-IAPP has promise for the treatment of neurodegenerative disorders with tauopathy, such as AD.

Structures of LRP2 reveal a molecular machine for endocytosis.

The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin) is representative of the phylogenetically conserved subfamily of giant LDL receptor-related proteins, which function in endocytosis and are implicated in diseases of the kidney and brain. Here, we report high-resolution cryoelectron microscopy structures of LRP2 isolated from mouse kidney, at extracellular and endosomal pH. The structures reveal LRP2 to be a molecular machine that adopts a conformation for ligand binding at the cell surface and for ligand shedding in the endosome. LRP2 forms a homodimer, the conformational transformation of which is governed by pH-sensitive sites at both homodimer and intra-protomer interfaces. A subset of LRP2 deleterious missense variants in humans appears to impair homodimer assembly. These observations lay the foundation for further understanding the function and mechanism of LDL receptors and implicate homodimerization as a conserved feature of the LRP receptor subfamily.

Extending genetic risk for Alzheimers disease from host to holobiont.

The gut microbiota is implicated in risk for Alzheimers disease (AD). A study in Science reports that depleting gut bacteria in mice with genetic risk for AD reduces neuropathology in a sex-dependent manner. This is reversed by administering short-chain fatty acids, suggesting that specific bacterial metabolites increase susceptibility to AD.

Abnormal

Since cholinergic dysfunction has been implicated in Alzheimers disease (AD), the effects of Aβ plaques on nicotinic acetylcholine receptors (nAChRs) α4β2 subtype, was studied using the transgenic 5xFAD mouse model of AD. Using the PET radiotracer

Alzheimers disease phenotypes show different sleep architecture.

Sleep-wake disturbances are a prominent feature of Alzheimers disease (AD). Atypical (non-amnestic) AD syndromes have different patterns of cortical vulnerability to AD. We hypothesized that atypical AD also shows differential vulnerability in subcortical nuclei that will manifest as different patterns of sleep dysfunction. Overnight electroencephalography monitoring was performed on 48 subjects, including 15 amnestic, 19 atypical AD, and 14 controls. AD was defined based on neuropathological or biomarker confirmation. We compared sleep architecture by visual scoring and spectral power analysis in each group. Overall, AD cases showed increased sleep fragmentation and N1 sleep compared to controls. Compared to atypical AD groups, typical AD showed worse N3 sleep dysfunction and relatively preserved rapid eye movement (REM) sleep. Results suggest differing effects of amnestic and atypical AD variants on slow wave versus REM sleep, respectively, corroborating the hypothesis of differential selective vulnerability patterns of the subcortical nuclei within variants. Optimal symptomatic treatment for sleep dysfunction in clinical phenotypes may differ. Alzheimers disease (AD) variants show distinct patterns of sleep impairment. Amnestictypical AD has worse N3 slow wave sleep (SWS) impairment compared to atypical AD. Atypical AD shows more rapid eye movement deficits than typical AD. Selective vulnerability patterns in subcortical areas may underlie sleep differences. Relatively preserved SWS may explain better memory scores in atypical versus typical AD.

Outcome measures for Alzheimers disease A global inter-societal Delphi consensus.

We aim to provide guidance on outcomes and measures for use in patients with Alzheimers clinical syndrome. A consensus group of 20 voting members nominated by 10 professional societies, and a non-voting chair, used a Delphi approach and modified GRADE criteria. Consensus was reached on priority outcomes (n 66), measures (n 49) and statements (n 37) across nine domains. A number of outcomes and measurement instruments were ranked for Cognitive abilities Functional abilitiesdependency Behavioural and neuropsychiatric symptoms Patient quality of life (QoL) Caregiver QoL Healthcare and treatment-related outcomes Medical investigations Disease-related life events and Global outcomes. This work provides indications on the domains and ideal pertinent measurement instruments that clinicians may wish to use to follow patients with cognitive impairment. More work is needed to develop instruments that are more feasible in the context of the constraints of clinical routine.

A discriminative event-based model for subtype diagnosis of sporadic Creutzfeldt-Jakob disease using brain MRI.

Sporadic Creutzfeldt-Jakob disease (sCJD) comprises multiple subtypes (MM1, MM2, MV1, MV2C, MV2K, VV1, and VV2) with distinct disease durations and spatiotemporal cascades of brain lesions. Our goal was to establish the ante mortem diagnosis of sCJD subtype, based on patient-specific estimates of the spatiotemporal cascade of lesions detected by diffusion-weighted magnetic resonance imaging (DWI). We included 488 patients with autopsy-confirmed diagnosis of sCJD subtype and 50 patients with exclusion of prion disease. We applied a discriminative event-based model (DEBM) to infer the spatiotemporal cascades of lesions, derived from the DWI scores of 12 brain regions assigned by three neuroradiologists. Based on the DEBM cascades and the prion protein genotype at codon 129, we developed and validated a novel algorithm for the diagnosis of the sCJD subtype. Cascades of MM1, MM2, MV1, MV2C, and VV1 originated in the parietal cortex and, following subtype-specific orderings of propagation, went toward the striatum, thalamus, and cerebellum conversely, VV2 and MV2K cascades showed a striatum-to-cortex propagation. The proposed algorithm achieved 76.5% balanced accuracy for the sCJD subtype diagnosis, with low rater dependency (differences in accuracy of ± 1% among neuroradiologists). Ante mortem diagnosis of sCJD subtype is feasible with this novel data-driven approach, and it may be valuable for patient prognostication, stratification in targeted clinical trials, and future therapeutics. Subtype diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) is achievable with diffusion MRI. Cascades of diffusion MRI abnormalities in the brain are subtype-specific in sCJD. We proposed a diagnostic algorithm based on cascades of diffusion MRI abnormalities and demonstrated that it is accurate. Our method may aid early diagnosis, prognosis, stratification in clinical trials, and future therapeutics. The present approach is applicable to other neurodegenerative diseases, enhancing the differential diagnoses.

Lecanemab (BAN2401) an anti-beta-amyloid monoclonal antibody for the treatment of Alzheimer disease.

Nearly a dozen monoclonal antibodies (mAbs) directed against beta-amyloid (Aβ) have been developed for the treatment of Alzheimer disease (AD), and most of these mAbs are undergoing clinical trials. Newer mAbs have targeted more specific Aβ types. Lecanemab Eisai has a high affinity for large and soluble Aβ protofibrils. Data from phase II clinical trials have suggested the possibility of a robust efficacy signal and manageable risk of amyloid-related imaging abnormalities (ARIAs). Lecanemab is currently being studied in phase III trials. This article briefly reviews mAbs that target Aβ in AD and discusses the biology, mechanism of action, and targets of lecanemab. mAbs that target Aβ are an important focus of therapeutic development for AD, with several soon to be considered for US Food and Drug Administration approval. The experience of aducanumab informs the development of other mAbs, such as lecanemab. One consideration is the conformation of Aβ targets. Targeting monomeric species has not resulted in robust clinical efficacy, whereas targeting Aβ in the form of oligomers, protofibrils, and plaques has shown evidence of slowing clinical decline. Another consideration is that mAbs will require safety monitoring for ARIAs.

Social cognition across bipolar disorder and behavioral variant frontotemporal dementia an exploratory study.

Bipolar Disorder type 1 (BD1) and behavioral variant frontotemporal dementia (bvFTD) share similar behavioral and cognitive symptoms, rendering the differential diagnosis between them a clinical challenge. We investigated the accuracy of social cognition measures to differentiate bvFTD from BD. We included three groups of participants early-onset BD1 (in remission, n 20), bvFTD (n 18), and cognitively healthy controls (HC, n 40), matched for age, schooling, and sex. All participants underwent cognitive assessment including the facial emotion recognition (FER) and the modified faux-pas tests, which assess mentalizing. Compared to HC, BD1, and bvFTD patients underperformed on both social cognition measures. BD1 and bvFTD did not differ on the FERs or faux pas tests total score, although bvFTD patients had significantly higher difficulties than BD1 to detect social faux-pas (p < 0.001, d 1.35). BD1 and bvFTD share deficits in the core social cognition functions. These findings should be considered in the development of tasks aiming to improve the clinical differentiation between both disorders.

Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms.

The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimers disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein.

Degradation of cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) using ozone process influencing factors and mechanism.

β-N-methylamino-L-alanine (BMAA), which has been considered as an environmental factor that caused amyotrophic lateral sclerosisparkinsonism-dementia complex (ALSPDC) or Alzheimers disease, could be produced by a variety of genera cyanobacteria. BMAA is widely present in water sources contaminated by cyanobacteria and may threaten human health through drinking water. Although oxidants commonly used in drinking water plants such as chlorine, ozone, hydrogen peroxide, and hydroxyl radicals have been shown to effectively degrade BMAA, there are limited studies on the mechanism of BMAA degradation by different oxidants, especially ozone. This work systematically explored the effectiveness of BMAA ozonation degradation, investigated the effect of the operating parameters on the effectiveness of degradation, and speculated on the pathways of BMAA decomposition. The results showed that BMAA could be quickly eliminated by ozone, and the removal rates of BMAA were nearly 100% in pure water, but the removal rates were reduced in actual water. BMAA was primarily degraded by direct oxidation of ozone molecules in acidic and near-neutral conditions, and indirect oxidation of •OH accounted for the main part under strong alkaline conditions. The pH value had a significant effect on the decomposition of BMAA, and the degradation rate of BMAA was fastest at near-neutral pH value. The degradation rates of TOC were significantly lower than that of BMAA, indicating that by-products were generated during the degradation process. Three by-products (M-H

Quantitative comparative analysis of amyloid PET images using three radiopharmaceuticals.

Amyloid positron emission tomography (PET) with F-18 florbetaben (FBB), F-18 flutemetamol (FMM), and F-18 florapronol (FPN) is being used clinically for the evaluation of dementia. These radiopharmaceuticals are commonly used to evaluate the accumulation of beta-amyloid plaques in the brain, but there are structural differences between them. We investigated whether there are any differences in the imaging characteristics. A total of 605 subjects were enrolled retrospectively in this study, including healthy subjects (HS) and patients with mild cognitive impairment or Alzheimers disease. Participants underwent amyloid PET imaging using one of the three radiopharmaceuticals. The PET images were analyzed visually and semi-quantitatively using a standardized uptake value ratio (SUVR). In addition, we calculated and compared the cut-off SUVR of the representative regions for each radiopharmaceutical that can distinguish between positive and negative scans. In the negative images of the HS group, the contrast between the white matter and the gray matter was high in the FMM PET images, while striatal uptake was relatively higher in the FPN PET images. The SUVR showed significant differences across the radiopharmaceuticals in all areas except the temporal lobe, but the range of differences was relatively small. Accuracy levels for the global cut-off SUVR to discriminate between positive and negative images were highest in FMM PET, with a value of 0.989. FBB PET also showed a high value of 0.978, while FPN PET showed a relatively low value of 0.901. Negative amyloid PET images using the three radiopharmaceuticals showed visually and quantitatively similar imaging characteristics except in the striatum. Binary classification using the cut-off of the global cortex showed high accuracy overall, although there were some differences between the three PET images.

A study of the relationship between serum uric acid levels and pain in patients with migraine.

Serum uric acid (SUA), the end product of purine metabolism acts as an antioxidant and is related to oxidative stress. It has been reported that SUA may be involved in the pathogenesis of neurodegenerative diseases including Alzheimer disease, Huntington disease, Parkinson disease, and multiple sclerosis. However, studies evaluating SUA levels in migraine are scarce. This study aimed to explore the relationship between pain characteristics and SUA levels in patients with migraine and compare SUA levels in migraine patients during a headache attack and headache-free period with those control groups. This prospective, cross-sectional study included 78 patients with migraine and 78 healthy subjects who were randomly selected from hospital personnel as the control group. Headache characteristics (duration of attack, pain intensity, and headache frequency) and sociodemographic features were recorded. The SUA level was measured once in the control group and twice in the migraine patients, during the migraine attack and headache-free periods. Although the SUA levels of the migraine group in the headache-free period were higher than those of the control group, the difference was not statistically significant. Gender was not significantly related to the change in SUA levels between the attack and headache-free period. When the correlation between age, duration of migraine, frequency, duration, and intensity of pain was evaluated the difference between SUA levels in female migraine patients was weakly correlated with headache intensity, whereas male patients had a moderate correlation. ( P < .05 R > 0.250, and R > 0.516, respectively). The difference in SUA level in the migraine attack period compared to the headache-free period showing a positive correlation with pain intensity suggested that SUA may have a role in migraine due to its antioxidant role.

Design of a Coumarin-Based Fluorescent Probe for Efficient

Amyloid-β (Aβ) is the core constituent protein of senile plaques, which is one of the key pathological hallmarks of Alzheimers disease (AD). Here we describe the design, synthesis, and evaluation of coumarin-derived small molecule fluorophores for Aβ imaging. By embedding the aromatic coumarin framework into π bridge of a push-pull chromophore, a novel fluorescence probe

Mechanistic Insight into the Inhibition of Choline Acetyltransferase by Proton Pump Inhibitors.

Various pharmacoepidemiological investigational studies have indicated that Proton Pump Inhibitors (PPIs) may increase the likelihood of developing Alzheimers disease (AD) and non-AD related dementias. Previously, we have reported the inhibition of the acetylcholine biosynthesizing enzyme choline acetyltransferase (ChAT) by PPIs, for which omeprazole, lansoprazole, and pantoprazole exhibited IC

Maitake Medicinal Mushroom, Grifola frondosa (Agaricomycetes), and Its Neurotrophic Properties A Mini-Review.

Neurodegeneration is one of the most common manifestations in an aging population. The occurrence of oxidative stress and neuroinflammation are the main contributors to the phenomenon. Neurologic conditions such as Alzheimers disease (AD) and Parkinsons disease (PD) are challenging to treat due to their irreversible manner as well as the lack of effective treatment. Grifola frondosa (Dicks. Fr.) S.F. Gray, or maitake mushroom, is believed to be a potential choice as a therapeutic agent for neurodegenerative diseases. G. frondosa is known to be a functional food that has a wide variety of medicinal purposes. Thus, this review emphasizes the neuroprotective effects and the chemical composition of G. frondosa. Various studies have described that G. frondosa can protect and proliferate neuronal cells through neurogenesis, antioxidative, anti-inflammatory, and anti-β-amyloid activities. The mechanism of action behind these therapeutic findings in various in vitro and in vivo models has also been intensively studied. In this mini review, we also summarized the chemical composition of G. frondosa to provide a better understanding of the presence of nutritional compounds in G. frondosa.

Impact of COVID‑19 infection in patients with neurodegenerative diseases with particular focus on Alzheimers and Parkinsons disease.

Neurodegenerative disorders (NDD) are chronic neurological diseases characterized by loss andor damage to neurons along with the myelin sheath, and patients are at higher risk of severe infection with the SARS‑CoV‑2. A comprehensive literature search was performed using relevant terms and inclusion‑exclusion criteria. Recent articles, subjects older than 50 years, and articles written in the English language were included, whereas letters to the editor and articles related to pregnant women were excluded from the review study. COVID‑19 appears to damage angiotensin‑II receptors which cause natural killer cells to lose the ability to clear virus‑infected cells, owing to worse outcomes in patients with NDD. COVID‑19 can worsen the symptoms of Alzheimers disease. In addition, COVID‑19 worsens drug‑responsive motor symptoms in Parkinsons disease (PD) and other symptoms like fatigue and urinary complaints. Vitamin D is essential in decreasing pro‑inflammatory and increasing anti‑inflammatory cytokines in ongoing COVID‑19 infections and reducing angiotensin receptors and, hence, decreasing COVID‑19 infection severity. Telemedicine shows promise for patients with NDD but is yet to overcome legal issues and personal barriers. COVID‑19 has a significant effect on neurodegenerative conditions, which appears partly to the nature of the NDD and the neuro‑invasive capabilities of the SARS‑CoV‑2. The protective role of vitamin D in patients with NDD further supports this hypothesis. Modifications in current health care, like the telemedicine platform, are required to address the increased risk of serious infection in this population. Further studies will be required to clarify conflicting reports in many fields.

Expectations and clinical meaningfulness of randomized controlled trials.

Alzheimers disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18-month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimers Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified.

Adult neurogenesis in Alzheimers disease.

Alzheimers disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD.

Congo Red-Derived Carbon Dots Simultaneously as Fluorescence Probe for Protein Aggregates, Inhibitor for Protein Aggregation, and Scavenger of Free Radicals.

The pathological aggregation of some proteins is claimed to be highly related to several human diseases, such as β-amyloid 1-42 (Aβ

Gene-SGAN a method for discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering.

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimers disease and brain endophenotypes associated with hypertension, from MRI and SNP data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-driven neuroimaging phenotypes.

Multi-region brain transcriptomes uncover two subtypes of aging individuals with differences in Alzheimer risk and the impact of

The heterogeneity of the older population suggests the existence of subsets of individuals which share certain brain molecular features and respond differently to risk factors for Alzheimers disease, but this population structure remains poorly defined. Here, we performed an unsupervised clustering of individuals with multi-region brain transcriptomes to assess whether a broader approach, simultaneously considering data from multiple regions involved in cognition would uncover such subsets. We implemented a canonical correlation-based analysis in a Discovery cohort of 459 participants from two longitudinal studies of cognitive aging that have RNA sequence profiles in three brain regions. 690 additional participants that have data in only one or two of these regions were used in the Replication effort. These clustering analyses identified two meta-clusters, MC-1 and MC-2. The two sets of participants differ primarily in their trajectories of cognitive decline, with MC-2 having a delay of 3 years to the median age of incident dementia. This is due, in part, to a greater impact of tau pathology on neuronal chromatin architecture and to broader brain changes including greater loss of white matter integrity in MC-1. Further evidence of biological differences includes a significantly larger impact of

Lost in space(s) multimodal neuroimaging of disorientation along the Alzheimers disease continuum.

Orientation is a fundamental cognitive faculty, allowing the behaving self to link hisher current state to their internal representations of the external world. Once exclusively linked to knowledge of the current place and present time, in recent years, the concept of orientation has evolved to include processing of social, temporal, and abstract relations. Concordantly with the growing focus on orientation, spatial disorientation has been increasingly recognized as a hallmark symptom of Alzheimers disease (AD). However, few studies have sought to explore disorientation along the AD continuum beyond the spatial domain. 51 participants along the AD continuum performed an orientation task in the spatial, temporal and social domains. Under functional magnetic resonance imaging (fMRI), participants determined which of two familiar placeseventspeople is geographicallychronologicallysocially closer to them, respectively. A series of analyses revealed disorientation along the AD-continuum to follow a three-way association between (1) orientation domain, (2) brain region, and (3) disease stage. Specifically, participants with MCI exhibited impaired spatio-temporal orientation and reduced task-evoked activity in temporoparietal regions, while participants with AD dementia exhibited impaired social orientation and reduced task-evoked activity in frontoparietal regions. Furthermore, these patterns of hypoactivation coincided with Default Mode Network (DMN) sub-networks, with spatio-temporal orientation activation overlapping DMN-C and social orientation with DMN-A. Finally, these patterns of disorientation-associated hypoactivations coincided with patterns of fluorodeoxyglucose (FDG) hypometabolism and cortical atrophy characteristic to AD-dementia. Taken together, our results suggest that AD may constitute a disorder of orientation, characterized by a biphasic process as (1) early spatio-temporal and (2) late social disorientation, concurrently manifesting in task-evoked and neurodegenerative changes in temporoparietal and parieto-frontal brain networks, respectively. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD.

Using Artificial Intelligence to Learn Optimal Regimen Plan for Alzheimers Disease.

Alzheimers Disease (AD) is a progressive neurological disorder with no specific curative medications. While only a few medications are approved by FDA (i.e., donepezil, galantamine, rivastigmine, and memantine) to relieve symptoms (e.g., cognitive decline), sophisticated clinical skills are crucial to optimize the appropriate regimens given the multiple coexisting comorbidities in this patient population. Here, we propose a study to leverage reinforcement learning (RL) to learn the clinicians decisions for AD patients based on the longitude records from Electronic Health Records (EHR). In this study, we withdraw 1,736 patients fulfilling our criteria, from the Alzheimers Disease Neuroimaging Initiative(ADNI) database. We focused on the two most frequent concomitant diseases, depression, and hypertension, thus resulting in five main cohorts, 1) whole data, 2) AD-only, 3) AD-hypertension, 4) AD-depression, and 5) AD-hypertension-depression. We modeled the treatment learning into an RL problem by defining the three factors (i.e., states, action, and reward) in RL in multiple strategies, where a regression model and a decision tree are developed to generate states, six main medications extracted (i.e., no drugs, cholinesterase inhibitors, memantine, hypertension drugs, a combination of cholinesterase inhibitors and memantine, and supplements or other drugs) are for action, and Mini-Mental State Exam (MMSE) scores are for reward. Given the proper dataset, the RL model can generate an optimal policy (regimen plan) that outperforms the clinicians treatment regimen. With the smallest data samples, the optimal-policy (i.e., policy iteration and Q-learning) gained a lesser reward than the clinicians policy (mean -2.68 and -2.76 Our results highlight the potential of using RL to generate the optimal treatment based on the patients longitude records. Our work can lead the path toward the development of RL-based decision support systems which could facilitate the daily practice to manage Alzheimers disease with comorbidities.

PolyAMiner-Bulk A Machine Learning Based Bioinformatics Algorithm to Infer and Decode Alternative Polyadenylation Dynamics from bulk RNA-seq data.

More than half of human genes exercise alternative polyadenylation (APA) and generate mRNA transcripts with varying 3 untranslated regions (UTR). However, current computational approaches for identifying cleavage and polyadenylation sites (CPASs) and quantifying 3UTR length changes from bulk RNA-seq data fail to unravel tissue- and disease-specific APA dynamics. Here, we developed a next-generation bioinformatics algorithm and application, PolyAMiner-Bulk, that utilizes an attention-based machine learning architecture and an improved vector projection-based engine to infer differential APA dynamics accurately. When applied to earlier studies, PolyAMiner-Bulk accurately identified more than twice the number of APA changes in an RBM17 knockdown bulk RNA-seq dataset compared to current generation tools. Moreover, on a separate dataset, PolyAMiner-Bulk revealed novel APA dynamics and pathways in scleroderma pathology and identified differential APA in a gene that was identified as being involved in scleroderma pathogenesis in an independent study. Lastly, we used PolyAMiner-Bulk to analyze the RNA-seq data of post-mortem prefrontal cortexes from the ROSMAP data consortium and unraveled novel APA dynamics in Alzheimers Disease. Our method, PolyAMiner-Bulk, creates a paradigm for future alternative polyadenylation analysis from bulk RNA-seq data.

Combination of Antidepressants and Antipsychotics as A Novel Treatment Option for Psychosis in Alzheimers Disease.

Psychotic symptoms are reported as one of the most common complications of Alzheimers disease (AD), affecting approximately half of AD patients, in whom they are associated with more rapid deterioration and increased mortality. Empiric treatments, namely first and second-generation antipsychotics, confer modest efficacy in AD patients with psychosis (ADP) and themselves increase mortality. A recent genome-wide meta-analysis and early clinical trials suggest the use and beneficial effects of antidepressants among ADP patients. This motivates our rationale for exploring their potential as a novel combination therapy option amongst these patients. We included University of Pittsburgh Medical Center (UPMC) electronic medical records (EMRs) of 10,260 AD patients from January 2004 and October 2019 in our study. Survival analysis was performed to assess the effects of the combination of antipsychotics and antidepressants on the mortality of these patients. To provide more valuable insights on the hidden mechanisms of the combinatorial therapy, a protein-protein interaction (PPI) network representing ADP was built, and network analysis methods were used to quantify the efficacy of these drugs on ADP. An indicator score combining the measurements on the separation between drugs and the proximity between the drugs and ADP was used to measure the effect of an antipsychotic-antidepressant drug pair against ADP. Our survival analyses replicated that antipsychotic usage is strongly associated with increased mortality in AD patients while the co-administration of antidepressants with antipsychotics showed a significant beneficial effect in reducing mortality. Our network analysis showed that the targets of antipsychotics and antidepressants are well-separated, and antipsychotics and antidepressants have similar proximity scores to ADP. Eight drug pairs, including some popular recommendations like AripiprazoleSertraline and other pairs not reported previously like IloperidoneMaprotiline showed higher than average indicator scores which suggest their potential in treating ADP via strong synergetic effects as seen in our study. Our proposed combinations of antipsychotics and antidepressants therapy showed a strong superiority over current antipsychotics treatment for ADP. The observed beneficial effects can be further strengthened by optimizing drug-pair selection based on our systems pharmacology analysis.

Linear and Nonlinear Effect of Years of Schooling, Sex, and Age on the CERAD-MX and Complementary Tasks in a Mexican Sample A Cross-Sectional Study.

Since evidence of adults cognition decline is based on standardized testing, we developed regression-based continuous norms by linear regression (LR) and nonlinear quantile regression (NQR) with years of schooling (YoS), age, and sex as covariates on the Mexican adaptation of the Consortium to Establish a Registry for Alzheimers Disease (CERAD-MX) and complementary tasks. 392 healthy, Spanish-speaking Mexican adults (50.25% women) aged 18-59 completed the 15 CERAD-MX cognitive tasks and complementary tasks. We used raw scores and examined YoS-related effects considering sex and age as covariates. For the NQR, we used calibrated scores for sex and age. While LR represents one line across the performance, NQR differentiated several nonlinear performance bands by quantiles. LR showed positive relationships between YoS and cognitive performance with a funnel variance pattern. Therefore, this relationship is better represented with NQR than LR. A small, but significant, negative effect of age was found for this age range (18-59 years). The band with fewer years of schooling (1-6) showed greater variability in the cognitive measures than those with more years of schooling (16-22). This study shows that NQR is useful for accurately positioning participants performance relative to their peers. NQR accounts more than LR for the inconsistent variability of cognitive performance as a function of YoS by identifying the variability according to YoS (low, medium, high). Thus, NQR represents an appropriate way to construct norms for the cognitive performance of adults.

Employing nanoparticle tracking analysis of salivary neuronal exosomes for early detection of neurodegenerative diseases.

Neurodegenerative diseases are a set of progressive and currently incurable diseases that are primarily caused by neuron degeneration. Neurodegenerative diseases often lead to cognitive impairment and dyskinesias. It is now well recognized that molecular events precede the onset of clinical symptoms by years. Over the past decade, intensive research attempts have been aimed at the early diagnosis of these diseases. Recently, exosomes have been shown to play a pivotal role in the occurrence and progression of many diseases including cancer and neurodegenerative diseases. Additionally, because exosomes can cross the blood-brain barrier, they may serve as a diagnostic tool for neural dysfunction. In this review, we detail the mechanisms and current challenges of these diseases, briefly review the role of exosomes in the progression of neurodegenerative diseases, and propose a novel strategy based on salivary neuronal exosomes and nanoparticle tracking analysis that could be employed for screening the early onset of neurodegenerative diseases.

Combined with UPLC-Triple-TOFMS-based plasma lipidomics and molecular pharmacology reveals the mechanisms of schisandrin against Alzheimers disease.

Alzheimers disease (AD), a type of neurodegeneration disease, is characterized by Aβ deposition and tangles of nerve fibers. Schisandrin is one of the main components of Fructus Schisandrae Chinensis. Researches showed that schisandrin can improve the cognitive impairment and memory of AD mice, but the specific mechanism has not been fully elucidated. The purpose of this study is to investigate the possible mechanism of schisandrin in improving AD pathology. The Morris water maze test was executed to detect spatial learning and memory. Ultra performance liquid chromatography-Triple time of flight mass spectrometry (UPLC-Triple-TOFMS)-based plasma lipidomics was used to study the changes of plasma lipids. Moreover, we measured the levels of protein and mRNA expression of APOE and ABCA1 in the rat brains and in BV2 microglia. Our study found that schisandrin could improve learning and memory, and reduce Aβ deposition in AD rats. Furthermore, we found that schisandrin can improve plasma lipid metabolism disorders. Therefore, we hypothesized schisandrin might act via LXR and the docking results showed that schisandrin interacts with LXRβ. Further, we found schisandrin increased the protein and mRNA expression of LXR target genes APOE and ABCA1 in the brain of AD rats and in BV2 microglia. Our study reveals the neuroprotective effect and mechanism of schisandrin improves AD pathology by activating LXR to produce APOE and ABCA1.

Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimers disease.

Alzheimers disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa, Grn and Ctsb in presence of amyloid-β oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell-cell interaction analyses reveal that perivascular SPP1 induces microglial phagocytic states in the hippocampus of a mouse model of AD. Altogether, we suggest a functional role for SPP1 in perivascular cells-to-microglia crosstalk, whereby SPP1 modulates microglia-mediated synaptic engulfment in mouse models of AD.