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Synthesis, in Vitro Cholinesterase Inhibition, Molecular Docking, DFT, and ADME Studies of Novel 1,3,4-Oxadiazole-2-Thiol Derivatives.

A series of 1,3,4-oxadiazole-2-thiol derivatives bearing various alkyl or aryl moieties were designed, synthesized, and characterized using modern spectroscopic methods to yield 17 compounds (6a-6q) that were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in the search for lead compounds for Alzheimers disease treatment (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC

Scan-Find-Scan-Model Discrete Site-Targeted Suppressor Design Strategy for Amyloid-β.

Alzheimers disease is undoubtedly the most well-studied neurodegenerative disease. Consequently, the amyloid-β (Aβ) protein ranks at the top in terms of getting attention from the scientific community for structural property-based characterization. Even after decades of extensive research, there is existing volatility in terms of understanding and hence the effective tackling procedures against the disease that arises due to the lack of knowledge of both specific target- and site-specific drugs. Here, we develop a multidimensional approach based on the characterization of the common static-dynamic-thermodynamic trait of the monomeric protein, which efficiently identifies a small target sequence that contains an inherent tendency to misfold and consequently aggregate. The robustness of the identification of the target sequence comes with an abundance of a priori knowledge about the length and sequence of the target and hence guides toward effective designing of the target-specific drug with a very low probability of bottleneck and failure. Based on the target sequence information, we further identified a specific mutant that showed the maximum potential to act as a destabilizer of the monomeric protein as well as enormous success as an aggregation suppressor. We eventually tested the drug efficacy by estimating the extent of modulation of binding affinity existing within the fibrillar form of the Aβ protein due to a single-point mutation and hence provided a proof of concept of the entire protocol.

Modifiable potential risk factors in familial and sporadic frontotemporal dementia.

Only a few studies have evaluated modifiable risk factors for frontotemporal dementia (FTD). Here, we evaluated several modifiable factors and their association with disease phenotype, genotype, and prognosis in a large study population including Finnish and Italian patients with FTD and control groups. In this case-control study, we compared the presence of several cardiovascular and other lifestyle-related diseases and education between Finnish and Italian patients with familial (n 376) and sporadic (n 654) FTD, between different phenotypes of FTD, and between a subgroup of Finnish FTD patients (n 221) and matched Finnish patients with Alzheimers disease (AD) (n 214) and cognitively healthy controls (HC) (n 100). Patients with sporadic FTD were less educated (p 0.042, B -0.560, 95% CI -1.101 to -0.019) and had more heart diseases (p < 0.001, OR 2.265, 95% CI 1.502-3.417) compared to patients with familial FTD. Finnish FTD patients were less educated (p 0.032, B 0.755, 95% CI 0.064-1.466) compared with AD patients. The Finnish FTD group showed lower prevalence of hypertension than the HC group (p 0.003, OR 2.162, 95% CI 1.304-3.583) and lower prevalence of hypercholesterolemia than in the HC group (p < 0.001, OR 2.648, 95%CI 1.548-4.531) or in the AD group (p < 0.001, OR 1.995, 95% CI 1.333-2.986). Within the FTD group, clinical phenotypes also differed regarding education and lifestyle-related factors. Our study suggests distinct profiles of several modifiable factors in the FTD group depending on the phenotype and familial inheritance history and that especially sporadic FTD may be associated with modifiable risk factors.

Dementia prevalence, a contextual factor associated with SARS-CoV-2 in veterans affairs community living centers.

Alzheimers disease and related dementias (ADRD) impact the diagnosis and infection control of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in nursing homes (NH) by influencing the behavior of residents and their caregivers. Health system data show an association between ADRD and SARS-CoV-2. Whether this association is present in NH populations remains unknown. How increased SARS-CoV-2 risk among residents with ADRD impacts the greater NH population also remains unknown. This retrospective cohort study used electronic health record data on Veterans residing in 133 Veterans Affairs Community Living Centers (CLC) and 15 spinal cord injury units from March 1, 2020 to December 13, 2020. We measured ADRD using diagnostic codes 12 months before an index SARS-CoV-2 test date for each resident. We used Poisson regression to determine the relative risk of SARS-CoV-2 for the highest quartile of facility ADRD prevalence versus the lowest, stratifying by individual ADRD status, and adjusting for covariates, with and without a random intercept to account for facility clustering. Across the study period, 15,043 residents resided in CLCs, 1952 (13.0%) had SARS-CoV-2, and 8067 (53.6%) had ADRD. There was an estimated 60% increased risk of SARS-CoV-2 in facilities with highest dementia prevalence versus lowest (relative risk, 1.6 95% confidence interval 0.95, 2.7). CLC residents had a greater likelihood of SARS-CoV-2 infection in facilities with greater ADRD prevalence. Facility characteristics other than ADRD prevalence may account for this association.

Association between human herpesvirus 6 (HHV-6) and cognitive function in the elderly population in Shenzhen, China.

Human herpesvirus 6 (HHV-6) is neurophilic, and its relationship with Alzheimers disease (AD) remains controversial. This study aimed to examine the relationships between HHV-6 and cognitive abilities in elderly people aged 60 years or above from communities in Shenzhen. We recruited participants from 10 community health service centers in Shenzhen. Participants were divided into case and control groups according to Mini-Mental State Examination (MMSE) scale standards and were included in this study with 11 matching based on sex and age (± 3 years). The HHV-6 gene was detected by real-time fluorescent quantitative PCR, and the HHV-6 copy number was quantified. A total of 580 participants (cases, n 290 controls, n 290), matched for gender and age was included in this study. A positive HHV-6 test was not associated with a significant difference in global cognitive performance (OR HHV-6 infection significantly associated with orientation, attention and calculation, and language in elderly individuals.

Cholinergic Senescence in the Ts65Dn Mouse Model for Down Syndrome.

Down syndrome (DS) induces a variable phenotype including intellectual disabilities and early development of Alzheimers disease (AD). Moreover, individuals with DS display accelerated aging that affects diverse organs, among them the brain. The Ts65Dn mouse is the most widely used model to study DS. Progressive loss of cholinergic neurons is one of the hallmarks of AD present in DS and in the Ts65Dn model. In this study, we quantify the number of cholinergic neurons in control and Ts65Dn mice, observing a general reduction in their number with age but in particular, a greater loss in old Ts65Dn mice. Increased expression of the m1 muscarinic receptor in the hippocampus counteracts this loss. Cholinergic neurons in the Ts65Dn mice display overexpression of the early expression gene c-fos and an increase in the expression of β-galactosidase, a marker of senescence. A possible mechanism for senescence induction could be phosphorylation of the transcription factor FOXO1 and its retention in the cytoplasm, which we are able to confirm in the Ts65Dn model. In our study, using Ts65Dn mice, we observe increased cholinergic activity, which induces a process of early senescence that culminates in the loss of these neurons.

Complement activation mainly mediates the association of heart rate variability and cognitive impairment in adults with obstructive sleep apnea without dementia.

The relationship between autonomic nervous system dysfunction measured by heart rate variability (HRV) and cognitive impairment in obstructive sleep apnea (OSA) patients is complex and still not well understood. We aimed to analyze the role of complement activation, Alzheimers disease (AD) biomarkers, and white matter hyperintensity (WMH) in modulating the association of HRV with cognitive performance. There were 199 subjects without dementia, including 42 healthy controls, 80 OSA patients with mild cognitive impairment (MCI), and 77 OSA patients without cognitive impairment. All participants who completed polysomnography, cognition, WMH volume, and 5-min HRV analysis were recorded during wakefulness and sleep periods. Neuron-derived exosome and astrocyte-derived exosome proteins were measured by ELISA kits. The OSA with MCI group were associated with a lower mean of standard deviations of R-R intervals for 5-min intervals (SDANN index) during wakefulness, standard deviation of the R-R interval (SDNN) during sleep stage and percentage of adjacent R-R intervals differing by more than 50 ms (PNN50) in each stage compared with OSA without MCI. The influence of HRV on cognition was partially mediated by complement activation (C5b-9 mediated a maximum of 51.21%), AD biomarkers, and WMH. Lower SDANN index and PNN50 during wakefulness and SDNN and PNN50 during sleep periods were found in OSA patients with MCI, suggesting potential vulnerability to autonomic and parasympathetic dysfunction. Complement activation, AD biomarkers, and WMH might partially mediate and interact with the influence of HRV on cognitive impairment in OSA patients. ChiCTR1900021544.

Reflections on Mentorship From Scientists and Mentors in an Alzheimers Disease Focused Research Training Program.

This paper presents reflections on mentorship from scientists and mentors of the National Institute on Aging (NIA)-funded Carolina Center on Alzheimers Disease and Minority Research (CCADMR). Using a network approach to mentoring, this program aims to increase the pipeline of underrepresented minority (URM) scientists studying Alzheimers disease (AD) disparities. Six mentors and five scientists participated in interviews. Thematic analysis identified recurring themes transcripts of mentors and scientists were compared. Most common thematic categories identified by mentors included experience interacting with scientists, goals as a mentor, recruitment of underrepresented minorities, scientists challenges, and programmatic qualities. The most mentioned categories by scientists were challenges, seminars, working with mentors, career development, and project experience. The CCADMR will use findings to enhance the experience and training methods for future grant years. Results can benefit other training programs focused on aging and AD.

Orthopedic Surgery Causes Gut Microbiome Dysbiosis and Intestinal Barrier Dysfunction in Prodromal Alzheimer Disease Patients A Prospective Observational Cohort Study.

To investigate gut microbiota and intestinal barrier function changes after orthopedic surgery in elderly patients with either normal cognition (NC) or a prodromal Alzheimer disease phenotype (pAD) comprising either subjective cognitive decline (SCD) or amnestic mild cognitive impairment (aMCI). Homeostatic disturbances induced by surgical trauma andor stress can potentially alter the gut microbiota and intestinal barrier function in elderly patients before and after orthopedic surgery. In this prospective cohort study, 135 patients were subject to preoperative neuropsychological assessment and then classified into NC (n40), SCD (n58), or aMCI (n37). Their gut microbiota, bacterial endotoxin (lipopolysaccharide), tight junction (TJ) protein, and inflammatory cytokines in blood were measured before surgery and on postsurgical day 1, 3, and 7 (or before discharge). The short-chain fatty acid (SCFA)-producing bacteria were lower while the gram-negative bacteria, lipopolysaccharide and TJ were higher preoperatively in both the SCD and aMCI (pAD) groups compared with the NC group. After surgery, a decrease in SCFA-producing bacteria, and an increase in both gram-negative bacteria and plasma claudin were significant in the pAD groups relative to the NC group. SCFA-producing bacteria were negatively correlated with TJ and cytokines in pAD patients on postsurgical day 7. Furthermore, surgery-induced perioperative metabolic stress and inflammatory responses were associated with gut microbiota alterations. Surgery exacerbates both preexisting microbiota dysbiosis and intestinal barrier dysfunction in pAD patients, all of which may be associated with systemic inflammation and, in turn, may lead to further cognitive deterioration.

Connectomic analysis of the

The circadian clock orchestrates daily changes in physiology and behavior to ensure internal temporal order and optimal timing across the day. In animals, a central brain clock coordinates circadian rhythms throughout the body and is characterized by a remarkable robustness that depends on synaptic connections between constituent neurons. The clock neuron network of Most organisms on Earth possess an internal timekeeping system which ensures that bodily processes such as sleep, wakefulness or digestion take place at the right time. These precise daily rhythms are kept in check by a master clock in the brain. There, thousands of neurons – some of which carrying an internal ‘molecular clock’ – connect to each other through structures known as synapses. Exactly how the resulting network is organised to support circadian timekeeping remains unclear. To explore this question, Shafer, Gutierrez et al. focused on fruit flies, as recent efforts have systematically mapped every neuron and synaptic connection in the brain of this model organism. Analysing available data from the hemibrain connectome project at Janelia revealed that that the neurons with the most important timekeeping roles were in fact forming the fewest synapses within the network. In addition, neurons without internal molecular clocks mediated strong synaptic connections between those that did, suggesting that ‘clockless’ cells still play an integral role in circadian timekeeping. With this research, Shafer, Gutierrez et al. provide unexpected insights into the organisation of the master body clock. Better understanding the networks that underpin circadian rhythms will help to grasp how and why these are disrupted in obesity, depression and Alzheimer’s disease.

Myelin loss in C9orf72 hexanucleotide expansion carriers.

The most frequent genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the hexanucleotide repeat expansion in C9orf72. An important neuropathological hallmark associated with this mutation is the accumulation of the phosphorylated form of TAR (trans-activation response element) DNA-binding protein 43 (pTDP-43). Glia plays a crucial role in the neurodegeneration observed in C9orf72-associated disorders. However, less is known about the role of oligodendrocytes (OLs). Here, we applied digital neuropathological methods to compare the expression pattern of glial cells in the frontal cortex (FrCx) of human post-mortem samples from patients with C9-FTLD and C9-FTLDALS, sporadic FTLD (sFTLD), and healthy controls (HCs). We also compared MBP levels in CSF from an independent clinical FTD cohort. We observed an increase in GFAP, and Iba1 immunoreactivity in C9 and sFTLD compared to controls in the gray matter (GM) of the FrCx. We observed a decrease in MBP immunoreactivity in the GM and white matter (WM) of the FrCx of C9, compared to HC and sFTLD. There was a negative correlation between MBP and pTDP-43 in C9 in the WM of the FrCx. We observed an increase in CSF MBP concentrations in C9 and sFTLD compared to HC. In conclusion, the C9 expansion is associated with myelin loss in the frontal cortex. This loss of MBP may be a result of oligodendroglial dysfunction due to the expansion or the presence of pTDP-43 in OLs. Understanding these biological processes will help to identify specific pathways associated with the C9orf72 expansion.

Waveform detection by deep learning reveals multi-area spindles that are selectively modulated by memory load.

Sleep is generally considered to be a state of large-scale synchrony across thalamus and neocortex however, recent work has challenged this idea by reporting isolated sleep rhythms such as slow oscillations and spindles. What is the spatial scale of sleep rhythms To answer this question, we adapted deep learning algorithms initially developed for detecting earthquakes and gravitational waves in high-noise settings for analysis of neural recordings in sleep. We then studied sleep spindles in non-human primate electrocorticography (ECoG), human electroencephalogram (EEG), and clinical intracranial electroencephalogram (iEEG) recordings in the human. Within each recording type, we find widespread spindles occur much more frequently than previously reported. We then analyzed the spatiotemporal patterns of these large-scale, multi-area spindles and, in the EEG recordings, how spindle patterns change following a visual memory task. Our results reveal a potential role for widespread, multi-area spindles in consolidation of memories in networks widely distributed across primate cortex. The brain processes memories as we sleep, generating rhythms of electrical activity called ‘sleep spindles’. Sleep spindles were long thought to be a state where the entire brain was fully synchronized by this rhythm. This was based on EEG recordings, short for electroencephalogram, a technique that uses electrodes on the scalp to measure electrical activity in the outermost layer of the brain, the cortex. But more recent intracranial recordings of people undergoing brain surgery have challenged this idea and suggested that sleep spindles may not be a state of global brain synchronization, but rather localised to specific areas. Mofrad et al. sought to clarify the extent to which spindles co-occur at multiple sites in the brain, which could shed light on how networks of neurons coordinate memory storage during sleep. To analyse highly variable brain wave recordings, Mofrad et al. adapted deep learning algorithms initially developed for detecting earthquakes and gravitational waves. The resulting algorithm, designed to more sensitively detect spindles amongst other brain activity, was then applied to a range of sleep recordings from humans and macaque monkeys. The analyses revealed that widespread and complex patterns of spindle rhythms, spanning multiple areas in the cortex of the brain, actually appear much more frequently than previously thought. This finding was consistent across all the recordings analysed, even recordings under the skull, which provide the clearest window into brain circuits. Further analyses found that these multi-area spindles occurred more often in sleep after people had completed tasks that required holding many visual scenes in memory, as opposed to control conditions with fewer visual scenes. In summary, Mofrad et al. show that neuroscientists had previously not appreciated the complex and dynamic patterns in this sleep rhythm. These patterns in sleep spindles may be able to adapt based on the demands needed for memory storage, and this will be the subject of future work. Moreover, the findings support the idea that sleep spindles help coordinate the consolidation of memories in brain circuits that stretch across the cortex. Understanding this mechanism may provide insights into how memory falters in aging and sleep-related diseases, such as Alzheimer’s disease. Lastly, the algorithm developed by Mofrad et al. stands to be a useful tool for analysing other rhythmic waveforms in noisy recordings.

Statistical power of transcriptome-wide association studies.

Transcriptome-Wide Association Studies (TWASs) have become increasingly popular in identifying genes (or other endophenotypes or exposures) associated with complex traits. In TWAS, one first builds a predictive model for gene expressions using an expression quantitative trait loci (eQTL) data set in stage 1, then tests the association between the predicted gene expression and a trait based on a large, independent genome-wide association study (GWAS) data set in stage 2. However, since the sample size of the eQTL data set is usually small and the coefficient of multiple determination (i.e.,

Angiotensin Receptor Blockers Are Associated With a Lower Risk of Progression From Mild Cognitive Impairment to Dementia.

Previous studies found that antihypertensive medications (AHMs) acting on the renin-angiotensin system had the potential to reduce the progression from mild cognitive impairment to dementia. However, it remains unclear whether this association differs between ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers. We conducted a retrospective cohort study in the Alzheimers Disease Neuroimaging Initiative among 403 participants with hypertension and mild cognitive impairment at baseline. Information on AHMs received during the follow-up period, including angiotensin receptor blockers, ACE inhibitors, beta-blockers, calcium channel blockers, and diuretics, were self-reported. Cox proportional hazards models adjusted for potential confounders were used in the time to event analysis with progression to dementia as outcome. Of the 403 participants, the mean (SD) age was 74.0 (7.3) years, 152 (37.7%) were female, 158 (39.2%) progressed to dementia over a median follow-up time of 3.0 years. Angiotensin receptor blockers were associated with a lower risk of progression to dementia as compared to ACE inhibitors (adjusted hazard ratio0.45 95% CI, 0.25-0.81 In patients with hypertension and mild cognitive impairment, angiotensin receptor blockers were associated with a lower risk of progression to dementia compared with ACE inhibitors and other classes of AHMs. Our findings may have important implications for clinical practice but still warrant further investigations in larger prospective cohorts or clinical trials.

Upregulation of ribosome complexes at the blood-brain barrier in Alzheimers disease patients.

The cerebrovascular-specific molecular mechanism in Alzheimers disease (AD) was investigated by employing comprehensive and accurate quantitative proteomics. Highly purified brain capillaries were isolated from cerebral gray and white matter of four AD and three control donors, and examined by SWATH (sequential window acquisition of all theoretical fragment ion spectra) proteomics. Of the 29 ribosomal proteins that were quantified, 28 (RPLP0, RPL4, RPL6, RPL7A, RPL8, RPL10A, RPL11, RPL12, RPL14, RPL15, RPL18, RPL23, RPL27, RPL27A, RPL31, RPL35A, RPS2, RPS3, RPS3A, RPS4X, RPS7, RPS8, RPS14, RPS16, RPS20, RPS24, RPS25, and RPSA) were significantly upregulated in AD patients. This upregulation of ribosomal protein expression occurred only in brain capillaries and not in brain parenchyma. The protein expression of protein processing and N-glycosylation-related proteins in the endoplasmic reticulum (DDOST, STT3A, MOGS, GANAB, RPN1, RPN2, SEC61B, UGGT1, LMAN2, and SSR4) were also upregulated in AD brain capillaries and was correlated with the expression of ribosomal proteins. The findings reported herein indicate that the ribosome complex, the subsequent protein processing and N-glycosylation-related processes are significantly and specifically upregulated in the brain capillaries of AD patients.

Network-based meta-analysis and the candidate gene association studies reveal novel ethnicity-specific variants in MFSD3 and MRPL43 associated with dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia in elderly people, following Alzheimers disease. Only three genes, SNCA (α-synuclein), APOE (apolipoprotein E), and GBA (glucosylceramidase), have been convincingly demonstrated to be associated with DLB. Here, we applied whole-genome sequencing to blood samples from 61 DLB patients and 45 cognitively normal controls. We used accumulation of candidate mutations to detect novel DLB-associated genes. Subsequent single nucleotide polymorphism (SNP) genotyping and association studies in a large number of samples from Japanese individuals revealed novel heterozygous variants in MFSD3 (rs143475431, c.888T>Ap.C296 n 5,421, p 0.00063) and MRPL43 (chr10102746730, c.241A>Cp.N81H n 4,782, p 0.0029). We further found that the MFSD3 variant increased plasma levels of butyrylcholinesterase (n 1,206, p 0.029). We believe that our findings will contribute to the understanding of DLB and provide insight into its pathogenic mechanism for future studies.

Striatal Blood-Brain Barrier Opening in Parkinsons Disease Dementia A Pilot Exploratory Study.

Parkinsons disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in β-amyloid uptake in the targeted region and no change in FDOPA PET. These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.

Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents.

Repositioning or repurposing drugs account for a substantial part of entering approval pipeline drugs, which indicates that drug repositioning has huge market potential and value. Computational technologies such as machine learning methods have accelerated the process of drug repositioning in the last few decades years. The repositioning potential of type 2 diabetes mellitus (T2DM) drugs for various diseases such as cancer, neurodegenerative diseases, and cardiovascular diseases have been widely studied. Hence, the related summary about repurposing antidiabetic drugs is of great significance. In this review, we focus on the machine learning methods for the development of new T2DM drugs and give an overview of the repurposing potential of the existing antidiabetic agents.

Novel insights into non-alcoholic fatty liver disease and dementia insulin resistance, hyperammonemia, gut dysbiosis, vascular impairment, and inflammation.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by multiple pathologies. The progression of dementia with NAFLD may be affected by various risk factors, including brain insulin resistance, cerebrovascular dysfunction, gut dysbiosis, and neuroinflammation. Many recent studies have focused on the increasing prevalence of dementia in patients with NAFLD. Dementia is characterized by cognitive and memory deficits and has diverse subtypes, including vascular dementia, Alzheimers dementia, and diabetes mellitus-induced dementia. Considering the common pathological features of NAFLD and dementia, further studies on the association between them are needed to find appropriate therapeutic solutions for diseases. This review summarizes the common pathological characteristics and mechanisms of NAFLD and dementia. Additionally, it describes recent evidence on association between NAFLD and dementia progression and provides novel perspectives with regard to the treatment of patients with dementia secondary to NAFLD.

Reassessment of Neuronal Tau Distribution in Adult Human Brain and Implications for Tau Pathobiology.

Tau is a predominantly neuronal, soluble and natively unfolded protein that can bind and stabilize microtubules in the central nervous system. Tau has been extensively studied over several decades, especially in the context of neurodegenerative diseases where it can aberrantly aggregate to form a spectrum of pathological inclusions. The presence of tau inclusions in the form of neurofibrillary tangles, neuropil threads and dystrophic neurites within senile plaques are essential and defining features of Alzheimers disease. The current dogma favors the notion that tau is predominantly an axonal protein, and that in Alzheimers disease there is a redistribution of tau towards the neuronal soma that is associated with the formation of pathological inclusions such as neurofibrillary tangles and neuropil threads. Using novel as well as previously established highly specific tau antibodies, we demonstrate that contrary to this overwhelmingly accepted fact, as asserted in numerous articles and reviews, in adult human brain, tau is more abundant in cortical gray matter that is enriched in neuronal soma and dendrites compared to white matter that is predominantly rich in neuronal axons. Additionally, in Alzheimers disease tau pathology is significantly more abundant in the brain cortical gray matter of affected brain regions compared to the adjacent white matter regions. These findings have important implications for the biological function of tau as well as the mechanisms involved in the progressive spread of tau associated with the insidious nature of Alzheimers disease.

CX3CR1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in Alzheimers disease.

Despite its identification as a key checkpoint regulator of microglial activation in Alzheimers disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood. Accumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFADCx3cr1 Disease progression in 5xFADCx3cr1 Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1

A novel simulation-based approach to training for recruitment of older adults to clinical trials.

The need to engage adults, age 65 and older, in clinical trials of conditions typical in older populations, (e.g. hypertension, diabetes mellitus, Alzheimers disease and related dementia) is exponentially increasing. Older adults have been markedly underrepresented in clinical trials, often exacerbated by exclusionary study criteria as well as functional dependencies that preclude participation. Such dependencies may further exacerbate communication challenges. Consequently, the evidence of what works in subject recruitment is less generalizable to older populations, even more so for those from racial and ethnic minority and low-income communities. To support capacity of research staff, we developed a virtual, three station simulation (Group Objective Structured Clinical Experience-GOSCE) to teach research staff communication skills. This 2-h course included a discussion of challenges in recruiting older adults skills practice with Standardized Participants (SPs) and faculty observer who provided immediate feedback and debrief to highlight best practices. Each learner had opportunities for active learning and observational learning. Learners completed a retrospective pre-post survey about the experience. SP completed an 11-item communication checklist evaluating the learner on a series of established behaviorally anchored communication skills (29). In the research staff survey, 92% reported the overall activity taught them something new 98% reported it provided valuable feedback 100% said they would like to participate again. In the SP evaluation there was significant variation the percent well-done of items by case ranged from 25-85%. Results from this pilot suggest that GOSCEs are a (1) acceptable (2) low cost and (3) differentiating mechanism for training and assessing research staff in communication skills and structural competency necessary for participant research recruitment.

Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion.

Hypoxic-ischemic injury has been linked with increased risk for developing Alzheimers disease (AD). The underlying mechanism of this association is poorly understood. Here, we report distinct roles for hypoxia-inducible factor-1α (Hif-1α) in the regulation of BACE1 and γ-secretase activity, two proteases involved in the production of amyloid-beta (Aβ). We have demonstrated that Hif-1α upregulates both BACE1 and γ-secretase activity for Aβ production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O

Effect of electroacupuncture on complement C1q and microglia phagocytosis in hippocampus of SAMP8 mice.

To observe the effect of electroacupuncture (EA) on the expression of Iba-1, complement C1q and CD68 in hippocampus of SAMP8 mice, so as to explore its mechanisms underlying improvement of Alzheimers disease (AD). Twenty-four male SAMP8 mice were randomly and equally divided into model and EA groups, and 12 SAMR1 mice were used as the control group. EA (2 Hz, 1.5-2.0 mA) was applied to Baihui (GV20), Dazhui(GV14) and Shen-shu(BL23) for 20 min once daily in the EA group, each course of treatment was 8 days, with an interval of 2 days between two courses, and the mice were treated for 3 courses. Morris water maze test was performed to assess the learning-memory ability of mice. The positive expression levels of Iba-1 and CD68 proteins in the hippocampus CA1 region were detected by immunohistochemistry. The mRNA and protein expression levels of Iba-1,C1q and CD68 in the hippocampus were detected by real-time PCR and Western blot, separately. Compared with the control group, the average escape latency of Morris water maze test was prolonged in the model group ( EA can improve the learning and memory ability of SAMP8 mice, which may be associated with its effect in inhibiting of complement C1q-dependent microglial phagocytosis in the hippocampus.

The association of depression and apathy with Alzheimers disease biomarkers in a cross-cultural sample.

Cross-cultural differences in the association between neuropsychiatric symptoms and Alzheimers disease (AD) biomarkers are not well understood. This study aimed to (1) compare depressive symptoms and frequency of reported apathy across diagnostic groups of participants with normal cognition (CN), mild cognitive impairment (MCI), and dementia, as well as ethnic groups of Hispanic Americans (HA) and European Americans (EA) (2) evaluate the relationship between depression and apathy with Aβ deposition and brain atrophy. Statistical analyses included ANCOVAs, chi-squared, nonparametric tests, correlations, and logistic regressions. Higher scores on the Geriatric Depression Scale (GDS-15) were reported in the MCI and dementia cohorts, while older age corresponded with lower GDS-15 scores. The frequency of apathy differed across diagnoses within each ethnicity, but not when comparing ethnic groups. Reduced volume in the rostral anterior cingulate cortex (ACC) significantly correlated with and predicted apathy for the total sample after applying false discovery rate corrections (FDR), controlling for covariates. The EA group separately demonstrated a significant negative relationship between apathy and superior frontal volume, while for HA, there was a relationship between rostral ACC volume and apathy. Apathy corresponded with higher Aβ levels for the total sample and for the CN and HA groups.

CSF phosphorylated tau as an indicator of subsequent tau accumulation.

We evaluated the relationship between baseline CSF p-tau181 and the rate of tau PET change in the temporal meta-ROI and entorhinal cortex (ERC) and how it varied by amyloid level (CSF Aβ42 or amyloid PET) among 143 individuals from the Mayo Clinic Study of Aging and Mayo Alzheimer Disease Research Center. Higher CSF p-tau181, lower CSF Aβ42, and higher amyloid PET levels were associated with faster rates of tau PET change in both the temporal meta-ROI and ERC. In the temporal meta-ROI, longitudinal tau PET accumulation occurred primarily in participants with abnormal biomarker levels and a diagnosis of dementia, which supports the hypothesis that tau aggregation begins later in the disease process. Compared to the temporal meta-ROI, the ERC showed greater change in tau PET in non-demented participants but less change in later disease stages, supporting ERC as a more sensitive marker of early tau PET changes but with less dynamic range over the disease spectrum. We found both amyloid and CSF p-tau181 were associated with rates of tau PET change but there were some differences in associations by region, amyloid biomarker, and disease stage.

Loss of SST and PV positive interneurons in the ventral hippocampus results in anxiety-like behavior in 5xFAD mice.

Neuropsychiatric symptoms, such as anxiety and depression often appear early in patients with Alzheimers disease (AD), and a comorbid, anxiety-like phenotype is also found in rodents with AD. However, the underlying mechanisms behind these conditions and potential therapeutic targets to treat them remain unclear. In this study, we used 5 familial AD mutations (5xFAD) mice that developed early amyloid β-amyloid deposition and related synaptic loss and memory deficits to identify a potential mechanism behind abnormally high anxiety levels observed in these subjects. We observed anxiety-like behavior in mice that had an excitatoryinhibitory (EI) imbalance in the ventral hippocampus (vHPC) of 5xFAD mice. Both the number of parvalbumin-positive (PV) and somatostatin-positive (SST) cells decreased in the ventral hippocampus of the subject 5xFAD mice, however, no reductions were observed in calretinin-positive cells. We found that selectively inhibiting vHPC pyramidal cells via hM4Di expression normalized anxiety-like behaviors and EI balance in 5xFAD mice. Finally, we found that the ventral hippocampus SST or PV neurons were activated through selectively expressed hM3Dq, which ameliorated anxiety-like behaviors and the synaptic EI imbalance of vCA1 in 5xFAD mice. These results determined that anxiety-like behaviors accompanied by hippocampal synaptic EI imbalance in 5xFAD mice are due to the loss of SST and PV interneurons in the vHPC. This provides a better understanding of high anxiety levels observed in patients with early-stage AD.

White matter lesions may be an early marker for age-related cognitive decline.

Research suggests that cerebral small vessel disease (CSVD), amyloid, and pTau contribute to age-related cognitive decline. It remains unknown how these factors relate to one another and how they jointly contribute to cognitive decline in normal aging. This project examines the association between these factors and their relationship to cognitive decline in cognitively unimpaired older adults without subjective cognitive decline. A total of 230 subjects with cerebrospinal fluid (CSF) Aß42, CSF pTau181, white matter lesions (WMLs) used as a proxy of CSVD, and cognitive scores from the Alzheimers Disease Neuroimaging Initiative were included. Associations between each factor and cognitive score were investigated using regression models. Furthermore, relationships between the three pathologies were also examined using regression models. At baseline, there was an inverse association between WML load and Aß42 (t -4.20, p <.001). There was no association between WML load and pTau (t 0.32, p 0.75), nor with Aß42 and pTau (t 0.51, p .61). Correcting for age, sex and education, baseline WML load was associated with baseline ADAS-13 scores (t 2.59, p .01) and lower follow-up executive functioning (t -2.84, p .005). Baseline Aß42 was associated with executive function at baseline (t 3.58, p<.004) but not at follow-up (t 1.05, p 0.30), nor with ADAS-13 at baseline (t -0.24, p 0.81) or follow-up (t 0.09, p 0.93). Finally, baseline pTau was not associated with any cognitive measure at baseline or follow-up. Both baseline Aß42 and WML load are associated with some baseline cognition scores, but only baseline WML load is associated with follow-up executive functioning. This finding suggests that WMLs may be one of the earliest clinical manifestations that contributes to future cognitive decline in cognitively healthy older adults. Given that healthy older adults with WMLs exhibit declines in cognitive functioning, they may be less resilient to future pathology increasing their risk for cognitive impairment due to dementia than those without WMLs.

AXS-05 an investigational treatment for Alzheimers disease-associated agitation.

Agitation is common in patients with Alzheimers disease (AD). Although nonpharmacologic de-escalation strategies are recommended as first-line treatment, medication is often needed to treat agitation. Currently, there are no FDA-approved medications for this indication. Psychotropics used to treat agitation include antipsychotics, which are notable for their efficacy but also their potential to cause serious side effects. AXS-05, a combination of dextromethorphan and bupropion, is currently being investigated for this indication. This review will discuss the pharmacology of AXS-05 and available clinical trial results from completed Phase I and Phase IIIII studies assessing the potential for this compound to treat agitation in patients with AD. Ongoing research investigating AXS-05 for this indication will also be highlighted. Resources used for this review include PubMed, Embase, clinicaltrials.gov, and literature available on the manufacturers website. Early released clinical trial data indicate that AXS-05 may be a useful option to treat agitation in patients with AD and that it appears to be generally well tolerated. AXS-05 may be especially helpful for patients with comorbid depression, when considering available data from separate phase III studies assessing the efficacy and safety of this compound in the treatment of depression.

Semiquantitative 3T Brain Magnetic Resonance Imaging for Dynamic Visualization of the Glymphatic-Lymphatic Fluid Transport System in Humans A Pilot Study.

Recently, a novel clearing system for interstitial solutes of the brain was described as a perivascular pathway named the glymphatic system. Furthermore, lymphatic vessels were found in the meninges to drain interstitial fluids. It is hypothesized that interstitial solutes, such as amyloid β, are firstly processed through the brain by the glymphatic system and secondly drained out of the brain by lymphatic vessels (glymphatic-lymphatic fluid transport system GLS). Since then, various neurological disorders, such as Alzheimer disease, have been associated with a dysfunction of the GLS. In the current study, we aimed to establish a clinical magnetic resonance imaging (MRI) study protocol for visualizing lymphatic vessels as part of the GLS in humans. More importantly, we aimed to describe the dynamic changes of a contrast agent in these lymphatic vessels over time. Twenty volunteers with an unremarkable neurologicalpsychiatric history were included in this 3T MRI study. Serial MRI sequence blocks were performed at 3 predefined time points (TPs) TP 1, precontrast MRI before administration of a gadolinium-based contrast agent (GBCA) TP 2, immediately post-GBCA (early ce-MRI) and TP 3, 60 minutes post-GBCA (late ce-MRI). Each MRI block contained the following sequences obtained in the same order whole-brain 3D T1-MPRAGE, whole-brain 3D T2-FLAIR, focused 2D T2-FLAIR, and whole-brain 3D T1-SPACE. Signal intensity (SI) in compartments of the GLS adjacent to the superior sagittal sinus, gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) was calculated by manually placed regions of interest. The time course of the signal intensities was examined by generalized linear mixed models. The data were adjusted for age, cognitive function (Montreal-Cognitive-Assessment test), and sleep quality (Pittsburgh Sleep Quality Index questionnaire). The GLS was best visualized in the 2D T2-FLAIR and 3D T1-SPACE sequences, enabling further SI measurement. In precontrast (TP 1), the SI within the GLS was significantly higher than in CSF and significantly lower than in GM and WM. In post-GBCA, a significant increase (TP 2) and decrease (TP 3), respectively, of the GLS SI values were noted (86.3 ± 25.2% increase and subsequent decrease by 25.4 ± 9% in the 3D T1-SPACE sequence). The SI values of CSF, GM, and WM did not change significantly between the 3 TPs. A clinical MRI study protocol was established for the visualization of lymphatic vessels as an important part of the GLS and therefore the brains clearing mechanism of interstitial solutes. Furthermore, dynamic changes in the GLS were described over time, possibly reflecting the clearing function of the GLS. This might constitute the basis for evaluating the GLS function in manifold neurological pathologies in the future.

Novel L-RNA Aptamer Controls

Guanine quadruplex (G4) structure is a four-stranded nucleic acid secondary structure motif with unique chemical properties and important biological roles. Amyloid precursor protein (APP) is an Alzheimers disease (AD)-related gene, and recently, we reported the formation of RNA G4 (rG4) at the 3UTR of

Amyloid, tau and metabolic PET correlates of cognition in early and late-onset Alzheimers disease.

Early-onset (age < 65) Alzheimers disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimers disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvianlanguage, frontalexecutive, occipitalvisuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimers disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimers disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimers disease across the broad spectrum of ages and clinical phenotypes in Alzheimers disease.

Molecular Simulations Reveal Distinct Energetic and Kinetic Binding Properties of

Tauopathies are a class of neurodegenerative disorders characterized by the accumulation of tau protein filaments in the brain. On the basis of isoforms with three or four microtubule-binding repeats (3R or 4R) that constitute tau filaments, tauopathies can be divided into 3R, 4R, and 3R4R tauopathies.

Antioxidant and copper-chelating power of new molecules suggested as multiple target agents against Alzheimers disease. A theoretical comparative study.

In this study, the scavenging activity against OOH radicals and the copper-chelating ability of two new synthesized molecules (named

Lamivudine, a reverse transcriptase inhibitor, rescues cognitive deficits in a mouse model of down syndrome.

An elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases. Down syndrome (DS) is the most common genetic disorder associated with intellectual disability and a genetic form of Alzheimers disease. For this reason, we hypothesized that treatment with reverse transcriptase inhibitors could ameliorate DS phenotypes. In this proof of concept study, we treated trisomic (Ts65Dn) mice, a model of DS, with lamivudine, a reverse transcriptase inhibitor. We detected a significant improvement of neurobehavioural phenotypes, and a complete rescue of the hippocampal-dependent recognition memory upon treatment with lamivudine. Despite clinical studies in patients with DS are warranted, this study lays the groundwork for a novel and actionable therapeutic approach.

Can the Montreal Cognitive Assessment and Mini-Mental State Examination detect cognitive decline in elderly patients with essential tremor

Older Adult Health Condition as a Moderator of How Middle-Aged Adults Ageist Attitudes and Aging Anxiety Relate to Their Compassion for and Emotional Distance from Older Adults.

Using Terror Management Theory and Social Identity Theory as frameworks, we examined whether the relationship of aging anxiety to compassion for and emotional distance from older adults was mediated by ageist attitudes and whether an older adults health condition moderated these relationships. Using an experimental design, 292 middle-aged adults (40-55 years) were assigned to read a description of an older adult with Alzheimers Disease (AD), prostate cancer, or who was healthy. The relationship of aging anxiety to compassion was mediated by ageist attitudes in both the AD and prostate cancer conditions. More ageist attitudes related to less compassion more strongly for unhealthy older adult conditions than for the healthy older adult condition as well as for the AD condition compared to the cancer condition. Ageist attitudes related to more emotional distance from the older adult with AD than the older adult with cancer. Older adults with AD may evoke a stronger relationship of ageist attitudes with emotions toward older adults. These findings extend previous research by examining middle-aged participants, a population often serving as caregivers to their aging relatives.

Protective effects of Liensinine, Isoliensinine, and Neferine on PC12 cells injured by amyloid-β.

Excessive accumulation of amyloid-β (Aβ) is the leading cause of Alzheimers disease (AD). Liensinine, Isoliensinine, and Neferine are main alkaloids in lotus seed embryos. In this paper, the protective effects of Liensinine, Isoliensinine, and Neferine on Aβ

N-Substituted Arylidene-3-(Methylsulfonyl)-2-Oxoimidazolidine-1-Carbohydrazide as Cholinesterase Inhibitors Design, Synthesis, and Molecular Docking Study.

The development of new enzyme inhibitors in degenerative brain diseases has gained more attention. Enzyme inhibitors play an effective role in controlling central nervous system diseases. For this purpose, a novel series of hydrazone derivatives containing imidazolidine ring aimed against Alzheimers disease (AD), have been designed and synthesized. The acetylcholinesterase (AChE) enzyme inhibitory activity of these compounds was investigated. The structures of the compounds were determined by IR,

Ketamine administration ameliorates anesthesia and surgery-induced cognitive dysfunction via activation of TRPV4 channel opening.

Perioperative neurocognitive disorder (PND) is a common complication associated with anesthesia and surgery in the elderly. The dysfunction of transient receptor potential vanilloid 4 (TRPV4) has been associated with a number of diseases, including Alzheimers disease. Given that ketamine can reportedly improve PNDs, the present study sought to determine whether ketamine-induced PND alleviation was mediated by activation of TRPV4 channel opening. A total of 120, 20-month-old male C57BL6 mice were randomly divided into five groups Vehicle, PND (tibial fracture surgery), PND ketamine (Ket), PND Ket HC-067047 (HC), and PND HC groups. Ketamine (0.5 mgkg) was administered intraperitoneally once a day for 3 days after surgery and HC-067047 (1 µmol2 µl), an antagonist of TRPV4, was administered via the left lateral ventricle 30 min before ketamine treatment. Superoxide dismutase (SOD), malondialdehyde (MDA), lipid peroxidation (LPO), IL-1β, IL-6, adenosine monophosphate-activated protein kinase (AMPK), NF-κB, TNF-α and IFN-β levels were determined 3 days after surgery. At 28 days after surgery, fear conditioning and novel object recognition were assessed, and Aβ1-42 levels were measured and ionized calcium binding adaptor molecule 1 (Iba1) staining was conducted on day 31 after surgery. The results revealed that ketamine administration upregulated total SOD activity, downregulated MDA and LPO content, mitigated phosphorylated (p)-NF-κB, TNF-α mRNA and IFN-β mRNA expression in the hippocampus, and promoted p-AMPK 3 days after surgery. Furthermore, it was found that ketamine increased both context- and tone-dependent fear conditioning, and the time spent exploring a novel object, and reduced Aβ peptide levels and microglial activation 30 days after surgery. Notably, these changes could be reversed by HC-067047 to a certain extent. In conclusion, ketamine improved PND in aged mice after tibial fracture surgery and the potential mechanism may involve activation of the TRPV4AMPKNF-κB signaling pathway.

Primary Sjögrens Syndrome Presenting with Rapidly Progressive Dementia A Case Report.

Rapidly progressive dementias (RPDs) are dementias that progress subacutely over a time period of weeks to months. Primary Sjögrens syndrome (pSS) is an autoimmune disease that can affect any organ system and may present with a wide range of clinical features that may mimic a plethora of medical conditions and, in rare cases, may manifest as RPD. We describe a unique case of pSS, in which rapidly progressive dementia (RPD) was the first disease manifestation, and the patients radiological and electroencephalogram findings were compatible with Creutzfeldt- Jakob disease (CJD). Here, we report a 58-year-old woman who presented with cognitive impairment rapidly deteriorating over the last 6 months prior to admission. Brain MRI and EEG were indicative of CJD. However, CSF 14-3-3 and tauphospho tau ratio were within normal limits and therefore alternative diagnoses were considered. Blood tests were significant for positive antinuclear antibodies, anti-ENA, and anti-SSA and a lip biopsy was consistent with pSS. The patient was started on intravenous steroids followed by oral prednisone taper, which prevented further deterioration. This rare case expands the spectrum of neurological manifestations in pSS and highlights the importance of considering pSS in the differential diagnosis of RPDs in order to avoid misdiagnosis and provide appropriate treatment in a timely fashion.

Effect of Simultaneous Dual-Task Training on Regional Cerebral Blood Flow in Older Adults with Amnestic Mild Cognitive Impairment.

No previous study has examined the effect of dual-task training using changes in regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT) as an outcome. This study aimed to examine the effects of simultaneous dual-task training of exercise and cognitive tasks on rCBF using SPECT in older adults with amnestic mild cognitive impairment (aMCI). In this non-randomized control trial, 40 older adults with aMCI participated from May 2016 to April 2018. Outpatients in the intervention group (n 22) underwent 24 sessions (12 months) of dualtask training twice a month for 60 mins per session. Participants in the control group (n 18) continued to have regular outpatient visits. The primary outcome was rCBF at baseline and after 12 months, which was compared in each group using the two-sample t-test. The secondary outcomes were the rate of reversion and conversion from aMCI after 12 months. Of the 22 participants in the intervention group, six dropped out therefore, 16 were included in the analysis. The intervention group showed more significant increases in rCBF in multiple regions, including the bilateral frontal lobes, compared with the control group. However, the rates of reversion or conversion from mild cognitive impairment (MCI) were not significantly different. Dual-task training for older adults with aMCI increased rCBF in the frontal gyrus but did not promote reversion from MCI to normal cognition. Future intervention studies, such as follow-up examinations after the intervention, are warranted to consider long-term prognosis.

Phytochemical based Modulation of Endoplasmic Reticulum Stress in Alzheimers Disease.

Alzheimers disease (AD) is a severe progressive neurodegenerative condition that shows misfolding and aggregation of proteins contributing to a decline in cognitive function involving multiple behavioral, neuropsychological, and cognitive domains. Multiple epi (genetic) changes and environmental agents have been shown to play an active role in ER stress induction. Neurodegeneration due to endoplasmic reticulum (ER) stress is considered one of the major underlying causes of AD. ER stress may affect essential cellular functions related to biosynthesis, assembly, folding, and post-translational modification of proteins leading to neuronal inflammation to promote AD pathology. Treatment with phytochemicals has been shown to delay the onset and disease progression and improve the well-being of patients by targeting multiple signaling pathways in AD. Phytochemicals protective effect against neuronal damage in AD pathology may be associated with the reversal of ER stress and unfolding protein response by enhancing the antioxidant and anti-inflammatory properties of the neuronal cells. Hence, pharmacological interventions using phytochemicals can be a potential strategy to reverse ER stress and improve AD management. Towards this, the present review discusses the role of phytochemicals in preventing ER stress in the pathology of AD.

Changes in Measures of Vestibular and Balance Function and Hippocampus Volume in Alzheimers Disease and Mild Cognitive Impairment.

To test the hypotheses that people with Alzheimers disease and mild cognitive impairment have increased frequency of vestibular impairments and decreased hippocampal volume compared with healthy age-matched controls. Retrospective, with some historical controls. Out-patient, tertiary care center. People with mild to moderate dementia diagnosed with Alzheimers disease and with mild cognitive impairment. Main Outcome Measures A standard clinical battery of objective tests of the vestibular system, and screening for balance available clinical diagnostic magnetic resonance imaging (MRIs) were reviewed and postprocessed to quantify the left and right hippocampal volumes utilizing both manual segmentation and computer automated segmentation. Study subjects (N 26) had significantly more vestibular impairments, especially on Dix-Hallpike maneuvers and cervical vestibular evoked myogenic potentials (cVEMP), than historical controls. No differences were found between mild and moderate dementia subjects. Independence on instrumental activities of daily living in subjects with age-normal balance approached statistical differences from subjects with age-abnormal balance. MRI data were available for 11 subjects. Subjects with abnormal cVEMP had significantly reduced left hippocampal MRIs using manual segmentation compared with subjects with normal cVEMP. The data from this small sample support and extend previous evidence for vestibular impairments in this population. The small MRI sample set should be considered preliminary evidence, and suggests the need for further research, with a more robust sample and high-resolution MRIs performed for the purpose of hippocampal analysis.

Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes.

Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult. We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. SORL1-LoF variants penetrance curves reached 100% (95% confidence interval 99-100%) by age 70 among APOE-ε4ε4 carriers only, compared with 56% 40-72% and 37% 26-51% in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data. We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.

Role of exosomes in the pathogenesis, diagnosis, and treatment of central nervous system diseases.

Central nervous system (CNS) diseases, such as multiple sclerosis, Alzheimers disease (AD), and Parkinsons disease (PD), affect millions of people around the world. Great efforts were put in disease related research, but few breakthroughs have been made in the diagnostic and therapeutic approaches. Exosomes are cell-derived extracellular vesicles containing diverse biologically active molecules secreted by their cell of origin. These contents, including nucleic acids, proteins, lipids, amino acids, and metabolites, can be transferred between different cells, tissues, or organs, regulating various intercellular cross-organ communications and normal and pathogenic processes. Considering that cellular environment and cell state strongly impact the content and uptake efficiency of exosomes, their detection in biological fluids and content composition analysis potentially offer a multicomponent diagnostic readout of several human diseases. Recently, studies have found that aberrant secretion and content of exosomes are closely related to the pathogenesis of CNS diseases. Besides, loading natural cargoes, exosomes can deliver drugs cross the blood brain barrier, making them emerging candidates of biomarkers and therapeutics for CNS diseases. In this review, we summarize and discuss the advanced research progress of exosomes in the pathological processes of several CNS diseases in regarding with neuroinflammation, CNS repair, and pathological protein aggregation. Moreover, we propose the therapeutic strategies of applying exosomes to the diagnosis, early detection, and treatment of CNS diseases.

Effects of Fibroblast Growth Factor 21 on Lactate Uptake and Usage in Mice with Diabetes-Associated Cognitive Decline.

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exerts beneficial effects on glucose and lipid metabolic homeostasis. However, the impact of FGF21 on type 1 diabetes-associated cognitive decline (DACD) and its mechanisms of action remain unclear. In this study, we aimed to evaluate the effects of FGF21 on lactate uptake and usage in a mouse model of streptozotocin-induced DACD. Six-week-old male C57BL6 mice were divided into the control, diabetic, and FGF21 (which received 2 mgkg recombinant human FGF21) groups. At the end of the treatment period, learning and memory performance, nuclear magnetic resonance-based metabonomics, and expressions of various hippocampal protein were analyzed to determine the efficacy of FGF21. The results showed that compared to the control mice, the diabetic mice had reduced long-term memory performance after the hyperglycemic insult decreased hippocampal levels of lactate dehydrogenase-B (LDH-B) activity, bioenergy metabolites, and monocarboxylate transporter 2 (MCT2) and increased lactate levels. Impaired phosphoinositide 3-kinase (PI3K) signaling was also observed in the diabetic mice. However, FGF21 treatment improved LDH-B activity, β-nicotinamide adenine dinucleotide, and ATP levels, and increased MCT2 expression and PI3K signaling pathway, which in turn improved the learning and memory defects. These findings demonstrated that the effects of FGF21 on DACD were associated with its ability to improve LDH-B-mediated lactate usage and MCT2-dependent lactate uptake. Further, these beneficial effects of FGF21 in the hippocampus were mediated by the PI3K signaling pathways.

Near-infrared light reduces glia activation and modulates neuroinflammation in the brains of diet-induced obese mice.

Neuroinflammation is a key event in neurodegenerative conditions such as Alzheimers disease (AD) and characterizes metabolic pathologies like obesity and type 2 diabetes (T2D). Growing evidence in humans shows that obesity increases the risk of developing AD by threefold. Hippocampal neuroinflammation in rodents correlates with poor memory performance, suggesting that it contributes to cognitive decline. Here we propose that reducing obesityT2D-driven neuroinflammation may prevent the progression of cognitive decline associated with AD-like neurodegenerative states. Near-infrared light (NIR) has attracted increasing attention as it was shown to improve learning and memory in both humans and animal models. We previously reported that transcranial NIR delivery reduced amyloid beta and Tau pathology and improved memory function in mouse models of AD. Here, we report the effects of NIR in preventing obesity-induced neuroinflammation in a diet-induced obese mouse model. Five-week-old wild-type mice were fed a high-fat diet (HFD) for 13 weeks to induce obesity prior to transcranial delivery of NIR for 4 weeks during 90-s sessions given 5 days a week. After sacrifice, brain slices were subjected to free-floating immunofluorescence for microglia and astrocyte markers to evaluate glial activation and quantitative real-time polymerase chain reaction (PCR) to evaluate expression levels of inflammatory cytokines and brain-derived neurotrophic factor (BDNF). The hippocampal and cortical regions of the HFD group had increased expression of the activated microglial marker CD68 and the astrocytic marker glial fibrillary acidic protein. NIR-treated HFD groups showed decreased levels of these markers. PCR revealed that hippocampal tissue from the HFD group had increased levels of pro-inflammatory interleukin (IL)-1β and tumor necrosis factor-α. Interestingly, the same samples showed increased levels of the anti-inflammatory IL-10. All these changes were attenuated by NIR treatment. Lastly, hippocampal levels of the neurotrophic factor BDNF were increased in NIR-treated HFD mice, compared to untreated HFD mice. The marked reductions in glial activation and pro-inflammatory cytokines along with elevated BDNF provide insights into how NIR could reduce neuroinflammation. These results support the use of NIR as a potential non-invasive and preventive therapeutic approach against chronic obesity-induced deficits that are known to occur with AD neuropathology.

HS3ST2 expression induces the cell autonomous aggregation of tau.

Heparan sulfates have long been known to intracellularly accumulate in Alzheimers disease neurons, where they colocalize with neurofibrillary tangles made of abnormally phosphorylated and aggregated tau protein. However, the reasons and consequences of the heparan sulfates accumulation in the Alzheimers cells are not yet well understood. Previously, we showed that the neural heparan sulfate 3-O-sulfotransferase HS3ST2 is critical for the abnormal phosphorylation of tau in Alzheimers disease-related tauopathy. Using cell models of tauopathy we showed that intracellular 3-O-sulfatated heparan sulfates interact with tau inducing its abnormal phosphorylation. However, it is unknown whether HS3ST2 expression induces the intracellular aggregation of tau in cells. Here, by using replicative pEBV plasmids, we engineered HEK293 cells to stably express HS3ST2 together with human tau carrying or not the P301S mutation. We show that HS3ST2 gain of function induces the cell autonomous aggregation of tau not only in cells expressing tau

A shared disease-associated oligodendrocyte signature among multiple CNS pathologies.

Alzheimers disease (AD) is a complex neurodegenerative disease, perturbing neuronal and non-neuronal cell populations. In this study, using single-cell transcriptomics, we mapped all non-immune, non-neuronal cell populations in wild-type and AD model (5xFAD) mouse brains. We identified an oligodendrocyte state that increased in association with brain pathology, which we termed disease-associated oligodendrocytes (DOLs). In a murine model of amyloidosis, DOLs appear long after plaque accumulation, and amyloid-beta (Aβ) alone was not sufficient to induce the DOL signature in vitro. DOLs could be identified in a mouse model of tauopathy and in other murine neurodegenerative and autoimmune inflammatory conditions, suggesting a common response to severe pathological conditions. Using quantitative spatial analysis of mouse and postmortem human brain tissues, we found that oligodendrocytes expressing a key DOL marker (SERPINA3NSERPINA3 accordingly) are present in the cortex in areas of brain damage and are enriched near Aβ plaques. In postmortem human brain tissue, the expression level of this marker correlated with cognitive decline. Altogether, this study uncovers a shared signature of oligodendrocytes in central nervous system pathologies.

Hsp multichaperone complex buffers pathologically modified Tau.

Alzheimers disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70Hsp90 machinery. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on Taus aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperonesubstrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative diseases.

Biological functions of kojic acid and its derivatives in medicine, cosmetics, and food industry Insights into health aspects.

This review traces the road leading to the demonstration of a variety of kojic acid chemical and biological properties. It illustrates the biological effects of several synthetic kojic acid derivatives. Besides the main capability of kojic acid to inhibit the activity of tyrosinase in melanin synthesis, the focus is also on antibacterial, antifungal, antiproliferative, anti-inflammatory, and other biological activities of kojic acid derivatives, which may be applicable in medicine. Kojic acid derivatives manifest antiparasitic effects and its metal complexes may serve as potential radioprotective agents. Several kojic acid derivatives exert antidiabetic therapeutic potential as nuclear peroxisome proliferator-activated receptor alphagamma dual agonists. Kojic acid derivatives show pancreatic lipase inhibitor properties and some of its derivatives are cognate ligands for the histamine H

Biofluid markers of blood-brain barrier disruption and neurodegeneration in Lewy body spectrum diseases A systematic review and meta-analysis.

Mixed evidence supports blood-brain barrier (BBB) dysfunction in Lewy body spectrum diseases. We compare biofluid markers in people with idiopathic Parkinsons disease (PD) and people with PD dementia (PDD) andor dementia with Lewy bodies (DLB), compared with healthy controls (HC). Seven databases were searched up to May 10, 2021. Outcomes included cerebrospinal fluid to blood albumin ratio (Q Of 13,949 unique records, 51 studies were meta-analyzed. Compared to HC, Q Biofluid markers suggest BBB disruption and neurodegenerative co-pathology involvement in common Lewy body diseases. Greater evidence of BBB breakdown was seen in Lewy body disease with cognitive impairment.

Selective Ablation of

Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimers disease are closely associated with mitochondrial dysfunction, increased reactive oxygen species, neuroinflammation, and astrogliosis. This study investigated the effects of decreased mitochondrial antioxidant response specifically in astrocytes on cognitive performance and neuronal function in C57BL6J mice using a tamoxifen-inducible astrocyte-specific knockout of manganese superoxide dismutase (aSOD2-KO), a mitochondrial matrix antioxidant that detoxifies superoxide generated during mitochondrial respiration. We reduced astrocyte SOD2 levels in male and female mice at 11-12 months of age and tested in an automated home cage (PhenoTyper) apparatus for diurnal patterns, spatial learning, and memory function at 15 months of age. aSOD2-KO impaired hippocampal-dependent spatial working memory and decreased cognitive flexibility in the reversal phase of the testing paradigm in males. Female aSOD2-KO showed no learning and memory deficits compared with age-matched controls despite significant reduction in hippocampal SOD2 expression. aSOD2-KO males further showed decreased hippocampal long-term potentiation, but paired-pulse facilitation was unaffected. Levels of d-serine, an NMDA receptor coagonist, were also reduced in aSOD2-KO mice, but female knockouts showed a compensatory increase in serine racemase expression. Furthermore, aSOD2-KO mice demonstrated increased density of astrocytes, indicative of astrogliosis, in the hippocampus compared with age-matched controls. These data demonstrate that reduction in mitochondrial antioxidant stress response in astrocytes recapitulates age-related deficits in cognitive function, d-serine availability, and astrogliosis. Therefore, improving astrocyte mitochondrial homeostasis may provide a therapeutic target for intervention for cognitive impairment in aging.

Ras Inhibitor Lonafarnib Rescues Structural and Functional Impairments of Synapses of Aβ

Alzheimers disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mgkg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Aβ

Primary Microglia Dysfunction or Microgliopathy A Cause of Dementias and Other Neurological or Psychiatric Disorders.

Microglia are unique cells in the central nervous system (CNS), being considered a sub-type of CNS macrophage. These cells monitor nearby micro-regions, having roles that far exceed immunological and scavengering functions, being fundamental for developing, protecting and maintaining the integrity of grey and white matter. Microglia might become dysfunctional, causing abnormal CNS functioning early or late in the life of patients, leading to neurologic or psychiatric disorders and premature death in some patients. Observations that the impairment of normal microglia function per se could lead to neurological or psychiatric diseases have been mainly obtained from genetic and molecular studies of Nasu-Hakola disease, caused by TYROBP or TREM2 mutations, and from studies of adult-onset leukoencephalopathy with axonal spheroids (ALSP), caused by CSF1R mutations. These classical microgliopathies are being named here Microgliopathy Type I. Recently, mutations in TREM2 have also been associated with Alzheimer Disease. However, in Alzheimer Disease TREM2 allele variants lead to an impaired, but functional TREM2 protein, so that patients do not develop Nasu-Hakola disease but are at increased risk to develop other neurodegenerative diseases. Alzheimer Disease is the prototype of the neurodegenerative disorders associated with these TREM2 variants, named here the Microgliopathies Type II. Here, we review clinical, pathological and some molecular aspects of human diseases associated with primary microglia dysfunctions and briefly comment some possible therapeutic approaches to theses microgliopathies. We hope that our review might update the interesting discussion about the impact of intrinsic microglia dysfunctions in the genesis of some pathologic processes of the CNS.

Progestogen-Mediated Neuroprotection in Central Nervous System Disorders.

Neuroactive steroids can be synthetic or endogenous molecules produced by neuronal and glial cells and peripheral glands. Examples include estrogens, testosterone, progesterone and its reduced metabolites such as 5α-dihydro-progesterone and allopregnanolone. Steroids produced by neurons and glia target the nervous system and are called neurosteroids. Progesterone and analog molecules, known as progestogens, have been shown to exhibit neurotrophic, neuroprotective, antioxidant, anti-inflammatory, glial modulatory, promyelinating, and remyelinating effects in several experimental models of neurodegenerative and injury conditions. Pleiotropic mechanisms of progestogens may act synergistically to prevent neuron degeneration, astrocyte and microglial reactivity, reducing morbidity and mortality. The aim of this review is to summarize the significant findings related to the actions of progesterone and other progestogens in experimental models and epidemiological and clinical trials of some of the most prevalent and debilitating chronic neurodegenerative disorders, namely, Alzheimers disease, Parkinsons disease, Huntingtons disease, amyotrophic lateral sclerosis, and multiple sclerosis. We evaluated progestogen alterations under pathological conditions, how pathology modifies their levels, as well as the intracellular mechanisms and glial interactions underlying their neuroprotective effects. Furthermore, an analysis of the potential of natural progestogens and synthetic progestins as neuroprotective and regenerative agents, when administered as hormone replacement therapy in menopause, is also discussed.

Disease severity and prefrontal cortex activation during obstacle negotiation among patients with Parkinsons disease Is it all as expected

Previous reports indicate that patients with Parkinsons disease (PD) activate the prefrontal cortex (PFC) during complex activities such as obstacle negotiation to compensate for impaired motor function. However, the influence of disease severity on PFC activation has not been systematically evaluated. Here, we examined the effects of disease severity on PFC activation during obstacle negotiation. 74 patients with PD (age 68.26 ± 7.54 yrs 62.2% men) were divided into three groups based on Hoehn and Yahr stages. All patients walked along an obstacle course while negotiating anticipated and unanticipated obstacles (longlow available response time) at heights of 50 mm and 100 mm. PFC activation was measured using functional near-infrared spectroscopy (fNIRS) and was compared between groups and tasks using mixed model analyses. Participants with more advanced PD (i.e., Hoehn Yahr 3) had higher PFC activation levels when negotiating anticipated obstacles, compared to participants with milder PD (i.e., Hoehn Yahr 1, 2) (p < 0.001). Moreover, higher LEDD correlated with higher prefrontal activation during the higher anticipated obstacle. In contrast, during the negotiation of unanticipated obstacles, the differences in PFC activation were not associated with disease severity in a linear manner. The present study suggests that with increased disease severity, patients with PD rely more on the PFC when negotiating anticipated obstacles, perhaps to compensate for attention and motor deficits. These findings support the role of cognition in fall risk and the need to improve attention and cognition in fall prevention programs, especially among patients with more advanced disease.

Relationship of Cognitive and Social Engagement to Health and Psychological Outcomes in Community-Dwelling Older Adults.

Cognitive and social engagement is an important yet underdocumented aspect of older adult engagement and function. The purpose of this study was to examine relationships between cognitive and social engagement and health and psychological outcomes in a cohort of community-dwelling older adults aged approximately 55-70 years. Analysis of data from the Wisconsin Registry for Alzheimers Prevention, a multiwave cohort study with 1,582 participants, using a 11 prospective case-control design to examine whether lower cognitive and social engagement at Visit 4 (baseline) is associated with worse health and psychological outcomes at Visit 5 (2 years after Visit 4). Wisconsin Registry for Alzheimers Prevention participants were included in this study if they had complete data on cognitive and social engagement and self-rated health at both visits. After matching potential covariates using propensity scores, participants with low cognitive and social engagement (cases) at baseline continued to have significantly lower cognitive and social engagement than the controls (participants with high cognitive and social engagement at baseline) at Visit 5, and they had lower self-rated health and higher surgery rate. Depressive symptoms, cognitive status, and hospitalization at Visit 5 did not significantly differ between cases and controls. This study provides evidence supporting cognitive and social engagement as an important marker of early decline in activity engagement that may indicate a potential later decline in functional, psychological, and health outcomes.

Rationally Designed Molecules Synergistically Modulate Multifaceted Aβ Toxicity, Microglial Activation, and Neuroinflammation.

Synergistic modulation of multifaceted toxicity is the key to tackle multifactorial Alzheimers disease (AD). The etiology of AD includes amyloid β (Aβ) amyloidosis, metal ion dyshomeostasis, reactive oxygen species (ROS), oxidative stress, mitochondrial damage, and neuroinflammation. We rationally designed multifunctional modulators by integrating pharmacophores for metal chelation, antioxidant and anti-inflammatory properties, and modulation of Aβ42 aggregation on the naphthalene monoimide (NMI) scaffold. The in vitro and cellular studies of NMIs revealed that M3 synergistically modulates metal-independent and -dependent amyloid toxicity, scavenges ROS, alleviates oxidative stress, and emulates Nrf2-mediated stress response in neuronal cells. M3 effectively reduced structural and functional damage of mitochondria, reduced Cyt

Near-Infrared Fluorescent Probes as Imaging and Theranostic Modalities for Amyloid-Beta and Tau Aggregates in Alzheimers Disease.

A person suspected of having Alzheimers disease (AD) is clinically diagnosed for the presence of principal biomarkers, especially misfolded amyloid-beta (Aβ) and tau proteins in the brain regions. Existing radiotracer diagnostic tools, such as PET imaging, are expensive and have limited availability for primary patient screening and pre-clinical animal studies. To change the status quo, small-molecular near-infrared (NIR) probes have been rapidly developed, which may serve as an inexpensive, handy imaging tool to comprehend the dynamics of pathogenic progression in AD and assess therapeutic efficacy

Molecular Dynamics Simulations of the Tau Amyloid Fibril Core Dimer at the Surface of a Lipid Bilayer Model I. In Alzheimers Disease.

A tau R3-R4 domain spanning residues 306-378 was shown to form an amyloid fibril core of a full-length tau in the brain of patients with Alzheimers disease. Recently, we studied the dynamics of a tau R3-R4 monomer at the surface of a lipid bilayer model and revealed deep insertion of the amino acids spanning the PHF6 motif (residues 306-311) and its flanking residues. Here, we explore the membrane-associated conformational ensemble of a tau R3-R4 dimer by means of atomistic molecular dynamics. Similar to the monomer simulation, the R3-R4 dimer has the propensity to form β-hairpin-like conformation. Unlike the monomer, the dimer shows insertion of the C-terminal R4 region and transient adsorption of the PHF6 motif. Taken together, these results reveal the multiplicity of adsorption and insertion modes of tau into membranes depending on its oligomer size.

Dementia and the aging population cognitive screening within correctional health.

The purpose of this study was to examine the literature surrounding dementia in the aging correctional population and assess the role of cognitive screening related to dementia detection within corrections. The literature regarding the role of dementia within the justice continuum is scant. Furthermore, correctional health researchers have not reached a consensus on the best age to administer cognitive screening in older persons or prioritizes a screening tool for the early detection of dementia. A key search term list including dementia screening and was developed to review the literature surrounding dementia and the aging correctional population. PubMed, Criminal Justice Abstracts (Ebsco) and the National Criminal Justice Reference Service were used within the academic search. A gray literature search using these same search terms was conducted reviewing criminal justice federal agencies and organizations for additional information on the dementia experience within correctional settings. Snowballing was used to capture relevant theoretical and empirical knowledge. Shortages in aging specialized health-care staffing presents a barrier for the clinical interpretation of Montreal Cognitive Assessment (MoCA) results. Correctional officers are also identified as useful candidates within the administration of cognitive screening with proper training. The MoCA may be the optimal cognitive screening tool for dementia, until an original cognitive screening tool is created specific to the correctional population. An age of 55 years or older may serve as the best cutoff score for classifying incarcerated individuals as older persons, and screening should be prioritized for these individuals. Finally, new specialized programs related to dementia within correctional settings are identified. A limitation of this research is the conflicting opinions among researchers regarding the use of general cognitive screening tools within the correctional setting. This research can inform correctional organizational policy and practices regarding the screening of older persons suspected of dementia. Most notably, this research proposes that correctional settings should incorporate the MoCA within initial screening of all individuals 55 years of age or older, enriching the job design of correctional officers job positions to include cognitive testing, and for correctional settings to provide dementia and age-associated training for correctional officers. Finally, this paper informs future research in the development of a cognitive assessment tool specific to the correctional population.

A predictive model using the mesoscopic architecture of the living brain to detect Alzheimers disease.

Alzheimers disease, the most common cause of dementia, causes a progressive and irreversible deterioration of cognition that can sometimes be difficult to diagnose, leading to suboptimal patient care. We developed a predictive model that computes multi-regional statistical morpho-functional mesoscopic traits from T1-weighted MRI scans, with or without cognitive scores. For each patient, a biomarker called Alzheimers Predictive Vector (ApV) was derived using a two-stage least absolute shrinkage and selection operator (LASSO). The ApV reliably discriminates between people with (ADrp) and without (nADrp) Alzheimers related pathologies (98% and 81% accuracy between ADrp - including the early form, mild cognitive impairment - and nADrp in internal and external hold-out test sets, respectively), without any a priori assumptions or need for neuroradiology reads. The new test is superior to standard hippocampal atrophy (26% accuracy) and cerebrospinal fluid beta amyloid measure (62% accuracy). A multiparametric analysis compared DTI-MRI derived fractional anisotropy, whose readout of neuronal loss agrees with ADrp phenotype, and This new data analytic method demonstrates potential for increasing accuracy of Alzheimer diagnosis.

Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline.

Accumulating data suggest that cerebrovascular disease contributes to Alzheimers disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimers disease pathology in the ageing brain and increases the risk of Alzheimers disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal β-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic β-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline 80.2 ± 7.1 years age at death 89.5 ± 6.7 years 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal β-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimers disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimers disease clinical trials and therapeutic development.

Association of APOE Genotypes and Chronic Traumatic Encephalopathy.

Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope. To test the association between APOE genotype and CTE neuropathology and related endophenotypes. This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022. One or more APOEε4 or APOEε2 alleles. CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8 pixel count per mm2), and dementia. Of 364 consecutive brain donors (100% male 53 14.6% self-identified as Black and 311 85.4% as White median IQR age, 65 47-77 years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio OR, 2.34 95% CI, 1.30-4.20 false discovery rate FDR-corrected P .01) and quantitative p-tau burden in the dorsolateral frontal lobe (β, 1.39 95% CI, 0.83-1.94 FDR-corrected P 2.37 × 10-5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 95% CI, 1.06-6.61 FDR-corrected P .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race. APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.

Deciphering the Role of ATP on PHF6 Aggregation.

The aggregation of Tau protein, which are involved in Alzheimers disease, are associated with the self-assembly of the hexapeptide sequence, paired helical filament 6 (PHF6) from repeat 3 of Tau. In order to treat Alzheimers disease and other such tauopathies, one of the therapeutic strategies is to inhibit aggregation of Tau and its nucleating segments. Therefore, we have studied the effect of adenosine triphosphate (ATP) on the aggregation of PHF6. ATP has, interestingly, demonstrated its ability to inhibit and dissolve protein aggregates. Using classical molecular dynamics simulations, we observed that the hydrophobic core of PHF6 segment displays extended β-sheet conformation, which stabilizes PHF6 aggregates. However, the distribution of ATP around the vicinity of the peptides enables PHF6 to remain discrete and attain random coil conformers. The interpeptide interactions are substituted by PHF6-ATP interactions through hydrogen bonding and hydrophobic interactions (including π-π stacking). Furthermore, the adenosine moiety of ATP contributes more than the triphosphate chain toward PHF6-ATP interaction. Ultimately, this work establishes the inhibitory activity of ATP against Tau aggregation hence, the therapeutic effect of ATP should be explored further in regard to the effective treatment of Alzheimers disease.

ShatiNat8l Overexpression Improves Cognitive Decline by Upregulating Neuronal Trophic Factor in Alzheimers Disease Model Mice.

Alzheimers disease (AD) is a type of dementia characterized by the deposition of amyloid β, a causative protein of AD, in the brain. ShatiNat8l, identified as a psychiatric disease related molecule, is a responsive enzyme of N-acetylaspartate (NAA) synthesis. In the hippocampi of AD patients and model mice, the NAA content and ShatiNat8l expression were reported to be reduced. Having recently clarified the involvement of ShatiNat8l in cognitive function, we examined the recovery effect of the hippocampal overexpression of ShatiNat8l in AD model mice (5XFAD). ShatiNat8l overexpression suppressed cognitive dysfunction without affecting the Aβ burden or number of NeuN-positive neurons. In addition, brain-derived neurotrophic factor mRNA was upregulated by ShatiNat8l overexpression in 5XFAD mice. These results suggest that ShatiNat8l overexpression prevents cognitive dysfunction in 5XFAD mice, indicating that ShatiNat8l could be a therapeutic target for AD.

Fine-tuning cell organelle dynamics during mitosis by small GTPases.

During mitosis, the allocation of genetic material concurs with organelle transformation and distribution. The coordination of genetic material inheritance with organelle dynamics directs accurate mitotic progression, cell fate determination, and organismal homeostasis. Small GTPases belonging to the Ras superfamily regulate various cell organelles during division. Being the key regulators of membrane dynamics, the dysregulation of small GTPases is widely associated with cell organelle disruption in neoplastic and non-neoplastic diseases, such as cancer and Alzheimers disease. Recent discoveries shed light on the molecular properties of small GTPases as sophisticated modulators of a remarkably complex and perfect adaptors for rapid structure reformation. This review collects current knowledge on small GTPases in the regulation of cell organelles during mitosis and highlights the mediator role of small GTPase in transducing cell cycle signaling to organelle dynamics during mitosis.

DEMA a distance-bounded energy-field minimization algorithm to model and layout biomolecular networks with quantitative features.

In biology, graph layout algorithms can reveal comprehensive biological contexts by visually positioning graph nodes in their relevant neighborhoods. A layout software algorithmengine commonly takes a set of nodes and edges and produces layout coordinates of nodes according to edge constraints. However, current layout engines normally do not consider node, edge or node-set properties during layout and only curate these properties after the layout is created. Here, we propose a new layout algorithm, distance-bounded energy-field minimization algorithm (DEMA), to natively consider various biological factors, i.e., the strength of gene-to-gene association, the genes relative contribution weight and the functional groups of genes, to enhance the interpretation of complex network graphs. In DEMA, we introduce a parameterized energy model where nodes are repelled by the network topology and attracted by a few biological factors, i.e., interaction coefficient, effect coefficient and fold change of gene expression. We generalize these factors as gene weights, protein-protein interaction weights, gene-to-gene correlations and the gene set annotations-four parameterized functional properties used in DEMA. Moreover, DEMA considers further attractionrepulsiongrouping coefficient to enable different preferences in generating network views. Applying DEMA, we performed two case studies using genetic data in autism spectrum disorder and Alzheimers disease, respectively, for gene candidate discovery. Furthermore, we implement our algorithm as a plugin to Cytoscape, an open-source software platform for visualizing networks hence, it is convenient. Our software and demo can be freely accessed at httpdiscovery.informatics.uab.edudema. Supplementary data are available at Bioinformatics online.

Acetylcholinesterase and butyrylcholinesterase inhibitory activities of antioxidant peptides obtained from enzymatic pea protein hydrolysates and their ultrafiltration peptide fractions.

This study optimized the enzymatic hydrolysis of yellow field pea proteins using alcalase (ACH), chymotrypsin (CHH), flavourzyme (FZH), pancreatin (PCH), pepsin (PEH), and trypsin (TPH) to obtain hydrolysates and ultrafiltered fractions (<1, 1-3, 3-5 and 5-10 kDa) that possess antioxidant plus acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. The hydrolysates exhibited varying degrees of radical scavenging and inhibition of linoleic acid peroxidation, as well as cholinesterase inhibition activities but the potency generally improved by >10% after UF separation into peptide fractions. ACH, FZH, and PEH exhibited significantly (p < .05) higher (20%-30% increases) radical scavenging activities than the other hydrolysates. The 1 and 3 kDa UF fractions of ACH, FZH, and PEH inhibited 20%-30% AChE activity, while ACH, PCH, TPH, and PEH inhibited 20%-40% BuChE activity. We conclude that the pea protein hydrolysates and their peptide fractions possess multifunctional properties with potential use against neurodegenerative disorders. PRACTICAL APPLICATIONS Alzheimers disease (AD) has multiple pathological pathways in addition to the loss of acetylcholine (ACh) catalyzed by acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The presence of severe oxidative stress triggered by lipid peroxidation and formation of free radicals is a common trait in AD patients. The concept of AChE and BuChE inhibition as an approach toward AD amelioration involves the use of compounds with a similar structure to ACh, the natural substrate. Peptides derived from food proteins consist of ester bonds with structural similarity to ACh and theoretically possess the ability to interact with AChE and BuChE. Results from the present study imply that pea protein-derived peptides are potential candidates for use as inhibitors of AChE and BuChE activities, with application in the prevention and management of AD.

Measurement of Oxygen Consumption Rate in Acute Striatal Slices from Adult Mice.

Mitochondria play an important role in cellular ATP production, reactive oxygen species regulation, and Ca

Characterization of Developmental Neurobehavioral Toxicity in a Zebrafish MPTP-Induced Model A Novel Mechanism Involving Anemia.

Zebrafish represent an economical alternative to rodents for developmental neurotoxicity (DNT) testing. Mechanistic understanding is the key to successfully translating zebrafish findings to humans. In the present study, we used a well-known dopaminergic (DA) neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a model chemical to uncover the molecular pathways for observed DNT effects. To enhance the specificity of potential molecular targets, we restricted our exposure to a concentration that is nonteratogenic yet exhibits high DNT effects and an exposure window sensitive to MPTP. Our DNT assessment based on a battery of motor and social behavioral tests revealed an effective concentration of 1 μM and a sensitive window of 48-96 h postfertilization (hpf) for MPTP-induced hypoactivity. It is worth noting that this hypoactivity persisted into later larval development until 28 dpf. We observed increased cell apoptosis, oxidative stress, and decreased ATP levels in larvae immediately after exposure at 96 hpf. Significant reductions of DA neurons were found in the retina at 72, 96, and 120 hpf. No visible deformity was found in motoneurons at 72, 96, and 120 hpf. Transcriptome analysis uncovered a novel pathway manifested by significant upregulation of genes enriched with erythropoiesis. Sensitive window exposure of MPTP and other DA neurotoxins rotenone and paraquat exhibited a concentration-dependent effect on transcriptional changes of embryonic hemoglobins and anemia. Given that anemia is a significant risk factor for Parkinsons disease and MPTP is known to cause parkinsonism in humans, we concluded that anemia resulting from dysregulation of primitive erythropoiesis during embryonic development might serve as a common mechanism underlying DA neurotoxin-induced DNT effects between zebrafish and humans.

Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia.

Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimers disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders.

Hypertension and Alzheimers disease pathology at autopsy A systematic review.

Hypertension is an important risk factor for Alzheimers disease (AD) and all-cause dementia. The mechanisms underlying this association are unclear. Hypertension may be associated with AD neuropathological changes (ADNC), but reports are sparse and inconsistent. This systematic review included 15 autopsy studies (n 5879) from observational cohorts. Studies were highly heterogeneous regarding populations, follow-up duration, hypertension operationalization, neuropathological methods, and statistical analyses. Hypertension seems associated with higher plaque and tangle burden, but results are inconsistent. Four studies (n 39935879 68%), reported clear associations between hypertension and ADNC. Another four suggested that antihypertensive medication may protect against ADNC. Larger studies with longer follow-up reported the strongest relationships. Our findings suggest a positive association between hypertension and ADNC, but effects may be modest, and possibly attenuate with higher hypertension age and antihypertensive medication use. Investigating interactions among plaques, tangles, cerebrovascular pathology, and dementia may be key in better understanding hypertensions role in dementia development.

Multifunctional Selenium Nanoparticles with Different Surface Modifications Ameliorate Neuroinflammation through the Gut Microbiota-NLRP3 Inflammasome-Brain Axis in APPPS1 Mice.

Neuroinflammation plays a critical role in Alzheimers disease (AD). However, it is still unknown if neuroinflammation can be effectively treated using selenium nanoparticles (SeNPs) with different surface modifications. In this study, SeNPs were coated with dihydromyricetin (DMY), a natural polyphenol, to obtain DMYSeNPs. Given that DMYSeNPs are unstable under physiological conditions, they were decorated step-by-step with chitosan (CSDMYSeNPs) and with the blood brain barrier (BBB) targeting peptide Tg (TGNYKALHPHNG) to yield Tg-CSDMYSeNPs, which significantly reduced the aggregation of Aβ and improved the anti-inflammatory effects of SeNPs

Dysregulation of Neuropeptide and Tau Peptide Signatures in Human Alzheimers Disease Brain.

Synaptic dysfunction and loss occur in Alzheimers disease (AD) brains, which results in cognitive deficits and brain neurodegeneration. Neuropeptides comprise the major group of synaptic neurotransmitters in the nervous system. This study evaluated neuropeptide signatures that are hypothesized to differ in human AD brain compared to age-matched controls, achieved by global neuropeptidomics analysis of human brain cortex synaptosomes. Neuropeptidomics demonstrated distinct profiles of neuropeptides in AD compared to controls consisting of neuropeptides derived from chromogranin A (CHGA) and granins, VGF (nerve growth factor inducible), cholecystokinin, and others. The differential neuropeptide signatures indicated differences in proteolytic processing of their proneuropeptides. Analysis of cleavage sites showed that dibasic residues at the N-termini and C-termini of neuropeptides were the main sites for proneuropeptide processing, and data also showed that the AD group displayed differences in preferred residues adjacent to the cleavage sites. Notably, tau peptide signatures differed in the AD compared to age-matched control human brain cortex synaptosomes. Unique tau peptides were derived from the tau protein through proteolysis using similar and differential cleavage sites in the AD brain cortex compared to the control. Protease profiles differed in the AD compared to control, indicated by proteomics data. Overall, these results demonstrate that dysregulation of neuropeptides and tau peptides occurs in AD brain cortex synaptosomes compared to age-matched controls, involving differential cleavage site properties for proteolytic processing of precursor proteins. These dynamic changes in neuropeptides and tau peptide signatures may be associated with the severe cognitive deficits of AD.

EEG Resting-State Functional Networks in Amnestic Mild Cognitive Impairment.

Fish and human health an umbrella review of observational studies.

Fish represents one of the most important dietary sources of omega-3 polyunsaturated fatty acids, which are known to be associated with various health benefits. This study aimed to systematically review existing meta-analyses of observational studies exploring the association between fish intake and various health outcomes. A systematic search of electronic databases was conducted to retrieve a total of 63 studies. Evidence was deemed as possible for the association between higher fish intake and decreased risk of the acute coronary syndrome, liver cancer, and depression, and limited for other outcomes (including age-related macular degeneration, Alzheimers disease, heart failure, all-cause and coronary heart disease mortality, total and ischaemic stroke) due to heterogeneity between results and potential otherwise inexplicable confounding factors. In conclusion, results from epidemiological studies support the mechanistic effects associated with omega-3 fatty acids from high fish consumption, but evidence needs to be further corroborated with more reliable results.

Evaluating Social Determinants of Health Domains and Their Predictive Validity Within BlackAfrican American and White Older Adults From the Active Trial.

To assess domains of social determinants of health (SDoH) and their associations with cognition and quality of life. This investigation uses baseline data from individuals participating in the ACTIVE trial (

ALZT-OP1 an experimental combination regimen for the treatment of Alzheimers disease.

For Alzheimers disease (AD) treatment, US FDA granted accelerated approval for aducanumab due to its amyloid-β (Aβ)-lowering effects, notwithstanding the reported poor correlation between amyloid plaque reduction and clinical change for this drug. The diversification of drug targets appears to be the future of the AD field and from this perspective, drugs modulating microglia dysfunction and combination treatment regimens offer some promise. The aim of the present article was to provide a comprehensive review of ALZT-OP1 (cromolyn sodium plus ibuprofen), an experimental combination treatment regimen for AD, discussing their mechanisms of action targeting Aβ and neuroinflammation, examining the role of microglia in AD and offering our own insights on the role of present and alternative approaches directed toward neuroinflammation. Enrolling high-risk participants with elevated brain amyloid could help to slow cognitive decline in secondary prevention trials during AD preclinical stages. Long-term follow-up indicated that non-steroidal anti-inflammatory drugs use begun when the brain was still normal may benefit these patients, suggesting that the timing of therapy could be crucial. However, previous clinical failures and the present incomplete understanding of the Aβ pathophysiological role in AD put this novel experimental combination regimen at substantial risk of failure.

Toward harmonization of strategies for investigating lucidity in ADADRD A preliminary research framework.

Episodes of lucidity (ELs) in Alzheimers disease and Alzheimers disease-related dementias (ADADRD), have garnered increasing attention as an important area of research. Efforts to study lucidity suffer from a lack of clear definitional criteria, inconsistent conceptualization, and diverse approaches to operationalizing features of these events. To advance systematic investigation of ELs in ADADRD, there is a need for clarity and precision in labeling event attributes, markers, and specific measurement strategies that enable operational harmonization across distinct approaches to investigating the relatively broad and nascent phenomenon. To that end, we propose a preliminary research framework to guide harmonization of approaches to investigating ELs in ADADRD. Our goal is to provide an initial schematic that encourages uniform labeling of operational decisions about ELs.

High Fall Risk Associated With Memory Deficit and Brain Lobes Atrophy Among Elderly With Amnestic Mild Cognitive Impairment and Mild Alzheimers Disease.

This study aimed to primarily examine the association between memory deficit and increased fall risk, second, explore the underlying neuroanatomical linkage of this association in the elderly with aMCI and mild AD. In this cross-sectional study, a total of 103 older adults were included (55 cognitively normal, CN 48 cognitive impairment, CI, elderly with aMCI, and mild AD). Memory was assessed by the Auditory Verbal Learning Test (AVLT). Fall risk was evaluated by the Timed Up and Go (TUG) Test, heel strike angles, and stride speed, which were collected by an inertial-sensor-based wearable instrument (the JiBuEn™ gait analysis system). Brain volumes were full-automatic segmented and quantified using AccuBrain Compared to CN, participants with aMCI and mild AD had poorer cognitive performance ( Our findings suggested that memory deficit was associated with increased fall risk in the elderly with aMCI and mild AD. The association might be mediated by the atrophy of medial temporal, frontal, and parietal lobes. Additionally, increased fall risk, tested by TUG time, heel stride angles, and stride speed, might be objective and convenient kinematics markers for dynamic monitoring of both memory function and fall risk.

Cell Non-autonomous Proteostasis Regulation in Aging and Disease.

Aging is a risk factor for a number of diseases, being the more notorious ones perhaps neurodegenerative diseases such as Alzheimers and Parkinsons. These and other age-related pathologies are often associated with accumulation of proteotoxic material inside cells, as well as with the accumulation of protein deposits extracellularly. It is widely accepted that this accumulation of toxic proteins trails a progressive decline in the mechanisms that regulate protein homeostasis, or proteostasis, during aging. However, despite significant efforts, the progress in terms of novel or improved therapies targeting accumulation of proteotoxic material has been rather limited. For example, clinical trials for new drugs aimed at treating Alzheimers disease, by preventing accumulation of toxic proteins, have notoriously failed. On the other hand, it is becoming increasingly apparent that regulation of proteostasis is not a cell autonomous process. In fact, cells rely on complex transcellular networks to maintain tissue and organ homeostasis involving endocrine and paracrine signaling pathways. In this review we will discuss the impact of cell non-autonomous proteostasis mechanisms and their impact in aging and disease. We will focus on how transcellular proteostasis networks can shed new light into stablished paradigms about the aging of organisms.

Strong Selectional Forces Fine-Tune CpG Content in Genes Involved in Neurological Disorders as Revealed by Codon Usage Patterns.

Neurodegenerative disorders cause irreversible damage to the neurons and adversely affect the quality of life. Protein misfolding and their aggregation in specific parts of the brain, mitochondrial dysfunction, calcium load, proteolytic stress, and oxidative stress are among the causes of neurodegenerative disorders. In addition, altered metabolism has been associated with neurodegeneration as evidenced by reductions in glutamine and alanine in transient global amnesia patients, higher homocysteine-cysteine disulfide, and lower methionine decline in serum urea have been observed in Alzheimers disease patients. Neurodegeneration thus appears to be a culmination of altered metabolism. The studys objective is to analyze various attributes like composition, physical properties of the protein, and factors like selectional and mutational forces, influencing codon usage preferences in a panel of genes involved directly or indirectly in metabolism and contributing to neurodegeneration. Various parameters, including gene composition, dinucleotide analysis, Relative synonymous codon usage (RSCU), Codon adaptation index (CAI), neutrality and parity plots, and different protein indices, were computed and analyzed to determine the codon usage pattern and factors affecting it. The correlation of intrinsic protein properties such as the grand average of hydropathicity index (GRAVY), isoelectric point, hydrophobicity, and acidic, basic, and neutral amino acid content has been found to influence codon usage. In genes up to 800 amino acids long, the GC3 content was highly variable, while GC12 content was relatively constant. An optimum CpG content is present in genes to maintain a high expression level as required for genes involved in metabolism. Also observed was a low codon usage bias with a higher protein expression level. Compositional parameters and nucleotides at the second position of codons played essential roles in explaining the extent of bias. Overall analysis indicated that the dominance of selection pressure and compositional constraints and mutational forces shape codon usage.

Combination of Acupoints for Alzheimers Disease An Association Rule Analysis.

Alzheimers disease (AD) is an ongoing neurological degeneration characterized by amnesia and a decline in cognitive abilities. Hippocampal neurogenesis is the leading cause of AD. Mild cognitive impairment (MCI), a prodromal state of AD, is mainly due to the degradation of neuropsychiatric manifestations. Previous systematic reviews demonstrated that treatment with acupuncture with Chinese herbs is tolerable and effective in improving cognitive function in patients with AD. Our investigation aimed to discover the main acupoint combination for AD management based on a preceding systematic review and meta-analysis of randomized control trials (RCTs). Our investigation was executed using association rule analysis, which is a common data mining technique accessible within R. Our study elucidated acupoint locations as binary data from 15 of the included studies using the Apriori algorithm. Thirty-two acupoints were selected from 15 RCTs. The 10 most frequent acupoints were selected. We inspected 503 association rules using the interpreted acupuncture data. The obtained results showed that SP6, BI10 ≥ HT7 and HT7, BI10 ≥ SP6 were the most associated rules in 15 RCTs. The combination of acupoints (SP6, BI10 ≥ HT7 and HT7, BI10 ≥ SP6) can be acknowledged as a core combination for future acupuncture regimens of AD.

Silibinin Ameliorates Formaldehyde-Induced Cognitive Impairment by Inhibiting Oxidative Stress.

Silibinin is a flavonoid extracted from the medicinal plant Silybum marianum (milk thistle), traditionally used to treat liver disease. Recent studies have shown that the antioxidative stress and anti-inflammatory effects of milk thistle are used in the treatment of neurological diseases. Silibinin has antioxidative stress and antiapoptotic effects and reduces cognitive impairment in models of Alzheimers disease (AD). However, the underlying mechanism of silibinin related to improvement of cognition remains poorly understood. In this study, we used the model of lateral ventricle injection of formaldehyde to examine the related mechanism of silibinin in improving cognitive impairment disorders. Oral administration of silibinin for three weeks significantly attenuated the cognitive deficits of formaldehyde-induced mice in a

Roles of Altered Macrophages and Cytokines Implications for Pathological Mechanisms of Postmenopausal Osteoporosis, Rheumatoid Arthritis, and Alzheimers Disease.

Postmenopausal osteoporosis (PMOP) is characterized by the uncoupling of bone resorption and bone formation induced by estrogen deficiency, which is a complex outcome related to estrogen and the immune system. The interaction between bone and immune cells is regarded as the context of PMOP. Macrophages act differently on bone cells, depending on their polarization profile and secreted paracrine factors, which may have implications for the development of PMOP. PMOP, rheumatoid arthritis (RA), and Alzheimers disease (AD) might have pathophysiological links, and the similarity of their pathological mechanisms is partially visible in altered macrophages and cytokines in the immune system. This review focuses on exploring the pathological mechanisms of PMOP, RA, and AD through the roles of altered macrophages and cytokines secretion. First, the multiple effects on cytokines secretion by bone-bone marrow (BM) macrophages in the pathological mechanism of PMOP are reviewed. Then, based on the thought of different tissue-same cell type-common pathological molecules-disease pathological links-drug targets and the methodologies of molecular network in bioinformatics, highlight that multiple cytokines overlap in the pathological molecules associated with PMOP vs. RA and PMOP vs. AD, and propose that these overlaps may lead to a pathological synergy in PMOP, RA, and AD. It provides a novel strategy for understanding the pathogenesis of PMOP and potential drug targets for the treatment of PMOP.

PD-1PD-L Axis in Neuroinflammation New Insights.

The approval of immune checkpoint inhibitors (ICIs) by the Food and Drug Administration (FDA) led to an improvement in the treatment of several types of cancer. The main targets of these drugs are cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein-1programmed death-ligand 1 pathway (PD-1PD-L1), which are important inhibitory molecules for the immune system. Besides being generally safer than common chemotherapy, the use of ICIs has been associated with several immune-related adverse effects (irAEs). Although rare, neurological adverse effects are reported within the irAEs in clinical trials, particularly in patients treated with anti-PD-1 antibodies or a combination of both anti-CTLA-4 and PD-1 drugs. The observations obtained from clinical trials suggest that the PD-1 axis may play a remarkable role in the regulation of neuroinflammation. Moreover, numerous studies in preclinical models have demonstrated the involvement of PD-1 in several neurological disorders. However, a comprehensive understanding of these cellular mechanisms remains elusive. Our review aims to summarize the most recent evidence concerning the regulation of neuroinflammation through PD-1PD-L signaling, focusing on cell populations that are involved in this pathway.

Whole Exome Sequencing Reveals a Novel APOE Mutation in a Patient With Sporadic Early-Onset Alzheimers Disease.

Apolipoprotein (APOE) is implicated and verified as the main risk factor for early-onset Alzheimers disease (AD). APOE is a protein that binds to lipids and is involved in cholesterol stability. Our paper reports a case of a sporadic early-onset AD (sEOAD) patient of a 54-year-old Korean man, where a novel

Rates of Cognitive Decline in 100 Patients With Alzheimer Disease.

Impact of Electronic Polarization on Preformed, β-Strand Rich Homogenous and Heterogenous Amyloid Oligomers.

Amyloids are a subset of intrinsically disordered proteins (IDPs) that self-assemble into cross-β oligomers and fibrils. The structural plasticity of amyloids leads to sampling of metastable, low-molecular-weight oligomers that contribute to cytotoxicity. Of interest are amyloid-β (Aβ) and islet amyloid polypeptide (IAPP), which are involved in the pathology of Alzheimers disease and Type 2 Diabetes Mellitus, respectively. In addition to forming homogenous oligomers and fibrils, these species have been found to cross-aggregate in heterogeneous structures. Biophysical properties, including electronic effects, that are unique or conserved between homogenous and heterogenous amyloids oligomers are thus far unexplored. Here, we simulated homogenous and heterogenous amyloid oligomers of Aβ

Functional amyloids from bacterial biofilms - structural properties and interaction partners.

Protein aggregation and amyloid formation have historically been linked with various diseases such as Alzheimers and Parkinsons disease, but recently functional amyloids have gained a great deal of interest in not causing a disease and having a distinct function

Deconvoluting the Complexity of Reactive Oxygen Species (ROS) in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are becoming a serious public health concern as the worlds population continues to age, demanding the discovery of more effective therapies. Excessive formation of reactive oxygen species (ROS) can result in oxidative stress (OS), which can be regarded as one of the common causes of neurodegenerative diseases (NDs). Thus, in this review, we focus on summarizing the consequences of ROS NDs, while taking the four prevalent NDs as examples, including Alzheimers disease (AD), Parkinsons disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntingtons disease (HD), to illustrate the key signaling pathways and relevant drugs. Together, these findings may shed new light on a field in which ROS-related pathways play a key role thereby setting the groundwork for the future therapeutic development of neurodegenerative diseases.

Study of BBB Dysregulation in Neuropathogenicity Using Integrative Human Model of Blood-Brain Barrier.

The blood-brain barrier (BBB) is a cellular and physical barrier with a crucial role in homeostasis of the brain extracellular environment. It controls the imports of nutrients to the brain and exports toxins and pathogens. Dysregulation of the blood-brain barrier increases permeability and contributes to pathologies, including Alzheimers disease, epilepsy, and ischemia. It remains unclear how a dysregulated BBB contributes to these different syndromes. Initial studies on the role of the BBB in neurological disorders and also techniques to permit the entry of therapeutic molecules were made in animals. This review examines progress in the use of human models of the BBB, more relevant to human neurological disorders. In recent years, the functionality and complexity of

Possible Neuropathology of Sleep Disturbance Linking to Alzheimers Disease Astrocytic and Microglial Roles.

Sleep disturbances not only deteriorate Alzheimers disease (AD) progress by affecting cognitive states but also accelerate the neuropathological changes of AD. Astrocytes and microglia are the principal players in the regulation of both sleep and AD. We proposed that possible astrocyte-mediated and microglia-mediated neuropathological changes of sleep disturbances linked to AD, such as astrocytic adenosinergic A1, A2, and A3 regulation astrocytic dopamine and serotonin astrocyte-mediated proinflammatory status (TNFα) sleep disturbance-attenuated microglial CX3CR1 and P2Y12 microglial Iba-1 and astrocytic glial fibrillary acidic protein (GFAP) and microglia-mediated proinflammatory status (IL-1b, IL-6, IL-10, and TNFα). Furthermore, astrocytic and microglial amyloid beta (Aβ) and tau in AD were reviewed, such as astrocytic Aβ interaction in AD astrocyte-mediated proinflammation in AD astrocytic interaction with Aβ in the central nervous system (CNS) astrocytic apolipoprotein E (ApoE)-induced Aβ clearance in AD, as well as microglial Aβ clearance and aggregation in AD proinflammation-induced microglial Aβ aggregation in AD microglial-accumulated tau in AD and microglial ApoE and TREM2 in AD. We reviewed astrocytic and microglial roles in AD and sleep, such as astrocytemicroglial-mediated proinflammation in AD and sleep astrocytic ApoE in sleep and AD and accumulated Aβ-triggered synaptic abnormalities in sleep disturbance. This review will provide a possible astrocytic and microglial mechanism of sleep disturbance linked to AD.

Identifying Possible AChE Inhibitors from Drug-like Molecules via Machine Learning and Experimental Studies.

Acetylcholinesterase (AChE) is one of the most important drug targets for Alzheimers disease (AD) treatment. In this work, a machine learning model was trained to rapidly and accurately screen large chemical databases for the potential inhibitors of AChE. The obtained results were then validated via in vitro enzyme assay. Moreover, atomistic simulations including molecular docking and molecular dynamics simulations were then used to understand molecular insights into the binding process of ligands to AChE. In particular, two compounds including benzyl trifluoromethyl ketone and trifluoromethylstyryl ketone were indicated as highly potent inhibitors of AChE because they established IC

Erratum Author correction to A nanocleaner specifically penetrates the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimers disease Acta Pharmaceutica Sinica B 12, (2021) 4032-4044.

This corrects the article DOI 10.1016j.apsb.2021.04.022..

Mitochondria targeting drugs for neurodegenerative diseases-Design, mechanism and application.

Neurodegenerative diseases (NDDs) such as Alzheimers disease (AD) and Parkinsons disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.

NMR-Driven Identification of Cinnamon Bud and Bark Components With Anti-Aβ Activity.

The anti-Alzheimer disease (AD) activity reported for an aqueous cinnamon bark extract prompted us to investigate and compare the anti-amyloidogenic properties of cinnamon extracts obtained from both bark and bud, the latter being a very little explored matrix. We prepared the extracts with different procedures (alcoholic, hydroalcoholic, or aqueous extractions). An efficient protocol for the rapid analysis of NMR spectra of cinnamon bud and bark extracts was set up, enabling the automatic identification and quantification of metabolites. Moreover, we exploited preparative reverse-phase (RP) chromatography to prepare fractions enriched in polyphenols, further characterized by UPLC-HR-MS. Then, we combined NMR-based molecular recognition studies, atomic force microscopy, and