bluuebunny/crossref_metadata_2025_split huggingface dataset:
3‐month melatonin supplementation to reduce brain oxidative stress and improve sleep in mild cognitive impairment: a randomised controlled feasibility trial
Authors: Schrire Zoe M , Phillips Craig L , Marshall Nathaniel , Mowszowski Loren , Naismith Sharon L , Grunstein Ron , Hoyos Camilla M 
Published: December 2023

AbstractBackgroundMelatonin has multiple proposed therapeutic benefits including antioxidant properties, circadian rhythm synchronisation and sleep promotion. Since these areas are also recognised risk factors for dementia, melatonin has been hypothesised to slow cognitive decline in older adults.MethodParticipants with Mild Cognitive Impairment (MCI) were recruited from the community for a 12‐week randomised placebo‐controlled parallel, feasibility trial of 25mg oral melatonin daily. Primary outcomes were feasibility, acceptability, and tolerability. Secondary outcomes were brain oxidative stress, cognition, mood, and sleep at 12 weeks.ResultForty participants were randomised to receive melatonin or placebo. Feasibility, determined by the percentage of people who met inclusion and exclusion criteria and could potentially join the study, was 42/389, 11%. The most common reason for exclusion was age. Acceptability, the number of people who agreed to be randomised as a fraction of all potential participants, was 40/42, 95%. Adherence to the intervention and completion of the main secondary outcome (oxidative stress) was over the pre‐defined 80% threshold for all participants and reported safety outcomes were balanced between groups. The current protocol was feasible and acceptable as we reached our target of 40 participants between 60‐80 years of age with MCI. All participants were able to complete all aspects of the trial, including online visits and assessments.ConclusionThis is promising for future trials which should conduct the study with a higher sample size and longer duration to yield necessary efficacy data.
Title: Barriers and Facilitators for American Indians and Alaska Natives to participate in Alzheimer’s Disease and Related Dementia Research
Authors: Johansson Patriki , Haakenstad Magdalena , London Sara , Mohammed Alaa , Jones Breanna , Buchwald Dedra 
Published: December 2023

AbstractBackgroundThe US National Plan for Alzheimer’s Disease prioritized the inclusion of health disparities groups in Alzheimer’s Disease and related dementia (ADRD) research in 2012, yet participation of American Indians and Alaska Natives (AI/AN) in ADRD research is significantly lower than the representation of other minorities. Among 47,165 participants in the US National Alzheimer’s Coordinating Center database, only 288 (0.6%) self‐identified as AI/AN. Without the representation of AI/AN people in ADRD research, results from studies may not benefit Tribal communities.MethodUsing community‐based participatory research methods, we conducted a qualitative study that included 6 in‐person and 1 virtual focus groups with 64 urban and rural AI/AN elders. We examined barriers to and promoters of participation in clinical ADRD research. We applied inductive thematic analysis to unpack the meanings of the qualitative data through systematic coding and identification of themes.ResultThe primary factors linked to increasing willingness to participate in ADRD research were awareness of the impact of ADRD in their community; having a family history of ADRD; having research conducted that benefits the community and future generations; and having a positive relationship to allopathic medicine and research. Challenges to research included mistrust of researchers and allopathic practitioners, concerns related to the invasiveness of the tests, cultural restrictions towards biospecimen donation, and lack of awareness and information about ADRD.ConclusionFuture research efforts seeking to recruit AI/AN participants should consider the need for raising ADRD awareness, community‐based ADRD education, and building trust and long‐term relationships with AI/AN communities.
Machine Learning Approach to Identify Dysregulation in the Plasma Proteome of CADASIL
Authors: Keller Jonah , Fitzsimons Stephen , Park Ryan , Moury Luana , Oh Bradley C , Treiman Scott , Radabaugh Hannah , Ferguson Adam , Elahi Fanny M 
Published: December 2023

AbstractBackgroundThe plasma proteome provides information to identify dysregulated molecular pathways underlying disease. Cerebrovascular diseases often manifest a significantly different plasma proteomic signature. Cerebral‐Autosomal‐Dominant‐Arteriopathy‐Subcortical‐Infarcts‐and‐Leukoencephalopathy (CADASIL) is one such vascular brain disease. The CADASIL plasma proteome has yet to be investigated.MethodTo investigate the plasma proteome in the context of CADASIL, we used large‐scale proteomics, measuring over 7,000 proteins via aptamer‐based technology (SomaLogic) from 53 study participants (nCADASIL = 25; nControl = 28).We employed machine learning (ML) methods as an unbiased approach to uncover disease‐associated change in proteomic networks. This approach is based on the premise that protein sets that best classify disease state could be important biological drivers of disease. We developed a novel ML method: coupling recursive feature extraction with logistic regression (LR) and XGBoost evaluators, as well maximum‐relevance‐minimum‐redundancy with Random‐Forest and F‐Statistic evaluators.The results of all four models were selectively aggregated in order to delineate the CADASIL plasma proteome signature while minimizing overfitting to the low sample size data. We developed a 45 protein model of the CADASIL proteomic signature from these results. To evaluate the classification ability, we tested the Repeated‐Stratified‐10‐fold‐Cross‐Validation accuracy of a LR classifier. Next, we investigated whether the CADASIL proteomic signature was relevant for other neurodegenerative diseases with vascular components; the classifier was applied to an Alzheimer’s Disease (AD) dataset. Finally, the functional signature of the 45 proteins was investigated through gene ontology (GO).ResultsThe LR classifier in CADASIL is 99.8% accurate. In AD, the accuracy is 71.2%. This implies the CADASIL signature shares commonalities as well as pertinent differences with other neurodegenerative diseases.The GO of the 45 proteins resulted in GO terms corresponding to extracellular matrix and collagen, cellular membrane lipoproteins and glycolipids, and proteasome biological pathways.ConclusionThe proposed method allows for an initial unbiased discovery of important proteomic changes associated with disease state. The identified proteins would provide starting points for mechanistic studies. In addition, a panel of proteins could be used for screening at population level for risk stratification and more in‐depth phenotyping. Next steps include investigating the biological relevance of findings in mechanistic models for therapeutic developments.
Deciphering the molecular signature of selective neuronal vulnerability in the wake‐promoting lateral hypothalamic area in Alzheimer’s disease: A digital multiplexed gene expression study across Braak stages
Authors: Satpati Abhijit , Pereira Felipe Luiz , Soloviev Alexander , Mladinov Mihovil , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Rodriguez Roberta Diehl , Paes Vitor Ribeiro , Walsh Christine M , Spina Salvatore , Seeley William W. , Pasquallucci Carlos Augusto , Jacob‐Filho Wilson , Neylan Thomas C. , Grinberg Lea T. 
Published: December 2023

AbstractBackgroundSleep/wake disturbance is a common and debilitating symptom of Alzheimer’s disease (AD) that precedes cognitive loss. The lateral hypothalamic area (LHA) is critical in orchestrating the sleep/wake cycle through the neuropeptide orexin and melanin‐concentrating hormone. We previously demonstrated that LHA neurons accumulate AD‐tau from Braak stage (BB) 0 and losses ∼72% of neurons by BB6. Little is known about the molecular changes underlying LHA vulnerability during AD progression. We investigated RNA expression changes in LHA across Braak stages to close this gap.MethodWe dissected LHA from 30um‐thick sections of the brain from healthy control (HC) and subjects at progressive AD stages and extracted RNA using conventional techniques. We ran RNA transcriptomic assay using customized and neuropathology nCounter® (Nanostring) panels. The Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when log2 fold‐change was > = |1| and the p‐value was <0.05.ResultWe found an upregulation of HCRTR1, LDHC, NKX6, and SLC11A1 from early stages (BB2‐3), whereas HCRTR2 RNA levels remained stable. Circadian gene PER2 was downregulated from the intermediate stages (BB4). Gene Ontology analyses detected dysregulation of neuropeptide‐ligand interaction pathways from early AD. Linoleic acid metabolism, fat digestion and absorption, and immune pathways became dysregulated at intermediate stages, while glycolysis and gluconeogenesis pathways were in late stages (BB5‐6). Of note, it is critical to consider that the massive LHA neuronal loss during AD progression may confound the interpretation of changes in late stages because of the few remaining neurons.ConclusionnCounter® is suitable for identifying transcriptome changes in LHA, even at early AD stages. Molecular profiling of LHA across the Braak stage revealed that the earliest changes are associated with an imbalance in neurotransmitter receptors, while the decline in metabolism and increased inflammation marked the intermediate stage. The late‐stage AD is characterized by hypoglycemia and energy deficit. Notably, discrepancies in receptor behavior can inform more effective symptomatic treatment for sleep dysfunction in AD.
Later life Body composition and Alzheimer’s disease
Authors: Canovas Rodrigo , Doecke James D , Huynh Andrew , Fowler Christopher J , Rainey‐Smith Stephanie R , Dore Vincent , Fripp Jurgen , Bourgeat Pierrick , Maruff Paul , Ames David , Rowe Christopher C , Villemagne Victor L , Ellis Kathryn A , Martins Ralph N , Masters Colin L , Yates Paul A 
Published: December 2023

AbstractBackgroundMid‐life obesity is linked with increased risk for late‐life dementia, however relationships between later‐life body composition and dementia are less clear.MethodUsing a combined cohort from two major observational studies (AIBL and ADNI) and categorising Body Mass Index (BMI) according to WHO criteria, we computed multivariable linear mixed‐effects models to determine association between BMI category and outcomes: brain beta‐amyloid PET quantification (centiloid); MRI (global, hippocampal and white matter hyperintensity volume); and cognition (PACC [preclinical Alzheimer cognitive composite], composite scores for attention, executive function and episodic memory). All models were adjusted by covariables age, gender, education, APOE ε4, and study (AIBL/ADNI).ResultsThe cohort included 4,668 observations from 2,828 individuals (49.4% male, mean age 73.8 years, 38.2% APOE ε4 carriage, 61.8% normal cognition [NC], 25.6% Mild Cognitive Impairment [MCI], 12.6% dementia due to Alzheimer’s disease). The average BMI was 26.8 kg/m2 (0.6% underweight, 37.7% normal‐range, 41.7% overweight, 20.0% obese [BMI <18, 18‐25, 25‐30 and >30 kg/m2, respectively]).Relative to normal‐range BMI, those with overweight‐or‐obese range BMI had a significant negative association with PET centiloid level, beta = ‐0.150 (0.037 se) and ‐0.309 (0.042), respectively (i.e. greater BMI had lower amyloid level). This remained significant for obese‐range BMI in fully‐adjusted models when restricted to only NC participants. Also, obesity was associated with greater hippocampal volume, beta = 0.192 (0.046), but this was not significant when restricted to NC only. Associations with total grey matter/cortical volume and white matter hyperintensities were not significant. Obese‐range BMI was associated with stronger performance on attention and episodic memory composites, but not for PACC and executive function. For NC‐only, there was only significant negative association between obesity and attention performance. In multivariate analyses, neither obesity category nor BMI were associated with longitudinal change in cognitive scores.ConclusionPresence of obesity in later life was associated with lower brain amyloid levels and less hippocampal atrophy in a mixed cohort including older adults with dementia, mild cognitive impairment and normal cognition. While mid‐life obesity is associated greater risk for AD, later life associations appear influenced by weight loss with emerging dementia.
Associations between neuropsychiatric symptoms, pathology in neuropathological cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies
Authors: Tremblay Cécilia , Shakir Neha , Zhang Nan , Adler Charles , Belden Christine , Mehta Shyamal , Shill Holly , Driver‐Dunckley Erika , Beach Thomas G , Serrano Geidy E , Atri Alireza , Choudhury Parichita 
Published: December 2023

AbstractBackgroundNeuropsychiatric symptoms (NPS) are frequent in Alzheimer’s Disease dementia (ADD) but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co‐occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). Previous studies have shown that both ADLB and DLB cases have faster cognitive and/or functional decline compared to AD. However, the differences in NPS severity over disease course and survival in these pathologic subgroups is not well understood.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a final neuropathologic diagnosis of DLB (±AD co‐pathology; n = 65), ADLB (n = 89), AD (without LB) (n = 140), and controls (no neuropathological diagnosis) (n = 82) were included. Total NPI‐Q (scores ranging from 0‐36) at time of enrollment and within 2.5 years of death were calculated for all groups. Statistical analysis utilizing ANCOVA (adjusting for age, sex, baseline MMSE and cognitive symptom duration) with pairwise comparisons, and Kaplan‐Meier curves were completed.ResultAge at onset of cognitive symptoms was not different between pathology groups. NPI‐Q scores at enrollment were highest in ADLB (7.33 ± 4.85), and higher (p<0.001) than DLB (5.10 ± 3.37), AD (4.54 ± 3.63) and controls (1.78 ± 1.70). At final evaluation, NPI‐Q scores were highest in DLB (10.04 ± 6.28), followed by ADLB (8.0 ± 4.), and ADD (7.61 ± 5.05) when compared to controls (2.78 ± 3.97) (all p<0.001). DLB and AD demonstrated significant increases in NPI‐Q severity during follow up (p < 0.001). AD had longer survival time (5.8 years) compared to ADLB (4.0 years) and DLB (3.9 years). Subjects with NPS had a shorter median survival time (3.4 years) compared to subjects without NPS (6.5 years; p = 0.002).ConclusionA higher NPS burden and shorter survival is seen in both DLB and ADLB, as compared with AD. This suggests that diffuse neocortical LB pathology is not the major driver of either NPS or survival.
Evaluating the therapeutic efficacy of phytochemicals in ameliorating cytotoxic effects of amyloid beta
Authors: Chakraborty Manas , Dhiman Kunal , Gupta Veer 
Published: December 2023

AbstractBackgroundThere is lack of reliable treatment approaches to combat early cognitive impairment, as well as Alzheimer’s disease (AD). Since AD is a multifactorial disease, therapeutic approaches must be targeted on disease specific multiple‐biochemical pathways. There is a need to explore and test alternative disease modifiers which can target multiple metabolic pathways i.e., phytochemicals to combat such perturbations. This project will identify bioenergetic and viability changes that occur in response to amyloid pathology in cell models. Further, the therapeutic potential of a set of phytochemicals (safranal, berberine, taxifolin, bilobalide and vinpocetine) will be evaluated in mitigating such changes.MethodNeuroblastoma cell lines SH‐SY5Y cells and BE (2)‐M17 have been used to model AD in vitro. They were differentiated into mature human neurons using 10 µM retinoic acid. Amyloid beta 1‐42 (Ab42) is being used to induce neurotoxicity in the cells, which will be followed by treatment with phytochemicals. MTT (3‐(4, 5‐dimethylthiazolyl‐2)‐2, 5‐diphenyltetrazolium bromide) assay and flow cytometry will be used to evaluate cell viability, followed by sea horse assay to evaluate the oxygen consumption rate. Confocal microscopy will be used to confirm the images of amyloidosis and will be compared with the phytochemically treated group and the control group. Western blotting will be used to study the targeted pathways and proteins.ResultDifferentiation of the cells have been successfully accomplished and confirmed through morphological changes in the cells. Treatment with Ab42 is currently under progress, which will be followed by treatment with phytochemicals. The protective effect of the phytochemicals will be evaluated through MTT, and sea horse assays and pathways will be studied using western blotting.ConclusionThis project will help to evaluate the therapeutic potential of selected phytochemicals, and thereby help to inform future pre‐clinical and clinical studies.
Human nasal beta‐amyloid 42 has a diagnostic value in discriminating Alzheimer’s disease
Authors: Jung Da Hae , Son Gowoon , Wang Shengmin , Lim Hyun Kook , Moon Cheil 
Published: December 2023

AbstractBackgroundThe key in Alzheimer’s disease (AD) therapy is a timely and accurate diagnosis for prompt drug intervention. However, due to the high cost and invasiveness of conventional biomarker analyses, including brain positron emission tomography (PET) imaging and cerebrospinal fluid (CSF)‐based assays, easy accessibility to these screening tests is often hindered. There is, therefore, a great need to develop a more accessible biomarker screening test using less invasive and cost‐effective peripheral body fluid biomarkers. Previous studies examined the non‐quantitative expression of beta‐amyloid (Aβ) in normal and AD patients' nasal discharge fluid. They identified higher expression of oligomeric Aβ in AD patients, showing a correlation with cognitive decline. However, the quantitative measurements of nasal Aβ42 levels, including the full AD continuum, remain unknown. Here, we assessed whether quantified human nasal Aβ42 levels have diagnostic performance and have the potential to be utilized as a biological risk factor in AD.Method161 subjects (cognitively normal (CN), n = 32; preclinical, n = 29; mild cognitive impairment (MCI), n = 73; AD, n = 27) underwent neuropsychological battery tests, including Mini‐Mental State Examination (MMSE), Clinical Dementia Rate (CDR), and Global Deterioration Scale (GDS), and amyloid‐PET scans (18F‐Flutemetamol). Their nasal discharge samples were collected, and nasal Aβ42 levels were measured via enzyme‐linked immunosorbent assay (ELISA).ResultWe found that the second‐highest quartile (Q3) group of nasal Aβ42 constituted the majority of patients with AD diagnosis (p = 0.036). The Q3 group also outnumbered the other groups in the most cognitively impaired subjects in all three neuropsychological battery tests (p = 0.008, p = 0.037, p = 0.023). Next we also found that subjects in the Q3 group exhibited most impaired cognitive function in all three neuropsychological battery tests with strong significance. When we examined the amyloid‐PET SUVR values, subjects with PET positive showed the highest SUVR.ConclusionQuantified nasal Aβ42 is strongly associated with cognition measurements. Nasal Aβ42 suggests the possibility for discriminating AD from non‐AD.
Assessment of racial/ethnic representation in Alzheimer’s disease genetics datasets
Authors: Xue Diane , Fohner Alison E 
Published: December 2023

AbstractBackgroundBiased representation of populations in genetic research leads to disparities in genetics knowledge and utility. Here, we compare the racial/ethnic demographics of all participants in nationally funded Alzheimer’s disease (AD) genetics cohorts to demographics of US AD mortality.MethodsWe used death certificate data from the CDC Wide‐ranging Online Data for Epidemiologic Research (WONDER) Database to calculate age‐adjusted AD mortality of adults aged 65 years and older for 2016‐2020. We compared the racial/ethnic distributions in mortality to the racial/ethnic distribution of AD genetics participants across 16 studies in the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) that met the following filters: Disease = `AD`; Molecular Data = `Genotype`; and Type = `GWAS` as well as five studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Demographic data was obtained directly from data or via literature review. In addition to the GWAS data, we also compared racial demographic data from sequencing studies released as part of the Alzheimer’s Disease Sequencing Project (ADSP) Umbrella (dssNIAGADS NG00067).ResultsTable 1 describes the racial/ethnic distribution of the age‐adjusted AD mortality rate of the US population from 2016‐2020. Non‐Hispanic Whites had the highest rate (per 100,000 person‐years): 254.2 (95% CI 253.5‐254.9), and Asian or Pacific Islander (AS/PI) had the lowest rate: 125.6 (123.6‐127.71). The racial/ethnic distribution of the 13,909 AD cases across 21 genotype datasets available in NIAGADS or CHARGE are presented in Table 1. Most (87.6%) of AD cases are non‐Hispanic White, with the least (0.25%) being AS/PI. Preliminary analysis of ADSP data show increased proportions of Hispanic and Black participants (Table 1).ConclusionThe racial/ethnic distribution of AD genetics participants is representative of proportion of deaths, but after adjusting for age and population distribution, AS/PI have 50% lower mortality rate compared to non‐Hispanic Whites while comprising less than 5% of participants in genetics cohorts. While progress is being made to diversify sequencing data, AS/PI and American Indian or Alaska Natives remain underrepresented in AD genetics research, which may lead to inequitable benefits from future research and pharmaceutical treatments.