bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s Disease as an Innate Autoimmune Disease Regulated by Tryptophan and Arginine Metabolism
Authors: Meek Autumn , Wang Yanfei , Wu Fan , Reed Mark , Barden Christopher , Weaver Donald F 
Published: December 2023

AbstractBackgroundThe identification of exploitable molecular pathogeneses for Alzheimer’s (AD) is an ongoing neurotherapeutic priority, yielding a range of different mechanistic proposals including proteopathy, immunopathy, gliopathy, synaptopathy, mitochondriopathy, oxidative stress, and metal dyshomeostasis. Rather than unconditionally accepting/rejecting the role of any one specific disease mechanism, the need for an innovative broadly‐encompassing model of AD, which harmonizes multiple divergent theories into a single unified comprehensive explanation, emerges as a much‐needed milestone on the road to a cure. Characterizing AD as a neurotoxic autoimmune‐inflammatory disorder, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses, may be such a milestone.MethodWe performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic‐molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, 981 new chemical entities were designed and synthesized to probe the biochemical pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small molecule therapeutics for AD.ResultIn response to various stimuli (infection, trauma, ischemia, air pollution), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon ‘self’ neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides such as Aβ. Following this self‐attack, the resulting necrotic neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Since autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1,137 small molecules normally present in human brain identified tryptophan and arginine metabolism as regulators of brain innate immunity and a source of endogenous anti‐Alzheimer’s molecules capable of modification into therapeutic modulators targeting AD’s complex immunopathic‐proteopathic pathogenesis.ConclusionConceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD.
Electronic Health Record Tools to Facilitate Diagnosis of Cognitive Impairment in Primary Care
Authors: Fitzpatrick Annette L. , Raetz Jaqueline G. , Belza Basia , Park Christina , McKiddy Sarah , Liao Joshua M. , Suchsland Monica Zigman , Singh Angad P. , Olivari Benjamin S. , Gaster Barak 
Published: December 2023

AbstractWith novel biomarkers and treatments for dementia on the horizon, the need to detect cognitive impairment at early stages is urgent. The role of primary care providers (PCPs) in the diagnosis of mild cognitive impairment and dementia is essential in meeting this need. Cognition in Primary Care (CPC) is a quality improvement program developed at the University of Washington (UW), Seattle, which includes a three‐part Continuing Medical Education (CME), clinical workflow, and electronic health record toolset to support PCPs in early diagnosis of mild cognitive impairment and dementia. This program was developed using input from UW providers in primary care practice and elements from the KAER (Kickstart, Assess, Evaluate, Refer) Toolkit developed by the Gerontological Society of America (GSA). Our pragmatic approach involved the development of tools integrated into Epic, the electronic health record system in place at UW, that can be used during a patient visit to guide PCPs through the process of evaluating cognitive function. The toolset includes 1) a list of signs that may trigger the need for a dedicated follow‐up visit to evaluate cognition; 2) a cognitive checklist for related conditions affecting cognition (e.g., potentially harmful medications, depressive symptoms, alcohol use, and obstructive sleep apnea); 3) a structured framework for cognitive evaluation including validated instruments (e.g., MoCA and AD8); 4) referrals to specialty care; 5) billing guidelines; and 6) community resources and materials that patients and care partners can use both pre‐ and post‐diagnosis. We have pilot‐tested these tools in UW primary care clinics and found high utilization both within and outside of targeted clinics indicating a halo effect of usage beyond those who attended the CME training. In this presentation, we will provide detailed descriptions of these Epic tools focusing on clinical application to total patient care. We plan to publish these workflow tools onto the Epic Digital Library to be downloaded and used by other health systems. Future plans include producing on‐demand CME training modules, a post‐diagnosis checklist, and applications for use of these tools in systems outside of Epic.
Isolation of spontaneously‐released brain extracellular vesicles: implications for brain pathology
Authors: Gomes Patrícia A. , Bodo Cristian , Nogueras‐Ortiz Carlos , Samiotaki Martina , Chen Minghao , Soares‐Cunha Carina , Silva Joana , Coimbra Bárbara , Stamatakis George , Santos Liliana , Panayotou George , Tzouanou Foteini , Waites Clarissa , Gatsogiannis Christos , Sousa Nuno , Kapogiannis Dimitrios , Costa‐Silva Bruno , Sotiropoulos Ioannis 
Published: December 2023

AbstractBackgroundIn the era of Precision Medicine, extracellular vesicles (EVs) exhibit great potential for the theragnostic of brain disorders such as Alzheimer’s disease (AD), a complex disease with no effective treatment and poorly understood risk factors, where pathological heterogeneity and diverse clinical presentations complicate the development of precise patient‐tailored therapies. Thus, the collection and characterization of physiologically relevant EVs, as well as the study of its precipitating/risk factors, are of the utmost importance. However, standard brain EV isolation approaches rely on tissue dissociation, which can contaminate EV preparations with intracellular vesicles.MethodBased on a multiscale analysis, including cryo‐EM, label‐free proteomics, and ExoView, we hereby present a novel purification method of small EVs (sEVs) based on the spontaneous release of EVs from the brain.ResultOur advanced EVs analysis demonstrated that our method represents an efficient purification method that captures a small EV‐enriched population spontaneously released by mouse and human brain tissue. In addition, we tested the significance of the release method under conditions where biogenesis/secretion of sEVs was pharmacologically manipulated and under exposure to chronic stress, a clinically‐relevant precipitant of AD. Here we found that the released method monitors the drug‐evoked inhibition or enhancement of sEVs secretion in a very sensitive manner, while chronic stress induces the secretion of brain exosomes accompanied by memory loss and mood deficits suggesting a potential role of sEVs in the brain response to stress and related stress‐driven brain pathologies.ConclusionOverall, this method will contribute to the characterization of the biomarker profile of physiologically relevant brain‐derived sEVs in brain function and pathology.
Downregulating functional hyperactivity in APOE ε4 carriers: an important avenue for early‐life risk reduction
Authors: Lancaster Claire L , Dowell Nicholas , Bakker Arnold , Hinds Chris , Nwaubani Prince , Bird Chris , Tabet Naji , Rusted Jennifer M 
Published: December 2023

AbstractBackgroundHyperactivity in the brain regions supporting episodic memory (the hippocampus and default mode network) drives the accumulation of Alzheimer’s Disease (AD) neuropathology and the resulting cascade of brain network disruption. Pharmacologically reducing hippocampal hyperactivity using the anti‐seizure medication Levetiracetam improves memory in individuals with prodromal AD. Carriers of an APOE e4 genetic risk variant show patterns of brain hyperactivity from youth. This study tests if Levetiracetam can prophylactically manage hippocampal hyperactivity in mid‐age APOE e4 carriers, and if such a reduction is associated with improved cognitive performance.MethodFifty cognitively healthy adults (aged 45‐65 years), differentiated by APOE genotype (25 e4 carriers, 25 e33 carriers), are participating in a double‐blind, placebo‐controlled trial of Levetiracetam (125mg bidaily for two‐weeks). Analyses will primarily focus on change in task‐related and resting functional magnetic resonance imaging (fMRI) brain blood‐oxygen‐level‐dependent response (BOLD) following Levetiracetam. In addition, the everyday cognitive effects of this manipulation will be evaluated, including on daily smartphone‐based measures of memory and attention.ResultTo date, 43 participants are enrolled in the 8‐week intervention (23 of whom have completed). Adverse events relating to the study drug have been minimal; only one participant has withdrawn in response to experiencing side‐effects. APOE genotype and treatment order (Levetiracetam, placebo) will be unblinded at the end of data collection (anticipated April 2023).ConclusionConclusions from this work will help expose routes to AD risk reduction, and the potential for repurposing an existing treatment for mid‐age individuals at elevated genetic risk for future dementia. This research will motivate longer‐term clinical trials for risk reduction strategies across the lifespan.
Cardiovascular risk factors and their relationship to age of onset of Alzheimer’s disease in people with Down syndrome
Authors: Pape Sarah 
Published: December 2023

AbstractBackgroundPeople with Down syndrome (DS) are at ultra‐high risk of developing Alzheimer’s dementia (AD). This is primarily due to the triplication of amyloid precursor protein on chromosome 21. Despite common genetic drivers there are large variations in the age of AD onset. In sporadic AD poor cardiovascular health has been associated with increased risk of AD. It has not been established whether the same risks apply to people with DS.MethodLarge population‐based cohort study utilising data from UK‐based primary care electronic health records. Measurements of nine cardiovascular parameters were used to analyse patterns across adulthood. These were systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), body mass index (BMI), total cholesterol, high and low density lipoproteins, triglycerides, and glycated haemoglobin (HbA1c). Survival curves were fitted with hazard ratios (HR) and crude incident rates calculated using cardiovascular parameters measured between age 25‐34 years as predictor variables and incidence of dementia as the outcome. Age, sex, level of intellectual disability, history of congenital heart disease (CHD), cardiovascular disease, hypothyroidism and diabetes were included as covariates.Result6,424 adults with DS were identified, matched to 23,143 controls. Low PP (<40mmHg), HR 1.45; low DBP (<62mmHg), HR 1.77, and low SBP (<100mmHg), HR 1.83 increased risk of dementia incidence. High SBP (>140mmHg), HR 2.04 increased risk but few people had high values. Raised BMI >25kg/m2 increased incidence dementia risk (HR 1.63). The risk was the same whether someone was overweight or obese. Hypothyroidism, history of CHD, male sex were significant contributors in the models. There was a cumulative effect of risk. People with 1 or 2 risk factors had HRs of 3.15 compared to those with zero risks, whilst people with 3 or more cardiovascular risk factors had HRs of 5.69.ConclusionCardiovascular health in earlier adulthood affects age of AD onset in people with DS. Cardiovascular multi‐morbidity was associated with increased incidence dementia risk suggesting that risks interact in a cumulative fashion. Reducing the number of risks by actively screening and managing medical co‐morbidities in people with DS may therefore help delay the onset of AD. Multi‐domain interventions may be particularly important.
Comparative evaluation of FDA‐approved drugs for managing the symptoms of AD
Authors: Ozsahin Ilker , Onakpojeruo Efe Precious , Uzun Berna , Ozsahin Dilber Uzun , Butler Tracy A 
Published: December 2023

AbstractBackgroundAD is a neurodegenerative disorder characterized by the gradual deterioration of mental abilities over time. According to estimates, 5.8 million Americans age 65 and older currently have AD dementia, and by the year 2050, that number is projected to reach 13.8 million. There is currently no cure for AD but medications have been shown to help some people manage the disease’s symptoms. Although there are disease modifying drugs target the amyloids such as Aducanumab and Lecanemab, high costs (around $30,000/year) and severe side effects make them unfavorable for many patients suffering from AD. However, prescribing the appropriate drug considering many factors affecting the decision‐making such as cost of the drug, safety of drug, and patient’s medical history might be a relatively challenging task for a physician and time‐consuming for patients in case the first prescribed drug is not tolerated or worsens the symptoms. Therefore, there is an urgent requirement for better tools to aid in prescribing the most appropriate drug.MethodsIn this regard, we propose using fuzzy Preference Ranking Organization Method for Enrichment of Evaluations (PROMETHEE), a multi‐criteria decision‐making (MCDM) method, to compare, evaluate, and rank the FDA‐approved drugs for managing AD symptoms. Drugs used in this study include Donepezil [Aricept], Rivastigmine [Exelon], Galantamine [Razadyne], Memantine [Namenda], and Memantine + Donepezil [Namzaric] with the following criteria: cost, safety of drug, tolerability, interaction with other drugs, response to cognitive impairment, symptoms management rate, and side effect. To the best of our knowledge, any decision‐making methodologies have not been proposed for use in identifying the most appropriate drugs for AD patients.ResultResults showed that [Namzaric] came first in the ranking, and followed by [Aricept], [Namenda], and [Razadyne] while [Exelon] ranked as the least favorable drug.ConclusionMCDM methods can be used as a decision‐aid system for evaluating AD drugs and this study can be extended including more criteria and new drugs as they become available.
Clusters of dementia risk factors are distinctively associated with socioeconomic factors
Authors: Delgado Carolina , Martin Consuelo San , Vergara Rodrigo , Rivero Juan JOSE Mariman 
Published: December 2023

AbstractBackgroundFor effective dementia prevention, the understanding of the local population’s risk profile and its socioeconomic associations is mandatory. Our aim is to explore if there are clusters of dementia risk factors in Chilean adults and if they are associated with different socioeconomic variables.MethodDementia‐free subjects ≥45 years old, from the 2016‐2017 Chilean National Health Survey, were analyzed stratified by sex and age (midlife/ later life), searching for profiles of association of 6 variables that had been related with dementia risk (years of education, systolic blood pressure, body mass index (BMI), alcohol consumption, physical activity, and depressive symptoms).ResultWe found 3 clusters that shared similar risk factors in each sex/age group (Figure 1 Women, Figure 2 Men). There was a cluster with high systolic blood pressure (HSBP) generally associated with high BMI in all sex/age groups; A cluster with depressive symptoms, and a physically inactive cluster in ¾ of sex/age groups. In men later life, in addition there was a cluster with excessive alcohol consumption and in women midlife a low risk profile. The cluster with HSBP alone or with high BMI, had lower years of education and lower family income than the other clusters. In contrast, the physically inactive and the low risk clusters had higher levels of education, while the depressive cluster had variable association with educational levels. The HSBP and the depressive clusters had a high proportion of multimorbidity, with a very high burden of risk factors for dementia.ConclusionThe clusters of health conditions related with dementia risk in Chilean adults that are distinctively associated with socioeconomic variables.
ALZHEIMER’S DEMENTIA EARLY DIAGNOSIS, CHARACTERIZATION, PROGNOSIS AND TREATMENT DECISION VIA A SOFTWARE‐AS‐MEDICAL DEVICE WITH AN ARTIFICIAL INTELLIGENT AGENT
Authors: Battista Petronilla , Nemni Raffaello , Vitali Paolo , Alì Marco , Zanardo Moreno , Salvatore Christian , Sirabian Graziella , Capelli Dario , Bet Luciano , Callus Edward , Bertoldo Enrico Giuseppe , Fiolo Valentina , Minafra Brigida , Fundarò Cira , Scotti Giuseppe , Sardanelli Francesco , Papa Sergio , Castiglioni Isabella 
Published: December 2023

AbstractBackgroundTRACE4AD (DeepTrace Technologies s.r.l, Italy) is a machine learning‐based software‐as‐medical device able to predict the conversion to Alzheimer’s disease (AD) dementia of subjects at risk within 24‐months exploiting automatic processing of T1‐weighted MPRAGE brain MRI study and neuropsychological tests. TRACE4AD provides a report with the predicted individual risk of conversion to AD dementia, specific cognitive deficits, and suggestions supporting neurologists in diagnosis and characterization, prognosis, and decision‐making. We tested TRACE4AD in the clinical setting in its ability, at baseline, to: a) predict amnestic Mild Cognitive Impairment (MCI) conversion to AD dementia within 24‐months; b) characterize cognitive deficits; c) support neurologists' decision‐making.MethodWe retrospectively included 92 subjects (mean age 73.12±7.6, 46% female): 32 patients from two Italian centers where TRACE4AD was implemented after user training; and 60 subjects from the ADNI dataset. All patients had a brain MPRAGE study at baseline, 77/92 patients (83.7%) also performed a neuropsychological assessment at baseline, 75/92 patients (81.5%) had a stable clinical diagnosis at 24‐month. TRACE4AD extracted the gray matter map from MPRAGE and used it (combined with cognitive measures when available) to make inferences. Reference standards were: a) the neurologist’s clinical diagnosis at 24‐months, b) the neuropsychological assessment at the baseline, c) the agreement with the neuro exam and intervention decision time and type defined by neurologists at the baseline.ResultTRACE4AD accurately predicted conversion to AD dementia in 93.3% of patients based on the MRI, and in 96.6% based on MRI and cognitive measures. Cognitive deficits were found in agreement with the neuropsychological assessment for all patients except one who presented with major depression. We found disagreement between the neurologist’s decision at baseline and the tool in only two patients, defined with normal cognition by the neurologist and predicted at high risk of AD dementia conversion by the tool. TRACE4AD supported neurologists' decision by 12 months in 15/17 patients for the prompt decision at baseline.ConclusionTRACE4AD is promising, safe, and effective in supporting neurologists in the clinical practice of MCI across different centers.
Cerebrovascular features of Alzheimer’s disease in adults with Down syndrome
Authors: Brickman Adam M. , Lao Patrick J. , Edwards Natalie C. , Rizvi Batool , Wilcock Donna M. , Gutierrez Jose , Head Elizabeth 
Published: December 2023

AbstractBackgroundCerebrovascular disease contributes to clinical onset and course of Alzheimer’s disease (AD) but it is unclear if it is related directly to AD pathogenesis. In late onset AD, MRI markers of small vessel cerebrovascular disease relate to AD diagnosis, genetic risk for AD, and severity of AD symptoms, but it is not possible to determine whether these associations reflect comorbidity due to risk factor exposure or whether they represent a core feature of AD. We have been studying cerebrovascular features of Alzheimer’s disease in adults with Down syndrome, who are at genetic risk for developing AD but have very low prevalence of classical vascular risk factors.MethodIn the context of the Alzheimer’s Biomarker Consortium – Down Syndrome (ABC‐DS), a US‐based multisite observational study of the clinical, biomarker, and pathological features of AD in adults with Down syndrome, our laboratory has analyzed high‐resolution, harmonized MRI scans for markers of cerebrovascular disease, including white matter hyperintensities (WMH), enlarged perivascular spaces, microbleeds, and infarcts, in adults with Down syndrome across the adult lifespan. We tested the association of these markers with age, AD‐related clinical diagnoses, proteomic profiles of vascular function and inflammation, and AD‐related biofluidic biomarker concentrations.ResultOur studies show that MRI‐derived markers of cerebrovascular disease are prevalent in adults with Down syndrome and increase in severity across AD‐associated clinical diagnoses. Age analyses suggest that there is an inflection of these markers at around age 40, when other pathological features also begin to emerge. Proteomic correlates of these cerebrovascular disease markers suggest an association with inflammatory processes in presymptomatic and neurodegenerative processes in symptomatic adults with Down syndrome. Finally, markers of cerebrovascular disease are particularly associated with plasma phosphorylated tau concentrations in adults with Down syndrome.ConclusionOur work shows that MRI‐derived markers of cerebrovascular disease are prevalent, related to AD symptoms, temporally track with AD pathology, relate to inflammation and neurodegeneration markers, and associate with markers of tau pathology. Without the confound of exposure to peripheral vascular risk factors, these observations suggest that cerebrovascular disease represents a “core feature” of AD that contributes both to symptoms and to disease pathogenesis.