bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex differences in familial forms of frontotemporal dementia
Authors: Memel Molly B , Staffaroni Adam M. , Illán‐Gala Ignacio , Kornak John , Saloner Rowan , VandeBunte Anna M. , Paolillo Emily W. , Cadwallader Claire J. , Chen Coty , Gendron Tania F , Heuer Hilary W. , Forsberg Leah K. , Boeve Brad F. , Boxer Adam L. , Rosen Howard J. , Casaletto Kaitlin B. , Consortium ALLFTD 
Published: January 2025

AbstractBackgroundSex differences in neurodegenerative diseases can impact accurate diagnosis and management. Emerging data suggest there may be sex differences in frontotemporal dementia (FTD) prevalence and clinical manifestation. However, prior studies lacked longitudinal assessment and were limited in capturing sex differences in earliest stages of disease (e.g., preclinical). We evaluated how sex impacts longitudinal clinical outcomes in individuals carrying autosomal dominant variants for FTD.Method337 participants carrying pathogenic variants in MAPT, GRN, or C9orf72 completed longitudinal evaluations (2.4 average visits, range = 1‐6), including neuropsychological and functional assessments, and plasma analyzed for neurofilament light chain (NfL). FTLD Clinical Dementia Rating Scale (FTLD‐CDR) classified disease stage at study entry (FTLD‐CDR = 0: asymptomatic; FTLD‐CDR = 0.5: MCI; FTLD‐CDR> 0.5: Dementia). Linear mixed‐effects models evaluated the effect of sex on longitudinal clinical trajectories, including the effect of disease stage at study entry.ResultMale and female carriers were similarly distributed with respect to baseline demographics and most clinical outcomes. However, women exhibited higher baseline NfL than men. Not accounting for disease stage, men and women did not show statistical differences on cognitive, functional, or NfL trajectories. However, when accounting for disease stage, there was a significant interaction between baseline disease stage, sex, and time on cognitive, NfL, and functional trajectories. While sex differences were not statistically significant among asymptomatic carriers, women with MCI/dementia evidenced more rapid cognitive, NfL and functional decline over time compared to men. To evaluate the role of pathology burden, we tested the interaction between baseline NfL, sex, and time on clinical outcomes stratified by disease stage. In asymptomatic participants, women showed an attenuated adverse relationship between baseline NfL and clinical trajectories compared to men. No statistically significant sex differences were evident in the relationship between baseline NfL and clinical outcomes in participants with MCI/dementia.ConclusionIn familial FTD, women evidenced steeper clinical declines than men after symptom onset. Accounting for pathology, baseline NfL was a stronger predictor of clinical decline in asymptomatic men compared to women. NfL may be a less sensitive prognostic tool for clinical progression in women with FTD, particularly early in disease. This may reflect early “cognitive resilience” to neurodegeneration in women.
“Systematic Review of Brief Cognitive Screening Tools for Identifying Dementia and Mild Cognitive Impairment in Illiterate and Low‐Educated Populations”
Authors: Zegarra‐Valdivia Jonathan Adrian , Chino‐Vilca Brenda Nadia , Tituana Kuripacha Alcamari , Zapata‐Restrepo Lina Maria , Unaucho Pilalumbo Maria M. , de Jesus Lopez Norori Milton Gerardo , Manrique Carmen Paredes , Custodio Nilton 
Published: January 2025

AbstractBackgroundThe increasing prevalence of dementia, particularly in low‐income regions, necessitates the development of effective cognitive screening methods. However, the suitability of many existing tools for illiterate and low‐educated populations is limited, resulting in significant diagnostic disparities. This review aims to evaluate global cognitive assessment instruments for the identification of Mild Cognitive Impairment (MCI) and dementia in older adults with limited education.MethodFollowing the guidelines outlined by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses), a systematic review was conducted. This review encompassed searches across three databases for studies published between 2000 and 2023, with a focus on individuals aged 45 and above. Out of 1511 studies screened, 26 studies met the predefined inclusion and exclusion criteria.ResultNumerous studies have endeavored to adapt existing cognitive assessment tools to local languages to suit low‐literacy populations. Within this group, twelve distinct tests were identified. Notably, while the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are frequently used, they exhibit a notable bias towards education levels. The Rowland Universal Dementia Assessment Scale (RUDAS) exhibited strong performance, particularly among individuals with limited education, displaying high sensitivity and specificity.ConclusionIn summary, adjusting cutoff scores can be a valuable strategy for assessing individuals with limited education, but the development of customized cognitive assessment tools is imperative. The creation of region‐specific, sensitive cognitive evaluations, encompassing functional assessments, is pivotal to achieving a comprehensive diagnostic evaluation.
Phenotypic characterization of a novel hAb‐KIloxP;hAPOE4;Trem2R47H_NSS mouse model
Authors: Gomez‐Arboledas Angela , Kramár Enikö , Kawauchi Shimako , Da Cunha Celia , Lu Yueh Hao , Milinkeviciute Giedre , Neumann Jonathan , Wood Marcelo A , Tenner Andrea J , LaFerla Frank M , MacGregor Grant R , Green Kim N. 
Published: January 2025

AbstractBackgroundGenome‐Wide Association Studies (GWAS) identified ApoE4 and Trem2*R47H as two of the strongest genetic risk factors for late‐onset Alzheimer’s Disease (LOAD). As part of our efforts to develop mouse models that better recapitulate LOAD, at Model Organism Development & Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) consortium at University of California – Irvine, we have created a triple homozygous mouse model that combines our previously developed hAb‐KIloxP mice (Jackson Lab #031050), Trem2R47H NSS (Jackson Lab #034036) and a humanized ApoE4 (Jackson Lab #027894), to evaluate the interactions between aging, hAPOE4, TREM2*R47H, and hAb.MethodBy breeding the hAb‐KIloxP, hApoE4 and Trem2R47H NSS, we obtained triple homozygous (HO) mice and we then generated four different groups: WT (C57BL6/J), hAb‐KIloxP HO, hAb‐KIloxP HO;hApoE4 HO and hAb‐KIloxP HO;hApoE4 HO;Trem2R47H NSS HO. All four groups were then aged to 4, 12, 18 and 24 months of age, when coronal hippocampal slices were prepared, and long‐term potentiation recordings were obtained. Additionally, we also measured soluble and insoluble Ab40 and Ab42 as well as plasma neurofilament light chain (NfL).ResulthAb‐KIloxP mice showed a significant reduction in mean potentiation 50‐60 minutes post TBS, when compared to WT mice at 4, 12, 18 and 24 months of age, indicative of an LTP deficit associated to human Ab. Interestingly, both hAPOE4 and Trem2R47H NSS variants completely prevent the LTP deficits observed on the hAb‐KIloxP mice from 4 months of age. In addition, cortical soluble Ab40, Ab42 and the Ab42/Ab40 ratio were significantly decreased in hAb‐KIloxP;hAPOE4 and hAb‐KIloxP;hAPOE4;Trem2R47H NSS mice at 24 m of age, when compared to hAb‐KIloxP. However, plasma NfL levels were significantly increased in hAb‐KIloxP;hAPOE4;Trem2R47H NSS mice at 24 months of age, indicative of axonal damage in this mouse model.ConclusionhAb induces robust LTP deficits that are prevent by either hAPOE4 or TREM2*R47H, contrary to expectations. However, hAPOE4 and Trem2R47H NSS variants have a cumulative detrimental effect on axonal damage when combined with aging.
Endothelial nitric oxide synthase deficiency exacerbates SARS‐CoV‐2 induced neuropathology in a mouse model of vascular dementia
Authors: Ismael Saifudeen , Umar Meenakshi , Bix Gregory J 
Published: January 2025

AbstractBackgroundSARS‐CoV‐2 causes a variety of neurological sequelae in COVID‐19 survivors, including fatigue and cognitive dysfunction. Endothelial dysfunction is the unifying and central mechanism of COVID‐19 illness and a major risk factor for vascular dementia (VaD). Endothelial dysfunction stems, in part, from an imbalance between nitric oxide (NO) generated by the endothelial nitric oxide synthase (eNOS) and reactive oxidant species produced by uncoupled‐eNOS. Clinical observations suggest that decreased NO bioavailability appears as a likely pathogenic factor of endothelial dysfunction in COVID‐19 patients. We hypothesize that eNOS deficiency contributes to brain endothelial dysfunction in SARS‐CoV‐2 infection and SARS CoV‐2 infection promotes early onset VaD in eNOS deficient mice.Methods6‐month‐old WT/eNOS± male mice were infected with 1 × 104‐pfu mouse‐adapted (MA10) SARS‐CoV‐2 intranasally and animals were evaluated acutely out to 3 days‐post‐infection (3dpi) for changes in body weight and clinical signs of illness. Genomic and sub‐genomic viral copy numbers were also quantified. RNA was isolated whole‐brain and was analyzed for quantitative PCR and immunofluorescence for markers of inflammation and blood‐brain barrier permeability.ResultsMA10 infection induced significant weight loss in WT and eNOS± mice. eNOS± mice exhibited more disease‐associated weight loss (∼15%) than WT‐infected mice, but no infection‐induced mortality was observed in either group. We then confirmed MA10 viral copy in the lungs of infected, but not uninfected, WT MA10 and eNOS± mice at 3 dpi (noted to be similar in both groups). However, we did not detect the virus in the brains of the MA10‐infected WT and eNOS± mice. Real‐time PCR analysis of mouse whole brain‐isolated mRNA showed that the proinflammatory mediators CCL2 and IL‐6 were elevated in both the WT and eNOS± mice (eNOS± > WT) following MA10 infection. Immunofluorescent analysis showed increased Iba1 (microglia marker) fluorescent intensity in the cortex of eNOS± mice following MA10 infection than WT mice (mock or MA10 infected) and eNOS± mock mice.ConclusionsThe eNOS± mice experience worsened acute SARS‐CoV‐2‐associated morbidity indicated by increased weight loss, glial activation, and neuroinflammation than WT mice despite a similar pulmonary viral load. This is the first experimental evidence investigating a link between eNOS and neuropathology associated with SARS‐CoV‐2.
Longitudinal cognitive outcomes are strongly correlated with the Alzheimer’s Disease microbiome
Authors: Zeamer Abigail L , Sanborn Victoria , Drake Jonathan D , Haran John P , Bucci Vanni 
Published: January 2025

AbstractBackgroundIt has been shown that dysbiosis, or dysfunction of the gastrointestinal (gut) microbiome is associated with Alzheimer’s disease (AD). Here, we aimed to expand on beyond our previously reported findings of the gut microbiome associating with AD and explore if the gut microbiome is predictive of cognitive performance in individuals with AD. We sought to identity what cognitive domains are associated with the microbiome in our cohort of AD patients and healthy controls without dementia.MethodOlder individuals residing in the general community of central Massachusetts were enrolled in our study. At each visit, fecal samples and clinical variables were collected in addition to cognitive testing using the ADAS‐Cog‐13 tool, such as delayed memory, word recall, recognition etc. Metagenomic profiling was performed on longitudinal fecal samples. Z‐scores for different cognitive domains, including memory, executive function and language were generated for the study population. Mixed‐effect random forest regression (MERFR) models were created to identify metagenomic features informative of cognitive performance across these different cognitive tests and domains.ResultReplicating our previous work, among AD diagnosed individuals, MERFR models predicted performance on ADAS‐Cog 13 from microbial abundance and pathways with a strong accuracy. The ADAS‐Cog 13 was not well predicted by the microbiome in the healthy controls. Additionally, in our new analysis across different cognitive domains, Z‐Scores were well predicted by MERFR models using microbial abundance and encoded pathways.ConclusionNot only is the gut microbiome composition highly predictive of AD diagnosis, but there is also a strong correlation of the gut microbiome and cognitive functioning. This is true across the multiple domains of cognition including memory, executive function and language, however different bacterial species were significant in associating with each domain. This work highlights the complexity of the microbiome‐gut‐brain axis and how the microbiome community makeup might play a role in cognitive decline.
Recurring genetic variant in LEADS
Authors: Rumbaugh Malia C. , Nudelman Kelly N. , Dage Jeffrey L. , Eloyan Ani , Hammers Dustin B. , Carrillo Maria C. , Dickerson Bradford C. , Rabinovici Gil D. , Apostolova Liana G. , Foroud Tatiana M. ,   the DIAN/DIAN‐TU Clinical Genetics Committee, and the LEADS Consortium
Published: January 2025

AbstractBackgroundThe Longitudinal Early‐onset Alzheimer’s Disease Study (LEADS) is analyzing the genetic etiology of early onset (40‐64 years) cognitive impairment, including amyloid‐positive early‐onset Alzheimer’s disease (EOAD) and amyloid‐negative early‐onset Alzheimer’s disease (EOnonAD). One goal of this investigation is to identify novel or under‐characterized genetic variants.MethodsCognitively impaired (CI) LEADS participants, including amyloid‐positive and amyloid‐negative early‐onset cases, were whole exome or genome sequenced (N = 361). Genetic and copy number variants in APP, PSEN1, PSEN2, GRN, MAPT and C9ORF72 were assessed. Variants in these genes were annotated with Annovar and assessed for potential pathogenicity with criteria including 1,000 genomes population frequency, computational functional prediction, and reported disease occurrence in databases including ClinVar and the Human Gene Mutation Database. Variants were reviewed manually as well as with VarSome and evaluated for pathogenicity using the American College of Medical Genetics criteria. Patient information for carriers of likely pathogenic variants not reported as pathogenic in ClinVar or included in the Dominantly Inherited Alzheimer Network Trial Unit (DIAN‐TU) Trial Eligible list were reviewed.ResultsThree CI participants were found to carry the p.I227L variant in PSEN1 (3/361, 1%), with no other pathogenic variants identified in these individuals in the six genes analyzed. This variant was previously described in a single individual. It is classified as likely pathogenic by Varsome based on In‐Silico predictors; however, it is listed as “Pathogenicity Not Classified” in AlzForum and as a Variant of Unknown Significance in ClinVar due to the lack of reported cases. The variant is not included in the DIAN‐TU Trial Eligible List. We describe the family history, demographic and clinical data for these three participants.ConclusionsThe PSEN1 variant p.I227L was identified in three LEADS CI participants and warrants further investigation as a potentially pathogenic variant.
Organizing Alzheimer’s Disease Endophenotypes Into Subdivisions of Biological Domains Improves Therapeutic Target Hypothesis Selection
Authors: Keegan Stephen , Cary Gregory A. , Wiley Jesse C , Leal Karina , Butler Robert R. , Greenwood Anna , Carter Gregory W ,   The Emory‐Sage‐SGC TREAT‐AD Center
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) therapeutics have largely been unsuccessful in alleviating disease burden in those afflicted by the disease. The TREAT‐AD Consortium is an international group of academic researchers dedicated to identifying novel molecular targets for AD from underexplored areas of disease linked pathology.MethodUtilizing a top‐down expert curation approach of organizing Gene Ontology terms into endophenotypes of AD, we developed 19 biological domains. To provide more functional insight of these biological domains impacts on AD, we recreated the process to make 80 subdomains. The biological domain describes the endophenotype, the subdomain describes the important functions of that endophenotype. The gene lists of these clusters are turned into protein‐protein interaction networks.ResultUsing the structures of the Gene Ontology, biological domains, and subdomains, it’s possible to identify a genes relationship to an endophenotype and its impact on other genes implicated in AD. Analyzing your target at a biological domain level connects endophenotypes and at the subdomain level it connects the functions that lead to the endophenotype.ConclusionA layered knowledge approach of investigating the impact a gene has on an endophenotype provides insight into how a potential therapeutic target would interact with other areas of disease biology. TREAT‐AD investigators will validate these targets in cell models and generate experimental resources to support further target development.
Distribution of cognitive domains and neuropathology of cases with mild cognitive impairment
Authors: Ho Andrew , Choudhury Parichita , Adler Charles , Shprecher David , Mehta Shyamal , Shill Holly , Driver‐Dunckley Erika , Belden Christine , Serrano Geidy E , Beach Thomas G. , Atri Alireza , Tremblay Cécilia 
Published: January 2025

AbstractBackgroundMild Cognitive Impairment (MCI) is a pre‐dementia state where impaired cognitive domains (memory, executive, visuospatial processing, language) may predict underlying pathology, e.g. Alzheimer’s disease(AD), Lewy body (LB), and other. Delineating neuropathological heterogeneity in MCI and their associations with neuropsychological profiles are important in identifying individuals at risk of further deterioration. We aimed to characterize the neuropathological heterogeneity in cases with a diagnosis of MCI.MethodCases with a final consensus cognitive diagnosis of MCI (n = 128) prior to death were selected from the Arizona Study of Aging and Neurodegenerative disorders (AZSAND). Groups were divided into amnestic (aMCI) and non‐amnestic MCI (naMCI), single and multi‐domain impairment, and specific domain impairment (executive, language, visuospatial) was explored. Presence and severity of neuropathology including AD, LB, cerebral white matter rarefaction (CWMR), cerebral amyloid angiopathy (CAA), cerebral infarcts and microinfarcts (cortical and subcortical), TAR DNA‐binding protein 43 (TDP‐43), and apolipoprotein E (ApoE) status were compared between MCI subtypes.ResultThe number of cases meeting neuropathological criteria for AD was not different between aMCI (36.4%) and naMCI (22.6%) while co‐existent PD was less frequent in aMCI (19.5% vs 38.7%). When compared to naMCI (n = 31), the aMCI (n = 85) group had an older age of death (p = 0.001), less educational years (p = 0.04), a higher number of subcortical infarcts (p = 0.012), a higher regional density of neurofibrillary tangles (p = 0.027) and a lower density of LB (p = 0.015) in the temporal lobe, and CWMR in tended to be more severe in the frontal lobe (p = 0.052). Those with single domain aMCI had less CWMR (p = 0.001) compared to the multidomain. Within the naMCI group, those with single domain MCI had higher proportions of CAA (p = 0.042), and lower LB density (p = 0.019) compared to multidomain. CWMR was more severe (p = 0.026) inConclusionA high heterogeneity was observed between MCI subtypes. While AD pathology was similar between groups, regional anatomical differences were observed. Vascular pathology including subcortical infarcts, CWMR and CAA appear to be commonly associated with both aMCI and naMCI respectively while CWMR was associated with executive dysfunctions. CWMR, CAA and LBs appear to be more frequent in multidomain aMCI and naMCI respectively.
Clinical Recognition of Frontotemporal Dementia with Right Anterior Temporal Predominance; Recommendations of the International Working Group
Authors: Ulugut Hulya 
Published: January 2025

AbstractBackgroundAlthough frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized as a separate FTD subtype, a uniform description of the syndrome is still missing. This multicenter study, led by an international working group (IWG), aims to establish a cohesive clinical phenotype and lay the groundwork for consensus on terminology and diagnostic standards.MethodRetrospective clinical data were systematically collected across 18 dementia centers. The harmonized data were interpreted by 90 FTD experts across over 30 centers. Visual assessments of initial neuroimaging identified study cases, culminating in a cohort of 360 FTD patients with predominant RATL atrophy.ResultCommon symptoms were mental rigidity and preoccupations (78%), disinhibition (74%), naming/word‐finding difficulties (70%), memory deficit (67%), apathy (65%), loss of empathy (65%), and face recognition deficit (60%), based on the chart reviews. Reviewing case notes beyond clinicians' interpretations unveiled impairments in identifying landmarks, smells, sounds, tastes, and bodily sensations, and altered reactions to those stimuli (74%). These symptoms, while not explicitly queried or examined, were often categorized under language, memory, behavioral, psychiatric, or other/unclassified problems by various centers. Available cognitive test scores indicated impairments in emotion, people, social interactions, and visual semantics related domains. Secondly, the IWG interpreted symptoms within three main domains; (i) semantic deficit for predominant non‐verbal information including people, taste, smell, sound, landmarks, bodily sensations, socioemotional information/ concepts/ facts (ii) socioemotional dysfunction including altered emotional expressivity, and emotional apathy, (iii) altered thought process including mental rigidity, hyper‐focused specific interests and altered hedonic valuation and prioritization. Lastly, 67 patients had genetic and/or pathological confirmation for FTLD, and 21 had amyloid positivity. Of note, caution is advised in interpreting amyloid positivity, and the distinct clinical nuances associated with each molecular subtype are emphasized by the IWG.ConclusionThis collaborative effort represents the first international initiative to establish the largest RATL cohort, resolving contradictions in the field and shedding light on challenges in recognizing RATL impairment in clinical practice. Our ultimate goals are reaching a consensus on diagnostic criteria that will facilitate the recognition of FTD associated with RATL atrophy and differentiate the syndrome from other dementia subtypes and psychiatric disorders.