bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysosomal defects in Grn loss of function modulate microglial cell state and immune responses
Authors: Tejwani Leon , Paolo Gilbert Di 
Published: January 2025

AbstractBackgroundMacrophages and microglia are myeloid cells that play critical roles in the surveillance of the local environment of the tissues in which they reside. The ability of these phagocytes to perform key functions is contingent on their capacity to sense extracellular cues and mount responses that involve chemotaxis, proliferation, cytokine secretion, and phagocytosis of various cargos for lysosomal clearance. Our overarching hypothesis is that lysosomal degradation of phagocytic cargoes is critical for the resolution of cellular/tissue damage, as well as of inflammation, and that failure to accomplish this step affects myeloid cell states and immune responses.MethodTo test this hypothesis, we examined the consequences of disrupting lysosomal function on myeloid cell state, using GRN deficiency as a model of primary lysosomal dysfunction.ResultGRN is highly expressed in these cells and encodes progranulin, a frontotemporal dementia‐linked protein critical for the regulation of lysosomal degradative processes. We first performed single‐nucleus RNA‐sequencing of purified microglia from aged wild‐type and Grn knockout (KO) mice, defining the diverse subpopulations that emerge with disease in this context. Next, we characterized primary microglia and macrophages from Grn KO mice cultured in the absence of other cell types, which revealed robust cell autonomous transcriptional and functional alterations resulting from Grn deficiency. To further examine how specific forms of lysosomal dysfunction impact myeloid cell state, we induced pharmacological and genetic perturbations of various lysosomal properties, which uncovered a robust response of myeloid cells to lysosomal deacidification that largely overlaps with that observed in Grn KO myeloid cells. Finally, we identified putative transcription factors that mediate the transcriptional remodeling of myeloid cells in response to lysosomal stress.ConclusionOverall, these data reveal a novel link between lysosomal health and myeloid cell transcriptional and functional states.
Factors influencing adults' willingness to be screened for dementia risk
Authors: Reed Alexandra M , Hooyman Andrew , Lee Nicole M , Fauth Elizabeth B. , Love Jill W , Schaefer Sydney Y 
Published: January 2025

AbstractBackgroundThe Alzheimer’s Association recommends early screening of Alzheimer’s disease and related dementias(ADRD), urging the development of biomarkers and other tools for early risk/detection. However, the general public’s willingness to be tested for early ADRD must be considered, particularly among minoritized populations. For example, Black older adults within the United States (U.S.) are twice as likely to develop ADRD compared to White non‐Hispanic older adults, but have lower rates of engagement/trust in the medical system.MethodThis study used Amazon MTurk to survey 572 U.S. adults on their willingness to take a (hypothetical) test for short‐term dementia risk. Mean participant age was 41.9±11.9. The sample was 47% Female, 77% non‐White, and 92% non‐Hispanic/Latino, with 37% having less than a bachelor’s degree. We also calculated an aggregated Area Deprivation Index (ADI) based on 5‐digit zip code to quantify a location’s relative advantage or disadvantage on a scale of 1‐100 compared to state and national percentiles, where lower ADI values represent greater area deprivation (mean±SE ADI = 47.65±24.51). All participants were non‐demented based on the Functional Assessment Questionnaire (score<9).ResultAlthough White and non‐White participants were both willing to test (∼77%), non‐White participants were approximately four times more likely to test only if their results were not shared with their medical provider/insurer. The desire to test outside of medical environments is further supported by the fact that the most common reason for taking the test was peace of mind (78%) rather than facilitating treatment plans, and that a positive test result would be most shared with family (62%) rather than with doctors right away. Older age was also associated with increased willingness to test, while ethnicity and socioeconomic status were not.ConclusionHistorical contexts and marginalization of minoritized groups may also impact willingness to screen for early ADRD risk/detection, which needs to be explored further. Building medical trust may take decades for some populations, thus supporting the need to develop options now for biomarkers or other ADRD‐risk screeners that are accessible and appropriate for culturally diverse groups, both within and outside of a medical context.
Atrophy Network Mapping of Anxiety in Cognitively Unimpaired Older Adults in Preclinical AD
Authors: Lee Soyoung , Palm Stephan T , Drew William J , Zide Benjamin S , Donovan Nancy , Fox Michael D , Siddiqi Shan 
Published: January 2025

AbstractBackgroundAnxiety is prevalent among cognitively unimpaired older adults and is associated with accelerated amyloid‐β‐related cognitive decline and incident cognitive impairment. Investigating these mechanisms is challenging due to low pathologic burden, high individual variability, and subsyndromal level of symptoms. Recently, brain networks involved in AD were successfully localized by mapping the brain connectivity of atrophy patterns associated with memory impairment and delusions. In this study, we investigated anxiety symptoms in older adults with elevated amyloid‐β using the novel method of atrophy network mapping.MethodWe utilized baseline data from ∼1800 cognitively unimpaired older adults, aged 65‐85, from the Anti‐Amyloid in Asymptomatic Alzheimer’s Disease (A4) trial, including clinical assessment of anxiety measured by the 6‐item State‐Trait Anxiety Inventory as well as structural brain MRI and amyloid‐β (18F‐florbetapir) PET acquisitions. We generated a vertex‐wise general linear model of cortical thickness to create individualized atrophy maps for each participant with elevated amyloid‐β deposition, using data from older adults with low amyloid‐β deposition as a control group. Then, we used a normative human connectome (n = 1000) to estimate the functional connectivity of each participant’s unique atrophy pattern. From the network connectivity maps, we identified atrophy‐based brain networks associated with higher anxiety. To validate this brain network, we performed a spatial correlation with a pre‐established anxiosomatic network derived from focal brain stimulation sites that selectively modify anxiety and assessed significance using permutation testing. We hypothesized that atrophy patterns associated with greater anxiety would correspond to this anxiosomatic network.ResultAnxiety symptoms localized to a distinct brain network based on individuals' atrophy patterns. The identified brain network was correlated to the anxiosomatic network (r = 0.65), and the correlation was stronger when controlled for depressive symptoms (r = 0.67). The network was more similar to the anxiosomatic network than expected by chance (p<0.05).ConclusionWe identified a brain network associated with anxiety symptoms in cognitively unimpaired older adults with elevated amyloid‐β. These findings help elucidate a neuropathophysiology of anxiety in preclinical AD and, possibly, its role in disease progression. The brain network identified in this project could yield new neurostimulation targets for anxiety in older adults across the AD continuum.
House dust mite‐induced asthma alters BBB integrity, increases amyloid beta accumulation, and alters brain cytokine levels in AppNL‐G‐F mice
Authors: Sahu Bijayani , Nookala Suba , Floden Angela M , Ambhore Nilesh , Venkatachalem Sathish , Combs Colin K 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is an age‐related neurodegenerative disorder affecting nearly 50 million individuals worldwide. Besides aging, various comorbidities can increase the risk of AD, such as asthma. However, the molecular mechanism(s) underlying this asthma‐associated AD exacerbation is unknown. This study was designed to explore the effects of house dust mite‐induced asthma on AD‐related brain changes using the AppNL‐G‐F transgenic mouse model.MethodMale and female C57BL/6 wild type and AppNL‐G‐F mice (8‐9 months old) were exposed to either saline or house dust mite (dose: 833µg/kg in saline) every alternate day for 16 weeks. Mice were sacrificed at the end of the experiment and broncho‐alveolar lavage fluid (BALF), lungs, blood, and brains were collected. BALF was analyzed for immune cell markers, inflammatory mediators, and LDH activity. Lung sections were stained with Alcian blue and Masson’s Trichrome to examine mucus and collagen production, respectively. The serum was analyzed for cytokine levels. Brain sections were immunostained for Aβ, GFAP, and collagen‐4. Finally, frozen hippocampi and cortices were used to perform Aβ ELISAs and cytokine arrays, respectively.ResultDust‐mite exposure increased inflammatory cells, cytokine levels, and LDH activity in the BALF and increased the mucus and collagen production in the lungs from both sexes and genotypes, suggesting induction of a severe asthma‐like condition. This correlated with increased levels of serum cytokines in all dust‐mite‐exposed groups. In agreement with this peripheral change, hippocampi from asthma‐induced male and female AppNL‐G‐F mice demonstrated elevated Aβ plaque load and increased soluble Aβ 1‐40/42 and insoluble Aβ 1‐40 levels. Dust‐mite exposure also increased astrogliosis in both sexes of AppNL‐G‐F mice, as indicated by GFAP immunoreactivity. Additionally, dust‐mite exposure‐induced asthma elevated cortical levels of several cytokines in both sexes and genotypes. Finally, dust‐mite exposed groups also showed a disturbed BBB integrity in the hippocampus of AppNL‐G‐F mice, as indicated by decreased collagen‐4 immunoreactivity.ConclusionDust‐mite exposure induced a severe asthma‐like condition that exacerbated Aβ pathology, astrogliosis, cytokine changes, and disturbed BBB integrity in the brains of male and female AppNL‐G‐F mice. Defining the mechanisms of secondary effects of asthma on the brain may provide a novel therapeutic approach for both asthma and AD.
Frailty and Cognition: Unravelling the Intricate Nexus
Authors: Partha Ajith , S Monisha , Stezin Albert , L Abhishek M , Mallikarjun Divya N , M Amitha C , HS Deva Kumar , Narayanasamy Rajitha , Menon Meenakshi , R Meghana , Vishwanath Vindhya , Velavarajan Goutham , Malo Palash K , Arvind Prathima , Hameed Shafeeq K Shahul , HS Sunitha , Singh Sadhana , Mondal Banashree , Agrawal Deepashri , Sundarakumar Jonas S. , Issac Thomas Gregor 
Published: January 2025

AbstractBackgroundFrailty, synonymous with physical vulnerability and decline, may exert nuanced effects on cognitive functions.(Borges, Canevelli, Cesari, & Aprahamian, 2019) This study assesses possible association between frailty and cognitive performance with the aim of identifying vulnerable cognitive domains.MethodWe analysed the baseline data from Tata Longitudinal Study of Ageing (TLSA)(Sundarakumar et al., 2020), an ongoing longitudinal study, based in urban Bangalore, India. Frailty was evaluated using clinical markers such as Timed Up and Go test (TUG), Hand Grip Strength right and left (HGSRt and HGSLt respectively), and Chair Stand test (CST). Cognitive function was evaluated using Addenbrooke’s Cognitive Examination III (ACE III), and Clinical Dementia Rating (CDR) scores. Generalized linear models/ Binary logistic regression were used to evaluate the relationship between frailty parameters and cognition.ResultIn a cohort of 1484 participants (51% males, 49% females; mean age 62.3 ± 9.6, mean education 15.2±3.8 years), significant positive correlation was found between HGS and ACE scores and significant negative correlation was found between TUG and ACE scores. Notably, no significant association was found between the Chair Stand Test (CST) and ACE scores (Table 1&2). Individuals with higher HGSRt (Odds Ratio [OR] = 0.967, 0.939‐0.996, p value 0.026), and CST (OR = 0.903, 0.839‐0.972, p value 0.006) exhibited a lower likelihood of Mild Cognitive Impairment (MCI). Additionally, those with MCI took longer duration in TUG test (OR = 1.209, 1.122‐1.304, p value <0.001) compared to normal participants. There was no significant association between MCI and HGSLt (OR = 0.973, 0.945‐1.002, p value <0.069).ConclusionThe study reveals a significant association between frailty parameters and cognitive functions. These findings demonstrate the impact of physical resilience on cognitive well‐being, emphasizing the importance of addressing frailty as a modifiable factor in promoting cognitive health among aging individuals.
Robust Symptomatic Subtypes of Typical Alzheimer’s Disease Characterized by Differential Neuropathological Patterns and Functional Decline
Authors: Zalzale Hussein , Ferreira Pamela C.L. , Lemaire Peter , Madeiros Marina Scop , Soares Carolina , Bellaver Bruna , Bauer‐Negrini Guilherme , Lussier Firoza Z , Povala Guilherme , Ferrari‐Souza João Pedro , Abbas Sarah , Aguzzoli Cristiano Schaffer , Rodrigues Matheus Scarpatto , Rohden Francieli , Amaral Livia , Leffa Douglas Teixeira , Oliveira Markley , Tudorascu Dana , Tissot Cécile , Rahmouni Nesrine , Ashton Nicholas J. , Blennow Kaj , Hong Chang Hyung , Son Sang Joon , Rosa‐Neto Pedro , Cohen Ann D , Lopez Oscar L. , Villemagne Victor L , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is classically viewed as a predominantly amnestic syndrome, with other cognitive and neuropsychiatric symptoms (NPS) being non‐integral associations. Emerging Evidence suggests that within typical AD, these symptoms are core features from the onset.MethodsWe employed K‐modes clustering on 2483 cognitively impaired (CI) individuals (CDR ≥ 0.5), excluding participants diagnosed with atypical AD, non‐amnestic MCI, or CI due to non‐AD dementias from five cohorts: TRIAD, ADNI, BICWALZS, OASIS‐III, and Pittsburgh. Cluster‐specific clinical and pathological profiles were established through comparison with 2670 cognitively unimpaired (CU) participants across plasma biomarkers (Ptau‐181, Ptau‐217, GFAP, Nfl, AB42/40 ratio) and neuroimaging (amyloid and tau PET, white matter hyperintensity, MRI‐derived degeneration maps). The rate of functional decline, modeled by increase in CDR‐SB, was assessed using a Cox‐proportional hazards model and a linear mixed‐effect model.ResultsWe identified five distinct clinical phenotypes within typical AD: ‘Pure Amnestic’ (30.2%), ‘Linguistic‐Hyperactive’ (14.7%), ‘Visuospatial‐Affective’ (14.7%), ‘Frontal’ (27.6%), and ‘Global’ (19.3%) (Figure 1, Figure 3). These phenotypes demonstrated consistency regardless of amyloid status or cohort. Each phenotype exhibited a unique neuropathological signature and a distinct pattern of neurodegeneration (Figure 2). A critical aspect of our findings is the differential rate of functional decline across these phenotypes. The ‘Pure Amnestic’ group showed the slowest decline, followed by ‘Linguistic‐Hyperactive’ (HR = 1.39; B = 0.2), ‘Visuospatial‐Affective’ (HR = 2.13; B = 1), ‘Frontal’ (HR = 2.23; B = 1.53), and the ‘Global’ phenotype showing the fastest decline (HR = 3.52; B = 2.66) (Figure 2, Figure 3).ConclusionOur results challenge the concept of “typical” AD by uncovering five robust clinical phenotypes with divergent neuropathological profiles and clinical characteristics. These results mark an important advancement toward personalized medicine in the landscape of emerging AD treatments.
Physical performance, frailty and BPSD in patients with dementia: a retrospective study
Authors: Bianco Maria Giovanna , Rogani Sara , Pullia Rosanna , Bianchi Elena , Carlo Ludovica Di , Bufi Gianluca , Carmassi Francesca , Silvestri Rosa , Calsolaro Valeria , Virdis Agostino 
Published: January 2025

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) can lead to loss of independence, increased risk of hospitalization and early institutionalization. This work aims to evaluate the relationship between physical performance and BPSD in older patients with dementia.MethodIn this observational single‐center study, patients with dementia underwent a Comprehensive Geriatric Assessment (ADL, IADL, CIRS, CFS) and cognitive and neuropsychiatric evaluation (MMSE, NPI). Through K‐means cluster analysis for frailty, disability and burden of comorbidities, we split the population in three clusters, according. BPSD were classified in three groups: “mood/apathy” (depression, apathy, appetite and sleep disturbances), “psychosis” (delusions, hallucinations, anxiety) and “hyperactivity” (agitation, euphoria, aberrant motor activity, irritability, disinhibition).Result263 patients aged > 65 years (mean age 83.6±5) were enrolled; 111 patients underwent a 12‐month follow‐up. The global population had low comorbidity burden (CIRS 1.33±1.4), mild frailty (CFS 5.4 ± 1.2, BADL 5±3, IADL 3±4) and moderate cognitive decline (MMSE 18.9±5). Based on physical performance and comorbidities (ADL, IADL, CIRS, CFS) three clusters were identified: cluster 1 (47 patients) showed higher comorbidity burden, cluster 2 (106 patients) mild frailty and younger patients, cluster 3 (110 patients) higher ADL/IADL disability. The three group significantly differed in cognitive performance (MMSE1 19.2 ± 5.3; MMSE2 20.8 ± 4.6; MMSE3 16.9 ± 4.5, respectively), particularly between clusters 1 and 3 (p = 0.01) and between clusters 2 and 3 (p<0.01). At baseline, there was no difference in the distribution of mood/apathy and psychosis symptoms, while the prevalence of hyperactivity symptoms was higher in cluster 3 (p <0.001). At 12‐month re‐evaluation, the prevalence of psychosis symptoms in clusters 2 and 3 was significantly higher (p = 0.008). A correlation was also highlighted between hyperactivity symptoms and IADL‐impairment at baseline. In addition, in all the three clusters a significant worsening in physical and functional performance was highlighted over 12‐months.ConclusionIn dementia patients with BPSD, cognitive and physical performance worsen over time. The presence of positive psychiatric symptoms was higher in clusters with a higher degree of frailty and disability, but we ignore the causality to one another. Larger studies are needed to assess the relation between BPSD and frailty.
Driving Behavior as a Functional Biomarker of Preclinical Alzheimer Disease
Authors: Wisch Julie K. , Morris John C. , Benzinger Tammie L.S. , Ances Beau , Babulal Ganesh M. 
Published: January 2025

AbstractBackgroundTrip chaining occurs when a driver departs from an origin and travels to multiple locations before returning. Increased trip complexity may require higher levels of executive function, memory, and navigational abilities. Subtle behavioral changes are apparent before a clinical diagnosis of Alzheimer Disease (AD); however, the correspondence between preclinical AD pathology (amyloid deposition, tauopathy, neurodegeneration), cognition, and changes in trip chaining behavior is unknown.Method46 individuals enrolled in the DRIVES study (µEnrollment = 2.7 years, ơEnrollment = 1.1 years) at Washington University in St. Louis completed longitudinal amyloid PET imaging and converted from amyloid negative (A‐) to amyloid positive (A+). All data were ordered temporally relative to date of conversion. We fit changepoint models to the average number of segments per departure and average number of trips away from home per month over time. After identifying key windows‐of‐change in trip‐related behavior, we extended our analysis of neuroimaging and cognitive data to all Knight Alzheimer Disease Research Center participants. We used a published analytical model to estimate time from A+ for all participants with amyloid PET (N = 1082). Then, we evaluated the spatial deposition of tau for individuals imaged within the time window‐of‐interest identified via changepoint model (N = 34). We applied linear mixed effects models to compare measures of brain structure and cognition between A‐ controls (N = 752, 195 respectively) and individuals within the window‐of‐interest (N = 105, 66).ResultThe total number of departures declined 6.3 (95% CI: 4.2, 6.7) years after becoming A+, and the number of segments per trip declined 8.2 (95% CI: 7.0, 9.3) years after becoming A+ (Figure 1). Within this key window (4.2 – 9.3 years post‐A+), tau was elevated in the earliest anticipated regions (Braak I/II), and 24/34 individuals were tau positive (Figure 2). Neurodegeneration was observable in the cortex, hippocampus, and regions associated with allocentric navigation but not egocentric navigation. Cognitive changes are not seen globally but were seen in attention and episodic memory (Figure 3).ConclusionChanges in amyloid burden, tauopathy, and neurodegeneration have real‐world effects on daily driving behavior even before global cognitive impairment is observed.
Does COVID‐19 Infection Accelerate Age‐Related Cognitive Decline?
Authors: Woods David L. , Hall Kathleen , Pebler Peter , Williams Garrett , Herron Timothy J , Blank Michael , Geraci Kristin , Johnson David K , Schendel Krista , Lwi Sandy J. , Chok Jas M. , Kahly Omar , Spinelli Maria G , Jaramillo Isabella , Baldo Juliana 
Published: January 2025

AbstractBackgroundSimilar neuroimaging abnormalities are reported in post‐COVID patients and patients with AD. Moreover, COVID‐19 and Alzheimer’s Disease (AD) share genetic vulnerabilities and have similar cognitive symptoms of COVID (e.g., memory impairment, mental fatigue, anosmia, etc.). These findings raise the concern that COVID infection may increase the risk that older patients will develop Alzheimer’s disease.MethodSelf‐reported COVID histories were recorded from 415 older participants (mean age 70.1 years), including 310 participants longitudinally tested beginning in 2022. The effects of COVID on cognitive performance were assessed with 32 computerized subtests of the California Cognitive Assessment Battery (CCAB). Omnibus z‐scores were averaged over 70 test measures at enrollment, and again at 6‐month and 18‐month post‐enrollment in the 310‐participant sample.ResultSignificant demographic differences were seen between COVID+ and COVID‐ groups (Table 1). COVID+ patients performed worse than COVID‐ patients overall (Figure 1, t(85) = ‐2.80, p<0.01) and when analyzed with a conventional model using Age, Education, and Gender (AEG) as regressors (t(85) = ‐3.07, p<0.005, Figure 2). However, inter‐group differences failed to reach significance (t(85) = ‐0.97, NS) when analyzed with a comprehensive 15‐factor model that factored out additional demographic influences including vocabulary, comorbidities, depression, anxiety, functional status, and race. In contrast, COVID infection severity (estimated from augmented WHO scores) correlated significantly with omnibus z‐scores when analyzed with the comprehensive model (r = ‐0.30, t(64) = ‐2.52, p<0.02) but correlations failed to reach significance when analyzed with the conventional (AEG) model.The effect of incidental “breakthrough” COVID infections in participants (97.35% were vaccinated prior to retest) was analyzed at 6‐months (38 cases) and 18‐months (50 cases). Breakthrough infections prior to 6‐month retest were paradoxically associated with improved 6‐month Omnibus scores (t(49) = 2.74, p < 0.01), while no significant differences were observed for breakthrough infections prior to the 18‐month retest (t(90) = 0.95, NS).ConclusionThese preliminary results suggest that infections with Wild Type and Delta variants early in the COVID pandemic produced cognitive deficits among older participants, particularly among patients hospitalized with COVID. In contrast, post‐inoculation breakthrough infections caused no significant decline in cognitive performance.