bluuebunny/crossref_metadata_2025_split huggingface dataset:
Marmoset cognitive aging: Heterogeneity and synaptic dysfunction
Authors: Glavis‐Bloom Courtney , Vanderlip Casey R , Asch Payton A , Novak Sammy P Weiser , Kuwajima Masaaki , Kirk Lyndsey M , Harris Kristen M , Manor Uri , Reynolds John H 
Published: January 2025

AbstractBackgroundAs humans age, some experience cognitive impairment while others do not. When impairment occurs, it varies in severity across individuals. Translationally relevant models are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain’s susceptibility to aging. The common marmoset has emerged as an advantageous non‐human primate model to investigate the biological consequences of aging due to shared behavioral, neuroanatomical, and age‐related neuropathological features with humans, and a short lifespan that facilitates longitudinal studies. Despite growing popularity as a model, robust cognitive phenotyping of marmosets, particularly as a function of age and across multiple cognitive domains, is lacking.MethodTo address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we developed a comprehensive touchscreen‐based neuropsychological test battery. We use this battery to longitudinally assess cognitive aging trajectories in marmosets across the lifespan. To characterize synaptic ultrastructure as a function of aging and cognitive status, we used electron microscopy.ResultSimilar to humans, we find that marmosets show age‐related impairment in motor speed, motivation, cognitive flexibility, and working memory, with a remarkable degree of heterogeneity. We also find that aged marmosets show synapse loss in the dorsolateral prefrontal cortex at a level consistent with aged macaques. Though synapse loss is widely considered a key determinant of cognitive impairment with age, we find an equivalent degree of synapse loss in aged cognitively unimpaired and aged cognitively impaired marmosets. Our findings indicate that the coordinated scaling of the sizes of synapses and mitochondria with associated boutons is crucial for preserving working memory with age. However, failure of synaptic mitochondria to scale with presynaptic boutons selectively underlies age‐related working memory impairment.ConclusionWe posit that failed scaling results in mismatched energy supply and demand, leading to impaired synaptic transmission. This novel mechanism of synapse dysfunction differentiates aged marmosets with cognitive impairment from those without. Together, this work demonstrates the importance of comprehensive cognitive phenotyping to uncover the neurobiological consequences of aging, and firmly establishes the common marmoset as an advantageous model for age‐related cognitive impairment.
Comparative Assessment of Human‐ vs. Murine‐ derived Microglia as a Model for pro‐Inflammation in Alzheimer’s Disease
Authors: Mitrasinovic Olivera M. 
Published: January 2025

AbstractBackgroundHigh‐throughput assays have attracted significant attention in Alzheimer’s Disease (AD) research, especially for enabling rapid diagnostics screening for factors at the molecular level contributing to the disease recurrence. With advances in laboratory automation, there is a growing need for quality pre‐clinical data. Assays such as Microarrays, Proteomics, or AI are all dependent on high‐quality input data that serve as a starting point. We have evaluated whether data from murine parallel human microglial cell cultures and have focused our study on three main biomarkers: proinflammatory inducer IL‐1α, neurotoxic iNOS and phagocytosis Fcγ Receptor system implicated in Aβ clearance after antibody mediated opsonization as an immunization paradigm.MethodTwo representative cell lines were included in this study: Human‐derived SV‐A3 microglia, cell count, viability and cytotoxicity matched for comparative analysis to well‐established, SV40 antigen immortalized Mouse BV‐2 as we described (O. Mitrasinovic et al. J.Biol.Chem. 276 (32): 30142‐9 (2001)); 24h post‐immune activation expression fold changes were assayed with SYBR/TaqMan qRT‐PCR. Computational AI method validation was done in MATLAB®.ResultNormalized relative to placebo treated cells by dose‐matched each respective transfection media only, average expression fold increases of IL‐1α in BV‐2 and SV‐A3 had comparable trend, but consistently slightly higher in later: 29.41 vs. 36.23. Similar observation was found for neurotoxic iNOS: 2.45 vs. 4.03, demonstrating similar neurotoxic pro‐ inflammatory response. Qualitatively, phagocytosis of Fluorescently labeled FITC‐ Aβ1‐40 was similar. However, differences in the uptake of Antibody‐Opsonized Aβ were prominent, consistently with structural and genetic differences in FcγR’s in between mouse and human microglia.ConclusionThe extent of induced inflammation in AD demonstrates species‐specificity, and while for a number of genetically conserved factors similarity responses exist, especially main pro‐inflammation and neurotoxicity biomarkers, human cells seem to activate more robust inflammatory responses. Existence of the unique human vs. mouse differences at the genetic level for Aβ phagocytic processing factors needs to be taken into consideration in any subsequent AI‐type studies or high‐throughput approximations at the cellular level.Acknowledgments: Alzheimer’s Association for funding, in part.
Identification of regional and cell type‐specific gene dysregulation in Progressive Supranuclear Palsy
Authors: Grundman Jennifer A , Chang Timothy S , Kawaguchi Riki , Qi Le , Chen Lawrence , Gao Kun , Ou Jing , Nguyen Jade , DeTure Michael , Rawlinson Bailey , Dalgard Clifton L. , Morris Huw R , Geschwind Daniel H. 
Published: January 2025

AbstractBackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder involving pathological deposition of tau that includes glial inclusions and specific regional vulnerability patterns. Therapeutic developments are hampered by incomplete understanding of disease mechanisms. Few studies have examined its cell type‐specific effects. We performed RNA‐sequencing in a large cohort of PSP patients and controls to understand molecular pathways disrupted across prefrontal cortex and caudate nucleus in PSP. We also performed multi‐omic single‐nucleus sequencing to deconvolute cell type‐specific changes.MethodRNA‐sequencing was conducted in 250 PSP patients and age‐ and sex‐matched controls, with a subset (N = 23) undergoing multi‐omic single‐nucleus RNA‐sequencing and ATAC‐sequencing (10x Genomics). Sequencing data was aligned to GRCh38 and quantified using STAR and RSEM (RNA‐seq) and CellRanger (single‐nucleus) and corrected for technical and biological covariates. Differential expression was calculated with Dream (RNA‐seq) and Dreamlet (single‐nucleus sequencing), and co‐expression network analysis (WGCNA) used to extract disease‐relevant gene modules.ResultRNA‐sequencing analysis identified ∼4000 differentially expressed genes in both brain regions. Despite differences in cellular composition and degree of disease impact, both regions share patterns of dysregulation related to protein folding and processing, indicating common pathological mechanisms. Differences between the regions includes disruption of cellular homeostasis and intracellular trafficking in caudate, while prefrontal cortex shows suppression of metabolic processes and immune response. Preliminary findings from the single cell genomic analyses suggest the greatest changes occur in neurons of both regions, where there is a shared pattern of protein processing dysregulation and a distinct enrichment in metabolic processing within prefrontal cortex interneurons.ConclusionWe identified thousands of dysregulated genes in two impacted brain regions in PSP and show that this dysregulation is reflected in specific neuronal populations in these regions. Identifying regional and specific cell type‐specific mechanisms related to PSP will further our understanding of causative disease mechanisms and provide new avenues for therapeutic developments.
Neurovascular dysfunction, ApoE and innate immunity: co‐conspirators in ARIA
Authors: Iadecola Costantino 
Published: January 2025

AbstractAmyloid related imaging abnormalities (ARIA) are side effects of anti‐Abeta immunotherapy, which are most frequent and associated with greater morbidity in ApoE4 individuals. ARIA are characterized by neurovascular inflammation, leading either to increased vascular permeability and edema (ARIA‐E), or to more severe vascular damage and microhemorrhages (ARIA‐H). The mechanisms by which Abeta immunotherapy leads to ARIA remain to be established but may involve overload of the cerebral microvasculature by Abeta released from amyloid plaques. Abeta has profound proinflammatory and vasotoxic effects that alter the ability of cerebral blood vessels to regulate blood flow and damage the cellular constituents of the vessel wall. Using animal models of amyloid accumulation (tg2576 mice), we found that the deleterious neurovascular effects of Abeta are mediated by reactive oxygen species generated by perivascular and leptomeningeal macrophages, brain‐resident innate immune cells distinct from microglia and closely associated with cerebral arterioles and veins. The molecular mechanisms of the effect involve Abeta engaging the innate immunity receptor CD36 on these macrophages leading to free radical production by the enzyme NOX2. Accordingly, depletion of perivascular and leptomeningeal macrophages or deletion of CD36 or NOX in these cells prevents in full the damaging neurovascular effects of Abeta. Importantly, lack of CD36 also reduces Abeta accumulation in cerebral arterioles (cerebral amyloid angiopathy), a beneficial effect mediated by the ability of CD36‐deficient cerebral blood vessels to clear Abeta more effectively. Interestingly, brain macrophages also produce large amounts of ApoE, and in mice expressing human ApoE4 (ApoE4‐TR) ApoE4 in these macrophages triggers vascular oxidative stress and neurovascular dysfunction. Importantly, switching the genotype of the macrophages from ApoE4 to ApoE3, completely reverses the neurovascular dysfunction. These observations, collectively, point to brain resident macrophages associated with the cerebral microvasculature as key effectors of the neurovascular inflammation, oxidative stress, dysfunction and damage produced by Abeta. Inasmuch as ARIA are related to Abeta overload of the neurovasculature, targeting ApoE4, CD36 or NOX2 in these cells may be a putative therapeutic approach to prevent this deleterious vascular complication of Abeta immunotherapy.
Midlife modifiable AD risk presentation in women across the menopause transition
Authors: Caldwell Jessica ZK 
Published: January 2025

AbstractBackgroundWomen are at increased risk for Alzheimer’s disease (AD) compared to men. Given research supporting up to 40% of AD cases as preventable with lifestyle modification, midlife represents a critical time of life to intervene on dementia risks; however, little research has examined women‐specific presentation of risk at midlife, or how menopause staging may impact risk presentation. The aim of this study was to assess dementia risk profiles in women at risk for AD due to family history, including self‐reported and lab‐based modifiable risks, and to determine the role of menopause on risk presentation.MethodWe analyzed baseline data from 207 women patients of a clinical AD risk reduction program (age M = 53.4; education M = 17.0; 88% White; 93% Non‐Hispanic). Total risk score was defined as sum of the following, which were assigned value of 0 (absent) or 1 (present): self‐reported history of diabetes, hypertension, obesity, head injury, sleep apnea, and hearing loss; current regular stress and presence of adequate social support; current and former use of tobacco; drinking more than 7 alcoholic beverages per week; physical and cognitive activity; years of education; and measured BMI>30 (Total possible score = 15). Given drawbacks of self‐report, where available, laboratory values including A1c, fasting glucose, total cholesterol, LDL, and triglycerides were assessed for comparison. Menopause stage was assessed via self‐report (pre‐ or post‐menopause), and for a subset of women, via blood‐based FSH level (pre‐, peri‐, and post‐menopause). Total risk score and lab value differences by menopause group were assessed using Mann‐Whitney and Chi‐square tests.ResultMost common risks included self‐reported regular stress and depression, and BMI>30 (Fig. 1‐2). Total risks and lab values did not differ by self‐reported (z = ‐0.797) or FSH‐based menopause stage (Chi‐square = 2.3). Qualitatively, elevated lab values and self‐reported symptoms were often more common than self‐reported health conditions.ConclusionTotal sum of modifiable risks, and lab‐based risk markers did not differ by menopause stage, but rather stress, depression, and BMI emerged as common targetable risks across midlife. Future work should explore whether common symptoms and lab abnormalities shown here in the absence of related diagnoses represent avenues for early screening and intervention.
Possible Mechanisms of Amyloid β‐Protein Protofibrils for Acceleration of Aggregation
Authors: Nakano Hiroto , Nakayama Takahiro , Hikishima Sadao , Mori Makoto , Minamikawa Jota , Muramatsu Daiki , Sakashita Yasuhiro , Ikeda Tokuhei , Shinohara Moeko , Ono Kenjiro 
Published: January 2025

AbstractBackgroundThe growing number of AD patients is a public concern all over the world. During the decade, anti‐amyloid beta‐proteins (Aβ) monoclonal antibodies for AD patients have been developed. Among the immunotherapeutic agents, lecanemab is an anti‐Aβ monoclonal antibody that binds to Aβ protofibrils (Aβ PFs), which is an intermediate molecule in Aβ species. Although Aβ PFs have been regarded as pathogenic aggregates among the Aβ species, the precise mechanisms of the molecular functions of Aβ PFs in the Aβ polymerization process have not been clarified. This research aims to reveal the molecular interactions of Aβ PFs against Aβ aggregation cascades in the mixed samples of low molecular weight (LMW) Aβ42 and different concentrations Aβ42 mature fibril (MF) seeds.MethodAfter confirming the morphological characteristics of Aβ PFs, we performed thioflavin T (ThT) assays using mixed samples containing LMW Aβ42 and MF seeds in various conditions in both the absence and the presence of Aβ PFs. The structural conversions of Aβ42 aggregates were evaluated using circular dichroism (CD) spectroscopy. Continuous observations of the fibril formations in the different Aβ samples were performed using high‐speed atomic force microscopy (HS‐AFM). Statistical analysis between two data was performed using a Mann‐Whitney U‐test. Statistical analysis among multiple data was performed using one‐way factorial ANOVA followed by Tukey post hoc comparisons.ResultWe could confirm Aβ PFs with clavate‐shaped structures. The results of the ThT assays and CD spectroscopy showed that the presence of 2% Aβ PFs significantly accelerated Aβ aggregations with rapid conformational changes in the LMW Aβ42 sample. Aβ PFs did not promote Aβ aggregations in the mixed sample of LMW Aβ42 in the presence of 10% MF seeds, and inhibited the fibril elongations in the mixed sample of LMW Aβ42 in the presence of 2% MF seeds. In HS‐AFM images, the interactions of LMW Aβ42 and attached Aβ PFs on mica showed hyperbolic fibril formations.ConclusionAβ PFs have potencies to accelerate LMW Aβ42 aggregation, and there would be possible mechanisms for Aβ PFs to promote LMW Aβ42 aggregations resulting from the superficial interactions between and Aβ PFs and LMW Aβ42.
Beyond Hypertension: Examining Variable Blood Pressure’s Role in Cognitive Decline and Brain Structure Changes, Longitudinal Insights From RUSH and ADNI
Authors: Morrison Cassandra , Oliver Michael , Kamal Farooq , Dadar Mahsa 
Published: January 2025

AbstractBackgroundHigh blood pressure (BP) is one of the twelve modifiable risk factors that contribute to 40% of dementia cases that could be delayed or prevented. Although high BP is associated with cognitive decline and structural brain changes, less is known about the long‐term association between variable BP and cognitive/brain changes. This study was designed to examine the relationship between variable BP and longitudinal cognitive, post‐mortem neuropathology, white matter hyperintensity (WMH), gray matter (GM) volume, and white matter (WM) volume change over time.MethodsA total of 4606 participants (3429 females, mean age = 76.8) with 32776 follow‐ups from RUSH and 2114 participants (1132 females, mean age = 73.3) with 9827 follow‐ups from ADNI were included in this study. Participants were divided into one of three groups: 1) normal BP, high BP, or variable BP. Linear mixed effects examined the relationship between the groups and cognitive and structural brain changes.ResultsOlder adults with variable BP exhibited the highest rate of cognitive decline followed by high BP and then normal BP. Increased GM volume loss and WMH burden was also observed in variable BP compared to high and normal BP. With respect to post‐mortem neuropathology, both variable and high BP had increased rates compared to normal BP. Results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings.ConclusionLimited research has examined the long‐term impact of variable BP on cognition and brain structure. These findings show the importance that both high and variable BP have on cognitive decline and structural brain changes. Damages caused by variable BP may reduce resilience to future dementia related pathology and increased risk of dementia. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population.
Genetic Screening of Frontotemporal Dementia Patients from a Memory Clinic in Argentina
Authors: Ojeda Ana Laura Martinez , Guimet Nahuel Magrath , Bagnati Pablo Miguel , Allegri Ricardo , Campos Jorge , Sevlever Gustavo , Surace Ezequiel Ignacio 
Published: January 2025

AbstractBackgroundFrontotemporal dementia (FTD) remains one of the most common forms of early‐onset dementia (45 to 65 years). FTD consists clinically and pathologically of a heterogeneous group of disorders characterized by progressive frontal and temporal lobe atrophy. Thirty to fifty percent of cases have a family history of the disease. In this work we aimed to characterize pathogenic variants implicated in familial FTD cases in a cohort from Argentina.MethodA total of 43 patients (23 women, 20 men) meeting clinical criteria for probable behavioral variant‐FTD, semantic or nonfluent primary progressive aphasia, according to the Rascovsky and Gorno‐Tempini criteria, were evaluated at a memory clinic in Buenos Aires, Argentina. Genomic DNA was obtained from peripheral blood leukocytes for all patients using standard protocols. C9ORF72 hexanucleotide repeat expansion (C9‐HRE) was assessed by repeat‐primed PCR. Whole exome sequencing and bioinformatic analysis of FTD‐causative genes was performed on C9‐HRE negative cases.Result29 out of 43 patients (67%) were familial cases, of which 3 were C9‐HRE positive (10.3%). Eleven familial cases who were C9‐HRE negative were studied by exome sequencing. We found previously reported pathogenic variants in 2 cases [GRN (NM_002087.4): c.1216C>T: p.Gln406Ter and GRN (NM_002087.4): c.709‐1G>A: p.?], respectively. Also, we found two variants of unknown significance in other two probands [PDE11A (NM_016953.4): c.2518G>A: p.Glu840Lys; PSEN2 (NM_000447.3): c.800T>G: p.Val267Gly], respectively.ConclusionHere we report the genetic screening of familial FTD cases from a memory clinic in Argentina. C9‐HRE is still the most common cause of familial FTD. Further studies are warranted on the role of the PSEN2 and PDE11A variants found in two probands. This work adds to the knowledge of the genetic landscape of FTD in our country.
Usability of a Self‐Administered Cognitive Assessment in Patients with Progressive Supranuclear Palsy and Correlation with Traditional Neuropsychological Tests: A Mayo Test Drive Pilot Study
Authors: Boots Elizabeth A. , Broeren Megan J. , Ali Farwa , Clark Heather M. , Stierwalt Julie A.G. , Botha Hugo , Stephens Yehkyoung C. , Josephs Keith A. , Whitwell Jennifer L. , Machulda Mary M. , Stricker Nikki H. 
Published: January 2025

AbstractBackgroundSelf‐administered cognitive assessments demonstrate usability and ability to detect cognitive decline in Alzheimer’s disease, but usability in other neurodegenerative diseases is understudied. We investigated whether Mayo Test Drive (MTD), a self‐administered multi‐device compatible cognitive assessment platform, demonstrates usability and correlation with traditional neuropsychological tests in a pilot study of individuals with progressive supranuclear palsy (PSP).MethodEleven individuals with PSP (mean age = 69.6±7.2 years; mean education = 15.3±2.7 years; 72.7% male; 90.9% white; PSP Rating Scale [PSPRS] = 32.4±15.5) enrolled in a Neurodegenerative Research Group study at Mayo Clinic participated. Participants completed neurological evaluation, traditional neuropsychological assessment, in‐person self‐administered MTD comprised of the Stricker Learning Span and Symbols Test, and a MTD usability questionnaire with quantitative and qualitative questions. Participants received diagnoses of PSP clinical variants per Movement Disorders Society‐PSP criteria. Seven participants had PSP‐Richardson, two had PSP‐postural instability, and two had PSP‐parkinsonism. We used descriptive analyses to examine usability questions, qualitative analyses for free text responses, and Spearman correlations to analyze associations between MTD and traditional tests of global cognition and five cognitive domains.ResultTen of eleven patients completed MTD (average completion time [minutes] = 22.2±6.5). Study staff terminated one participant’s session early due to an appointment conflict; we excluded this participant from analyses. Six participants completed MTD with tablets and four used smartphones. Participants reported high ease completing MTD (9.00±1.76 on 0‐10 scale) and comfortability using their devices (9.40±1.58). All participants reported they could complete MTD independently, with one participant indicating need for assistance with hyperlinks and three reporting need for assistance with QR codes. Qualitative data suggested three participants had motoric difficulty using the tablets; these individuals had the greatest PSPRS symptom severity, although MTD performance was not correlated with the PSPRS (rho = ‐.122; p>.05). MTD performance significantly correlated with the MoCA (rho = 0.88) and tests of attention, executive, and visuospatial function (Table).ConclusionIn a MTD usability pilot for participants with PSP, participants reported high ease and comfort completing MTD independently; those with greater motor symptoms had more difficulty navigating technology. Additionally, performances on MTD were correlated with the MoCA and other in‐person assessments, demonstrating convergent validity.