bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variability in Reaction Time Predicts Transition to Mild Alzheimer Disease and is Sensitive to CSF Biomarkers in Cognitively Normal Older Adults
Authors: Welhaf Matthew S. , Balota David A. , Schindler Suzanne E. , Morris John C. , Hassenstab Jason J. , Aschenbrenner Andrew J. 
Published: January 2025

AbstractBackgroundThe ability to detect cognitive impairment from Alzheimer Disease (AD) in its earliest possible symptomatic stage is a highly desirable characteristic for neuropsychological measures. Because early cognitive changes are often subtle, measures with high sensitivity are of great importance. Variability in attention, often assessed using reaction time (RT) tasks, have been shown to discriminate between cognitively normal older individuals with and without positive AD biomarkers and is correlated with biological markers of neurodegeneration. However, what is less clear is how well measures of RT variability predict later development of cognitive symptoms of AD and whether common AD biomarkers predict declines in attention.MethodCognitively normal older adults (N = 478, baseline age = 66.8 ± 8.9 years) completed a go/no‐go task, the Sustained Attention to Response Task (SART). Participants were instructed to respond to all numbers except for the digit “3”. Variability in RT was measured using the Coefficient of Variation (CoV) to correct “go” trials. Cognitive status was assessed using the Clinical Dementia Rating® (CDR®). Logistic regression was used to test for the sensitivity of RT CoV in predicting eventual conversion to CDR > 0, adjusted for baseline age, education, and gender. A subset (N = 197) of participants had CSF Aβ42/Aβ40 within 3 years of the first SART assessment and 2+ visits allowing for testing longitudinal changes. Mixed effect models were used to track longitudinal change in RT CoV based on amyloid status.ResultGreater RT CoV (and thus poorer attention) predicted later conversion to CDR > 0 (p = 0.008), after accounting for baseline levels of education, age, and gender. There was a significant interaction between amyloid status and time (p = 0.048). Increases in RT CoV over time occurred for individuals designated as being amyloid positive (Aβ42/Aβ40<0.0673), but not for those initially identified as amyloid negative (see Figure 1).ConclusionVariability in RT is a significant predictor of later development of cognitive symptoms associated with AD. Longitudinal changes in RT CoV are also sensitive to baseline amyloid status. These findings highlight the sensitivity of within‐person fluctuations of attention as a cognitive biomarker for AD.
Bin1 regulates synaptic endocytic trafficking compromised by Alzheimer’s genetic risk variants
Authors: Almeida Claudia G. , Barata Mariana Afonso , Perdigão Catarina , Ramalho Jose 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), an untreatable synaptic disorder, is the most frequent cause of dementia. It is still unclear which mechanisms drive the early synapse dysfunction in the most common late‐onset AD (LOAD). The second most important LOAD risk gene identified, BIN1, is an endocytic regulator. We implicated Bin1 in BACE1 recycling with Bin1 loss of function, increasing axonal beta‐amyloid42. Since endocytic trafficking is essential for synapse function, we hypothesize that Bin1 may regulate synaptic endocytic trafficking, which may be disrupted by Bin1’s loss of function or beta‐amyloid42. We aim to dissect Bin1 causal mechanisms of synaptic dysfunction to assess how the risk for LOAD increases.MethodSynaptically mature mouse primary cortical neurons and brain hippocampus were used to investigate Bin1 synaptic endocytic localization with immunofluorescence and synaptosomes. Using knockdown, overexpression, and rescue approaches the impact on synaptic endosome size and synaptic density was determined using super‐resolution fluorescence microscopy and quantitative subcellular image analysis.ResultBin1 was enriched in synaptic vesicle brain fractions, supporting its presynaptic function. Unexpectedly, Bin1 is enriched proximal synapses, identified as inhibitory GABAergic presynaptic terminals in primary neurons and the brain. Notably, Bin1 down‐regulation specifically reduced inhibitory synapse density and increased neuronal excitability. Bin1 loss increased inhibitory synaptic vesicle release and endocytosis, exhausting presynaptic endosomes. Interestingly, the impact on inhibitory synapses is independent of beta‐amyloid production. Moreover, Bin1 LOAD mutations interfere with Bin1 function and are likely to cause loss of function.ConclusionBin1 is an inhibitory presynaptic protein. The LOAD mutations may cause Bin1 loss of function, affecting inhibitory synapses. Losing inhibitory transmission may turn excitatory neurons hyperactive, accelerating the loss of excitatory synapses. In the future, we aim to dissect the underlying mechanisms by which Bin1 mutations interfere with Bin1’s role in synaptic vesicle mechanisms at inhibitory presynaptic terminals.
Known and novel genes significant to AD across tissues may help to uncover comprehensive changes of disease
Authors: Moore Anni , Bradford Yuki , Kumar Rachit , Venkatesh Rasika , Shivakumar Manu , Bao Jingxuan , Shen Li , Kim Dokyoon , Ritchie Marylyn D. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is neurodegenerative disease brought on by a combination of changes in multiple pathways that conglomerate to promote disease progression. AD often occurs alongside comorbid diseases, most often immune or vascular in nature, which have been shown to further increase AD risk. We previously showed that known AD variants also associate with secondary diseases in these categories, including rheumatoid arthritis, ischemic myocardial infarction, and both Type 1 and Type 2 diabetes. To better understand which pathways play a significant role in AD etiology and how comorbid diseases may contribute to risk through shared pathways, we aimed to identify gene expression changes associated with AD status in tissues throughout the body.MethodWe conducted a transcriptome‐wide association study (TWAS) using genotypes from the Alzheimer’s Disease Sequencing Project (ADSP) including 11,074 cases and 14,310 controls from multiple ancestry groups and reference expression‐trait quantitative loci (eQTLs) from 49 tissues in Genotype‐Tissue Expression (GTEx) Project (v8). Using an ensemble approach we first predicted genetically regulated gene expression (GREx) and gene‐associations per tissue within each of the 49 tissues available in GTEx using PrediXcan. Secondly, to better predict cross‐tissue signals we used MulTiXcan with GREx to test for gene‐associations across tissues.ResultBoth known and novel genes appeared in the single tissue and cross tissue gene associations. Previously AD‐associated genes PET117, RAB35, NECTIN2, APOC1, and TOMM40 were significantly associated (p<1.51e‐7) with AD across tissues, with many of these known to lie within the APOE region. Additionally, genes previously unreported with AD, but involved in relevant disease processes including macro‐autophagy (SUPT20H), nucleosome binding (HMGN2), histone acetylation (KAT14), DNA damage repair (HFM1), and immune response (TSPAN2) showed significance. Many of these novel genes have previously been associated with immune, vascular and other neurological diseases, many of which are better known to appear as AD comorbidities.ConclusionIn addition to known APOE region genes, novel genes with implications relevant to AD etiology and ties to other immune, vascular, and neurological diseases also appeared significant across tissues. Next we will investigate how these gene expression changes apply to pathways within relevant tissues.
Intracranial atherosclerosis is linked to lower volume in the posterior portion of the hippocampus
Authors: Chowdhury Gulam Mahfuz , Tazwar Mahir , Evia Arnold M , Kapasi Alifiya , Agrawal Sonal , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: January 2025

AbstractBackgroundIntracranial atherosclerosis is a common age‐related neuropathology that has been linked to cognitive decline and dementia and often mixed with Alzheimer’s and other neuropathologies. But the association of atherosclerosis with brain morphometric abnormalities has not been explored. This work combined Deformation‐based morphometry on ex‐vivo MRI with detailed neuropathological examination in a large number of community‐based older adults to investigate the association.MethodHemispheres from 891 community‐based older adults from four cohort studies of aging: the Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and African American Clinical Core of the Rush Alzheimer’s Disease Research Center were imaged ex‐vivo on 3T clinical MRI scanners using a multi‐echo spin‐echo sequence with a voxel size = 0.6 × 0.6 × 1.5 mm3. All images were non‐linearly registered to an ex vivo brain hemisphere template using ANTs. The logarithm of the Jacobian determinant of the deformation fields was calculated in each voxel and the resulting maps were smoothed using a Gaussian filter with a FWHM = 4mm. All hemispheres underwent detailed neuropathologic examination. The assessed pathologies included atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts, Alzheimer’s pathology, Lewy bodies, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change, and hippocampal sclerosis.Voxel wise linear regression was used to test the association of atherosclerosis with deformations shown in the smoothed LogJ maps, controlling for other age‐related neuropathologies, demographics (age at death, sex, years of education), postmortem interval to fixation, postmortem interval to imaging, and scanner (Fig. 1,2). The FSL PALM tool with 1000 permutations, threshold‐free cluster enhancement, and tail acceleration was used for the statistical analysis. Associations were considered significant at p<0.05 after family‐wise error rate correction for multiple comparisons.ResultVoxel‐wise linear regression showed that intracranial atherosclerosis was significantly associated with lower volume in the posterior body and tail of the hippocampus (p<0.05), independently of the effects of other age‐related neurodegenerative and vascular pathologies (Fig. 3). No part of the brain showed significantly higher volume with atherosclerosis.ConclusionThis work demonstrated that intracranial atherosclerosis is associated with lower volume of the posterior body and tail of the hippocampus. This finding is of great interest due to the important role of the hippocampus in cognition.
Altered neutrophil glycolysis contributes to microvascular inflammation in an AD mouse model
Authors: Bracko Oliver 
Published: January 2025

AbstractBackgroundCerebral blood flow is decreased in mouse models and patients of Alzheimer’s disease (AD). We identified that about 2% of cortical capillaries in the APP/PS1 mouse model of AD had stalled blood flow due to neutrophils obstructing capillaries and contributing to vascular inflammation. Neutrophils are more reactive in AD. Here we are investigating if changes in metabolism contribute to reactive neutrophils driving low‐level chronic vascular inflammation and cerebral blood flow (CBF) reductions in mouse models of AD.MethodsAD and control neutrophils were isolated and transferred into donor mice. The number of stalled capillaries and blood flow speeds were measured using high‐resolution from in vivo two‐photon imaging. Mitochondrial stress and glycolysis were determined using the Seahorse platform.ResultsWe found that neutrophils from AD mice caused capillary stalling and contributed to CBF reductions in control mice. Furthermore, we identified that glycolysis is reduced, and mitochondrial stress is increased in AD neutrophils compared to controls. Lastly, the maximal oxygen consumption rate is reduced in AD neutrophils indicating mitochondrial dysfunction.ConclusionThis data demonstrates that reactive neutrophils in AD mice contribute to capillary stalling and CBF reductions. Glucose metabolism is reduced in neutrophils, indicating a metabolic shift from aerobic to anaerobic glycolysis. Overall, the data shows that neutrophils are more reactive at baseline in AD mice and likely contribute directly to chronic inflammation seen in mouse models and patients with AD.
Multi‐day at‐home assessments of speech acoustics in Dutch cognitively normal adults with‐and without AD pathology
Authors: van den Berg Rosanne L. , de Boer Casper , Zwan Marissa D. , Robin Jessica , Simpson William , Jutten Roos J , Dubbelman Mark A. , Barkhof Frederik , Collij Lyduine E. , van Harten Argonde C. , Schlüter Lisa‐Marie , Teunissen Charlotte , van der Flier Wiesje M. , Sikkes Sietske A.M. 
Published: January 2025

AbstractBackgroundAutomated analysis of natural speech is emerging as a promising digital biomarker of Alzheimer’s disease (AD). As speech is a complex process, relying on multiple interacting cognitive functions, fine‐grained analysis of speech may have the potential to capture subtle cognitive deficits in the very early stages of AD. Here, we examined the association between amyloid‐beta (Aβ) pathology and acoustic speech characteristics in a group of cognitively normal Dutch adults.MethodWe included 50 cognitively normal (n = 23 Aβ‐positive, 46%) older adults from three clinical cohorts at the Alzheimer Center Amsterdam (Table 1). Aβ‐status was based on local cut‐offs for Aβ1‐42‐concentrations in cerebrospinal‐fluid or visual inspection of amyloid positron emission tomography (PET)‐imaging. In a five day remote burst assessment, seventeen tablet‐based tasks (picture description, journal‐prompt storytelling, verbal‐fluency) were administered, with a daily administration time of approximately 10 minutes. Various acoustic features, including silent pauses, pause‐to‐word‐ratio, and perceived loudness, were extracted from the voice recordings. Mean burst scores were calculated over the five‐day period. The association between Aβ‐pathology and acoustic features was investigated using linear regression models separately for each subtask.ResultsPause‐to‐word ratio was higher in Aβ‐positive individuals in the repetitive picture description subtask (β = ‐0.05, p = 0.04) and the journaling subtask (β = ‐0.07, p = 0.03) compared to the Aβ‐negative individuals. Although statistical significance between groups was not reached for other acoustic features, a pattern was observed that the Aβ‐positive group consistently displayed more medium pauses, longer audio duration, more local jitter, higher intensity variance, a higher fundamental frequency, and fewer long pauses in all multi‐day subtasks (Figure 1).ConclusionOur results demonstrated that Aβ‐pathology was associated with more pauses during free speech in cognitively healthy adults. This supports the notion that remote multi‐day speech assessments have the potential to monitor cognitive changes, for example in observational studies and decentralized clinical trials in preclinical AD. Next steps include examining the association between Aβ‐pathology and linguistic features using the same sample.
The neurophysiological effects of frontotemporal lobar degeneration: linking synaptic loss, network connectivity and cognitive decline
Authors: Rowe James B 
Published: January 2025

AbstractBackgroundFrontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) have distinct molecular pathologies, with Tau and TDP43 aggregation, and distinct patterns of regional brain atrophy. However, they share the synaptotoxicity of protein aggregation, and neurotransmitter loss (including GABA), which contribute to clinical and neurophysiological similarities. Defining the relationships between synaptic loss, network physiology and cognition builds bridges between preclinical and clinical studies, and facilitates early phase trials.MethodWe quantified the effect of behavioural variant frontotemporal dementia (±parkinsonism) and progressive supranuclear palsy (Richardson’s syndrome, and PSP‐F), and controls with Magnetoencephalography (resting state, mismatch task, and motor control task); 11‐C‐UCBJ PET estimation of synaptic density; 3T T1w and fMRI.ResultParticipants with bvFTD showed severe synaptic loss compared to controls which correlated strongly with baseline cognitive function (ACE‐r r∼0.8, p<0.001). Participants with PSP showed severe synaptic loss, which progressed over 12 months; the degree of synaptic loss over prefrontal cortex correlated with functional decline (PSPRS, r∼0.47, p<0.03. In both PSP and FTD, synaptic loss was more severe and widespread than cortical atrophy; prefrontal/ACC atrophy was significant in PSP, but less than in bvFTD. Synaptic loss correlated with the loss of weighted dress of fMRI‐based cortical network measures. On MEG, deviant‐versus‐repeat tones evoked the frontotemporal peak 160‐200ms and induced loss of beta‐power (∼20Hz) during this window. Both bvFTD and PSP reduced/abolished the effect of deviant stimuli on prefrontal beta power, and this reduction in beta‐power correlated with clinical severity, as FRS (in bvFTD) and PSPRS (in PSP). Inversion of the MEG response to biophysically informed dynamic causal models accurately explained the causes of the evoked response (r>0.9). Bayesian Model Comparison and second level parametric empirical Bayes analysis with UCBJ priors indicated the effect of bvFTD and PSP was attributable to loss of synapses from superficial cortical layers.ConclusionMEG, PET and MRI are each well tolerated by people with PSP/bvFTD. These methods indicate severe and progressive synaptic loss, more than atrophy, with resulting behaviourally‐relevant changes in prefrontal network beta‐power and connectivity. Biophysical modelling confirms in vivo the post mortem observation of superficial cortical vulnerability to PSP/bvFTD.
Trajectory of patients over five years in Multispecialty Interprofessional Team Memory Clinics
Authors: Jones Aaron , Lee Linda , Patel Tejal 
Published: January 2025

AbstractBackgroundMultispecialty Interprofessional Team (MINT) Memory Clinics manage dementia care in primary care, allowing for more efficient use of limited specialist resources. This study examined the characteristics of patients on their initial assessment in the MINT clinic and investigated the five‐year trajectory of patients with mild cognitive impairment (MCI).MethodWe conducted a retrospective chart review of 751 patients assessed within a MINT Memory Clinic between June 2006 and May 2019 to collect data on age, gender, diagnosis, and MoCA scores. We plotted the five‐year trajectory of MoCA scores for patients with an initial diagnosis of MCI and calculated product‐limit estimates of the five‐year conversion rate to dementia. We also performed a Cox regression to investigate associations with receiving a dementia diagnosis.ResultThe median age of our cohort was 75 years; 54% were female. The majority of patients (70%) had a MoCA score of 25 or less; 35% had a score of 20 or less. Diagnoses at the initial assessment included MCI (37%), dementia (20%), subjective cognitive decline (SCD; 12%), and other miscellaneous diagnoses (3%); 27% did not a receive a definitive diagnosis, pending further investigations. Of the 214 patients with an initial diagnosis of MCI and at least one follow‐up visit, 28% (N = 60) received a dementia diagnosis at a later date, with 58% being diagnosed with mixed dementia, 22% with Alzheimer’s Disease, and 20% with other dementias. The product‐limit estimates of the five‐year conversion rate was 48.8% (39.5%, 59.2%). Lower MoCA scores at the initial visit were associated with a higher risk of a dementia diagnosis; each one‐point increase in MoCA was associated with a 10% decrease in the risk of a dementia diagnosis (aHR: 0.90, 95%CI: 0.85‐0.96). Similarly, age was significantly associated with a higher risk of a dementia diagnosis within five years; each five‐year increase in age was associated with a 37% increase in risk (aHR: 1.37, 95% CI: 1.12‐1.67).ConclusionAs nearly half of the patients presenting to MINT Memory Clinics have MCI or SCD on initial assessment, MINT clinics provide a significant opportunity for detection and potential intervention at early disease stages.
A spatial transcriptomics platform for characterizing cellular vulnerability and molecular changes in AD‐affected human brain tissue
Authors: Close Jennie 
Published: January 2025

AbstractBackgroundAlzheimer’s disease is defined by deposition of pathological proteins in spatially reproducible patterns within the tissue of affected individuals. Prominent pathological protein species found in Alzheimer’s disease are amyloid beta plaques and phospho‐tau tangles, which spread through a succession of brain areas. As this pathology spreads and worsens, it is accompanied by glial reactivity and activation and neuronal loss. Characterization of cell types changing or lost during disease progression and where those changes occur will be important for finding mechanisms of disease onset and progression.MethodsnRNAseq analysis from Alzheimer’s donors was used to determine which cell types are present and what changes in gene expression, if any, can be observed at the highest resolution of cell type identity: the supertype. We mapped these supertypes using highly multiplexed spatial transcriptomics on the same donor set to determine where these supertypes are in the tissue, where vulnerable types are lost at which stages, and whether gene expression changes can be observed in specific types near pathology.ResultWe have found that certain vulnerable cellular supertypes are more likely to be affected early, and a reproducible sequence of neuronal loss follows with increasing pathology. Surprisingly, one of the first neuronal subtypes to be affected are somatostatin inhibitory neurons, followed by L2/3IT excitatory neurons and parvalbumin inhibitory neurons. We have corroborated these results in human donor tissue using spatial transcriptomics to map and characterize loss of abundance of vulnerable cell types. We find that vulnerable neuronal types are predominately localized in supragranular layers.ConclusionSpatial methods are key to relating these neuronal vulnerabilities with pathological protein locations and specific locations within affected tissue. We have adapted spatial profiling and analysis methods to characterize the spatial relationships between specific neuronal types, amyloid plaques, tau tangles, and observed changes in gene expression. These data will offer novel insight into cell and molecular changes occurring at each phase of the disease and may inform the development of promising therapeutic interventions.