Journal of Alzheimer's Disease

BACKGROUND: Neuropsychiatric symptoms (NPS) are prevalent and debilitating in Alzheimer's disease (AD). Existing pharmacologic treatments are often ineffective and associated with serious adverse events. Identifying modifiable risk factors (MRFs) is critical for prevention and treatment. METHODS: Capitalizing on data from 14,497 individuals with AD from the National Alzheimer's Coordinating Center (NACC) database, we examined longitudinal associations between modifiable risk factors, APOE genotype and NPI-Q-assessed NPS using Cox proportional hazards models adjusted for demographics. RESULTS: Diabetes, alcohol consumption, smoking, and TBI were associated with an increased risk of specific NPS in AD. APOE{varepsilon}4 carrier status was linked to multiple NPS, showing a dose-response relationship. Education, LDL-C, and corrective lenses were protective; hypertension showed no associations. CONCLUSION: These findings strongly suggest that individual MRFs are associated with specific NPS in line with a complex etiology underlying these symptoms. Early detection and management of vascular, lifestyle and sensory factors could reduce NPS.

PURPOSE: Alzheimer disease (AD) is associated with cognitive impairment, brain atrophy, and elevated amyloid-beta and tau. The study aimed to characterize regional atrophy associated with elevated amyloid-beta and tau, as measured by [18F]florbetapir (FBP) and [18F]flortaucipir (FTP) positron emission tomography (PET), respectively, and determine whether combining PET and atrophy data improves the prediction of cognitive impairment. METHODS: Alzheimer Disease Neuroimaging Initiative data (n = 381) were retrospectively analyzed. PET results were correlated with cortical thickness, gray matter (GM) volumes, Mini-Mental State Examination, and Montreal Cognitive Assessment. Linear/logistic regression and area under the curve (AUC) were used to evaluate for significant correlations and compare performances in distinguishing cognitive impairment, respectively. RESULTS: Incremental loss of cortical thickness and GM volume was observed from FBP-/FTP- (n = 205) to single PET-positive (FBP+/FTP-, n = 133; FBP-/FTP+, n = 5) and FBP+/FTP+ (n = 38) groups, particularly in the temporal and parietal lobes. FBP+/FTP+ showed the most severe cortical thickness loss in the entorhinal cortex, temporal lobe GM atrophy, and cognitive impairment. Adding brain atrophy as the third variable resulted in higher odds ratios and improved AUCs for cognitive impairment, with FBP+/FTP+/temporal GM or entorhinal cortical atrophy+ demonstrating the strongest associations with cognitive impairment. CONCLUSION: A multimodal approach combining PET and MRI may help improve the assessment of cognitive impairment in AD.

Background: People affected by dementia experience intersecting care inequalities. We explored relationships between ethnicity and health and social care resource use among people with dementia in an ethnically diverse urban region. Methods: We conducted a retrospective observational cohort study using Discover-NOW, including patients with dementia between 1.4.2015 and 1.4.2025. We calculated ethnic density as the percentage of the Middle Layer Super Output Area (SOA) population self-identifying with the same ethnic group. Regression models, clustered by Local SOA, tested whether ethnic density moderated relationships between ethnicity and primary care, outpatient, inpatient, emergency and social care service use, controlling for sociodemographic characteristics, deprivation, comorbidities and time of diagnosis. Findings: We included 30,704 people with dementia. People from Black and Mixed ethnic groups used more primary care, and those from Asian ethnic groups less primary and secondary care, than White ethnic groups. Rates of local authority social care packages were similar across ethnic groups. High ethnic density predicted fewer GP consultations in Black ethnic groups, but more in South Asian groups. Interpretation: Among Black ethnic groups, primary care use was relatively high, especially in areas of low ethnic density, perhaps reflecting greater needs among communities at risk of racism and isolation. The trend towards increased primary care use among South Asian people in areas of higher ethnic density may reflect communities mitigating help-seeking hesitancy related to cultural and language barriers. Greater care integration could reduce care inequalities among minority ethnic communities who may experience fewer barriers to social relative to health care.

Background and Objectives: Older adults with epilepsy are at increased risk for Alzheimer's disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy. Methods: Participants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE. Results: Participants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, p<0.001), reflecting reduced thickness/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, p=0.050), memory performance ({beta}= 0.30, p=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction p=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age. Discussion: AD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.

Using data from a randomized clinical trial, we examined whether daily biofeedback training that modulates heart rate oscillations is associated with changes in microstructural brain texture in Alzheimer's disease signature cortical (ADSC) and hippocampal regions. Younger and older adults were randomly assigned to one of two daily biofeedback practices for five weeks: slow-paced breathing designed to increase heart rate oscillations (Osc+) or self-selected strategies aimed at decreasing oscillations (Osc-). Intervention effects were observed in both ADSC and hippocampus regions and were confined to a composite texture factor dominated by uniformity and entropy. Across regions, effects were expressed primarily as Time x Condition interactions, indicating differential texture trajectories between Osc+ and Osc-. In the hippocampus, this pattern was further qualified by a Time x Condition x Age Group interaction, reflecting more pronounced effects in older adults, whereas younger adults showed no reliable texture modulation. Partial least squares correlation analyses further demonstrated that training-related texture changes in the left hippocampus, right fusiform gyrus, and right entorhinal cortex covaried with concurrent changes in plasma AD-related biomarkers, with tau- and p-tau related measures contributing most strongly to the multivariate association. Together, these findings suggest that HRV biofeedback may selectively influence specific dimensions of brain microstructural texture and that such changes are meaningfully coupled with plasma AD-related biomarker profiles.

Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+/-}SD, 25.9{+/-}3.2 years), sex (53% female), or number of visits (2.1{+/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Background and Objectives: Arts and cultural engagement may contribute to well-being in later life. However, evidence from longitudinal studies from Asia, including Japan, remains limited. This study examined the association of arts and cultural engagement with subsequent multidimensional well-being among older adults in Japan, one of the fastest-aging countries. Research Design and Methods: This longitudinal study used panel data from 354 individuals aged 60 and older (mean age 74.0 years; 78.6% women) who completed self-administered questionnaires by mail between 2022 and 2024. The PERMA-Profiler was used to assess five multifaceted aspects of psychological well-being: positive emotion, engagement, relationships, meaning, and accomplishment. Frequencies of arts and cultural engagement at baseline were measured for active (e.g., activities by individuals and participation in groups, such as music and painting) and receptive (e.g., visiting museums, galleries, and theaters) forms. Results: Multivariable linear regression analysis, adjusted for the covariates including baseline PERMA scores, showed that higher frequencies of active engagement were positively associated with higher PERMA scores for all domains. Higher frequencies of receptive engagement were associated with the domains of positive emotion, meaning, and accomplishment, but not clearly associated with engagement and relationships. Restricted cubic spline analyses suggested clearer positive frequency-response patterns for active engagement than for receptive engagement. Discussion and Implications: Arts and cultural engagement, both active and receptive forms, was associated with subsequent multiple aspects of well-being in later life. These findings suggest the importance of ensuring access to arts and cultural opportunities for older adults to create, participate, and connect.

Background: In the UK, over 36 million contacts are made annually by people living with dementia (PLWD) to either primary or secondary community mental health services. As dementia progresses, PLWD may experience increased distress and resort to 999 calls for an ambulance, which may in turn result in conveyance to Accident & Emergency (A&E). Nearly 1 million A&E attendances are made by PLWD. This trend is set to rise sharply as the prevalence rates of dementia increase over time and as the condition progresses, with associated healthcare costs impacting overall care delivery. This may lead to reduced resource allocation for dementia emergency services, negatively affecting the experiences of both providers and service users. Aim(s): To explore ways to improve access and quality of care to emergency crisis care for PLWD from the perspective of healthcare staff providing this type of support. Methods: This qualitative study explored (1) the experiences, resources, and needs of healthcare professionals in emergency and community settings to support access for PLWD, and (2) the mechanisms influencing dementia crisis response. The COREQ Checklist was used to improve transparency, credibility, and reproducibility. Inter-rater reliability was calculated. PPIE contributors co-developed recommendations for healthcare professionals, and study findings informed a comic-based dissemination resource shared with third-sector organisations to support community awareness and engagement. Results: Fifteen interviews were held with emergency services staff. Inter-rater reliability was substantial between two raters (k = 0.62). Four overarching themes, with associated subthemes, were identified relating to crisis care delivery, barriers to effective response, and strategies employed to address these challenges. Additional themes captured decision-making processes at key points in the care pathway, including initial crisis response, during intervention, and at discharge from emergency and community services. Decision-making was characterised by the need to balance patient safety with autonomy in determining care in the best interests of PLWD and their informal carers. Discussion: This exploratory study reveals frontline staff perspectives on challenges and actionable strategies for dementia crisis care. Findings support targeted service improvements, cross-sector collaboration, and co-produced resources to enhance outcomes for PLWD and their informal carers.

Introduction: Aphasia is an acquired language disorder with a significant negative functional impact. Much of the research on aphasia has focused on word-level language comprehension and production. Further evaluation of discourse-level tasks, both at behavioral and neural levels, will allow for an ecologically valid understanding of the functional implications of language impairment in this population. Method: This study evaluated bilateral frontal, temporal, and parietal cortical activity during computer-based narrative production in 14 young neurotypical individuals, 17 individuals with post-stroke aphasia, and 15 age-matched neurotypical participants using functional near-infrared spectroscopy (fNIRS). Oxygenated hemoglobin (HbO) was measured during narrative production following short video clips and compared to HbO during counting aloud. In addition, behavioral measures quantifying in-task performance were correlated with averaged HbO values. Results: Young neurotypical individuals showed greater cortical activity in bilateral language regions for narrative production compared to counting aloud. In contrast, people with aphasia showed positive condition-related effects in the right frontal ROI and the age-matched group showed positive condition-related effects in the left frontal and right precentral ROIs. Each group showed different patterns in relationships between cortical activity and discourse performance measures. Conclusion: Overall, young participants showing more consistent condition-related effects for narrative discourse production than individuals with aphasia and age-matched controls. This study shows the potential for fNIRS to evaluate cortical activity for ecologically valid language tasks in individuals with post-stroke aphasia.

Introduction: Brain-predicted age, estimated from structural MRI data, is a machine-learning biomarker of biological brain aging. Greater brain age gap (BAG) indicates advanced brain aging and is associated with cognitive decline and mortality. Cardiometabolic risk factors, including elevated blood glucose, body mass index (BMI), blood pressure, and cholesterol, increase risk of cognitive impairment and dementia in aging. Their relationship with BAG in severe obesity remains poorly characterized despite increased prevalence of cardiometabolic risk factors among this population. Methods: T1-weighted MRI data from 97 adults (BMI 35-73) were used to calculate BAG using ENIGMA and Pyment brain age models. Associations between BAG and HbA1c, BMI, hypertension, and hyperlipidemia were examined using multiple linear regression and MM-estimation robust regression, adjusting for age, sex, and race. Post hoc analyses stratified models by clinical HbA1c cutoffs (normoglycemic, prediabetic, diabetic). Results: Higher HbA1c was associated with greater BAGENIGMA (B = 1.58, p = .014) and BAGPyment (B = 0.93, p = .013) in linear regression models. In robust models, HbA1c remained significantly associated with BAGENIGMA (B = 1.70, p = .002) but not BAGPyment (B = 0.71, p = .13). BMI, hypertension, and hyperlipidemia were not associated with BAG in either linear or robust models. HbA1c was associated with greater BAGENIGMA (B = 2.15, p = .01) and BAGPyment (B =1.21, p = .04) in those at or above prediabetic levels and with BAGENIGMA (B = 2.49, p = .047) in those with diabetes. Conclusions: Elevated HbA1c is associated with accelerated brain aging in individuals with severe obesity. BAG was not associated with BMI, hypertension, and hyperlipidemia, which may reflect the restricted BMI range inherent to the sample with severe obesity.

Age-related hearing loss is a leading modifiable risk factor for dementia and is increasingly recognized as a non-motor feature of Parkinson's disease (PD). The apolipoprotein E (APOE) E4 allele is the strongest genetic risk factor for Alzheimer's disease and is associated with cognitive decline in PD, yet its relationship to hearing loss remains unclear. Therefore, we examined the independent and interactive effects of PD status and APOE E4 carrier status on age-related hearing loss using a validated web-based speech-in-noise (SIN) assessment in 239,620 23andMe Research Institute participants without PD and 4,361 PD cases. Generalized additive models for location, scale, and shape (GAMLSS) showed that both PD and APOE E4 independently exacerbated age-related hearing decline, with speech reception thresholds (SRTs) worsening non-linearly with advancing age, but without evidence of synergistic interaction. However, longitudinal analyses in a subcohort completing at least two assessments (1,434 PD cases; 36,242 controls) using GAMLSS mixed models showed a significant three-way interaction between PD status, APOE E4, and age2, such that SIN hearing loss accelerated more steeply with age in APOE E4 carriers with PD. Males and individuals with lower educational attainment also exhibited worse SIN hearing loss. These results identify APOE E4 carriers with PD as a priority population for hearing screening and intervention, and support the integration of SIN assessments into routine PD care to detect hearing decline that may compound cognitive and communicative burden in aging.

Background Slow walking in older adults with mild parkinsonian signs (MPS) is a complex, multifactorial phenomenon arising from the cumulative burden of subclinical age-associated pathologies. This decline reflects age-associated neuronal loss in the dopaminergic system. A recent study suggests that levodopa treatment may enhance gait parameters. The goal of this small pilot study is to explore the effect of levodopa treatment on slow walking gait in older adults with MPS. Method This study was a randomized, placebo-controlled clinical pilot trial. Slow walking older adults without clinical evidence of PD were recruited and randomized into 2 groups (active treatment group or placebo control group). Participants in the active group were pre-treated with carbidopa for three days, followed by carbidopa-levodopa for seven days. Spatiotemporal gait parameters were evaluated at baseline and post-intervention. Results Gait factor analysis identified three main factors explaining gait characteristics at baseline, which included gait efficiency, gait rhythmicity, and gait turning.No effect of treatment was observed in the placebo group (p=0.111, p=0.616), no group difference was observed between the placebo and active group at baseline ({beta}=0.310, p=0.547), but a strong trend for a treatment-related increase was observed in the active treatment group ({beta}=0.506, p=0.076). Conclusion Our preliminary data suggest that sustained levodopa treatment (one week) in conjunction with carbidopa pre-treatment and concomitant carbidopa supplementation is feasible in slow walking older adults with MPS. Moreover, the data indicate potential efficacy, showing improvements in cadence, and step durations.

Background: Vascular cognitive impairment (VCI) and small vessel disease (SVD) involve many interconnected factors influencing multiple outcomes, also beyond cognitive decline. Bayesian networks (BNs) can help unravel these complex interrelations, which we demonstrate in this proof-of-concept study in the Heart-Brain Connection cohort, including memory-clinic patients with SVD, patients with heart failure, carotid occlusive disease, and reference participants. Methods: We trained BNs and jointly modelled cognitive decline (Clinical Dementia Rating (CDR) increase) and major adverse cardiovascular events (MACE) over five years as outcomes in relation to multiple demographic and disease factors and emerging imaging and plasma biomarkers, also considering possible non-random dropout. Results: Of 566 individuals (median age 68, 64% men), 134 had MACE and 112 experienced CDR increase. Diagnostic group and baseline cognition were key determinants of both outcomes. The BN identified baseline clinical severity as a non-random dropout source. Plasma biomarkers formed an interconnected subnetwork, linked to demographic and vascular factors, but without direct dependencies with outcomes. The trained BN also provides individualized inference under partial evidence, informing on outcome probabilities. Conclusion: This proof-of-concept study demonstrates how BNs quantify and visualize the dependency structure underlying prognostic heterogeneity in VCI and SVD, including non-random dropout and positioning of emerging biomarkers.

Background: Cognitive assessments are sparsely documented in electronic health records (EHRs), limiting scalable detection of cognitive worsening in real-world clinical settings. Methods: We applied a deep neural network optimized for identifying clinical event timing from sparsely labeled gold-standard data (label-efficient incident phenotyping from longitudinal EHR, LATTE) to predict time-to-first sustained cognitive worsening in AD patients from a large healthcare system (2011-2022) with linkage to an AD Research Center registry in a subset. Sustained cognitive worsening was defined as cognitive decline persisting over [&ge;]2 consecutive visits within 3 years. Separate LATTE models were trained with worsening labels from Clinical Dementia Rating (CDR), Mini-Mental Status Examination (MMSE), and Montreal Cognitive Assessment (MoCA) scores; semi-supervised learning scaled predictions to larger imputation cohorts lacking sufficient longitudinal scores. We evaluated model performance using average time-specific area under the receiver operating characteristic curve (AUC), area between curves (ABC), and Brier scores. To demonstrate clinical utility, we examined whether predicted time-to-worsening differentiated clinically meaningful patient subgroups using competing-risk Cox proportional hazards models accounting for death. Findings: The cohort comprised 27,614 AD patients (65% women, 91% non-Hispanic White, mean [SD] age at start of follow-up 78.76 [9.53] years). In gold-standard cohorts (n: CDR=632, MMSE=710, MoCA=752; remaining patients formed imputation cohorts), LATTE demonstrated robust predictive performance (average time-AUC: CDR 0.816, MMSE 0.694, MoCA 0.710; ABC: CDR 0.067, MMSE 0.293, MoCA 0.078; Brier score: CDR 0.252, MMSE 0.437, MoCA 0.295). APOE-{varepsilon}4 carriers had shorter predicted time-to-worsening compared to non-carriers across all assessments in the imputation cohorts (HRs 1.241-1.376, all p<0.025), and k-means derived patient clusters showed differential time-to-worsening in the overall and imputation cohorts (HRs 0.777-0.908, all p<.001). Interpretation: LATTE enables scalable prediction of sustained cognitive worsening timing, differentiating clinically meaningful patient subgroups. This approach could improve AD clinical monitoring and decision-making in routine care and support targeted clinical trial enrichment.

INTRODUCTION Severe acute brain injury (stroke, traumatic brain injury or hypoxic-ischemic encephalopathy; SABI) is increasingly recognized as a chronic condition with care and communication needs beyond the initial hospitalization. This study aimed to characterize post-acute care patterns among SABI survivors, focusing on healthcare utilization and outpatient communication. METHODS Data were collected from a prospective cohort of hospitalized SABI patients using surveys, chart reviews, and the ED Information Exchange database. Socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), and qualitative analysis of outpatient notes examined conversations around palliative care needs and goals-of-care. RESULTS Two-thirds of patients (140/222) survived until discharge, primarily to nursing facilities (39%) or inpatient rehabilitation (38%). Among 109 with one-year follow-up, there were 89 hospitalizations, 104 ED visits, and 28 deaths. Patients from the most disadvantaged neighborhoods had significantly higher odds of rehospitalization or ED use within 30 days (OR 3.37, p=0.036). ADI was not linked to one-year utilization. seen outpatient by primary care (40%), neurology/neurosurgery (57%), and palliative care (1%), but conversations rarely revisited prognosis or goals-of-care. CONCLUSIONS Our findings highlight the need for improved long-term care planning and communication, particularly for socioeconomically disadvantaged survivors of SABI.

High placebo response is an obstacle in developing drugs to treat agitation in Alzheimer's disease (AAD), a prevalent and burdensome symptom. However, it has proved challenging to develop actionable models of placebo response that 1) can be applied prospectively, requiring only information available at screening or baseline, 2) yield strategies for reducing placebo response without equally depressing drug response, and 3) show generalizability across trials. Here, we first investigated placebo response in AAD at the trial level using meta-regression applied to 23 clinical trials. Meta-regression identified several factors associated with increased placebo response, but most of these factors were non-specific such that they predicted improvements in drug response as well. We therefore turned to individual level clinical trial datasets and applied causal modeling to predict which participants would have high placebo response relative to predicted drug response. We successfully built and validated the causal model across two independent clinical trials of risperidone and haloperidol at the level of individual patients (ability to predict subsequent improvement on drug or placebo). Crucially, we also found efficacy improvements in the overall trial through in silico exclusion/screen failing of high placebo-predicted subjects. We further characterized features most associated with placebo response to improve explainability and, lastly, validated the effect of these features at the trial level in clinical trials of galantamine, an acetylcholinesterase inhibitor (hence in a different class of drugs than those in the other two trials used). Taken together, we have developed and applied a causal modeling framework for reducing placebo response and increasing trial-level efficacy in neuropsychiatry clinical trials using historical trial datasets.

Brain-derived tau (BD-tau) is an emerging blood-based biomarker for neurodegeneration, yet there are currently limited well validated BD-tau assays available for research and clinical use. To enhance access to this vital biomarker for neurological disorders including traumatic brain injury (TBI), we developed a novel blood-based immunoassay for BD-tau on the ultra-sensitive Quanterix HD-X platform using Single Molecule Array technology. Analytical validation assessed dilution linearity, specificity, precision, detection limits, and spike recovery, each recording robust metrics in agreement with international expert recommendations. The assay demonstrated robust validation metrics, achieving between-run stability of 95% when analyzing aliquots from six independent plasma and serum samples across five analytical runs. It also showed strong dilution linearity when diluted four-fold and achieved over 90% recovery when spiked with cerebrospinal fluid. Next, we evaluated the clinical utility of the assay in cohorts of individuals with traumatic brain injury (TBI), where strong performances were recorded whether using the 2-step or 3-step assay formats ({rho}= 0.94; p < 0.0001). Furthermore, plasma BD-tau distinguished samples from TBI patients based on time from injury and severity (AUC=0.93). Plasma BD-tau differentiated between favorable and unfavorable functional outcomes in the acute-severe group. Our findings underscore the significant potential of the BD-tau assay as a biomarker for TBI in the severe phase.

Background: Cognitive impairment in Parkinson's disease (PD) is linked to degeneration of the cholinergic basal forebrain, particularly cholinergic nucleus 4 (Ch4) in the nucleus basalis of Meynert. Structural and diffusion MRI separately detect this degeneration, but few studies have combined these modalities across the PD cognitive spectrum. Methods: We analyzed 92 participants: 14 healthy controls (HC), 35 PD with normal cognition (PD-NC), 33 with mild cognitive impairment (PD-MCI), and 10 with dementia (PDD). For Ch4 and cholinergic nuclei 1, 2, and 3 (Ch1-3) in the medial septal/diagonal band complex, we determined TIV-normalized gray matter density (GMD) and free-water (FW) fraction. We evaluated group differences, cognitive correlations, adjusted multivariable regression, and exploratory ROC discrimination. Results: Ch4 GMD was significantly lower in PDD compared to PD-MCI (p=0.007), PD-NC (p<0.001), and HC (p<0.001). Ch4 GMD was also lower in PD-MCI versus HC (p=0.028); the PD-MCI versus PD-NC difference was not significant after correction (p=0.074). Ch1-3 GMD was lower in PDD versus PD-NC (p=0.008) and HC (p=0.009). Ch4 and Ch1-3 FW were elevated in PDD versus all other groups (all p<0.01). Among PD patients (n=78), MoCA was positively correlated with Ch4 GMD ({rho}=0.49) and Ch1-3 GMD ({rho}=0.42) and negatively correlated with Ch4 FW ({rho}=-0.51) and Ch1-3 FW ({rho}=-0.40; all p<0.001). In the full four-metric model, Ch4 GMD and Ch4 FW were the only independent basal forebrain predictors (Ch4 GMD {beta}=+2.04, p<0.001; Ch4 FW {beta}=-1.46, p=0.005) of MoCA score. The combined Ch4 GMD + Ch4 FW model showed high discrimination for PDD versus non-demented PD (AUC=0.934; optimism-corrected AUC=0.925). Conclusions: Structural and free-water diffusion MRI provide complementary information about Ch4 degeneration in PD. The combined Ch4 model showed promising exploratory discrimination of PDD; validation in larger independent samples is needed.

Background: It is an everyday observation that people of the same chronological age differ with respect to their physical and mental capacity. However, assessing these differences in biological age remains challenging. Methods: Here, we aggregate 89 age-associated variables from the Berlin Aging Study II (BASE-II, n=1,631) to generate MultiAge, a new marker of biological age that summarizes information from ten domains reflecting organ health and global biological age. We then used methylation data obtained from an Illumina MethylationEPIC array and supervised machine learning to translate MultiAge into a DNA methylation signature, MultiAgeEpi (309 CpGs), which was subsequently validated in four independent external validation cohorts (KORA FF4, KORA Age, SHIP-TREND, BiDirect, total n=4,339). MultiAgeEpi results were compared with previously published epigenetic clocks (GrimAge, DunedinPACE, SystemsAge). Results: We report that MultiAgeEpi showed similar, and in several cases, stronger associations with age-associated outcomes such as diabetes, metabolic syndrome, multimorbidity, frailty and mortality (q < 0.05) compared to the other clocks. Conclusions: MultiAge and MultiAgeEpi thus provide a comprehensive assessment of biological age through aggregation of numerous age-associated variables and the use of the high-resolution methylomics data makes transfer of this marker to other cohorts possible.

Background: Wheeled walkers can improve safety during walking, but improper use may increase fall risk among frail older adults. No suitable tool exists to assess safe indoor wheeled walker use in this population. This study aimed to develop and validate a video-based expert assessment tool. Methods: Based on the literature and expert consensus, seven problematic indoor situations were identified, and an assessment tool with five safety criteria per situation was developed (maximum score = 35). Fifty participants (mean age 83.9 years, 64% women) from a geriatric rehabilitation clinic and a nursing home were video-recorded while using a rollator. Expert ratings were compared with nursing staff ratings, self-ratings, and the Timed Up and Go test to evaluate validity. Intra- and inter-rater reliability were determined from independent ratings by two physiotherapists and a repeated expert rating after seven days. Sensitivity to change was assessed after two weeks of rehabilitation, and feasibility by the time required for assessment. Results: The expert score of rater 1 at baseline was 28.5 points, and assessment required a mean of 17.5 minutes. Intra-rater reliability was excellent (ICC = 0.98) and inter-rater reliability was good (ICC = 0.80). Validity analyses showed the strongest association with nursing staff assessments (r = 0.74) and a moderate association with the Timed Up and Go test (r = -0.45). After two weeks, patients improved by an average of 2.38 points (8.4% of baseline score). Conclusions: The new instrument demonstrated high reliability, acceptable validity, sensitivity to change, and good feasibility for assessing safe wheeled walker use in frail older adults. Trial registration number and date of registration: DRKS00038358, 07/11/2025