Recent ucdavisneurology items

Influence of an AQP4 haplotype and sleep duration on early Alzheimers disease.

Wed, 17 Jun 2026 00:00:00 +0000

Introduction

Aquaporin-4 (AQP4) is thought to facilitate Alzheimers disease (AD) protein clearance during sleep. We examined whether AQP4 genetic variation was associated with AD pathology or modified the association between sleep duration and AD biomarkers.

Methods

A total of 450 dementia-free participants (mean age = 58 ± 9.9; women = 54%) from the Framingham Heart Study (FHS) with sleep duration measured by self-report and amyloid-β (Aβ) and tau burden quantified using positron emission tomography (PET) were analyzed.

Results

AQP4 was not associated with Aβ or tau burden in the overall sample. However, for participants aged less than 60, minor allele carriers displayed lower regional tau burden compared to homozygote majors. AQP4 modified the relationship between short sleep (≤6 hours) and medial temporal tau; short sleep duration was associated with higher medial temporal tau in minor allele carriers, while the opposite...

Challenges in Automatic Speech Recognition for Adults with Cognitive Impairment

Tue, 9 Jun 2026 00:00:00 +0000

Millions of people live with cognitive impairment from Alzheimer’s disease and related dementias (ADRD). Voice-enabled smart home systems offer promise for supporting daily living but rely on automatic speech recognition (ASR) to transcribe their speech to text. Prior work has shown reduced ASR performance for adults with cognitive impairment; however, the acoustic factors underlying these disparities remain poorly understood. This paper evaluates ASR performance for 83 older adults across cognitive groups (cognitively normal, mild cognitive impairment, dementia) reading commands to a voice assistant (Amazon Alexa). Results show that ASR errors are significantly higher for individuals with dementia, revealing a critical usability gap. To better understand these disparities, we conducted an acoustic analysis of speech features and found that a speaker’s intensity, voice quality, and pause ratio predicted ASR accuracy. Based on these findings, we outline HCI design implications...

Elevated AD biomarkers do not explain cognitive performance in a community‐recruited clinical trial cohort

Thu, 4 Jun 2026 00:00:00 +0000

INTRODUCTION: To examine the generalizability of Alzheimer's disease (AD) biomarker models in real-world older adults, we examined AD biomarker relationships with cognition in two multicenter cohorts that differ with respect to recruitment approach and health risk factors but were matched on a variety of characteristics. METHODS: We compared harmonized health and demographic data, AD and cerebrovascular biomarkers, and cognitive performance in the community-recruited U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) Imaging substudy and a matched sample from the Alzheimer's Disease Neuroimaging Initiative (ADNI) which recruited primarily from academic specialty clinics. RESULTS: Elevated β-amyloid (Aβ) and tau were associated with cognitive performance in ADNI but not U.S. POINTER. Findings were consistent across different cohort matching schemes, and were not explained by discrepancies in vascular risk. DISCUSSION: The role of Aβ...

Genetic Variation and Stroke Recovery: The STRONG Study

Tue, 12 May 2026 00:00:00 +0000

BACKGROUND: Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes. METHODS: For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin...

Genetic modifiers of APOE-ε4-associated cognitive decline

Mon, 27 Apr 2026 00:00:00 +0000

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4–associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains,...

Clinical and pathologic correlations of machine learning quantification of Aβ deposits across 3 brain regions of decedents with Alzheimer disease

Mon, 27 Apr 2026 00:00:00 +0000

Machine learning enables scalable quantification of neuropathology, offering deeper phenotyping of Alzheimer's disease (AD). In this validation study, we quantified amyloid-beta (Aβ) deposits, evaluating multiple brain regions across institutions, and evaluated associations with clinical, demographic, and genetic factors in persons pathologically diagnosed with AD. All linear models were adjusted for sex, age of death, ethnicity, and center. We analyzed densities (#/mm2) of cored plaques, diffuse plaques, and cerebral amyloid angiopathy (CAA) in 273 individuals from 3 Alzheimer's Disease Research Centers. Formalin-fixed paraffin-embedded sections of frontal, temporal, and parietal cortices were immunostained and digitized, generating 799 whole-slide images (WSIs). Following log transformation, mixed-effects modeling revealed the parietal cortex had the highest cored plaque densities (P < .001); the temporal cortex had the highest diffuse plaque (P < .001); CAA showed no...

Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Wed, 22 Apr 2026 00:00:00 +0000

Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

The role of social context in cognitive and neurobehavioural outcomes in epilepsy

Wed, 25 Feb 2026 00:00:00 +0000

Cognitive and psychiatric comorbidities are among the most persistent and disabling challenges experienced by children and adults with epilepsy, with serious implications for daily functioning, health-care utilization, long-term social outcomes and quality of life. Traditionally, research has focused on epilepsy-specific biological risk factors, such as seizure frequency or epilepsy syndrome, but growing evidence indicates that non-medical factors also shape neurodevelopmental, cognitive and neurobehavioural trajectories. This Review explores how individual-level and neighbourhood-level social factors, including income, education, health-care access and neighbourhood deprivation, contribute to disparities in cognitive and neurobehavioural outcomes across the lifespan in people with epilepsy. We propose the SocioBioCognitive Epilepsy framework, which integrates biological and social factors to better explain the heterogeneity of these outcomes, emphasizing critical developmental...

Characterizing amyloid and tau positron emission tomography‐based stages across the clinical continuum

Fri, 30 Jan 2026 00:00:00 +0000

INTRODUCTION: We standardized positron emission tomography (PET) data across multiple cohorts and tracers to characterize the frequency of amyloid and tau PET severity along the clinical continuum. METHODS: Clinical stage was defined using cohort-specific criteria and included cognitively unimpaired (CU), mild cognitive impairment (MCI), and dementia. Amyloid severity was staged using Centiloids (CL). Tau severity was staged using a hierarchical Braak-based schema. The cumulative probabilities of PET-based stages were estimated using ordinal logistic regressions. RESULTS: Among 10,396 individuals (mean [standard deviation] age: 71.9 [7.1] years), amyloid levels ≥ 25 CL increased with age among CU and MCI, while amyloid levels ≥ 100 CL were most common in dementia. In 3295 with tau PET, tau severity increased with amyloid and clinical stage and showed complex associations with age. Within each clinical stage, the full spectrum of amyloid and tau PET severity was observed. DISCUSSION:...

Automating quantitative morphometric analysis of arteriolosclerotic blood vessels using machine learning

Wed, 28 Jan 2026 00:00:00 +0000

AbstractBackground

Current methods for assessment of brain arteriolosclerosis involve semi‐quantitative scales completed through manual histological examination of glass slides by humans. Such manual evaluations offer modest inter‐rater reliability at best and do not provide specific quantitative metrics. Not infrequently, arteriolosclerosis is assessed globally, as region‐specific evaluations with greater spatial resolution may be labor‐intensive and impractical for manual analysis.

Method

To fill these gaps, we present a machine learning (ML)‐based algorithm – Arteriolosclerosis Segmentation (ArtS) followed by Sclerotic Index and Thickness Extractor (SITE) – that can automatically conduct morphometric analysis of arteriolosclerotic blood vessels on whole slide images (WSIs). We digitized hematoxylin and eosin‐stained glass slides of frontal and occipital lobe gray and/or white matter, collected from three brain banks (UCD ADRC, UCI ADRC, and UCLA ADRC), from 13 participants...

Evaluating segregated school attendance as a mediator of geographic inequities in late‐life cognitive function: evidence from the Study of Healthy Aging in African Americans (STAR)

Thu, 8 Jan 2026 00:00:00 +0000

INTRODUCTION: Birth in the Southern United States is associated with poorer late-life cognitive health, especially among Black Americans, yet the role of school segregation is unclear. METHODS: Utilizing decomposition methods, we estimated the total effect, natural direct effect (NDE), and natural indirect effect (NIE) of Southern birth on domain-specific cognition among 727 older Black adults, adjusting for early-life covariates. We also estimated the proportion of the total effect mediated by self-reported segregated school attendance. RESULTS: Southern birth was associated with lower late-life executive function and semantic memory; estimates were negative but not significant for verbal episodic memory. The direct effect of Southern birth was negative but not significant for all domains. Attending a segregated school mediated 35% and 49% of the total association between Southern birth and executive function (NIE: -0.07, 95% confidence interval [CI]: [-0.18, 0.02]) and...

Use of Cigarettes, Cannabis, and Alcohol Among Asian American, Native Hawaiian, and Pacific Islander Adults: Community-Based National Survey Analysis

Tue, 23 Dec 2025 00:00:00 +0000

Background: Asian American, Native Hawaiian, and Pacific Islander (AANHPI) populations have diverse cultural, immigration, and sociodemographic characteristics. Aggregated data could mask substantial differences in substance use between cultural subgroups in this population. Yet, studies examining substance use among the AANHPI population are limited. Objective: This study aimed to describe cigarette, cannabis, and alcohol use among AANHPI adults by cultural subgroup and sex. Methods: We analyzed data from 3411 AANHPI respondents of a multilingual national survey "COMPASS" during December 2021-May 2022. Primary outcomes were self-report current (every day or some days) use of cigarettes, cannabis, and alcohol. Cultural subgroups included Asian Indian, Ethnic Chinese, Filipino, Japanese, Korean, Native Hawaiian and Pacific Islander, Vietnamese, other cultural groups, and multicultural groups. Other covariates include sex, other sociodemographics, experiences of discrimination (Everyday...

Parallel paths: A narrative review exploring autism and its co-occurring conditions

Fri, 5 Dec 2025 00:00:00 +0000

Autism is a heterogeneous condition with rising prevalence and demand for specialized care. Autistic children are more likely than neurotypical peers to experience co-occurring conditions (CCs), including medical, psychiatric, and behavioral issues, highlighting the urgent need for autism-competent healthcare providers in general healthcare. This review aims to equip primary care providers (PCPs) with a concise summary of common CCs and strategies for effective identification. A panel of experts with extensive experience in caring for autistic children care collaboratively summarized key literature, research evidence, and existing clinical trial outcomes, supplementing their clinical expertise. Autistic children consistently show higher rates of both medical and mental health issues. Despite greater healthcare utilization, many report unmet needs. CCs can impair behavior, functioning, and well-being but are often treatable when recognized early. Timely identification and management...

Differential roles of NaV1.2 and NaV1.6 in neocortical pyramidal cell excitability

Wed, 3 Dec 2025 00:00:00 +0000

Mature neocortical pyramidal cells functionally express two sodium channel (Na V ) isoforms: Na V 1.2 and Na V 1.6. These isoforms are differentially localized to pyramidal cell compartments, and as such are thought to contribute to different aspects of neuronal excitability. But determining their precise roles in pyramidal cell excitability has been hampered by a lack of tools that allow for selective, acute block of each isoform individually. Here, we leveraged aryl sulfonamide-based molecule (ASC) inhibitors of Na V channels that exhibit state-dependent block of both Na V 1.2 and Na V 1.6, along with knock-in mice with changes in Na V 1.2 or Na V 1.6 structure that prevents ASC binding. This allowed for acute, potent, and reversible block of individual isoforms that permitted dissection of the unique contributions of Na V 1.2 and Na V 1.6 in pyramidal cell excitability. Remarkably, block of each isoform had contrasting—and in some situations, opposing—effects on neuronal action...

Multiscale red blood cell hitchhiking for targeted deep tissue gene delivery in lungs

Tue, 25 Nov 2025 00:00:00 +0000

The clinical impact of gene therapies is constrained by poor delivery to target tissues beyond the liver after intravenous administration. Current molecular targeting strategies, such as capsid engineering or gene-carrier surface modification, have achieved only limited success due to their inability to overcome the hierarchical barriers from injection to deep tissue transduction. Here, we introduce a Multiscale Approach using RBC-mediated hitchhiking and Vascular Endothelium Leakage (MARVEL), which integrates red blood cell hitchhiking with VEGF-induced vascular permeabilization to enhance accumulation and penetration of cargoes. Using adeno-associated viruses (AAVs) as a model, MARVEL markedly increases AAV localization in the lungs, improves endothelial transcytosis, and enables gene expression in deeper tissue layers while maintaining a favorable safety profile. We further demonstrate that MARVEL can be adopted into an in situ hitchhiking approach, bypassing the need for ex...

Association of epigenetic aging with plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation in Hispanic/Latino adults

Fri, 7 Nov 2025 00:00:00 +0000

BackgroundBlood-based biomarkers hold significant promise for the early detection and diagnosis of Alzheimer’s disease (AD) and other dementias. Age-related changes in blood levels of AD biomarkers are well-documented but poorly understood. Epigenetic clocks are mathematical models based on DNA methylation patterns that reflect various aspects of the multidimensional aging process. We investigated the associations of epigenetic aging with five blood-based AD biomarkers in 2656 Hispanic/Latino adults (mean age 62.5 years; 65% females) from the Hispanic Community Health Study/Study of Latinos. We used multivariable linear regression models to estimate the associations of acceleration in each of five epigenetic clocks with each biomarker in the total sample and in sex-specific strata, controlling for chronological age, sex (except in sex-stratified analyses), Hispanic/Latino background, recruitment site, risk factors, and comorbid medical conditions.ResultsThere were varying...

Sleep duration and brain MRI measures: Results from the SOL‐INCA MRI study

Fri, 7 Nov 2025 00:00:00 +0000

INTRODUCTION: Sleep duration has been associated with dementia and stroke. Few studies have evaluated sleep pattern-related outcomes of brain disease in diverse Hispanics/Latinos. METHODS: The SOL-INCA (Study of Latinos-Investigation of Neurocognitive Aging) magnetic resonance imaging (MRI) study recruited diverse Hispanics/Latinos (35-85 years) who underwent neuroimaging. The main exposure was self-reported sleep duration. Our main outcomes were total and regional brain volumes. RESULTS: The final analytic sample included n = 2334 participants. Increased sleep was associated with smaller brain volume (β_{total_brain} = -0.05, p < 0.01) and consistently so in the 50+ subpopulation even after adjusting for mild cognitive impairment status. Sleeping >9 hours was associated with smaller gray (β_{combined_gray} = -0.17, p < 0.05) and occipital matter volumes (β_{occipital_gray} = -0.18,...

Kidney function is associated with plasma ATN biomarkers among Hispanics/Latinos: SOL-INCA and HCHS/SOL results

Fri, 7 Nov 2025 00:00:00 +0000

BackgroundPlasma amyloid-tau-neurodegeneration (ATN) biomarker levels may be influenced by non-brain systems, such as kidney function, which could impact the interpretation of ATN biomarker results, particularly in groups like Hispanic/Latino individuals with higher rates of cardiometabolic health issues. Here, we examine the association between kidney function and plasma ATN markers among a diverse sample of Hispanic/Latino individuals living in the U.S.MethodsData was collected from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL, Visit 1, 2008–2011), the largest prospective cohort study of noninstitutionalized Hispanic/Latino adults in the U.S., and its ancillary study, the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA) which was conducted during the second visit of the parent HCHS/SOL study (Visit 2, 2015–2018). SOL-INCA aimed to examine the neurocognitive decline of middle-aged and older Hispanic/Latino adults, and the inclusion criteria...

Multimodal Associations of Modifiable Risk Factors on White Matter Injury: The SOL-INCA-MRI Study (HCHS/SOL)

Fri, 7 Nov 2025 00:00:00 +0000

BACKGROUND: Modifiable risk factors play a central role in the development and course of neurodegenerative disorders of later life, including dementias. Although past research has focused on independent associations of modifiable risk factors, including cardiovascular disease risk factors using Framingham cardiovascular risk score, physical activity, dietary quality, body mass index, and sleep, on neurodegeneration, the impact of all 5 factors simultaneously in a multimodal model has not been studied. We examined independent associations and an overall combined model with 5 modifiable risk factors with white matter injury, a recognized risk factor for dementia, ≈10 years later in a diverse Hispanic/Latino population. METHODS: Participants were from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) Investigation of Nerocognitive Aging-Magnetic Resonance Imaging longitudinal study (n=2667; clinical visit 1 mean age, 52.01 [8.90] years). We conducted path and mediation...

Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program

Fri, 7 Nov 2025 00:00:00 +0000

To better characterize the potential biological mechanisms underlying insulin resistance (IR) and dementia, we derive cross-population and population specific polygenic scores [PSs] for fasting insulin and IR-related partitioned PSs [pPSs]. We conduct a cross-sectional study of the associations of these genetic scores with neurological outcomes in >17k participants (36% men, mean age 55 yrs) from the Trans-Omics for Precision Medicine (TOPMed) program (50% Non-Hispanic White, 23% Black/African American, 21% Hispanic/Latino American, and 4% Asian American). We report significant negative associations (P < 0.002) of the cross-population (P = 1.3 × 10-5) and European (PEA = 3.0 × 10-8) fasting insulin PSs with total cranial volume, and of a metabolic syndrome European PS with general cognitive function (BEA = -0.13, PEA = 0.0002) and lateral ventricular volume (BEA = 0.09, PEA = 0.002). We identify suggestive negative associations (P < 0.007) of metabolic syndrome and obesity...

Genetic Architecture of Cerebral White Matter Hyperintensities in Diverse Hispanic/Latino Adults

Thu, 30 Oct 2025 00:00:00 +0000

Background and Objectives: Cerebral white matter hyperintensities (WMHs) on MRI are part of the spectrum of age-related brain vascular injury and are associated with increased risk of stroke and dementia. Genome-wide association studies (GWASs) conducted mostly in populations of European ancestry have identified several genetic loci. Although Hispanic/Latino adults have a greater burden of WMHs than their non-Hispanic White counterparts, they are vastly underrepresented in genetic studies. We sought to characterize the genetic architecture of WMHs in a Hispanic/Latino cohort by investigating the transferability of known WMH genetic loci and by leveraging Hispanic/Latino genetic diversity to map novel loci. Methods: We conducted genome-wide association and admixture mapping analyses of WMH volume in a sample of 2,159 diverse Hispanic/Latino adults (mean age: 62.4 years; 66% female). We investigated associations at 27 previously identified WMH loci. To identify additional loci,...

Are You Really the Doctor? Physician Experiences with Gendered Microaggressions from Patients

Mon, 13 Oct 2025 00:00:00 +0000

Background: In contrast to physician implicit bias toward patients, bias and microaggressions from patients toward physicians have received comparatively less attention. Materials and Methods: We captured physician experiences of gendered microaggressions from patients by conducting a mixed-methods survey-based study of physicians at a single academic health care institution in May 2019. A quantitative portion assessed the frequency of gendered microaggressions (microaggression experiences [ME] score) and the association with measures of perceived impacts (job satisfaction, burnout, perceived career impacts, behavioral modifications). A one-tailed Wilcoxon rank sum test compared distributional frequencies of microaggressions by gender, and by gender and race. Chi-square tests measured the associations between gendered microaggressions and perceived impacts. Welch two-sample t-tests assessed differences in ME scores by rank and specialty. Linear...

CRISPR activation for SCN2A-related neurodevelopmental disorders

Thu, 9 Oct 2025 00:00:00 +0000

Most neurodevelopmental disorders with single gene diagnoses act via haploinsufficiency, in which only one of the two gene copies is functional1. SCN2A haploinsufficiency is one of the most frequent causes of neurodevelopmental disorder, often presenting with autism spectrum disorder, intellectual disability and, in a subset of children, refractory epilepsy2. Here, using SCN2A haploinsufficiency as a proof-of-concept, we show that upregulation of the existing functional gene copy through CRISPR activation (CRISPRa) can rescue neurological-associated phenotypes in Scn2a haploinsufficient mice. We first show that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency (Scn2a+/−). Next, using an adeno-associated virus CRISPRa-based treatment in adolescent mice, we show that we can correct intrinsic and synaptic deficits in neocortical pyramidal cells, a major cell type that...

Optimizing automated detection of high frequency oscillations using visual markings does not improve SOZ localization

Tue, 7 Oct 2025 00:00:00 +0000

OBJECTIVE: High frequency oscillations (HFOs) are a biomarker of the seizure onset zone (SOZ) and can be visually or automatically detected. In theory, one can optimize an automated algorithm's parameters to maximize SOZ localization accuracy; however, there is no consensus on whether or how this should be done. Therefore, we optimized an automated detector using visually identified HFOs and evaluated the impact on SOZ localization accuracy. METHODS: We detected HFOs in intracranial EEG from 20 patients with refractory epilepsy from two centers using (1) unoptimized automated detection, (2) visual identification, and (3) automated detection optimized to match visually detected HFOs. RESULTS: SOZ localization accuracy based on HFO rate was not significantly different between the three methods. Across patients, visually optimized detector settings varied, and no single set of settings produced universally accurate SOZ localization. Exploratory analysis suggests that, for many patients,...

Neural Mechanisms of Object Prioritization in Vision

Thu, 2 Oct 2025 00:00:00 +0000

Selective attention is widely thought to be sensitive to visual objects. This is commonly observed in cueing studies, which show that when attention is deployed to a known target location that happens to fall on a visual object, responses to targets that unexpectedly appear at other locations on that object are faster and more accurate, as if the object in its entirety has been visually prioritized. However, this notion has recently been challenged by results suggesting that putative object-based effects may reflect the influence of hemifield anisotropies in attentional deployment, or of unacknowledged influences of perceptual complexity and visual clutter. Studies employing measures of behavior provide limited opportunity to address these challenges. Here, we used EEG to directly measure the influence of task-irrelevant objects on the deployment of visual attention. We had participants complete a simple visual cueing task involving identification of a target that appeared at...

Modeling the importance of life exposure factors on memory performance in diverse older adults: A machine learning approach

Sat, 23 Aug 2025 00:00:00 +0000

INTRODUCTION: Many health life exposure factors (LEFs) influence cognitive decline and dementia incidence, but their relative importance to episodic memory (an early indicator of cognitive decline) among diverse older adults is unclear. We used machine learning to rank LEFs for memory performance in a large and diverse US cohort. METHODS: Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) and Study of Healthy Aging in African Americans (STAR), participants underwent neuropsychological testing and answered questionnaires about multiple LEFs. XGBoost and Shapley Additive exPlanation values ranked the importance of factors influencing cross-sectional episodic memory in the full sample and by sex and ethnic group. RESULTS: Among 2245 adults (mean age: 74 years; range 54-90), age, sex, education, volunteering, income, vision, hearing, sleep, and exercise contributed to memory performance regardless of group stratification. DISCUSSION: This innovative methodology can help identify...

Association between self-reported multimorbidity and longitudinal brain Aβ deposition in Alzheimer’s disease

Wed, 20 Aug 2025 00:00:00 +0000

Multimorbidity is common in older adults. However, whether multimorbidity accelerates brain beta-amyloid (Aβ) deposition, the molecular driver of Alzheimer’s disease (AD), in humans remains largely unknown. In this study, we selected 435 brain Aβ-positive participants with available longitudinal Aβ-PET data (mean duration 3.9 years) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Twenty-two self-reported chronic disorders were considered as a measure of the severity of multimorbidity. After adjustment for age, sex, education level, APOE-ε4 status and baseline cognitive state, individuals with a high or medium multimorbidity burden had faster rates of brain Aβ accumulation than individuals with a low multimorbidity burden. Moreover, both the central nervous system and peripheral system multimorbidity burdens were associated with longitudinal brain Aβ deposition. These results indicate that peripheral organ and tissue dysfunctions may contribute to AD pathogenesis,...

TP53 oncogenic variants as prognostic factors in individuals with glioblastoma: a systematic review and meta-analysis.

Fri, 1 Aug 2025 00:00:00 +0000

BACKGROUND: This systematic review and meta-analysis investigated the relationship between somatic TP53 oncogenic variants and prognosis, specifically with overall survival (OS) and progression-free survival (PFS) in patients diagnosed with supratentorial glioblastoma. METHODS: We included longitudinal studies and clinical trials involving a minimum of 40 adult participants diagnosed with supratentorial glioblastoma, wherein the status of TP53 variants was assessed. We conducted searches in multiple databases. We assessed bias risk using a modified version of the Quality in Prognosis Studies tool, and the certainty of evidence was evaluated following the principles of the GRADE approach. RESULTS AND CONCLUSION: This study encompassed 23 papers involving 2,555 patients, out of which 716 had reported oncogenic variants. TP53 oncogenic variants were associated with a reduced likelihood of 1-year survival (OR 0.52, 95% CI 0.29-0.94). However, our analysis did not reveal any significant...

Case report: Recurrence of psychosis after the surgical resection and radiation of a temporal lobe astrocytoma

Fri, 1 Aug 2025 00:00:00 +0000

It is estimated that the incidence of first episode psychotic disorder is about 33 people out of 100,000 each year. Beyond primary psychotic illness (e.g., schizophrenia, schizophreniform disorder), some of these patients will develop psychotic disorder due to a complex interplay of genetics, anatomical variations, traumatic brain injury (TBI), environment, substance use, and/or other causes. A small subset of patients will develop psychotic disorder due to a structural anatomic lesion, such as a CNS tumor. Here we present a 35-year-old male with worsening auditory hallucinations after surgical resection and radiation of a right temporal lobe astrocytoma in the setting of co-morbid methamphetamine usage. This case report helps illustrate how a neuroimaging work-up is important for the first incidence of psychotic disorder and how a tumor can produce a psychotic disorder that persists after oncologic treatment. This paper adds to the literature on the presentation and treatment...

Development of a machine learning algorithm to predict the residual cognitive reserve index

Wed, 30 Jul 2025 00:00:00 +0000

Elucidating the mechanisms by which late-life neurodegeneration causes cognitive decline requires understanding why some individuals are more resilient than others to the effects of brain change on cognition (cognitive reserve). Currently, there is no way of measuring cognitive reserve that is valid (e.g. capable of moderating brain-cognition associations), widely accessible (e.g. does not require neuroimaging and large sample sizes), and able to provide insight into resilience-promoting mechanisms. To address these limitations, this study sought to determine whether a machine learning approach to combining standard clinical variables could (i) predict a residual-based cognitive reserve criterion standard and (ii) prospectively moderate brain-cognition associations. In a training sample combining data from the University of California (UC) Davis and the Alzheimer's Disease Neuroimaging Initiative-2 (ADNI-2) cohort (N = 1665), we operationalized cognitive reserve using an...

The development of aperiodic neural activity in the human brain

Fri, 18 Jul 2025 00:00:00 +0000

The neurophysiological mechanisms supporting brain maturation are fundamental to attention and memory capacity across the lifespan. Human brain regions develop at different rates, with many regions developing into the third and fourth decades of life. Here, in this preregistered study (https://osf.io/gsru7), we analysed intracranial electroencephalography recordings from widespread brain regions in a large developmental cohort. Using task-based (that is, attention to to-be-remembered visual stimuli) and task-free (resting-state) data from 101 children and adults (5.93–54.00 years, 63 males; n electrodes = 5,691), we mapped aperiodic (1/ƒ-like) activity, a proxy of neural noise, where steeper slopes indicate less noise and flatter slopes indicate more noise. We reveal that aperiodic slopes flatten with age into young adulthood in both association and sensorimotor cortices, challenging models of early sensorimotor development based on brain structure. In the prefrontal cortex (PFC),...

Applying machine learning to assist in the morphometric assessment of brain arteriolosclerosis through automation

Wed, 2 Jul 2025 00:00:00 +0000

Objective quantification of brain arteriolosclerosis remains an area of ongoing refinement in neuropathology, with current methods primarily utilizing semi-quantitative scales completed through manual histological examination. These approaches offer modest inter-rater reliability and do not provide precise quantitative metrics. To address this gap, we present a prototype end-to-end machine learning (ML)-based algorithm, Arteriolosclerosis Segmentation (ArtSeg), followed by Vascular Morphometry (VasMorph) - to assist persons in the morphometric analysis of arteriolosclerotic vessels on whole slide images (WSIs). We digitized hematoxylin and eosin-stained glass slides (13 participants, total 42 WSIs) of human brain frontal or occipital lobe cortical and/or periventricular white matter collected from three brain banks (University of California, Davis, Irvine, and Los Angeles Alzheimer's Disease Research Centers). ArtSeg comprises three ML models for blood vessel detection, arteriolosclerosis...

Neonatal Seizures and Associated Neurobehavioral Profiles in Preschool Age Children

Fri, 27 Jun 2025 00:00:00 +0000

BACKGROUND: Neonatal seizures are common with acute brain injury. Up to 25% of survivors develop postneonatal epilepsy. We hypothesized postneonatal epilepsy diagnosed by age 24 months would increase risk for early markers of neurobehavioral disorders than acute provoked neonatal seizures alone. METHODS: Neonates with acute provoked seizures born from July 2015 to March 2018 were enrolled at nine Neonatal Seizure Registry sites. Composite scores from parent-completed standardized ratings assessed Adaptive, Social, Externalizing, Internalizing, Self-Regulation, and Sensory Seeking domains. Linear regression demonstrated relationships between composite scores for children who developed postneonatal epilepsy compared with those who did not. Results were adjusted for seizure etiology, sex, gestational age, and cerebral palsy (CP) severity. RESULTS: A total of 151 children (n = 20, 13% with postneonatal epilepsy), 4.1 years median age, participated. Children with epilepsy...

Preferred Parental Language and Neurodevelopmental Outcomes Among Infants With Acute Provoked Neonatal Seizures in the United States

Fri, 27 Jun 2025 00:00:00 +0000

BACKGROUND: Parental non-English language preference (NELP) is associated with worse pediatric health outcomes. However, little is known about its relationship with developmental outcomes in infants with neonatal seizures. This study evaluated the relationship between parental NELP and neurodevelopment in a multicenter cohort of infants with neonatal seizures. METHODS: Infants in the Neonatal Seizure Registry-II were included. Parental NELP was defined by the use of a professional interpreter for research consent and survey completion. The Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) assessment was conducted at age 24 months. Multivariate regression was used to examine the association between parental NELP and WIDEA-FS. Functional developmental impairment was defined as a WIDEA-FS score 2 S.D.s below the normative mean. RESULTS: Among 270 infants with neonatal seizures, 15 (6%) had parental NELP. Children with parental NELP had a WIDEA-FS...

Sleep Disturbance Phenotype Trajectories and Associated Multimorbidity in Children With New-Onset Seizures Over 36 Months

Wed, 4 Jun 2025 00:00:00 +0000

BACKGROUND: Children with epilepsy exhibit heterogeneity and variability in comorbidities including sleep disturbance, cognitive dysfunction, and behavioral impairments. This heterogeneity raises the question of whether there are unique sleep phenotypes associated with epilepsy. Here we investigate the presence and progression of sleep phenotypes in youth with new-onset epilepsy over a three-year period and, in addition, characterize their associated cognitive and behavioral profiles to inform the presence and degree of multimorbidity. METHODS: A total of 312 subjects (aged 6-16 years) were recruited within six weeks of their first recognized seizure. Sleep was evaluated in each child using the Sleep Behavior Questionnaire, assessing five areas of sleep disturbance-bedtime difficulties, parent-child interactions, sleep fragmentation, parasomnia, and daytime drowsiness. Each child also underwent a comprehensive neuropsychologic and behavior assessment. All sleep, cognitive, and...

Prosthesis Embodiment in Lower Extremity Limb Loss: A Narrative Review

Wed, 21 May 2025 00:00:00 +0000

Lower limb prosthesis abandonment is a significant challenge, leading to reliance on walking aids, such as wheelchairs, which frequently do not match the patient’s needs and lead to increased morbidity. Prosthesis abandonment is driven by a lack of embodiment, the latter defined as the integration of a prosthetic device into one’s body schema. This review evaluates interventions enhancing embodiment through three dimensions: ownership, agency, and co-location. The aim of this narrative review is to ask what interventions are available to improve embodiment, and what dimensions of embodiment should be included in the standard of care for lower-limb amputation surgery and componentry development. This narrative is constructed through a thorough literature search on how the aforementioned dimensions of embodiment can be optimized. In the studies reviewed, standardization of embodiment metrics and longitudinal data are lacking, hindering clinical translation. Future work must prioritize...

Stratifying risk of Alzheimer’s disease in healthy middle-aged individuals with machine learning

Thu, 24 Apr 2025 00:00:00 +0000

Alzheimer's disease has a prolonged asymptomatic phase during which pathological changes accumulate before clinical symptoms emerge. This study aimed to stratify the risk of clinical disease to inform future disease-modifying treatments. Cerebrospinal fluid analysis from participants in the Emory Healthy Brain Study was used to classify individuals based on amyloid beta 42 (Aβ42), total tau (tTau) and phosphorylated tau (pTau) levels. Cognitively normal (CN), biomarker-positive (CN)/BM+individuals were identified using a tTau: Aβ42 ratio > 0.24, determined by Gaussian mixture models. CN/BM+ individuals (n = 134) were classified as having asymptomatic Alzheimer's disease (AsymAD), while CN, biomarker-negative (CN/BM-) individuals served as controls (n = 134). Cognitively symptomatic, biomarker-positive individuals with an Alzheimer's disease diagnosis confirmed by the Emory Cognitive Neurology Clinic were labelled as Alzheimer's disease (n = 134). Study...

Sociodemographic modifiers of effects of statin initiation on dementia incidence: An emulated trial design in a large health care member population with 10+ years of follow‐up

Wed, 23 Apr 2025 00:00:00 +0000

INTRODUCTION: Mixed evidence on how statin use affects risk of Alzheimer's disease and related dementias (ADRD) may reflect heterogeneity across sociodemographic factors. Few studies have sufficient power to evaluate effect modifiers. METHODS: Kaiser Permanente Northern California (KPNC) members (n = 705,061; n = 202,937 with sociodemographic surveys) who initiated statins from 2001 to 2010 were matched on age and low-density lipoprotein cholesterol (LDL-C) with non-initiators and followed through 2020 for incident ADRD. Inverse probability-weighted Cox proportional hazards models were used to evaluate effect modification by age, gender, race/ethnicity, education, marital status, income, and immigrant generation. RESULTS: Statin initiation (vs non-initiation) was not associated with ADRD incidence in any of the 32 subgroups (p > .05). Hazard ratios ranged from 0.964 (95% CI: 0.923 to 1.006) among Asian-identified participants to 1.122 (95% CI:...

Targeting of phosphorylated tau at threonine 181 by a Qβ virus‐like particle vaccine is safe, highly immunogenic, and reduces disease severity in mice and rhesus macaques

Mon, 21 Apr 2025 00:00:00 +0000

INTRODUCTION: Pathological accumulation of tau (pTau) contributes to various tauopathies, including Alzheimer's disease (AD), and correlates with cognitive decline. A rapid surge in tau-targeted approaches via anti-sense oligonucleotides, active/passive immunotherapies suggests that targeting p-Tau is a viable strategy against tauopathies. METHOD: We describe a multi-species validation of our previously described Qß virus-like particle (VLP)-based vaccine technology targeting phosphorylated tau on threonine 181 (pT181-Qß). RESULTS: Two vaccine doses of pT181-Qß, without any adjuvants, elicited robust antibody responses in two different mouse models of tauopathy (PS19 and hTau) and rhesus macaques. In mouse models, vaccination reduced AT180+ hyperphosphorylated, Sarkosyl insoluble, Gallyas silver positive tau, inflammasomes/neuroinflammation, and improved recognition memory and motor function without inducing adverse T-cell activation. Anti-pT181 antibodies are reactive to pTau...

Increasing representation of Asian American, Native Hawaiian, and Pacific Islander communities in aging, dementia, and caregiving research: An update from the CARE registry

Sat, 19 Apr 2025 00:00:00 +0000

INTRODUCTION: Asian American, Native Hawaiian, and Pacific Islander (AANHPI) communities are among the fastest growing segments of older adults in the United States yet remain underrepresented in aging, dementia, and caregiving research. METHODS: The Collaborative Approach for AANHPI Research & Education (CARE), a recruitment registry, aims to improve the representation of AANHPI older adults in research. We describe activity to date, as well as planned expansions in cultural groups, language capacity, and data collection in the registry. RESULTS: Between October 15, 2020, and November 4, 2024, 10,367 total AANHPI adults enrolled in the CARE registry, including 50.0% with limited English proficiency, 35.1% age ≥ 65, and 80.2% with no prior participation in research. CARE has made more than 13,954 referrals of 6868 unique registrants to at least one study. DISCUSSION: Through collaborative partnerships with AANHPI communities and researchers, the CARE Registry is achieving...

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles

Mon, 14 Apr 2025 00:00:00 +0000

Neuroinflammation, blood-brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute-phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well-cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible...

The Association Between Physical Activity and Cognition in a Racially/Ethnically Diverse Cohort of Older Adults

Sat, 12 Apr 2025 00:00:00 +0000

OBJECTIVE: Most prior research on physical activity (PA) and cognition is based on predominantly white cohorts and focused on associations of PA with mean (average) cognition versus the distribution of cognition. Quantile regression offers a novel way to quantify how PA affects cognition across the entire distribution. METHODS: The Kaiser Healthy Aging and Diverse Life Experiences study includes 30% white, 19% black, 25% Asian, and 26% Latinx adults age 65+ living in Northern California (n = 1600). The frequency of light or heavy PA was summarized as 2 continuous variables. Outcomes were z-scored executive function, semantic memory, and verbal episodic memory. We tested associations of PA with mean cognition using linear regression and used quantile regression to estimate the association of PA with the 10th-90th percentiles of cognitive scores. RESULTS: Higher levels of PA were associated with higher mean semantic memory (b = 0.10; 95% CI: 0.06, 0.14) and executive function (b...

Amyloid PET predicts longitudinal functional and cognitive trajectories in a heterogeneous cohort

Fri, 11 Apr 2025 00:00:00 +0000

INTRODUCTION: Amyloid positron emission tomography (PET) is increasingly available for diagnosis of Alzheimer`s disease (AD); however, its practical implications in heterogenous cohorts are debated. METHODS: Amyloid PET from 890 National Alzheimer`s Coordinating Center participants with up to 10 years post-PET follow up was analyzed. Cox proportional hazards and linear mixed models were used to investigate amyloid burden prediction of etiology and prospective functional status and cognitive decline. RESULTS: Amyloid positivity was associated with progression from unimpaired to mild cognitive impairment and dementia. Amyloid burden in the unimpaired group was associated with lower initial memory levels and faster decline in memory, language, and global cognition. In the Impaired group, amyloid was associated with lower initial levels and faster decline for memory, language, executive function, and global cognition. DISCUSSION: Amyloid burden is an important prognostic marker in...

APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimer’s disease pathology

Fri, 11 Apr 2025 00:00:00 +0000

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option.

Spatiotemporal perturbations of the plasminogen activation system in a rat model of acute organophosphate intoxication

Thu, 10 Apr 2025 00:00:00 +0000

Neuroinflammation is widely posited to be a key pathogenic mechanism linking acute organophosphate (OP)-induced status epilepticus (SE) to persistent brain injury and abnormal electrical activity that contribute to epilepsy and cognitive impairment. The plasminogen activation system (PAS) promotes neuroinflammation in diverse neurological diseases but whether it is activated following acute OP intoxication has yet to be evaluated. To address this data gap, we characterized the spatiotemporal expression patterns of multiple components of the PAS in a rat model of acute intoxication with the OP, diisopropylfluorophosphate (DFP). Adult male Sprague Dawley rats administered DFP (4 mg/kg, sc), atropine sulfate (2 mg/kg, im) and 2-pralidoxime (25 mg/kg, im) went into SE that persisted for hours. One day after acute DFP-induced SE, plasmin activity and protein concentrations of plasminogen activator inhibitor-1 (PAI-1) in the plasma were increased, though not significantly....

Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats

Thu, 10 Apr 2025 00:00:00 +0000

Aims

Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP-induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman-induced SE.

Methods

Soman-intoxicated male rats with robust seizure behavior and high-amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses.

Results

Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure...

Healthy dietary intake diminishes the effect of cerebral small vessel disease on cognitive performance in older adults

Fri, 4 Apr 2025 00:00:00 +0000

Introduction: We evaluated whether regular dietary intake of nutrients commonly found in fish, unsaturated oils, and nuts would moderate the associations between neuroimaging biomarkers of cerebral small vessel disease (cSVD) and cognitive function in older adults. Methods: Dietary information, Montreal Cognitive Assessment (MoCA) scores, and magnetic resonance imaging (MRI) scans were collected from 71 older adults without dementia (60-86 years). MRI biomarkers of cSVD were calculated for each participant. Multivariate linear regression models were computed using dietary intake as the moderating variable. Covariates included age, sex, and estimated intracranial volume. Results: Dietary intake moderated the association between several cSVD biomarkers and MoCA scores such that the expected negative association between cSVD biomarkers and cognition was seen at low levels of healthy dietary intake, but not at medium or high levels. A dietary intake by age moderation was not observed. Discussion:...

Spatiotemporal perturbations of the plasminogen activation system in a rat model of acute organophosphate intoxication

Fri, 4 Apr 2025 00:00:00 +0000

Structural variants linked to Alzheimer’s disease and other common age-related clinical and neuropathologic traits

Fri, 4 Apr 2025 00:00:00 +0000

Abstract BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci.MethodsBy leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimer’s disease and other common age-related clinical and neuropathologic traits were examined.ResultsFirst, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and...

Ginsenoside Rg1 Protects against Oxidative Stress-induced Neuronal Apoptosis through Myosin IIA-actin Related Cytoskeletal Reorganization