Development and validation of novel cognitive tests in Mandarin‐speaking older Americans

Abstract INTRODUCTION Mandarin Chinese has the largest number of native speakers globally, yet few Mandarin cognitive tests have undergone rigorous validation in multicultural settings for Alzheimer's disease (AD) detection. METHODS We adapted or developed Mandarin cognitive tests to assess memory, executive, and language functions (including new Chinese character, phoneme, and homophone fluency tasks) and then prospectively recruited 208 older adults at two US centers to determine the tests’ reliability as well as convergent, construct, and concurrent validity. RESULTS All Mandarin cognitive measures had high test–retest reliability (intraclass correlation coefficients of 0.680to 0.849), and English letter‐guided fluency best correlated with Chinese phoneme and homophone fluency. Factor analysis revealed six factors that underlie 16 cognitive measures, with at least one abnormal executive function or a story memory test associated with mild cognitive impairment and elevated plasma p‐Tau 217 . DISCUSSION Validated cognitive measures provide culturally and linguistically appropriate tools to detect early AD among older Chinese Americans.

Relationship between age and severity of cognitive impairment at diagnosis for early‐onset and late‐onset Alzheimer's disease: Comparison of LEADS and ADNI

INTRODUCTION Recent work has identified unique cognitive profiles for early‐onset Alzheimer's disease (EOAD) relative to late‐onset Alzheimer's disease (LOAD), however, examination has been limited in determining whether the association between age and cognitive severity at presentation also differs across conditions. METHODS A series of linear spline regression models was conducted across baseline cognitive data from 325 EOAD and 314 LOAD participants, after accounting for education, sex, and apolipoprotein ε4 status. RESULTS Significant differences existed in the relationship between baseline age and cognitive performance between EOAD and LOAD samples for Processing Speed/Attention, Executive Functioning, and Episodic Immediate Memory. Younger participants from both EOAD and LOAD groups performed disproportionately worse on non‐amnestic cognitive domains, with this occurring to a greater extent in EOAD than LOAD. DISCUSSION In the age of disease‐modifying treatments, results highlight the importance of assessing for cognitive declines in individuals starting much earlier than age 65. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) participants each displayed cognitive impairments relative to same‐aged peers across most domains. Both groups displayed positive relationships between impairment among non‐amnestic cognitive domains and baseline age. This relationship displayed a significantly greater effect in EOAD than LOAD, with domains of Processing Speed/Attention and Executive Functioning skills being the most pronounced. Of those participants developing AD, age displayed a disproportionate impact on their symptom onset.

APOE ‐mediated sex differences in microvascular pathology and AD‐associated proteinopathies in the medial temporal lobe

Abstract INTRODUCTION Cerebral small vessel disease (CSVD) contributes to the development of Alzheimer's disease (AD) dementia and co‐occurs with AD‐associated proteinopathies. However, how sex modulates the interaction between CSVD and AD‐associated proteinopathies in the medial temporal lobe (MTL) remains unclear. METHODS One hundred fifty‐two autopsy cases from the Massachusetts Alzheimer's Disease Research Center were included. Deep‐learning and semiquantitative scores were applied to MTL histological sections to obtain quantitative measures of proteinopathies and CSVD (cerebral amyloid angiopathy [CAA] and arteriolosclerosis). The effect of sex on AD‐associated proteinopathies and the interaction between sex, CSVD, and apolipoprotein E ( APOE ) genotype were analyzed using linear mixed‐effect models. RESULTS In women, higher CAA burden was associated with lower amyloid beta (Aβ) plaques but higher tau tangles density. No interaction effect was found for arteriolosclerosis. Women <75 years of age carrying the APOE ε4 allele had higher Aβ plaque burden than ε4 non‐carriers. DISCUSSION Our results highlight the complex effect of sex on microvascular and AD‐associated pathologies in the MTL.

MarkVCID2 Consortium for Clinical Validation of Biomarkers of Cerebral Small Vessel Disease: Validation Framework and Baseline Characteristics

Objective To establish a framework for validating candidate biomarkers of cerebral small vessel diseases (SVD) associated with cognitive impairment and characterize individuals enrolled by the MarkVCID2 consortium under this framework. Methods Participants age 60 to 90 years were enrolled across 17 MarkVCID2 sites. Recruitment was targeted to enrich in cognitive symptoms (mild dementia, mild cognitive impairment, subjective cognitive decline), defined risk factors (diabetes mellitus, advanced hypertension), and Black/African American, White, and Hispanic/Latino subgroups. Enrolled participants underwent baseline visits that included cognitive testing, multimodal magnetic resonance imaging (MRI), and biofluid collection. Provisional risk for SVD‐related cognitive decline was estimated primarily by baseline cognitive symptoms plus SVD risk factors. Adjudicated risk status was estimated by cognitive symptoms plus presence of moderate‐to‐severe white matter hyperintensities, microbleeds, or lacunes on baseline MRI. Results MarkVCID2 enrolled 1883 individuals age 73.4 ± 7.5 years, 65.0% female, 24.2% Hispanic, and 27.1% non‐Hispanic Black. Among enrollees, 44.8% were provisionally designated high‐risk. After baseline MRI, 48.5% were categorized as adjudicated high‐risk status, with substantial recategorization both from low‐ to high‐risk (primarily because of MRI lesions without SVD risk factors) and high‐ to low‐risk (primarily suspected cognitive impairment at screening not confirmed by baseline testing). Interpretation MarkVCID2 baseline data indicate successful enrollment of diverse individuals enriched in factors associated with SVD‐related cognitive decline. Changes over 3 years of longitudinal follow‐up will be analyzed to validate the candidate biomarkers for 2 projected contexts of use: subject selection (identifying likelihood of future SVD progression) and study outcome (efficiently measuring SVD progression). ANN NEUROL 2026;99:449–458

Late Pregnancy Antiseizure Medication Exposure and Offspring Neurodevelopmental Risk: A Multi‐Child Cohort Study

Objective Antiseizure medication (ASM) use during pregnancy has increased over the past decade. However, evidence linking prenatal ASM exposure to neurodevelopmental disorders (NDDs) in offspring remains inconsistent. This study evaluated whether prenatal ASM exposure increases the risk of NDDs in children. Methods We analyzed data from 5 population‐based cohorts of live‐born children in Canada (Alberta, Manitoba, Ontario, Quebec; the Canadian Mother‐Child Cohort [CAMCCO] cohorts) and the United States (AM‐PREGNANT cohort). ASM exposure was defined as maternal prescription fills overlapping the 60 days before birth. NDDs were identified using validated algorithm based on the International Classification of Disease‐9/10 codes from inpatient and outpatient records. Within each cohort, Cox proportional hazards models were applied, with adjustment performed separately using (1) covariates and (2) propensity scores. Pooled estimates were obtained using random‐effects meta‐analysis. Results Of 2,910,206 children, 0.47% were exposed to ASMs in the 60 days before birth. Prenatal ASM exposure was associated with a 29% increased risk of NDDs (pooled‐adjusted hazard ratio [p‐aHR], 1.29; 95% CI: 1.22–1.37; 1,805 exposed cases). In the Canadian cohorts, risks of combined NDDs varied by medication: carbamazepine (p‐aHR: 1.50; 95% CI: 1.20–1.87; 262 exposed cases), clonazepam (p‐aHR 1.22; 95% CI: 1.12–1.33; 585 exposed cases), topiramate (p‐aHR 1.56; 95% CI: 1.04–2.34; 69 exposed cases), and valproic acid (p‐aHR 1.38; 95% CI: 1.16–1.65; 134 exposed cases). Although point estimates were higher for polytherapy than monotherapy, the difference was not statistically significant. Interpretation Prenatal exposure to certain ASMs was consistently associated with increased risks of NDDs in offspring. These findings support careful, individualized decision‐making regarding prenatal ASM use to minimize neurodevelopmental risks. ANN NEUROL 2026;99:761–776

In Memoriam: W. King Engel, MD (1930–2025)

Synthesis and Physical Properties of Hempseed and High‐Oleic Hempseed Oil Estolides

ABSTRACT Hempseed oil (HSO) bears the unique property of its fatty acid profiles being unusually rich with polyunsaturated fatty acids. While the presence of numerous olefins would make this oil prone to oxidation, the presence of this functional group can be exploited to form oligomers called estolides, improving their oxidative stability and cold flow properties. In this work, a series of estolides were synthesized from HSO and high‐oleic HSO (HOHSO) which are capped with fatty acids of varying chain length and esterified with 2‐ethylhexanol (2‐EH). The estolides capped with shorter chain saturated fatty acids (C8–C14) exhibited excellent cold flow properties, with pour points of −36°C and lower. Estolides prepared from HSO had higher kinematic viscosities than those prepared from HOHSO. HOHSO estolides bore physical properties similar to estolides synthesized from oleic‐rich oils, which is advantageous for applications as bio‐based motor oils. Furthermore, the HSO/2‐EH estolide capped with a shorter chain fatty acid of the series synthesized (specifically caprylic/octanoic acid, C8:0) bore an unusually high kinematic viscosity compared to the rest of the series capped with longer chain fatty acids.

B‐Staging and Crosslinking of Polycarbosilane at Room Temperature: Cure Mechanism and Properties

ABSTRACT The viscosity of polycarbosilane (PCS) polymers is not advantageous for free forming. Various fillers and heat are used to obtain a formable paste. Due to the low yield stress, structures and preforms tend to slump or resin will flow out, especially during the curing of the polymer. B‐staging of PCS allows for a more stable structure from room temperature until the full cure of the allyl groups occurs with heat. Additionally, hydrosilation is an effective means of crosslinking at room temperature and controlling viscosity. A network structure was formed in SMP‐10 using silane and a vinyl‐based crosslinker to bridge each polymer chain. Pt addition catalysts were added to enhance the increase in viscosity to make a lightly crosslinked gel to aid in thickening and forming and to improve the ceramic yield at 1000°C. This enables several options for controlling rheology and improving the properties of preceramic polymers to avoid slumping during curing.

Micromechanical Analysis of Flat Multilayer Composites

ABSTRACT A micromechanical model has been developed to predict effective tensile properties of a flat, planar, multilayer composite based on the tensile properties of each component layer with emphasis on the Young's modulus. The model is challenged to characterize a composite membrane comprised of a central amorphous fluoropolymer layer bound by an upper and lower layer of expanded polytetrafluoroethylene. Experimental measurements of Young's modulus are shown to be in reasonable to excellent agreement with predicted values. Further, the model demonstrates a means to predict tensile properties along material coordinates that might not be readily navigated using typical experimental techniques. Given the favorable results, the model establishes confidence and a firm foundation for future experiments seeking to characterize the stress distribution within planar composite materials resulting from imposed mechanical and/or thermal perturbation.

Noradrenergic and cholinergic innervation of the normal human heart and changes associated with cardiomyopathy

Abstract Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure‐perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.