Development and validation of a nonverbal consensus-based semantic memory paradigm in patients with epilepsy.

OBJECTIVE: Brain areas implicated in semantic memory can be damaged in patients with epilepsy (PWE). However, it is challenging to delineate semantic processing deficits from acoustic, linguistic, and other verbal aspects in current neuropsychological assessments. We developed a new Visual-based Semantic Association Task (ViSAT) to evaluate nonverbal semantic processing in PWE. METHOD: The ViSAT was adapted from similar predecessors (Pyramids & Palm Trees test, PPT; Camels & Cactus Test, CCT) comprised of 100 unique trials using real-life color pictures that avoid demographic, cultural, and other potential confounds. We obtained performance data from 23 PWE participants and 24 control participants (Control), along with crowdsourced normative data from 54 Amazon Mechanical Turk (Mturk) workers. RESULTS: ViSAT reached a consensus >90% in 91.3% of trials compared to 83.6% in PPT and 82.9% in CCT. A deep learning model demonstrated that visual features of the stimulus images (color, shape; i.e., non-semantic) did not influence top answer choices (p = 0.577). The PWE group had lower accuracy than the Control group (p = 0.019). PWE had longer response times than the Control group in general and this was augmented for the semantic processing (trial answer) stage (both p < 0.001). CONCLUSIONS: This study demonstrated performance impairments in PWE that may reflect dysfunction of nonverbal semantic memory circuits, such as seizure onset zones overlapping with key semantic regions (e.g., anterior temporal lobe). The ViSAT paradigm avoids confounds, is repeatable/longitudinal, captures behavioral data, and is open-source, thus we propose it as a strong alternative for clinical and research assessment of nonverbal semantic memory.

Depression, loneliness, and lower social activity as partial mediators of the association between visual impairment and cognitive decline.

OBJECTIVES: Sensory impairment is a hypothesized risk factor for cognitive decline; however, the psychosocial pathways are not well understood. We evaluated whether the association between visual impairment (VI) and cognitive decline was partially mediated via depressive symptoms, loneliness, or social activity. METHODS: We used data from 2601 older adults enrolled in the Memory and Aging Project in 1997 and the Minority Aging Research Study in 2004 with neuropsychological tests across five domains measured annually for up to 16 years. VI was assessed with the Rosenbaum Pocket Vision Screener. Depressive symptoms, loneliness, and social activity were self-reported using validated scales. We used structural equation models to estimate the associations of VI with baseline and change in cognitive function, directly and indirectly through each mediator (depressive symptoms, loneliness, and social activity). We evaluated mediation via "psychological distress" using a latent variable combining depressive symptoms and loneliness. RESULTS: The association between VI and global cognitive decline was mediated via lower social activity (indirect effect) [95% confidence interval (CI)] of linear slope: -0.025 (-0.048, -0.011), via loneliness (-0.011 [95% CI: -0.028, -0.002]), and via psychological distress (-0.017 [95% CI: -0.042, -0.003]). We did not find sufficient evidence for mediation via depressive symptoms alone. CONCLUSIONS: The harmful effect of VI on cognitive decline may be partially mediated through loneliness and lower social activity.

Does education moderate gender disparities in later-life memory function? A cross-national comparison of harmonized cognitive assessment protocols in the United States and India.

INTRODUCTION: We compared gender disparities in later-life memory, overall and by education, in India and the United States (US). METHODS: Data (N = 7443) were from harmonized cognitive assessment protocols (HCAPs) in the Longitudinal Aging Study of India-Diagnostic Assessment of Dementia (LASI-DAD; N = 4096; 2017-19) and US Health and Retirement Study HCAP (HRS-HCAP; N = 3347; 2016-17). We derived harmonized memory factors from each study using confirmatory factor analysis. We used multivariable-adjusted linear regression to compare gender disparities in memory function between countries, overall and by education. RESULTS: In the United States, older women had better memory than older men (0.28 SD-unit difference; 95% CI: 0.22, 0.35). In India, older women had worse memory than older men (-0.15 SD-unit difference; 95% CI: -0.20, -0.10), which attenuated with increasing education and literacy. CONCLUSION: We observed gender disparities in memory in India that were not present in the United States, and which dissipated with education and literacy.

Sex and gender differences in cognitive resilience to aging and Alzheimer's disease.

Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Biomarkers of endothelial dysfunction and cognition: A two-step IPD meta-analysis.

INTRODUCTION: This study assessed the association of plasma biomarkers of endothelial dysfunction with cognitive performance and decline. METHODS: Data from 9414 individuals from eight Dutch cohorts were included (Ø  age-range: 57-93 years). Plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin) were combined into a standardized composite score. Cognitive outcomes included executive function, processing speed, immediate and delayed memory, attention, and language. Linear regressions and linear mixed models were run in the individual cohorts and standardized coefficients were subsequently pooled using random-effects meta-analyses. RESULTS: A higher endothelial dysfunction composite score was cross-sectionally associated with worse performance on executive function, processing speed, delayed memory, and attention, but not immediate memory or language (pooled ß-range: -0.04, -0.02). We found no association with change in cognition over time. DISCUSSION: This comprehensive two-step, individual participant data (IPD) meta-analysis showed a small, consistent cross-sectional association between endothelial dysfunction and worse cognitive performance across multiple domains but no support for a longitudinal association. HIGHLIGHTS: Prior evidence on endothelial dysfunction (ED) biomarkers and cognition is conflicting. This two-step, individual participant data (IPD) meta-analysis used data from eight Dutch cohorts. ED was consistently associated with concurrent cognition. ED was not associated with a change in cognition over time. The association of ED with current cognition may be generic.

Longitudinal decline in semantic versus letter fluency, but not their ratio, marks incident Alzheimer's disease in Latinx Spanish-speaking older individuals.

OBJECTIVE: To compare longitudinal verbal fluency performance among Latinx Spanish speakers who develop Alzheimer's disease to those who do not develop dementia in absolute number of words produced on each task and their ratio to combine both scores. METHOD: Participants included 833 Latinx Spanish-speaking older adults from a community-based prospective cohort in Manhattan. We performed growth curve modeling to investigate the trajectories of letter and semantic fluency, and their ratio (i.e., 'semantic index'), between individuals who developed Alzheimer's disease and those who did not (i.e., controls). The semantic index quantifies the proportion of words generated for semantic fluency in relation to the total verbal fluency performance. RESULTS: Letter fluency performance did not decline in controls; we observed a linear decline in those who developed Alzheimer's disease. Semantic fluency declined in both groups and showed an increased rate of change over time in the incident Alzheimer's disease group; in comparison, the control group had a linear and slower decline. There were no group differences in the longitudinal trajectory (intercept and slope) of the semantic index. CONCLUSION: A decline in letter fluency and a more rapid and accelerating decline over time in semantic fluency distinguished people who developed Alzheimer's disease from controls. Using the semantic index was not a superior marker of incident Alzheimer's disease compared to examining the two fluency scores individually. Results suggest the differential decline in verbal fluency tasks, when evaluated appropriately, may be useful for early identification of Alzheimer's disease in Latinx Spanish speakers, a historically understudied population.

Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico.

OBJECTIVE: To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes and investigate the impact of midlife cardiovascular risk factors on late-life MCI among the aging Mexican population. METHOD: Analyses included a sample of non-demented adults over the age of 55 living in both urban and rural areas of Mexico (N = 1807). MCI diagnosis was assigned based on a comprehensive cognitive assessment assessing the domains of memory, executive functioning, language, and visuospatial ability. The normative sample was selected by means of the robust norms approach. Cognitive impairment was defined by a 1.5-SD cut-off per cognitive domain using normative corrections for age, years of education, and sex. Risk factors included age, education, sex, rurality, depression, insurance status, workforce status, hypertension, diabetes, stroke, and heart disease. RESULTS: The prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged from 4.2% to 7.7%. MCI with and without memory impairment was associated with older age (OR = 1.01 [1.01, 1.05]; OR = 1.03 [1.01, 1.04], respectively) and residing in rural areas (OR = 1.49 [1.08, 2.06]; OR = 1.35 [1.03, 1.77], respectively). Depression (OR = 1.07 [1.02, 1.12]), diabetes (OR = 1.37 [1.03, 1.82]), and years of education (OR = 0.94 [0.91, 0.97]) were associated with MCI without memory impairment. Midlife CVD increased the odds of MCI in late-life (OR = 1.76 [1.19, 2.59], which was driven by both midlife hypertension and diabetes (OR = 1.70 [1.18, 2.44]; OR = 1.88 [1.19, 2.97], respectively). CONCLUSIONS: Older age, depression, low education, rurality, and midlife hypertension and diabetes were associated with higher risk of late-life MCI among older adults in Mexico. Our findings suggest that the causes of cognitive impairment are multifactorial and vary by MCI subtype.

Consideration of sex and gender in Alzheimer's disease and related disorders from a global perspective.

Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. HIGHLIGHTS: The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.

Dementia risk in the general population: large-scale external validation of prediction models in the AGES-Reykjavik study.

We aimed to evaluate the external performance of prediction models for all-cause dementia or AD in the general population, which can aid selection of high-risk individuals for clinical trials and prevention. We identified 17 out of 36 eligible published prognostic models for external validation in the population-based AGES-Reykjavik Study. Predictive performance was assessed with c statistics and calibration plots. All five models with a c statistic > .75 (.76-.81) contained cognitive testing as a predictor, while all models with lower c statistics (.67-.75) did not. Calibration ranged from good to poor across all models, including systematic risk overestimation or overestimation for particularly the highest risk group. Models that overestimate risk may be acceptable for exclusion purposes, but lack the ability to accurately identify individuals at higher dementia risk. Both updating existing models or developing new models aimed at identifying high-risk individuals, as well as more external validation studies of dementia prediction models are warranted.

Education differentially contributes to cognitive reserve across racial/ethnic groups.

INTRODUCTION: We examined whether educational attainment differentially contributes to cognitive reserve (CR) across race/ethnicity. METHODS: A total of 1553 non-Hispanic Whites (Whites), non-Hispanic Blacks (Blacks), and Hispanics in the Washington Heights-Inwood Columbia Aging Project (WHICAP) completed structural magnetic resonance imaging. Mixture growth curve modeling was used to examine whether the effect of brain integrity indicators (hippocampal volume, cortical thickness, and white matter hyperintensity [WMH] volumes) on memory and language trajectories was modified by education across racial/ethnic groups. RESULTS: Higher educational attainment attenuated the negative impact of WMH burden on memory (ß = -0.03; 99% CI: -0.071, -0.002) and language decline (ß = -0.024; 99% CI:- 0.044, -0.004), as well as the impact of cortical thinning on level of language performance for Whites, but not for Blacks or Hispanics. DISCUSSION: Educational attainment does not contribute to CR similarly across racial/ethnic groups.

Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults.

Verbal fluency tasks are generally thought to be mediated by frontal brain regions for letter fluency and temporal regions for category fluency. This idea, however, is primarily based on lesion studies and adapted versions of the fluency tasks in functional neuroimaging, without fundamental evidence from structural neuroimaging in healthy individuals. We investigated the cortical structural correlates of letter and category fluency, including overlapping and different regions, in 505 individuals who participated in a community-based study of healthy aging. The correlation between cortical thickness and verbal fluency in whole-brain analyses revealed distinct cortical signatures for letter fluency, primarily in frontal regions, and category fluency, in frontal and temporal-parietal regions. There was a dissociation in the left inferior frontal gyrus between letter and category fluency, with increased thickness in the posterior-dorsal versus anterior-ventral parts, respectively. These results distinguish the detailed anatomical correlates for verbal fluency within the coarse frontal-temporal distinction inferred from lesion studies and among the mixture of regions identified in functional neuroimaging. The evidence for the anatomical substrates of letter and category fluency, each recruiting slightly different language and cognitive processes, can serve both clinical applications as well as a deeper theoretical understanding of the organization of the cerebral cortex.

Semantic and lexical features of words dissimilarly affected by non-fluent, logopenic, and semantic primary progressive aphasia.

OBJECTIVE: To determine the effect of three psycholinguistic variables-lexical frequency, age of acquisition (AoA), and neighborhood density (ND)-on lexical-semantic processing in individuals with non-fluent (nfvPPA), logopenic (lvPPA), and semantic primary progressive aphasia (svPPA). Identifying the scope and independence of these features can provide valuable information about the organization of words in our mind and brain. METHOD: We administered a lexical decision task-with words carefully selected to permit distinguishing lexical frequency, AoA, and orthographic ND effects-to 41 individuals with PPA (13 nfvPPA, 14 lvPPA, 14 svPPA) and 25 controls. RESULTS: Of the psycholinguistic variables studied, lexical frequency had the largest influence on lexical-semantic processing, but AoA and ND also played an independent role. The results reflect a brain-language relationship with different proportional effects of frequency, AoA, and ND in the PPA variants, in a pattern that is consistent with the organization of the mental lexicon. Individuals with nfvPPA and lvPPA experienced an ND effect consistent with the role of inferior frontal and temporoparietal regions in lexical analysis and word form processing. By contrast, individuals with svPPA experienced an AoA effect consistent with the role of the anterior temporal lobe in semantic processing. CONCLUSIONS: The findings are in line with a hierarchical mental lexicon structure with a conceptual (semantic) and a lexeme (word-form) level, such that a selective deficit at one of these levels of the mental lexicon manifests differently in lexical-semantic processing performance, consistent with the affected language-specific brain region in each PPA variant.

Secular trends in cognitive trajectories of diverse older adults.

INTRODUCTION: This study aimed to determine if later birth year influences trajectory of age-related cognitive decline across racial/ethnic groups and to test whether years of school, childhood socioeconomic status, and cardiovascular disease burden explain such secular trends. METHODS: We compared cognitive trajectories of global cognition and subdomains in two successive racially/ethnically and educationally diverse birth cohorts of a prospective cohort study. RESULTS: Later birth year was associated with higher initial cognitive levels for Whites and Blacks, but not Hispanics. Later birth year was also associated with less rapid rate of decline in all three racial/ethnic groups. More years of education, higher childhood socioeconomic status, and, to a smaller extent, greater cardiovascular disease burden accounted for higher intercepts in the later-born cohort, but did not account for attenuated slope of cognitive decline. DISCUSSION: Later birth year is related to a slower rate of age-related decline in some cognitive domains in some racial/ethnic groups. Our analyses suggest that racial/ethnic and social inequalities are part of the mechanisms driving secular trends in cognitive aging and dementia.

Sex/gender differences in cognitive trajectories vary as a function of race/ethnicity.

INTRODUCTION: The present study sought to determine whether cognitive trajectories differ between men and women across and within racial/ethnic groups. METHODS: Participants were 5258 non-Hispanic White (NHW), Black, and Hispanic men and women in the Washington/Hamilton Heights-Inwood Columbia Aging Project who were administered neuropsychological tests of memory, language, and visuospatial abilities at 18- to 24-month intervals for up to 25 years. Multiple-group latent growth curve modeling examined trajectories across sex/gender by race/ethnicity. RESULTS: After adjusting for age and education, the largest baseline differences were between NHW men and Hispanic women on visuospatial and language, and between NHW women and Black men on memory. Memory and visuospatial decline was steeper for Black women compared with Hispanic men and NHW women, respectively. DISCUSSION: This study takes an important first step in understanding interactions between race/ethnicity and sex/gender on cognitive trajectories by demonstrating variability in sex/gender differences across race/ethnicity.

Levels of Abstractness in Semantic Noun and Verb Processing: The Role of Sensory-Perceptual and Sensory-Motor Information.

Effects of concreteness and grammatical class on lexical-semantic processing are well-documented, but the role of sensory-perceptual and sensory-motor features of concepts in underlying mechanisms producing these effects is relatively unknown. We hypothesized that processing dissimilarities in accuracy and response time performance in nouns versus verbs, concrete versus abstract words, and their interaction can be explained by differences in semantic weight-the combined amount of sensory-perceptual and sensory-motor information to conceptual representations-across those grammatical and semantic categories. We assessed performance on concrete and abstract subcategories of nouns and verbs with a semantic similarity judgment task. Results showed that when main effects of concreteness and grammatical class were analyzed in more detail, the grammatical-class effect, in which nouns are processed more accurately and quicker than verbs, was only present for concrete words, not for their abstract counterparts. Moreover, the concreteness effect, measured at different levels of abstract words, was present for both nouns and verbs, but it was less pronounced for verbs. The results do not support the grammatical-class hypothesis, in which nouns and verbs are separately organized, and instead provide evidence in favor of a unitary semantic space, in which lexical-semantic processing is influenced by the beneficial effect of sensory-perceptual and sensory-motor information of concepts.

Cognitive reserve in individuals with frontotemporal dementia: a systematic review.

As the literature related to cognitive reserve (CR) in individuals with frontotemporal dementia (FTD) is only emerging, a clear consensus on the relationship among CR proxies, brain status, and clinical performance has not been reached. The primary aim of this systematic review was to examine the relationship among sociobehavioral proxies of CR, brain status, and clinical performance in individuals with various types of FTD. Additionally, characteristics of patient population, sociobehavioral proxies, disease severity tools, and brain status measures used were identified. The systematic review was conducted using comprehensive search terms in Medline, PsychINFO, PubMed, and Web of Science. Eligibility criteria were for studies to include at least one CR and one brain status measure for individuals with FTD, be published in a peer-reviewed journal, and be published in English. The Newcastle-Ottawa Quality Assessment Scale was used to assess study quality and bias risk. A total of 237 titles and abstracts were screened, with 13 studies meeting inclusion criteria. Together, these studies report 1,423 participants with FTD. Based on the included studies, partial support was demonstrated for CR in individuals with FTD when education, occupation, and leisure were utilized as CR proxies. The variability in results among studies could be related to the different tools used to measure CR, brain status, and disease severity. This review provides recommendations for future studies: incorporating longitudinal designs, in depth neuropsychological testing, consistent disease duration measure, and transparant statistical output reporting.

A scoping review of neuropsychological assessment for Asian Indians in the United States - research and clinical recommendations.

Objective: There is an increasing focus on understanding health disparities among various cultural groups in the United States. The need for heterogeneity in norms and test stimuli across ethnically diverse individuals are being increasingly recognized. However, to date it remains unknown whether and to what extent differences in cognitive norms and tests exist in Asian Indians, a fast-growing population in the U.S. It is essential to understand these differences to improve diagnostic accuracy and provide timely and appropriate clinical care. Method: In this study, we conducted a scoping review of available cognitive tests that were normed, developed, or adapted for Asian Indians living in the U.S. Results: The results suggested a paucity of norms and tests specifically examining cognition in this community. Conclusions: Based on the findings, we provide suggestions for research directions focusing on the development of culturally sensitive neuropsychological tools, normative data representative of this demographic, and interventions addressing healthcare access barriers. Overall, this review provides readers with relevant clinical information to immediately enhance patient care as well as provide actionable items in research to improve the future utility of neuropsychology for Asian Indians in the United States.

The association of sociodemographic factors with total and item-level semantic fluency metrics.

OBJECTIVE: We aimed to estimate the association of age, education, and sex/gender with semantic fluency performance as measured by the standard total number of words as well as novel item-level metrics and to descriptively compare associations across cohorts with different recruitment strategies and sample compositions. METHOD: Cross-sectional data from 2,391 individuals from three cohorts were used: Washington Heights/Inwood Columbia Aging Project, a community-based cohort; Second Manifestations of ARTerial disease-Magnetic Resonance, a clinic-based cohort; and African American Alzheimer's Disease Genetics Study, a volunteer-based cohort. Total number of correct words and six item-level semantic fluency metrics were included as main outcomes: average cluster size, number of cluster switches, lexical/Zipf frequency, age of acquisition, and lexical decision response time. General linear models were run separately in each cohort to model the association between sociodemographic variables and semantic fluency metrics. RESULTS: Across cohorts, older age was associated with a lower total score and fewer cluster switches. Higher level of education was associated with naming more words, performing more cluster switches, and naming words with a longer lexical decision response time, lower frequency of occurrence, or later age of acquisition. Being female compared to male was associated with naming fewer words, smaller cluster sizes, naming words with a longer lexical decision response time, and lower age of acquisition. The effects varied in strength but were in a similar direction across cohorts. CONCLUSIONS: Item-level semantic fluency metrics-similar to the standard total score-are sensitive to the effects of age, education, and sex/gender. The results suggest geographical, cultural, and cross-linguistic generalizability of these sociodemographic effects on semantic fluency performance. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Digital language markers distinguish frontal from right anterior temporal lobe atrophy in frontotemporal dementia.

Background and Objectives: Within frontotemporal dementia (FTD), the behavioral variant (bvFTD) characterized by frontal atrophy, and semantic behavioral variant (sbvFTD) characterized by right anterior temporal lobe (rATL) atrophy, present diagnostic challenges due to overlapping symptoms and neuroanatomy. Accurate differentiation is crucial for clinical trial inclusion targeting TDP-43 proteinopathies. This study investigated whether automated speech analysis can distinguish between FTD-related rATL and frontal atrophy, potentially offering a non-invasive diagnostic tool. Methods: In a cross-sectional design, we included 40 participants with FTD-related predominant frontal atrophy (n=16) or predominant rATL atrophy (n=24) and 22 healthy controls from the UCSF Memory and Aging Center. Using stepwise logistic regression and receiver operating characteristic (ROC) curve analysis, we analyzed 16 linguistic and acoustic features that were extracted automatically from audio-recorded picture description tasks. Neuroimaging data were analyzed using voxel-based morphometry to examine brain-behavior relationships of regional atrophy with the features selected in the regression models. Results: Logistic regression identified three features (content units, lexical frequency, familiarity) differentiating the overall FTD group from controls (AUC=.973), adjusted for age. Within the FTD group, five features (adpositions/total words ratio, arousal, syllable pause duration, restarts, words containing 'thing') differentiated frontal from rATL atrophy (AUC=.943). Neuroimaging analyses showed that semantic features (lexical frequency, content units, 'thing' words) were linked to bilateral inferior temporal lobe structures, speech and lexical features (syllable pause duration, adpositions/total words ratio) to bilateral inferior frontal gyri, and socio-emotional features (arousal) to areas known to mediate social cognition including the right insula and bilateral anterior temporal structures. As a composite score, this set of five features was uniquely associated with rATL atrophy. Discussion: Automated speech analysis effectively distinguished the overall FTD group from controls and differentiated between frontal and rATL atrophy. The neuroimaging findings for individual features highlight the neural basis of language impairments in these FTD variants, and when considered together, underscore the importance of utilizing features' combined power to identify impaired language patterns. Automated speech analysis could enhance early diagnosis and monitoring of FTD, offering a scalable, non-invasive alternative to traditional methods, particularly in resource-limited settings. Further research should aim to integrate automated speech analysis into multi-modal diagnostic frameworks.

Microvascular Dysfunction and Whole-Brain White Matter Connectivity: The Maastricht Study.

BACKGROUND: Microvascular dysfunction is involved in the development of various cerebral disorders. It may contribute to these disorders by disrupting white matter tracts and altering brain connectivity, but evidence is scarce. We investigated the association between multiple biomarkers of microvascular function and whole-brain white matter connectivity. METHODS AND RESULTS: Cross-sectional data from The Maastricht Study, a Dutch population-based cohort (n=4326; age, 59.4±8.6 years; 49.7% women). Measures of microvascular function included urinary albumin excretion, central retinal arteriolar and venular calibers, composite scores of flicker light-induced retinal arteriolar and venular dilation, and plasma biomarkers of endothelial dysfunction (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and von Willebrand factor). White matter connectivity was calculated from 3T diffusion magnetic resonance imaging to quantify the number (average node degree) and organization (characteristic path length, global efficiency, clustering coefficient, and local efficiency) of white matter connections. A higher plasma biomarkers of endothelial dysfunction composite score was associated with a longer characteristic path length (ß per SD, 0.066 [95% CI, 0.017-0.114]) after adjustment for sociodemographic, lifestyle, and cardiovascular factors but not with any of the other white matter connectivity measures. After multiple comparison correction, this association was nonsignificant. None of the other microvascular function measures were associated with any of the connectivity measures. CONCLUSIONS: These findings suggest that microvascular dysfunction as measured by indirect markers is not associated with whole-brain white matter connectivity.