Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. RESULTS: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.

The aging brain: risk factors and interventions for long term brain health in women.

PURPOSE OF REVIEW: Poor cognitive aging and dementia pose a significant public health burden, and women face unique risks compared to men. Recent research highlights the role of genetics, menopause, chronic disease, and lifestyle in risk and resilience in women's cognitive aging. This work suggests avenues for clinical action at midlife that may change the course of brain health in aging. RECENT FINDINGS: Studies indicate women's risk for poor cognitive aging relates in part to hormone changes at menopause, a time when memory, brain structure and function, and Alzheimer's pathology may be observed in women and not men. Medical and lifestyle risks including diabetes, hypertension, and low physical activity also contribute to women's unique risks. At the same time, literature on resilience suggests women may benefit from lifestyle and chronic disease intervention, possibly more than men. Current studies emphasize the importance of interacting genetic and lifestyle risks, and effects of social determinants of health. SUMMARY: Women have greater risk than men for poor cognitive aging; however, by treating the whole person, including genetics, lifestyle, and social environment, clinicians have an opportunity to support healthy cognitive aging in women and reduce the future public health burden of dementia.

Story Memory Impairment Rates and Association with Hippocampal Volumes in a Memory Clinic Population.

OBJECTIVE: Story memory tasks are among the most commonly used memory tests; however, research suggests they may be less sensitive to memory decline and have a weaker association with hippocampal volumes than list learning tasks. To examine its utility, we compared story memory to other memory tests on impairment rates and association with hippocampal volumes. METHOD: Archival records from 1617 older adults (Mage = 74.41, range = 65-93) who completed the Wechsler Memory Scale - 4th edition (WMS-IV) Logical Memory (LM), Hopkins Verbal Learning Test - Revised (HVLT-R), and Brief Visuospatial Memory Test - Revised (BVMT-R) as part of a clinical neuropsychological evaluation were reviewed. Scores >1.5 SD below age-adjusted means were considered impaired, and frequency distributions were used to examine impairment rates. A subset of participants (n = 179) had magnetic resonance imaging (MRI) data that underwent image quality assessment. Partial correlations and linear regression analyses, accounting for age, education, and total intracranial volume (TIV), examined associations between memory raw scores and hippocampal volumes. RESULTS: For delayed recall, nearly half of the sample was impaired on HVLT-R (48.8%) and BVMT-R (46.1%), whereas a little more than a third was impaired on LM (35.7%). Better performance on all three measures was related to larger hippocampal volumes (r's =. 26-.43, p's < .001). Individually adding memory scores to regression models predicting hippocampal volumes improved the model fit for all measures. CONCLUSIONS: Despite findings suggesting that story memory is less sensitive to memory dysfunction, it was not differentially associated with hippocampal volumes compared to other memory measures. Results support assessing memory using different formats and modalities in older adults.

Inflammatory cytokine levels implicated in Alzheimer's disease moderate the effects of sex on verbal memory performance.

Despite having an initial verbal memory advantage over men, women have greater rates of Alzheimer's disease and more rapid cognitive decline once diagnosed. Moreover, although Alzheimer's disease is influenced by inflammation, which itself has known sex differences, no study has investigated whether sex differences in memory are moderated by peripheral inflammatory activity. To address this issue, we analyzed data from 109 individuals (50 women, Mage = 71.62, range = 55-87) diagnosed as cognitively normal, or having mild cognitive impairment or Alzheimer's disease dementia. We then followed the sample for 12 months, as part of a longitudinal study of aging and Alzheimer's disease. At baseline, we assessed levels of the inflammatory cytokines interleukin (IL)-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) in plasma. At baseline and 12 months, we assessed verbal memory using the Rey Auditory Verbal Learning Test and nonverbal memory using the Brief Visuospatial Memory Test-Revised. As hypothesized, for the full sample, women exhibited stronger verbal (but not nonverbal) memory than men. In women, but not men, higher IL-1ß at baseline related to poorer verbal learning across both time points and delayed recall at 12 months. The effect of sex on memory also differed by IL-1ß level, with women exhibiting a memory advantage both at baseline and 12 months, but only for those with low-to-moderate IL-1ß levels. Therefore, high peripheral inflammation levels may lead to a sex-specific memory vulnerability relevant for Alzheimer's disease.

Sex Differences in Cognitive Changes in De Novo Parkinson's Disease.

OBJECTIVE: To evaluate the sex differences in cognitive course over 4 years in Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls. METHODS: Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson's Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared. RESULTS: Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period). CONCLUSIONS: Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

ADSS: A Composite Score to Detect Disease Progression in Alzheimer's Disease.

Background: Composite scores have been increasingly used in trials for Alzheimer's disease (AD) to detect disease progression, such as the AD Composite Score (ADCOMS) in the lecanemab trial. Objective: To develop a new composite score to improve the prediction of outcome change. Methods: We proposed to develop a new composite score based on the statistical model in the ADCOMS, by removing duplicated sub-scales and adding the model selection in the partial least squares (PLS) regression. Results: The new AD composite Score with variable Selection (ADSS) includes 7 cognitive sub-scales. ADSS can increase the sensitivity to detect disease progression as compared to the existing total scores, which leads to smaller sample sizes using the ADSS in trial designs. Conclusions: ADSS can be utilized in AD trials to improve the success rate of drug development with a high sensitivity to detect disease progression in early stages.

Classifying Alzheimer's Disease Neuropathology Using Clinical and MRI Measurements.

Background: Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data. Objective: Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features. Methods: AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women). Results: Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status. Conclusions: Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons.

Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.

Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied.

Compassion training alters altruism and neural responses to suffering.

Compassion is a key motivator of altruistic behavior, but little is known about individuals' capacity to cultivate compassion through training. We examined whether compassion may be systematically trained by testing whether (a) short-term compassion training increases altruistic behavior and (b) individual differences in altruism are associated with training-induced changes in neural responses to suffering. In healthy adults, we found that compassion training increased altruistic redistribution of funds to a victim encountered outside of the training context. Furthermore, increased altruistic behavior after compassion training was associated with altered activation in brain regions implicated in social cognition and emotion regulation, including the inferior parietal cortex and dorsolateral prefrontal cortex (DLPFC), and in DLPFC connectivity with the nucleus accumbens. These results suggest that compassion can be cultivated with training and that greater altruistic behavior may emerge from increased engagement of neural systems implicated in understanding the suffering of other people, executive and emotional control, and reward processing.

Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment.

Purpose: To assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process. Materials and Methods: Two hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI. Results: The MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10-7, right: P = 3.37 × 10-8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI. Conclusion: Sex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.

Brain functional topology differs by sex in cognitively normal older adults.

Introduction: Late onset Alzheimer's disease (AD) is the most common form of dementia, in which almost 70% of patients are women. Hypothesis: We hypothesized that women show worse global FC metrics compared to men, and further hypothesized a sex-specific positive correlation between FC metrics and cognitive scores in women. Methods: We studied cognitively healthy individuals from the Alzheimer's Disease Neuroimaging Initiative cohort, with resting-state functional Magnetic Resonance Imaging. Metrics derived from graph theoretical analysis and functional connectomics were used to assess the global/regional sex differences in terms of functional integration and segregation, considering the amyloid status and the contributions of APOE E4. Linear mixed effect models with covariates (education, handedness, presence of apolipoprotein [APOE] E4 and intra-subject effect) were utilized to evaluate sex differences. The associations of verbal learning and memory abilities with topological network properties were assessed. Result: Women had a significantly lower magnitude of the global and regional functional network metrics compared to men. Exploratory association analysis showed that higher global clustering coefficient was associated with lower percent forgetting in women and worse cognitive scores in men. Conclusion: Women overall show lower magnitude on measures of resting state functional network topology and connectivity. This factor can play a role in their different vulnerability to AD. Significance statement: Two thirds of AD patients are women but the reasons for these sex difference are not well understood. When this late onset form dementia arises is too late to understand the potential causes of this sex disparities. Studies on cognitively healthy elderly population are a fundamental approach to explore in depth this different vulnerability to the most common form of dementia, currently affecting 6.2 million Americans aged 65 and older are, which means that >1 in 9 people (11.3%) 65 and older are affected by AD. Approaches such as resting-state functional network topology and connectivity may play a key role in understanding and elucidate sex-dependent differences relevant to late-onset dementia syndromes.

Neural correlates of psychodynamic and non-psychodynamic therapies in different clinical populations through fMRI: A meta-analysis and systematic review.

Background: The COVID-19 pandemic has exacerbated the ongoing crisis in psychiatric and psychological care, contributing to what we have identified as a new psychological and psychiatric pandemic. Psychotherapy is an effective method for easing the psychological suffering experienced also by the various impacts of COVID-19. This treatment can be examined from a neurological perspective, through the application of brain imaging techniques. Specifically, the meta-analysis of imaging studies can aid in expanding researchers' understanding of the many beneficial applications of psychotherapy. Objectives: We examined the functional brain changes accompanying different mental disorders with functional Magnetic Resonance Imaging (fMRI), through a meta-analysis, and systematic review in order to better understand the general neural mechanism involved in psychotherapy and the potential neural difference between psychodynamic and non-psychodynamic approaches. Data sources: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were employed for our systematic review and meta-analysis. We conducted a computer-based literature search, following the Population, Intervention, Comparison and Outcomes (PICO) approach, to retrieve all published articles in English regarding the above-described topics from PubMed (MEDLINE), Scopus, and Web of Science. Study eligibility criteria participants and interventions: We combined terms related to psychotherapy and fMRI: ("psychotherapy" [All Fields] OR "psychotherapy" [MeSH Terms] OR "psychotherapy" [All Fields] OR "psychotherapies" [All Fields] OR "psychotherapy s" [All Fields]) AND ("magnetic resonance imaging" [MeSH Terms]) OR ("magnetic"[All Fields] AND "resonance"[All Fields] AND "imaging"[All Fields]) OR ("magnetic resonance imaging"[All Fields] OR "fmri"[All Fields]). We considered (1) whole brain fMRI studies; (2) studies in which participants have been involved in a clinical trial with psychotherapy sessions, with pre/post fMRI; (3) fMRI results presented in coordinate-based (x, y, and z) in MNI or Talairach space; (4) presence of neuropsychiatric patients. The exclusion criteria were: (1) systematic review or meta-analysis; (2) behavioral study; (3) single-case MRI or fMRI study; and (4) other imaging techniques (i.e., PET, SPECT) or EEG. Results: After duplicates removal and assessment of the content of each published study, we included 38 sources. The map including all studies that assessed longitudinal differences in brain activity showed two homogeneous clusters in the left inferior frontal gyrus, and caudally involving the anterior insular cortex (p < 0.0001, corr.). Similarly, studies that assessed psychotherapy-related longitudinal changes using emotional or cognitive tasks (TASK map) showed a left-sided homogeneity in the anterior insula (p < 0.000) extending to Broca's area of the inferior frontal gyrus (p < 0.0001) and the superior frontal gyrus (p < 0.0001). Studies that applied psychodynamic psychotherapy showed Family-Wise Error (FWE) cluster-corrected (p < 0.05) homogeneity values in the right superior and inferior frontal gyri, with a small cluster in the putamen. No FWE-corrected homogeneity foci were observed for Mindful- based and cognitive behavioral therapy psychotherapy. In both pre- and post-therapy results, studies showed two bilateral clusters in the dorsal anterior insulae (p = 0.00001 and p = 0.00003, respectively) and involvement of the medial superior frontal gyrus (p = 0.0002). Limitations: Subjective experiences, such as an individual's response to therapy, are intrinsically challenging to quantify as objective, factual realities. Brain changes observed both pre- and post-therapy could be related to other factors, not necessary to the specific treatment received. Therapeutic modalities and study designs are generally heterogeneous. Differences exist in sample characteristics, such as the specificity of the disorder and number and duration of sessions. Moreover, the sample size is relatively small, particularly due to the paucity of studies in this field and the little contribution of PDT. Conclusions and implications of key findings: All psychological interventions seem to influence the brain from a functional point of view, showing their efficacy from a neurological perspective. Frontal, prefrontal regions, insular cortex, superior and inferior frontal gyrus, and putamen seem involved in these neural changes, with the psychodynamic more linked to the latter three regions.

Sex Differences of Brain Functional Topography Revealed in Normal Aging and Alzheimer's Disease Cohort.

We applied graph theory analysis on resting-state functional magnetic resonance imaging data to evaluate sex differences of brain functional topography in normal controls (NCs), early mild cognitive impairment (eMCI), and AD patients. These metrics were correlated with RAVLT verbal learning and memory scores. The results show NCs have better functional connectivity (FC) metrics than eMCI and AD, and NC women show worse FC metrics compared to men, despite performing better on the RAVLT. FC differences between men and women diminished in eMCI and disappeared in AD. Within women, better FC metrics relate to better RAVLT learning in NCs and eMCI groups.

Brain Entropy During Aging Through a Free Energy Principle Approach.

Neural complexity and brain entropy (BEN) have gained greater interest in recent years. The dynamics of neural signals and their relations with information processing continue to be investigated through different measures in a variety of noteworthy studies. The BEN of spontaneous neural activity decreases during states of reduced consciousness. This evidence has been showed in primary consciousness states, such as psychedelic states, under the name of "the entropic brain hypothesis." In this manuscript we propose an extension of this hypothesis to physiological and pathological aging. We review this particular facet of the complexity of the brain, mentioning studies that have investigated BEN in primary consciousness states, and extending this view to the field of neuroaging with a focus on resting-state functional Magnetic Resonance Imaging. We first introduce historic and conceptual ideas about entropy and neural complexity, treating the mindbrain as a complex nonlinear dynamic adaptive system, in light of the free energy principle. Then, we review the studies in this field, analyzing the idea that the aim of the neurocognitive system is to maintain a dynamic state of balance between order and chaos, both in terms of dynamics of neural signals and functional connectivity. In our exploration we will review studies both on acute psychedelic states and more chronic psychotic states and traits, such as those in schizophrenia, in order to show the increase of entropy in those states. Then we extend our exploration to physiological and pathological aging, where BEN is reduced. Finally, we propose an interpretation of these results, defining a general trend of BEN in primary states and cognitive aging.

Machine learning methods to predict amyloid positivity using domain scores from cognitive tests.

Amyloid-[Formula: see text] (A[Formula: see text]) is the target in many clinical trials for Alzheimer's disease (AD). Preclinical AD patients are heterogeneous with regards to different backgrounds and diagnosis. Accurately predicting A[Formula: see text] status of participants by using machine learning (ML) models based on easily accessible data, could improve the effectiveness of AD clinical trials. We will develop optimal ML models for each subpopulation stratified by sex and disease stages using sub scores from screening neurological tests. Data from the AD Neuroimaging Initiative (ADNI) were used to build the ML models, for three groups: individuals with significant memory concern, early mild cognitive impairment (MCI), and late MCI. Data were further separated into 6 groups by disease stage (3 levels) and sex (2 categories). The outcome was defined as the A[Formula: see text] status confirmed by the PET imaging, and the features include demographic data, newly identified risk factors, screening tests, and the domain scores from screening tests. Monte Carlo simulation studies were used together with k-fold cross-validation technique to compute model performance metric. We also develop a new feature selection method based on the stochastic ordering to avoiding searching all possible combinations of features. Accuracy of the identified optimal model for SMC male was over 90% by using domain scores, and accuracy for LMCI female was above 86%. Domain scores can improve the ML model prediction as compared to the total scores. Accurate ML prediction models can identify the proper population for AD clinical trials.

Partial correlation coefficient for a study with repeated measurements.

Repeated data are increasingly collected in studies to investigate the trajectory of change in measurements over time. Determining a link between one repeated measurement with another that is considered as the biomarker for disease progression, may provide a new target for drug development. When a third variable is associated with one of the two measurements, partial correlation after eliminating the effect of that variable is able to provide reliable estimate for association as compared to the existing raw correlation for repeated data. We propose using linear regression models to compute residuals by modeling a relationship between each measurement and a third variable. The computed residuals are then used in a linear mixed model (implemented by SAS Proc Mixed) to compute partial correlation for repeated data. Alternatively, the partial correlation may be computed as the average of partial correlations at each visit. We provide two real examples to illustrate the application of the proposed partial correlation, and conduct extensive numerical studies to compare the proposed partial correlation coefficients.

Sex differences in Alzheimer's disease: do differences in tau explain the verbal memory gap?

To determine if sex differences in verbal memory in AD are related to differences in extent or distribution of pathological tau, we studied 275 participants who were amyloid PET positive and carried clinical classifications of normal cognition, mild cognitive impairment (MCI) or dementia, and had tau (AV1451) PET. We compared tau distribution between men and women, and as a function of genetic risk. In MCI we further explored the relationship between quantity and distribution of tau in relation to verbal memory scores. Women had more tau burden overall, but this was driven by sex differences at the MCI stage. There was no significant difference in tau load by APOE e4 status. Within the MCI group the association between tau and performance in verbal memory tasks was stronger in women than men. The topography of the associations between tau and verbal memory also differed in MCI; women demonstrated stronger relationships between tau distribution and verbal memory performance, especially in the left hemisphere. These findings have implications for understanding tau distribution and spread, and in interpretation of verbal memory performance.

The longitudinal associations between cognition, mood and striatal dopaminergic binding in Parkinson's Disease.

Cognitive decline and mood symptoms are common in Parkinson's disease (PD). Reductions in striatal dopaminergic binding have been associated with worse cognition and mood. We investigated whether this association persists throughout the disease progression in newly diagnosed PD. Four-year data from Parkinson's Progression Markers Initiative (PPMI) were used. Groups consisted of left and right limb dominantly affected PD patients, and controls. Longitudinal relationships between cognition, mood and striatal binding ratios were assessed by repeated measures correlations. Reduced binding was associated with general cognitive decline in controls, reduced processing speed and increased mood symptoms in PD. Anxiety was associated with striatum only in left limb dominantly affected PD. Dominantly affected limb side did not impact striatum and cognition association. There are longitudinal associations between striatum, processing speed and anxiety. Dopamine transporter availability imaging may have some prognostic value for cognition and mood in PD.

Influence of sex differences in interpreting learning and memory within a clinical sample of older adults.

Sex is an important factor to consider when evaluating memory with older adults. This present study aimed to examine sex differences in memory within a clinical sample of older adults (N = 1084). Raw learning and recall scores on the Hopkins Verbal Learning Test, Revised (HVLT-R) and Brief Visuospatial Memory Test, Revised (BVMT-R) were compared between sexes within the entire sample and cohorts stratified by age. Within the entire sample, women outperformed men in HVLT-R learning and recall, and there were no sex differences in BVMT-R performance. These sex differences, however, were absent or reversed for those with impaired HVLT-R performance and functional deficits, indicating that women retain an early advantage in verbal memory, which is lost with greater indication of disease severity. These findings indicate that women retain an advantage in verbal learning and memory, at least before significant levels of impairment, within a sample of older adults seen at an outpatient neurology clinic, which may have implications for diagnosing memory disorders.

Cognitively normal women with Alzheimer's disease proteinopathy show relative preservation of memory but not of hippocampal volume.

BACKGROUND: We examined interactive effects of sex, diagnosis, and cerebrospinal fluid (CSF) amyloid beta/phosphorylated tau ratio (Aß/P-tau) on verbal memory and hippocampal volumes. METHODS: We assessed 682 participants (350 women) from BioFINDER (250 cognitively normal [CN]; and 432 symptomatic: 186 subjective cognitive decline [SCD], 246 mild cognitive impairment [MCI]). General linear models evaluated effects of Alzheimer's disease (AD) proteinopathy (CSF Aß/p-tau ratio), diagnosis, and sex on verbal memory (ADAS-cog 10-word recall), semantic fluency (animal naming fluency), visuospatial skills (cube copy), processing speed/attention functions (Symbol Digit Modalities Test and Trail Making Part A), and hippocampal volumes. RESULTS: Amyloid-positive (Aß/P-tau+) CN women (women with preclinical AD) showed memory equivalent to amyloid-negative (Aß/P-tau-) CN women. In contrast, Aß/P-tau+ CN men (men with preclinical AD) showed poorer memory than Aß/P-tau- CN men. Symptomatic groups showed no sex differences in effect of AD proteinopathy on memory. There was no interactive effect of sex, diagnosis, and Aß/P-tau on other measures of cognition or on hippocampal volume. CONCLUSIONS: CN women show relatively preserved verbal memory, but not general cognitive reserve or preserved hippocampal volume in the presence of Aß/P-tau+. Results have implications for diagnosing AD in women, and for clinical trials.