Better cardiovascular health is associated with slowed clinical progression in autosomal dominant frontotemporal lobar degeneration variant carriers.

INTRODUCTION: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: Two hundred forty-seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non-carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing. RESULTS: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories. DISCUSSION: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD. HIGHLIGHTS: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD). Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD. More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume. Optimized cardiovascular health relates to more favorable outcomes in genetic dementia.

Characterizing cancer-related cognitive impairments and impact on quality of life in women with metastatic breast cancer.

PURPOSE: Little is known about cancer-related cognitive impairments (CRCI) in women with metastatic breast cancer (MBC). The purpose of this study is to (1) comprehensively describe CRCI and any associated psychosocial and behavioral symptoms, (2) determine observable sociodemographic and clinical risk factors for CRCI, and (3) explore cognitive and psychosocial predictors of quality of life and social functioning in women living with MBC. METHODS: Using a cross-sectional design, women with MBC completed assessments (objective and subjective measures of CRCI including 3 open-ended questions, measures of psychosocial and behavioral factors, and assessments of quality of life and social function), and data were analyzed using descriptive statistics, qualitative content analysis, correlation analyses, t tests, analysis of variance, and linear regression models. RESULTS: Data from 52 women were analyzed. 69.2% of the sample reported clinically significant CRCI and 46% of the sample scored < 1 standard deviation below the standardized mean on one or more cognitive tests. Those with triple-negative MBC (compared to HER2+), recurrent MBC (compared to de novo), and no history of chemotherapy had worse subjective CRCI, and those without history of surgery and older age had worse objective CRCI. Subjective CRCI, but not objective CRCI, was significantly associated with quality of life and social functioning. CONCLUSION: Subjective and objective CRCI are likely a common problem for those with MBC. Subjective CRCI is associated with poorer quality of life and lower social functioning. Healthcare providers should acknowledge cognitive symptoms, continually assess cognitive function, and address associated unmet needs across the MBC trajectory.

Predicting brain atrophy and cognitive aging trajectories with baseline subjective cognitive concerns in cognitively normal older adults.

Subjective cognitive concerns (SCC) are common even in cognitively normal older adults who lack objectively-detectable deficits on standard neuropsychological evaluation. The clinical relevance of these concerns, particularly considering the nature of concerns (e.g., memory versus non-memory), remains unclear. Thus, we examined whether baseline memory and non-memory SCC relate to longitudinal change in brain volume and neuropsychological test performance in 476 functionally-intact, objectively unimpaired older adults (Mage = 72y, 56 % female, follow-up time = 1 - 9 years). Mixed-effects models revealed that both higher baseline memory and non-memory SCC predicted greater atrophy in total gray matter and dorsolateral prefrontal cortex atrophy over time, while only memory SCC predicted steeper medial temporal lobe atrophy. Regarding neuropsychological performance, higher non-memory SCC predicted decline in processing speed performance, while memory SCC did not predict neuropsychological trajectories. SCC are a risk factor for more adverse brain and cognitive aging trajectories, even in functionally-intact, seemingly cognitively normal older adults.

Associations of cerebrovascular disease and Alzheimer's disease pathology with cognitive decline: Analysis of the National Alzheimer's Coordinating Center Uniform Data Set.

Cerebrovascular disease (CVD) and Alzheimer's disease (AD) often co-occur and may impact specific cognitive domains. This study's goal was to determine effects of CVD and AD burden on cross-sectional and longitudinal executive function (EF) and memory in older adults. Longitudinally followed participants from the National Alzheimer Coordinating Center database (n = 3342) were included. Cognitive outcomes were EF and memory composite scores. Baseline CVD presence was defined by moderate-to-severe white matter hyperintensities or lacunar infarct on MRI. Baseline AD pathology was defined by amyloid positivity via PET or CSF. Linear mixed models examined effects of CVD, AD, and time on cognitive outcomes, controlling for sex, education, baseline age, MoCA score, and total number of study visits. At baseline, CVD associated with lower EF (p < 0.001), while AD associated with lower EF and memory (ps < 0.001). Longitudinally only AD associated with faster declines in memory and EF (ps < 0.001). These results extend our understanding of CVD and AD pathology, highlighting that CVD does not necessarily indicate accelerated decline.

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. RESULTS: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). CONCLUSIONS: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

Neuropsychiatric Profiles and Cerebral Amyloid Burden in Adults without Dementia.

INTRODUCTION: We comprehensively evaluated how self- and informant-reported neuropsychiatric symptoms (NPS) were differentially associated with cerebral amyloid-beta (Aß) PET levels in older adults without dementia. METHODS: Two hundred and twenty-one participants (48% female, age = 73.4 years ± 8.4, Clinical Dementia Rating = 0 [n = 184] or 0.5 [n = 37]) underwent an Aß-PET scan (florbetapir or PIB), comprehensive neuropsychological testing, and self-reported (Geriatric Depression Scale - 30 item [GDS-30]) and informant-reported interview (Neuropsychiatric Inventory Questionnaire [NPI-Q]) of NPS. Cerebral Aß burden was quantified using centiloids (CL). NPI-Q and GDS-30 queried the presence of NPS within 4 subdomains and 6 subscales, respectively. Regression models examined the relationship between NPS and Aß-PET CL. RESULTS: Both higher self- and informant-reported NPS were associated with higher Aß burden. Among specific NPI-Q subdomains, informant-reported changes in depression, anxiety, and irritability were all associated with higher Aß-PET. Similarly, self-reported (GDS-30) subscales of depression, apathy, anxiety, and cognitive concern were associated with higher Aß-PET. When simultaneously entered, only self-reported cognitive concern was associated with Aß-PET in the GDS-30 model, while both informant-reported anxiety and depression were associated with Aß-PET in the NPI-Q model. Clinical status moderated the association between self-reported NPS and Aß-PET such that the positive relationship between self-perceived NPS and Aß burden strengthened with increasing functional difficulties. CONCLUSIONS: In a cohort of older adults without dementia, both self- and informant-reported measures of global NPS, particularly patient-reported cognitive concerns and informant-reported anxiety and depression, corresponded with cerebral Aß burden. NPS may appear early in the prodromal disease state and relate to initial AD proteinopathy burden, a relationship further exaggerated in those with greater clinical severity.

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

The clinical utility of three frailty measures in identifying HIV-associated neurocognitive disorders.

OBJECTIVE: Frailty measures vary widely and the optimal measure for predicting HIV-associated neurocognitive disorders (HAND) is unclear. DESIGN: A study was conducted to examine the clinical utility of three widely used frailty measures in identifying HIV-associated neurocognitive disorders. METHODS: The study involved 284 people with HIV (PWH) at least 50 years enrolled at UC San Diego's HIV Neurobehavioral Research Program. Frailty measurements included the Fried Phenotype, the Rockwood Frailty Index, and the Veterans Aging Cohort Study (VACS) Index. HAND was diagnosed according to Frascati criteria. ANOVAs examined differences in frailty severity across HAND conditions. ROC analyses evaluated sensitivity and specificity of each measure to detect symptomatic HAND [mild neurocognitive disorder (MND) and HIV-associated dementia (HAD)] from no HAND. RESULTS: Across all frailty measures, frailty was found to be higher in HAD compared with no HAND. For Fried and Rockwood (not VACS), frailty was significantly more severe in MND vs. no HAND and in HAD vs. ANI (asymptomatic neurocognitive impairment). For discriminating symptomatic HAND from no HAND, Fried was 37% sensitive and 92% specific, Rockwood was 85% sensitive and 43% specific, and VACS was 58% sensitive and 65% specific. CONCLUSION: These findings demonstrate that Fried and Rockwood outperform VACS in predicting HAND. However, ROC analyses suggest none of the indices had adequate predictive validity in detecting HAND. The results indicate that the combined use of the Rockwood and Fried indices may be an appropriate alternative.

Multimodal lifestyle engagement patterns support cognitive stability beyond neuropathological burden.

BACKGROUND: Modifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline. METHODS: Participants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer's Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer's disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia. RESULTS: Five classes were identified: Class 1Low Life Space (lowest lifestyle engagement), Class 2PA (high physical activity), Class 3Low Avg (low to average lifestyle engagement), Class 4Balanced (high average lifestyle engagement), and Class 5Social (large social network). Classes 4Balanced and 5Social had the lowest AD burden, and Class 2PA had the lowest CVD burden. Classes 2-5 had significantly less steep global cognitive decline compared to Class 1Low Life Space, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4Balanced and 5Social exhibited the lowest rates of incident MCI/dementia. CONCLUSIONS: Lifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.

Assessing cancer-related cognitive function in the context of everyday life using ecological mobile cognitive testing: A protocol for a prospective quantitative study.

Objective: Millions of cancer survivors are at risk for cancer-related cognitive impairment (CRCI), yet accurate and accessible assessments of cognitive functioning remain limited. Ecological mobile cognitive testing (EMCT) could offer a solution. This paper presents the protocol for a study that aims to (1) establish the reliability and validity of EMCT to assess CRCI in breast cancer survivors, and (2) prospectively evaluate within-person processes (and interactions) among context, mood, and behavior that explain cognitive variability, everyday functioning, and quality of life of cancer survivors. Methods: Participants will include breast cancer survivors (>21 years old) who are within 5 years of completing chemotherapy treatment. Participants will complete two virtual visits (baseline, follow-up) 2 months apart to assess self-reported cognitive symptoms and cognitive performance, sociodemographic characteristics, clinical history, everyday functioning, and quality of life. Between virtual visits, EMCT will be used to sample cognitive functioning every other day (28 times total). We will use linear mixed-effect regressions and single-level multiple regression models to analyze the data. Results: We anticipate a minimum of 124 breast cancer survivors enrolling and completing data collection. Study results will be published in peer-reviewed scientific journals. Conclusions: Our findings will have broad implications for assessing CRCI in an ecologically valid and person-centered way using EMCT. We aim to provide this protocol to aid researchers who would like to apply this approach to their studies.

Moderating role of physical activity on hippocampal iron deposition and memory outcomes in typically aging older adults.

Physical activity (PA) is linked to better cognitive and brain health, though its mechanisms are unknown. While brain iron is essential for normal function, levels increase with age and, when excessive, can cause detrimental neural effects. We examined how objectively measured PA relates to cerebral iron deposition and memory functioning in normal older adults. Sixty-eight cognitively unimpaired older adults from the UCSF Memory and Aging Center completed neuropsychological testing and brain magnetic resonance imaging, followed by 30-day Fitbit monitoring. Magnetic resonance imaging quantitative susceptibility mapping (QSM) quantified iron deposition. PA was operationalized as average daily steps. Linear regression models examined memory as a function of hippocampal QSM, PA, and their interaction. Higher bilateral hippocampal iron deposition correlated with worse memory but was not strongly related to PA. Covarying for demographics, PA moderated the relationship between bilateral hippocampal iron deposition and memory such that the negative effect of hippocampal QSM on memory performances was no longer significant above 9120 daily steps. PA may mitigate adverse iron-related pathways for memory health.

Data-driven physical actigraphy patterns relate to cognitive and vascular health in older adults.

Health benefits of physical activity (PA) are well known; however, specific PA patterns that relate most strongly to cognitive aging outcomes are poorly understood. We characterized latent profiles of PA among older adults and examined associations with cognition and vascular burden. 124 functionally normal older adults wore a Fitbit™ for 30 days. Daily average step count, sedentary time (0 steps/min), and high-intensity time (≥120 steps/min) were calculated. Participants completed neurocognitive testing assessing cognitive domains of executive functioning and memory; medical history, from which vascular burden (i.e., a count of cardiovascular conditions) was calculated; and brain MRI (n = 44). Subgroups with similar PA patterns were identified via latent profile analysis. Three latent PA classes emerged: Class 1Low PA (n = 49), Class 2Average PA (n = 59), and Class 3High-intensity PA (n = 16). PA class related to executive functioning and vascular burden, driven by better outcomes in Class 3 than Class 1. Sex-stratified analyses revealed these associations were strongest in males. Post hoc analyses showed a positive association between high-intensity PA and white matter integrity among males. High-intensity PA related to better cognitive and vascular health, particularly among males. Findings inform physical activity-specific and person-specific recommendations for optimal cognitive aging.

Neuropsychiatric predictors of cognitive functioning over a one-year follow-up period in HIV.

BACKGROUND: Neuropsychiatric symptoms (NPS) and cognitive impairment are highly prevalent among persons with HIV (PWH). We examined the effect of the most common NPS, depression and anxiety, on cognitive change among PWH and compared these associations to those among persons without HIV (PWoH). METHODS: Participants included 168 PWH and 91 PWoH who completed baseline self-report measures of depression (Beck Depression Inventory-II) and anxiety (Profile of Mood States [POMS] - Tension-anxiety subscale) and completed a comprehensive neurocognitive evaluation at baseline and at 1-year follow-up. Demographically-corrected scores from 15 neurocognitive tests were used to calculate global and domain-specific T-scores. Linear mixed-effects models examined the effect of depression and anxiety and their interaction with HIV-serostatus and time on global T-scores. RESULTS: There were significant depression-by-HIV and anxiety-by-HIV interactions on global T-scores such that, among PWH only, greater depressive and anxiety symptoms at baseline related to worse global T-scores across visits. Non-significant interactions with time suggest stability in these relationships across visits. Follow-up analyses examining cognitive domains revealed that both the depression-by-HIV and the anxiety-by-HIV interactions were driven by learning and recall. LIMITATIONS: Follow-up was limited to one-year and there were fewer PWoH than PWH, creating a differential in statistical power. CONCLUSION: Findings suggest that anxiety and depression have stronger links to worse cognitive functioning in PWH than PWoH, particularly learning and memory, and that these associations seem to persist for at least one-year.

A longitudinal study of cannabis use and risk for cognitive and functional decline among older adults with HIV.

Cannabis use is rapidly increasing among older adults in the United States, in part to treat symptoms of common health conditions (e.g., chronic pain, sleep problems). Longitudinal studies of cannabis use and cognitive decline in aging populations living with chronic disease are lacking. We examined different levels of cannabis use and cognitive and everyday function over time among 297 older adults with HIV (ages 50-84 at baseline). Participants were classified based on average cannabis use: frequent (> weekly) (n = 23), occasional (≤ weekly) (n = 83), and non-cannabis users (n=191) and were followed longitudinally for up to 10 years (average years of follow-up = 3.9). Multi-level models examined the effects of average and recent cannabis use on global cognition, global cognitive decline, and functional independence. Occasional cannabis users showed better global cognitive performance overall compared to non-cannabis users. Rates of cognitive decline and functional problems did not vary by average cannabis use. Recent cannabis use was linked to worse cognition at study visits when participants had THC+ urine toxicology-this short-term decrement in cognition was driven by worse memory and did not extend to reports of functional declines. Occasional (≤ weekly) cannabis use was associated with better global cognition over time in older adults with HIV, a group vulnerable to chronic inflammation and cognitive impairment. Recent THC exposure may have a temporary adverse impact on memory. To inform safe and efficacious medical cannabis use, the effects of specific cannabinoid doses on cognition and biological mechanisms must be investigated in older adults.

RESUMEN: El consumo de cannabis está aumentando rápidamente entre los adultos mayores en los Estados Unidos, en parte para tratar síntomas de afecciones de salud comunes (p. ej. dolor crónico, problemas de dormir). Actualmente, hay pocos estudios longitudinales sobre el consumo de cannabis y el deterioro cognitivo en poblaciones que envejecen y viven con enfermedades crónicas. Examinamos diferentes niveles del consumo de cannabis y funciones cognitivas a lo largo del tiempo entre 297 adultos mayores con VIH (de 50 a 84 años al principio de la investigación). Los participantes se clasificaron según el consumo promedio de cannabis: consumidores de cannabis frecuentes (> semanal) (n = 23) ocasionales (≤ semanal) (n = 83), y no consumidores de cannabis (n=191) fueron seguidos longitudinalmente hasta por 10 años (promedio = 3,9 años). Los modelos multinivel investigaron los efectos del consumo promedio y reciente de cannabis en la cognición global, el deterioro cognitivo global, y la independencia funcional. Los consumidores ocasionales de cannabis mostraron un mejor rendimiento cognitivo global en comparación con los no consumidores. El nivel de deterioro cognitivo y problemas funcionales no estuvieron asociado con el uso de cannabis. El consumo reciente de cannabis se vinculó con una peor cognición en las visitas del estudio cuando los participantes tenían toxicología de orina de THC positivo­esta disminución a corto plazo de la cognición se debió a una peor memoria, pero no se extendió a los informes de deterioros funcionales. El consumo ocasional (≤ semanal) de cannabis se asoció con una mejor cognición global a lo largo del tiempo en adultos mayores con VIH, un grupo susceptible a la inflamación crónica y la disfunción cognitiva. La exposición reciente al THC puede tener un impacto negativo temporal en la memoria. Los efectos de dosis específicas de cannabinoides en la cognición y sus mecanismos de acción biológicos deben ser investigados en personas mayores con el fin de informar el uso seguro y eficaz del cannabis medicinal.

Remote Digital Technologies for the Early Detection and Monitoring of Cognitive Decline in Patients With Type 2 Diabetes: Insights From Studies of Neurodegenerative Diseases.

Type 2 diabetes (T2D) is a risk factor for cognitive decline. In neurodegenerative disease research, remote digital cognitive assessments and unobtrusive sensors are gaining traction for their potential to improve early detection and monitoring of cognitive impairment. Given the high prevalence of cognitive impairments in T2D, these digital tools are highly relevant. Further research incorporating remote digital biomarkers of cognition, behavior, and motor functioning may enable comprehensive characterizations of patients with T2D and may ultimately improve clinical care and equitable access to research participation. The aim of this commentary article is to review the feasibility, validity, and limitations of using remote digital cognitive tests and unobtrusive detection methods to identify and monitor cognitive decline in neurodegenerative conditions and apply these insights to patients with T2D.

Sex-specific effects of SNAP-25 genotype on verbal memory and Alzheimer's disease biomarkers in clinically normal older adults.

INTRODUCTION: We tested sex-dependent associations of variation in the SNAP-25 gene, which encodes a presynaptic protein involved in hippocampal plasticity and memory, on cognitive and Alzheimer's disease (AD) neuroimaging outcomes in clinically normal adults. METHODS: Participants were genotyped for SNAP-25 rs1051312 (T > C; SNAP-25 expression: C-allele > T/T). In a discovery cohort (N = 311), we tested the sex by SNAP-25 variant interaction on cognition, Aß-PET positivity, and temporal lobe volumes. Cognitive models were replicated in an independent cohort (N = 82). RESULTS: In the discovery cohort, C-allele carriers exhibited better verbal memory and language, lower Aß-PET positivity rates, and larger temporal volumes than T/T homozygotes among females, but not males. Larger temporal volumes related to better verbal memory only in C-carrier females. The female-specific C-allele verbal memory advantage was evidenced in the replication cohort. CONCLUSIONS: In females, genetic variation in SNAP-25 is associated with resistance to amyloid plaque formation and may support verbal memory through fortification of temporal lobe architecture. HIGHLIGHTS: The SNAP-25 rs1051312 (T > C) C-allele results in higher basal SNAP-25 expression. C-allele carriers had better verbal memory in clinically normal women, but not men. Female C-carriers had higher temporal lobe volumes, which predicted verbal memory. Female C-carriers also exhibited the lowest rates of amyloid-beta PET positivity. The SNAP-25 gene may influence female-specific resistance to Alzheimer's disease (AD).

Impact of PTSD and Obstructive Sleep Apnea on Cognition in Older Adult Veterans.

Background: Posttraumatic stress disorder (PTSD) and obstructive sleep apnea (OSA) are highly prevalent and comorbid among older adult male veterans. Both PTSD and OSA are independently associated with cognitive deficits in older adults, but little research regarding the impact of comorbid PTSD and OSA among older adults exists. Purpose: The current study aimed to examine the independent and interactive effects of PTSD and OSA on cognitive functioning in older adult veterans. Study Sample: Older adult male veterans with (n = 106) and without PTSD (n = 69), ranging in age from 55 to 89 (M = 63.35). Data Collection: Participants underwent polysomnography evaluation to assess severity of OSA symptoms and comprehensive neuropsychological evaluation to assess cognitive functioning in 3 domains: attention and processing speed, learning and memory, and executive functioning. Results: Multiple regression analyses showed that the interaction between PTSD and OSA did not predict cognitive performance. However, PTSD significantly predicted poorer attention and processing speed, and increased OSA severity predicted poorer learning and memory. Conclusions: While PTSD and OSA did not have a synergistic detrimental impact on cognition, each independently predicted poorer cognitive functioning within certain domains, suggesting that older adults with these comorbid conditions may experience a wider array of cognitive difficulties.

Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk.

Many factors outside of cardiovascular health can impact the structure of white matter. Identification of reliable and clinically meaningful biomarkers of the neural effects of systemic and cardiovascular health are needed to refine etiologic predictions. We examined whether the corpus callosum demonstrates regional vulnerability to systemic cardiovascular risk factors. Three hundred and ninety-four older adults without dementia completed brain MRI, neurobehavioral evaluations, and blood draws. A subset (n = 126, n = 128) of individuals had blood plasma analyzed for inflammatory markers of interest (IL-6 and TNF-alpha). Considering diffusion tensor imaging (DTI) is a particularly reliable measure of white matter integrity, we utilized DTI to examine fractional anisotropy (FA) of anterior and posterior regions of the corpus callosum. Using multiple linear regression models, we simultaneously examined FA of the genu and the splenium to compare their associations with systemic and cardiovascular risk factors. Lower FA of the genu but not splenium was associated with greater systemic and cardiovascular risk, including higher systolic blood pressure (ß = -0.17, p = .020), hemoglobin A1C (ß = -0.21, p = .016) and IL-6 (ß = -0.34, p = .005). FA of the genu was uniquely associated with cognitive processing speed (ß = 0.20, p = .0015) and executive functioning (ß = 0.15, p = .012), but not memory performances (ß = 0.05, p = .357). Our results demonstrated differential vulnerability of the corpus callosum, such that frontal regions showed stronger, independent associations with biomarkers of systemic and cardiovascular health in comparison to posterior regions. Posterior white matter integrity may not reflect cardiovascular health. Clinically, these findings support the utility of examining the anterior corpus callosum as an indicator of cerebrovascular health.

Sex Differences in the Relationship between Perceived Stress and Cognitive Trajectories.

OBJECTIVE: Chronic stress adversely affects cognition, in part due to stress-induced inflammation. Rodent models suggest females are more resilient against stress-related cognitive dysfunction than males; however, few studies have examined this in humans. We examined sex differences in the relationship between perceived stress, cognitive functioning, and peripheral inflammation over time among cognitively normal older adults. DESIGN: Longitudinal observational study. SETTING: University research center. PARTICIPANTS: 274 community-dwelling older adults (baseline age: M=70.7, SD=7.2; 58% women; Clinical Dementia Rating=0) who completed at least two study visits. MEASUREMENTS: Neurocognitive functioning and perceived stress (Perceived Stress Scale [PSS]) were assessed at each visit. Plasma was analyzed for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a subset of 147 participants. Linear mixed effects models examined the interaction between average PSS (i.e., averaged within persons across visits), sex, and time on cognitive domains and on inflammatory markers. RESULTS: The interaction between stress, sex, and time predicted executive functioning (ß = 0.26, SE = 0.10, p = 0.01) such that higher average PSS related to steeper declines in men, but not in women. Among the 147 participants with inflammatory data, higher average PSS was associated with steeper increases in IL-6 over time in men, but not in women. CONCLUSION: Consistent with animal models, results showed older men were more vulnerable to negative effects of stress on cognitive aging, with domain-specific declines in executive function. Findings also suggest systemic immunological mechanisms may underlie increased risk for cognitive decline in men with higher levels of stress. Future work is needed to examine the potential efficacy of person-specific stress interventions.