Poor cardiovascular health occurs with age and is associated with increased dementia risk, yet its impact on frontotemporal lobar degeneration (FTLD) and autosomal dominant neurodegenerative disease has not been well established. Examining cardiovascular risk in a population with high genetic vulnerability provides an opportunity to assess the impact of lifestyle factors on brain health outcomes. In the current study, we examined whether systemic vascular burden associates with accelerated cognitive and brain aging outcomes in genetic FTLD.

166 adults with autosomal dominant FTLD (C9orf72 n= 97; GRN n= 34; MAPT n= 35; 54% female; Mage = 47.9; Meducation = 15.6 years) enrolled in the Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Longitudinal FTD study (ALLFTD) were included. Participants completed neuroimaging and were screened for cardiovascular risk and functional impairment during a comprehensive neurobehavioral and medical interview. A vascular burden score (VBS) was created by summing vascular risk factors (VRS) [diabetes, hypertension, hyperlipidemia, and sleep apnea] and vascular diseases (VDS) [cerebrovascular disease (e.g., TIA, CVA), cardiac arrhythmia (e.g., atrial fibrillation, pacemaker, defibrillator), coronary artery disease (e.g., myocardial infarction, cardiac bypass, stent), and congestive heart failure] following a previously developed composite (range 0 to 8). We examined the interaction between each vascular health metric (VBS, VDS, VRS) and age (vascular health*age) on clinical severity (CDR plus NACC FTLD-SB), and white matter hyperintensity (WMH) volume outcomes, adjusting for age and sex. Vascular risk, disease, and overall burden scores were examined in separate models.

There was a statistically significant interaction between total VBS and age on both clinical severity (ß=0.20, p=0.044) and WMH burden (ß=0.20, p=0.032). Mutation carriers with higher vascular burden evidenced worse clinical and WMH outcomes for their age. When breaking down the vascular burden score into (separate) vascular risk (VRS) and vascular disease (VDS) scores, the interaction between age and VRS remained significant only for WMH (ß=0.26, p=0.009), but not clinical severity (ß=0.04, p=0.685). On the other hand, the interaction between VDS and age remained significant only for clinical severity (ß=0.20, p=0.041) but not WMH (ß=0.17, p=0.066).

Our results demonstrate that systemic vascular burden is associated with an “accelerated aging” pattern on clinical and white matter outcomes in autosomal dominant FTLD. Specifically, mutation carriers with greater vascular burden show poorer neurobehavioral outcomes for their chronological age. When separating vascular risk from disease, risk was associated with higher age-related WMH burden, whereas disease was associated with poorer age-related clinical severity of mutation carriers. This pattern suggests preferential brain-related effects of vascular risk factors, while the functional impact of such factors may be more closely aligned with fulminant vascular disease. Our results suggest cardiovascular health may be an important, potentially modifiable risk factor to help mitigate the cognitive and behavioral disturbances associated with having a pathogenic variant of autosomal dominant FTLD. Future studies should continue to examine the neuropathological processes underlying the impact of cardiovascular risk in FTLD to inform more precise recommendations, particularly as it relates to lifestyle interventions.

Depression is a common problem among older adults and is further exacerbated by poor treatment response. The vascular depression hypothesis suggests that white matter hyperintensities (WMH) and executive dysfunction are main contributors to treatment non-response in older adults. While a previous meta-analysis has demonstrated the effects of executive dysfunction on treatment response, similar techniques have not been used to address the relationship between WMH and treatment response. Multiple commonly-cited studies demonstrate a relationship between WMH and treatment response, however, the literature on the predictive nature of the relationship is quite inconsistent. Additionally, many studies supporting this relationship are not randomized controlled studies. Critically examining data of well-controlled treatment response outcome studies using meta-analytic methods will allow for an aggregate evaluation of the relationship between WMH burden and treatment response.

A MEDLINE search was conducted to identify regimented antidepressant treatment trials contrasting white matter hyperintensity burden between remitters and non-remitters. Only regimented treatment trials for depressed outpatients aged 50 and older that had a pre-treatment measure of WMH burden and remitter/non-remitter comparison were included. Hedge’s g was calculated for each trial’s treatment effect. A Bayesian meta-analysis was used to estimate an aggregate effect size.

Eight studies met inclusion criteria. The log odds ratios average was significantly less than zero (.25, SE=.12, p=.019), suggesting that there is a significant effect of WMH hyperintensity burden on antidepressant remission status.

The purpose of this meta-analysis was to rigorously evaluate randomized controlled trials to determine the relationship between WMH burden and antidepressant treatment response. Findings revealed that WMH burden predicted antidepressant remission, that is, individuals with high WMH burden are less likely to meet remission criteria compared to individuals with low WMH burden. Results suggest that it may be important to consider vascular depression as a distinct treatment target of alternate interventions.

Drawing on the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS), this study aimed to investigate the direct and indirect associations between vascular risk factors/cardiovascular disease (CVD), pharmacological treatment (of CVD), and white matter hyperintensity (WMH) burden on overall cognition and decline trajectories in a cognitively diverse sample of older adults.

Participants were 1,049 cognitively diverse older adults drawn from a larger NACC data repository of 22,684 participants whose data was frozen as of December 2019. The subsample included only participants who were aged 60-97 (56.7% women) who completed at least one post-baseline neuropsychological evaluation, had medication data, and both T1 and FLAIR neuroimaging scans. Cognitive composites (Memory, Attention, Executive Function, Language) were derived factor analytically using harmonized data. Baseline WMH volumes were quantified using UBO Detector. Baseline health screening and medication data was used to determine overall CVD burden and total medication. Longitudinal latent growth curve models were estimated adjusting for demographics.

More CVD medication was associated with greater CVD burden; however, no direct effects of medication were found on any of the cognitive composites or WMH volume. While no direct effects of CVD burden on cognition (overall or rate of decline) were observed, instead we found that greater CVD burden had small, but significant, negative indirect effects on Memory, Attention, Executive Functioning and Language (all p’s < .01) after controlling for CVD medication use. Whole brain WMH volume served as the mediator of this relationship, as it did for an indirect effect of baseline CVD on 6-year rate of decline in Memory and Executive function.

Findings from this study were generally consistent with previous literature and extend extant knowledge regarding the direct and indirect associations between CVD burden, pharmacological treatment, and neuropathology of presumed vascular origin on cognitive decline trajectories in an older adult sample. Results reveal the subtle importance of CVD risk factors on late life cognition even after accounting for treatment and WHM volume and highlight the need for additional research to determine sensitive windows of opportunity for intervention.

Vascular complications, including elevated body mass index (BMI), are known risk factors for cognitive impairment. Obtaining a cognitive baseline is commonplace in pre-surgical protocols, including for Parkinson’s disease and epilepsy. Currently, routine evaluations for bariatric surgery candidates do not include neuropsychological assessment. This setting provides a unique opportunity to identify cognitive profiles of younger individuals at risk for cognitive impairment. Here, we argue for the standard implementation of a brief, online cognitive battery via telemedicine, to enhance existing protocols of bariatric pre-surgical evaluations.

Nineteen bariatric surgery candidates were referred to a private neuropsychological assessment practice for pre-surgical cognitive/psychological evaluation. Assessments were conducted by a neuropsychologist and a psychology graduate student, via remote video conferencing, between April 2020 and June 2022. Candidates completed a clinical interview, intake form, and the Behavior Rating Inventory of Executive Function for Adults (BRIEF-A), and were administered a battery of cognitive measures: Wechsler Test of Adult Reading (WTAR), Hopkins Verbal Learning Test-Revised (HVLT-R); and select subtests from the TestMyBrain Digital Neuropsychology Toolkit: Trail Making Tests A and B (TMT-A/B), Matrix Reasoning (MR), Digit Span Forward and Backward (DSF, DSB), Gradual Onset Continuous Performance Test (CPT), and Simple and Choice Reaction Time (SRT, CRT). Descriptive statistics were conducted to analyze sample demographics. Raw scores on cognitive measures were converted to z-scores and averaged across the sample.

The average age at evaluation was 38.2 (9.6) years and average pre-surgical BMI was 46.6k/m2 (9.3), indicating morbid obesity (BMI>40k/ m2). Ten (52.6%) candidates identified as female, 10 (52.6%) identified as White, 8 (42.1%) had 12 years of education or less, 4 (21.1%) were unemployed, and 9 (47.4%) had comorbid psychiatric diagnoses. BRIEF-A sub-scales were within the average range (T’s= 47.9 - 52.9, SD’s [10.1 - 12.8]). Estimated premorbid IQ was average at 102.7 (11.4). Neuropsychological data revealed group performance within the average range on DSF and DSB (z’s= 0.00), TMT-A (z= -0.16), MR (z= -0.53), CPT (z= -0.39), and HVLT-R False Positives (z= 0.05) and Recognition Discriminability (z= -0.44). SRT (z= -0.70), CRT Accuracy (z= -1.37), TMT-B (z= -0.79), HVLT-R Total Recall and Percent Retained (z’s= -0.88), and Delayed Recall and True Positives (z’s= -1.27) were low average.

In this sample of pre-surgical bariatric candidates with average intelligence, baseline evaluations revealed mild deficits in reaction time accuracy, visual motoric set-shifting, and verbal learning/memory. These deficits may be the result of microvascular changes in the brain secondary to physical compromise. Results provide additional insight into potential early-onset executive dysfunction, psychomotor slowing, and verbal learning/memory difficulties. In addition to these relative areas of neuropsychological weakness, candidates demonstrated relative strengths in attention, working memory, and visuospatial functioning. These insights provide pre-surgical evaluators with additional information to tailor recommendations and treatment approaches that foster surgical success. With a remote, concise, easy-to-administer battery of tests, routine neuropsychological assessment for bariatric surgery candidates is both a feasible and a useful tool for identifying areas of cognitive strengths and weaknesses. Documenting a patients’ cognitive baseline can assist with monitoring long-term vascular risk-factors and potential cognitive impairment.

Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.

Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.

Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.

This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.

The National Institute of Neurological Disease and Stroke-Canadian Stroke Network (NINDS-CSN) 5-minute neuropsychology protocol consists of only verbal tasks, and is proposed as a brief screening method for vascular cognitive impairment. We evaluated its feasibility within two weeks after stroke and ability to predict the development of post-stroke dementia (PSD) at 3 months after stroke.

We prospectively enrolled subjects with ischemic stroke within seven days of symptom onset who were consecutively admitted to 12 university hospitals. Neuropsychological assessments using the NINDS-CSN 5-minute and 60-minute neuropsychology protocols were administered within two weeks and at 3 months after stroke onset, respectively. PSD was diagnosed with reference to the American Heart Association/American Stroke Association statement, requiring deficits in at least two cognitive domains.

Of 620 patients, 512 (82.6%) were feasible for the NINDS-CSN 5-minute protocol within two weeks after stroke. The incidence of PSD was 16.2% in 308 subjects who had completed follow-up at 3 months after stroke onset. The total score of the NINDS-CSN 5-minute protocol differed significantly between those with and without PSD (4.0 ± 2.7, 7.4 ± 2.7, respectively; p < 0.01). A cut-off value of 6/7 showed reasonable discriminative power (sensitivity 0.82, specificity 0.67, AUC 0.74). The NINDS-CSN 5-minute protocol score was a significant predictor for PSD (adjusted odds ratio 6.32, 95% CI 2.65–15.05).

The NINDS-CSN 5-minute protocol is feasible to evaluate cognitive functions in patients with acute ischemic stroke. It might be a useful screening method for early identification of high-risk groups for PSD.

Cerebral small vessel disease (SVD) is the common cause of cognitive decline in the old population. MRI can be used to clarify its mechanisms. However, the surrogate markers of MRI for early cognitive impairment in SVD remain uncertain to date. We investigated the cognitive impacts of cerebral microbleeds (CMBs), diffusion tensor imaging (DTI), and brain volumetric measurements in a cohort of post-stroke non-dementia SVD patients.

Fifty five non-dementia SVD patients were consecutively recruited and categorized into two groups as no cognitive impairment (NCI) (n = 23) or vascular mild cognitive impairment (VaMCI) (n = 32). Detailed neuropsychological assessment and multimodal MRI were completed.

The two groups differed significantly on Z scores of all cognitive domains (all p < 0.01) except for the language. There were more patients with hypertension (p = 0.038) or depression (p = 0.019) in the VaMCI than those in the NCI group. Multiple regression analysis of cognition showed periventricular mean diffusivity (MD) (β = −0.457, p < 0.01) and deep CMBs numbers (β = −0.352, p < 0.01) as the predictors of attention/executive function, which explained 45.2% of the total variance. Periventricular MD was the independent predictor for either memory (β = −0.314, p < 0.05) or visuo-spatial function (β = −0.375, p < 0.01); however, only small proportion of variance could be accounted for (9.8% and 12.4%, respectively). Language was not found to be correlated with any of the MRI parameters. No correlation was found between brain atrophic indices and any of the cognitive measures.

Arteriosclerotic CMBs and periventricular white matter disintegrity seem to be independent MRI surrogated markers in the early stage of cognitive impairment in SVD.