Framingham Stroke Risk Profile Score Research Articles

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (β±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Abstract WMP22: Higher Burden of Cerebral Small Vessel Disease is Associated With Risk of Incident Stroke in Community-Dwelling Individuals

Background: Mild manifestations of individual cerebral small vessel disease (CSVD) markers are common and may not denote increased risk, but high CSVD burden identifies individuals at increased risk of stroke and dementia. Scores incorporating multiple CSVD markers may better identify a person’s risk, but it remains unclear if they offer benefit beyond tools based on clinical factors alone such as the revised Framingham Stroke Risk Profile (FSRP). Therefore, we related a multi-marker CSVD score to risk of incident stroke and compared the findings with the FSRP in community-dwelling individuals. Methods: Framingham Heart Study (FHS) participants aged ≥55 years, free of stroke and dementia and with brain magnetic resonance imaging (MRI) ratings of CSVD markers were included. A multi-marker CSVD score reflecting increasing CSVD burden was used (one point each for presence of cerebral microbleeds, severe perivascular spaces, extensive white matter hyperintensities, covert brain infarcts, and cortical superficial siderosis, ranging 0-5). Multivariable Cox proportional hazards regression analyses were used to relate CSVD score to incident stroke. Results: Among 1,154 participants (46% male, mean age 70.9±8.7), 590 (51%) had score 0, 352 (31%) had score 1, 164 (14%) had score 2, and 48 (4%) had score ≥ 3. Over a median follow-up of 8.2 years (Q1-Q3: 5.1-12.5) from the time of MRI, 92 (8%) developed stroke. In models adjusting for time interval between clinic exam and MRI, FHS cohort, and FSRP score, number of CSVD manifestations was associated with increased risk of stroke in a dose-dependent manner: score 1 (HR: 1.73; 95% CI 1.05-2.84), score 2 (HR 1.83; 95% CI: 1.01-3.30), and score ≥ 3 (HR: 3.31; 95% CI: 1.50-7.28) in relation to participants with no CSVD markers. In comparison, a 5-percent increase in FSRP alone was associated with increased risk of stroke (HR: 1.25; 95% CI 1.15-1.36). Interpretation: Higher CSVD burden is associated with increased risk of stroke, beyond the effect explained by risk factors in the FSRP. These findings support consideration of CSVD burden to identify risk of stroke in community-dwelling individuals.

The investigation of hippocampal free‐water as a biomarker for cognitive impairment and decline in older adults

AbstractBackgroundWhile diffusion MRI derived free‐water (FW) metrics have shown promise in predicting cognitive impairment and decline in aging and Alzheimer’s disease (AD), it is unclear whether hippocampal FW metrics would be superior to traditional structural neuroimaging biomarkers (i.e., hippocampal volume, AD Schwarz Signature, AD McEvoy Signature). We examined the relationships between hippocampal FW metrics and traditional neuroimaging biomarkers with longitudinal memory and executive function.MethodVanderbilt Memory &amp; Aging Project participants [n = 298, age at baseline: 73 ± 7 years, 40% mild cognitive impairment (MCI)] underwent longitudinal neuropsychological assessment and brain MRI over a 7 year follow‐up (mean: 3 ± 2 years) period. Structural MRI was used to quantify hippocampal volume in addition to Schwarz and McEvoy signatures. Diffusion MRI in conjunction with the FW elimination technique was used to quantify hippocampal FW and FW‐corrected fractional anisotropy (FAFWcorr). Linear regression was used to determine the association of each biomarker with baseline memory and executive function. A subsequent competitive model analysis was conducted to determine how much additional variance was provided by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein‐e4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. Additionally, linear mixed‐effects regression was used to determine the association between baseline biomarker values with longitudinal memory and executive function scores. All analyses were corrected for multiple comparisons using the FDR procedure.ResultAt baseline, all biomarkers (excluding hippocampal FAFWcorr) were significantly associated with cognitive performance (Table 1), with hippocampal FW exhibiting the most significant association for memory (pFDR = 3.92×10‐6) and executive function (pFDR = 5.35×10‐3). Competitive models revealed that hippocampal FW contributed the most unique variance beyond covariates for memory (ΔRadj2 = 3.87%) and executive function (ΔRadj2 = 1.59%). Longitudinal models (Table 2, Figure 1) largely mirrored cross‐sectional models by demonstrating that hippocampal FW was most significantly associated with longitudinal decline in memory (pFDR = 5.04×10‐13) and executive function (pFDR = 6.15×10‐5).ConclusionThis study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.

The investigation of hippocampal free‐water as a biomarker for cognitive impairment and decline in older adults

AbstractBackgroundWhile diffusion MRI derived free‐water (FW) metrics have shown promise in predicting cognitive impairment and decline in aging and Alzheimer’s disease (AD), it is unclear whether hippocampal FW metrics would be superior to traditional structural neuroimaging biomarkers (i.e., hippocampal volume, AD Schwarz Signature, AD McEvoy Signature). We examined the relationships between hippocampal FW metrics and traditional neuroimaging biomarkers with longitudinal memory and executive function.MethodVanderbilt Memory &amp; Aging Project participants [n = 298, age at baseline: 73 ± 7 years, 40% mild cognitive impairment (MCI)] underwent longitudinal neuropsychological assessment and brain MRI over a 7 year follow‐up (mean: 3 ± 2 years) period. Structural MRI was used to quantify hippocampal volume in addition to Schwarz and McEvoy signatures. Diffusion MRI in conjunction with the FW elimination technique was used to quantify hippocampal FW and FW‐corrected fractional anisotropy (FAFWcorr). Linear regression was used to determine the association of each biomarker with baseline memory and executive function. A subsequent competitive model analysis was conducted to determine how much additional variance was provided by each biomarker compared to the covariate only model, which included age, sex, race/ethnicity, apolipoprotein‐e4 status, cognitive status, and modified Framingham Stroke Risk Profile scores. Additionally, linear mixed‐effects regression was used to determine the association between baseline biomarker values with longitudinal memory and executive function scores. All analyses were corrected for multiple comparisons using the FDR procedure.ResultAt baseline, all biomarkers (excluding hippocampal FAFWcorr) were significantly associated with cognitive performance (Table 1), with hippocampal FW exhibiting the most significant association for memory (pFDR = 3.92×10−6) and executive function (pFDR = 5.35×10−3). Competitive models revealed that hippocampal FW contributed the most unique variance beyond covariates for memory (ΔRadj 2 = 3.87%) and executive function (ΔRadj 2 = 1.59%). Longitudinal models (Table 2, Figure 1) largely mirrored cross‐sectional models by demonstrating that hippocampal FW was most significantly associated with longitudinal decline in memory (pFDR = 5.04×10−13) and executive function (pFDR = 6.15×10−5).ConclusionThis study shows that hippocampal FW is a sensitive biomarker for cognitive impairment and decline, and provides strong evidence for further exploration of this measure in aging and AD.

Area Deprivation Index is associated with biomarkers of inflammation cross‐sectionally and longitudinally over a 9‐year follow‐up period

AbstractBackgroundLiving in a socioeconomically disadvantaged neighborhood has a negative impact on health outcomes, including increased risk for Alzheimer’s disease (AD). The biological mechanisms underlying this risk are poorly understood. We examined how neighborhood disadvantage relates to core AD pathology, neurodegeneration, and inflammatory biomarkers in community‐dwelling older adultsMethodVanderbilt Memory and Aging Project participants (n = 327, 73±8 years, 41% female) underwent fasting blood and cerebrospinal fluid (CSF) acquisition serially over a 9‐year follow‐up period (mean follow‐up = 5.8 years). Area Deprivation Index (ADI), representing neighborhood disadvantage, was quantified at baseline based on 17 components [e.g., housing, income, education, and household characteristics (Kind &amp; Buckingham, 2018)]. Ordinary least squares regressions cross‐sectionally related ADI to plasma and CSF biomarkers adjusting for age, sex, race/ethnicity, education, modified Framingham Stroke Risk Profile score, apolipoprotein E‐e4 status, and cognitive status. Linear mixed‐effects regression models related baseline ADI to longitudinal biomarkers with identical baseline covariates plus follow‐up time. Outcomes included CSF chitinase‐3‐like protein 1 (YKL‐40), CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2), CSF amyloid‐b40 (Ab40), CSF amyloid‐b42 (Ab42), CSF Ab40/Ab42 ratio, CSF tau, CSF phosphorylated tau (ptau), plasma high sensitivity C‐reactive protein (CRP), and plasma and CSF neurofilament light chain (NfL).ResultOn average, the sample was from relatively less disadvantaged neighborhoods (ADI national decile = 35.4±25.0, range = 1‐98). Greater neighborhood disadvantage at study entry was cross‐sectionally associated with elevated CSF YKL‐40 (β = ‐0.733, p = 0.003), sTREM2 (β = 19.74, p = 0.04), Aβ40 (β = 35.96, p = 0.01), tau (β = 2.31, p = 0.02), and ptau (β = 0.33, p = 0.03). Greater neighborhood disadvantage at study entry related to longitudinal increases in CRP (β = 0.012, p&lt;0.001) and decreases in plasma NfL (β = ‐0.025, p = 0.04) over the follow‐up period.ConclusionAmong community‐dwelling older adults, greater neighborhood disadvantage was associated with elevated inflammatory and AD CSF biomarkers cross‐sectionally, and longitudinal increases in a non‐specific inflammatory blood biomarker. Collectively, findings suggest that neighborhood disadvantage confers immediate risk for systemic neuroinflammation and AD and future risk for non‐specific inflammation, providing valuable evidence of a sociobiological mechanism underlying health disparities in aging adults based on geographic location. Funding. R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082

CSF‐plasma albumin ratio differs by sex in community dwelling older adults

AbstractBackgroundBlood‐brain barrier (BBB) permeability is associated with Alzheimer’s disease (AD) and neurodegeneration. Cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is a biomarker commonly used to approximate BBB and blood‐CSF barrier (BCSFB) integrity. While sex‐based differences in AD risk are well‐established, limited work has evaluated these differences with QAlb and neurodegeneration and neuropsychological outcomes. Here, we examine if sex modifies the association of QAlb with neuropsychological and structural neuroimaging markers of neurodegeneration in community‐dwelling older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, 72±7 years, 33% female) completed a fasting blood draw, lumbar puncture, neuropsychological assessment, and multimodal 3T brain magnetic resonance imaging (MRI) to capture grey matter volumes and white matter hyperintensities (WMHs). Ordinary least squares regressions cross‐sectionally related sex to QAlb. Follow‐up models tested a sex x QAlb interaction with neuropsychological and MRI outcomes. Models adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile score (minus age), apolipoprotein (APOE)‐e4 status, and (for MRI outcomes) intracranial volume.ResultFemale sex was associated with lower QAlb (p&lt;0.001). However, sex did not interact with QAlb on any neuropsychological (p‐values&gt;0.7) or neuroimaging outcomes (p‐values&gt;0.2). Models stratified by sex were also null for neuropsychological (p‐values&gt;0.93) and neuroimaging outcomes (p‐values&gt;0.11).ConclusionElevated QAlb is believed to reflect disrupted brain‐barrier integrity such that blood‐based albumin (which lacks an active transport mechanism across the BBB) can enter the brain parenchyma and travel to the CSF. We found that female sex is associated with lower QAlb levels but does not interact with early cognitive or neuroimaging markers of AD‐associated neurodegeneration. The strong association between female sex and higher brain‐barrier integrity highlights the importance of considering sex differences when applying QAlb in clinical and research settings. Funding: R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082

Predicting acute ischemic stroke using the revised Framingham stroke risk profile and multimodal magnetic resonance imaging.

Patients with transient ischemic attacks (TIA) have a significant risk of developing acute ischemic strokes (AIS), emphasizing the critical need for hierarchical management. This study aims to develop a clinical-imaging model utilizing multimodal magnetic resonance imaging (mMRI) and the revised Framingham Stroke Risk Profile (FSRP) to predict AIS and achieve early secondary prevention. mMRI scans were conducted on patients with symptomatic intracranial atherosclerotic disease (ICAD) to assess vascular wall features and cerebral perfusion parameters. Based on diffusion-weighted imaging (DWI), patients were divided into two groups: TIA and AIS. Clinical data were evaluated to calculate the FSRP score. Differences in clinical and imaging characteristics between the groups were analyzed, and a predictive model for AIS probability in patients with ICAD was established. A total of 112 TIA and AIS patients were included in the study. The results showed that the AIS group had higher proportions of FSRP-high risk, hyperhomocysteinemia, and higher value of low-density lipoprotein (LDL), standardized plaque index (SQI), and enhancement rate (ER) compared to the TIA group (p < 0.05). Mean transit time (MTT) and time to peak (TTP) in the lesion area were significantly longer in the AIS group (p < 0.05). Multivariate analysis identified FSRP-high risk (p = 0.027) and high ER (p = 0.046) as independent risk factors for AIS. The combined clinical and mMRI model produced an area under the curve (AUC) of 0.791 in receiver operating characteristic (ROC) analysis. The constructed nomogram model combining clinical and mMRI features demonstrated favorable clinical net benefits. FSRP-high risk and high ER were confirmed as independent risk factors for AIS. The combined prediction model utilizing clinical and imaging markers effectively predicts stroke risk in symptomatic ICAD patients.

Inactivity is associated with worse cognition and neurodegeneration in aging adults

AbstractBackgroundGreater physical activity is known to be beneficial for healthier brain aging outcomes. However, less is known about how inactivity might influence the aging brain. Inactivity is highly prevalent in older adulthood and may be an important modifiable risk factor. We examined how inactivity relates to cognitive performance and structural imaging variables in community‐dwelling older adults, particularly among individuals at genetic risk for sporadic AD (i.e., apolipoprotein E (APOE)‐e4 carriers).MethodVanderbilt Memory and Aging Project (n = 265, 74±8 years, 37% female) participants completed at least 7 days of wrist actigraphy, neuropsychological assessment, and 3T brain MRI. Actigraphy data was processed using the GGIR package. Linear regression analyses related average daily minutes spent in inactivity during wake periods to cognition and brain structure adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile score, APOE‐e4 status, cognitive status, actigraphy wear time, and intracranial volume (for MRI outcomes). Models were repeated testing interactions with APOE‐e4 status.ResultThe total sample was inactive for 14±2 hours/day. More minutes of inactivity related to worse episodic memory performance (β = ‐0.001, p = 0.03), a smaller AD‐signature composite of cortical thickness (β = ‐0.0002, p = 0.008), and lower occipital lobe grey matter volume (β = ‐10.01, p = 0.01). Inactivity time interacted with APOE‐e4 status on naming (β = ‐0.01, p = 0.01) and visuospatial performances (β = ‐0.02, p = 0.04); total grey matter volume (β = ‐201.40, p&lt;0.001); and frontal (β = ‐96.24, p = 0.001), temporal (β = ‐27.13, p = 0.03), and parietal lobe volumes (β = ‐54.72, p&lt;0.001). In stratified models, more minutes of inactivity related to worse neuropsychological performance and smaller brain volumes among APOE‐e4 carriers. All stratified models in non‐carriers were null (p‐values&gt;0.12).ConclusionAmong community‐dwelling older adults, more time spent inactive each day related to worse episodic memory performance and lower cortical thickness in regions susceptible to AD‐related neurodegeneration. Results were stronger among APOE‐e4 carriers. This study supports the importance of not just increasing physical activity but also reducing the time spent inactive each day, particularly among aging adults at genetic risk for AD.Funding: IIRG‐08‐88733, P20‐AG068082, R01‐AG034962, K24‐AG046373

Glucose variability and predicted cardiovascular risk after gastrectomy.

To investigate the correlation between glycemic trends and cardiovascular risk after gastrectomy for gastric cancer. We enrolled 105 gastric cancer patients who underwent gastrectomy at our hospital between October 2017 and July 2020. Postoperative glucose concentrations, trends, and patterns were recorded using a continuous glucose monitoring (CGM) device. Cardiovascular risk was calculated using the Framingham stroke risk profile score (FSRPS), the Framingham risk score (FRS), and the Suita score. We examined the correlations between glycemic variability and cardiovascular risk scores. There were significant differences in the standard deviation (SD) of glucose levels between the high and low FSRPS groups (p = 0.049), the high and low FRS groups (p = 0.011), and the high and low Suita score groups (p = 0.044). The SD of glucose levels was significantly higher in patients with diabetes mellitus (DM) (p < 0.001) and those who underwent total gastrectomy (TG) (p = 0.017). Additionally, the CGM data available for 38 patients 1year post-gastrectomy were analyzed for glucose level dynamics, and the SD was found to be significantly higher than that at 1month (p < 0.001). Our findings suggest that long-term follow-up and therapeutic strategies tailored to glycemic trends may be necessary for gastric cancer patients after gastrectomy, especially those with DM and those who have undergone TG, to prevent cardiovascular events.

Microstructural alterations in medial temporal and frontal white matter tracts are associated with subjective cognitive decline

AbstractBackgroundSubjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer’s disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis.MethodVanderbilt Memory &amp; Aging Project participants with diffusion MRI data and a 45‐item measure of SCD were included (n=237, 73±7 years, 37% female). A subset of participants (n=104) underwent a fasting lumbar puncture for quantification of amyloid‐β (CSF Aβ42). Diffusion MRI data was post‐processed using the free‐water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive‐related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto‐parietal tracts. General linear modeling related each tract to SCD adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE‐ε4 carrier status, diagnosis, Geriatric Depression Scale scores, and total white matter volume. Competitive model analyses were conducted to determine if white matter microstructural values have a unique role in SCD separate from CSF Aβ42.ResultFW‐corrected radial diffusivity (RDT) was related to SCD in 6 tracts: cingulum bundle (β=3.52x106; p=0.001), inferior longitudinal fasciculus (β=2.77x106; p=0.005), as well as inferior frontal gyrus (IFG) pars opercularis (β=1.98x106; p=0.008), IFG pars triangularis (β=2.69x106; p=0.008), medial frontal gyrus (β=2.46x106; p=0.007), and middle frontal gyrus (β=2.47x106; p=0.014) transcallosal tracts. While CSF Aβ42 was related to SCD in our cohort (β=‐0.021; p=0.020), competitive model analyses revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD beyond CSF Aβ42.ConclusionMedial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD independent of early AD pathology. Given RDT appears to be the most significant predictor of SCD, demyelination may be an early contributor to cognitive decline. These results highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.

Vascular risk factors as predictors of epilepsy in older age: The Framingham Heart Study.

Stroke is the most common cause of epilepsy in older age. Subclinical cerebrovascular disease is believed to underlie some of the 30%-50% of late-onset epilepsy without a known cause (Li et al. Epilepsia. 1997;38:1216; Cleary et al. Lancet. 2004;363:1184). We studied the role of modifiable vascular risk factors in predicting subsequent epilepsy among participants ages 45 or older in the Framingham Heart Study (FHS), a longitudinal, community-based study. Participants of the Offspring Cohort who attended FHS exam 5 (1991-1995) were included who were at least 45-years-old at that time, had available vascular risk factor data, and epilepsy follow-up (n=2986, mean age 58, 48% male). Adjudication of epilepsy cases included review of medical charts to exclude seizure mimics and acute symptomatic seizures. The vascular risk factors studied included hypertension, diabetes mellitus, smoking, and hyperlipidemia. The role of the Framingham Stroke Risk Profile score was also investigated. Cox proportional hazards regression models were used for the analyses. Fifty-five incident epilepsy cases were identified during a mean of 19years of follow-up. Hypertension was associated with a near 2-fold risk (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.10-3.37, p=.022) of developing epilepsy, even after adjustment for prevalent and interim stroke. In secondary analysis, excluding patients with normal blood pressure who were receiving anti-HTN (anti-hypertensive) treatment (n=2613, 50 incident epilepsy cases) the association was (HR: 2.44, 95% CI: 1.36-4.35, p=.003). Our results offer further evidence that hypertension, a potentially modifiable and highly prevalent vascular risk factor in the general population, increases 2- to 2.5-fold the risk of developing late-onset epilepsy.

The relationship between white matter microstructure and self-perceived cognitive decline

Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer’s disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45-item measure of SCD were included [n = 236, 137 cognitively unimpaired (CU), 99 with mild cognitive impairment (MCI), 73 ± 7 years, 37% female]. A subset of participants (64 CU, 40 MCI) underwent a fasting lumbar puncture for quantification of cerebrospinal fluid (CSF) amyloid-β(CSF Aβ42), total tau (CSF t-tau), and phosphorylated tau (CSF p-tau). Diffusion MRI data was post-processed using the free-water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive-related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto-parietal tracts using a region of interest approach. General linear modeling related each tract to SCD scores adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE ε4 carrier status, diagnosis, Geriatric Depression Scale scores, hippocampal volume, and total white matter volume. Competitive models were analyzed to determine if white matter microstructural values have a unique role in SCD scores separate from CSF Aβ42. FW-corrected radial diffusivity (RDT) was related to SCD scores in 8 tracts: cingulum bundle, inferior longitudinal fasciculus, as well as inferior frontal gyrus (IFG) pars opercularis, IFG orbitalis, IFG pars triangularis, tapetum, medial frontal gyrus, and middle frontal gyrus transcallosal tracts. While CSF Aβ42 was related to SCD scores in our cohort (Radj2 = 39.03%; β = −0.231; p = 0.020), competitive models revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD scores beyond CSF Aβ42 (Radj2 = 44.35% and Radj2 = 43.09%, respectively), with several other tract measures demonstrating nominal significance. All tracts which demonstrated nominal significance (in addition to covariates) were input into a backwards stepwise regression analysis. ILF RDT, fornix RDT, and UF FW were best associated with SCD scores (Radj2 = 46.69%; p = 6.37 × 10-12). Ultimately, we found that medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD scores independent of early amyloid deposition. Our results highlight the potential importance of abnormal white matter diffusivity as an early contributor to cognitive decline. These results also highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.

Increased self‐reported sleepiness is associated with larger brain volume and less ischemic brain injury in a community sample

AbstractBackgroundSleepiness has been associated with an increased risk of Alzheimer’s disease (AD) and vascular dementia, but few studies have investigated its association with markers of accelerated brain aging. We evaluated the association between sleepiness and MRI measures; and whether the apolipoprotein E4 (APOE4) allele status moderates this relationship.MethodWe studied 492 participants (58.8 ± 8.8 years, 49.4%M) in the Framingham Heart Study aged &gt;40 years without significant neurological diseases, such as dementia and stroke. We used the Epworth Sleepiness Scale (ESS) to assess sleepiness. Brain MRI metrics were volumes of white matter hyperintensities (WMH), total brain, cortical gray matter (GM) and subcortical GM, all investigated as a percentage of total intracranial volume; we also identified covert brain infarcts (CBI). Linear and logistic regressions were used to assess the association between ESS scores and brain structure. Model 1 adjusted for age, age squared, sex, and time between the ESS and MRI (3.3 ± 1.0 years). Model 2 additionally adjusted for APOE4 allele carrier status, Framingham Stroke Risk Profile scores, sleep medication, body mass index, and depression. We included an interaction term between APOE4 allele status and ESS score, adjusted for model 1 covariates, to evaluate potential effect modification.ResultHigher ESS scores, indicating greater sleepiness, were associated with higher total brain volume (b = 0.33; SE = 0.13; p = 0.02), higher cortical GM volume (b = 0.26; SE = 0.12; p = 0.03), and a lower risk of CBI (OR = 0.57; 95%CI = 0.36‐0.93; p = 0.02) adjusted for both models 1 and 2 covariates. These associations were present when further adjusting for the apnea‐hypopnea index, education and habitual sleep duration. A significant interaction was observed between APOE4 and ESS scores (p = 0.008), where higher ESS was associated with higher cortical GM in non‐carriers (b = 0.43; SE = 0.14; p = 0.002). Conversely, in carriers, higher ESS was associated with lower cortical GM (b = ‐0.36; SE = 0.22; p = 0.09, trend).ConclusionIncreased self‐reported sleepiness was associated with findings of better brain health, including higher cortical GM volume and less CBI. Genetic susceptibility to AD modified this relationship, where increased sleepiness was associated with higher cortical GM volume only in APOE4 non‐carriers. Better brain health may be associated with higher self‐reported sleepiness via better cognition and self‐awareness in those who are not at increased risk of developing AD.

Lower Cardiac Output Relates to Longitudinal Cognitive Decline in Aging Adults.

BackgroundSubclinical reductions in cardiac output correspond to lower cerebral blood flow (CBF), placing the brain at risk for functional changes.ObjectivesThis study aims to establish the consequences of reduced cardiac output on longitudinal cognitive outcomes in aging adults.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and heart failure (n = 306, 73 ± 7, 58% male) underwent baseline echocardiography to assess cardiac output (L/min) and longitudinal neuropsychological assessment at baseline, 18 months, 3 and 5 years. Linear mixed-effects regressions related cardiac output to trajectory for each longitudinal neuropsychological outcome, adjusting for age, sex, race/ethnicity, education, body surface area, Framingham Stroke Risk Profile score, apolipoprotein E (APOE) ε4 status and follow-up time. Models were repeated, testing interactions with cognitive diagnosis and APOE-ε4 status.ResultsLower baseline cardiac output related to faster declines in language (β = 0.11, p = 0.01), information processing speed (β = 0.31, p = 0.006), visuospatial skills (β = 0.09, p = 0.03), and episodic memory (β = 0.02, p = 0.001). No cardiac output x cognitive diagnosis interactions were observed (p > 0.26). APOE-ε4 status modified the association between cardiac output and longitudinal episodic memory (β = 0.03, p = 0.047) and information processing speed outcomes (β = 0.55, p = 0.02) with associations stronger in APOE-ε4 carriers.ConclusionThe present study provides evidence that even subtle reductions in cardiac output may be associated with more adverse longitudinal cognitive health, including worse language, information processing speed, visuospatial skills, and episodic memory performances. Preservation of healthy cardiac functioning is important for maintaining optimal brain aging among older adults.

Serum and CSF Metabolites in Stroke-Free Patients Are Associated With Vascular Risk Factors and Cognitive Performance.

Background and purpose: The aggregation of vascular risk factors (VRFs) can aggravate cognitive impairment in stroke-free patients. Metabolites in serum and cerebrospinal fluid (CSF) may irreversibly reflect early functional deterioration. This study evaluated small-molecule metabolites (<1,000 Da) in the serum and CSF of patients with different degrees of cerebrovascular burden and investigated the correlation between metabolism and cognitive performance associated with VRFs.Methods: The subjects were divided into a low-risk group (10-year stroke risk ≤ 5%), a middle-risk group (10-year stroke risk >5% and <15%), and a high-risk group (10 years stroke risk ≥ 15%) according to the Framingham stroke risk profile (FSRP) score, which was used to quantify VRFs. We assess the cognitive function of the participants. We semiquantitatively quantified the small molecules using liquid chromatography–tandem mass spectrometry (LC-MS/MS). The correlation between the small molecules and cognitive function, along with VRFs, was investigated to identify key small molecules and possible underlying metabolic pathways.Results: When the FSRP scores increased, the cognitive performances of the subjects decreased, specifically the performance regarding the tasks of immediate memory, delayed recall, and executive function. Seven metabolites (2-aminobutyric acid, Asp Asp Ser, Asp Thr Arg, Ile Cys Arg, 1-methyluric acid, 3-tert-butyladipic acid, and 5α-dihydrotestosterone glucuronide) in serum and three metabolites [Asp His, 13-HOTrE(r), and 2,5-di-tert-Butylhydroquinone] in CSF were significantly increased, and one metabolite (arachidonoyl PAF C-16) in serum was significantly decreased in high-risk group subjects. Among these metabolites, 1-methyluric acid, 3-tert-butyladipic, acid and Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone, and Asp His in CSF were found to be negatively related with cognitive performance in the high-risk group. Arachidonoyl PAF C-16 in serum was found to be associated with better cognitive performance. Caffeine metabolism and the tricarboxylic acid cycle (TCA cycle) were identified as key pathways.Conclusions: 1-Methyluric acid, 3-tert-butyladipic acid, arachidonoyl PAF C-16, and Ile Cys Arg in serum and 13-HOTrE(r), 2,5-di-tert-butylhydroquinone, and Asp His in CSF were identified as potential biomarkers of vascular cognitive impairment (VCI) at the early stage. Caffeine metabolism and the TCA cycle may play important roles in the pathophysiology of VRF-associated cognitive impairment.

Abstract TP419: Medication Adherence as a Modulator of Ischemic Stroke Recurrence in the Veteran Population - The MISTER-VA Study

Introduction: Recurrent strokes make up 25% of the annual stroke incidence with 10% of the Veteran population suffering a recurrent stroke within 1 year. The role of adherence to a post-stroke medication regimen and its effect on stroke recurrence is unknown. Methods: Veterans evaluated in a vascular neurology specialty clinic from July 2010 to June 2016 underwent a detailed medical chart review and assessment of medication adherence to stroke prevention medications including anti-thrombotic use, anti-coagulants, anti-hypertensives, lipid-lowering therapy, and anti-hyperglycemic therapy. Medication adherence was measured by 90d refill history with &gt;75% medication possession ratio (MPR) indicating adherence. A Framingham Stroke Risk Profile (FSRP) Score was calculated for each patient. Relative risk calculations were generated using a bivariate analysis and means compared via t-test. Results: 162 of 245 patients who were newly referred to the clinic underwent a detailed chart review and medication adherence profile. In this cohort, 93.8% were male and ranged in age between 35-94 years old (mean 69.2±10.2). The mean age of first stroke was 62.9±10.5 and the frequency of recurrent stroke was 26.5% (43 patients). The median time to recurrent stroke was 2.59 years. The average FSRP score for all subjects was 0.087±0.09 and did not differ between those with or without a recurrent stroke (0.103 vs. 0.082, p= 0.18). The rate of medication adherence in all subjects was 69.8% and differed greatly between those without and with a recurrent stroke, 79.0% vs. 44.2%, respectively. Median time to recurrent stroke was 2.59 years in those with MPR &gt;75% and 1.91 years in those with MPR &lt;75%. Strict adherence with a stroke prevention medication regimen was associated with a lower risk of recurrent stroke (relative risk = 0.34, 95% CI 0.21-0.57, p -value &lt;0.0001) while poor adherence, was associated with a 2.91-fold increased risk ( p -value &lt;0.0001) of recurrent stroke in the Veteran population. Conclusion: In this high-risk Veteran population, strict adherence with a stroke prevention medication regimen is associated with a lower risk of recurrent stroke. Efforts to measure and encourage medication adherence in patients with prior stroke may reduce the risk of recurrence.

Association between vascular comorbidity and progression of Alzheimer\u2019s disease: a two-year observational study in Norwegian memory clinics

BackgroundVascular risk factors increase the risk of Alzheimer’s disease (AD), but there is limited evidence on whether comorbid vascular conditions and risk factors have an impact on disease progression. The aim of this study was to examine the association between vascular disease and vascular risk factors and progression of AD.MethodsIn a longitudinal observational study in three Norwegian memory clinics, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16–37) months. Vascular risk factors and vascular diseases were registered at baseline, and the vascular burden was estimated by the Framingham Stroke Risk Profile (FSRP). Cerebral medical resonance images (MRIs) were assessed for white matter hyperintensities (WMH), lacunar and cortical infarcts. The associations between vascular comorbidity and progression of dementia as measured by annual change in Clinical Dementia Rating Sum of Boxes (CDR-SB) scores were analysed by multiple regression analyses, adjusted for age and sex.ResultsHypertension occurred in 83%, hypercholesterolemia in 53%, diabetes in 9%, 41% were overweight, and 10% were smokers. One third had a history of vascular disease; 16% had heart disease and 15% had experienced a cerebrovascular event. MRI showed lacunar infarcts in 16%, WMH with Fazekas score 2 in 26%, and Fazekas score 3 in 33%. Neither the vascular risk factors and diseases, the FSRP score, nor cerebrovascular disease was associated with disease progression in AD.ConclusionsAlthough vascular risk factors and vascular diseases were prevalent, no impact on the progression of AD after 2 years was shown.

Lower cardiac index levels relate to lower cerebral blood flow in older adults.

To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults. Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), APOE ε4 status, cognitive diagnosis, and regional tissue volume. Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, p = 0.001) and right (β = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, p = 0.003; right temporal lobe β = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes. Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.

Association of Ambulatory Blood Pressure Monitoring parameters with the Framingham Stroke Risk Profile

The Framingham Stroke Risk Profile (FSRP) is a novel and reliable tool for estimating the 10-year probability for incident stroke in stroke-free individuals, while the predictive value of ambulatory blood pressure monitoring (ABPM) for first-ever and recurrent stroke has been well established. We sought to evaluate cross-sectionally the association of ABPM parameters with FSRP score in a large sample of 2343 consecutive stroke-free individuals (mean age: 56.0±12.9, 49.1% male) who underwent 24-hour ABPM. True hypertensives showed significantly higher FSRP (11.2±5.0) compared to the normotensives (8.2±5.0, p<0.001), while subjects with white coat hypertension also had higher FSRP (10.2±4.7) than normotensives (8.2±5.0, p<0.001). Compared to dippers that exhibited the lowest FSRP, non-dippers and reverse-dippers exhibited significantly higher FSRP (9.8±4.8 for dippers vs 10.6±5.2 and 11.5±5.0 for non-dippers and reverse-dippers respectively, p≤0.001 for comparisons). In univariate analyses, the ABPM parameters that had the strongest correlation with FSRP were 24-hour (r=0.440, p<0.001), daytime (r=0.435, p<0.001) and night-time (r=0.423; p<0.001) pulse pressure (PP). The best fitting model for predicting FSRP (R2=24.6%) on multiple linear regression analyses after adjustment for vascular risk factors not included in FSRP comprised the following parameters in descending order: 24-hour PP (β=0.349, p<0.001), daytime SBP variability (β=0.124, p<0.001), 24-hour HR variability (β=−0.091, p<0.001), mean 24-hour HR (β=−0.107, p<0.001), BMI (β=0.081, p<0.001) and dipping percentage (β=−0.063, p=0.001). 24-hour PP and daytime SBP variability are the two ABPM parameters that were more strongly associated with FSRP-score. Reverse dippers had the highest FSRP among all dipping status profiles.

WHITE MATTER VULNERABILITY AND CARDIOVASCULAR RISK IN OLDER HISPANICS/LATINOS: EVIDENCE FOR EARLIER NEURODEGENERATION?

Hispanics 65 years and older are one of the fastest growing minority populations in the US and also one of the most medically underserved. For example, when compared to non-Hispanic whites, Hispanics have higher rates of uncontrolled cardiovascular disease risk factors (CVD-RFs) including hypertension and diabetes and twice the risk of dementia including Alzheimer's disease. Evidence suggests that cardiovascular disease risk factors may contribute to the earlier development of cognitive (i.e., executive functioning and information processing speed) and cerebral white matter alterations (i.e., white matter hyperintensities; WMH) in Hispanics. Overt white matter damage including WMHs may be driven, in part, by alterations in myelin integrity. We quantified myelin integrity using multicomponent relaxometry (MCR) in Hispanics and non-Hispanic Whites to explore for ethnic differences in associations to cardiovascular disease risk factors in these groups. We obtain the risk of stroked based on cardiovascular disease risk factors using the Framingham Stroke Risk Profile Score and acquired MCR data using a 3T GE MRI. 15 Hispanics (x̅age=62.7 years & FSRP=7.5; 66% women) and 15 non-Hispanic Whites (x̅age=69.7 years & FSRP=11.1; 40% women) with documented cardiovascular risk factor burden were compared to a group of 11 non-Hispanic whites (x̅age=71.0 years) without any cardiovascular risk factors. Figure 4 shows comparable differences in myelin degradation between Hispanics (yellow) and non-Hispanic whites (green) despite the fact that Hispanics were significantly younger (mean age=62.7 versus non-Hispanic whites mean age=69.7; p<0.001) with significantly lower cardiovascular disease scores as measured by the Framingham Stroke Risk Profile (FSRP) Score (FSRP=7.5 versus non-Hispanic whites’ mean=11.1; p<0.01). This preliminary study suggests that myelin degradation, associated with even mild vascular disease burden, is detectable using MCR. Furthermore, despite being significantly younger with less stroke risk associated with cardiovascular disease risk factors, Hispanics displayed comparable myelin degradation to older non-Hispanic whites with greater cardiovascular risk. Myelin integrity associated with cardiovascular disease risk burden was greater for Hispanics (yellow) than non-Hispanic whites (green) when compared to healthier controls.