Lower White Matter Hyperintensity Volume Research Articles

Plasma trimethylamine N-oxide (TMAO): associations with cognition, neuroimaging, and dementia

BackgroundThe gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine – have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain.MethodsIn the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n = 318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function.ResultsOverall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses.ConclusionsPlasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms.

39 Relationships among Cardiovascular Risk Factors, White Matter Hyperintensities, and Depressive Symptoms in Black and White Older Adults

Objective:The vascular depression hypothesis posits that there is a relationship between vascular disease and geriatric depressive symptoms. Black Americans are at higher risk for cardiovascular disease (CVD) than their White counterparts. However, it is not fully understood whether risk for CVD or potentially related neurovascular changes have a differential relationship in Black and White Americans. We investigated differences in the relationships between white matter hyperintensities, risk for CVD, and depressive symptoms in Black and White older adults.Participants and Methods:Participants were derived from the National Alzheimer Coordinating Center database. Black (N = 120) and White (N = 120) participants were matched on age, sex, and education. White matter hyperintensity (WMH) and CVD burden data (sum of vascular conditions) on 320 individuals were analyzed (mean age = 75.9; 69.4% female). Age, sex, race, and education were included as covariates in separate regression models in which WMH and CVD burden predicted scores on the 15-item Geriatric Depression Scale (GDS-15). Follow-up stratified analyses were conducted to explore the relationship between WMH and CVD burden on GDS scores in the Black and White samples.Results:Lower WMH volume and higher CVD burden were associated with higher GDS scores in the total sample. Analyses stratified by race showed a positive effect of CVD burden on GDS scores only for the Black sample and a trend effect of WMH on GDS scores only for the White sample, with higher WMH volume associated with lower rather than higher GDS scores.Conclusions:These findings are consistent with previous research showing that WMH and CVD burden are related to depression in older adults. Contrary to expectation, WMH had a negative trend association with GDS scores in the White sample. Findings also suggest that different etiologies may play a role in the clinical presentation of depression in Black and White Americans. Additional research is needed to further explore the relationships among CVD, its neural correlates, and depressive symptoms in diverse samples.

“Life's Essential 8” Cardiovascular Health and Dementia Risk, Cognition, and Neuroimaging Markers of Brain Health

ObjectiveTo evaluate associations of Life's Essential 8 (LE8) score, the recently updated metric for promoting cardiovascular health (CVH), with the risk of incident dementia and its subtypes, cognition, and neuroimaging outcomes and to determine whether these associations differ among apolipoprotein E (APOE)-ε4 genotypes. DesignProspective cohort study. Setting and ParticipantsA total of 316,669 participants [mean (SD) age, 56.3 (8.1) years] without prior cardiovascular disease or dementia from the UK Biobank study at baseline survey (2006–2010) were enrolled. MethodsA modified version of the LE8 score was created (range: 0–100) and categorized into poor (0–49), intermediate (50–79), and optimal (80–100) CVH. Cox proportional hazard and multivariable linear regression models were used. ResultsDuring a median 12.6 years of follow-up, 4238 all-cause dementia cases including 1797 Alzheimer's disease and 939 vascular dementia (VaD) occurred. Individuals with optimal CVH had 44% (95% CI, 0.48–0.64) lower incident all-cause dementia risk and 71% (95% CI, 0.22–0.38) lower VaD risk compared with those who had poor CVH. A 10-point increment in LE8 was associated with higher fluid intelligence scores (β, 0.088; 95% CI, 0.073–0.102) and numeric memory scores (β, 0.054; 95% CI, 0.043–0.065), and was also associated with lower white matter hyperintensity volume (β, −0.673; 95% CI, −0.751 to −0.596), larger total brain volume (β, 77.93; 95% CI, 62.03–93.84), and hippocampal volume (β, 0.197; 95% CI, 0.106–0.288). In addition, the association between LE8 profiles and dementia diagnosis differed by APOE genotype (all P for interaction ≤ .001), and was more evident among APOE-ε4 noncarriers. Conclusions and ImplicationsIndividuals with a higher LE8 score experienced fewer dementia events (driven especially by incident VaD) and were associated with better neurocognitive brain health profiles. CVH optimization may be beneficial to the maintenance of brain health.

Apolipoprotein C proteins in plasma non‐high‐density lipoprotein fractions and development of Alzheimer’s disease, central arterial stiffness, and cerebral small vessel disease in older adults

AbstractBackgroundPlasma non‐high‐density lipoproteins impact development of central arterial stiffness and cerebral small vessel disease (cSVD), significantly contributing to Alzheimer’s disease (AD) and related dementias (ADRDs) through an increase in cerebral amyloid beta (Aβ) burden and acceleration of atrophy in susceptible brain regions. We sought to identify proteins in three non‐HDL plasma lipoproteins (very‐low density lipoprotein [VLDL], intermediate‐density lipoprotein [IDL], low‐density lipoprotein [LDL]) and their cross‐sectional associations with brain amyloid deposition, central arterial stiffness, neuroimaging features of cSVD (e.g., white matter hyperintensity volume), brain volumes susceptible to AD and cSVD, and incidence of dementia.MethodPlasma samples from 66 participants of the Atherosclerosis Risk in Communities (ARIC) study were fractionated to isolate VLDL, IDL, and LDL and analyzed using label‐free liquid chromatography‐mass spectrometry (LC‐MS) with Data‐Independent Acquisition. Acquired MS spectra were processed using Spectronaut™ to give protein identification and relative protein abundances were calculated using R. Linear regression models were used to examine the cross‐sectional associations between protein abundances in VLDL, IDL or LDL and brain amyloid deposition (measured by amyloid PET scan), white matter hyperintensities (WMH) volume (measured by brain MRI), central arterial stiffness (carotid‐femoral and heart‐femoral pulse wave velocity), AD‐signature region, frontal, parietal, and hippocampal brain region volumes (measured by brain MRI), and incidence of dementia. Regression models were adjusted for age, sex, race, number of APOε4 alleles, and cholesterol level (if applicable). Additionally, differential analysis (student’s t‐test) was used to compare protein abundances in non‐HDL lipoproteins between participants with elevated versus normal brain amyloid deposition.ResultWe identified 50, 78, 81 proteins in VLDL, IDL, and LDL, respectively. The most significant findings were: 1) higher levels of apolipoprotein C proteins in VLDL, IDL, and LDL were associated with lower WMH volume or less central arterial stiffness; 2) lower levels of apolipoprotein C proteins in VLDL, IDL, and LDL were associated with less incidence of dementia; 3) lower levels of apolipoprotein C proteins in VLDL, IDL, and LDL for participants with elevated amyloid deposition.ConclusionThese results suggest the possible role of apolipoprotein C proteins present in non‐HDL‐lipoproteins in the development of AD, central arterial stiffness, and cSVD.

Clonal hematopoiesis with DNMT3A mutation is associated with lower white matter hyperintensity volume.

Clonal hematopoiesis of indeterminate potential (CHIP) increases the risk of cerebrovascular events, while its association with cerebral white matter hyperintensity (WMH) is undemonstrated. We evaluated the effect of CHIP and its major driving mutations on cerebral WMH severity. From an institutional cohort of a routine health check-up program with a DNA repository database, subjects who were ≥50 years of age, with one or more cardiovascular risk factors but no central nervous system disorder, and performed brain MRI were included. Along with the presence of CHIP and its major driving mutations, clinical and laboratory data were obtained. WMH volume was measured in total, periventricular, and subcortical regions. Among the total 964 subjects, 160 subjects were classified as CHIP positive group. CHIP was most frequently associated with DNMT3A mutation (48.8%), followed by TET2 (11.9%) and ASXL1 (8.1%) mutations. Linear regression analysis adjusting for age, sex, and conventional cerebrovascular risk factors suggested that CHIP with DNMT3A mutation was associated with the lower log-transformed total WMH volume, unlike other CHIP mutations. When classified according to variant allele fraction (VAF) value of DNMT3A mutation, higher VAF classes were associated with the lower log-transformed total WMH and the lower log-transformed periventricular WMH volume, but not with the log-transformed subcortical WMH volumes. Clonal hematopoiesis with DNMT3A mutation is quantitatively associated with a lower volume of cerebral WMH, especially in the periventricular region. CHIP with DNMT3A mutation might have a protective role in the endothelial pathomechanism of WMH.

Mediterranean diet and structural neuroimaging biomarkers of Alzheimer’s and cerebrovascular disease: a systematic review

AbstractBackgroundAdherence to the Mediterranean diet (MedDiet) has been associated with better cognitive performance, lower incidence of dementia, stroke and lower Alzheimer’s disease (AD) biomarker burden (Scarmeas et al, 2018). Improving dietary patterns in at‐risk populations may improve brain health, reducing incidence of dementia and stroke (Lewis et al, 2014; Feigin et al, 2019). The aim of this systematic review was to evaluate the evidence base for the MedDiet in relation to hippocampal volume and white matter hyperintensity volume (WMHV) (PROSPERO Registration: CRD42021269620).MethodWe systematically searched for studies on MedDiet and hippocampal volume or WMHV in MedLine, EMBASE, CINAHL and PsycInfo. The review was carried out in line with PRISMA methodology. We included studies with adult participants in any setting, time or language. Searches were initially carried out between 21st July 2021 and 19th August 2021. Papers were screened independently by two authors against eligibility criteria. Data on participant demographics, MedDiet calculation and adherence, hippocampal volume and/or WMHV was extracted and narratively synthesised.ResultOf an initial 112 papers identified, six papers, enrolling 21,750 participants, were eligible for inclusion in the review. The mean age of participants in studies ranged from 53.8 years to 80.3 years and participants were healthy volunteers, had subjective cognitive decline, or dementia. All studies included in the review were cross‐sectional or cohort studies. Four studies reported on hippocampal volume, with inconclusive or no associations seen with MedDiet adherence. One study found a significant association between higher MedDiet adherence and lower WMHV, while two other studies found no significant associations.ConclusionOverall, these results highlight a gap in our knowledge about the associations between MedDiet and AD and cerebrovascular related structural neuroimaging findings. Future research is needed including increased frequency of dietary assessments, more sensitive and specific imaging outcomes and the inclusion of data from low‐ and middle‐income countries.

Poststroke White Matter Hyperintensities and Physical Activity: A CANVAS Study Exploratory Analysis.

White matter hyperintensities (WMHs) are associated with poststroke cognitive decline and mortality. Physical activity (PA) may decrease WMH risk by reducing vascular risk factors and promoting cerebral perfusion. However, the association between poststroke PA and WMH progression remains unclear. We examined the association between PA and WMH volume 12 months after stroke, and between PA and change in WMH volume between 3 and 12 months after stroke. We included ischemic stroke survivors from the Cognition And Neocortical Volume After Stroke cohort with available brain magnetic resonance imaging and objective PA data. Total, periventricular, and deep WMH volumes (in milliliters) were estimated with manually edited, automated segmentations (Wisconsin White Matter Hyperintensities Segmentation toolbox). Moderate-to-vigorous intensity PA (MVPA) was estimated using the SenseWear® Armband. Participants with MVPA ≥30 min·d -1 were classified as "meeting PA guidelines." We used quantile regression to estimate the associations between PA (MVPA and meeting PA guidelines) with WMH volume at 12 months and change in WMH volume between 3 and 12 months after stroke. A total of 100 participants were included (median National Institutes of Health Stroke Scale 2; interquartile range, 1-4). MVPA was not associated with WMH volume. In univariable analysis, meeting PA guidelines was associated with lower total, periventricular, and deep WMH volumes by 3.0 mL (95% confidence interval (CI), 0.5-9.7 mL), 2.8 mL (95% CI, 0.5-7.1 mL), and 0.9 mL (95% CI, 0.1-3.0 mL), respectively. However, in multivariable analysis, meeting PA guidelines was not associated with WMH volume, and older age was associated with greater WMH volume at 12 months. PA was not associated with change in WMH volume. Meeting PA guidelines was associated with lower WMH volume at 12 months in univariable analysis, but not in multivariable analysis. Age consistently predicted greater WMH volume.

Cognitive activity, cognitive function, and structural MRI findings

AbstractBackgroundMore frequent engagement in late‐life cognitive activities (e.g. reading, playing games) has been associated with slower cognitive decline in old age. Even after adjusting for neuropathological burden, cognitive activities were associated with less cognitive decline. However, it is not known whether people who engage more frequently in cognitive activities show differences in brain anatomy compared to those who participate less frequently. We tested the hypothesis that brain anatomy, as measured by structural MRI indices, mediates the association of cognitive activities and cognitive decline in old age.MethodIn a sample of 975 participants (60% African American and 60% female) from the Chicago Health and Aging Project, late‐life cognitive activities were collected at baseline; MRI was conducted an average of 7.9 years later. We identified several significant correlations of late‐life cognitive activity with MRI indices (brain regions and cortical thickness) and then used linear mixed‐effects regression models to examine those associations with global cognition. Global cognition was assessed using a standardized measure of episodic memory, perceptual speed, and the MMSE, before and after MRI scans.ResultHigher frequency of overall cognitive activity was associated with seven brain volumes and two cortical thicknesses, which were associated with global cognitive level. Of those associations, five were associated with cognitive decline and explained about 42% of the cognitive activity association with cognitive decline. Specifically, a higher reading frequency was associated with lower white matter hyperintensity volume (WMH) and third ventricular volume. Higher WMH and third ventricle volumes were also associated with lower global cognition and a faster rate of cognitive decline. We also found that a higher frequency of playing games was positively associated with greater hippocampal and parahippocampal volumes and caudal anterior cingulate thickness in the left hemisphere.ConclusionIndividuals who engage more frequently in cognitively stimulating activities show differences in brain anatomy compared to those who participate less frequently, as measured by structural MRI. These results suggest that cognitive activities are related to improved structure and function of the brain, thereby shedding light on the well‐established findings that cognitive activities are associated with cognitive decline independent of neuropathologic burden.

Association between cerebral small‐vessel disease and Alzheimer’s disease pathologies

AbstractBackgroundControversy exists regarding the etiological role of cerebral small vessel disease (CSVD) in Alzheimer's disease (AD). We thus evaluated the association between brain Aβ/tau burden and white matter hyperintensity (WMH) volume among subjects with varying severity levels of cognitive impairment.MethodA total of 84 stroke‐free subjects (healthy controls [HC]=10; subjective cognitive decline [SCD]=32; mild cognitive impairment [MCI]=26; dementia =16) were included. All patients underwent structural MRI, 11C‐ PIB, and 18F‐T807 PET to measure CSVD makers, Aβ deposition (A+) and pathologic tau (T+), respectively. WMH volume was quantified by automatic segmentation using AccuBrain® IV 1.1 (BrainNow Medical Technology Company Ltd.).ResultNo significant association was found between A+T+ and WMH volume in the overall population (β =‐0.03 ;95% CI, ‐0.04‐0.11; p=0.10). There was also no significant association found within different cognitive diagnostic group except in those with dementia, where we found that increasing global 11C‐ PIB SUVR correlated with lower WMH volume (B=‐1.76 ;95% CI, ‐2.92‐ ‐0.59; p=0.007). No significant association between 18F‐T807 SUVR and WMH volume was observedConclusionWe found no association between brain Aβ/tau burden and WMH volume except an inverse association was noted between Aβ and WMH in dementia patients. PiB retention might be restrained by WMH in those patients with higher CSVD burden.

Abstract P323: Stroke Lesion Pattern-Specific Influence of White Matter Hyperintensities on Stroke Severity in Acute Ischemic Stroke

Introduction: MRI-detected white matter hyperintensity (WMH) burden is linked to the overall brain health and incident stroke outcomes. However, data are limited as to whether specific acute stroke lesion patterns purport greater stroke severity in patients with extensive pre-existing WMH. In this analysis, we sought to investigate lesion pattern-specific WMH effects on AIS severity. Methods: We analyzed clinical and lesion data from 621 AIS patients enrolled in the multi-site MRI-GENIE study. The acute NIHSS was modelled via Bayesian hierarchical regression. Using ten stroke lesion patterns, that served as input variables of main interest, we introduced a hierarchical level differentiating between patients with higher and lower than median WMH volume (WMHv). Lesion pattern posterior distributions for higher and lower WMHv patients were subtracted to infer substantial differences. Results: In this AIS cohort [age: 65.3±14.6, 60% male], a higher WMHv was associated with greater stroke severity only when specific left-hemispheric brain regions were infarcted. This “lesion pattern 3” was mainly characterized by left middle and inferior frontal gyrus, insular and opercular cortex, pre- and post-central gyrus, and subcortical basal ganglia regions ( Fig ). Conclusions: Higher WMH burden appears to enhance the detrimental effect of acute stroke lesions involving left-hemispheric brain regions underlying language and motor functions. This effect might be due to an exacerbated disruption of functional network integrity by the combination of WMH and stroke lesions and could be explored further in functional imaging studies that simultaneously considered information from both lesion types.

HbA1c and brain health across the entire glycaemic spectrum.

AimTo understand the relationship between HbA1c and brain health across the entire glycaemic spectrum.Materials and MethodsWe used data from the UK Biobank cohort consisting of 500,000 individuals aged 40–69 years. HbA1c and diabetes diagnosis were used to define baseline glycaemic categories. Our outcomes included incident all‐cause dementia, vascular dementia (VD), Alzheimer's dementia (AD), hippocampal volume (HV), white matter hyperintensity (WMH) volume, cognitive function and decline. The reference group was normoglycaemic individuals (HbA1c ≥35 & <42 mmol/mol). Our maximum analytical sample contained 449,973 individuals with complete data.ResultsPrediabetes and known diabetes increased incident VD (HR 1.54; 95% CI = 1.04, 2.28 and HR 2.97; 95% CI = 2.26, 3.90, respectively). Known diabetes increased all‐cause and AD risk (HR 1.91; 95% CI = 1.66, 2.21 and HR 1.84; 95% CI = 1.44, 2.36, respectively). Prediabetes and known diabetes elevated the risks of cognitive decline (OR 1.42; 1.48, 2.96 and OR 1.39; 1.04, 1.75, respectively). Prediabetes, undiagnosed and known diabetes conferred higher WMH volumes (3%, 22% and 7%, respectively) and lower HV (36, 80 and 82 mm3, respectively), whereas low‐normal HbA1c had 1% lower WMH volume and 12 mm3 greater HV.ConclusionBoth prediabetes and known diabetes are harmful in terms of VD, cognitive decline and AD risks, as well as lower HV. Associations appeared to be somewhat driven by antihypertensive medication, which implies that certain cardiovascular drugs may ameliorate some of the excess risk. Low‐normal HbA1c levels, however, are associated with more favourable brain health outcomes and warrant more in‐depth investigation.

Mediterranean Diet and Structural Neuroimaging Biomarkers of Alzheimer's and Cerebrovascular Disease: A Systematic Review

Background: Adherence to the MedDiet has been associated with better cognitive performance, lower incidence of dementia, stroke and lower Alzheimer’s disease (AD) biomarker burden. The aim of this study was to evaluate the evidence base for the MedDiet in relation to hippocampal volume and white matter hyperintensity volume (WMHV). Methods: For the systematic review we searched for studies reporting on MedDiet and hippocampal volume or WMHV in MedLine, EMBASE, CINAHL and PsycInfo. We included studies with adult participants in any setting, time or language. Searches were initially carried out on 21 st July 2021 with final searches run on 19 th August 2021. Papers were screened independently by two authors (SG and HP) against eligibility criteria. Data on participant demographics, MedDiet calculation and adherence, hippocampal volume and/or WMHV was extracted by one author (SG) and checked by a second author (SG). Data was narratively synthesised. Findings: Of an initial 111 papers identified, five papers, enrolling 2566 participants, were eligible for inclusion in the review. The mean age of participants in studies ranged from 68.8 years to 80.3 years and participants were healthy volunteers, had subjective cognitive decline, or dementia. All studies included in the review were cross-sectional or cohort studies. Three studies reported on hippocampal volume, with inconclusive or no associations seen with MedDiet adherence. One study found a significant association between higher MedDiet adherence and lower WMHV, while two other studies found no significant associations. Interpretation: Overall these results highlight a gap in our knowledge about the associations between MedDiet and AD and cerebrovascular related structural neuroimaging findings. Future research is needed to increase the frequency of dietary assessments, alternative imaging outcomes and data from low and middle income countries. Registration Details: PROSPERO Registration: CRD42021269620 Funding Information: This systematic review was funded by the MRC (MRC UK Nutrition Research Partnership (NRP) Collaboration Award (MR/T001852/1). Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/disclosure-of-interest/. SG and OS receive support from the MRC for this work. OS has received a research grant from the Newcastle NIHR BRC; CWR has received consultancy fees from Biogen, Eisai, MSD, Actinogen, Roche, and Eli Lilly, as well as payment or honoraria from Roche and Eisai; no other relationships or activities that could appear to have influenced the submitted work.

Neuronal insulin signaling and brain structure in nondemented older adults: the Atherosclerosis Risk in Communities Study

We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities–Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults.

Cardiorespiratory fitness diminishes the effects of age on white matter hyperintensity volume.

White matter hyperintensities (WMHs) are among the most commonly observed marker of cerebrovascular disease. Age is a key risk factor for WMH development. Cardiorespiratory fitness (CRF) is associated with increased vessel compliance, but it remains unknown if high CRF affects WMH volume. This study explored the effects of CRF on WMH volume in community-dwelling older adults. We further tested the possibility of an interaction between CRF and age on WMH volume. Participants were 76 adults between the ages of 59 and 77 (mean age = 65.36 years, SD = 3.92) who underwent a maximal graded exercise test and structural brain imaging. Results indicated that age was a predictor of WMH volume (beta = .32, p = .015). However, an age-by-CRF interaction was observed such that higher CRF was associated with lower WMH volume in older participants (beta = -.25, p = .040). Our findings suggest that higher levels of aerobic fitness may protect cerebrovascular health in older adults.

Genetic determinants of blood lipids and cerebral small vessel disease: role of high-density lipoprotein cholesterol.

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

Diastolic Blood Pressure Is Associated With Regional White Matter Lesion Load: The Northern Manhattan Study.

Background and Purpose- Few studies have examined the separate contributions of systolic blood pressure and diastolic blood pressures (DBP) on subclinical cerebrovascular disease, especially using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. Furthermore, associations with region-specific white matter hyperintensity volume (WMHV) are underexplored. Methods- Using data from the NOMAS (Northern Manhattan Study), a prospective cohort study of stroke risk and cognitive aging, we examined associations between systolic blood pressure and DBP, defined by the 2017 American College of Cardiology/American Heart Association guidelines, with regional WMHV. We used a linear mixed model approach to account for the correlated nature of regional brain measures. Results- The analytic sample (N=1205; mean age 64±8 years) consisted of 61% women and 66% Hispanics/Latinos. DBP levels were significantly related to WMHV differentially across regions (P for interaction<0.05). Relative to those with DBP 90+ mm Hg, participants with DBP <80 mm Hg had 13% lower WMHV in the frontal lobe (95% CI, -21% to -3%), 11% lower WMHV in the parietal lobe (95% CI, -19% to -1%), 22% lower WMHV in the anterior periventricular region (95% CI, -30% to -14%), and 16% lower WMHV in the posterior periventricular region (95% CI, -24% to -6%). Participants with DBP 80 to 89 mm Hg also exhibited about 12% (95% CI, -20% to -3%) lower WMHV in the anterior periventricular region and 9% (95% CI, -18% to -0.4%) lower WMHV in the posterior periventricular region, relative to participants with DBP 90≥ mm Hg. Post hoc pairwise t tests showed that estimates for periventricular WMHV were significantly different from estimates for temporal WMHV (Holms stepdown-adjusted P<0.05). Systolic blood pressure was not strongly related to regional WMHV. Conclusions- Lower DBP levels, defined by the 2017 American College of Cardiology/American Heart Association guidelines, were related to lower white matter lesion load, especially in the periventricular regions relative to the temporal region.

Specific nutrient patterns are associated with higher structural brain integrity in dementia-free older adults

Optimal nutrition may play a beneficial role in maintaining a healthy brain. However, the relationship between nutrient intake and brain integrity is largely unknown. We investigated the association of specific nutrient dietary patterns with structural characteristics of the brain. Within the population-based Swedish National study on Aging and Care-Kungsholmen (SNAC-K), a cross-sectional study of 417 dementia-free participants aged ≥60 years who underwent structural magnetic resonance imaging (MRI) scans during 2001–2003, was carried-out. Data on dietary intake were collected using a food frequency questionnaire, from which intake of 21 nutrients was estimated. By principal component analysis, five nutrient patterns were extracted: (1) NP1 was characterized by fiber, vitamin C, E, β-carotene, and folate [Fiber&Antioxidants], (2) NP2 by eicosapentaenoic (EPA, 20:5 ω-3) and docosahexaenoic (DHA, 22:6 ω-3) polyunsaturated fatty acids (PUFAs), proteins, cholesterol, vitamin B3, B12, and D [long chain (LC) ω-3PUFAs&Proteins], (3) NP3 by α-linoleic (18:2 ω-6) and α-linolenic (18:3 ω-3) PUFAs, monounsaturated fatty acids (MUFAs), and vitamin E [MUFAs&ω-3,6PUFAs], (4) NP4 by saturated fatty acids (SFAs), trans fats, MUFAs, and cholesterol [SFAs&Trans fats], (5) NP5 by B-vitamins, retinol, and proteins [B-Vitamins&Retinol]. Nutrient patterns scores were tertiled with the lowest tertile as reference, and were related to total brain volume (TBV) and white matter hyperintensities volume (WMHV) using linear regression models adjusting for potential confounders. In the multi-adjusted model, compared to the lowest intake for each pattern, the highest intake of NP1 (β = 11.11, P = 0.009), NP2 (β = 7.47, P = 0.052), and NP3 (β = 10.54, P = 0.005) was associated with larger TBV whereas NP5 was related to smaller TBV (β = −12.82, P = 0.001). The highest intake of NP1 was associated with lower WMHV (β = −0.32, P = 0.049), whereas NP4 was associated with greater WMHV (β = 0.31, P = 0.036). In sum, our results suggest that the identified brain-health specific nutrient combinations characterized by higher intake of fruit, vegetables, legumes, olive and seed oils, fish, lean red meat, poultry and low in milk and dairy products, cream, butter, processed meat and offal, were strongly associated with greater brain integrity among older adults.

Antihypertensive Treatment is associated with MRI-Derived Markers of Neurodegeneration and Impaired Cognition: A Propensity-Weighted Cohort Study.

Hypertension is an important risk factor for Alzheimer's disease (AD) and cerebral small vessel disease. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are common anti-hypertensive treatments, but have differential effects on cortical amyloid. The objective of this study was to evaluate associations between anti-hypertensive treatment, brain volume, and cognition, using a propensity-weighted analysis to account for confounding by indication. We identified a cohort of normal elderly adults and individuals with mild cognitive impairment (MCI) or AD (N = 886; mean age = 75.0) from the Alzheimer's Disease Neuroimaging Initiative. Primary outcomes were brain parenchymal fraction, total hippocampal volume, and white matter hyperintensity (WMH) volume. Secondary outcomes were standardized scores on neuropsychological tests. Propensity-weighted adjusted multivariate linear regression was used to estimate associations between anti-hypertensive treatment class and MRI volumes and cognition. Individuals treated with ARBs showed larger hippocampal volumes (R2 = 0.83, p = 0.05) and brain parenchymal fraction (R2 = 0.83, p = 0.01) than those treated with ACEIs. When stratified by diagnosis, this effect remained only in normal elderly adults and MCI patients, and a significant association between ARBs and lower WMH volume (R2 = 0.83, p = 0.03) emerged for AD patients only. ARBs were also associated with significantly better performance on tests of episodic and verbal memory, language, and executive function (all p < 0.05). Findings are consistent with evidence for a neuroprotective effect of treatment with ARBs for brain structure and cognition. This study has potential implications for the treatment of hypertension, particularly in elderly adults at risk of cognitive decline and AD.

Late-life Depression Modifies the Association Between Cerebral White Matter Hyperintensities and Functional Decline Among Older Adults.

Vascular lesions seen through brain imaging as hyperintensities are associated with both depression and functional impairment in older adults. Our objective was to determine if the relationship between the volume of cerebral white matter hyperintensities (WMHs) and functional decline differed in the presence of late life depression. Secondary analysis of data collected through the Neurocognitive Outcomes of Depression Study. Analysis techniques included general linear mixed models examining trajectories of functional change predicted by lesion volume at baseline. 381 participants (244 patients diagnosed with major depression and 137 never depressed comparison participants) ages 60 years and older followed for up to 16 years. WMH volume was measured through analysis of brain magnetic resonance imaging data. Functional limitations included difficulties with basic activities of daily living tasks, instrumental activities of daily living tasks, and mobility. Those participants who were both depressed and had a higher volume of WMHs at baseline were most at risk for functional decline across all measures of function. Among the never depressed, those with a higher WMH volume at baseline had a more accelerated rate of functional decline than those with lower WMH volume, and those who were depressed with lower volume of WMH started with more limitations than the never depressed but appeared to progress at a rate similar to those who were never depressed with lower WMH. Older patients with both cerebrovascular risk factors and depression are at an increased risk for functional decline, and may benefit from the treatment of both conditions.

P03-10 - Remission of poststroke cognitive impairment no dementia: Clinical and imaging correlates

IntroductionCerebral microbleeds (CMBs) may contribute to cognitive deficits in stroke. Cognitive impairment that does not meet the criteria for dementia (cognitive impairment no dementia [CIND]) is common in stroke, and patients with such impairment can revert to normal cognition.ObjectiveTo investigate the association of CMBs and remission of poststroke CIND.AimTo understand the evolution of poststroke cognitive impairment no dementia (CIND) is bi-directional.Methods143 patients with CIND at three months after stroke were recruited and followed up for one year. Remission of CIND was defined as a conversion of cognitive status from CIND to cognitively intact at follow-up. MRI variables in terms of infarction, cerebral microbleeds (CMBs), and white matter hyperintensities (WMHs) and hippocampal volume were analyzed. Logistic regression was performed to find the predictors of the remission of poststroke CIND.Results30 (21.0%) out of the 143 patients converted to cognitive intact at follow-up. In univariate comparisons, subjects with remission of CIND had younger age (67.1 ± 9.5 vs.73.6 ± 7.6 years, p &lt; 0.001) and higher education years (5.1 ± 4.0 vs.3.6 ± 4.0, p = 0.039). They also had lower WMHs volume (8.2 ± 8.2 vs. 18.6 ± 19.7 cm3, p &lt; 0.001), lower frequency of CMBs (10.0% vs. 31.0%, p = 0.021) and lower volume of the lateral ventricle (33.3 ± 16.5 vs.42.6 ± 19.4 cm3, p = 0.017). In logistic regression, age (odds ratio [OR] = 0.913, 95%C.I. = 0.866–0.962, p = 0.001) and absence of CMBs (OR = 4.292, 95%C.I. = 1.174–15.625, p = 0.028) were significant predictors of remission of CIND.ConclusionsYounger age and absence of CMBs predict the remission of poststroke CIND.