Cerebral White Matter Hyperintensity Volume Research Articles

Abstract TP29: Neurodegenerative Plasma Biomarker Associations With Cognitive Resilience in Adults With High White Matter Hyperintensity Volume: A Post-Hoc Analysis of Systolic Blood Pressure Intervention Trial Memory & Cognition in Decreased Hypertension (SPRINT MIND)

Introduction: Although high cerebral white matter hyperintensity volume (WMHv) is associated with cognitive decline, many adults with high WMHv show no cognitive deficits. Neurodegenerative plasma biomarkers may be associated with cognitive decline via vascular processes causing higher WMHv such as cerebral amyloid angiopathy & inflammatory small vessel disease. We determined associations of plasma amyloid β 42 (AB42), amyloid β 40 (AB40), AB42/AB40, total tau, & neurofilament light chain (NfL) with cognitive resilience (CR) in adults with high WMHv using baseline MRIs & measurements from SPRINT MIND. Methods: This study included baseline data from 186 SPRINT MIND participants who were in the highest WMHv tertile & had available plasma biomarker concentrations & Montreal Cognitive Assessment (MoCA) scores. We defined CR two ways: A) MoCA score >25 or B) MoCA score >22. We determined univariate & adjusted odds ratios (OR) & 90% confidence intervals (CI) for each aforementioned plasma biomarker with CR. Confounders in adjusted models were: age, sex, race-ethnicity (Non-Hispanic white, Non-Hispanic Black, Hispanic, or other) education (no college education, college education, or post-graduate education), smoking history (never smoker, prior smoker, or current smoker) physical activity (0, 1-4, or ≥ 5 days of vigorous physical activity), diabetes, having insurance, & average systolic blood pressure. Residual confounding and effect modification by WMHv were tested in sensitivity analyses. Results: In our sample, the mean age was 72.6 years, 45.7% were female & 66% were Non-Hispanic white. The median WMHv was 10.0 cm 3 (25%-75% range: 6.3 - 16.9 cm 3 ). . CR defined as MoCA scores > 25 & >22 was present in 28.5% & 56.5% of participants respectively. Lower plasma AB40 was marginally associated with CR using a MoCa cutoff of >25 (OR 1.003, 90% CI: 1.001-1.006) in univariate analyses. There were no other significant (P>0.1) univariate or adjusted associations between plasma biomarkers with CR using either MoCa cutoff, nor significant confounding or effect modification by WMHv (P> 0.1). Conclusion: There were no significant adjusted associations between any plasma biomarker with CR. Future work should identify factors associated with CR in adults with high WMHv.

Association between serum free hemoglobin level and cerebral white matter hyperintensity volume in older adults

The association between serum free hemoglobin (sfHb) level and white matter hyperintensity (WMH) volume is controversial. This study is to examine this association considering nonlinearity, sex dimorphism, and WMH type. We enrolled 704 older adults among the participants of the Korean Longitudinal Study on Cognitive Aging and Dementia and visitors to the Dementia Clinic of Seoul National University Bundang Hospital. We measured sfHb level in the venous blood and WMH volume (VWMH) using fluid-attenuated inversion recovery magnetic resonance images. The association between sfHb level and periventricular VWMH was linear in men (linear regression; β = − 0.18, p = 0.006) and U-shaped in women (restricted cubic spline; F = 6.82, p < 0.001). sfHb level was not associated with deep VWMH in either sex. These findings were also observed in participants without anemia. To conclude, sfHb level is associated with periventricular VWMH in older adults of both sexes. Maintaining an optimal sfHb level may contribute to the prevention of WMH.

Abstract P409: Cerebellar Atrophy and Its Clinical Implications in Cerebral Amyloid Angiopathy

Background: Recent data show that cerebral amyloid angiopathy (CAA) might cause hemorrhagic lesions in cerebellar cortex as well as cerebral atrophy. However, the potential effect of CAA on cerebellar tissue loss and its clinical implications have not been investigated. Methods: We compared cerebellar volumes in 70 nondemented patients with probable CAA to 70 age-matched healthy controls (HC) and 70 age-matched Alzheimer’s disease (AD) patients. Volumetric analyses including cerebellar cortical volume (pCbll-CV), cerebellar subcortical volume (pCbll-ScV), cerebral white matter volume (pWMV), and cerebral white matter hyperintensity volume (pWMH) were calculated as percent of total intracranial volume. Gait velocity (meters/seconds) was used to investigate the potential effect of cerebellar tissue loss on gait function. Results: Patients with CAA had significantly lower pCbll-ScV and pCbll-CV compared to HC (1.49%±0.17 vs 1.71%±0.23, p&lt;0.001 and 6.03%±0.50 vs 6.23%±0.56, p&lt;0.027 respectively). When compared to AD, pCbll-ScV but not pCbll-CV was significantly lower in CAA (1.49%±0.17 vs 1.670.24, p&lt;0.001). Diagnosis of CAA was independently associated with lower pCbll-ScV in a general linear model adjusting for age, sex and presence of hypertension when compared to both HCs and patients with AD (p&lt;0.0001 for all associations, after Bonferroni correction for multiple comparisons). Lower pCbll-ScV was associated with lower gait velocity score in univariate and multivariate analysis adjusted for relevant variables (adjusted β=0.826, 95%CI 0.357-1.295, p=0.001). Conclusion: Patients with CAA show cerebellar atrophy; predominantly in the subcortical cerebellum when compared to both HC and AD patients. Cerebellar tissue loss independently correlated with worse gait function in CAA patients. Overall, this study supports the view that CAA causes cerebellar injury which might mediate gait disturbance in patients with CAA.

Genome‐wide association study identifies two novel chromosome loci associated with cerebral white matter hyperintensity volume in Japanese population

AbstractBackgroundCerebral white matter hyperintensity (WMH) is highly prevalent in the elderly population, and increases the risk of dementia and stroke . The genetic underpinnings of WMH are still incompletely characterized, especially in Asian. To identify novel genetic variants influencing WMH burden, we conducted a genome‐wide association studies (GWAS) in Japanese population.MethodWe included outpatients who visited National Center for Geriatrics and Gerontology (NCGG) without symptomatic heart failure, ischemic heart disease, atrial fibrillation or stroke. The clinical data and blood samples used in this study were distributed from the NCGG Biobank, which collects and stores biological material and associated clinical information for biomedical research. WMH volume were analyzed by an automatic segmentation application (SNIPER). To identify WMH associated loci, we conducted a GWAS with linear regression analysis adjusted with age and gender as covariates using approximately 4,300,000 single nucleotide polymorphisms (SNP) imputed based on reference panel from large Japanese sequences. This study was approved by the Ethics Review Board of NCGG.ResultA total of 813 patients were enrolled in the present study (mean age 75.4 ± 8.1 years), including 503 female patients (61.9%). The clinical profiles of the study participants are normal control: n = 184; Alzheimer’s disease: n = 375; other: n = 254. The mean MMSE score was 24.2 ± 4.5.In the GWAS, we have identified two novel loci on chromosome 1 and 2 associated with WMH volume with GWAS significance (P &lt; 5 × 10‐8). We also identified several WMH volume associated loci with suggestive significance (P &lt; 1 × 10‐6).ConclusionThis GWAS of WMH burden in outpatients of our hospital identifies 2 novel genetic loci with GWAS significance and several candidate loci. This is the first report on WMH associated loci of Japanese population. Further characterization of these loci may provide novel insights into the pathogenesis of cerebral WMH in Japanese population.

Association of moderate alcohol intake with in vivo amyloid-beta deposition in human brain: A cross-sectional study.

BackgroundAn emerging body of literature has indicated that moderate alcohol intake may be protective against Alzheimer disease (AD) dementia. However, little information is available regarding whether moderate alcohol intake is related to reductions in amyloid-beta (Aβ) deposition, or is protective via amyloid-independent mechanisms in the living human brain. Here we examined the associations of moderate alcohol intake with in vivo AD pathologies, including cerebral Aβ deposition, neurodegeneration of AD-signature regions, and cerebral white matter hyperintensities (WMHs) in the living human brain.Methods and findingsThe present study was part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study that started in 2014. As of November 2016, 414 community-dwelling individuals with neither dementia nor alcohol-related disorders (280 cognitively normal [CN] individuals and 134 individuals with mild cognitive impairment [MCI]) between 56 and 90 years of age (mean age 70.9 years ± standard deviation 7.8; male, n [%] = 180 [43.5]) were recruited from 4 sites (i.e., 2 university hospitals and 2 public centers for dementia prevention and management) around Seoul, South Korea. All the participants underwent comprehensive clinical assessments comprising lifetime and current histories of alcohol intake and multimodal brain imaging, including [11C] Pittsburgh compound B positron emission tomography (PET), [18F] fluorodeoxyglucose (FDG) PET, and magnetic resonance imaging (MRI) scans. Lifetime and current alcohol intake were categorized as follows: no drinking, <1 standard drink (SD)/week, 1–13 SDs/week, and 14+ SDs/week. A moderate lifetime alcohol intake (1–13 SDs/week) was significantly associated with a lower Aβ positivity rate compared to the no drinking group, even after controlling for potential confounders (odds ratio 0.341, 95% confidence interval 0.163–0.714, p = 0.004). In contrast, current alcohol intake was not associated with amyloid deposition. Additionally, alcohol intake was not related to neurodegeneration of AD-signature regions or cerebral WMH volume. The present study had some limitations in that it had a cross-sectional design and depended on retrospective recall for alcohol drinking history.ConclusionsIn this study, we observed in middle- and old-aged individuals with neither dementia nor alcohol-related disorders that moderate lifetime alcohol intake was associated with lower cerebral Aβ deposition compared to a lifetime history of not drinking. Moderate lifetime alcohol intake may have a beneficial influence on AD by reducing pathological amyloid deposition rather than amyloid-independent neurodegeneration or cerebrovascular injury.

Aortic valve calcification volumes and chronic brain infarctions in patients undergoing transcatheter aortic valve implantation

Chronic silent brain infarctions, detected as new white matter hyperintensities on magnetic resonance imaging (MRI) following transcatheter aortic valve implantation (TAVI), are associated with long-term cognitive deterioration. This is the first study to investigate to which extent the calcification volume of the native aortic valve (AV) measured with cardiac computed tomography angiography (CTA) predicts the increase in chronic white matter hyperintensity volume after TAVI. A total of 36 patients (79 ± 5 years, median EuroSCORE II 1.9%, Q1–Q3 1.5–3.4%) with severe AV stenosis underwent fluid attenuation inversion recovery (FLAIR) MRI < 24 h prior to TAVI and at 3 months follow-up for assessment of cerebral white matter hyperintensity volume (mL). Calcification volumes (mm3) of the AV, aortic arch, landing zone and left ventricle were measured on the CTA pre-TAVI. The largest calcification volumes were found in the AV (median 692 mm3) and aortic arch (median 633 mm3), with a large variation between patients (Q1–Q3 482–1297 mm3 and 213–1727 mm3, respectively). The white matter hyperintensity volume increased in 72% of the patients. In these patients the median volume increase was of 1.1 mL (Q1–Q3 0.3–4.6 mL), corresponding with a 27% increase from baseline (Q1–Q3 7–104%). The calcification volume in the AV predicted the increase of white matter hyperintensity volume (Δ%), with a 35% increase of white matter hyperintensity volume, per 100 mm3 of AV calcification volume (SE 8.5, p < 0.001). The calcification volumes in the aortic arch, landing zone and left ventricle were not associated with the increase in white matter hyperintensity volume. In 72% of the patients new chronic white matter hyperintensities developed 3 months after TAVI, with a median increase of 27%. A higher calcification volume in the AV was associated with a larger increase in the white matter hyperintensity volume. These findings show the potential for automated AV calcium screening as an imaging biomarker to predict chronic silent brain infarctions.

White matter hyperintensities in migraine: Clinical significance and central pulsatile hemodynamic correlates.

Background The role of central pulsatile hemodynamics in the pathogenesis of white matter hyperintensities in migraine patients has not been clarified. Methods Sixty patients with migraine (20-50 years old; women, 68%) without overt vascular risk factors and 30 demographically-matched healthy controls were recruited prospectively. Cerebral white matter hyperintensities volume was determined by T1-weighted magnetic resonance imaging with CUBE-fluid-attenuated-inversion-recovery sequences. Central systolic blood pressure, carotid-femoral pulse wave velocity, and carotid augmentation index were measured by applanation tonometry. Carotid pulsatility index was derived from Doppler ultrasound carotid artery flow analysis. Results Compared to the controls, the migraine patients had higher white matter hyperintensities frequency (odds ratio, 2.75; p = 0.04) and greater mean white matter hyperintensities volume (0.174 vs. 0.049, cm3, p = 0.04). Multivariable regression analysis showed that white matter hyperintensities volume in migraine patients was positively associated with central systolic blood pressure ( p = 0.04) and carotid-femoral pulse wave velocity ( p < 0.001), but negatively associated with carotid pulsatility index ( p = 0.04) after controlling for potential confounding factors. The interaction effects observed indicated that the influence of carotid-femoral pulse wave velocity ( p = 0.004) and central systolic blood pressure ( p = 0.03) on white matter hyperintensities formation was greater for the lower-carotid pulsatility index subgroup of migraine patients. White matter hyperintensities volume in migraine patients increased with decreasing carotid pulsatility index and with increasing central systolic blood pressure or carotid-femoral pulse wave velocity. Conclusions White matter hyperintensities are more common in patients with migraine than in healthy controls. Increased aortic stiffness or central systolic blood pressure in the presence of low intracranial artery resistance may predispose patients with migraine to white matter hyperintensities formation.

Elevated circulating vascular cell Adhesion Molecule-1 (sVCAM-1) is associated with concurrent depressive symptoms and cerebral white matter Hyperintensities in older adults.

BackgroundCirculating vascular adhesion molecule-1 (sVCAM-1) is a presumed marker of endothelial activation and dysfunction, but little is known about its association with mood. We hypothesized that elevated plasma concentrations of sVCAM-1 may be a marker of depressive symptoms due to cerebral vascular disease.MethodsWe studied 680 community-dwelling participants in the MOBILIZE Boston Study, aged 65 years and older. sICAM-1 and sVCAM-1 were measured by ELISA assay and depressive symptoms were assessed during home interviews using the Revised Center for Epidemiological Studies Depression Scale (CESD-R). Cerebral White Matter Hyperintensities (WMHs) were quantified by MRI in a subgroup of 25 participants.ResultsOne hundred seventy nine (27 %) subjects had a CESD-R Score ≥ 16, indicative of depressive symptoms. The mean sVCAM-1 concentration (±SD) was 1176 ± 417 ng/mL in a group with CESD-R Scores <16 and 1239 ± 451 ng/mL in those with CESD-R Scores ≥16 (p = 0.036). CESD-R Score was positively associated with sVCAM-1 (r = 0.11, p = 0.004). The highest quintile of sVCAM-1, which is indicative of endothelial dysfunction, was significantly associated with depressive symptoms compared to the lowest quintile (OR = 1.97 (1.14-3.57) p = 0.015). In a subset of subjects, sVCAM-1 concentration was positively correlated with cerebral WMHs volume (p = 0.018).ConclusionsThe association between high levels of sVCAM-1 and depressive symptoms may be due to endothelial dysfunction from cerebral microvascular damage. Future longitudinal studies are needed to determine whether sVCAM-1 can serve as a biomarker for cerebrovascular causes of depression.