Increase In White Matter Hyperintensities Volume Research Articles

Abstract WP122: Statins May Increase White Matter Hyperintensity Burden in Older Adults: A Systematic Review and Meta-Analysis

Introduction: White matter hyperintensities (WMH) are a hallmark radiographic finding of cerebral microangiopathy. Longitudinal studies have shown varying effects of statins on accrual of WMH over time. We aimed to understand the impact of statins on WMH volume over time through a systematic review and meta-analysis. Methods: We performed a systematic review using standard search and risk of bias assessment practices. We included statin-exposed and statin-naive adults with longitudinal brain MRIs with computer-generated WMH volumetric analyses. The primary outcome was change in WMH volume (mL). Allowing for curvilinear change, a mixed-effects model was applied to capture the dynamic change over time. Model forecasts were used to visualize results, comparing changes over time among younger cohorts (60 years) and older cohorts (75 years) based on the the cohort mean age standard deviation. A p value ≤ 0.05 was considered significant. Results: We identified 6 studies enrolling 1911 participants from China, Europe, and North America (2 studies each); mean age 67.5 (± 7.5). The maximal study duration was 60-months. All studies had a least some degree of bias. Control groups had steady increase in WMH volume over time, Figures. The younger statin-exposed cohort developed statistically less WMH after 40 months of use. Older statin exposed patients had an increase in WMH volume compared with naïve patients which remained over the study duration. Conclusion: The impact of statins on WMH volume may be age dependent whereby older patients may have an accelerated accumulation. Further studies are warranted to confirm this data and investigate underlying mechanisms leading to this finding.

Association of Poor Oral Health With Neuroimaging Markers of White Matter Injury in Middle-Aged Participants in the UK Biobank.

Poor oral health is a modifiable risk factor that is associated with clinically observed cardiovascular disease. However, the relationship between oral and brain health is not well understood. We tested the hypothesis that poor oral health is associated with worse neuroimaging brain health profiles in middle-aged persons without stroke or dementia. We performed a 2-stage cross-sectional neuroimaging study using UK Biobank data. First, we tested for association between self-reported poor oral health and MRI neuroimaging markers of brain health. Second, we used Mendelian randomization (MR) analyses to test for association between genetically determined poor oral health and the same neuroimaging markers. Poor oral health was defined as the presence of dentures or loose teeth. As instruments for the MR analysis, we used 116 independent DNA sequence variants linked to increased composite risk of dentures or teeth that are decayed, missing, or filled. Neuroimaging markers of brain health included white matter hyperintensity (WMH) volume and aggregate measures of fractional anisotropy (FA) and mean diffusivity (MD), 2 metrics indicative of white matter tract disintegrity obtained through diffusion tensor imaging across 48 brain regions. We included 40,175 persons (mean age 55 years, female sex 53%) enrolled from 2006 to 2010, who underwent a dedicated research brain MRI between 2014 and 2016. Among participants, 5,470 (14%) had poor oral health. Poor oral health was associated with a 9% increase in WMH volume (β = 0.09, SD = 0.014, p < 0.001), 10% change in aggregate FA score (β = 0.10, SD = 0.013, p < 0.001), and 5% change in aggregate MD score (β = 0.05, SD = 0.013, p < 0.001). Genetically determined poor oral health was associated with a 30% increase in WMH volume (β = 0.30, SD = 0.06, p < 0.001), 43% change in aggregate FA score (β = 0.43, SD = 0.06, p < 0.001), and 10% change in aggregate MD score (β = 0.10, SD = 0.03, p < 0.01). Among middle age Britons without stroke or dementia, poor oral health was associated with worse neuroimaging brain health profiles. Genetic analyses confirmed these associations, supporting a potentially causal association. Because the neuroimaging markers evaluated in this study precede and are established risk factors of stroke and dementia, our results suggest that oral health, an easily modifiable process, may be a promising target for very early interventions focused on improving brain health.

Is coronary artery calcium an independent risk factor for white matter hyperintensity?

BackgroundCardiovascular diseases have been considered the primary cause of disability and death worldwide. Coronary artery calcium (CAC) is an important indicator of the severity of coronary atherosclerosis. This study is aimed to investigate the relationship between CAC and white matter hyperintensity (WMH) in the context of diagnostic utility.MethodsA retrospective analysis was conducted on 342 patients with a diagnosis of WMH on magnetic resonance images (MRI) who also underwent chest computed tomography (CT) scans. WMH volumes were automatically measured using a lesion prediction algorithm. Subjects were divided into four groups based on the CAC score obtained from chest CT scans. A multilevel mixed-effects linear regression model considering conventional vascular risk factors assessed the association between total WMH volume and CAC score.ResultsOverall, participants with coronary artery calcium (CAC score > 0) had larger WMH volumes than those without calcium (CAC score = 0), and WMH volumes were statistically different between the four CAC score groups, with increasing CAC scores, the volume of WMH significantly increased. In the linear regression model 1 of the high CAC score group, for every 1% increase in CAC score, the WMH volume increases by 2.96%. After including other covariates in model 2 and model 3, the β coefficient in the high CAC group remains higher than in the low and medium CAC score groups.ConclusionIn elderly adults, the presence and severity of CAC is related to an increase in WMH volume. Our findings suggest an association between two different vascular bed diseases in addition to traditional vascular risk factors, possibly indicating a comorbid mechanism.

Longitudinal Relationships of White Matter Hyperintensities and Alzheimer Disease Biomarkers Across the Adult Life Span.

White matter hyperintensities (WMH) correlate with Alzheimer disease (AD) biomarkers cross-sectionally and modulate AD pathogenesis. Longitudinal changes have been reported for AD biomarkers, including concentrations of CSF β-amyloid (Aβ) 42, Aβ40, total tau and phosphorylated tau181, standardized uptake value ratio from the molecular imaging of cerebral fibrillar Aβ with PET using [11C] Pittsburgh Compound-B, MRI-based hippocampal volume, and cortical thickness. Correlations between established AD biomarkers and the longitudinal change for WMH have not been fully evaluated, especially among cognitively normal individuals across the adult life span. We jointly analyzed the longitudinal data of WMH volume and each of the established AD biomarkers and cognition from 371 cognitively normal individuals whose baseline age spanned from 19.6 to 88.20 years from 4 longitudinal studies of aging and AD. A 2-stage algorithm was applied to identify the inflection point of baseline age whereby older participants had an accelerated longitudinal change in WMH volume, in comparison with the younger participants. The longitudinal correlations between WMH volume and AD biomarkers were estimated from the bivariate linear mixed-effects models. A longitudinal increase in WMH volume was associated with a longitudinal increase in PET amyloid uptake and a decrease in MRI hippocampal volume, cortical thickness, and cognition. The inflection point of baseline age in WMH volume was identified at 60.46 (95% CI 56.43-64.49) years, with the annual increase for the older participants (83.12 [SE = 10.19] mm3 per year) more than 13 times faster (p < 0.0001) than that for the younger participants (6.35 [SE = 5.63] mm3 per year). Accelerated rates of change among the older participants were similarly observed in almost all the AD biomarkers. Longitudinal correlations of WMH volume with MRI, PET amyloid biomarkers, and cognition seemed to be numerically stronger for the younger participants, but not significantly different from those for the older participants. Carrying APOE ε4 alleles did not alter the longitudinal correlations between WMH and AD biomarkers. Longitudinal increases in WMH volume started to accelerate around a baseline age of 60.46 years and correlated with the longitudinal change in PET amyloid uptake, MRI structural outcomes, and cognition.

Physical Frailty and Brain White Matter Abnormalities: The Atherosclerosis Risk in Communities Study.

Physical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty. Atherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline. In the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk. The current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

Progression in WMH volume is accompanied by higher gray matter loss: One‐year follow‐up MRI study in TATA Longitudinal Study on Aging Cohort of India

AbstractBackgroundSmall vessel disease pathologies such as white matter hyperintensity (WMH) and loss in neuroanatomical volumes with aging have been investigated across various cross‐ sectional and longitudinal‐aging studies in different parts of world. However, it is yet not extensively investigated whether the changes in WMH kinetics over the period impacts the neuroanatomical health? Here, we have measured changes in WMH and neuroanatomic‐volumes, in an ongoing longitudinal study on aging in India called TATA longitudinal study on aging (TLSA), at the baseline and one‐year‐follow‐up visit. The TLSA‐study is a prospective, community‐based, cohort study that comprises of cognitively healthy, educated, and multilingual individuals of both genders aged ≥45 years. The subjects are recruited from urban‐Bangalore, a large metropolitan city in southern India.MethodMRI measurements were conducted on 3T whole‐body‐scanner. MRI study performed close to the first clinical and cognitive‐examination is termed as baseline visit (V0), while MRI close to one‐year follow‐up is termed as V1. T2w‐FLAIR, 3D‐MPRAGE and DWI MRI were performed at both V0‐ and V1‐visits. WMH was quantified using T2w‐FLAIR and MPRAGE‐T1w images. Anatomical volumes were determined using Freesurfer. The volumes were normalized to the total‐intracranial‐volume. Changes in WMH and anatomic volume were calculated as (Volume at V1 – Volume at V0).ResultChanges in WMH and neuroanatomic volumes were evaluated for 128‐subjects who had MRI at both the visits, V0 and V1. Quantification of change in WMH (Delta‐WMH) in the TLSA‐subjects revealed that 65% of the subjects showed progression in WMH‐volume while another 35% did not show WMH‐progression. This indicated that there is a subset of cohorts that showed progression in WMH volume (+0.5‐7.9 ml) while another subset of subjects had no change in WMH over the period. Segmentation of neuroanatomical‐volume showed that the subset of the cohort that showed WNH‐progression over the one‐year period had significantly larger reduction in gray‐matter and increase in CSF volume at V1 compared to another subset that did not had changes in WMH.ConclusionProgression in WMH may be associated with increased vascular insult to the brain resulting in substantial gray‐matter loss and ventricular increase. Increase in WMH volume may fasten the neuroanatomic deteriorations with aging.

Elevated Aortic Pulse Wave Velocity Relates to Longitudinal Gray and White Matter Changes.

To determine whether baseline aortic stiffness, measured by aortic pulse wave velocity (PWV), relates to longitudinal cerebral gray or white matter changes among older adults. Baseline cardiac magnetic resonance imaging will be used to assess aortic PWV while brain magnetic resonance imaging will be used to assess gray matter and white matter hyperintensity (WMH) volumes at baseline, 18 months, 3 years, 5 years, and 7 years. Approach and Results: Aortic PWV (m/s) was quantified from cardiac magnetic resonance. Multimodal 3T brain magnetic resonance imaging included T1-weighted imaging for quantifying gray matter volumes and T2-weighted fluid-attenuated inversion recovery imaging for quantifying WMHs. Mixed-effects regression models related baseline aortic PWV to longitudinal gray matter volumes (total, frontal, parietal, temporal, occipital, hippocampal, and inferior lateral ventricle) and WMH volumes (total, frontal, parietal, temporal, and occipital) adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham stroke risk profile, APOE (apolipoprotein E)-ε4 carrier status, and intracranial volume. Two hundred seventy-eight participants (73±7 years, 58% male, 87% self-identified as non-Hispanic White, 159 with normal cognition, and 119 with mild cognitive impairment) from the Vanderbilt Memory & Aging Project (n=335) were followed on average for 4.9±1.6 years with PWV measurements occurring from September 2012 to November 2014 and longitudinal brain magnetic resonance imaging measurements occurring from September 2012 to June 2021. Higher baseline aortic PWV was related to greater decrease in hippocampal (β=-3.6 [mm3/y]/[m/s]; [95% CI, -7.2 to -0.02] P=0.049) and occipital lobe (β=-34.2 [mm3/y]/[m/s]; [95% CI, -67.8 to -0.55] P=0.046) gray matter volume over time. Higher baseline aortic PWV was related to greater increase in WMH volume over time in the temporal lobe (β=17.0 [mm3/y]/[m/s]; [95% CI, 7.2-26.9] P<0.001). All associations may be driven by outliers. In older adults, higher baseline aortic PWV related to greater decrease in gray matter volume and greater increase in WMHs over time. Because of unmet cerebral metabolic demands and microvascular remodeling, arterial stiffening may preferentially affect certain highly active brain regions like the temporal lobes. These same regions are affected early in the course of Alzheimer disease.

Consistency of associations of systolic and diastolic blood pressure with white matter hyperintensities: A meta-analysis.

BackgroundWhite matter hyperintensities are the commonest manifestation of cerebral small vessel disease, associated with stroke, functional impairment, and cognitive decline. They are commonly preceded by hypertension, but the magnitude and clinical importance of this association is unclear.AimsQuantify the relationship between blood pressure and white matter hyperintensities across studies.MethodsPubMed and EMBASE were searched for studies reporting associations between concurrent or historic blood pressure and white matter hyperintensities. Beta coefficients from linear models were extracted, whether standardized, unstandardized, unadjusted or adjusted for age, sex, and cardiovascular risk factors. Beta-coefficients were combined by fixed and random effects meta-analysis, combining standardized beta-coefficients or unstandardized coefficients measured by consistent methods.ResultsTwenty-five of 3230 papers were eligible, including 53,392 participants. Systolic blood pressure was significantly associated with white matter hyperintensity volume (WMHV) after maximal adjustment (standardized beta 0.096, 95%CI 0.06–0.133, p < 0.001, I2 = 65%), including for concurrent readings (b = 0.106, p < 0.001) or readings five years previously (b = 0.077, p < 0.001), and for younger or older populations (mean age < 65: b = 0.114; >65 b = 0.069). Unstandardized, adjusted associations were similar for raw WMHV, log-transformed WMHV, or WMHV as percentage of intracranial volume. Unadjusted associations with systolic blood pressure (SBP) were greater (standardized beta = 0.273, 0.262–0.284, p < 0.0001). However, while associations with DBP were weaker than SBP (standardized beta = 0.065, p < 0.001), they were minimally affected by adjustment for age.ConclusionsA standard deviation increase in SBP is associated with 10% of a standard deviation increase in WMHV, providing the current best estimate of the potential reduction in progression of white matter hyperintensities expected with good control of blood pressure.

Longitudinal Association between White Matter Hyperintensities and White Matter Beta-Amyloid Deposition in Cognitively Unimpaired Elderly.

White matter (WM) beta-amyloid uptake has been used as a reference region to calculate the cortical standard uptake value ratio (SUVr). However, white matter hyperintensities (WMH) may have an influence on WM beta-amyloid uptake. Our study aimed to investigate the associations between WMH and WM beta-amyloid deposition in cognitively unimpaired elderly. Data from 83 cognitively unimpaired individuals in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset were analyzed. All participants had complete baseline and four-year follow-up information about WMH volume, WM 18F-AV-45 SUVr, and cognitive function, including ADNI-Memory (ADNI-Mem) and ADNI-Executive function (ADNI-EF) scores. Cross-sectional and longitudinal linear regression analyses were used to determine the associations between WMH and WM SUVr and cognitive measures. Lower WM 18F-AV-45 SUVr at baseline was associated with younger age (β=0.01, P=0.037) and larger WMH volume (β=-0.049, P=0.048). The longitudinal analysis found an annual increase in WM 18F-AV-45 SUVr was associated with an annual decrease in WMH volume (β=-0.016, P=0.041). An annual decrease in the ADNI-Mem score was associated with an annual increase in WMH volume (β=-0.070, P=0.001), an annual decrease in WM 18F-AV-45 SUVr (β=0.559, P=0.030), and fewer years of education (β=0.011, P=0.044). There was no significant association between WM 18F-AV-45 SUVr and ADNI-EF (P>0.05). Reduced beta-amyloid deposition in WM was associated with higher WMH load and memory decline in cognitively unimpaired elderly. WMH volume should be considered when WM 18F-AV-45 SUVr is used as a reference for evaluating cortical 18F-AV-45 SUVr.

Abstract MP13: Polygenic Susceptibility to Atrial Fibrillation is Associated With Silent Cerebrovascular Disease in Stroke-Free Persons Without Atrial Fibrillation

Introduction: Clinically silent cerebrovascular disease is present in 40% of persons over the age of 60. We hypothesize that polygenic susceptibility to atrial fibrillation is associated with the burden of white matter disease in persons without atrial fibrillation or history of ischemic stroke. Methods: We conducted a nested genetic and neuroimaging study within the UK Biobank, a large cohort study that enrolled community dwelling Britons aged 40 to 65 at recruitment. We used data on a subcohort of patients evaluated with brain MRIs. The volume of white matter hyperintensities (WMH) was estimated using the BIANCA lesion segmentation tool. Genomic data was ascertained via genotyping with the Affymetrix UK Biobank Axiom array followed by imputation with 1000 Genomes reference panels. To model the polygenic susceptibility to atrial fibrillation (AFIB), we constructed a polygenic risk score (PRS) using 957 independent genetic risk variants known to significantly associate with atrial fibrillation. We used logistic and linear regression to test for association between the PRS and WMH. Results: A total of 38,914 study participants underwent brain MRI imaging in the UK Biobank. Of these, we excluded 124 (0.3%) with a history of stroke and 926 (2.4%) with AFIB. 37,864 study participants were included in this study, of which 19,059 (50.3%) had WMH. High genetic risk of AFIB was not associated with no-versus-any WMH (p=0.51). When evaluating persons with WMH lesions, high genetic risk of AFIB was associated with higher WMH volume (per 1 SD increase of the PRS, beta 0.019, SE 0.006; p=0.01). Gender was an important effect modifier of this association (interaction p=0.03): while high genetic risk of AFIB was associated with a significant increase in WMH volume in females (per 1 SD increase of the PRS, beta 0.03, SE 0.008; p&lt;0.001), no association was found for males (p=0.99). Conclusions: Polygenic susceptibility to atrial fibrillation is associated with more severe silent cerebrovascular disease in persons without atrial fibrillation. Further research should evaluate whether this genetic information can be used to identify persons for tailored diagnostic or therapeutic interventions.

Alzheimer-Related Cerebrovascular Disease in Down Syndrome.

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

Intracranial hemodynamic relationships in patients with cerebral small vessel disease.

ObjectiveTo investigate cerebrovascular reactivity (CVR), blood flow, vascular and CSF pulsatility, and their independent relationship with cerebral small vessel disease (SVD) features in patients with minor ischemic stroke and MRI evidence of SVD.MethodsWe recruited patients with minor ischemic stroke and assessed CVR using blood oxygen level–dependent MRI during a hypercapnic challenge, cerebral blood flow (CBF), vascular and CSF pulsatility using phase-contrast MRI, and structural magnetic resonance brain imaging to quantify white matter hyperintensities (WMHs) and perivascular spaces (PVSs). We used multiple regression to identify parameters associated with SVD features, controlling for patient characteristics.ResultsFifty-three of 60 patients completed the study with a full data set (age 68.0% ± 8.8 years, 74% male, 75% hypertensive). After controlling for age, sex, and systolic blood pressure, lower white matter CVR was associated with higher WMH volume (−0.01%/mm Hg per log10 increase in WMH volume, p = 0.02), basal ganglia PVS (−0.01%/mm Hg per point increase in the PVS score, p = 0.02), and higher venous pulsatility (superior sagittal sinus −0.03%/mm Hg, p = 0.02, per unit increase in the pulsatility index) but not with CBF (p = 0.58). Lower foramen magnum CSF stroke volume was associated with worse white matter CVR (0.04%/mm Hg per mL increase in stroke volume, p = 0.04) and more severe basal ganglia PVS (p = 0.09).ConclusionsLower CVR, higher venous pulsatility, and lower foramen magnum CSF stroke volume indicate that dynamic vascular dysfunctions underpin PVS dysfunction and WMH development. Further exploration of microvascular dysfunction and CSF dynamics may uncover new mechanisms and intervention targets to reduce SVD lesion development, cognitive decline, and stroke.

Effect of Low-Dose Statins and Apolipoprotein E Genotype on Cerebral Small Vessel Disease in Older Hypertensive Patients: A Subgroup Analysis of a Randomized Clinical Trial

ObjectivesTo investigate the effect of low-dose statins and apolipoprotein E (APOE) genotypes on cerebral small vessel disease (CSVD) to prevent CSVD in older hypertensive patients. DesignA subgroup analysis of a randomized clinical trial. SettingShandong area, China. ParticipantsHypertensive patients aged ≥60 years were recruited from April 2008 to November 2010. MeasurementsPatients were randomly assigned to rosuvastatin (10 mg/day) or placebo groups. APOE genotypes were categorized as ε4 carriers and non-ε4 carriers. White matter hyperintensities (WMH), Fazekas scale, lacunes, and microbleeds were assessed. ResultsAfter an average of intervention period of 61.8 months, WMH volume increased 1.45 ± 0.52 mL. There were 107 new-incident Fazekas scale ≥2, 65 new-incident lacunes, and 63 new-incident microbleeds. The increase in WMH volume was significantly lower in the rosuvastatin group than in the placebo group and was higher in APOE ε4 carriers than in non-ε4 carriers (all adjusted P < .001). The risk of new-incident Fazekas scale ≥2 was higher in the placebo group than in the rosuvastatin group (hazard ratio 2.150, 95% confidence interval 1.443–3.203; P < .001). APOE ε4 carriers were associated with an increased risk of new-incident Fazekas scale ≥2 compared with non-ε4 carriers (hazard ratio 1.973, 95% confidence interval 1.334−2.920; P = .001). There were no statistically significant differences in the risk of new-incident cerebral microbleeds between the rosuvastatin and placebo groups or between APOE ε4 carriers and non-ε4 carriers. There were no significant interactions between rosuvastatin use and APOE ε4 status regarding increased WMH volume (F = 1.020, P = .313) or for new-incident Fazekas scale ≥2 (P = .377), lacunes (P = .232), and microbleeds (P = .362). Conclusions/ImplicationsLow-dose rosuvastatin is an effective and safe therapy for CSVD. The presence of APOE ε4 allele may not be able to predict rosuvastatin treatment outcomes for preventing and/or treating CSVD in older hypertensive patients.

Progression of Cerebral White Matter Hyperintensities and the Associated Sonographic Index.

Purpose To evaluate the relationship between penetrating arterial pulsation and the progression of white matter hyperintensities (WMHs) by using the sonographic resistance index (RI) along the M1 segment of the middle cerebral artery (MCA). Materials and Methods The study design was approved by the institutional review board of Seoul National University Hospital. The study included 450 individuals who had undergone initial transcranial Doppler (TCD) sonography and magnetic resonance imaging, with follow-up imaging performed within 34-45 months, and who had no stenosis of 30% or more in the internal carotid artery or MCA or a history of stroke other than an old lacunar infarction. MRIR was defined as distal RI divided by proximal RI, where the distance between proximal MI and distal M1 was approximately 20 mm based on TCD evaluation. WMH progression was quantitatively evaluated by subtracting WMH volume at baseline from WMH volume at follow-up. Results At baseline, mean MRIR was 0.974 ± 0.045 (standard deviation), and mean WMH volume was 9.66 mL ± 14.54. After a mean of 38.3 months ± 3.4, the WMH volume change was 4.06 mL ± 7.35. WMH volume change was linearly associated with MRIR (r = 0.328, P < .001), along with the baseline WMH volume (r = 0.433, P < .001) and mean MCA pulsatility index (r = 0.275, P = .037). MRIR values greater than or equal to 1.000 were associated with a greater increase in WMH volume (P < .001). Conclusion MRIR might reflect the pulsation of penetrating arteries and is independently associated with WMH progression. © RSNA, 2017 Online supplemental material is available for this article.

Abstract 36: Association of Parental Stroke with Cognitive and Brain MRI Measures in Offspring - The Framingham Heart Study

Objectives- Parental stroke is related to an increased risk of stroke among the offspring. Vascular related brain changes, however, often occur before clinical stroke and the association of parental history of stroke and structural brain measures and cognition has not been fully explored. We hypothesized that prospectively verified parental stroke will be associated with increased vascular brain injury and poorer cognitive performance. Methods- A total of 1,297 Framingham offspring (mean age: 61 ± 9 years, 54% women) were studied. Of these, 9.9% had prospectively identified stroke in one or both parents before age 65. Volumetric brain MRI measures of total cerebral brain volume (TCBV), regional brain volumes, white matter hyperintensity volume (WMHV), and covert brain infarcts (CBI) and performance on tests of verbal memory, abstract reasoning, verbal learning and visuospatial memory (VRd) were compared for offspring with and without parental history of stroke. All measures were assessed cross-sectionally and longitudinally (mean duration of follow-up was 6.1±1.2 years). We used models adjusted only for age, sex, education and also additionally adjusted for vascular risk factors and for WMHV as an index of subclinical vascular brain injury. GEE models were used to adjust for sibling relationships among offspring. Results- Higher WMHV (β±SE=0.17±0.08;p=0.027) and lower VRd scores (β±SE=-0.80±0.34; p=0.017) at baseline were found in offspring with parental history of stroke. In addition, participants with parental stroke by age 65 years were more likely to be in the highest quintile of increase in WMHV (OR=1.87;p=0.04) as well as worsening executive function (Trails B-A) (OR:1.81;p=0.03). Parental stroke was not associated with total and regional brain volumes or with memory, abstract reasoning and verbal learning. Conclusions- In our community-based sample of middle-aged asymptomatic subjects, the occurrence of parental stroke by age 65 years is associated with higher baseline WMHV and with a more rapid increase in WMHV. Further, parental stroke is also associated with poorer performance on VRd and a decline in executive function. The effects on baseline WMH and VRd were substantial equivalent to 2.8 and 7 years of brain aging, respectively.

Brain atrophy and white matter hyperintensity change in older adults and relationship to blood pressure

Hypertension is a major risk factor for stroke and dementia and is associated with white matter hyperintensities (WMH) and reduced brain volumes. We measured the increase in WMH volume, and rate of cerebral atrophy over two years, in hypertensive subjects participating in the Study on COgnition and Prognosis in the Elderly (SCOPE), receiving candesartan or placebo, and normotensive controls. We recruited 163 subjects who had MRI (FLAIR and volumetric T1) at 2 and 4 years after baseline assessment. From these two scans, volumetric change in WMH (n = 133) and brain atrophy rates (n = 95) were determined. Total WMH fraction increased in both normotensive and treated hypertensive groups (p < 0.01) median change: 0.05% of brain volume [range: -0.45% to 1.51%]. Deep WMH increased in hypertensive (p = 0.001) but not the normotensive group. The number of subjects with an increase of total WMH in the 5(th) quintile differed between the treatment groups (chi square p = 0.006), being greatest in the placebo group (32%), then candesartan (20%) then normotensive (5%). Regression analysis found significant predictors of change in WMH to be blood pressure and initial deep WMH, but not treatment group. Increased atrophy rate was predicted by baseline systolic blood pressure (p = 0.02) but was not associated with measures of WMH. Similar to WMH, there was a trend with treatment, with atrophy in normotensive < Candesartan < Placebo (Spearman's rho = 0.23, p = 0.026). Hypertension in older people is associated with increased rates of progressive whole brain atrophy and an increase in WMH. These changes are independent. Successful hypertension treatment was associated with reduced risk of WMH progression and possibly brain atrophy.

Progression of White Matter Hyperintensities in Alzheimer Disease, Dementia With Lewy Bodies, and Parkinson Disease Dementia: A Comparison With Normal Aging

The objective of this study was to investigate cross-sectional and longitudinal white matter hyperintensity (WMH) changes in older subjects with clinically diagnosed dementia. Fluid-attenuated inversion recovery images were acquired one year apart in subjects with dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), Alzheimer disease (AD), and also healthy elderly comparison subjects. WMH volume was quantified using an automated technique. Baseline WMH (as a percent of brain volume) was significantly greater compared with healthy subjects (N=33, geometric mean WMH: 0.4%) in subjects with AD (N=23 [1.3%], analysis of variance post hoc p <0.001) but not PDD (N=13 [0.6%]) or DLB (N=14 [0.4%]). Increase in WMH volume (as a percent of brain volume) was not significantly different (Kruskal-Wallis p=0.4) between groups (AD median change: 0.08%; DLB: 0.025%; PDD: 0.07%, healthy: 0.02%). Severity of baseline WMH, rather than diagnosis or severity of dementia, was a significant predictor of lesion progression. Rate of change of WMH had no association with change in global cognitive performance. Significant WMH progression occurs in degenerative dementias with rates influenced by severity of lesions at baseline rather than dementia type or cognitive decline.

Longitudinal increase in the volume of white matter hyperintensities in late-onset depression.

Cerebrovascular disease is thought to play a role in the pathogenesis of geriatric major depression. One finding supporting such a "vascular depression" is the increased neuropathology in the form of white matter hyperintensities (WMH) found in patients diagnosed with a late-onset depression. However, at present there is little evidence that a longitudinal increase in WMH burden within an individual is associated with the onset of a late-life depression. This study examined three-year longitudinal change in WMH volume and in cognition in: (a) an older man who developed his first episode of major depression during the study period, and (b) a comparison group of twelve older individuals who remained depression free. All subjects received at baseline and three years later a structural magnetic resonance imaging (MRI) using fast-FLAIR technology. The images were analyzed with semi-automated computerized software to obtain WMH volumes. Subjects also received at both time points the Mini Mental State Exam (MMSE) as well a series of cognitive tasks assessing executive abilities (verbal fluency, Trail Making Test and Stroop test) since executive dysfunction is thought to be characteristic of a vascular depression. The individual who became depressed during the followup showed an increase in WMH volume that exceeded the 95% Confidence Intervals (CI) for change in the comparison group. This individual also showed a similar decline on the measures of executive function but not on the MMSE. These results are consistent with cerebrovascular disease being a factor in the pathogenesis of late-onset depression (i.e. "vascular depression").