Background and objectives

Perivascular spaces (PVS) visible on MRI scans may represent key aspects in the pathophysiology of stroke and dementia, including cerebral small vessel disease and glymphatic dysfunction. This study aimed to determine the association between MRI-visible PVS burden and the risk of incident dementia.

Methods

This study included community-dwelling Framingham Heart Study Original and Offspring cohort participants with available brain MRI-PVS ratings, free of stroke and dementia. Multivariable Cox proportional hazard regression was used to obtain hazard ratios (HRs) and 95% CIs of the association between MRI-visible PVS and incident dementia. PVS were rated using validated methods in the basal ganglia (BG) and centrum semiovale (CSO). The outcomes included all-cause dementia, Alzheimer dementia (AD), and vascular dementia (VaD).

Results

One thousand four hundred forty-nine participants 50 years or older (46% male) were included. Over a median follow-up period of 8.3 years, the incidence of all-cause dementia, AD, and VaD was 15.8%, 12.5%, and 2.5%, respectively. In models that adjusted for vascular risk factors and cardiovascular disease, the hazard for dementia increased steadily as PVS burden increased, rising 2-fold for those with grade II PVS (HR 2.44, 95% CI 1.51-3.93) to 5-fold in participants with grade IV (HR 5.05, 95% CI 2.75-9.26) compared with grade I PVS in CSO. In the BG, hazards increased 1.6-fold (HR 1.62, 95% CI 1.15-2.27) for grade II to 2.6-fold (HR 2.67, 95% CI 1.04-6.88) for grade IV compared with grade I PVS. The association remained significant for CSO but not for BG, after adjustment for white matter hyperintensity volume (WMHV), covert infarcts, and total brain volume. Similar findings were observed for AD, but VaD, limited by a small number of events, was not statistically significant.

Discussion

Higher burden of PVS in CSO was associated with increased risk of developing dementia, independent of vascular risk factors, total brain volume, WMHVs, and covert infarcts. This finding supports a role for PVS as a subclinical MRI marker to identify individuals in subclinical stages at high risk of developing dementia who may benefit from early intervention.

Background and purpose

Lacunar stroke (LS) and intracerebral hemorrhage (ICH) are 2 diverse manifestations of small vessel disease. What predisposes some patients to ischemic stroke and others to hemorrhage is not well understood.

Methods

We performed a nested case-control study within the FHS (Framingham Heart Study) comparing people with incident ICH and lacunar ischemic stroke, to age- and sex-matched controls for baseline prevalence and levels of cardiovascular risk factors.

Results

We identified 118 LS (mean age 74 years, 51% male) and 108 ICH (75 years, 46% male) events. Hypertension, diabetes mellitus, smoking, and obesity were strongly associated with LS. Hypertension, but not diabetes mellitus, smoking, or cholesterol levels increased the odds of ICH. Contrary to LS, ICH cases had lower body mass index (BMI) than their controls (26 versus 27); BMI <20 was associated with 4-fold higher odds for ICH. In direct comparison, LS cases had higher BMI (28 versus 26) and obesity prevalence (odds ratio, 3.1); BMI <20 was associated with significantly lower odds of LS (odds ratio, 0.1).

Conclusions

LS and ICH share hypertension, but not diabetes mellitus, as a common risk factor. ICH cases had lower BMI compared with not only LS but their controls as well; this finding is unexplained and merits further exploration.

The duration and lifetime pattern of hypertension is related to risk of stroke and dementia. In turn, cerebral small vessel disease (CSVD) is the most frequent form of cerebrovascular disease underlying dementia and stroke. Thus, study of the relation of mid to late life hypertension trends with CSVD late in life will help understand hypertension's role and inform preventive efforts of CSVD consequences. We studied 1686 Framingham Heart Study Offspring cohort participants free of stroke and dementia, who were examined in mid and late life, and had available brain magnetic resonance imaging during late life. We related hypertension trends between mid and late life (normotension-normotension N-N, normotension-hypertension N-H, hypertension-hypertension H-H) to cerebral microbleeds and covert brain infarcts (CBI), overall and stratified by brain topography. We used multivariable logistic regression analyses to calculate odds ratio and 95% CIs for CSVD measures. The prevalence of CSVD in late life was 8% for cerebral microbleeds and 13% for covert brain infarcts and increased with longer hypertension exposure across all brain regions. Compared with the trend pattern of N-N, both N-H and H-H trends had higher odds of mixed cerebral microbleeds (2.71 [1.08-6.80], and 3.44 [1.39-8.60], respectively); H-H also had higher odds of any cerebral microbleeds or covert brain infarcts (1.54 [1.12-2.20]), and any covert brain infarcts (1.55 [1.08-2.20]). The burden of CSVD also increased with longer hypertension exposure. Our results highlight hypertension having a major role in subclinical CSVD, across subtypes and brain regions, and call attention to improve recognition and treatment of hypertension early in life.

Higher plasma total-tau level is associated with incident dementia, but its relationship with stroke risk is unknown. In this prospective community-based study, we evaluated plasma total-tau level as a biomarker of stroke risk in 2,794 Framingham Heart Study participants. Persons with plasma total-tau levels in the top quintile, versus the bottom 4, had an increased risk of incident stroke over a mean follow-up of 8.3 years (hazard ratio = 2.01; 95% confidence interval = 1.32-3.08) following adjustments for age, sex, and stroke risk factors. Our findings demonstrate that plasma total-tau relates to the risk of stroke in a community sample. ANN NEUROL 2019;86:463-467.

Background and purpose

Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB.

Methods

We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [APOE]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed).

Results

CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (P<0.0001) and was higher in men (P<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (P<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (P<0.05). Statin use increased risk of lobar and mixed location CMB (P<0.05). The latter association was not affected by adjustment for cholesterol levels or concomitant medication use.

Conclusions

We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.

Objective

To test the hypothesis that reduced slow-wave sleep, or N3 sleep, which is thought to underlie the restorative functions of sleep, is associated with MRI markers of brain aging, we evaluated this relationship in the community-based Framingham Heart Study Offspring cohort using polysomnography and brain MRI.

Methods

We studied 492 participants (age 58.8 ± 8.8 years, 49.4% male) free of neurological diseases who completed a brain MRI scan and in-home overnight polysomnography to assess slow-wave sleep (absolute duration and percentage of total sleep). Volumes of total brain, total cortical, frontal cortical, subcortical gray matter, hippocampus, and white matter hyperintensities were investigated as a percentage of intracranial volume, and the presence of covert brain infarcts was evaluated. Linear and logistic regression models were adjusted for age, age squared, sex, time interval between polysomnography and MRI (3.3 ± 1.0 years), APOE ε4 carrier status, stroke risk factors, sleeping pill use, body mass index, and depression.

Results

Less slow-wave sleep was associated with lower cortical brain volume (absolute duration, β [standard error] = 0.20 [0.08], p = 0.015; percentage, 0.16 [0.08], p = 0.044), lower subcortical brain volume (percentage, 0.03 [0.02], p = 0.034), and higher white matter hyperintensities volume (absolute duration, -0.12 [0.05], p = 0.010; percentage, -0.10 [0.04], p = 0.033). Slow-wave sleep duration was not associated with hippocampal volume or the presence of covert brain infarcts.

Conclusion

Loss of slow-wave sleep might facilitate accelerated brain aging, as evidence by its association with MRI markers suggestive of brain atrophy and injury. Alternatively, subtle injuries and accelerated aging might reduce the ability of the brain to produce slow-wave sleep.

Perivascular spaces (PVS) visible on brain MRI signal cerebral small vessel disease (CSVD). The coexistence of PVS with other CSVD manifestations likely increases the risk of adverse neurological outcomes. We related PVS to other CSVD manifestations and brain volumes that are markers of vascular brain injury and neurodegeneration. Framingham Heart Study (FHS) participants with CSVD ratings on brain MRI were included. PVS were rated in the basal ganglia (BG) and centrum semiovale (CSO) into grades I-IV and a category reflecting high burden in single or mixed CSO-BG regions. We related PVS to covert brain infarcts (CBI), white matter hyperintensities (WMH), cerebral microbleeds (CMB), total brain, hippocampal, and cortical gray matter volumes using adjusted multivariable regression analyses. In 2454 participants (mean age 54 ± 12 years), we observed that higher PVS burden in both BG and CSO was related to CMB in lobar and deep brain regions and increased WMH. Greater CSO PVS burden was associated with decreased total cortical gray volumes. PVS are associated with ischemic markers of CSVD and neurodegeneration markers. Further studies should elucidate the causality between PVS and other CSVD manifestations.

Introduction

The Boston criteria are the basis for a noninvasive diagnosis of cerebral amyloid angiopathy (CAA) in the setting of lobar intracerebral hemorrhage (ICH). We assessed the accuracy of these criteria in individuals with lobar microbleeds (MBs) without ICH.

Methods

We identified individuals aged >55 years having brain magnetic resonance imaging (MRI) and pathological assessment of CAA in a single academic hospital and a community-based population (Framingham Heart Study [FHS]). We determined the positive predictive value (PPV) of the Boston criteria for CAA in both cohorts, using lobar MBs as the only hemorrhagic lesion to fulfill the criteria.

Results

We included 102 individuals: 55 from the hospital-based cohort and 47 from FHS (mean age at MRI 74.7 ± 8.5 and 83.4 ± 10.9 years; CAA prevalence 60% and 46.8%; cases with any lobar MB 49% and 21.3%; and cases with ≥2 strictly lobar MBs 29.1% and 8.5%, respectively). PPV of "probable CAA" (≥2 strictly lobar MBs) was 87.5% (95% confidence interval [CI], 60.4-97.8) and 25% (95% CI, 13.2-78) in hospital and general populations, respectively.

Discussion

Strictly lobar MBs strongly predict CAA in non-ICH individuals when found in a hospital context. However, their diagnostic accuracy in the general population appears limited.

Objective

We investigated differences in the anatomical distribution of cerebral microbleeds (CMBs) on MRI, hypothesized to indicate the type of underlying cerebral small vessel disease (SVD), between Eastern and Western general populations.

Methods

We analyzed data from 11 studies identified by a PubMed search between 1996 and April 2014 according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data. Study quality measures indicated low or medium risk of bias. We included stroke-free participants from populations aged between 55 and 75 years, categorized by geographic location (Eastern or Western). We categorized CMB distribution (strictly lobar, deep and/or infratentorial [D/I], or mixed [i.e., CMBs located in both lobar and D/I regions]). We tested the hypothesis that Eastern and Western populations have different anatomical distributions of CMBs using multivariable mixed effects logistic regression analyses adjusted for age, sex, and hypertension and clustering by institution.

Results

Among 8,595 stroke-free individuals (mean age [SD] 66.7 [5.6] years; 48% male; 42% from a Western population), 624 (7.3%) had CMBs (strictly lobar in 3.1%; D/I or mixed in 4.2%). In multivariable mixed effects models, Eastern populations had higher odds of D/I or mixed CMBs (adjusted odds ratio 2.78, 95% confidence interval [CI] 1.77-4.35) compared to Western populations. Eastern populations had a higher number of D/I or mixed CMBs (adjusted prevalence ratio 2.83, 95% CI 1.27-6.31).

Conclusions

Eastern and Western general populations have different anatomical distributions of CMBs, suggesting differences in the spectrum of predominant underlying SVDs, with potential implications for SVD diagnosis and treatment.

Introduction

Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease.

Methods

Surveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis.

Results

A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository.

Conclusions

The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.