Cerebral Small Vessel Disease Tied to Significant MCI Risk

Damian McNamara

January 17, 2019

The first study to examine cognitive changes over time in a solely hypertensive population shows that marked progression in periventricular white matter hyperintensities (WMHs) is tied to an increased risk of mild cognitive impairment (MCI).

Investigators at Vall d'Hebron Research Institute in Barcelona, Spain, found hypertensive patients who showed progression of these lesions had a sixfold increased risk of MCI.

MCI is a prodromal dementia stage, and so finding new markers associated with MCI diagnosis "is beneficial in the prediction and the characterization of the early stages of dementia," study investigator Joan Jiménez Balado, MSc, a PhD student at Vall D'Hebron, told Medscape Medical News.

The study was published online January 4 in Hypertension.  

Sustained Structural Damage?

Although the brain is routinely exposed to a high volume of blood flow, "it is very vulnerable to sustained high blood pressure levels," said Jiménez Balado.

Hypertension can adversely affect the anatomical structure of brain blood vessels in several ways. Over time, this sustained damage can compromise blood supply and reduce integrity of the blood-brain barrier. In turn, this can produce brain vascular lesions, including WMHs.

WMHs are important because, along with cerebral microbleeds and lacunar infarcts, hyperintensities are characteristic magnetic resonance imaging (MRI) markers of cerebral small vessel disease.

They can accumulate on brain parenchyma and have been associated with increased risk for cognitive impairment.  

To date, no research has assessed the importance of these markers in a strictly hypertensive population, the researchers note.

"[C]onsidering that hypertension is one of the principal risk factors for cognitive impairment and the progression of cerebral small vessel disease, this is an important gap in the literature," they write.

To learn more, the investigators studied 317 adults age 50 to 70 years with well-controlled hypertension. Participants had no history of dementia or stroke at baseline.

The average systolic blood pressure was 144.5 mm Hg and the average diastolic blood pressure was 76.5 mm Hg at follow-up. Almost all (94%) of the participants were taking antihypertensive medication.

Longitudinal Data

The investigators measured the prevalence of changes to periventricular WMHs, deep WMHs, incident infarcts and cerebral microbleeds over a mean 3.95 years of follow-up.

They also assessed cognition using the Dementia Rating Scale, 2nd version (DRS-2). Participants with suspected cognitive impairment at baseline underwent further workups consisting of cognitive, functional, and behavioral assessment, including neurologic and neuropsychological evaluation.

Raw DRS-2 scores were standardized into Z-scores. The investigators adjusted all models for DRS-2 Z-scores, cerebral small vessel disease markers, diastolic blood pressure at baseline, as well as age, sex, education level and follow-up time.

Three fourths of participants (75%) showed no signs of cognitive dysfunction at baseline or follow-up. Another 7% of those with baseline MCI reverted to a non-affected status at follow-up; 9% had stable MCI and 9% developed incident MCI during the study.

Baseline and average follow-up diastolic blood pressure positively correlated with the total attention and executive function DRS-2 Z-scores. In contrast, no association was observed between baseline or average systolic blood pressure and cognition at follow-up.

Patients with incident MCI showed a higher prevalence of baseline abdominal obesity (90%) compared to those without cognitive changes (67%) and those with MCI at baseline but not at follow-up (57%) (P = .032).

Diabetes mellitus and other vascular risk factors were not associated with changes in cognitive status.

In terms of markers of progression of cerebral small vessel disease, the prevalence of incident infarcts was 6%; incident cerebral microbleeds 6%, progression of periventricular WMHs 22%; and progression of deep WMHs 48%.

Cognitive Decline

Participants with marked progression of periventricular WMHs showed a significant decrease in global cognition compared to those without progression (adjusted mean, -0.519; standard error, 0.176 vs adjusted mean 0.057; standard error 0.044, respectively; P = .004). These participants also were more likely to develop incident MCI (odds ratio [OR] 6.184, 95% confidence interval [CI], 1.506 - 25.370; P = .011).

Incident cerebral microbleeds were associated with a decline in the attention Z-score (β = -0.473; 95% CI, -0.945 to -0.001; P = .049). Significant differences did not emerge regarding other cognitive functions, however.

The researchers found no association between incidental infarcts and cognitive changes.

The proportion of participants converting from unaffected at baseline to incident MCI at follow-up was 9% and is "relatively similar" to other reports in the literature, the researchers write. For example, another community-based study showed almost 14% of participants developed new onset MCI over 6 years of follow-up.

Other research also supports the current observation that periventricular WMHs changes predict cognitive decline, the researchers note. For example, in a study published in 2006, progression of periventricular WMHs was associated with decreases in executive function and information processing speed.

Given the high prevalence of hypertension, it would be impractical to screen the general population for cognitive risk using a series of MRI studies, Jiménez Balado said.

MRI "certainly has a high economic cost and may not be feasible to apply as a systematic evaluation in patients with hypertension. Therefore, it would be very interesting to find new clinical variables or biological markers which could help to detect the progression of brain vascular changes," he noted.

Serial cognitive evaluations, blood pressure metrics, blood protein assays, or genetic testing may someday play a role in patient assessment, he added.

"We plan to find surrogate markers of the progression of these brain vascular changes in order to screen which patients are at risk of cognitive impairment," said Jiménez Balado. "Besides, these markers may also represent good therapeutic targets as modifiable risk factors in preventive actions."

Identifying Risk

Commenting on the findings for Medscape Medical News, Keenan Walker, PhD, of the Department of Neurology at Johns Hopkins University School of Medicine in Baltimore, Maryland, said the study is important and provides "further support for the importance of clinically silent cerebrovascular disease in the progression of cognitive decline and the development of mild cognitive impairment."

"This study is unique because it looks at a cohort of participants with hypertension, a condition which is both highly prevalent among adults and known to be associated with an increased risk of later dementia when present during midlife," said Walker, lead author of a review article examining the link between hypertension, cognitive decline, and dementia.

"Importantly, the findings of this study suggest that while not all adults with hypertension show signs of cerebral small vessel disease, many do, and those who show significant progression in periventricular white matter hyperintensities, in particular, are more likely to have accompanying cognitive decline."

Jiménez Balado and Walker have disclosed no relevant financial relationships. The research was funded by the Instituto de Salud Carlos III, with the support of the Secretary of Universities and Research of the Department of Economy and Knowledge (Generalitat de Catalunya) and co-financed by the European Regional Development Fund. The neurovascular research lab receives funds from the Spanish research stroke network.

Hypertension. Published online January 4, 2019. Abstract

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