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Advanced Neurology Covert cerebral small vessel disease

prevalent in elderly populations and healthy community- made in exploring alternative non-imaging biomarkers for
dwelling adults with vascular risk factors. The prevalence covert CSVD.
of silent lacunar infarcts and microbleeds varies between Identifying patients with asymptomatic CSVD presents
8% – 20% and 3% – 15%, respectively, and it has been a significant challenge that requires the development and
estimated that approximately 20% of those over 60 years validation of both imaging and non-imaging biomarkers.
old exhibit lacunes. WMHs of varying severity are more While brain MRI biomarkers are considered the gold
prevalent and age-dependent, affecting 85% – 95% of standard, alternative biomarkers must be established to
the elderly population and 40% – 65% of hypertensive help identify higher-risk individuals in the community
patients. Consequently, the burden of covert CSVD in the who may benefit from brain imaging. Among the
community is high, which is likely to impact the future promising biomarkers investigated to date are ambulatory
prevalence of clinically relevant neurological sequelae, blood pressure measurement, brain-specific blood-based
including stroke, cognitive decline, dementia, and gait biomarkers, quantitative EEG, retinal microvascular
and balance disturbance. A considerable proportion assessments, carotid ultrasonography, and neurocognitive
of ischemic strokes and about half of all dementias are studies. 4,14-19 Individuals exhibiting altered non-imaging
attributed to CSVD. Therefore, timely identification of biomarkers could subsequently be referred for brain MRI
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covert CSVD would assist in early detection, which may evaluation.
help reduce long-term progression and the burden of overt
neurological manifestations. Strategies for the early identification of covert CSVD may
vary across different age groups, as the prevalence increases
Several vascular risk factors contribute to the
development of CSVD. The predominant factors associated significantly with age. For screening purposes, younger
individuals (under 50 – 60 years) should be prioritized. Key
with CSVD risk include age, hypertension, type 2 diabetes, indicators for concern include the severity and quantity of
hyperlipidemia, and smoking. In addition, other vascular risk factors, which may already be affecting brain
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conditions, such as sleep apnea, atrial fibrillation and other health. Non-imaging biomarkers could aid in determining
heart conditions, chronic kidney disease, and chronic the need for a brain MRI in these cases. In contrast, elderly
obstructive pulmonary disease significantly influence individuals typically exhibit a higher physiological burden
the pathogenesis of CSVD. 9,10 In a recent meta-analysis of CSVD, with most presenting vascular risk factors. The
involving 13,000 individuals across 221 studies, Zhou et al. primary challenge here is to determine any unrecognized
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emphasized that CSVD is frequently detected in patients clinical manifestations of CSVD, which often present
with different heart conditions, such as atrial fibrillation, as subtle neurocognitive, language, and gait issues. The
coronary artery disease, heart failure or cardiomyopathy, selection of appropriate biomarkers is important. Future
and heart valve disease, regardless of prior stroke history. investigations in younger populations could help identify
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It is essential to consider the common underlying causes the most effective biomarkers, while in elderly individuals;
from which these vascular risk factors originate. The a greater emphasis should be placed on neurocognitive
relationship between cardiac dysfunction and clinical or studies, which have been underexplored as potential
subclinical brain disease is primarily associated with shared biomarkers in CSVD.
cardiovascular risk factors that may lead to endothelial
dysfunction in both the heart and brain. This dysfunction Despite ongoing investigations into non-imaging
can subsequently lead to impaired microcirculation and biomarkers, no validated biomarkers currently exist that
BBB function. 10 can effectively predict CSVD. This gap arises from several
challenges that must be addressed moving forward. Most
The significance of CSVD in asymptomatic healthy
populations remains a highly controversial issue. One studies involve single-center, small-sized cohorts, with
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considerable variability between studies regarding cohort
pertaining question is whether asymptomatic individuals features (age, geographical region, type, and stage of
should be screened for covert CSVD. Currently, there is disease), imaging protocols, and classification standards for
insufficient scientific evidence supporting the benefits of
screening asymptomatic individuals in terms of reducing brain MRI lesions, assay reliability, and analytical models.
adverse health events or demonstrating cost-effectiveness. Our group mainly focused on blood-based biomarkers,
High-quality longitudinal studies are needed to address suggesting that brain-derived proteins may offer promising
this gap. Considering the limited evidence, the statement perspectives for predicting CSVD burden in asymptomatic
published by the AHA/ASA in 2017 suggested that individuals. Blood levels of these brain-derived proteins
screening for covert CSVD in asymptomatic individuals are more specific indicators of brain damage compared
is not warranted. Since then, no substantial evidence has to peripheral biomarkers and have garnered increasing
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emerged to change this stance; however, progress has been attention over the past two decades. 4,20

Volume 4 Issue 4 (2025) 50 doi: 10.36922/an.4841