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Advanced Neurology Covert cerebral small vessel disease

3. Brain-specific blood-based biomarkers summarizes the studies conducted to date associating
CSVD burden with circulating brain-specific protein levels
A significant increase has been observed in the in neurologically asymptomatic cohorts. To the best of our
measurement of various brain-specific proteins to evaluate knowledge, the first report was published by Gonzalez-
the degree of central nervous system (CNS) injury across Quevedo et al., a small pilot study evaluating the association
33
multiple acute neurological conditions, including stroke, of NSE and S100B with neuroimaging findings of CSVD
traumatic brain injury, cardiac arrest, cardiac surgery, heat in asymptomatic hypertensive subjects. Following this,
33
stroke, electroconvulsive therapy, and COVID-19. These several studies have measured blood-based brain-specific
biomarkers are used for differential diagnosis, monitoring proteins, adding other biomarkers to the list, including
disease progression, and predicting neurological UCHL1, NFLC, NR2ab, and amyloid beta. 34-43 GFAP,
outcomes. 21-29 The rationale for measuring these proteins an astrocyte marker extensively studied in neurological
in the blood is based on two factors: (i) the BBB is often diseases, has yet to be evaluated in asymptomatic CSVD.
compromised in many CNS diseases, allowing brain-
specific proteins to be released from injured neural cells Numerous studies have investigated systemic or
to enter the bloodstream and (ii) the development of more peripheral blood biomarkers related to CSVD, focusing
sensitive techniques that enabled the detection of these on inflammatory markers, endothelial dysfunction,
15
low-concentration brain cell-specific molecules in blood cardiovascular indicators, and oxidative stress. While
samples. Recently, interest has grown in these biomarkers these markers may assist clinicians in assessing the risk of
for assessing sustained, low-grade CNS injury, particularly potential CNS impairment in susceptible individuals, their
15
in asymptomatic CSVD and in athletes experiencing non-specific nature can lead to misleading information due
repetitive subconcussive events in sports such as soccer, to contamination by systemic vascular and inflammatory
ice hockey, and American football. 30 processes. In contrast, brain-derived proteins and their
autoantibodies provide a more reliable indication of brain
CSVD arises from subtle and prolonged injury to impairment, reflecting the neurochemical manifestations
brain parenchyma over decades due to aging, arterial of chronic, sustained, and low-grade brain damage
hypertension, diabetes mellitus, and other vascular risk associated with asymptomatic CSVD.
factors. The main pathological changes associated with
CSVD include endothelial dysfunction, BBB breakdown, Undoubtedly, there is an urgent need for future research
inflammation, and arteriolosclerosis. These changes into the development and validation of biomarkers in this
facilitate a slow and continuous release of cytosolic promising field, which could enhance primary prevention
and membrane proteins from damaged brain cells and efforts and improve management strategies, ultimately
the neurovascular unit into the interstitial fluid and reducing morbidity and mortality related to CSVD. To
cerebrospinal fluid, eventually reaching the bloodstream. achieve this, it is crucial to replicate existing results and
Among the most promising biomarkers investigated to establish more homogenous study designs. A major
date are neuron-specific enolase (NSE), glial fibrillary concern is the variability among different cohorts in
acidic protein (GFAP), S100B protein, ubiquitin which sample sizes are often inconsistent. Some of these
C-terminal hydrolase-L1 (UCHL1), neurofilament light studies were conducted within population-based surveys
chain (NFLC), amyloid beta peptide and autoantibodies of elderly individuals, while others focused on hospital
against the NR2 peptide of the glutamatergic N-methyl cohorts or asymptomatic individuals with vascular-related
4,20
D-aspartate receptor (NR2ab). The CNS parenchyma risk factors without age limits.
expresses many antigens that are either absent or present Considering the widespread prevalence of covert CSVD
in negligible amounts in other tissues or exist as unique and its serious consequences, rigorous and organized
isoforms not found outside the nervous system. These research into non-imaging biomarkers remains a critical
brain-derived products in the circulation can trigger a challenge that should be actively pursued. Such efforts
systemic adaptive immune response involving B and T could lower screening costs for higher-risk populations
lymphocytes that may not recognize them as self-antigens, and offer more accessible options, particularly in low- and
potentially leading to an autoimmune response. These middle-income countries where brain MRI may not be
autoantibodies could serve as a more enduring signature readily available.
during chronic stages of cerebral injury compared to their
corresponding antigens. 31,32 4. Management and treatment of covert
CSVD
Blood measurements of these proteins and
autoantibodies have been associated with the neuroimaging Following the identification of covert CSVD, clinicians
burden of CSVD in asymptomatic individuals. Figure 1 face the ordeal of determining how to proceed with

Volume 4 Issue 4 (2025) 51 doi: 10.36922/an.4841