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Advanced Neurology Covert cerebral small vessel disease

with statins should be implemented for covert CSVD. Although the LACI-2 trial was conducted in
Nonetheless, statins possess additional pharmacological clinical lacunar stroke patients, these promising
effects, exhibiting direct endothelial and anti-inflammatory results could help in designing future trials not only
properties, which may benefit CSVD. The ESO guidelines for symptomatic lacunar stroke but also for treating
recommended the use of statins, given that covert CSVD covert CSVD using endothelial-active drugs such as
is associated with an increased risk of vascular events and ISMN and cilostazol. There is extensive experience with
that lipid-lowering has been proven beneficial in primary both drugs for the treatment of ischemic heart disease,
prevention. 12 peripheral vascular disease, or secondary prevention of
atherothromboembolic stroke. Moreover, they are widely
The pathogenesis of CSVD fundamentally differs
from that of other stroke etiologies. It is characterized by available and inexpensive. This combination could be
perforating arteriolar disorder with dysfunction of the small tested in covert CSVD to delay cognitive decline and
vessel endothelium, which compromises blood supply to prevent other adverse outcomes in patients with a higher
subcortical tissues. Therefore, treatments should target the disease burden. The findings from the LACI-2 trial
underlying pathogenic mechanisms and be investigated in also support the repurposing of existing drugs and the
well-characterized CSVD cohorts. The efficacy of drugs development of new molecular candidates to improve
designed to stabilize endothelial function on long-term endothelial function.
clinical, cognitive, and functional consequences of CSVD Shortly thereafter, an international group of experts
requires evaluation. Recently, endothelial-stabilizing drugs convened under the auspices of the International Society
such as isosorbide mononitrate (ISMN), a nitric oxide (NO) of Vascular Behavioral and Cognitive Disorders proposed
donor, and cilostazol, a phosphodiesterase-3 inhibitor a framework for designing clinical trials in CSVD, known
that augment the NO-cyclic guanosine monophosphate as FINESSE. This group developed recommendations
phosphodiesterase PDE5-inhibitor and the prostacyclin- that included several key aspects: optimal choice of study
cyclic adenosine monophosphate pathways, were populations, clinical endpoints, the use of brain imaging
investigated in the Lacunar Intervention Trial-2 (LACI-2). as a surrogate outcome measure, the incorporation of
This trial demonstrated feasibility and safety, suggesting circulating biomarkers for participant selection and as
that this drug combination may reduce recurrent stroke, surrogate markers, novel trial designs, and prioritization of
dependence, and cognitive impairment following lacunar therapeutic agents using genetic data through Mendelian
ischemic stroke, warranting further testing in large phase randomization. The main goal was to unify efforts to attain
III trials. 45 sufficiently powered high-quality randomized clinical

Figure 2. Schematic representation of the framework for community-based management strategies for covert cerebral small vessel disease.
Abbreviations: ABPM: Ambulatory blood pressure monitoring; CSVD: Cerebral small vessel disease; EEG: Electroencephalography; GFAP: Glial fibrillary
acidic protein; HR: High resolution; MRI: Magnetic resonance imaging; NFL: Neurofilament light chain; NR2ab: Autoantibodies against the NR2 peptide
of the NMDA receptor; NSE: Neuron-specific enolase, S100B: S100B protein, UCHL1: Ubiquitin C-terminal hydrolase-L1.

Volume 4 Issue 4 (2025) 53 doi: 10.36922/an.4841