EPVS burden a potential marker of CSVD, AD-related pathology

A study from Singapore reports the potential of enlarged perivascular space (EPVS) burden as a marker of cerebral small vessel disease (CSVD) and Alzheimer’s disease (AD)-related blood-based biomarker (BBM) pathology.

The BBMs quantified include β-amyloid (Aβ) oligomers Aβ42 and Aβ40, phosphorylated tau 181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Key MRI CSVD markers include EPVS, white matter hyperintensities (WMH), lacunes, and microbleeds. [Front Neurol 2020;11:927]

“EPVS remains relatively underexplored. Given its potential role in dementia pathophysiology, additional investigation into EPVS is essential to better understand its contribution to neurodegenerative processes,” the researchers said.

Elevated EPVS burden positively correlated with NfL (ρ=0.169; p<0.005), GFAP (ρ=0.166; p<0.005), and p-tau181 (ρ=0.087; p<0.005), and negatively with Aβ42/40 ratio (ρ=-0.077; p<0.05), grey matter/total intracranial volume (GM/TIV; ρ=-0.100; p<0.005), and WM/TIV (ρ=-0.161; p<0.005). [Neurology 2025;105:e213836]

According to the investigators, the elevated NfL and GFAP levels likely reflect astrocytic activation and axonal injury secondary to vascular dysfunction, local inflammation, and accumulation of toxic metabolites tied to PVS enlargement.

Among the CSVD markers, EPVS had the strongest association with Aβ pathology in participants with mild cognitive impairment, which was retained in the final regression model (odds ratio, 1.877; p=0.035), whereas the associations with WMH and other CSVD markers were not.

“This finding carries substantial clinical implications. Although WMH is more widely used in clinical practice due to its recognizability and substantial literature base, our results suggest that EPVS may hold unique prognostic value in detecting AD pathology at the prodromal stage … EPVS quantification could provide complementary information for risk stratification and clinical decision making,” the researchers explained.

Improved detection, management strategies warranted

Approximately 80 million individuals are estimated to have dementia by 2030, which could increase to around 140 million by 2050. [https://www.who.int/news-room/fact-sheets/detail/dementia, accessed December 15, 2025] “Asia is expected to bear a disproportionate share of new cases because of rapid demographic ageing,” the researchers said.

“This growing crisis underscores the urgent need for improved early detection and management strategies, with neuroimaging biomarkers emerging as promising, cost-effective tools for clinical diagnosis and risk stratification,” they continued.

A total of 979 community-dwelling participants (mean age 58.2 years, 60.7 percent women) from the Biomarkers and Cognition Study, Singapore, were included in the analysis. Most participants had low EPVS burden (Staals 0; n=748), whereas the remainder had high EPVS burden (Staals 1; n=231).

“Given that MRI is a routine component of the diagnostic workup for cognitive impairment, our findings underscore the potential utility of EPVS as an early, cost-effective imaging biomarker for AD,” the investigators said.

The results highlight EPVS as a more beneficial alternative to WMH, which remains the most studied CSVD marker in AD diagnostics, as the former appears earlier in the course of CSVD and exhibits domain-specific effects on cognition. [Nat Rev Neurol 2020;16:137-153; Neurology 2022;99:e1414-e1421; Neurology 2022;99:e1791-e1802]

“Identifying high EPVS load … may enable healthcare providers to implement regular monitoring and encourage patients to be proactive about their cognitive health by taking preventative steps before marked symptom deterioration,” the researchers said.

Incorporating WMH and EPVS ratings into standard MRI protocols may facilitate concurrent review of complementary neuroimaging data, thus streamlining the diagnostic process for prodromal and clinical AD, they added. “This could help triage further targeted cognitive and biochemical testing. This cost-effective approach reduces the need for expensive biomarker testing and extensive neuropsychological assessments, making it particularly beneficial in hospital settings with limited resources.”

The investigators recommended evaluating causal relationships between EPVS, AD biomarkers, and cognitive decline. “Further investigation into the mechanistic pathways linking EPVS burden to glymphatic dysfunction and neurodegeneration may clarify EPVS’s role as an imaging biomarker for prodromal AD.”