Neurovascular Unit Dysfunction and Cerebral Small Vessel Disease in Parkinson Disease: A Systematic Review and a Meta Analysis

Clinical Snapshot

Key Findings

• P Value: Not explicitly reported but confidence intervals exclude null

• Effect Size: SMD 0.36 for WMH volume, SMD 0.27 for global WMH visual rating

• Primary Outcome: White matter hyperintensity burden significantly higher in PD patients

• Nnt Or Sensitivity: Midbrain ePVS showed largest effect size (SMD 1.80, 95% CI 0.15-3.44)

• Confidence Interval: 95% CI 0.11-0.62 for WMH volume, 95% CI 0.08-0.46 for global WMH

Clinical Application

Requires MRI imaging capabilities and expertise in CSVD assessment Relevant to Australian neurologists and movement disorder specialists; MRI accessible through Medicare for PD patients; aligns with RACGP guidelines for neurological assessment Adults with idiopathic Parkinson disease in neurological practice

Abstract

BACKGROUND AND OBJECTIVES: Parkinson disease (PD) pathogenesis remains incompletely understood; beyond nigrostriatal loss, nondopaminergic mechanisms including neurovascular unit dysfunction may contribute to disability. Cerebral small vessel disease (CSVD) burden reflects neurovascular dysfunction in the form of white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMB), and enlarged perivascular spaces (ePVS). In PD cohorts, CSVD burden correlates with worse motor and gait scores. The aim of the study was to explore whether patients with PD exhibit greater CSVD burden than healthy controls (HC). METHODS: We conducted a PRISMA-conformant systematic review and meta-analysis of studies including adults with idiopathic PD and a HC group that presented data comparing CSVD burden in these 2 groups. Six databases (MEDLINE, Embase, CINAHL Plus, CENTRAL, Scopus, and Web of Science) were searched on May 14 and 15, 2024. Two reviewers independently screened records, extracted data, and assessed risk of bias, with discrepancies resolved by consensus. Continuous outcomes were pooled as standardized mean differences (SMD); dichotomous outcomes as odds ratios (ORs). We evaluated small-study effects for pooled analyses with 10 or more studies using funnel plots and Egger regression test. RESULTS: We examined 13,403 records. Forty-six studies (45 cross-sectional) met inclusion criteria, totaling 3,817 PD and 2,593 HC (mean ages: 66.9 and 66.5, respectively). WMH volume (k = 21) was higher in PD (SMD 0.36, 95% CI 0.11-0.62). Visual ratings also indicated higher WMH in PD: global (k = 14) SMD 0.27 (95% CI 0.08-0.46); periventricular (k = 11) SMD 0.32 (95% CI 0.12-0.51); deep (k = 8) SMD 0.20 (95% CI 0.09-0.31). Differences in CMB (k = 6; OR 1.18, 95% CI 0.57-2.42) and lacunes (k = 4; OR 1.48, 95% CI 0.58-3.78) were not significant. ePVS results were heterogeneous but trended toward greater burden in PD, most notably in the midbrain (k = 3; SMD 1.80, 0.15-3.44). Overall evidence quality was rated as low, reflecting the observational nature of the included studies. DISCUSSION: Our analysis showed PD to be associated with greater WMH burden and increased midbrain ePVS. Pooled differences in CMB and lacunes were not significant. Substantial heterogeneity and cross-sectional designs limit certainty; standardized imaging and prospective cohorts are needed to define mechanisms and clinical implications.

References

1. 1.Del Papa, D. F., Herman, J., Kunju, A. T., Najafi, T., O'Boyle, R., Salama, A., Hneiny, L., Samarakoon, T., Peabody, T., Marmol, S., Feldman, M., & Haq, I. U. (2026). Neurovascular unit dysfunction and cerebral small vessel disease in Parkinson disease: A systematic review and a meta analysis. Neurology. https://doi.org/10.1212/WNL.0000000000214873