Familial Microvascular Traits and Neuropsychiatric Factors Reflected in Brain Perivascular Space Morphometry

Highlight

• Brain perivascular spaces (PVS) morphometry on MRI reflects familial microvascular architecture independent of hypertension and aging.
• PVS burden correlates with neuropsychiatric factors including depressive symptoms and physiological stress indicated by hair cortisol levels.
• Weaker muscle strength is linked to distinct PVS morphometric changes, particularly in the centrum semiovale region.
• PVS morphometric parameters may serve as accessible neuroimaging markers of cerebral microvascular health, integrating genetic and environmental influences.

Study Background

Brain perivascular spaces (PVS), also known as Virchow-Robin spaces, are fluid-filled compartments surrounding cerebral small vessels that play a pivotal role in cerebral microvascular function and glymphatic clearance of metabolic waste. Enlarged PVS visible on conventional magnetic resonance imaging (MRI) have been increasingly recognized as imaging markers of cerebral small vessel disease (SVD) and have been associated with aging, hypertension, and cognitive decline. However, the extent to which PVS morphometric characteristics reflect inherited familial microvascular traits rather than solely individual vascular risk factors remains unclear.

Understanding the relationship between PVS morphology and familial microvascular architecture could advance the use of PVS as biomarkers that integrate genetic, physiological, and neuropsychiatric contributors to cerebral vascular health. Furthermore, neuropsychiatric conditions such as depression and physiological stress might influence or be influenced by cerebral microvascular health, as reflected in PVS alterations. This interplay could enhance the understanding of microvascular contributions to neuropsychiatric disorders.

Study Design

The present study analyzed data from 1183 participants enrolled in the Stratifying Depression and Resilience Longitudinally (STRADL) cohort, a family-based population sample with detailed neuroimaging and clinical phenotyping. Among these, 324 individuals had first-degree relatives also participating, facilitating investigation of familial clustering.

MRI scans underwent automated segmentation to quantify PVS characteristics including volume, count, density, and median length within anatomically distinct regions: the centrum semiovale and basal ganglia. The study applied linear mixed-effects models to examine associations between PVS morphometry and age, hypertension status, measures of physiological stress as assessed by hair cortisol concentration, depressive symptom scores, and hand grip strength, while accounting for familial clustering effects.

Key Findings

Analysis included 1050 participants (59.5% female, mean age 59.3 ± 10.1 years). Principal findings were:

1. Age and PVS burden: PVS volume, expressed as a percentage of the region of interest (ROI), increased significantly with advancing age (centrum semiovale and basal ganglia combined; β=0.18; 95% CI, 0.11–0.26; P<0.0001), consistent with prior literature linking aging to cerebrovascular changes.

2. Familial clustering: Significant familial clustering was observed for PVS volume (β=0.22; 95% CI, 0.096–0.52; P=0.013) and median length (β=0.28; 95% CI, 0.16–0.49; P=0.0003), supporting the concept that PVS morphometry captures shared inherited microvascular phenotypes beyond conventional vascular risk factors.

3. Neuropsychiatric influences: Current depressive symptoms correlated positively with PVS density in both regions (centrum semiovale β=0.092, P=0.009; basal ganglia β=0.11, P=0.002), relationships which largely persisted after false discovery rate correction. Additionally, higher hair cortisol—a biomarker of chronic physiological stress—was marginally associated with increased PVS count (β=0.08; P=0.041), although this association approached, but did not robustly surpass, multiple comparison correction thresholds.

4. Muscle strength: Weaker hand grip strength was associated with lower PVS volume percentage in the centrum semiovale (β=-0.09; P=0.013), indicating an inverse relationship between neuromuscular function and perivascular space enlargement, a novel finding warranting further exploration.

5. Hypertension: Interestingly, hypertension did not show significant association with PVS morphometric indices in the multivariable models, highlighting that familial and neuropsychiatric factors may contribute independently to PVS burden.

Expert Commentary

This study provides compelling evidence that PVS morphometry captures complex cerebral microvascular features influenced by familial genetic architecture and modulated by neuropsychiatric and physiological factors. The robust familial clustering suggests that PVS traits may represent heritable microvascular phenotypes, possibly reflecting shared genetic influences on vessel integrity, blood-brain barrier function, or glymphatic clearance efficiency.

The observed associations with depressive symptoms and hair cortisol highlight the bidirectional interface between brain vascular health and neuropsychiatric states, potentially mediated by neuroinflammation, endothelial dysfunction, or altered cerebrovascular reactivity. The inverse link with grip strength suggests systemic physiological reserve and muscle function might also intersect with cerebral microvascular status.

These findings extend the utility of PVS morphometry beyond traditional cerebrovascular risk profiling, suggesting it could serve as a multidimensional biomarker for brain health integrating genetic predisposition and environmental/psychological influences. Nevertheless, causality cannot be inferred given the cross-sectional design. Longitudinal studies are warranted to detail temporal dynamics and mechanistic pathways.

Moreover, replication in ethnically diverse cohorts and exploration of molecular genetic correlates could enhance generalizability and biological understanding. Potential confounders such as medication use, comorbidities, and lifestyle factors should be considered in future studies.

Conclusion

Brain PVS morphometry as measured by automated MRI segmentation reflects shared familial microvascular architecture and is associated with neuropsychiatric factors independently of hypertension and age. These results underscore the role of inherited microvascular phenotypes and the impact of physiological stress and depressive symptoms on cerebral small vessel compartments.

PVS morphometric measures hold promise as noninvasive neuroimaging biomarkers for cerebral microvascular health, offering insights into genetic and neuropsychiatric contributions to brain vascular aging and disease. Incorporating PVS analysis into clinical and research neuroimaging protocols may facilitate improved risk stratification and personalized therapeutic approaches targeting cerebral microvascular dysfunction.

Funding and Clinical Trials

The original study was supported by institutional and research grants related to neurological and psychiatric disorders, though no specific funding source was detailed in the abstract. The STRADL cohort is a family-based longitudinal study aimed at dissecting depression and resilience mechanisms.

References

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