Association of Baseline Cerebrovascular Reactivity and Development of Enlarged Perivascular Spaces in the Basal Ganglia, 2023, Libecap et al.

[SNT Gatchaman]

Now published - link here
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Preprint
Association of Baseline Cerebrovascular Reactivity and Development of Enlarged Perivascular Spaces in the Basal Ganglia
Timothy J Libecap; Christopher E Bauer; Valentinos Zachariou; Colleen A Pappas; Flavius D Raslau; Peiying Liu; Hanzhang Lu; Brian T Gold

Background:
Increasing evidence suggests that enlarged perivascular spaces (ePVS) are associated with cognitive dysfunction in aging. However, the etiology of ePVS remains unknown. Here we tested the possibility that baseline cerebrovascular dysfunction, as measured by an MRI measure of cerebrovascular reactivity (CVR), contributes to the later development of ePVS.

Methods:
A total of 79 cognitively normal, older adults (46 women, age range 60-84) were recruited to undergo MRI scanning at baseline and 50 participants returned for a follow-up scan approximately 2.5 years later. ePVS were counted in the basal ganglia, centrum semiovale, midbrain, and hippocampus. CVR, an index of the vasodilatory capacity of cerebral small vessels, was assessed using carbon-dioxide inhalation while acquiring blood oxygen-level dependent (BOLD) MR images.

Results:
Low baseline CVR values in the basal ganglia were associated with increased follow-up ePVS counts in the basal ganglia after controlling for age, sex, and baseline ePVS values (coefficient estimate (SE) = -15.87 (3.92), p < 0.001, 95% confidence interval [CI] -23.68 to -8.05). This effect remained significant after accounting for self-reported risk factors of cerebral small vessel disease (cSVD) (coefficient estimate (SE) = -15.03 (4.00), p < 0.001, CI -23.02 to -7.05) and neuroimaging markers of cSVD (coefficient estimate (SE) = -13.99 (4.02), p < 0.001, CI -22.03 to -5.95).

Conclusions:
Our results demonstrate that low baseline CVR is a risk factor for later development of ePVS. MRI-based CVR may represent a promising biomarker of cSVD.

Link | PDF (Preprint: MedRxiv)

 

[SNT Gatchaman]

Perivascular spaces (PVS) are pial-lined, fluid-filled spaces surrounding penetrating brain arteries . PVS are integral to neuroimmune function and clearance of metabolites via the brain’s glymphatic system as the site of interchange between interstitial fluid (ISF) and cerebrospinal fluid (CSF). Enlarged perivascular spaces (ePVS) can be detected as dilated PVS on magnetic resonance imaging (MRI). While originally considered a benign radiological finding, increasing evidence suggests that ePVS may represent microvascular dysfunction and impaired ISF-CSF interchange.

Functionally-based cerebrovascular dysfunction could represent a contributing factor to structural PVS enlargement. For instance, reduced vascular compliance could disrupt ISF-CSF interchange and impair waste clearance. The reduced clearance of brain waste could in turn promote PVS enlargement.

Testing this possibility requires a valid measure of cerebrovascular compliance. Recently, a blood oxygen-level dependent (BOLD)-fMRI cerebrovascular reactivity (CVR) method has been developed and validated as a measure of cerebrovascular compliance. [...] Specifically, participants’ cerebrovascular response to an inscanner hypercapnia challenge is measured by dividing the percent change in BOLD-fMRI signal by the change in end-tidal CO2 (mmHg) between normal room air breathing and hypercapnic air breathing.

ePVS were differentiated from cerebral microbleeds (CMBs) by their absence of prominent associated blooming artifact on QSM [Quantitative Susceptibility Mapping].

Whole brain white matter hyperintensity (WMH) volumes were computed for use as a control variable in our models testing if CVR predicts change in ePVS after controlling for neuroimaging cSVD [cerebral Small Vessel Disease] variables.

 

[SNT Gatchaman]

High intra-rater reliability was achieved for ePVS counts (ICC = 0.9) on a subset of 20 randomly selected participants. The mean follow-up time between the baseline and follow-up scan was 2.56 years (SD = 0.16 years).

Two additional models were conducted to determine the impact of including additional cSVD [cerebral Small Vessel Disease] covariates on the significance of the CVR-ePVS basal ganglia models. Model 2 accounted for participant-reported cSVD risk factors including hypertension status, type 2 diabetes status, and body mass index (BMI).

Model 3 further accounted for several known cSVD neuroimaging markers: lacunes, CMBs [Cerebral Microbleeds], and log-transformed whole brain WMH [white matter hyperintensity] volume. Results indicated that CVR remained a significant predictor of increased ePVS counts in the basal ganglia over time after controlling for participant-reported cSVD risk factors

Our results showed that lower CVR values in the basal ganglia at baseline predicted a longitudinal increase in ePVS counts in the basal ganglia over a 2.5-year follow-up period. This finding supports a view that cerebrovascular dysfunction contributes to the development of ePVS in the basal ganglia.

Importantly, the relationship we observed between CVR and ePVS could not be accounted for by other commonly studied markers of cSVD.

Together, these results indicate that cerebrovascular compliance in the basal ganglia, as measured by BOLD-CVR, contributes to the subsequent development of ePVS in the basal ganglia.

 

[SNT Gatchaman]

One pathway through which reduced cerebrovascular compliance may lead to increased ePVS burden relates to glymphatic waste removal. The functional measure of cerebrovascular reactivity (BOLD-CVR) is an indicator of cerebrovascular compliance and reserve capacity. Diminished cerebrovascular compliance and reduced reserve capacity may impair vasomotion and pulsatility, which are required for effective glymphatic waste elimination [...] Reduced glymphatic waste removal may in turn lead to accumulation within the PVS and increased ePVS burden.

 

[SNT Gatchaman]

Published as —

Association of Baseline Cerebrovascular Reactivity and Longitudinal Development of Enlarged Perivascular Spaces in the Basal Ganglia (2023)
T.J. Libecap; Christopher E. Bauer; Valentinos Zachariou; Colleen A. Pappas; Flavius D. Raslau; Peiying Liu; Hanzhang Lu; Brian T. Gold

BACKGROUND
Increasing evidence suggests that enlarged perivascular spaces (ePVS) are associated with cognitive dysfunction in aging. However, the pathogenesis of ePVS remains unknown. Here, we tested the possibility that baseline cerebrovascular dysfunction, as measured by a magnetic resonance imaging measure of cerebrovascular reactivity, contributes to the later development of ePVS.

METHODS
Fifty cognitively unimpaired, older adults (31 women; age range, 60–84 years) underwent magnetic resonance imaging scanning at baseline and follow-up separated by ≈2.5 years. ePVS were counted in the basal ganglia, centrum semiovale, midbrain, and hippocampus. Cerebrovascular reactivity, an index of the vasodilatory capacity of cerebral small vessels, was assessed using carbon dioxide inhalation while acquiring blood oxygen level-dependent magnetic resonance images.

RESULTS
Low baseline cerebrovascular reactivity values in the basal ganglia were associated with increased follow-up ePVS counts in the basal ganglia after controlling for age, sex, and baseline ePVS values (estimate [SE]=−3.18 [0.96]; P=0.002; [95% CI, −5.11 to −1.24]). This effect remained significant after accounting for self-reported risk factors of cerebral small vessel disease (estimate [SE]=−3.10 [1.00]; P=0.003; [CI, −5.11 to −1.09]) and neuroimaging markers of cerebral small vessel disease (estimate [SE]=−2.72 [0.99]; P=0.009; [CI, −4.71 to −0.73]).

CONCLUSIONS
Our results demonstrate that low baseline cerebrovascular reactivity is a risk factor for later development of ePVS.

Link | PDF (Stroke)