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. 2021 Mar:99:28-43.
doi: 10.1016/j.neurobiolaging.2020.12.010. Epub 2020 Dec 16.

Volumetric distribution of perivascular space in relation to mild cognitive impairment

Farshid Sepehrband  1 , Giuseppe Barisano  2 , Nasim Sheikh-Bahaei  3 , Jeiran Choupan  4 , Ryan P Cabeen  5 , Kirsten M Lynch  5 , Malcolm S Crawford  6 , Haoyu Lan  5 , Wendy J Mack  7 , Helena C Chui  8 , John M Ringman  8 , Arthur W Toga  9 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Volumetric distribution of perivascular space in relation to mild cognitive impairment

Farshid Sepehrband et al. Neurobiol Aging. 2021 Mar.

Abstract

Vascular contributions to early cognitive decline are increasingly recognized, prompting further investigation into the nature of related changes in perivascular spaces (PVS). Using magnetic resonance imaging, we show that, compared to a cognitively normal sample, individuals with early cognitive dysfunction have altered PVS presence and distribution, irrespective of Amyloid-β. Surprisingly, we noted lower PVS presence in the anterosuperior medial temporal lobe (asMTL) (1.29 times lower PVS volume fraction in cognitively impaired individuals, p < 0.0001), which was associated with entorhinal neurofibrillary tau tangle deposition (beta (standard error) = -0.98 (0.4); p = 0.014), one of the hallmarks of early Alzheimer's disease pathology. We also observed higher PVS volume fraction in centrum semi-ovale of the white matter, but only in female participants (1.47 times higher PVS volume fraction in cognitively impaired individuals, p = 0.0011). We also observed PVS changes in participants with history of hypertension (higher in the white matter and lower in the asMTL). Our results suggest that anatomically specific alteration of the PVS is an early neuroimaging feature of cognitive impairment in aging adults, which is differentially manifested in female.

Keywords: Alzheimer’s disease; Clearance system; Cognitive decline; Perivascular space.

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Conflict of interest statement

Disclosure statement

Authors have no conflict of interest to declare.

Verification

Authors have no any actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence (bias) their work.

None of the authors has contracts relating to this research through which it or any other organization may stand to gain financially now or in the future.

None of the authors has other agreements of authors or their institutions that could be seen as involving a financial interest in this work.

Figures

Figure 1.
Figure 1.. Maps of the perivascular space (PVS)
in cognitively normal (CN: n=424) and mild cognitively impaired (MCI: n=173) participants of Alzheimer’s Disease Neuroimaging Initiative 3 (ADNI-3). Normative maps of PVS across CN and MCI are presented, which were obtained by averaging PVS maps across the group (presenting percentage of overlapping PVS content across group). Overall, a higher amount of PVS was observed in global white matter and specifically in the centrum semi-ovale (CSO-WM) region of the MCI participants. Surprisingly, in the MCI group, a lower amount of PVS was observed in anterosuperior medial temporal lobe white matter. As comparison references, total standardized uptake value ratio (SUVR) of cerebral Aβ, and Tau PET SUVR in the regions associated with Braak stage 1 (i.e. entorhinal cortex) were included. D and p values are Cohen’s d (effect size) and p-value of the group differences, measured using estimation statistics.
Figure 2.
Figure 2.. PVS volume fraction in anterosuperior medial temporal lobe (asMTL) was significantly lower in mild cognitive impairment (MCI) participants compared to cognitively normal (CN).
A 3D render of the asMTL on template space is presented in (a). Bilateral and significant PVS volume fraction differences between CN and MCI participants were observed in asMTL (b and c). Unpaired Cohen’s d effect size and confident intervals were reported (d [CI]) for the group differences between CN and MCI using estimation statistics (Ho et al., 2019). Two-sided p-value of Mann-Whitney test was also reported. The PVS volume fraction in asMTL was asymmetrical across both CN and MCI groups (e); mean and standard errors are shown. Diagnostic group comparison on PVS volume fraction across the centrum semi-ovale of the white matter (CSO-WM) is shown in (d). (f-h) plots compare PVS volume fraction of the asMTL (f-g) and CSO-WM (h) when study participants were categorized based on clinical dementia rating (CDR).
Figure 3.
Figure 3.. PVS volume fraction was associated with early AD pathology.
Studied regions of interest are shown in (a). PVS volume fraction of the anterosuperior medial temporal lobe (asMTL) was a predictor of Tau uptake (AV1451 PET Tau SUVR) in entorhinal cortex (ERC) (b) (right asMTL: p=0.01, left asMTL: p=0.07, corrected for age, sex, education and brain size), in contrast with PVS volume fraction of the centrum semi-ovale of the white matter (CSO-WM) (p=0.4) (e). A non-significant correlation between PVS volume fraction of asMTL and Tau uptake in ERC and parahippocampal cortex (PHC) was observed (c-d). Participants with lower PVS volume fraction in asMTL appeared to have higher amount of Tau in ERC. The correlation between asMTL PVS volume fraction and Tau SUVR was highest in regions involved in early AD pathology (i.e. ERC as per Braak stage I), and the association was weaker for PHC (f). The association analysis was performed in a subset of the population including participants with both Tau PET and MRI data (n=319; n(CN)=240, n(MCI)=79).
Figure 4.
Figure 4.. PVS volume fraction of the anterosuperior medial temporal lobe (asMTL) and centrum semi-ovale of the white matter (CSO-WM) were not associated with the amyloid beta uptake, as measured by positron emission tomography.
Aβ−/+ categorization was applied based on Florbetapir cortical summary measurement (SUVR). Florbetapir cutoff of 1.11 using the whole cerebellum region as a reference. Equivalent statistical conclusions were drawn when we used a cutoff of 0.79 in a composite reference region including cerebellum, brainstem/pons, and eroded subcortical white matter. Linear regression analysis using Aβ SUVR also showed no association between Aβ uptake and PVS volume fraction (p=0.61). When regional values of Aβ SUVR were used (instead of global SUVR), no associations were observed (p>0.6 for all tests).
Figure 5.
Figure 5.. PVS volume fraction of the anterosuperior medial temporal lobe (asMTL) and centrum semi-ovale of the white matter (CSO-WM) were not associated with APOE ε4 allele repeats.
Participants were categorized based on the number of APOE ε4 allele repeats.
Figure 6.
Figure 6.. History of hypertension and respiration rate are differentially associated with the PVS volume fraction.
First row: respiratory rate (number of breaths per minute) is negatively associated with PVS volume fraction in anterosuperior medial temporal lobe (asMTL), but not associated with PVS volume fraction in centrum semi-ovale of the white matter (CSO-WM). Second row: Participants with history of hypertension had significantly higher PVS volume fraction in CSO-WM; PVS volume fraction in asMTL was lower in participants with history of hypertension (but not significant after correcting for covariates).
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