Association of MRI Indices of Glymphatic System With Amyloid Deposition and Cognition in Mild Cognitive Impairment and Alzheimer Disease

Abstract

Background and Objectives:The glymphatic system is a whole-brain perivascular network, which promotes CSF/interstitial fluid exchange. Alterations to this system may play a pivotal role in amyloid β (Aβ) accumulation. However, its involvement in Alzheimer’s disease (AD) pathogenesis is not fully understood. Here, we investigated the changes in noninvasive MRI measurements related to the perivascular network in patients with mild cognitive impairment (MCI) and AD. Additionally, we explored the associations of MRI measures with neuropsychological score, PET standardized uptake value ratio (SUVR), and Aβ deposition.Methods:MRI measures, including perivascular space (PVS) volume fraction (PVSVF), fractional volume of free water in white matter (FW-WM), and index of diffusivity along the perivascular space (ALPS index) of patients with MCI, those with AD, and healthy controls from the Alzheimer’s Disease Neuroimaging Initiative database were compared. MRI measures were also correlated with the levels of CSF biomarkers, PET SUVR, and cognitive score in the combined subcohort of patients with MCI and AD. Statistical analyses were performed with age, sex, years of education, and APOE status as confounding factors.Results:In total, 36 patients with AD, 44 patients with MCI, and 31 healthy controls were analyzed. Patients with AD had significantly higher total, WM, and basal ganglia PVSVF (Cohen’s d = 1.15-1.48; p < 0.001), and FW-WM (Cohen’s d = 0.73; p < 0.05) and a lower ALPS index (Cohen’s d = 0.63; p < 0.05) than healthy controls. Meanwhile, the MCI group only showed significantly higher total (Cohen’s d = 0.99; p < 0.05) and WM (Cohen’s d = 0.91; p < 0.05) PVSVF. Low ALPS index was associated with lower CSF Aβ42 (rs = 0.41, pfdr = 0.026), FDG-PET uptake (rs = 0.54, pfdr < 0.001), and worse multiple cognitive domain deficits. High FW-WM was also associated with lower CSF Aβ42 (rs = −0.47, pfdr = 0.021) and worse cognitive performances.Conclusion:Our study indicates that changes in PVS-related MRI parameters occur in MCI and AD, possibly due to impairment of the glymphatic system. We also report the associations between MRI parameters and Aβ deposition, neuronal change, and cognitive impairment in AD.

Reduced glymphatic function after traumatic brain injury measured using diffusion MRI

“…As shown in Figure 1 , because the direction of PVS is orthogonal to projection and association white matter fiber tracks, axial diffusion at high b-value (to suppress intravascular venous flow) is uniquely sensitive to perivenous flow. 12, 13 Decreased glymphatic function was very recently demonstrated using this method in subjects with AD 14 and TBI. 15 Here we apply DTI-ALPS to assessing glymphatic function in subacute TBI and in relation to blood levels of neurofilament light protein (NFL) – a robust biomarker of TBI severity.…”

A critical guide to the automated quantification of perivascular spaces in magnetic resonance imaging

“…In disease, abnormal PVS measures have been observed in patients with depression, COVID-19, traumatic brain injury, Multiple Sclerosis (MS), Parkinson's disease (PD), mild cognitive impairment (MCI), and Alzheimer's disease (AD) (Table 2; Cai et al, 2015;Ramirez et al, 2015Ramirez et al, , 2016Ramirez et al, , 2022Niazi et al, 2018;Donahue et al, 2021Donahue et al, , 2022George et al, 2021;Piantino et al, 2021;Sepehrband et al, 2021;Shen et al, 2021;Kamagata et al, 2022;Langan et al, 2022;Ranti et al, 2022). Significant higher PVS counts, but not volumes, have been found in COVID-19 patients, compared to controls (Langan et al, 2022).…”

“…Furthermore, patients diagnosed with mild cognitive impairment (MCI) appear to have a higher WM-PVS volume fraction compared to controls (Niazi et al, 2018;Kamagata et al, 2022). However, no associations between PVS-VF, in either the WM or BG, were observed with hippocampal volumes, CSF levels of Aβ42, or neuropsychological scores (Kamagata et al, 2022). In contrast, reduced WM-PVS volume fraction in the antero-superior medial temporal lobe has been observed in MCI patients compared to controls (Sepehrband et al, 2021).…”

“…In AD, both greater WM-PVS volume fractions and greater BG-PVS volumes have been observed in patients compared to age-matched controls (Cai et al, 2015;Ramirez et al, 2015;Kamagata et al, 2022). The enlargement of PVS has been widely implicated in a number of neurodegenerative diseases, exclusively in cross-sectional studies.…”

“…Ramirez et al, 2015Berezuk et al, 2015Cai et al, 2015Zong et al, 2016Wang et al, 2016Niazi et al, 2018Piantino et al, 2020Ballerini et al, 2020aBallerini et al, 2020bValdés Hernández et al, 2020Zong et al, 2020Barisano et al, 2021bSepehrband et al, 2021 Ramirez et al, 2021Shen et al, 2021George et al, 2021Piantino et al, 2021Donahue et al, 2021 Langan et al, 2022Ranti et al, 2022Lynch et al, 2022, Preprint Barisano et al, 2022bHupfeld et al, 2022Barnes et al, 2022Kamagata et al, 2022Donahue et al, 2022Ramirez et al, 2022Jokinen et al, 2020Zong et al, 2020Wang et al, 2021Huang et al, 2021 Spijkerman et al, 2022 PVS measures can be broadly categorized as quantitative metrics (volume, count, and volume fractions), and morphological metrics (length, width, solidity, and tortuosity). Listed first are the methods that utlize classical image filtering technique.…”