Association between enlarged perivascular spaces and cerebrospinal fluid aquaporin-4 and tau levels: report from a memory clinic

Sacchi, Luca; Arcaro, Marina; Carandini, Tiziana; Pietroboni, Anna M.; Fumagalli, Giorgio; Fenoglio, Chiara; Serpente, María; Sorrentino, Federica; Visconte, Caterina; Pintus, Maria Cristina; Conte, Giorgio; Contarino, Valeria Elisa; Scarpini, Elio; Triulzi, Fabio; Galimberti, Daniela; Arighi, Andrea

doi:10.3389/fnagi.2023.1191714

Cited by 5 publications

(1 citation statement)

References 29 publications

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“… 4 Although the pathophysiology of the enlargement of PVS is still not fully understood, it has been shown to be associated with a higher level of aquaporin‐4, breakdown of the blood–brain barrier (BBB), cerebral amyloid angiopathy (CAA), hypertension, and small vessel disease (SVD). 5 , 6 , 7 , 8 , 9 We hypothesized an impaired drainage could be a potential cause of enlarged PVS due to fluid residue and stasis. The enlargement of PVS might further decrease the CSF flow due to more fluid away from the vessel wall and fluid accumulation.…”

Section: Introductionmentioning

confidence: 99%

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET

Zhou,

Nguyen,

Chiang

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONMapping of microscopic changes in the perivascular space (PVS) of the cerebral cortex, beyond magnetic resonance‐visible PVS in white matter, may enhance our ability to diagnose Alzheimer's disease (AD) early.METHODSWe used the cerebrospinal fluid (CSF) water fraction (CSFF), a magnetic resonance imaging–based biomarker, to characterize brain parenchymal CSF water, reflecting microscopic PVS in parenchyma. We measured CSFF and amyloid beta (Aβ) using 11C Pittsburgh compound B positron emission tomography to investigate their relationship at both the subject and voxel levels.RESULTSOur research has demonstrated a positive correlation between the parenchymal CSFF, a non‐invasive imaging biomarker indicative of parenchymal glymphatic clearance, and Aβ deposition, observed at both individual and voxel‐based assessments in the posterior cingulate cortex.DISCUSSIONThis study shows that an increased parenchymal CSFF is associated with Aβ deposition, suggesting that CSFF could serve as a biomarker for brain glymphatic clearance, which can be used to detect early fluid changes in PVS predisposing individuals to the development of AD.Highlights Cerebrospinal fluid fraction (CSFF) could be a biomarker of parenchymal perivascular space. CSFF is positively associated with amyloid beta (Aβ) deposition at subject level. CSFF in an Aβ+ region is higher than in an Aβ– region in the posterior cingulate cortex. Correspondence is found between Aβ deposition and glymphatic clearance deficits measured by CSFF.

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Section: Introductionmentioning

confidence: 99%

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET

Zhou,

Nguyen,

Chiang

et al. 2024

Alzheimer's & Dementia

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A “glympse” into neurodegeneration: Diffusion MRI and cerebrospinal fluid aquaporin‐4 for the assessment of glymphatic system in Alzheimer's disease and other dementias

Sacchi,

D'Agata,

Campisi

et al. 2024

Human Brain Mapping

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The glymphatic system (GS) is a whole‐brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non‐invasive methods based on magnetic resonance imaging (MRI) along with aquaporin‐4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi‐shell diffusion‐weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF‐AQP4. CSF‐AQP4 levels and MRI measures—including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW‐WM) and mean kurtosis (MK‐WM), diffusion tensor imaging analysis along the perivascular spaces (DTI‐ALPS) (mean, left and right)—were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF‐AQP4 (exp(b) = 2.05, p = .005) and FW‐WM FW‐WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF‐AQP4 and FW‐WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK‐WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF‐AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage.

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Lifetime history of head injury is associated with reduced perivascular space number in acute mild traumatic brain injury

Garcia,

Brolly,

et al. 2024

Brain Communications

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Traumatic brain injury impairs function of the glymphatic system, a perivascular network involved in waste clearance. Enlarged perivascular spaces visible on MRI are an emerging biomarker of glymphatic function. This study characterized enlarged perivascular spaces in acute head injury with 7-Tesla MRI. Healthy controls (n=8) and patients (n=11) with mild traumatic brain injury underwent MRI within 7 days of injury and were evaluated for lifetime history of head injury, neurobehavioral symptoms, and sleep disturbances. MRI-visible perivascular spaces were quantified and assessed according to published criteria. The number of enlarged perivascular spaces was significantly higher in traumatic brain injury patients than controls (P = .015). Among healthy controls, 6/8 scored “none” or “mild” on the perivascular space rating scale, while 10/11 patients scored “moderate”, “frequent”, or “severe.” There was an inverse relationship between perivascular space number and number of lifetime head injuries. Patients with more prior head injuries exhibited fewer enlarged perivascular spaces (P = .014). These results indicate that mild head injury results in acute alterations in perivascular space number, and this effect is mediated by previous head injury history. Enlarged perivascular spaces may reflect a glymphatic response that is diminished after multiple head injuries, although this will require further study.

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Association between enlarged perivascular spaces and cerebrospinal fluid aquaporin-4 and tau levels: report from a memory clinic

Cited by 5 publications

References 29 publications

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET

A “glympse” into neurodegeneration: Diffusion MRI and cerebrospinal fluid aquaporin‐4 for the assessment of glymphatic system in Alzheimer's disease and other dementias

Lifetime history of head injury is associated with reduced perivascular space number in acute mild traumatic brain injury

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