Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease: a population-based study

Tian, Yu; Cai, Xueli; Zhou, Yijun; Jin, Aoming; Wang, Suying; Yang, Yingying; Mei, Lin; Jing, Jing; Li, Shan; Meng, Xia; Wei, Tiemin; Liu, Tao; Wang, Yongjun; Pan, Yuesong; Wang, Yilong

doi:10.1136/svn-2022-002191

Cited by 30 publications

(12 citation statements)

References 46 publications

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“…In this study, we found that a novel magnetic resonance marker of PVS function (DTI-ALPS) predicted both dementia and cognitive decline over a 5-year follow-up period in patients with CSVD. Many previous studies have shown associations between DTI-ALPS and cognition in CSVD, but these have been largely cross-sectional, 20,30,31 with few longitudinal studies, 21 and cannot determine whether PVS diffusion, as measured on DTI-ALPS, causally contributes to CSVD progression. Our data, demonstrating its predictive ability for dementia over a 5-year follow-up, support a potential causal role in cognitive impairment in CSVD.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown DTI-ALPS changes in patients with a variety of neurological diseases, including Alzheimer disease, 17 Parkinson disease, 34 and traumatic brain injury. 35 Many cross-sectional studies have also implicated glymphatic dysfunction assessed by DTI-ALPS in patients with CSVD 18,20 and vascular risk factors 19 and have reported associations with the severity of cognitive impairment in both CSVD and vascular cognitive impairment 30,31 and Alzheimer disease. 36 However, few studies have determined whether DTI-ALPS changes predict future cognitive decline and dementia.…”

Section: Discussionmentioning

confidence: 99%

“…17 It measures the directionality and magnitude of water diffusion along PVS. 18 Previous studies using this approach have revealed correlations between DTI-ALPS and vascular risk factors, 19 with other imaging markers of CSVD, 20 and with cognitive performance. 21 However, it is important to note that the existing studies have been primarily cross-sectional, and whether the associations reported are causal is uncertain.…”

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confidence: 96%

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Relationship of Perivascular Space Markers With Incident Dementia in Cerebral Small Vessel Disease

Hong,

Tozer,

Markus

2024

Stroke

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BACKGROUND: Recent studies, using diffusion tensor image analysis along the perivascular space (DTI-ALPS), suggest impaired perivascular space (PVS) function in cerebral small vessel disease, but they were cross-sectional, making inferences on causality difficult. We determined associations between impaired PVS, measured using DTI-ALPS and PVS volume, and cognition and incident dementia. METHODS: In patients with lacunar stroke and confluent white matter hyperintensities, without dementia at baseline, recruited prospectively in a single center, magnetic resonance imaging was performed annually for 3 years, and cognitive assessments, including global, memory, executive function, and processing speed, were performed annually for 5 years. We determined associations between DTI-ALPS and PVS volume with cerebral small vessel disease imaging markers (white matter hyperintensity volume, lacunes, and microbleeds) at baseline and with changes in imaging markers. We determined whether DTI-ALPS and PVS volume at baseline and change over 3 years predicted incident dementia. Analyses were controlled for conventional diffusion tensor image metrics using 2 markers (median mean diffusivity [MD] and peak width of skeletonized MD) and adjusted for age, sex, and vascular risk factors. RESULTS: A total of 120 patients, mean age 70.0 years and 65.0% male, were included. DTI-ALPS declined over 3 years, while no change in PVS volume was found. Neither DTI-ALPS nor PVS volume was associated with cerebral small vessel disease imaging marker progression. Baseline DTI-ALPS was associated with changes in global cognition (β=0.142, P =0.032), executive function (β=0.287, P =0.027), and long-term memory (β=0.228, P =0.027). Higher DTI-ALPS at baseline predicted a lower risk of dementia (hazard ratio, 0.328 [0.183–0.588]; P <0.001), and this remained significant after including median MD as a covariate (hazard ratio, 0.290 [0.139–0.602]; P <0.001). Change in DTI-ALPS predicted dementia conversion (hazard ratio, 0.630 [0.428–0.964]; P =0.048), but when peak width of skeletonized MD and median MD were entered as covariates, the association was not significant. There was no association between baseline PVS volume, or PVS change over 3 years, and conversion to dementia. CONCLUSIONS: DTI-ALPS predicts future dementia risk in patients with lacunar strokes and confluent white matter hyperintensities. However, the weakening of the association between change in DTI-ALPS and incident dementia after controlling for peak width of skeletonized MD and median MD suggests part of the signal may represent conventional diffusion tensor image metrics. PVS volume is not a predictor of future dementia risk.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

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Relationship of Perivascular Space Markers With Incident Dementia in Cerebral Small Vessel Disease

Hong,

Tozer,

Markus

2024

Stroke

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“…Also, CSVD burden, leukoaraiosis, and EPVS have been extensively found to be associated with stroke recurrence 22–26 . It is worth noting that the glymphatic system, as a new fluid‐clearance pathway in brain, 27,28 has been recently found to be associated with WMHs, lacunae, cerebral microbleeds, and EPVS in patients with CSVD 29,30 . Therefore, potential connection between glymphatic clearance dysfunction and CSVD may be involved in the recurrence of ESUS.…”

Section: Discussionmentioning

confidence: 99%

MRI‐based risk stratification for recurrent ischemic stroke in embolic stroke of undetermined source

Liu

Dai

et al. 2023

Ann Clin Transl Neurol

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ObjectiveLeukoaraiosis and other brain MRI‐assessed parameters were shown to be associated with recurrent stroke in this population. We aimed to develop an MRI‐based predictive tool for risk stratification of ESUS patients.MethodsWe retrospectively assessed consecutive patients who were diagnosed with ESUS and underwent brain MRI and performed a multivariable analysis with the outcome of recurrent stroke/TIA. Based on the coefficient of each covariate, we generated an integer‐based point scoring system. The discrimination and calibration of the score were assessed using the area under the receiver operator characteristic curve, net reclassification improvement, integrated discrimination improvement, calibration curve, and decision curve analysis. Also, we compared the new score with a previously published score (ALM score).ResultsAmong 176 patients followed for an overall period of 902.3 patient‐years (median of 74 months), there were 39 recurrent ischemic stroke/TIAs (4.32 per 100 patient‐years). Fazekas score (HR: 1.26, 95% CI: 1.03–1.54), enlarged perivascular space (EPVS) (HR: 2.76, 95% CI: 1.12–6.17), NIHSS at admission (HR: 1.11, 95% CI: 1.02–1.18), and infarct subtypes (HR: 2.88, 95% CI: 1.34–6.17) were associated with recurrent stroke/TIA. Accordingly, a score (FENS score) was developed with AUC‐ROC values of 0.863, 0.788, and 0.858 for 1, 3, and 5 years, respectively. These were significantly better than the AUC‐ROC of ALM score (0.635, 0.695, and 0.705, respectively). The FENS score exhibited better calibration and discrimination ability than the ALM score (Hosmer–Lemeshow test χ2: 4.402, p = 0.819).ConclusionThe MRI‐based FENS score can provide excellent predictive performance for recurrent stroke/TIA and may assist in risk stratification of ESUS patients.

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“…18,19 Additionally, it has been demonstrated that individuals with a lower DTI-ALPS index-interpreted as reduced fluid diffusivity in venous PVS-had larger total cSVD burden, as well as an increased risk of WMH burden, lacunes, and brain atrophy. 40 PVS dysfunction has also been linked to the clinical manifestations of cSVD, such as cognitive impairment and lacunar stroke. Both the number of PVS in the BG 41 and the DTI-ALPS index 42 have been associated with the presence of vascular cognitive impairment.…”

Section: Pvs In Ageing and Cardiovascular Risk Factorsmentioning

confidence: 99%

Blood–Brain Barrier Disruption and Perivascular Spaces in Small Vessel Disease and Neurodegenerative Diseases: A Review on MRI Methods and Insights

Voorter,

van Dinther,

Jansen

et al. 2023

Magnetic Resonance Imaging

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Perivascular spaces (PVS) and blood–brain barrier (BBB) disruption are two key features of cerebral small vessel disease (cSVD) and neurodegenerative diseases that have been linked to cognitive impairment and are involved in the cerebral waste clearance system. Magnetic resonance imaging (MRI) offers the possibility to study these pathophysiological processes noninvasively in vivo. This educational review provides an overview of the MRI techniques used to assess PVS functionality and BBB disruption. MRI‐visible PVS can be scored on structural images by either (subjectively) counting or (automatically) delineating the PVS. We highlight emerging (diffusion) techniques to measure proxies of perivascular fluid and its movement, which may provide a more comprehensive understanding of the role of PVS in diseases. For the measurement of BBB disruption, we explain the most commonly used MRI technique, dynamic contrast‐enhanced (DCE) MRI, as well as a more recently developed technique based on arterial spin labeling (ASL). DCE MRI and ASL are thought to measure complementary characteristics of the BBB. Furthermore, we describe clinical studies that have utilized these MRI techniques in cSVD and neurodegenerative diseases, particularly Alzheimer's disease (AD). These studies demonstrate the role of PVS and BBB dysfunction in these diseases and provide insight into the large overlap, but also into the differences between cSVD and AD. Overall, MRI techniques may provide valuable insights into the pathophysiological mechanisms underlying these diseases and have the potential to be used as markers for disease progression and treatment response.Level of Evidence3Technical EfficacyStage 2

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Impaired glymphatic system as evidenced by low diffusivity along perivascular spaces is associated with cerebral small vessel disease: a population-based study

Cited by 30 publications

References 46 publications

Relationship of Perivascular Space Markers With Incident Dementia in Cerebral Small Vessel Disease

Relationship of Perivascular Space Markers With Incident Dementia in Cerebral Small Vessel Disease

MRI‐based risk stratification for recurrent ischemic stroke in embolic stroke of undetermined source

Blood–Brain Barrier Disruption and Perivascular Spaces in Small Vessel Disease and Neurodegenerative Diseases: A Review on MRI Methods and Insights

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