Search

Early detection of cognitive dysfunction in patients with type 2 diabetes mellitus (T2DM) is important for preventive measures due to the lack of effective treatments. The purpose of this study is to investigate the relationship between enlarged perivascular space in the hippocampus (H-EPVS) and cognitive performance in patients with T2DM, and to determine whether it can serve as an imaging marker for cognitive dysfunction. 66 T2DM patients with cognitive impairment (T2DM-CI) and 71 T2DM patients with normal cognitive function (T2DM-NC) underwent cranial MRI scans and comprehensive neuropsychological assessments. H-EPVS counts were visually calculated on T2WI imaging according to a previous scale. The differences in the counts of H-EPVS, demographic data, laboratory test results, and cognitive assessment scores between the two groups were compared. The partial correlation analysis was used to explore the relationship between H-EPVS and glymphatic system function (indicated by the DTI-ALPS index), as well as markers of CSVD. Multiple linear regression models were conducted to explore the association between H-EPVS and cognitive functions. Compared with the T2DM-NC group, T2DM-CI exhibited significantly higher counts of H-EPVS in both the total (sum of the left and right side) and left side (P < 0.001). The T2DM-CI group had lower DTI-ALPS index and RAVLT total score. The total H-EPVS counts were significantly correlated with the DTI-ALPS index (r = − 0.240, P = 0.005), BG-EPVS (r = 0.325, P < 0.001), and CSO-EPVS (r = 0.183, P = 0.033). Multiple linear regression showed the total H-EPVS counts exhibited a negative correlation with MMSE (β = − 0.324, 95% CI: − 0.091, − 0.320), immediate memory (β = − 0.380, 95% CI: − 0.673, − 1.766) and delayed recall (β = − 0.252, 95% CI: − 0.052, − 0.463). H-EPVS may serve as a potential neuroimaging biomarker for cognitive impairment in patients with T2DM, warranting further investigation and validation in future studies. [ABSTRACT FROM AUTHOR]

Introduction: Patent foramen ovale (PFO) patients may experience states of hypoxia and hypoperfusion, which may increase the burden of enlarged perivascular spaces (EPVS). However, to our knowledge, no data are available regarding EPVS in PFO patients. This study sought to investigate if patients with PFO exhibit a heightened burden of EPVS and to identify the mediating factors between PFO and EPVS. Methods: A total of 108 consecutive PFO patients (PFO group) and 110 healthy controls (HC group) from January 2022 to February 2024 were enrolled. The differences in centrum semiovale EPVS (CSO-EPVS) and basal ganglia EPVS (BG-EPVS) scores between PFO and HC groups were compared. The correlations among PFO diameters, laboratory indexes, and EPVS burdens were analyzed. The relationships among them were obtained using mediation analysis. Results: Mean age of PFO and HC group was 47.68 ± 14.47 and 48.14 ± 12.84 years. The CSO-EPVS and BG-EPVS scores were higher in PFO group than HC group (P < 0.001). The CSO-EPVS and BG-EPVS scores for PFO group were concentrated in the ranges 1–3 and 1–2 points, while for HC group were concentrated in the range 0–1 points. A positive correlation among PFO diameters and CSO-EPVS score (r = 0.62, P < 0.001), BG-EPVS score (r = 0.63, P < 0.001), and homocysteine (HCY)(r = 0.21, P = 0.03) was observed. Mediation analysis indicated that higher HCY significantly mediated the relationship between PFO diameter and BG-EPVS burden in PFO patients (P < 0.05). Conclusion: These findings revealed the presence of glymphatic dysfunction in patients with PFO. HCY may mediate the impact of PFO diameter on glymphatic function. [ABSTRACT FROM AUTHOR]

Enlarged perivascular spaces have been previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, but their significance and pathophysiology remains unclear. We investigated associations of white matter enlarged perivascular spaces with classical imaging measures, cognitive measures and plasma proteins to better understand what enlarged perivascular spaces represent in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and whether radiographic measures of enlarged perivascular spaces would be of value in future therapeutic discovery studies for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Twenty-four individuals with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and 24 age- and sex-matched controls were included. Disease status was determined based on the presence of NOTCH3 mutation. Brain imaging measures of white matter hyperintensity, brain parenchymal fraction, white matter enlarged perivascular space volumes, clinical and cognitive measures as well as plasma proteomics were used in models. White matter enlarged perivascular space volumes were calculated via a novel, semiautomated pipeline, and levels of 7363 proteins were quantified in plasma using the SomaScan assay. The relationship of enlarged perivascular spaces with global burden of white matter hyperintensity, brain atrophy, functional status, neurocognitive measures and plasma proteins was modelled with linear regression models. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and control groups did not exhibit differences in mean enlarged perivascular space volumes. However, increased enlarged perivascular space volumes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy were associated with increased white matter hyperintensity volume (β = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (β = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.10). In interaction term models, the interaction term between cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease status and enlarged perivascular space volume was associated with increased white matter hyperintensity volume (β = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (β = 0.52, P = 0.02), Mini-Mental State Examination score (β = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (β = -0.03, P = 0.07). Proteins positively associated with enlarged perivascular space volumes were found to be related to leukocyte migration and inflammation, while negatively associated proteins were related to lipid metabolism. Two central hub proteins were identified in protein networks associated with enlarged perivascular space volumes: CXC motif chemokine ligand 8/interleukin-8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. The levels of CXC motif chemokine ligand 8/interleukin-8 were also associated with increased white matter hyperintensity volume (β = 42.86, P = 0.03), and levels of C-C motif chemokine ligand 2/monocyte chemoattractant protein 1 were further associated with decreased brain parenchymal fraction (β = -0.0007, P < 0.01) and Mini-Mental State Examination score (β = -0.02, P < 0.01) and increased Trail Making Test B completion time (β = 0.76, P < 0.01). No proteins were associated with all three studied imaging measures of pathology (brain parenchymal fraction, enlarged perivascular spaces, white matter hyperintensity). Based on associations uncovered between enlarged perivascular space volumes and cognitive functions, imaging and plasma proteins, we conclude that white matter enlarged perivascular space volumes may capture pathologies contributing to chronic brain dysfunction and degeneration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Abstract Background Perivascular space (PVS) enlargement in ageing and Alzheimer’s disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD. Methods We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre “DZNE Longitudinal Cognitive Impairment and Dementia Study” (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39). Results PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p A-T-, p FDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, p FDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, p FDR = 0.021). Conclusion Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies. Trial registration German Clinical Trials Register DRKS00007966. Registered 04.05.2015 – retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 .

Background: Enlarged perivascular spaces (EPVSs) are commonly detected via magnetic resonance imaging. It is unclear whether EPVSs are associated with cognitive impairment within one month after an acute ischemic stroke (AIS) (i.e., early AIS with cognitive impairment (EAIS-CI)). This study explored the severity and location of EPVSs and their association with EAIS-CI severity and provides clinicians with early warning indicators before the onset of typical clinical symptoms in the Chinese population. Methods: The clinical data of 208 patients (176 AIS patients and 32 controls) were prospectively analyzed using the Montreal Cognitive Assessment Beijing version (MoCA-BJ) score as the primary group criterion and the Mini-Mental State Examination (MMSE) score as a supplementary criterion. When EPVS I as the main EPVS type detected by imaging, the basal ganglia (BG) is the area most severely affected. Statistical analysis was conducted on the relevant clinical data. Results: AIS patients were grouped based on MoCA-BJ scores. Age (p < 0.01), education level (p = 0.02), EPVS I as the main EPVS type (p < 0.01), the number of right-sided BG-EPVSs (p = 0.04), white matter hyperintensities (WMHs) (Fazekas scores: p = 0.02), brain atrophy (global cortical atrophy scores: p < 0.01, Koedam posterior atrophy visual scale scores: p = 0.01, medial temporal lobe atrophy scores: p < 0.01) and AIS lesion volume (p = 0.01) were significantly greater in the EAIS-CI group than in the EAIS without cognitive impairment group. The cognitive domains of attention (p = 0.04) and orientation (p < 0.01) were more closely associated with EPVS I as the main EPVS type. However, multivariate regression analysis did not identify EPVS I as the main EPVS type as the main risk factor for EAIS-CI (p = 0.098). Grouping by MMSE scores revealed that EPVS I as the main EPVS type was linked to low education level (p < 0.01) and was significantly associated with EAIS in individuals with cognitive dementia (p < 0.01). Conclusions: As a result of multiple factors, EAIS-CI is significantly associated with a low education level, BG-EPVS, WMHs, and worsening brain atrophy severity. Imaging markers, such as the severity of BG-EPVS, can assist in the early diagnosis and assessment of EAIS-CI. Clinical Trial Registration: The study was registered with the China Clinical Trial Registry (https://www.chictr.org.cn/), registration number: ChiCTR2000038819. [ABSTRACT FROM AUTHOR]

Background: Perivascular space (PVS) enlargement in ageing and Alzheimer's disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD. Methods: We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; meanage = 70.78 ± 5.78) of the ongoing observational multicentre "DZNE Longitudinal Cognitive Impairment and Dementia Study" (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39). Results: PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant's age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρspearman = -0.17, pFDR = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T + > A-T-, pFDR = 0.004) or who were amyloid positive but tau negative (A + T + > A + T-, pFDR = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T + > A-T-, pFDR = 0.021). Conclusion: Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies. Trial registration: German Clinical Trials Register DRKS00007966. Registered 04.05.2015 – retrospectively registered, https://drks.de/search/en/trial/DRKS00007966. [ABSTRACT FROM AUTHOR]

Background: Recent studies have demonstrated an association between pulse wave velocity (PWV), cerebral small vessel disease (SVD), and cognitive impairment such as Alzheimer's disease. However, the association between brachial-ankle PWV and enlarged perivascular spaces (EPVS), one component of cerebral SVD remains controversial. Objective: To investigate the relationship between brachial-ankle PWV and EPVS severity in participants without dementia. Methods: We performed a cross-sectional study of data of 74 participants from sub-analysis of ongoing research. We assessed cognitive function, brachial-ankle PWV, and brain magnetic resonance imaging (MRI) features. Using brain MRI, EPVS were separately assessed as basal ganglia (BG)-EPVS or centrum semiovale (CSO)-EPVS on the basis of their location. The relationship between EPVS severity and brachial-ankle PWV was evaluated using multivariable ordinal logistic regression analyses. Results: We analyzed 74 participants (women: 47%, mean age: 73 years, mild cognitive impairment [MCI]: 74%). Compared with participants with normal cognition, those with MCI were more likely to have both severe BG-EPVS and severe CSO-EPVS. In multivariable analyses, high brachial-ankle PWV and age were independently associated with BG-EPVS severity (odds ratio [95% confidence interval]: 1.19 [1.02–1.38], 1.09 [1.01–1.17], respectively), whereas only age was independently associated with CSO-EPVS severity. A causal mediation analysis under a counterfactual approach revealed a significant pure natural indirect effect of brachial-ankle PWV on MCI that was mediated by BG-EPVS (estimate: 1.04, 95% CI: 1.01–1.12, p = 0.006). Conclusions: Brachial-ankle PWV was associated with BG-EPVS severity. High PWV may cause cerebrovascular pulsatility, which accelerates BG-EPVS and may worsen cognitive impairment. [ABSTRACT FROM AUTHOR]

In this paper, we present a cascaded deep convolution neural network (CNN) for assessing enlarged perivascular space (ePVS) within the basal ganglia region using T2-weighted MRI. Enlarged perivascular spaces (ePVSs) are potential biomarkers for various neurodegenerative disorders, including dementia and Parkinson's disease. Accurate assessment of ePVS is crucial for early diagnosis and monitoring disease progression. Our approach first utilizes an ePVS enhancement CNN to improve ePVS visibility and then employs a quantification CNN to predict the number of ePVSs. The ePVS enhancement CNN selectively enhances the ePVS areas without the need for additional heuristic parameters, achieving a higher contrast-to-noise ratio (CNR) of 113.77 compared to Tophat, Clahe, and Laplacian-based enhancement algorithms. The subsequent ePVS quantification CNN was trained and validated using fourfold cross-validation on a dataset of 76 participants. The quantification CNN attained 88% accuracy at the image level and 94% accuracy at the subject level. These results demonstrate significant improvements over traditional algorithm-based methods, highlighting the robustness and reliability of our deep learning approach. The proposed cascaded deep CNN model not only enhances the visibility of ePVS but also provides accurate quantification, making it a promising tool for evaluating neurodegenerative disorders. This method offers a novel and significant advancement in the non-invasive assessment of ePVS, potentially aiding in early diagnosis and targeted treatment strategies. [ABSTRACT FROM AUTHOR]

Background and objective: Enlarged perivascular spaces in basal ganglia (BGEPVS) are considered an imaging marker of cerebral small vessel disease (CSVD), but its pathogenesis and pathophysiological process remain unclear. While decreased cerebral perfusion is linked to other CSVD markers, the relationship between BG-EPVS and cerebral perfusion remains ambiguous. This study aimed to explore this association. Methods: Elderly individuals with severe BG-EPVS (n = 77) and age/sex-matched controls (n = 89) underwent head CT perfusion imaging. The cerebral perfusion parameters including mean transit time (MTT), time to maximum (TMAX), cerebral blood flow (CBF), and cerebral blood volume (CBV) were quantitatively measured by symmetric regions of interest plotted in the basal ganglia region. Point-biserial correlation and logistics regression analysis were performed to investigate the association between BG-EPVS and cerebral perfusion. Results: There were no significant differences in MTT, TMAX, or CBF between BG-EPVS group and control group. CBV was significantly lower in the BGEPVS group (p = 0.035). Point-biserial correlation analysis showed a negative correlation between BG-EPVS and CBV (r = -0.198, p = 0.011). BG-EPVS group and control group as the dependent variable, binary logistics regression analysis showed that CBV was not an independent risk factor for severe BG-EPVS (p = 0.448). All enrolled patients were divided into four groups according to the interquartile interval of CBV. The ordered logistic regression analysis showed severe BG-EPVS was an independent risk factor for decreased CBV after adjusting for confounding factors (OR = 2.142, 95%CI: 1.211-3.788, p = 0.009). Conclusion: Severe BG-EPVS is an independent risk factor for decreased CBV in the elderly, however, the formation of BG-EPVS is not solely dependent on changes in CBV in this region. This finding provides information about the pathophysiological consequence caused by severe BG-EPVS. [ABSTRACT FROM AUTHOR]

Background: Growing evidence links brain-MRI enlarged perivascular spaces (EPVS) and multiple sclerosis (MS), but their role remains unclear. Objective: This study aimed to investigate the cross-sectional associations of EPVS with several neuroinflammatory and neurodegenerative features in a large multicentric-MS cohort. Methods: In total, 207 patients underwent 3T axial-T2-weighted brain-MRI for EPVS assessment (EPVS dichotomized into high/low according to ⩾ 2/< 2 rating categories). MRI biomarkers included brain-predicted age and brain-predicted age difference (brain-PAD), central vein sign (CVS)-positive lesion percentage (CVS%), paramagnetic rim and cortical lesions, T2-lesion load, and brain volumetry. The variable relative importance for EPVS-category prediction was explored using a classification random forest approach. Results: High EPVS patients were older (49 vs 44 years, p = 0.003), had ⩾ 1 vascular risk factors (VRFs; p = 0.005), lower CVS% (67% vs 78%, p < 0.001), reduced brain volumes (whole brain: 0.63 vs 0.73, p = 0.01; gray matter: 0.36 vs 0.40; p = 0.002), and older brain-predicted age (58 vs 50 years, p < 0.001). No differences were found for neuroinflammatory markers. After adjusting for age and VFRs (multivariate analyses), the high EPVS category correlated with lower CVS% (odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96–0.99; p = 0.02), lower whole brain (OR = 0.01, 95% CI = 0.0003–0.5; p = 0.02), gray matter (OR = 0.0004, 95% CI = 0.0000004–0.4; p = 0.03) volumes, and higher brain-PAD (OR = 1.05, 95% CI = 1.01–1.09; p = 0.02). Random forest identified brain-PAD as the most important predictor of high EPVS. Conclusion: EPVS in MS likely reflect microangiopathic disease rather than neuroinflammation, potentially contributing to accelerated neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: We sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults. Methods: This population‐based study included 1191 dementia‐free participants (age ≥60 years) in the MIND‐China MRI Substudy (2018–2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models. Results: Greater BG‐EPVS load was associated with lower z‐scores in memory, verbal fluency, and global cognition (p < 0.05); these associations became non‐significant when controlling for other cerebral small vessel disease (CSVD) markers (e.g., WMHs, lacunes, and mixed CMBs). Overall, CSO‐EPVS load was not associated with cognitive z‐scores (p > 0.05); among apolipoprotein E (APOE) ‐ε4 carriers, greater CSO‐EPVS load was associated with lower verbal fluency z‐score, even when controlling for other CSVD markers (p < 0.05). Discussion: The associations of BG‐EPVS with poor cognitive function in older adults are largely attributable to other CSVD markers. HIGHLIGHTS: The association of enlarged perivascular spaces (EPVS) with cognitive function in older people is poorly defined.The association of basal ganglia (BG)‐EPVS with poor cognition is attributed to other cerebral small vessel disease (CSVD) markers.In apolipoprotein E (APOE) ε4 carriers, a higher centrum semiovale (CSO)‐EPVS load is associated with poorer verbal fluency. [ABSTRACT FROM AUTHOR]

Ning Li,&ast; Jia-Min Shao,&ast; Ye Jiang, Chu-Han Wang, Si-Bo Li, De-Chao Wang, Wei-Ying Di Department of Neurology, Affiliated Hospital of Hebei University, Baoding, Hebei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei-Ying Di, Email diweiying@126.comBackground: This study addresses the predictive modeling of Enlarged Perivascular Spaces (EPVS) in neuroradiology and neurology, focusing on their impact on Cerebral Small Vessel Disease (CSVD) and neurodegenerative disorders.Methods: A retrospective analysis was conducted on 587 neurology inpatients, utilizing LASSO regression for variable selection and logistic regression for model development. The study included comprehensive demographic, medical history, and laboratory data analyses.Results: The model identified key predictors of EPVS, including Age, Hypertension, Stroke, Lipoprotein a, Platelet Large Cell Ratio, Uric Acid, and Albumin to Globulin Ratio. The predictive nomogram demonstrated strong efficacy in EPVS risk assessment, validated through ROC curve analysis, calibration plots, and Decision Curve Analysis.Conclusion: The study presents a novel, robust EPVS predictive model, providing deeper insights into EPVS mechanisms and risk factors. It underscores the potential for early diagnosis and improved management strategies in neuro-radiology and neurology, highlighting the need for future research in diverse populations and longitudinal settings.Keywords: Enlarged Perivascular Spaces, cerebral small vessel disease, predictive model, risk factors, neuro-radiology, LASSO regression

Abstract Previous studies have demonstrated associations between enlarged perivascular spaces (EPVS) and dementias such as Alzheimer’s disease. However, an association between EPVS and dementia with Lewy bodies (DLB) has not yet been clarified. We performed a cross-sectional analysis of our prospective study cohort of 109 participants (16 with DLB). We assessed cognitive function, pulse wave velocity (PWV), and brain magnetic resonance imaging features. The relationships between EPVS and DLB were evaluated using multivariable logistic regression analyses. Compared with the non-dementia group, the DLB group was more likely to have EPVS in the basal ganglia. Compared with participants without EPVS, those with EPVS were older and had cognitive impairment and high PWV. In multivariable analyses, EPVS in the basal ganglia was independently associated with DLB. High PWV was also independently associated with EPVS in both the basal ganglia and centrum semiovale. High PWV may cause cerebrovascular pulsatility, leading to accelerated EPVS in DLB participants.

Previous studies have demonstrated associations between enlarged perivascular spaces (EPVS) and dementias such as Alzheimer's disease. However, an association between EPVS and dementia with Lewy bodies (DLB) has not yet been clarified. We performed a cross-sectional analysis of our prospective study cohort of 109 participants (16 with DLB). We assessed cognitive function, pulse wave velocity (PWV), and brain magnetic resonance imaging features. The relationships between EPVS and DLB were evaluated using multivariable logistic regression analyses. Compared with the non-dementia group, the DLB group was more likely to have EPVS in the basal ganglia. Compared with participants without EPVS, those with EPVS were older and had cognitive impairment and high PWV. In multivariable analyses, EPVS in the basal ganglia was independently associated with DLB. High PWV was also independently associated with EPVS in both the basal ganglia and centrum semiovale. High PWV may cause cerebrovascular pulsatility, leading to accelerated EPVS in DLB participants. [ABSTRACT FROM AUTHOR]

Background: High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in ischemic stroke. However, the role of NLR in cerebral small vessel disease (CSVD) is controversial. Herein, we evaluated the value of NLR in identifying CSVD and its relationship with the common imaging markers of CSVD. Methods: A total of 667 patients were enrolled in this study, including 368 in the CSVD group and 299 in the non‐CSVD group. Clinical, laboratory, and imaging data were collected. The relationship of NLR with CSVD and common imaging markers of CSVD were analyzed with univariate and multivariate logistic regression analysis. The predictive value of NLR was assessed with the receiver operating characteristic curve. Results: NLR (odds ratio [OR] = 1.929, 95% confidence interval [CI] = 1.599–2.327, p <.001) was an independent risk factor for CSVD. NLR was also independently associated with moderate to severe white matter hyperintensity (WMH) (OR = 2.136, 95% CI = 1.768–2.580, p <.001), moderate to severe periventricular WMH (OR = 2.138, 95% CI = 1.771–2.579, p <.001), and moderate to severe deep WMH (OR = 1.654, 95% CI = 1.438–1.902, p <.001), moderately to severely enlarged perivascular spaces (EPVS) (OR = 1.248, 95% CI = 1.110–1.402, p <.001), moderately to severely EPVS in the basal ganglia (OR = 1.136, 95% CI = 1.012–1.275, p =.030), and moderately to severely EPVS in the centrum semiovale (OR = 1.140, 95% CI = 1.027–1.266, p =.014). However, NLR was not statistically significantly associated with lacune. The optimal cutoff point of NLR in predicting CSVD was 2.47, with sensitivity and specificity of 84.2% and 66.9%, respectively (p <.01). The diagnostic effect was maximized when NLR was combined with other risk factors. Conclusions: NLR is an independent risk factor for CSVD and is independently associated with common imaging markers of CSVD. NLR may serve as a valid and convenient biomarker for assessing CSVD. [ABSTRACT FROM AUTHOR]

We examined whether there were differences in the presence of centrum semiovale-enlarged perivascular spaces (CSO-ePVS) and basal ganglia-ePVS (BG-ePVS) among patients with Alzheimer disease-related cognitive impairment (ADCI) based on their age of onset. Out of a total of 239 patients with cognitive impairment, 155 with positive amyloid-PET results were included. Among these, 43 had early-onset ADCI (EOADCI) and 112 had late-onset ADCI (LOADCI). Patients with LOADCI exhibited a higher prevalence of hypertension, lacunes, white matter hyperintensities, and BG-ePVS than those with EOADCI. BG-ePVS showed a significant correlation with age at the onset and the number of lacunes, whereas CSO-ePVS did not exhibit any association. The higher prevalence of BG-ePVS in patients with LOADCI might be attributable to vascular risk factors (hypertension) and cerebral small vessel disease (CSVD). These findings support the hypothesis that BG-ePVS is associated with CSVD and vascular risk factors, whereas CSO-ePVS is associated with cerebral amyloid angiopathy. [ABSTRACT FROM AUTHOR]

Abstract Introduction We sought to characterize cognitive profiles associated with enlarged perivascular spaces (EPVS) among Chinese older adults. Methods This population‐based study included 1191 dementia‐free participants (age ≥60 years) in the MIND‐China MRI Substudy (2018–2020). We visually evaluated EPVS in basal ganglia (BG) and centrum semiovale (CSO), white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and cortical superficial siderosis. We used a neuropsychological test battery to assess cognitive function. Data were analyzed using general linear models. Results Greater BG‐EPVS load was associated with lower z‐scores in memory, verbal fluency, and global cognition (p 0.05); among apolipoprotein E (APOE) ‐ε4 carriers, greater CSO‐EPVS load was associated with lower verbal fluency z‐score, even when controlling for other CSVD markers (p

Astrocytes (ACs) are the most abundant cells in the brain and, importantly, are the master connecting and communicating cells that provide structural and functional support for brain cells at all levels of organization. Further, they are recognized as the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste. They comprise the glymphatic system, which is critically dependent on proper waste removal by the pvACef polarized aquaporin-4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role in synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI), and are associated with white matter hyperintensities, lacunes, and aging, and are accepted as biomarkers for cerebral small vessel disease, increased obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS.

Background: The subarachnoid space is continuous with the perivascular compartment in the central nervous system. However, whether the topography and severity of enlarged perivascular spaces (EPVS) correlates with spontaneous subarachnoid hemorrhage (SAH) remains unknown. Based on the underlying arteriopathy distributions, we hypothesized that EPVS in basal ganglia (BGEPVS) are more closely associated with aneurysmal subarachnoid hemorrhage (aSAH) than other SAH without aneurysm. Methods: Magnetic resonance imaging (MRI) scans of 271 consecutive SAH survivors with and without aneurysm were analyzed for EPVS and other markers of imaging data. In the subgroup analysis, we compared the clinical characteristics and EPVS of SAH participants with and without pre-existing known risk factors (hypertension, diabetes, and smoking history) using multivariable logistic regression. Results: Patients with aSAH (n = 195) had a higher severity of BG-EPVS and centrum semiovale EPVS (CSO-EPVS) than those without aneurysm (n = 76). Importantly, BG-EPVS predominance pattern (BG-EPVS>CSO-EPVS) only existed in aSAH survivors rather than other SAH without aneurysm. In the subgroup analysis, interestingly, we also found that a high degree of BG-EPVS showed an independent relationship with aSAH in patients without pre-existing risk factors (e.g., hypertension). Conclusion: In this cohort study, BG-EPVS predominance pattern was associated with aSAH patients compared with those without aneurysm. Moreover, BGEPVS still showed a strong association with aSAH survivors without pre-existing vascular risk factors. Our present study suggested the BG-EPVS as a potential MRI-visible characteristic would shed light on the pathogenesis of glymphatic function at the skull base for aSAH. [ABSTRACT FROM AUTHOR]

Background: The glymphatic system is reportedly involved in Parkinson's disease (PD). Based on previous studies, we aimed to confirm the correlation between the glymphatic system and PD progression by combining two imaging parameters, diffusion tensor image analysis along the perivascular space (DTI-ALPS), and enlarged perivascular spaces (EPVS). Methods: Fifty-one PD patients and fifty healthy control (HC) were included. Based on the Hoehn-Yahr scale, the PD group was divided into early-stage and medium-to late-stage. All PD patients were scored using the Unified PD Rating Scale (UPDRS). We assessed the DTI-ALPS indices in the bilateral hemispheres and EPVS numbers in bilateral centrum semiovale (CSO), basal ganglia (BG), and midbrain. Results: The DTI-ALPS indices were significantly lower bilaterally in PD patients than in the HC group, and EPVS numbers in any of the bilateral CSO, BG, and midbrain were significantly higher, especially for the medium- to late-stage group and the BG region. In PD patients, the DTI-ALPS index was significantly negatively correlated with age, while the BG-EPVS numbers were significantly positively correlated with age. Furthermore, the DTI-ALPS index was negatively correlated with UPDRS II and III scores, while the BG-EPVS numbers were positively correlated with UPDRS II and III scores. Similarly, the correlation was more pronounced in the medium- to late-stage group. Conclusion: The DTI-ALPS index and EPVS numbers (especially in the BG region) are closely related to age and PD progression and can serve as non-invasive assessments for glymphatic dysfunction and its interventions in clinical studies. [ABSTRACT FROM AUTHOR]

The recently described perivascular unit (PVU) resides immediately adjacent to the true capillary neurovascular unit (NVU) in the postcapillary venule and contains the normal-benign perivascular spaces (PVS) and pathological enlarged perivascular spaces (EPVS). The PVS are important in that they have recently been identified to be the construct and the conduit responsible for the delivery of metabolic waste from the interstitial fluid to the ventricular cerebrospinal fluid for disposal into the systemic circulation, termed the glymphatic system. Importantly, the outermost boundary of the PVS is lined by protoplasmic perivascular astrocyte endfeet (pvACef) that communicate with regional neurons. As compared to the well-recognized and described neurovascular unit (NVU) and NVU coupling, the PVU is less well understood and remains an emerging concept. The primary focus of this narrative review is to compare the similarities and differences between these two units and discuss each of their structural and functional relationships and how they relate not only to brain homeostasis but also how they may relate to the development of multiple clinical neurological disease states and specifically how they may relate to obesity, metabolic syndrome, and type 2 diabetes mellitus. Additionally, the concept and importance of a perisynaptic astrocyte coupling to the neuronal synapses with pre- and postsynaptic neurons will also be considered as a perisynaptic unit to provide for the creation of the information transfer in the brain via synaptic transmission and brain homeostasis. Multiple electron microscopic images and illustrations will be utilized in order to help explain these complex units. [ABSTRACT FROM AUTHOR]

Astrocytes (ACs) are the most abundant cells in the brain and, importantly, are the master connecting and communicating cells that provide structural and functional support for brain cells at all levels of organization. Further, they are recognized as the guardians and housekeepers of the brain. Protoplasmic perivascular astrocyte endfeet and their basal lamina form the delimiting outermost barrier (glia limitans) of the perivascular spaces in postcapillary venules and are important for the clearance of metabolic waste. They comprise the glymphatic system, which is critically dependent on proper waste removal by the pvACef polarized aquaporin-4 water channels. Also, the protoplasmic perisynaptic astrocyte endfeet (psACef) are important in cradling the neuronal synapses that serve to maintain homeostasis and serve a functional and supportive role in synaptic transmission. Enlarged perivascular spaces (EPVS) are emerging as important aberrant findings on magnetic resonance imaging (MRI), and are associated with white matter hyperintensities, lacunes, and aging, and are accepted as biomarkers for cerebral small vessel disease, increased obesity, metabolic syndrome, and type 2 diabetes. Knowledge is exponentially expanding regarding EPVS along with the glymphatic system, since EPVS are closely associated with impaired glymphatic function and waste removal from the brain to the cerebrospinal fluid and systemic circulation. This review intends to focus on how the pvACef play a crucial role in the development of EPVS. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to explore the association between cerebral hemodynamic parameters focused on the critical closing pressure (CCP) and enlarged perivascular spaces (EPVS). Methods: Cerebral blood velocity in the middle cerebral artery (MCAv) and non-invasive continuous blood pressure (NIBP) were measured using a transcranial Doppler (TCD) and Finometer, followed by the calculation of cerebral hemodynamic parameters including CCP, resistance area product (RAP), pulsatility index (PI), and pulse pressure (PP). EPVS were graded separately in the basal ganglia (BG) and centrum semiovale (CSO), using a visual semiquantitative ordinal scale. Patients with EPVS >10 were classified into the severe BG-EPVS group and severe CSO-EPVS group, and the remainder into the mild BG-EPVS group and the mild CSO-EPVS group. Spearman's correlation and binary logistic regression analysis were performed to analyze the relationship between hemodynamic parameters and BG-EPVS and CSO-EPVS, respectively. Results: Overall, 107 patients were enrolled. The severe BG-EPVS group had higher CCP, mean arterial blood pressure (MABP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) than that in the mild BG-EPVS group (p < 0.05). There was no statistical difference in hemodynamic parameters between the severe CSO-EPVS group and the mild CSO-EPVS group. Spearman's correlation analysis showed that CCP was positively associated with BG-EPVS (rho = 0.331, p <0.001) and CSO-EPVS (rho = 0.154, p = 0.044). The binary logistic regression analysis showed that CCP was independently associated with severe BG-EPVS (p < 0.05) and not with CSO-EPVS (p > 0.05) after adjusting for confounders. Conclusion: CCP representing cerebrovascular tension was independently associated with BG-EPVS. [ABSTRACT FROM AUTHOR]

The brain endothelial cell (BEC) glycocalyx (ecGCx) is a BEC surface coating consisting of a complex interwoven polysaccharide (sweet husk) mesh-like network of membrane-bound proteoglycans, glycoproteins, and glycosaminoglycans (GAGs) covering the apical luminal layer of the brain endothelial cells. The ecGCx may be considered as the first barrier of a tripartite blood–brain barrier (BBB) consisting of (1) ecGCx; (2) BECs; and (3) an extravascular compartment of pericytes, the extracellular matrix, and perivascular astrocytes. Perturbations of this barrier allow for increased permeability in the postcapillary venule that will be permissive to both fluids, solutes, and proinflammatory peripherally derived leukocytes into the perivascular spaces (PVS) which result in enlargement as well as increased neuroinflammation. The ecGCx is known to have multiple functions, which include its physical and charge barrier, mechanical transduction, regulation of vascular permeability, modulation of inflammatory response, and anticoagulation functions. This review discusses each of the listed functions in detail and utilizes multiple transmission electron micrographs and illustrations to allow for a better understanding of the ecGCx structural and functional roles as it relates to enlarged perivascular spaces (EPVS). This is the fifth review of a quintet series that discuss the importance of EPVS from the perspective of the cells of brain barriers. Attenuation and/or loss of the ecGCx results in brain barrier disruption with increased permeability to proinflammatory leukocytes, fluids, and solutes, which accumulate in the postcapillary venule perivascular spaces. This accumulation results in obstruction and results in EPVS with impaired waste removal of the recently recognized glymphatic system. Importantly, EPVS are increasingly being regarded as a marker of cerebrovascular and neurodegenerative pathology. [ABSTRACT FROM AUTHOR]

Keywords: Enlarged perivascular spaces; Glial fibrillary acidic protein astrocytopathy; Magnetic resonance imaging EN Enlarged perivascular spaces Glial fibrillary acidic protein astrocytopathy Magnetic resonance imaging 3751 3754 4 09/13/23 20231001 NES 231001 Shugang Cao and Yunfei Zhu contributed equally to this work. 1K, L) were noted on brain MRI; spinal MRI showed a significant reduction in spinal cord lesions (Fig. Non-enhanced brain MRI in 2020 suggested marked progression of paraventricular lesions with EPVSs (E, F) and contrast-enhanced MRI demonstrated linear perivascular radial gadolinium enhancement (G, H thick arrows). [Extracted from the article]

Background: Lacunes, microbleeds, enlarged perivascular spaces (EPVS), and white matter hyperintensities (WMH) are brain imaging features of cerebral small vessel disease (SVD). Based on these imaging markers, we aimed to identify subtypes of SVD and to evaluate the validity of these markers as part of clinical ratings and as biomarkers for stroke outcome. Methods: In a cross-sectional study, we examined 1207 first-ever anterior circulation ischemic stroke patients (mean age 69.1 ± 15.4 years; mean NIHSS 5.3 ± 6.8). On acute stroke MRI, we assessed the numbers of lacunes and microbleeds and rated EPVS and deep and periventricular WMH. We used unsupervised learning to cluster patients based on these variables. Results: We identified five clusters, of which the last three appeared to represent distinct late stages of SVD. The two largest clusters had no to only mild or moderate WMH and EPVS, respectively, and favorable stroke outcome. The third cluster was characterized by the largest number of lacunes and a likewise favorable outcome. The fourth cluster had the highest age, most pronounced WMH, and poor outcome. Showing the worst outcome, the fifth cluster presented pronounced microbleeds and the most severe SVD burden. Conclusion: The study confirmed the existence of different SVD types with different relationships to stroke outcome. EPVS and WMH were identified as imaging features of presumably early progression. The number of microbleeds and WMH severity appear to be promising biomarkers for distinguishing clinical subgroups. Further understanding of SVD progression might require consideration of refined SVD features, e.g., for EPVS and type of lacunes. [ABSTRACT FROM AUTHOR]

Yuyuan Yang,1 Meng Wang,1 Moxin Luan,1 Xiaoqian Song,1 Yajuan Wang,2 Lulu Xu,3 Meixiang Zhong,4 Xueping Zheng1 1Department of Geriatric Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Geriatric Medicine, The Qingdao Eighth People’s Hospital, Qingdao, People’s Republic of China; 3Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China; 4Department of Geriatric Medicine, The Chengdu Eighth People’s Hospital, Chengdu, People’s Republic of ChinaCorrespondence: Xueping Zheng, Email simplexueping@163.comAbstract: Perivascular spaces are the fluid-filled areas surrounding small blood vessels in the brain, and they may play a role similar to lymphatic vessels in clearing metabolic waste. When their diameters exceed 1 mm, as measured by structural magnetic resonance imaging, they are classified as enlarged perivascular spaces (EPVS). Previously, EPVS were considered to be benign, but increasing evidence suggests that their existence may be associated with various clinical diseases. Here, we review recent clinical studies to understand the potential clinical implications of EPVS. We also review the anatomy and imaging characteristics of EPVS and discuss four causal hypotheses for their formation and associated risk factors. Due to differences in research methods and concerns across studies, unified conclusions are difficult to achieve. Overall, more basic high-quality research is needed to clarify the subject and provide more concrete theoretical support.Keywords: cerebral small vessels, enlarged perivascular spaces, cognitive decline, cerebral amyloid angiopathy, Parkinson’s disease, aging

Background: This study aimed to investigate the correlation between enlarged perivascular space (EPVS) and white matter hyperintensities (WMH) at different locations in patients with recent small subcortical infarct (RSSI). Methods: Data were collected from patients with RSSI who were hospitalized at Changzhou Second People's Hospital between October 2020 and December 2021. All patients underwent cranial magnetic resonance imaging, and the grades of EPVS and WMH were assessed, including basal ganglia EPVS (BG‐EPVS), centrum semiovale EPVS (CSO‐EPVS), deep WMH (DWMH), and periventricular WMH (PWMH). The volumes of EPVS and WMH at different locations were quantified using 3D Slicer software. Patients were grouped according to the severity of BG‐EPVS and CSO‐EPVS. Univariate and multivariate analyses were used to analyze the relationship between EPVS and WMH. Results: A total of 215 patients with RSSI were included in the analysis. Patients with moderate‐to‐severe BG‐EPVS had higher DWMH and PWMH severity than those with mild BG‐EPVS, both in terms of volume and grade. There was no significant difference in WMH severity between patients with mild CSO‐EPVS and those with moderate‐to‐severe CSO‐EPVS. Multivariate analysis indicated that after adjustments were made for confounding factors, DWMH volume (β = 0.311; 95% CI, 0.089–0.400; p =.002) and PWMH volume (β = 0.296; 95% CI, 0.083–0.424; p =.004) were independently associated with BG‐EPVS. Pearson correlation showed that PWMH volume (r =.589; p <.001) and DWMH volume (r =.596; p <.001) were positively related to BG‐EPVS volume. Conclusion: DWMH and PWMH are closely related to BG‐EPVS in patients with RSSI. [ABSTRACT FROM AUTHOR]

Embryonic genetic mechanisms are present in the brain and ready to be placed into action upon cellular injury, termed the response to injury wound-healing (RTIWH) mechanism. When injured, regional brain endothelial cells initially undergo activation and dysfunction with initiation of hemostasis, inflammation (peripheral leukocytes, innate microglia, and perivascular macrophage cells), proliferation (astrogliosis), remodeling, repair, and resolution phases if the injurious stimuli are removed. In conditions wherein the injurious stimuli are chronic, as occurs in obesity, metabolic syndrome, and type 2 diabetes mellitus, this process does not undergo resolution and there is persistent RTIWH with remodeling. Indeed, the brain is unique, in that it utilizes its neuroglia: the microglia cell, along with peripheral inflammatory cells and its astroglia, instead of peripheral scar-forming fibrocytes/fibroblasts. The brain undergoes astrogliosis to form a gliosis scar instead of a fibrosis scar to protect the surrounding neuropil from regional parenchymal injury. One of the unique and evolving remodeling changes in the brain is the development of enlarged perivascular spaces (EPVSs), which is the focus of this brief review. EPVSs are important since they serve as a biomarker for cerebral small vessel disease and also represent an impairment of the effluxing glymphatic system that is important for the clearance of metabolic waste from the interstitial fluid to the cerebrospinal fluid, and disposal. Therefore, it is important to better understand how the RTIWH mechanism is involved in the development of EPVSs that are closely associated with and important to the development of premature and age-related cerebrovascular and neurodegenerative diseases with impaired cognition. [ABSTRACT FROM AUTHOR]

Objective: Deep medullary veins (DMVs) were not considered a typical marker of cerebral small vessel disease (CSVD) due to limited understanding of their involvement in pathology of CSVD. This study aimsto investigate potential vascular risk factors for DMVs and their associations with CSVD. Methods: In total, 1909 community‐dwelling participants were included in this analysis. Demographic, clinical, laboratory, and imaging data were collected. DMV scores (0–18) werecalculated as the sum of bilateral frontal, parietal, and occipital regional scores using a semiquantitative visual scale (0–3). The presence, total burden, and imaging markers of CSVD were assessed. Linear regression analyses were conducted to explore potential vascular factors for DMV scores. Binary and ordinal logistic regression analyses were performed to investigate the associations of DMV scores with CSVD and its markers. Results: Mean age was 61.8 (SD 6.5) years, and 1027 (53.8%) of participants were men. The median DMV scores were14 (IQR 12–16). DMV scores wererelated to age, male sex, body mass index, diastolic blood pressure, hypercholesterolaemia, atrial fibrillation, current drinking, total cholesterol, triglycerides, low‐density lipoprotein, hemoglobin A1c, leukocytes, lymphocytes, hemoglobin, and platelets (p <.05). DMV scores wereassociated with the presence and total burden of CSVD (Rothwell's scale), modified white matter hyperintensity burden, and enlarged perivascular spaces in centrum semiovale (p <.05). However, these associations between DMV scores and CSVD disappeared after adjusting for potential confounders. Conclusion: Several conventional vascular factors were associated with DMVs. The relationship between DMVs and CSVD was vulnerable, suggesting decreased visible and discontinuous DMVs may differ mechanistically from traditional markers of CSVD. [ABSTRACT FROM AUTHOR]

Perivascular spaces (PVS) and their enlargement (EPVS) have been gaining interest as EPVS can be visualized non-invasively by magnetic resonance imaging (MRI) when viewing T-2-weighted images. EPVS are most commonly observed in the regions of the basal ganglia and the centrum semiovale; however, they have also been identified in the frontal cortex and hippocampal regions. EPVS are known to be increased in aging and hypertension, and are considered to be a biomarker of cerebral small vessel disease (SVD). Interest in EPVS has been significantly increased because these PVS are now considered to be an essential conduit necessary for the glymphatic pathway to provide the necessary efflux of metabolic waste. Metabolic waste includes misfolded proteins of amyloid beta and tau that are known to accumulate in late-onset Alzheimer's disease (LOAD) within the interstitial fluid that is delivered to the subarachnoid space and eventually the cerebral spinal fluid (CSF). The CSF acts as a sink for accumulating neurotoxicities and allows clinical screening to potentially detect if LOAD may be developing early on in its clinical progression via spinal fluid examination. EPVS are thought to occur by obstruction of the PVS that associates with excessive neuroinflammation, oxidative stress, and vascular stiffening that impairs flow due to a dampening of the arterial and arteriolar pulsatility that aids in the convective flow of the metabolic debris within the glymphatic effluxing system. Additionally, increased EPVS has also been associated with Parkinson's disease and non-age-related multiple sclerosis (MS). [ABSTRACT FROM AUTHOR]

Enlarged perivascular spaces (ePVS) are difficult to quantify, and their etiologies and consequences are poorly understood. Vanderbilt Memory and Aging Project participants (n = 327, 73 ± 7 years) completed 3T brain MRI to quantify ePVS volume and count, longitudinal neuropsychological assessment, and cardiac MRI to quantify aortic stiffness. Linear regressions related (1) PWV to ePVS burden and (2) ePVS burden to cross-sectional and longitudinal neuropsychological performance adjusting for key demographic and medical factors. Higher aortic stiffness related to greater basal ganglia ePVS volume (β = 7.0×10−5, p = 0.04). Higher baseline ePVS volume was associated with worse baseline information processing (β = -974, p = 0.003), executive function (β = -81.9, p < 0.001), and visuospatial performances (β = -192, p = 0.02) and worse longitudinal language (β = -54.9, p = 0.05), information processing (β = -147, p = 0.03), executive function (β = -10.9, p = 0.03), and episodic memory performances (β = -10.6, p = 0.02). Results were similar for ePVS count. Greater arterial stiffness relates to worse basal ganglia ePVS burden, suggesting cardiovascular aging as an etiology. ePVS burden is associated with adverse cognitive trajectory, emphasizing the clinical relevance of ePVS. [ABSTRACT FROM AUTHOR]

Abstract Background Homocysteine is correlated with several imaging features of cerebral small vessel disease including white matter hyperintensities, lacunes, and enlarged perivascular spaces (EPVS) in the basal ganglia. However, little is known about EPVS in the brainstem. This study aimed to investigate the correlation between serum total homocysteine (tHcy) and EPVS in the brainstem in patients with acute isolated pontine infarction. Methods Consecutive patients with isolated pontine infarction were retrospectively enrolled. Clinical characteristics and laboratory tests including tHcy were recorded. Imaging markers of cerebral small vessel disease including EPVS in the basal ganglia (BG-EPVS), EPVS in the centrum semiovale, and EPVS in the midbrain or pons (brainstem-EPVS) were assessed using conventional magnetic resonance imaging. The relation between tHcy and EPVS of different parts in the brain was analyzed using univariate and multivariate regression model. Results A total of 227 patients were included (mean age 67.10 ± 9.38 years, male sex 58.6%). The frequencies of brainstem-EPVS and moderate to severe BG-EPVS accounted for 40.1% (91/227) and 40.5% (92/227) respectively. After controlling for confounding factors, multivariate logistic regression analyses showed that tHcy was an independent risk factor for both moderate to severe BG-EPVS (P = 0.003, P for trend < 0.001) and the presence of brainstem-EPVS (P < 0.001, P for trend < 0.001) in a dose-dependent manner. Furthermore, multivariate linear regression model indicated that the presence of brainstem-EPVS (β = 0.264, 95% confidence interval = 0.143-0.402, P < 0.001) and the severity of BG-EPVS (β = 0.162, 95% confidence interval = 0.024-0.197, P = 0.013) were positively associated with serum tHcy. Conclusions Serum tHcy is correlated with brainstem-EPVS and BG-EPVS dose-dependently. This study may support a contributing role for homocysteine in the pathophysiology of EPVS in the brainstem and the basal ganglia.

Abstract Introduction The widespread use of brain magnetic resonance imaging (MRI) has revealed the correlation between enlarged perivascular spaces (EPVS) and cognitive impairment (CI). However, few studies have examined the correlation between MRI-visible EPVS and CI in patients with Parkinson’s disease (PD) and vascular parkinsonism (VaP). This study explored how the number and main location of EPVS in PD and VaP are correlated with the occurrence of CI in these diseases to provide radiology markers and other evidence for early clinical diagnosis in a Chinese cohort. Methods Clinical data were prospectively collected from 77 patients: 26 patients clinically diagnosed with PD or probable PD, 19 patients clinically diagnosed with VaP, and 32 control subjects with normal cognitive function and no stroke or parkinsonism. The patients with PD and VaP were divided into a CI group and a no CI (NCI) group according to the Montreal Cognitive Assessment Beijing version (MoCA-BJ). The relevant clinical data were statistically analysed. Results The centrum semiovale (CSO)-EPVS, lacunes, Fazekas scores, global cortical atrophy scale (GCA) scores, Koedam posterior atrophy visual scale (KS) scores, and medial temporal atrophy (MTA) scores were higher in the PD-CI and VaP-CI groups than in the control group (adjusted P 0.05). Conclusion VaP-CI results from multiple factors and is significantly associated with BG-EPVS, lacunes, white matter hyperintensities and brain atrophy. BG-EPVS can be used as an imaging marker to distinguish VaP-CI from PD-CI.

The recently described perivascular unit (PVU) resides immediately adjacent to the true capillary neurovascular unit (NVU) in the postcapillary venule and contains the normal-benign perivascular spaces (PVS) and pathological enlarged perivascular spaces (EPVS). The PVS are important in that they have recently been identified to be the construct and the conduit responsible for the delivery of metabolic waste from the interstitial fluid to the ventricular cerebrospinal fluid for disposal into the systemic circulation, termed the glymphatic system. Importantly, the outermost boundary of the PVS is lined by protoplasmic perivascular astrocyte endfeet (pvACef) that communicate with regional neurons. As compared to the well-recognized and described neurovascular unit (NVU) and NVU coupling, the PVU is less well understood and remains an emerging concept. The primary focus of this narrative review is to compare the similarities and differences between these two units and discuss each of their structural and functional relationships and how they relate not only to brain homeostasis but also how they may relate to the development of multiple clinical neurological disease states and specifically how they may relate to obesity, metabolic syndrome, and type 2 diabetes mellitus. Additionally, the concept and importance of a perisynaptic astrocyte coupling to the neuronal synapses with pre- and postsynaptic neurons will also be considered as a perisynaptic unit to provide for the creation of the information transfer in the brain via synaptic transmission and brain homeostasis. Multiple electron microscopic images and illustrations will be utilized in order to help explain these complex units.

Shuna Yang, Xuanting Li, Wei Qin, Lei Yang, Wenli Hu Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, People’s Republic of ChinaCorrespondence: Wenli Hu, Email wenlihu3366@126.comBackground and Objective: Motor dysfunction is common in the elderly, and is associated with adverse consequences. Enlarged perivascular spaces in basal ganglia (BG-EPVSs) are considered an MRI marker of cerebral small-vessel diseases. However, the consequences of BG-EPVSs are largely unknown. In the present study, we aimed to explore the association between large numbers of BG-EPVSs and motor performance.Methods: We prospectively recruited elderly individuals in the Neurology Department of our hospital from December 1, 2020 to January 31, 2022. Participants with > 20 BG-EPVSs on the unilateral side of the slice containing the most EPVSs were classified as the BG-EPVS group (n=99) and the rest as controls (n=193). Motor performance was assessed by quantitative gait analysis, Tinetti test, timed up-and-go (TUG) test, and the Short Physical Performance Battery (SPPB). Spearman correlation analysis and multivariate linear regression analysis were performed to investigate the association between BG-EPVSs and motor performance.Results: Compared with the control group, the BG-EPVS group had lower gait speed and cadence, shorter stride length, longer TUG duration, and lower Tinetti gait test, Tinetti balance test, and SPPB scores (P< 0.01). Spearman correlation analysis showed that BG-EPVSs were negatively related to gait speed, gait cadence, stride length, and Tinetti gait test, Tinetti balance test, and SPPB scores (ρ= – 0.539 to – 0.223, P< 0.001) and positively related to TUG duration (ρ=0.397, P< 0.001). Regression analysis indicated that BG-EPVSs were an independent risk factor of lower gait speed, shorter stride length, poor balance, and poor general physical performance after adjusting for confounders (β= – 0.313 to – 0.206, P< 0.01).Conclusion: Large numbers of BG-EPVSs were independently related to poor gait, balance, and general physical performance in elderly individuals, which provides information about the consequences of BG-EPVSs and risk factors for motor dysfunction.Keywords: cerebral small-vessel diseases, enlarged perivascular spaces, motor, gait, balance, physical performance

Objectives: Perivascular spaces have been involved in neuroinflammatory and neurodegenerative diseases. Upon a certain size, these spaces can become visible on magnetic resonance imaging (MRI), referred to as enlarged perivascular spaces (EPVS) or MRI-visible perivascular spaces (MVPVS). However, the lack of systematic evidence on etiology and temporal dynamics of MVPVS hampers their diagnostic utility as MRI biomarker. Thus, the goal of this systematic review was to summarize potential etiologies and evolution of MVPVS. Methods: In a comprehensive literature search, out of 1,488 unique publications, 140 records assessing etiopathogenesis and dynamics of MVPVS were eligible for a qualitative summary. 6 records were included in a meta-analysis to assess the association between MVPVS and brain atrophy. Results: Four overarching and partly overlapping etiologies of MVPVS have been proposed: (1) Impairment of interstitial fluid circulation, (2) Spiral elongation of arteries, (3) Brain atrophy and/or perivascular myelin loss, and (4) Immune cell accumulation in the perivascular space. The meta-analysis in patients with neuroinflammatory diseases did not support an association between MVPVS and brain volume measures [R: -0.15 (95%-CI -0.40-0.11)]. Based on few and mostly small studies in tumefactive MVPVS and in vascular and neuroinflammatory diseases, temporal evolution of MVPVS is slow. Conclusion: Collectively, this study provides high-grade evidence for MVPVS etiopathogenesis and temporal dynamics. Although several potential etiologies for MVPVS emergence have been proposed, they are only partially supported by data. Advanced MRI methods should be employed to further dissect etiopathogenesis and evolution of MVPVS. This can benefit their implementation as an imaging biomarker. [ABSTRACT FROM AUTHOR]

(1) Background: to investigate the prevalence of white matter hyperintensities (WMH), risk factors, and correlation with enlarged perivascular spaces (ePVS) among young patients (age, 16–45 years) in a neurological outpatient clinic. (2) Methods: a total of 887 young patients who underwent a head magnetic resonance imaging (MRI)examination between 1 June 2021, and 30 November 2021, were included in this study. Paraventricular WMH (PWMH), deep WMH (DWMH), ePVS in the centrum semiovale (CSO-ePVS), and basal ganglia (BG-ePVS) were rated. Logistic regression analysis was used to identify the best predictors for the presence of WMH and, for the association of the severity of ePVS with the presence of WMH. Goodman–Kruskal gamma test was used to assess the correlation between the severity of ePVS and WMH. (3) Results: the prevalence of WMH was 37.0%, with low severity. Age, hypertension (p < 0.001), headache (p = 0.031), syncope (p = 0.012), and sleep disturbance (p = 0.003) were associated with the presence of DWMH. Age, sex (p = 0.032), hypertension (p = 0.004) and sleep disturbance (p < 0.001) were associated with the presence of PWMH. The severity of CSO-ePVS was associated with the presence and the severities of DWMH. The severity of BG-ePVS was associated with the presence and severities of DWMH and PWMH. (4) Conclusions: the prevalence of WMH was 37% and mild in young patients without specific causes. Older age, female, hypertension, headache, syncope, and sleep disturbance were associated with WMH. The severity of ePVS had an impact on the presence and severity of WMH in the corresponding brain regions. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to investigate the associations of enlarged perivascular spaces (EPVS) in the basal ganglia (BG) and centrum semiovale (CSO) with beta‐amyloid (Aβ) and tau deposition in older adults with a diverse cognitive spectrum. Methods: A total of 163 (68 cognitively normal and 95 cognitively impaired) older participants underwent [11C] Pittsburgh compound B and [18F] AV‐1451 PET, and MRI. EPVS in the BG and CSO and other small vessel disease markers, such as white matter hyperintensities, lacunes, and deep and lobar microbleeds, were assessed. Results: Increased EPVS in the BG showed a significant association with lower cerebral tau deposition, even after controlling for other small vessel disease markers. Further exploratory analyses showed that this association was significant in cognitively impaired, Aβ‐positive, or APOE4‐positive individuals, but not significant in the cognitively normal, Aβ‐negative, or APOE4‐negative participants. In contrast to EPVS in the BG, EPVS in the CSO did not have any relationship with cerebral tau deposition. In addition, none of the two types of EPVS were associated with cerebral Aβ deposition. Conclusion: Brain tau deposition appears to be reduced with increased EPVS in the BG, especially in individuals with cognitive impairment, pathological amyloid burden, or genetic Alzheimer's disease risk. [ABSTRACT FROM AUTHOR]

Background: The clinical significance of enlarged perivascular spaces (EPVS) in Alzheimer' s disease (AD) was ambiguous., Objective: To investigate whether EPVS contribute to blood-brain barrier (BBB) leakage and cognition in AD., Methods: The study included a total of 64 participants (26 healthy controls and 38 patients with AD). The evaluation of EPVS and BBB permeability was performed in specific anatomical locations: the centrum semiovale (CSO), basal ganglia, and hippocampus. The EPVS ratings were performed according to Potter's instructions. BBB permeability was evaluated using dynamic contrast-enhanced-MRI. The relationship between EPVS and global cognition (Mini-Mental State Examination and Montreal Cognitive Assessment), cognitive subdomains, and BBB permeability were examined in both groups. Finally, the relationship between CSO BBB permeability and cognition in AD patients was investigated., Results: High-grade CSO EPVS was found associated with AD (OR: 3.40, 95% CI: 1.11-11.90, p = 0.04). In the AD group, a significant correlation was observed between high-grade CSO EPVS and lower MMSE score (r = -0.36, p = 0.03) and verbal fluency (r = -0.44, p = 0.01). High-grade CSO EPVS positively correlated with BBB leakage (r = 0.58, p < 0.001). The BBB permeability of CSO negatively correlated with verbal fluency (r = -0.52, p < 0.001) and attention (r = -0.40, p = 0.01)., Conclusions: High-grade CSO EPVS is related to BBB leakage, which contributes to cognitive impairment in AD patients, especially verbal frequency. CSO EPVS can function as a convenient AD marker for intervention and therapy., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: To determine whether the severity of cerebral small vessel disease (SVD) is associated with prehospital delay in acute ischemic stroke., Methods: Consecutive patients with ischemic stroke were included in this study. We evaluated the SVD burden using the total SVD score. Patients were divided into 2 groups: onset-to-door time within 4.5 hours (early arrival group) and onset-to-door time over 4.5 hours (delayed arrival group). First, we assessed whether the total SVD score was related to prehospital delay using a logistic regression analysis. Second, we assessed which item of the score was independently associated with delays. Finally, we determined whether the item had a linear association with the delay., Results: Of the 2,112 screened patients, 1,754 were enrolled in the study (1,253 males [71%]; median age, 69 years). There were 1,105 patients (63%) in the delayed arrival group. The total SVD score was independently associated with delay (OR 1.11, 95% CI 1.01-1.21, p=0.025). Among the 4 items of the score, only enlarged perivascular spaces (EPVS) in the basal ganglia was independently associated with delay (OR 1.37, 95% CI 1.05-1.80, p=0.022). A linear trend was observed between EPVS grade and delay with reference to EPVS grade 0-1 (EPVS grade 2: OR 1.22, 95% CI 0.92-1.62, p=0.170, EPVS grade 3: OR 1.69, 95% CI 1.20-2.38, p=0.002, EPVS grade 4: OR 2.17, 95% CI 1.37-3.44, p=0.001)., Conclusions: Prehospital delay in acute ischemic stroke could be associated with the severity of SVD, particularly EPVS in the basal ganglia.

ObjectivesPerivascular spaces have been involved in neuroinflammatory and neurodegenerative diseases. Upon a certain size, these spaces can become visible on magnetic resonance imaging (MRI), referred to as enlarged perivascular spaces (EPVS) or MRI-visible perivascular spaces (MVPVS). However, the lack of systematic evidence on etiology and temporal dynamics of MVPVS hampers their diagnostic utility as MRI biomarker. Thus, the goal of this systematic review was to summarize potential etiologies and evolution of MVPVS.MethodsIn a comprehensive literature search, out of 1,488 unique publications, 140 records assessing etiopathogenesis and dynamics of MVPVS were eligible for a qualitative summary. 6 records were included in a meta-analysis to assess the association between MVPVS and brain atrophy.ResultsFour overarching and partly overlapping etiologies of MVPVS have been proposed: (1) Impairment of interstitial fluid circulation, (2) Spiral elongation of arteries, (3) Brain atrophy and/or perivascular myelin loss, and (4) Immune cell accumulation in the perivascular space. The meta-analysis in patients with neuroinflammatory diseases did not support an association between MVPVS and brain volume measures [R: −0.15 (95%-CI −0.40–0.11)]. Based on few and mostly small studies in tumefactive MVPVS and in vascular and neuroinflammatory diseases, temporal evolution of MVPVS is slow.ConclusionCollectively, this study provides high-grade evidence for MVPVS etiopathogenesis and temporal dynamics. Although several potential etiologies for MVPVS emergence have been proposed, they are only partially supported by data. Advanced MRI methods should be employed to further dissect etiopathogenesis and evolution of MVPVS. This can benefit their implementation as an imaging biomarker.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=346564, identifier CRD42022346564.

Background and purpose: Cerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In subjects with Alzheimer’s disease (AD), we assessed characteristic features and amounts of WMH, lacunes, and ePVS in four CAA categories (no, mild, moderate and severe CAA) and correlated these with Clinical Dementia Rating sum of boxes (CDRsb) score, ApoE genotype, and neuropathological changes at autopsy. Methods: The study included patients with a clinical diagnosis of dementia due to AD and neuropathological confirmation of AD and CAA in the National Alzheimer’s Coordinating Center (NACC) database. The WMH, lacunes, and ePVS were evaluated using semi-quantitative scales. Statistical analyses compared the WMH, lacunes, and ePVS values in the four CAA groups with vascular risk factors and AD severity treated as covariates, and to correlate the imaging features with CDRsb score, ApoE genotype, and neuropathological findings. Results: The study consisted of 232 patients, of which 222 patients had FLAIR data available and 105 patients had T2-MRI. Occipital predominant WMH were significantly associated with the presence of CAA (p = 0.007). Among the CAA groups, occipital predominant WMH was associated with severe CAA (β = 1.22, p = 0.0001) compared with no CAA. Occipital predominant WMH were not associated with the CDRsb score performed at baseline (p = 0.68) or at follow-up 2–4 years after the MRI (p = 0.92). There was no significant difference in high grade ePVS in the basal ganglia (p = 0.63) and centrum semiovale (p = 0.95) among the four CAA groups. The WMH and ePVS on imaging did not correlate with the number of ApoE ε4 alleles but the WMH (periventricular and deep) correlated with the presence of infarcts, lacunes and microinfarcts on neuropathology. Conclusion: Among patients with AD, occipital predominant WMH is more likely to be found in patients with severe CAA than in those without CAA. The high-grade ePVS in centrum semiovale were common in all AD patients regardless of CAA severity.

Objective: To explore the related factors of enlarged perivascular spaces (EPVS) and lacunes in the patients with hypertension, and to provide a basis for the prevention and treatment of cerebral small vessel disease. Methods: A total of 1 070 patients with essential hypertension without stroke history were enrolled, and the data was analyzed retrospectively. All patients received MRI scanning and ambulatory blood pressure monitoring. According to MRI images, they were divided into normal control, EPVS and lacunes groups, respectively. Univariate and multivariate logistic regression were performed among three groups to determine the factors related to EPVS and lacunes. Results: The indexes including age, gender, smoking, diabetes history, antiplatelet drugs, statins, hypertension duration, nocturnal blood pressure dip degree, mean systolic blood pressure, cholesterol, triglyceride, high-density lipoprotein, low density lipoprotein, urea nitrogen, creatinine, homocysteine and carotid plaque were significantly different among EPVS, lacunes and controls groups. Mean high systolic blood pressure and age were independent risk factors for EPVS, while the dipping degree of blood pressure, antiplatelet medicines and statins were independent protective factors for it. High mean systolic blood pressure, old age, smoking, and diabetes were independent risk factors for lacunes, while the dipping degree of nocturnal blood pressure, antiplatelet medicines and statins were independent protective factors for lacunes. Conclusions: For the patients with hypertension, the increase of mean systolic blood pressure and the decrease of nocturnal blood pressure dipping are the risk factors for EPVS and lacunes. Besides controlling mean systolic blood pressure level, the patients with hypertension should also receive chronotherapy to restore the normal nocturnal blood pressure dipping through changing the time of taking medicine.

Embryonic genetic mechanisms are present in the brain and ready to be placed into action upon cellular injury, termed the response to injury wound-healing (RTIWH) mechanism. When injured, regional brain endothelial cells initially undergo activation and dysfunction with initiation of hemostasis, inflammation (peripheral leukocytes, innate microglia, and perivascular macrophage cells), proliferation (astrogliosis), remodeling, repair, and resolution phases if the injurious stimuli are removed. In conditions wherein the injurious stimuli are chronic, as occurs in obesity, metabolic syndrome, and type 2 diabetes mellitus, this process does not undergo resolution and there is persistent RTIWH with remodeling. Indeed, the brain is unique, in that it utilizes its neuroglia: the microglia cell, along with peripheral inflammatory cells and its astroglia, instead of peripheral scar-forming fibrocytes/fibroblasts. The brain undergoes astrogliosis to form a gliosis scar instead of a fibrosis scar to protect the surrounding neuropil from regional parenchymal injury. One of the unique and evolving remodeling changes in the brain is the development of enlarged perivascular spaces (EPVSs), which is the focus of this brief review. EPVSs are important since they serve as a biomarker for cerebral small vessel disease and also represent an impairment of the effluxing glymphatic system that is important for the clearance of metabolic waste from the interstitial fluid to the cerebrospinal fluid, and disposal. Therefore, it is important to better understand how the RTIWH mechanism is involved in the development of EPVSs that are closely associated with and important to the development of premature and age-related cerebrovascular and neurodegenerative diseases with impaired cognition.