Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

High pulse wave velocity is associated with enlarged perivascular spaces in dementia with Lewy bodies.

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.

Unraveling the Predictors of Enlarged Perivascular Spaces: A Comprehensive Logistic Regression Approach in Cerebral Small Vessel Disease.

Background: 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.

Enlarged perivascular spaces are associated with brain microangiopathy and aging in multiple sclerosis.

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.

Alterations in brain fluid physiology during the early stages of development of ischaemic oedema.

Oedema occurs when higher than normal amounts of solutes and water accumulate in tissues. In brain parenchymal tissue, vasogenic oedema arises from changes in blood-brain barrier permeability, e.g. in peritumoral oedema. Cytotoxic oedema arises from excess accumulation of solutes within cells, e.g. ischaemic oedema following stroke. This type of oedema is initiated when blood flow in the affected core region falls sufficiently to deprive brain cells of the ATP needed to maintain ion gradients. As a consequence, there is: depolarization of neurons; neural uptake of Na+ and Cl- and loss of K+; neuronal swelling; astrocytic uptake of Na+, K+ and anions; swelling of astrocytes; and reduction in ISF volume by fluid uptake into neurons and astrocytes. There is increased parenchymal solute content due to metabolic osmolyte production and solute influx from CSF and blood. The greatly increased [K+]isf triggers spreading depolarizations into the surrounding penumbra increasing metabolic load leading to increased size of the ischaemic core. Water enters the parenchyma primarily from blood, some passing into astrocyte endfeet via AQP4. In the medium term, e.g. after three hours, NaCl permeability and swelling rate increase with partial opening of tight junctions between blood-brain barrier endothelial cells and opening of SUR1-TPRM4 channels. Swelling is then driven by a Donnan-like effect. Longer term, there is gross failure of the blood-brain barrier. Oedema resolution is slower than its formation. Fluids without colloid, e.g. infused mock CSF, can be reabsorbed across the blood-brain barrier by a Starling-like mechanism whereas infused serum with its colloids must be removed by even slower extravascular means. Large scale oedema can increase intracranial pressure (ICP) sufficiently to cause fatal brain herniation. The potentially lethal increase in ICP can be avoided by craniectomy or by aspiration of the osmotically active infarcted region. However, the only satisfactory treatment resulting in retention of function is restoration of blood flow, providing this can be achieved relatively quickly. One important objective of current research is to find treatments that increase the time during which reperfusion is successful. Questions still to be resolved are discussed.

Systematic review and meta-analysis of automated methods for quantifying enlarged perivascular spaces in the brain.

Research into magnetic resonance imaging (MRI)-visible perivascular spaces (PVS) has recently increased, as results from studies in different diseases and populations are cementing their association with sleep, disease phenotypes, and overall health indicators. With the establishment of worldwide consortia and the availability of large databases, computational methods that allow to automatically process all this wealth of information are becoming increasingly relevant. Several computational approaches have been proposed to assess PVS from MRI, and efforts have been made to summarise and appraise the most widely applied ones. We systematically reviewed and meta-analysed all publications available up to September 2023 describing the development, improvement, or application of computational PVS quantification methods from MRI. We analysed 67 approaches and 60 applications of their implementation, from 112 publications. The two most widely applied were the use of a morphological filter to enhance PVS-like structures, with Frangi being the choice preferred by most, and the use of a U-Net configuration with or without residual connections. Older adults or population studies comprising adults from 18 years old onwards were, overall, more frequent than studies using clinical samples. PVS were mainly assessed from T2-weighted MRI acquired in 1.5T and/or 3T scanners, although combinations using it with T1-weighted and FLAIR images were also abundant. Common associations researched included age, sex, hypertension, diabetes, white matter hyperintensities, sleep and cognition, with occupation-related, ethnicity, and genetic/hereditable traits being also explored. Despite promising improvements to overcome barriers such as noise and differentiation from other confounds, a need for joined efforts for a wider testing and increasing availability of the most promising methods is now paramount.

The Ocular Glymphatic System-Current Understanding and Future Perspectives.

The ocular glymphatic system subserves the bidirectional polarized fluid transport in the optic nerve, whereby cerebrospinal fluid from the brain is directed along periarterial spaces towards the eye, and fluid from the retina is directed along perivenous spaces following upon its axonal transport across the glial lamina. Fluid homeostasis and waste removal are vital for retinal function, making the ocular glymphatic fluid pathway a potential route for targeted manipulation to combat blinding ocular diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Several lines of work investigating the bidirectional ocular glymphatic transport with varying methodologies have developed diverging mechanistic models, which has created some confusion about how ocular glymphatic transport should be defined. In this review, we provide a comprehensive summary of the current understanding of the ocular glymphatic system, aiming to address misconceptions and foster a cohesive understanding of the topic.

Non-hemorrhagic imaging markers of cerebral amyloid angiopathy in memory clinic patients.

INTRODUCTION: The Boston criteria v2.0 for cerebral amyloid angiopathy (CAA) incorporated non-hemorrhagic imaging markers. Their prevalence and significance in patients with cognitive impairment remain uncertain. METHODS: We studied 622 memory clinic patients with available magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers. Two raters assessed non-hemorrhagic markers, and we explored their association with clinical characteristics through multivariate analyses. RESULTS: Most patients had mild cognitive impairment; median age was 71 years and 50% were female. Using the v2.0 criteria, possible or probable CAA increased from 75 to 383 patients. Sixty-eight percent of the sample had non-hemorrhagic CAA markers, which were independently associated with age (odds ratio [OR] = 1.04, 95% confidence interval [CI] = 1.01-1.07), female sex (OR = 1.68, 95% CI = 1.11-2.54), and hemorrhagic CAA markers (OR = 2.11, 95% CI = 1.02-4.35). DISCUSSION: Two-thirds of patients from a memory clinic cohort had non-hemorrhagic CAA markers, increasing the number of patients meeting the v2.0 CAA criteria. Longitudinal approaches should explore the implications of these markers, particularly the hemorrhagic risk in this population. HIGHLIGHTS: The updated Boston criteria for cerebral amyloid angiopathy (CAA) now include non-hemorrhagic markers. The prevalence of non-hemorrhagic CAA markers in memory clinic patients is unknown. Two-thirds of patients in our memory clinic presented non-hemorrhagic CAA markers. The presence of these markers was associated with age, female sex, and hemorrhagic CAA markers. The hemorrhagic risk of patients presenting these type of markers remains unclear.

Multimodal neuroimaging fusion unravel structural-functional-neurotransmitter change in Parkinson's disease with impulse control disorders.

BACKGROUND: Impulse control disorders (ICD) in Parkinson's disease (PD) is highly multifactorial in etiology and has intricate neural mechanisms. Our multimodal neuroimaging study aimed to investigate the specific patterns of structure-function-neurotransmitter interactions underlying ICD. METHODS: Thirty PD patients with ICD (PD-ICD), 30 without ICD (PD-NICD) and 32 healthy controls (HCs) were recruited. Gyrification and perivascular spaces (PVS) were computed to capture the alternations of cortical surface morphology and glymphatic function. Seed-based functional connectivity (FC) were performed to identify the corresponding functional changes. Further, JuSpace toolbox were employed for cross-modal correlations to evaluate whether the spatial patterns of functional alterations in ICD patients were associated with specific neurotransmitter system. RESULTS: Compared to PD-NICD, PD-ICD patients showed hypogyrification and enlarged PVS volume fraction in the left orbitofrontal gyrus (OFG), as well as decreased FC between interhemispheric OFG. The interhemispheric OFG connectivity reduction was associated with spatial distribution of µ-opioid pathway (r = -0.186, p = 0.029, false discovery rate corrected). ICD severity was positively associated with the PVS volume fraction of left OFG (r = 0.422, p = 0.032). Furthermore, gyrification index (LGI) and percent PVS (pPVS) in OFG and their combined indicator showed good performance in differentiating PD-ICD from PD-NICD. CONCLUSIONS: Our findings indicated that the co-altered structure-function-neurotransmitter interactions of OFG might be involved in the pathogenesis of ICD.

Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies.

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

[Assessment of the significance of dilated perivascular spaces and nocture arterial hypertension in the development of Alzheimer's disease]. / Otsenka znacheniya rasshirennykh perivaskulyarnykh prostranstv i nochnoi arterial'noi gipertenzii v razvitii bolezni Al'tsgeimera.

OBJECTIVE: To study the severity and localization of dilated perivascular spaces (DPVS), the levels of protein markers of amyloidosis and neurodegeneration in the cerebrospinal fluid (CSF) at different daily blood pressure (BP) profiles in patients with Alzheimer's disease (AD) and other types of cognitive impairment. MATERIAL AND METHODS: A total of 119 people, aged 53 to 92 years, including 55 patients with AD, 27 patients with vascular cognitive disorders (VCD), 19 patients with frontotemporal degeneration (FTD). All patients underwent BP monitoring for 24 hours using a standard oscillometric measurement method, lumbar puncture to assess Aß-42 and Aß-40 amyloid protein, total and phosphorylated tau protein in the CSF, magnetic resonance imaging tomography of the brain with subsequent assessment of the severity of expansion and localization of DPVS according to the G.M. Potter scale. RESULTS: In 58.3% of patients with AD, there is no adequate reduction in BP at night in comparison with patients with VCD (p<0.05). A significant degree of expansion of the DPVS turned out to be most typical for patients with AD: grade 3 was detected in 45.7% of patients, and the maximum, grade 4, was detected in 13.4%. At the same time, DPVSs were significantly more often detected in the group of subjects with insufficient reduction in diastolic BP (DBP) at night. A strong inverse correlation was established between the level of Aß-42 in the CSF and the variability of DBP at night (r= -0.92; p<0.05). The decrease in the level of Aß-42 in AD, especially at the prodromal stage, is directly related to the low variability of DBP at night, which is more characteristic of an insufficient decrease or increase in BP during night sleep. CONCLUSION: Patients with AD were characterized by an insufficient decrease in BP at night, which is associated with the severity and degree of maximum expansion of the DPVS. A decrease in the level of Aß-42 amyloid protein in the CSF strongly correlates with the variability of DBP at night.

Evaluating the glymphatic system via magnetic resonance diffusion tensor imaging along the perivascular spaces in brain tumor patients.

PURPOSE: To investigate glymphatic system function in patients with brain tumors, including both primary and secondary tumors, using diffusion tensor imaging along perivascular spaces (DTI-ALPS). METHODS: We retrospectively analyzed the MR DTI of 24 patients with unilateral brain tumors and compared them with age and sex-matched controls. We compared the DTI-ALPS index of the ipsi- and contralateral brain hemispheres. The region of interest was placed in the periventricular vessels adjacent to the lateral ventricles. Differences between sex, age, and kind of tumor (primary or brain metastasis) were evaluated. Correlations between DTI-ALPS index and age and the tumor's apparent diffusion coefficient (ADC) were also investigated. RESULTS: The DTI-ALPS index was significantly lower (p < 0.05) in the tumor-affected hemisphere (mean = 1.26 ± 0.24) than contralateral (mean = 1.43 ± 0.28). A comparison with healthy controls revealed no significant difference on the matched ipsilateral side. However, the DTI-ALPS index of the contralateral side of the patients was larger than the HC. Additionally, no statistically significant differences were found when analyzing the DTI-ALPS index vs. age, sex, and tumor entity. Additionally, we did not find a correlation between the DTI-ALPS index and patient age or tumor ADC. CONCLUSION: The decreased DTI-ALPS index in the tumor-affected hemisphere may be related to impaired glymphatic system function. However, cancer is often a systemic disease; thus, the DTI-ALPS index from the contralateral brain hemisphere may not generally be considered as a normal control. Nonetheless, the DTI-ALPS index does not only reflect diffusion in the perivascular spaces but it can also be influenced by factors such as axonal degeneration. Therefore, it does not directly reflect brain waste clearance and changes in the index should be interpreted carefully.

Effects of prospective motion correction on perivascular spaces at 7T MRI evaluated using motion artifact simulation.

PURPOSE: The effectiveness of prospective motion correction (PMC) is often evaluated by comparing artifacts in images acquired with and without PMC (NoPMC). However, such an approach is not applicable in clinical setting due to unavailability of NoPMC images. We aim to develop a simulation approach for demonstrating the ability of fat-navigator-based PMC in improving perivascular space (PVS) visibility in T2-weighted MRI. METHODS: MRI datasets from two earlier studies were used for motion artifact simulation and evaluating PMC, including T2-weighted NoPMC and PMC images. To simulate motion artifacts, k-space data at motion-perturbed positions were calculated from artifact-free images using nonuniform Fourier transform and misplaced onto the Cartesian grid before inverse Fourier transform. The simulation's ability to reproduce motion-induced blurring, ringing, and ghosting artifacts was evaluated using sharpness at lateral ventricle/white matter boundary, ringing artifact magnitude in the Fourier spectrum, and background noise, respectively. PVS volume fraction in white matter was employed to reflect its visibility. RESULTS: In simulation, sharpness, PVS volume fraction, and background noise exhibited significant negative correlations with motion score. Significant correlations were found in sharpness, ringing artifact magnitude, and PVS volume fraction between simulated and real NoPMC images (p ≤ 0.006). In contrast, such correlations were reduced and nonsignificant between simulated and real PMC images (p ≥ 0.48), suggesting reduction of motion effects with PMC. CONCLUSIONS: The proposed simulation approach is an effective tool to study the effects of motion and PMC on PVS visibility. PMC may reduce the systematic bias of PVS volume fraction caused by motion artifacts.

Relationship of neutrophil/lymphocyte ratio with cerebral small vessel disease and its common imaging markers.

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.

Gaps in the wall of a perivascular space act as valves to produce a directed flow of cerebrospinal fluid: a hoop-stress model.

The flow of cerebrospinal fluid (CSF) along perivascular spaces (PVSs) is an important part of the brain's system for clearing metabolic waste. Astrocyte endfeet bound the PVSs of penetrating arteries, separating them from brain extracellular space. Gaps between astrocyte endfeet might provide a low-resistance pathway for fluid transport across the wall. Recent studies suggest that the astrocyte endfeet function as valves that rectify the CSF flow, producing the net flow observed in pial PVSs by changing the size of the gaps in response to pressure changes. In this study, we quantify this rectification based on three features of the PVSs: the quasi-circular geometry, the deformable endfoot wall, and the pressure oscillation inside. We provide an analytical model, based on the thin-shell hoop-stress approximation, and predict a pumping efficiency of about 0.4, which would contribute significantly to the observed flow. When we add the flow resistance of the extracellular space (ECS) to the model, we find an increased net flow during sleep, due to the known increase in ECS porosity (decreased flow resistance) compared to that in the awake state. We corroborate our analytical model with three-dimensional fluid-solid interaction simulations.

Serum uric acid is associated with midbrain enlarged perivascular spaces: Results from Multi-modality Medical imaging sTudy bAsed on KaiLuan Study (META-KLS).

BACKGROUND: Serum uric acid (SUA) is a major cause of cardiovascular and cerebrovascular diseases. Whether and to what extent the excess risk of enlarged perivascular spaces (EPVS) conferred by SUA is unknown. The study was conducted to investigate the association between SUA and EPVS in different brain regions. METHODS: Data are from Multi-modality medical imaging study based on Kailuan study (META-KLS) in this cross-sectional study. Participants were divided into five groups based on SUA levels, and EPVS in basal ganglia (BG), centrum semiovale (CSO) and midbrain (MB) was systematically assessed and divided into Low and High group. Odds ratio (OR) and 95% confidence intervals (95% CIs) for high EPVS outcomes were estimated using multivariable logistic regression analysis. Restricted cubic spline (RCS) was used to further investigate dose-response relationship. RESULTS: A total of 1014 participants aged 25-83 years from 11 centers were enrolled in the study. In the multivariable-adjusted model, SUA, as an independent risk factor, correlated positively with high degree of MB-EPVS (OR, 1.002; 95% CI, 1.000 to 1.004; p = 0.023) in general population. In addition, RCS further demonstrated the linear association between SUA and MB-EPVS (p = 0.072). No association was found between SUA and BG-EPVS or CSO-EPVS. CONCLUSION: SUA was an independent risk factor of MB-EPVS. High SUA levels were more predictive of increased risk occurrence of high degree of MB-EPVS, supporting a linear association between SUA and MB-EPVS and further indicating that SUA may play an important role in cerebral small vessel disease. TRIAL REGISTRATION: The KaiLuan Study and META-KLS were registered online (ChiCTR2000029767 on chictr.org.cn and NCT05453877 on Clinicaltrials.gov, respectively).

Enlarged perivascular spaces are associated with white matter injury, cognition and inflammation in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

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 (ß = 0.57, P = 0.05), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.49, P = 0.04) and marginally with decreased brain parenchymal fraction (ß = -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 (ß = 0.57, P = 0.02), Clinical Dementia Rating Sum-of-Boxes score (ß = 0.52, P = 0.02), Mini-Mental State Examination score (ß = -1.49, P = 0.03) and marginally with decreased brain parenchymal fraction (ß = -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 (ß = 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 (ß = -0.0007, P < 0.01) and Mini-Mental State Examination score (ß = -0.02, P < 0.01) and increased Trail Making Test B completion time (ß = 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.

Cerebral Small Vessel Disease Burden in Patients with Transient Global Amnesia and its Relationship with Recurrence.

OBJECTIVE: Cerebral Small Vessel Disease (CSVD) has not been systematically studied in patients with Transient Global Amnesia (TGA). We aimed to investigate the CSVD burden in patients with TGA and its relationship with TGA recurrence. METHODS: We retrospectively examined 69 patients diagnosed with TGA in a single center between January 2015 and November 2023. The overall CSVD burden and single CSVD imaging markers, including enlarged perivascular spaces in the hippocampus (H-EPVS), were measured in each patient and compared with those in 69 age- and sex-matched healthy controls. Multivariate logistic regression was performed to determine independent predictors of recurrence. RESULTS: Of the 69 included patients, 40 (58%) were female, and the median age was 67 years (range 42-83 years). Twenty-one patients (30.4%) showed dot-like hippocampal hyperintensities on diffusion-weighted imaging (DWI). The mean follow-up was 51 months. Sixteen patients (23.2%) experienced TGA recurrence. The burden of overall CSVD, lacunes, WMH, EPVS, and extensive H-EPVS was higher in TGA patients than in controls. TGA patients who experienced recurrence had a heavier overall CSVD burden, lower frequency of hippocampal DWI hyperintensities, and longer follow-up duration than those who had with single episode. In the multivariate analysis, only follow-up duration was an independent predictor of TGA recurrence. CONCLUSION: The overall CSVD burden and extensive H-EPVS burden were higher in patients with TGA than healthy controls. Follow-up duration but not overall CSVD burden may predict TGA recurrence.

Assessment of Perivascular Space Morphometry Across the White Matter in Huntington's Disease Using MRI.

Background: Perivascular spaces (PVS) are fluid-filled cavities surrounding small cerebral blood vessels. There are limited reports of enlarged PVS across the grey matter in manifest Huntington's disease (HD). Little is known about how PVS morphometry in the white matter may contribute to HD. Enlarged PVS have the potential to both contribute to HD pathology and affect the distribution and success of intraparenchymal and intrathecally administered huntingtin-lowering therapies. Objective: To investigate PVS morphometry in the global white matter across the spectrum of HD. Relationships between PVS morphometry and disease burden and severity measures were examined. Methods: White matter PVS were segmented on 3T T2 W MRI brain scans of 33 healthy controls, 30 premanifest HD (pre-HD), and 32 early manifest HD (early-HD) participants from the Vancouver site of the TRACK-HD study. PVS count and total PVS volume were measured. Results: PVS total count slightly increased in pre-HD (p = 0.004), and early-HD groups (p = 0.005), compared to healthy controls. PVS volume, as a percentage of white matter volume, increased subtly in pre-HD compared to healthy controls (p = 0.044), but not in early-HD. No associations between PVS measures and HD disease burden or severity were found. Conclusions: This study reveals relatively preserved PVS morphometry across the global white matter of pre-HD and early-HD. Subtle morphometric abnormalities are implied but require confirmation in a larger cohort. However, in conjunction with previous publications, further investigation of PVS in HD and its potential impact on future treatments, with a focus on subcortical grey matter, is warranted.

Spaceflight-associated neuro-ocular syndrome: potential etiologies and connections to the glymphatic system.

The etiology of spaceflight-associated neuro-ocular syndrome (SANS) is a developing field of research, with many current hypotheses receiving varying degrees of support. This syndrome affects ∼70% of astronauts both during and after long-duration space missions, resulting in impaired near vision and visual scotomas (blind spots). In this article, three prominent risk factors for SANS including zero gravity conditions, extraterrestrial hypercapnic environments, and individual genetic predisposition are described. These risk factors are then compared and their pathophysiological pathways are divided into five current hypotheses for the development of SANS. Finally, glymphatic system impairment is explored as a potential mutual end point for these pathways in the development of SANS.