The glymphatic system and cerebral small vessel disease.

OBJECTIVES: Cerebral small vessel disease is a group of pathologies in which alterations of the brain's blood vessels contribute to stroke and neurocognitive changes. Recently, a neurotoxic waste clearance system composed of perivascular spaces abutting the brain's blood vessels, termed the glymphatic system, has been identified as a key player in brain homeostasis. Given that small vessel disease and the glymphatic system share anatomical structures, this review aims to reexamine small vessel disease in the context of the glymphatic system and highlight novel aspects of small vessel disease physiology. MATERIALS AND METHODS: This review was conducted with an emphasis on studies that examined aspects of small vessel disease and on works characterizing the glymphatic system. We searched PubMed for relevant articles using the following keywords: glymphatics, cerebral small vessel disease, arterial pulsatility, hypertension, blood-brain barrier, endothelial dysfunction, stroke, diabetes. RESULTS: Cerebral small vessel disease and glymphatic dysfunction are anatomically connected and significant risk factors are shared between the two. These include hypertension, type 2 diabetes, advanced age, poor sleep, obesity, and neuroinflammation. There is clear evidence that CSVD hinders the effective functioning of glymphatic system. CONCLUSION: These shared risk factors, as well as the model of cerebral amyloid angiopathy pathogenesis, hint at the possibility that glymphatic dysfunction could independently contribute to the pathogenesis of cerebral small vessel disease. However, the current evidence supports a model of cascading dysfunction, wherein concurrent small vessel and glymphatic injury hinder glymphatic-mediated recovery and promote the progression of subclinical to clinical disease.

[Cerebral small vessel disease]. / Microangiopathie cérébrale.

Cerebral microangiopathy is the second leading cause of dementia after Alzheimer's disease and is a co-factor in the majority of dementias. Its clinical manifestations are multiple and include in addition to cognitive and neuropsychiatric manifestations, also problems of gait, urinary continence, and lacunar-ischaemic and haemorrhagic strokes. Patients with similar radiologic images can present very variable clinical pictures, partially resulting from damage to the neurovascular unit, not visible on conventional MRI, and affecting different neural networks. Management and prevention are possible and effective with well-known, readily available and affordable treatments, through aggressive management of cerebrovascular risk factors.

La microangiopathie cérébrale est la deuxième cause de démence après la maladie d'Alzheimer et est un cofacteur dans la majorité des démences. Ses manifestations cliniques sont multiples et incluent, en plus des troubles cognitifs, des troubles de la marche, de la continence urinaire, neuropsychiatriques, et des AVC lacunaires-ischémiques et hémorragiques. Des patients avec des images radiologiques similaires peuvent présenter des tableaux cliniques très variables, en partie découlant d'atteintes de l'unité neurovasculaire, non visibles en IRM conventionnelle, et altérant des réseaux neuronaux différents. Une prise en charge et une prévention sont possibles et efficaces avec des traitements bien connus, disponibles à un prix abordable, par un traitement agressif des facteurs de risque cérébrovasculaire.

Excessive salt intake accelerates the progression of cerebral small vessel disease in older adults.

BACKGROUND: It is unclear whether excessive salt intake accelerates the progression of cerebral small vessel disease (CSVD). The major objective of this study was to investigate the harmful effect of excessive salt intake on the progression of CSVD in older individuals. METHODS: Between May 2007 and November 2010, 423 community-dwelling individuals aged 60 years and older were recruited from the Shandong area, China. Salt intake was estimated using 24-hour urine collection for 7 consecutive days at baseline. Participants were classified into low, mild, moderate and high groups according to the salt intake estimation. CSVD including white matter hyperintensities (WMHs), lacunes, microbleeds and an enlarged perivascular space (EPVS) were determined using brain magnetic resonance imaging. RESULTS: During an average of five years of follow-up, the WMH volume and WMH-to-intracranial ratio were increased in the four groups. However, the increasing trends in the WMH volume and WMH-to-intracranial ratio were significantly faster in the higher salt intake groups compared with the lower salt intake groups (Padjusted < 0.001). The cumulative hazard ratios of new-incident WMHs (defined as those with Fazekas scale scores ≥ 2), new-incident lacunes, microbleeds or an EPVS, as well as composites of CSVD, were respectively 2.47, 2.50, 3.33, 2.70 and 2.89 for the mild group; 3.72, 3.74, 4.66, 4.01 and 4.49 for the moderate group; and 7.39, 5.82, 7.00, 6.40 and 6.61 for the high group, compared with the low group after adjustment for confounders (Padjusted < 0.001). The risk of new-incident WMHs, lacunes, microbleeds or an EPVS, and composites of CSVD was significantly increased with each 1-standard-deviation increment in salt intake (Padjusted < 0.001). CONCLUSION: Our data indicates that excessive salt intake is an important and independent contributor to the progression of CVSD in older adults.

Glymphatic pathway in sporadic cerebral small vessel diseases: From bench to bedside.

Cerebral small vessel diseases (CSVD) consist of a group of diseases with high heterogeneity induced by pathologies of intracranial small blood vessels. Endothelium dysfunction, bloodbrain barrier leakage and the inflammatory response are traditionally considered to participate in the pathogenesis of CSVD. However, these features cannot fully explain the complex syndrome and related neuroimaging characteristics. In recent years, the glymphatic pathway has been discovered to play a pivotal role in clearing perivascular fluid and metabolic solutes, which has provided novel insights into neurological disorders. Researchers have also explored the potential role of perivascular clearance dysfunction in CSVD. In this review, we presented a brief overview of CSVD and the glymphatic pathway. In addition, we elucidated CSVD pathogenesis from the perspective of glymphatic failure, including basic animal models and clinical neuroimaging markers. Finally, we proposed forthcoming clinical applications targeting the glymphatic pathway, hoping to provide novel ideas on promising therapies and preventions of CSVD.

Progress on Prevention and Treatment of Cerebral Small Vascular Disease Using Integrative Medicine.

Cerebral small vessel disease (CSVD) is a senile brain lesion caused by the abnormal structure and function of arterioles, venules and capillaries in the aging brain. The etiology of CSVD is complex, and disease is often asymptomatic in its early stages. However, as CSVD develops, brain disorders may occur, such as stroke, cognitive dysfunction, dyskinesia and mood disorders, and heart, kidney, eye and systemic disorders. As the population continues to age, the burden of CSVD is increasing. Moreover, there is an urgent need for better screening methods and diagnostic markers for CSVD, in addition to preventive and asymptomatic- and mild-stage treatments. Integrative medicine (IM), which combines the holistic concepts and syndrome differentiations of Chinese medicine with modern medical perspectives, has unique advantages for the prevention and treatment of CSVD. In this review, we summarize the biological markers, ultrasound and imaging features, disease-related genes and risk factors relevant to CSVD diagnosis and screening. Furthermore, we discuss IM-based CSVD prevention and treatment strategies to stimulate further research in this field.

Annual exposure to PM10 is related to cerebral small vessel disease in general adult population.

Ambient air pollution is one of the most important global health issues. Although several studies have been reported the associations between air pollution and brain function or structure, impact of the air pollution on cerebral small vessel disease (cSVD) have rarely been explored in Asian adult population. We evaluated the association between exposure to air pollutants and cSVD in Korean asymptomatic adults. This cross-sectional study included 3257 participants of a health screening program from January 2006 to December 2013. All participants performed brain magnetic resonance imaging. To assess the cSVD, we considered three features such as white matter hyperintensities (WMH), silent lacunar infarction (SLI), and cerebral microbleeds (CMBs). The annual average exposure to air pollutants [particulate matter ≤ 10 µm in aerodynamic diameter (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO)] was generated. The mean [standard deviation (SD)] age of the total 3257 participants was 56.5 (9.5) years, and 54.0% of them were male. Among all the included participants, 273 (8.4%) had SLI and 135 (4.1%) had CMBs. The mean volume (± SD) of WMH was 2.72 ± 6.57 mL. In result of linear regression analysis, the volume of WMH was associated with various potential factors including age, height, weight, smoking and alcohol consumption status, blood pressure (BP), hypertension, and diabetes mellitus. SLI-positive group, compared to the SLI-negative group, was older, shorter, and had higher BP as well as higher frequency of hypertension and diabetes mellitus. After adjusting for covariates, the annual average concentration of PM10 was significantly associated with the volume of WMH [ß (95% CI) for Model 1 = 0.082 (0.038- 0.125), p < 0.001; ß (95% CI) for Model 2 = 0.060 (0.013, 0.107), p = 0.013]. CMBs were not associated with the annual average concentration of PM10. No significant associations of NO2, SO2, and CO with cSVD were observed. In conclusion, PM10 exposure is associated with significant increases in brain WMH' volume and silent lacunar infarcts in asymptomatic adults.

Could salt intake directly affect the cerebral microvasculature in hypertension?

OBJECTIVES: Excess dietary salt and chronic kidney disease (CKD) are acknowledged stroke risk factors. The development of small vessel disease, similarly affecting the cerebral and renal microvasculatures, may be an important mechanistic link underlying this interaction. Therefore, we aimed to evaluate if the dietary salt intake and markers of CKD (estimated glomerular filtration rate, albuminuria) relate to transcranial Doppler (TCD) markers of cerebral small vessel disease (CSVD) in hypertensive patients. MATERIALS AND METHODS: Fifty-six hypertensive patients (57% with diabetes) underwent TCD monitoring in the middle (MCA) and posterior (PCA) cerebral arteries for evaluating neurovascular coupling (NVC), dynamic cerebral autoregulation (dCA), and vasoreactivity to carbon dioxide (VRCO2). We investigated the relation between renal parameters and TCD studies using Pearson's correlation coefficient and linear regression analyses. RESULTS: There were no associations between dCA, VRCO2, NVC, and renal function tests. However, there was a negative association between the daily salt intake and the natural frequency during visual stimulation (r2=0.101, ß=-0.340, p=0.035), indicative of increased rigidity of the cerebral resistance vessels that react to cognitive activation. CONCLUSIONS: In this cross-sectional study, we found an association between excess dietary salt consumption and CSVD in hypertensive patients. Future research is needed to evaluate whether the natural frequency could be an early, non-invasive, surrogate marker for microvascular dysfunction in hypertension.

Cerebral Small Vessel Disease and Depression Among Intracerebral Hemorrhage Survivors.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is an acute manifestation of cerebral small vessel disease (CSVD), usually cerebral amyloid angiopathy or hypertensive arteriopathy. CSVD-related imaging findings are associated with increased depression incidence in the general population. Neuroimaging may, therefore, provide insight on depression risk among ICH survivors. We sought to determine whether CSVD CT and magnetic resonance imaging markers are associated with depression risk (before and after ICH), depression remission, and effectiveness of antidepressant treatment. METHODS: We analyzed data from the single-center longitudinal ICH study conducted at Massachusetts General Hospital. Participants underwent CT and magnetic resonance imaging imaging and were followed longitudinally. We extracted information for neuroimaging markers of CSVD subtype and severity. Outcomes of interest included pre-ICH depression, new-onset depression after ICH, resolution of depressive symptoms, and response to antidepressant treatment. RESULTS: We followed 612 ICH survivors for a median of 47.2 months. Multiple CSVD-related markers were associated with depression risk. Survivors of cerebral amyloid angiopathy-related lobar ICH were more likely to be diagnosed with depression before ICH (odds ratio, 1.68 [95% CI, 1.14-2.48]) and after ICH (sub-hazard ratio, 1.52 [95% CI, 1.12-2.07]), less likely to achieve remission of depressive symptoms (sub-hazard ratio, 0.69 [95% CI, 0.51-0.94]), and to benefit from antidepressant therapy (P=0.041). Cerebral amyloid angiopathy disease burden on magnetic resonance imaging was associated with depression incidence and treatment resistance (interaction P=0.037), whereas hypertensive arteriopathy disease burden was only associated with depression incidence after ICH. CONCLUSIONS: CSVD severity is associated with depression diagnosis, both before and after ICH. Cerebral amyloid angiopathy-related ICH survivors are more likely to experience depression (both before and after ICH) than patients diagnosed with hypertensive arteriopathy-related ICH, and more likely to report persistent depressive symptoms and display resistance to antidepressant treatment.

Effect of obstructive sleep apnea on cerebrovascular compliance and cerebral small vessel disease.

Reduced cerebrovascular compliance is the major mechanism of cerebral small vessel disease (SVD). Obstructive sleep apnea (OSA) also promotes SVD development, but the underlying mechanism was not elucidated. We investigated the association among OSA, cerebrovascular compliance, and SVD parameters. This study retrospectively included individuals ≥ 50 years of age, underwent overnight polysomnographic (PSG) for the evaluation of OSA, and performed MRI and transcranial Doppler (TCD) within 12 months of interval without a neurological event between the evaluations. TCD parameters for the cerebrovascular compliance included middle cerebral artery pulsatility index (MCA PI) and mean MCA resistance index ratio (MRIR). SVD parameters included white matter hyperintensity (WMH) volume, number of lacunes, enlarged perivascular space (ePVS) score, and the presence of microbleeds or lacunes. Ninety-seven individuals (60.8% male, mean age 70.0±10.5 years) were included. MRIR was associated with higher respiratory distress index (B = 0.003; 95% confidence interval [CI] 0.001-0.005; P = 0.021), while MCA PI was not associated with any of the PSG markers for OSA severity. Apnea-hypopnea index was associated with the log-transformed total WMH volume (B = 0.008; 95% confidence interval [CI] 0.001-0.016; P = 0.020), subcortical WMH volume (B = 0.015; 95% CI 0.007-0.022; P<0.001), total ePVS score (B = 0.024; 95% CI 0.003-0.045; P = 0.026), and centrum semiovale ePVS score (B = 0.026; 95% CI 0.004-0.048; P = 0.019), and oxygen-desaturation index with periventricular WMH volume, independently from age, MCA PI, and MRIR. This study concluded that OSA is associated with reduced cerebrovascular compliance and also with SVD independently from cerebrovascular compliance. Underlying pathomechanistic link might be region specific.

Atrial Fibrillation, Stroke, and Silent Cerebrovascular Disease: A Population-based MRI Study.

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) has been associated with cognitive decline and dementia. However, the mechanisms behind these associations are not clear. Examination of cerebrovascular pathology on MRI may shed light on how AF affects the brain. This study aimed to determine whether AF is associated with a broad range of cerebrovascular diseases beyond the well-known association with symptomatic stroke, including silent infarcts and markers of small vessel disease, i.e., cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), and lacunes, in a population-based sample of 70-year-olds. METHODS: Data were obtained from the Gothenburg H70 Birth Cohort Studies, in which individuals are invited based on birthdate. This study has a cross-sectional design and includes individuals born in 1944 who underwent structural brain MRI in 2014 to 2017. AF diagnoses were based on self-report, ECG, and register data. Symptomatic stroke was based on self-report, proxy interviews, and register data. Brain infarcts and CMBs were assessed by a radiologist. WMH volumes were measured on fluid-attenuated inversion recovery images with the Lesion Segmentation Tool. Multivariable logistic regression was used to study the association between AF and infarcts/CMBs, and multivariable linear regression was used to study the association between AF and WMHs. RESULTS: A total of 776 individuals were included, and 65 (8.4%) had AF. AF was associated with symptomatic stroke (odds ratio [OR] 4.5, 95% confidence interval [CI] 2.1-9.5) and MRI findings of large infarcts (OR 5.0, 95% CI 1.5-15.9), lacunes (OR 2.7, 95% CI 1.2-5.6), and silent brain infarcts (OR 3.5; 95% CI 1.6-7.4). Among those with symptomatic stroke, individuals with AF had larger WMH volumes (0.0137 mL/total intracranial volume [TIV], 95% CI 0.0074-0.0252) compared to those without AF (0.0043 mL/TIV, 95% CI 0.0029-0.0064). There was no association between AF and WMH volumes among those without symptomatic stroke. In addition, AF was associated to CMBs in the frontal lobe. DISCUSSION: AF was associated with a broad range of cerebrovascular pathologies. Further research is needed to establish whether cerebrovascular MRI markers can be added to current treatment guidelines to further personalize anticoagulant treatment in patients with AF and to further characterize the pathogenetic processes underlying the associations between AF and cerebrovascular diseases, as well as dementia.

Early life predictors of late life cerebral small vessel disease in four prospective cohort studies.

Development of cerebral small vessel disease, a major cause of stroke and dementia, may be influenced by early life factors. It is unclear whether these relationships are independent of each other, of adult socio-economic status or of vascular risk factor exposures. We examined associations between factors from birth (ponderal index, birth weight), childhood (IQ, education, socio-economic status), adult small vessel disease, and brain volumes, using data from four prospective cohort studies: STratifying Resilience And Depression Longitudinally (STRADL) (n = 1080; mean age = 59 years); the Dutch Famine Birth Cohort (n = 118; mean age = 68 years); the Lothian Birth Cohort 1936 (LBC1936; n = 617; mean age = 73 years), and the Simpson's cohort (n = 110; mean age = 78 years). We analysed each small vessel disease feature individually and summed to give a total small vessel disease score (range 1-4) in each cohort separately, then in meta-analysis, adjusted for vascular risk factors and adult socio-economic status. Higher birth weight was associated with fewer lacunes [odds ratio (OR) per 100 g = 0.93, 95% confidence interval (CI) = 0.88 to 0.99], fewer infarcts (OR = 0.94, 95% CI = 0.89 to 0.99), and fewer perivascular spaces (OR = 0.95, 95% CI = 0.91 to 0.99). Higher childhood IQ was associated with lower white matter hyperintensity burden (OR per IQ point = 0.99, 95% CI 0.98 to 0.998), fewer infarcts (OR = 0.98, 95% CI = 0.97 to 0.998), fewer lacunes (OR = 0.98, 95% CI = 0.97 to 0.999), and lower total small vessel disease burden (OR = 0.98, 95% CI = 0.96 to 0.999). Low education was associated with more microbleeds (OR = 1.90, 95% CI = 1.33 to 2.72) and lower total brain volume (mean difference = -178.86 cm3, 95% CI = -325.07 to -32.66). Low childhood socio-economic status was associated with fewer lacunes (OR = 0.62, 95% CI = 0.40 to 0.95). Early life factors are associated with worse small vessel disease in later life, independent of each other, vascular risk factors and adult socio-economic status. Risk for small vessel disease may originate in early life and provide a mechanistic link between early life factors and risk of stroke and dementia. Policies investing in early child development may improve lifelong brain health and contribute to the prevention of dementia and stroke in older age.

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease.

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Association of autosomal dominant polycystic kidney disease with cerebral small vessel disease.

Cilia dysfunction in autosomal-dominant polycystic kidney disease (ADPKD) may impair the integrity of glymphatic system and be implicated in the progression of cerebral small vessel disease (SVD), although the link between the two diseases has not been investigated. We evaluated the association of ADPKD pathology with SVD pattern and severity. Overall, 304 individuals in an ADPKD (chronic kidney disease stage ≤4 and age ≥50 years) cohort and their age, sex, and estimated glomerular filtration rate (eGFR)-matched controls were retrospectively included. ADPKD severity was classified into 1 A-B, 1 C, and 1 D-E, according to age and height-adjusted total kidney volume. SVD parameters included white-matter hyperintensity (WMH) severity scale, enlarged perivascular space (ePVS) score, and degree of lacunes or cerebral microbleeds (CMBs). After adjustments for age, sex, eGFR, and cerebrovascular risk factor parameters, ADPKD was associated with higher ePVS scores (P < 0.001), but not with the WMH severity or degree of lacunes or CMBs. In the ADPKD subgroup, higher ADPKD severity class was associated with higher ePVS scores (P < 0.001), WMH severity (P = 0.003), and degree of lacunes (P = 0.002). ADPKD associated cilia dysfunction may induce chronic cerebral glymphatic system dysfunction, which may contribute to the specific progression of ePVS compared with other SVD markers.

Resistance to developing brain pathology due to vascular risk factors: the role of educational attainment.

Brain pathology develops at different rates between individuals with similar burden of risk factors, possibly explained by brain resistance. We examined if education contributes to brain resistance by studying its influence on the association between vascular risk factors and brain pathology. In 4111 stroke-free and dementia-free community-dwelling participants (62.9 ± 10.7 years), we explored the association between vascular risk factors (hypertension and the Framingham Stroke Risk Profile [FRSP]) and imaging markers of brain pathology (markers of cerebral small vessel disease and brain volumetry), stratified by educational attainment level. Associations of hypertension and FSRP with markers of brain pathology were not significantly different between levels of educational attainment. Certain associations appeared weaker in those with higher compared to lower educational attainment, particularly for white matter hyperintensities (WMH). Supplementary residual analyses showed significant associations between higher educational attainment and stronger resistance to WMH among others. Our results suggest a role for educational attainment in resistance to vascular brain pathology. Yet, further research is needed to better characterize determinants of brain resistance.

COVID-19 Infection and Circulating Microparticles-Reviewing Evidence as Microthrombogenic Risk Factor for Cerebral Small Vessel Disease.

Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) due to novel coronavirus disease 2019 (COVID-19) has affected the global society in numerous unprecedented ways, with considerable morbidity and mortality. Both direct and indirect consequences from COVID-19 infection are recognized to give rise to cardio- and cerebrovascular complications. Despite current limited knowledge on COVID-19 pathogenesis, inflammation, endothelial dysfunction, and coagulopathy appear to play critical roles in COVID-19-associated cerebrovascular disease (CVD). One of the major subtypes of CVD is cerebral small vessel disease (CSVD) which represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger subsequent neuroinflammation and neurodegeneration. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, and Alzheimer's disease. In the background of COVID-19 infection, the heightened cellular activations from inflammations and oxidative stress may result in elevated levels of microthrombogenic extracellular-derived circulating microparticles (MPs). Consequently, MPs could act as pro-coagulant risk factor that may serve as microthrombi for the vulnerable microcirculation in the brain leading to CSVD manifestations. This review aims to appraise the accumulating body of evidence on the plausible impact of COVID-19 infection on the formation of microthrombogenic MPs that could lead to microthrombosis in CSVD manifestations, including occult CSVD which may last well beyond the pandemic era.

Amylin Dyshomeostasis Hypothesis: Small Vessel-Type Ischemic Stroke in the Setting of Type-2 Diabetes.

Recent histological analyses of human brains show that small vessel-type injuries in the setting of type-2 diabetes colocalize with deposits of amylin, an amyloid-forming hormone secreted by the pancreas. Amylin inclusions are also identified in circulating red blood cells in people with type-2 diabetes and stroke or cardiovascular disease. In laboratory models of type-2 diabetes, accumulation of aggregated amylin in blood and the cerebral microvasculature induces brain microhemorrhages and reduces cerebral blood flow leading to white matter ischemia and neurological deficits. At the cellular level, aggregated amylin causes cell membrane lipid peroxidation injury, downregulation of tight junction proteins, and activation of proinflammatory signaling pathways which, in turn, induces macrophage activation and macrophage infiltration in vascular areas positive for amylin deposition. We review each step of this cascade based on experimental and clinical evidence and propose the hypothesis that systemic amylin dyshomeostasis may underlie the disparity between glycemic control and stroke risk and may be a therapeutic target to reduce the risk of small vessel ischemic stroke in patients with type-2 diabetes.

Contribution of Racial and Ethnic Differences in Cerebral Small Vessel Disease Subtype and Burden to Risk of Cerebral Hemorrhage Recurrence.

OBJECTIVE: Black and Hispanic survivors of intracerebral hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic cerebral small vessel disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk. METHODS: We analyzed data from the Massachusetts General Hospital ICH study (n = 593) and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n = 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)-related, hypertensive arteriopathy (HTNA)-related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk. RESULTS: We analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD (p = 0.011) and HTNA burden (p = 0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed-etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all p < 0.05). CONCLUSIONS: We uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial/ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity and investigating social determinants of health.

PIP2 corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.1 activity.

Cerebral small vessel diseases (SVDs) are a central link between stroke and dementia-two comorbidities without specific treatments. Despite the emerging consensus that SVDs are initiated in the endothelium, the early mechanisms remain largely unknown. Deficits in on-demand delivery of blood to active brain regions (functional hyperemia) are early manifestations of the underlying pathogenesis. The capillary endothelial cell strong inward-rectifier K+ channel Kir2.1, which senses neuronal activity and initiates a propagating electrical signal that dilates upstream arterioles, is a cornerstone of functional hyperemia. Here, using a genetic SVD mouse model, we show that impaired functional hyperemia is caused by diminished Kir2.1 channel activity. We link Kir2.1 deactivation to depletion of phosphatidylinositol 4,5-bisphosphate (PIP2), a membrane phospholipid essential for Kir2.1 activity. Systemic injection of soluble PIP2 rapidly restored functional hyperemia in SVD mice, suggesting a possible strategy for rescuing functional hyperemia in brain disorders in which blood flow is disturbed.

Increased Premature Cerebral Small Vessel Diseases in Dialysis Patients: A Retrospective Cross-Sectional Study.

BACKGROUND: Growing data indicate a higher prevalence of cerebrovascular diseases in patients with ESRD. Cerebral small-vessel disease (CSVD) is an important risk factor of stroke and dementia. A comprehensive assessment of CSVD in a dialysis population is needed. METHODS: In this retrospective cross-sectional study, we enrolled 179 dialysis patients and 351 controls matched by sex and age with normal serum creatinine. The presence and locations of 3 main features of CSVD in dialysis patients, including lacunes, cerebral microbleeds (CMBs), and white matter hyperintensities (WMHs), were evaluated with brain magnetic resonance imaging and compared with controls. Univariate and multivariate analyses were performed to identify risk factors. RESULTS: Compared with controls, the prevalence of CSVD was significantly increased in dialysis patients (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.26-5.62). Among them, risks of CMBs and WMHs were increased in dialysis (OR 4.01, 95% CI 1.78-9.42; 3.91, 95% CI 1.67-9.15), except for lacunes. The age of subjects with CSVD detected was significantly younger in the dialysis group (p = 0.002). Unlike controls, basal ganglia were most affected by lacunes and CMBs in dialysis patients. In dialysis patients, multivariate analysis further revealed that aging, smoking, and hyperlipidemia were significantly associated with CSVD, while dialysis modality was not significant. CONCLUSION: We demonstrated a higher prevalence and early-onset tendency of CSVD in dialysis patients, especially for CMBs and WMHs. Dialysis patients showed different patterns and associated factors for CSVD.

Late vascular complications after cranial radiotherapy: A report of two illustrative cases.

Cranial radiotherapy (CRT) is used to treat a large variety of benign and malignant disorders. We present two cases of late neurological complications after CRT and briefly discuss its diagnosis and their shared pathophysiological aspects. The first case is a patient with cognitive impairment associated to mineralizing microangiopathy ten years after CRT for nasopharyngeal carcinoma and the second one is a woman with Stroke-like Migraine Attacks after Radiation Therapy (SMART) syndrome two years after CRT for anaplastic meningioma. Nowadays, higher survival rates might cause an increase in appearance of late neurological complications after CTR. These reported cases show that late complications can mimic a wide variety of neurological conditions and the importance of magnetic resonance image (MRI) to get a diagnosis.