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.

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.

Pathogenesis of Cerebral Small Vessel Disease: Role of the Glymphatic System Dysfunction.

Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood-brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood-brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further.

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.

[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.

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.

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.

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.

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.

The dynamic change of phenotypic markers of smooth muscle cells in an animal model of cerebral small vessel disease.

BACKGROUND: The pathological character of cerebral small vessel disease (CSVD) is the dysfunction of cerebral small arteries caused by risk factors. A switch from the contractile phenotype to the synthetic phenotype of vascular smooth muscle cells (SMCs) can decrease the contractility of arteries. The alteration of the vascular wall extracellular matrix (ECM) is found to regulate the process. We speculated that SMCs phenotype changes may also occur in CSVD induced by hypertension and the alteration of ECM especially fibronectin and laminin may regulate the process. METHOD: Male spontaneously hypertensive rats (SHR) were used as a CSVD animal model. SMCs phenotypic markers and the ECM expression of the cerebral small arteries of SHR at different ages were evaluated by immunofluorescence. The phenotype changes of primary brain microvascular SMCs cultured on laminin-coating dish or fibronectin-coating dish were evaluated by western blot. RESULT: A switch from the contractile phenotype to synthetic phenotype in SHR at 10 and 22 weeks of age was observed. Meanwhile, increased expression of fibronectin and a temporary decline of laminin was found in small arteries of SHR at 22 weeks. In vitro experiments also convinced that SMCs cultured on a fibronectin-coating dish failed to maintain contractile phenotype. While at 50 weeks, significant drops of both synthetic and contractile phenotypic markers were witnessed in SHR, with high expressions of four kinds of ECM. CONCLUSION: SMCs in cerebral small arteries exhibited a switch from the contractile phenotype to synthetic phenotype during the chronic process of hypertension and aging. Moreover, the change of fibronectin and laminin may regulate the process.

Left ventricular ejection fraction and right atrial diameter are associated with deep regional CBF in arteriosclerotic cerebral small vessel disease.

BACKGROUND: Systemic cardiac hypoperfusion is a well-acknowledged contributor to ischemic leukoencephalopathy. However, it has remained elusive how atherosclerosis-mediated cardiac remodelling modifies cerebral perfusion homeostasis as well as neuroimaging burden in cerebral small vessel disease (CSVD) development. METHODS: This retrospective study identified 103 arteriosclerotic CSVD (aCSVD) patients (CSVD burdenlow 0 ~ 1, n = 61 and CSVD burdenhigh 2 ~ 4, n = 42) from Sep. 2017 to Dec. 2019 who underwent transthoracic echocardiography(n = 81), structural magnetic resonance imaging and arterial spin labelling (ASL). Total CSVD burden was graded according to the ordinal "small vessel disease" rating score (0-4). We investigated the univariate and multivariate linear regression of mean deep regional cerebral blood flow (CBF) as well as logistic regression analysis of CSVD burdenhigh. RESULTS: Right atrial diameter (B coefficient, - 0.289; 95% CI, - 0.578 to - 0.001; P = 0.049) and left ventricular ejection fraction (B coefficient, 32.555; 95% CI, 7.399 to 57.711; P = 0.012) were independently associated with deep regional CBF in aCSVD patients. Binary logistic regression analysis demonstrated decreased deep regional CBF (OR 0.894; 95% CI 0.811-0.985; P = 0.024) was independently associated with higher CSVD burden after adjusted for clinical confounders. Multivariate receiver operating characteristics curve integrating clinical risk factors, mean deep CBF and echocardiographic parameters showed predictive significance for CSVD burdenhigh diagnosis (area under curve = 84.25, 95% CI 74.86-93.65%, P < 0.0001). CONCLUSION: The interrelationship of "cardiac -deep regional CBF-neuroimaging burden" reinforces the importance and prognostic significance of echocardiographic and cerebral hemodynamic assessment in CSVD early-warning.

Diurnal Blood Pressure and Heart Rate Variability in Hypertensive Patients with Cerebral Small Vessel Disease: A Case-Control Study.

BACKGROUND: Whether autonomic dysfunction contributes to cerebral small vessel disease (CSVD) remains unclear. This study aimed to explore the relationship between CSVD and blood pressure variability (BPV) and heart rate variability (HRV). METHODS: This case-control study recruited 50 patients with CSVD and 50 non-CSVD hypertensive age- and gender-matched controls. All participants completed a 24-h ambulatory electrocardiogram recording and ambulatory BP monitoring (ABPM). Differences in HRV and BPV between the two groups were examined. BPV indices assessed by ABPM included mean systolic BP (SBP), mean diastolic BP (DBP), coefficient of variation and weighted standard deviation of SBP and DBP. RESULTS: CSVD patients had significant higher 24-h mean systolic BP (SBP), 24-h mean diastolic BP (DBP), daytime mean SBP, nocturnal mean SBP, and nocturnal mean DBP (P < .05 for all). CSVD patients had a significant lower nocturnal SBP fall rate compared with controls (median: 1.0 versus 6.2, respectively; P < .001) and were more likely to be non-dippers and reverse dippers. There were no differences in HRV variables between the two groups. Five logistic models were built to explore the correlations between BPV indices and CSVD. BPV indices were separately entered into the logistic regression models, together with hyperlipidemia, ischemic stroke history, current use of anti-hypertensive agents, and serum blood urea nitrogen. In models 1-3, 24-h mean SBP and nocturnal mean SBP and DBP were significantly correlated with CSVD (r2 = 0.308-0.340). In model 4, the nocturnal SBP fall rate was negatively correlated with CSVD (odds ratio [OR] = 0.871, 95% confidence interval [CI] = 0.804-0.943; P = .001), with r2 = 0.415 fitting the model. In model 5, the pattern of SBP dipping was significantly associated with CSVD, with non-dipper (OR = 8.389, 95%CI = 1.489-47.254; P = .016) and reverse dipper (OR = 27.008, 95%CI = 3.709-196.660; P = .001) having the highest risks of CSVD (r2 = 0.413). CONCLUSIONS: Lower nocturnal SBP fall rate is associated with CSVD. Non-dipper and reverse dipper hypertensive patients have a higher risk of CSVD.

Neuropathologic Findings in Chronic Kidney Disease (CKD).

Studying the neuropathologic autopsy findings in subjects with chronic kidney disease (CKD) or chronic renal failure (CRF) is difficult for several reasons: etiology of the CKD may be heterogeneous, affected patients may have one or more major co-morbidities that themselves can cause significant neurologic disease, and agonal events may result in significant findings that were of minimal significance earlier in a patient's life. We studied the constellation of neuropathologic abnormalities in 40 autopsy brains originating from subjects of ages 34-95 years (no children in the study). The most common pathologic change was that of ischemic infarcts (cystic, lacunar and/or microinfarcts), which were seen in over half of subjects. These were associated with both large artery atherosclerosis and arteriolosclerosis (A/S), the latter finding being present in 29/40 subjects. Charcot-Bouchard microaneurysms were present in the brains of three subjects, in one case associated with severe amyloid angiopathy. Microvascular calcinosis (medial sclerosis in the case of arterioles) was seen in the basal ganglia (n=8) and/or endplate region of the hippocampus (n=7) and occasional ischemic infarcts in one brain showed severe calcification. Sequelae of cerebrovascular disease (especially A/S or microvascular disease) are a common neuropathologic substrate for neurologic disability and brain lesions in this complex group of patients. Regulation of calcium metabolism within brain microvessel walls may be worthy of further research in both human brain specimens and animal models.

The Cerebro-Renal System- Anatomical and Physiological Considerations.

The brain and kidney both uniquely are highly susceptible to vascular injury from shared vascular risk factors. However these are not sufficient to explain the complete extent of cerebrovascular disease especially small vessel disease in its myriad presentations that patients with chronic kidney disease manifest. They both require a large amount of blood supply to function optimally. Shared anatomical and physiological factors such as the presence of strain vessels, the local vascular autoregulation that control blood supply possible, results in the vulnerability of these organs to the vascular risk factors. Because it is a bidirectional system where each affects the other, it is best considered as a cerebro-renal unit.

Cocaine Use and White Matter Hyperintensities in Homeless and Unstably Housed Women.

OBJECTIVES: Cocaine use has been linked to stroke in several studies. However, few studies have considered the influence of cocaine use on stroke mechanisms such as small vessel disease (SVD). We conducted a study to assess associations between the toxicology-confirmed use of multiple drugs, including cocaine, and a marker of SVD, white matter hyperintensities (WMH). MATERIALS AND METHODS: We conducted a nested case-control study (n = 30) within a larger cohort study (N = 245) of homeless and unstably housed women recruited from San Francisco community venues. Participants completed six monthly study visits consisting of an interview, blood draw, vital sign assessment and baseline brain MRI. We examined associations between toxicology-confirmed use of multiple substances, including cocaine, methamphetamine, heroin, alcohol and tobacco, and WMH identified on MRI. RESULTS: Mean study participant age was 53 years, 70% of participants were ethnic minority women and 86% had a history of cocaine use. Brain MRIs indicated the presence of WMH (i.e., Fazekas score>0) in 54% (18/30) of imaged participants. The odds of WMH were significantly higher in women who were toxicology-positive for cocaine (Odd Ratio=7.58, p=0.01), but not in women who were toxicology-positive for other drugs or had several other cerebrovascular risk factors. CONCLUSIONS: Over half of homeless and unstably housed women showed evidence of WMH. Cocaine use is highly prevalent and a significant correlate of WMH in this population, while several traditional CVD risk factors are not. Including cocaine use in cerebrovascular risk calculators may improve stroke risk prediction in high-risk populations and warrants further investigation.

Mechanisms of Cerebral Microvascular Disease in Chronic Kidney Disease.

Numerous studies report linkage between chronic kidney disease (CKD) and cerebrovascular disease. This association has been particularly strong for cerebral small vessel disease. Significant findings have emerged from studies ranging from case reports, small case series, and larger cohort investigations. The latter show a relationship between declining renal function, microvascular disease, and cognitive impairment. One troubling aspect has been the relative paucity of mechanistic investigations addressing the CKD-cerebrovascular disease linkage. Nevertheless, mechanistic observations have begun to emerge, showing cerebral microhemorrhage development in animal models of CKD independent of hypertension, an important co-morbidity in clinical studies. Initial cell culture studies show endothelial monolayer disruption by CKD serum, consistent with blood-brain barrier injury. It is noteworthy that CKD serum is known to contain multiple plausible mediators of microvascular injury. Further studies are on the horizon to address the critical question of potential linkage of renal dysfunction with vascular cognitive impairment.

Asymptomatic Striatocapsular slit-like Hemorrhage as a Severity Marker in Patients with Hypertensive Angiopathy.

BACKGROUND: Concomitant asymptomatic striatocapsular slit-like hemorrhage (SSH) is occasionally found in patients of spontaneous intracerebral hemorrhage (ICH), but was seldomly described in the literature. In this study, we described the clinico-radiological features of asymptomatic SSH in ICH patients with hypertensive microangiopathy. METHODS AND RESULTS: 246 patients with strictly deep or mixed deep and lobar ICH/microbleeds were included. SSH was defined as hypointense lesions involving the lateral aspect of lentiform nucleus or external capsule in slit shape (>1.5 cm) on susceptibility-weighted imaging without history of associated symptoms. Demographics and neuroimaging markers were compared between patients with SSH and those without. Patients with SSH (n=24, 10%) and without SSH had comparable age (62.0 ± 12.6 vs. 62.3 ± 13.5, p = 0.912) and vascular risk factor profiles including the diagnosis of chronic hypertension, diabetes, and dyslipidemia (all p>0.05). SSH was associated with more common lobar microbleeds (79.2% vs 48.2%, p = 0.005), lacunes (75% vs. 41.4%, p = 0.002) and higher white matter hyperintensity (WMH) volumes (24.1 [10.4-46.3] vs. 13.9 [7.0-24.8] mL, p = 0.012) on MRI, as well as more frequent left ventricular hypertrophy (LVH) (50.0% vs. 20.5%, p = 0.004) and albuminuria (41.7% vs. 19.4%, p = 0.018). In multivariable analyses, SSH remains independently associated with LVH (p = 0.017) and albuminuria (p = 0.032) after adjustment for age, sex, microbleed, lacune and WMH volume. CONCLUSIONS: Asymptomatic SSH is associated with more severe cerebral small vessel disease-related change on brain MRI, and hypertensive cardiac and renal injury, suggesting a more advanced stage of chronic hypertension.

Stroke and COVID19: Not only a large-vessel disease.

Recent evidence has underlined the association between large-vessel stroke and COVID-19, probably due to a proinflammatory and prothrombotic microenvironment induced by SARS-CoV-2. Here, we report the case of a young fit woman affected by COVID-19 without any flu-like symptom, who suffered from speech disorder and left hemiparesis. Brain magnetic resonance evidenced two small acute brain infarctions in right perirolandic cortex without signs of previous ischemic lesions and hemorrhagic infarction. Diagnostic workup excluded cardiac embolic sources, acquired and inherited thrombophilia or autoimmune diseases. Two positive nasopharyngeal swab tests and high titers of serum specific IgA/IgM confirmed COVID-19 diagnosis. In our case stroke seems to be the only manifestation of SARS-COV-2 infection. Therefore the hypothesis of an underlying viral infection, as COVID-19, should be investigated in all the cases of small vessel cryptogenic stroke.

Effect of Enzyme Replacement Therapy on Basilar Artery Diameter in Male Patients With Fabry Disease.

Background and Purpose- The effect of enzyme replacement therapy (ERT) on cerebrovascular complications remains largely unexplored. We aimed to investigate the relationship between basilar artery (BA) diameter and long-term ERT in patients with Fabry disease. Methods- We obtained baseline magnetic resonance imaging data from 30 patients (40.5±16.3 years, male: 14) in the single institution; among them, 21 patients prospectively had follow-up magnetic resonance imaging assessments. The short axis of BA diameter was measured at the midpons level on axial T2-weighted images. Brain magnetic resonance imaging measurements included markers of cerebral small vessel disease (lacunas, white matter hyperintensities, and cerebral microbleeds). We assessed variables associated with baseline BA diameter and annual BA diameter change using linear regression analyses. Results- Hypertension, left ventricular hypertrophy, estimated glomerular filtration rate, and white matter hyperintensities correlated with the initial BA diameter. After a mean interval of 7.2±4.6 years, the annual BA diameter change correlated positively with severe white matter hyperintensities and inversely with the duration of ERT (ß=-0.48, P=0.033). After stratifying patients by sex, a significant correlation between the duration of ERT and BA diameter was found only in men (ß=-0.72, P=0.019). Conclusions- Our results show a possible relationship between ERT and changes in BA diameter. Future studies to elucidate the clinical impact of BA changes as a potential surrogate marker are needed.

Dietary Patterns Are Not Associated with Brain Atrophy or Cerebral Small Vessel Disease in Older Adults with and without Type 2 Diabetes.

BACKGROUND: Unhealthy dietary patterns (DPs) are associated with poorer cognition, but few studies have investigated the underlying brain structural mechanisms. OBJECTIVE: We aimed to examine the relations between DPs, brain structure, and cognition in older people with and without type 2 diabetes. METHODS: This cross-sectional study consisted of a sample of people with (n = 343) and without type 2 diabetes (n = 346) aged 55-90 y. The 80-item Cancer Council of Victoria FFQ was used to assess dietary intake. Two DPs (prudent and traditional) for people with type 2 diabetes and 3 DPs (prudent, traditional, and Western) for those without type 2 diabetes were derived using principal component analysis. Neuropsychological tests assessed 6 cognitive domains. Brain MRI was performed to obtain gray, white matter, and hippocampal volumes and markers of small vessel disease (microbleeds, infarcts, and white matter hyperintensities). Multivariable linear regression was used to assess the cross-sectional associations between DPs, brain MRI, and cognitive variables. RESULTS: For those without type 2 diabetes, higher adherence to the Western DP was associated with lower gray matter volume (ß = -3.03 95% CI: -5.67, -0.38; P = 0.03). The addition of a cardiovascular risk score, mood, and physical activity weakened associations such that they were no longer significant (ß = -1.97 (95% CI: -4.68, 0.74) P = 0.15) for the Western DP. There were no significant associations for the other DPs in people with and without type 2 diabetes. CONCLUSIONS: In this cross-sectional study, DPs were not independently associated with brain structure in people with or without type 2 diabetes. Future prospective studies are needed to clarify the role of vascular risk factors on associations between DPs and brain health.