Cerebral tau pathology in cerebral amyloid angiopathy.

Tau, a hallmark of Alzheimer's disease, is poorly characterized in cerebral amyloid angiopathy. We aimed to assess the clinico-radiological correlations between tau positron emission tomography scans and cerebral amyloid angiopathy. We assessed cerebral amyloid and hyperphosphorylated tau in patients with probable cerebral amyloid angiopathy (n = 31) and hypertensive small vessel disease (n = 27) using 11C-Pittsburgh compound B and 18F-T807 positron emission tomography. Multivariable regression models were employed to assess radio-clinical features related to cerebral tau pathology in cerebral amyloid angiopathy. Cerebral amyloid angiopathy exhibited a higher cerebral tau burden in the inferior temporal lobe [1.25 (1.17-1.42) versus 1.08 (1.05-1.22), P < 0.001] and all Braak stage regions of interest (P < 0.05) than hypertensive small vessel disease, although the differences were attenuated after age adjustment. Cerebral tau pathology was significantly associated with cerebral amyloid angiopathy-related vascular markers, including cortical superficial siderosis (ß = 0.12, 95% confidence interval 0.04-0.21) and cerebral amyloid angiopathy score (ß = 0.12, 95% confidence interval 0.03-0.21) after adjustment for age, ApoE4 status and whole cortex amyloid load. Tau pathology correlated significantly with cognitive score (Spearman's ρ=-0.56, P = 0.001) and hippocampal volume (-0.49, P = 0.007), even after adjustment. In conclusion, tau pathology is more frequent in sporadic cerebral amyloid angiopathy than in hypertensive small vessel disease. Cerebral amyloid angiopathy-related vascular pathologies, especially cortical superficial siderosis, are potential markers of cerebral tau pathology suggestive of concomitant Alzheimer's disease.

Differences in lobar microbleed topography in cerebral amyloid angiopathy and hypertensive arteriopathy.

Lobar cerebral microbleeds are a characteristic neuroimaging finding in cerebral amyloid angiopathy (CAA) but can also be found in hypertensive arteriolosclerosis. We aimed to investigate whether CAA is more associated with intracortical lobar microbleeds than hypertensive arteriosclerosis. Ninety-one survivors of spontaneous intracerebral hemorrhage with at least one lobar microbleed were included and underwent brain MRI and amyloid PET. We categorized lobar microbleeds as intracortical, juxtacortical, or subcortical. We assessed the associations between the lobar microbleed categories and microangiopathy subtypes or cerebral amyloid load based on the Pittsburgh Compound-B PET standardized uptake value ratio (SUVR). Patients with CAA had a higher prevalence of intracortical lobar microbleeds (80.0% vs. 50.8%, P = 0.011) and lower prevalence of subcortical lobar microbleeds (13.3% vs. 60.1%, P < 0.001) than patients with hypertensive arteriolosclerosis. Strictly intracortical/juxtacortical lobar microbleeds were associated with CAA (OR 18.9 [1.9-191.4], P = 0.013), while the presence of subcortical lobar microbleeds was associated with hypertensive arteriolosclerosis (OR 10.9 [1.8-68.1], P = 0.010). Amyloid retention was higher in patients with strictly intracortical/juxtacortical CMBs than those without (SUVR = 1.15 [1.05-1.52] vs. 1.08 [1.02-1.19], P = 0.039). Amyloid retention positively correlated with the number of intracortical lobar microbleeds (P < 0.001) and negatively correlated with the number of subcortical lobar microbleeds (P = 0.018). CAA and cortical amyloid deposition are more strongly associated with strictly intracortical/juxtacortical microbleeds than subcortical lobar microbleeds. Categorization of lobar microbleeds based on anatomical location may help differentiate the underlying microangiopathy and potentially improve the accuracy of current neuroimaging criteria for cerebral small vessel disease.

Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage.

Primary aldosteronism is associated with various types of cardiovascular and cerebrovascular damage independently of hypertension. Although chronic hypertension and related cerebral arteriosclerosis are the main risk factors for intracerebral hemorrhage, the effects of aldosteronism remain poorly understood. We enrolled 90 survivors of hypertensive intracerebral hemorrhage, 21 of them with aldosteronism and 69 with essential hypertension as controls in this study. Clinical parameters and neuroimaging markers of cerebral small vessel disease were recorded, and its correlations with aldosteronism were investigated. Our results showed that the aldosteronism group (55.2 ± 9.7 years, male 47.6%) had similar hypertension severity but exhibited a higher cerebral microbleed count (interquartile range) (8.5 [2.0‒25.8] vs 3 [1.0‒6.0], P = 0.005) and higher severity of dilated perivascular space in the basal ganglia (severe perivascular space [number >20], 52.4% vs. 24.6%, P = 0.029; large perivascular space [>3 mm], 52.4% vs. 20.3%, P = 0.010), compared to those with essential hypertension (53.8 ± 11.7 years, male 73.9%). In multivariate models, aldosteronism remained an independent predictor of a higher (>10) microbleed count (odds ratio = 8.60, P = 0.004), severe perivascular space (odds ratio = 4.00, P = 0.038); the aldosterone-to-renin ratio was associated with dilated perivascular space (P = 0.043) and large perivascular space (P = 0.008). In conclusions, survivors of intracerebral hemorrhage with aldosteronism showed a tendency towards more severe hypertensive arteriopathy than the essential hypertension counterparts independently of blood pressure; aldosteronism may contribute to dilated perivascular space around the deep perforating arteries. Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage.

In vivo detection of poststroke cerebral cell proliferation in rodents and humans.

OBJECTIVE: F-18-fluorothymidine (FLT) is a positron emission tomography (PET) tracer for imaging cell proliferation in vivo. We aimed to assess FLT uptake as a marker for cerebral cell proliferation in a rat model of ischemic stroke and patients with cerebral infarct, correlating with disease severity and outcomes. METHODS: Cerebral FLT PET was performed in rats subjected to transient middle cerebral artery occlusion (MCAO) and patients with cerebral infarct. PET data were analyzed and expressed as average standardized uptake value ratios (SUVRs) using cerebellar cortex as reference. Infarct volume was analyzed by 2,3,5-triphenyltetrazolium chloride staining in rats and by magnetic resonance imaging in patients. Neurological function was assessed using modified Neurological Severity Score (mNSS) for rats and National Institutes of Health Stroke Scale (NIHSS) for patients. RESULTS: Seven days post-MCAO, rats' FLT PET displayed higher SUVRs in the infarcted brain, declining gradually until Day 28. FLT-binding ratio (SUVR in the infarcted brain divided by that in contralateral side) correlated positively with stroke severity (p < 0.001), and to early mNSS decline in rats with mild to moderate stroke severity (p = 0.031). In 13 patients with cerebral infarct, FLT PET showed high SUVR in the infarcted regions. FLT-binding ratio correlated positively with infarct volume (p = 0.006). Age-adjusted initial NIHSS (p = 0.035) and early NIHSS decline (p = 0.076) showed significance or a trend toward positive correlation with the FLT-binding ratio. INTERPRETATION: In vivo FLT PET detects poststroke cerebral cell proliferation, which is associated with stroke severity and/or outcomes in MCAO rats and patients with cerebral infarct.

Interaction between cerebral small vessel disease, blood pressure, and remote ischemic lesions in acute spontaneous intracerebral hemorrhage.

BACKGROUND: Acute blood pressure (BP) reduction is the first-line treatment for acute spontaneous intracerebral hemorrhage (ICH); however, recent research suggests that intensive BP reduction along with cerebral small vessel disease (cSVD) is a risk factor for remote DWI lesions (RDWILs). We aimed to delineate the interplay between cSVD and BP reduction therapy on the risk of RDWILs. METHODS: We enrolled 303 patients who underwent brain magnetic resonance imaging within 7 days after acute spontaneous ICH. RDWILs were categorized as occurring in borderzone (BZ) or non-BZ areas. We examined the effect of cSVD, acute BP reduction, and their interaction on RDWILs. RESULTS: RDWILs were observed in 34 (11%) patients (59.8 ± 10.3-years-old, 24% male). RDWILs were associated with a larger acute weighted average mean arterial pressure (MAP) reduction in the initial 24 h after ICH onset and a higher total cerebral microbleed (CMB) count. Intensive MAP changes (odds ratio (OR) per 10 mmHg 1.76, 95% confidence interval (CI) 1.03-3.20), total CMBs burden (OR per 10 CMBs 1.21, 95% CI 1.08-1.39), and presence of lobar CMBs (OR 7.33, 95% CI 1.59-55.6) were risk factors for RDWILs at BZ, but not at non-BZ. Furthermore, a significant interaction was observed between lobar CMBs and MAP reduction on increased risk of RDWILs at BZ (p = 0.030). CONCLUSION: cSVD modulates the effect of acute BP reduction on the risk of RDWILs. Patients with extensive microangiopathy have a higher risk of developing cerebral ischemic changes in BZ during unstable hemodynamic status.

Cerebral amyloid deposition predicts long-term cognitive decline in hemorrhagic small vessel disease.

BACKGROUND: To investigate the association between cerebral amyloid deposition and long-term cognitive outcomes in patients with hemorrhagic small vessel disease (SVD) and survivors of intracerebral hemorrhage (ICH). METHODS: Patients experiencing an ICH without overt dementia were prospectively recruited (n = 68) for brain MRI and Pittsburgh compound B (PiB) positron emission tomography scans at baseline. Cognitive function was assessed using the mini-mental status examination (MMSE) and clinical dementia rating after an overall median follow-up of 3.8 years. A positive amyloid scan was defined as a global PiB standardized uptake value ratio >1.2. Associations between follow-up cognitive outcomes and neuroimaging markers were explored using multivariable Cox regression models. RESULTS: PiB(+) patients were older (72.1 ± 7.8 vs. 59.9 ± 11.7, p = .002) and more frequently had cerebral amyloid angiopathy (CAA) (63.6% vs. 15.8%, p = .002) than PiB(-) patients. PiB(+) was associated with a higher risk of dementia conversion (32.9 vs. 4.0 per 100-person-years, hazard ratio [HR] = 15.7 [3.0-80.7], p = .001) and MMSE score decline (58.8 vs. 9.9 per 100-person-years, HR = 6.2 [1.9-20.0], p = .002). In the non-CAA subgroup (n = 52), PiB(+) remained an independent predictor of dementia conversion, p = .04). In the Cox models, PiB(+) was an independent predictor of dementia conversion (HR = 15.8 [2.6-95.4], p = .003) and MMSE score decline (HR = 5.7 [1.6-20.3], p = .008) after adjusting for confounders. CONCLUSIONS: Cerebral amyloid deposition potentially contributes to long-term cognitive decline in SVD-related ICH.

Associations of Cerebral Small Vessel Disease on the Features of Hematoma and Hematoma Expansion in Intracerebral Hemorrhage.

INTRODUCTION: Several early noncontrast CT (NCCT) signs of spontaneous intracerebral hemorrhage (ICH) can predict hematoma expansion (HE). However, the associations of underlying cerebral small vessel disease (SVD) on early NCCT signs and HE have been less explored. METHODS: We conducted an analysis of all patients with spontaneous supratentorial ICH and received follow-up imaging between 2016-2020 at a stroke center. The early NCCT signs were categorized as shape or density signs. HE was defined as an increase in hematoma volume ≥6 ml or 33% from baseline. The severity of SVD was assessed by both a 3-point CT-based and a 4-point MRI-based SVD scores. Regression models were used to examine the associations between SVD score and hematoma volume, NCCT signs, and HE. RESULTS: A total of 328 patients (median age: 64 years; 38% female) were included. The median baseline ICH volume was 8.6 ml, with 38% of the patients had shape signs and 52% had density signs on the initial NCCT. Higher MRI-SVD scores were associated with smaller ICH volumes (P = 0.0006), fewer shape (P = 0.001) or density signs (P = 0.0003). Overall, 16% of patients experienced HE. A higher MRI-SVD score was inversely associated with HE (adjusted odds ratio 0.71, 95% CI 0.53 - 0.96). Subgroup analysis revealed that this association was primarily observed in patients who were younger (< 65 years), male, had deep hemorrhage, or did not meet the criteria for cerebral amyloid angiopathy diagnosis. CONCLUSIONS: In patients with spontaneous ICH, a more severe SVD was associated with smaller hematoma volume, fewer NCCT signs, and a lower risk of HE. Further research is required to investigate why a higher burden of severely diseased cerebral small blood vessels is associated with less bleeding.

Amyloid and tau PET in cerebral amyloid angiopathy-related inflammation two case reports and literature review.

Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a clinical syndrome characterized by MRI findings of amyloid-related imaging abnormalities-edema (ARIA-E) suggestive of autoimmune and inflammatory reaction and hemorrhagic evidence of cerebral amyloid angiopathy. The longitudinal variation of amyloid PET and its imaging association with CAA-ri are undetermined. Moreover, tau PET in CAA-ri has been rarely investigated. Method: We retrospectively described two cases of CAA-ri. We provided the temporal change of amyloid and tau PET in the first case, and the cross-sectional finding of amyloid and tau PET in the second case. We also performed a literature review of the imaging features of amyloid PET in reported cases of CAA-ri. Results: In the first case, an 88-year-old male presented with progressive consciousness and gait disturbances over 2 months. MRI showed disseminated cortical superficial siderosis. Amyloid PET prior to and after the CAA-ri revealed focally decreased amyloid load in the region of ARIA-E. In the second case, a 72-year-old male was initially suspected to have central nervous system cryptococcosis but later diagnosed with CAA-ri because of the characteristic MRI features and good response to corticosteroid treatment; a subsequent amyloid scan revealed positive amyloid deposition of the brain. Neither case suggested an association between the region of ARIA-E and higher amyloid uptake on PET before or after onset of CAA-ri. Our literature review revealed variable findings related to amyloid burden in post-inflammatory regions in previously reported CAA-ri cases with available amyloid PET. Our case is the first report of longitudinal changes on amyloid PET and show focal decreases in amyloid load after the inflammatory process. Conclusion: This case series highlights the need to better explore the potential of longitudinal amyloid PET in the understanding of the mechanisms of CAA-ri.

Cerebral Venous Reflux and Cerebral Amyloid Angiopathy: An Magnetic Resonance Imaging/Positron Emission Tomography Study.

BACKGROUND: Cerebral venous outflow alterations contribute to central nervous system pathology in aging and neurodegenerative disorders and are potentially linked to underlying cerebral microangiopathy. We investigated whether cerebral venous reflux (CVR) is more closely associated with cerebral amyloid angiopathy (CAA) than hypertensive microangiopathy in intracerebral hemorrhage (ICH) survivors. METHODS: This cross-sectional study included 122 patients of spontaneous ICH with magnetic resonance and positron emission tomography imaging studies (2014-2022) in Taiwan. The presence of CVR was defined as abnormal signal intensity in the dural venous sinus or internal jugular vein on magnetic resonance angiography. Cerebral amyloid load was measured using the Pittsburgh compound B standardized uptake value ratio. Clinical and imaging characteristics associated with CVR were evaluated in univariable and multivariable analyses. In the subset of patients with CAA, we applied univariable and multivariable linear regression analyses to evaluate the association between CVR and cerebral amyloid retention. RESULTS: Compared with patients without CVR (n=84, 64.5±12.1 years), patients with CVR (n=38, 69.4±11.5 years) were significantly more likely to have CAA-ICH (53.7% versus 19.8%; P<0.001) and had a higher cerebral amyloid load (standardized uptake value ratio [interquartile range], 1.28 [1.12-1.60] versus 1.06 [1.00-1.14]; P<0.001). In a multivariable model, CVR was independently associated with CAA-ICH (odds ratio, 4.81 [95% CI, 1.74-13.27]; P=0.002) after adjustment for age, sex and conventional small vessel disease markers. In CAA-ICH, higher PiB retention was observed in patients with CVR than patients without CVR (standardized uptake value ratio [interquartile range], 1.34 [1.08-1.56] versus 1.09 [1.01-1.26]; P<0.001). In multivariable analysis after adjustment for potential confounders, the presence of CVR was independently associated with a higher amyloid load (standardized ß=0.40; P=0.001). CONCLUSIONS: In spontaneous ICH, CVR is associated with CAA and a higher amyloid burden. Our results suggest venous drainage dysfunction potentially plays a role in CAA and cerebral amyloid deposition.

Cerebral Venous Reflux and Dilated Basal Ganglia Perivascular Space in Hypertensive Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Cerebral venous flow alterations potentially contribute to age-related white matter changes, but their role in small vessel disease has not been investigated. METHODS: This study included 297 patients with hypertensive intracerebral hemorrhages (ICH) who underwent magnetic resonance imaging. Cerebral venous reflux (CVR) was defined as the presence of abnormal signal intensity in the dural venous sinuses or internal jugular vein on time-of-flight angiography. We investigated the association between CVR, dilated perivascular spaces (PVS), and recurrent stroke risk. RESULTS: CVR was observed in 38 (12.8%) patients. Compared to patients without CVR those with CVR were more likely to have high grade (>20 in the number) dilated PVS in the basal ganglia (60.5% vs. 35.1%; adjusted odds ratio [aOR], 2.64; 95% confidence interval [CI], 1.25 to 5.60; P=0.011) and large PVS (>3 mm in diameter) (50.0% vs. 18.5%; aOR, 3.87; 95% CI, 1.85 to 8.09; P<0.001). During a median follow-up of 18 months, patients with CVR had a higher recurrent stroke rate (13.6%/year vs. 6.2%/year; aOR, 2.53; 95% CI, 1.09 to 5.84; P=0.03) than those without CVR. CONCLUSIONS: CVR may contribute to the formation of enlarged PVS and increase the risk of recurrent stroke in patients with hypertensive ICH.

Functional Investigation of Meningeal Lymphatic System in Experimental Intracerebral Hemorrhage.

BACKGROUND: Promotion of hematoma resolution in a timely manner reduces intracerebral hemorrhage (ICH) brain injury induced by toxic blood components and subsequent neuroinflammation. The meningeal lymphatic system is responsible for clearance of macromolecules and pathogenic substances from the central nervous system; however, its role in intraparenchymal hematoma clearance and ICH outcomes is unknown. In the present study, we aimed to understand the contribution of the meningeal lymphatic system to ICH pathologies and to test whether pharmacological enhancement of meningeal lymphatic function promotes hematoma resolution and brain recovery after ICH. METHODS: Immunofluorescence of whole-mount meninges was used to measure complexity and coverage level of meningeal lymphatic vasculature following ICH induction. Fluorescent microbeads and PKH-26-labeled erythrocytes were used to evaluate drainage function of the meningeal lymphatic system. Visudyne treatment, deep cervical lymph node ligation, and VEGF (vascular endothelial growth factor)-C injection were performed to manipulate meningeal lymphatic function. Neurobehavioral performance and hematoma volume were assayed by the cylinder test and histological measurements. Iron deposition, residual erythrocytes, neuronal loss, and astrogliosis were assessed by immunohistochemistry and antibody-based fluorescence staining. RESULTS: Meningeal lymphangiogenesis and enhanced lymphatic drainage occurred during the late phase of ICH. Ablation and blockage of meningeal lymphatic vessels impeded hematoma clearance, whereas pharmacological enhancement of their function reduced hematoma volume, improved behavioral performance, and reduced brain residual erythrocytes, iron deposition, neuronal loss, and astroglial activation. CONCLUSIONS: Early enhancement of meningeal lymphatic function is beneficial for ICH recovery. Targeting the meningeal lymphatic system is therefore a potential therapeutic approach for treating ICH.

Spatial distribution of cerebral microbleeds reveals heterogeneous pathogenesis in CADASIL.

OBJECTIVES: Radiological diagnosis of subtypes of cerebral small vessel diseases remains challenging. This study aimed to explore the spatial distribution of cerebral microbleeds (CMBs) in cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) in contrast to cerebral amyloid angiopathy (CAA) in the lobar regions. METHODS: Thirty-two patients with CADASIL and 33 patients with probable CAA were prospectively and consecutively included. On 3-Tesla susceptibility-weighted magnetic resonance images, CMBs were analyzed for incidence and volume within atlas-based regions of interest, followed by voxel-wise analysis using risk mapping. The distribution of CMBs was correlated with the status of hypertension. Correlation and group differences with a p-value less than 0.05 were considered to be significant. RESULTS: As compared with the CAA group, the CADASIL group presents a larger CMB volume in hippocampus/amygdala and white matter (nonparametric analysis of covariance, p = 0.014 and 0.037, respectively), a smaller CMB volume in parietal lobe (p = 0.038), and a higher incidence in hippocampus/amygdala, white matter, and insula (logistic regression, p = 0.019, 0.024, and 0.30, respectively). As part of the exclusion criteria of probable CAA, thalamus, basal ganglia, and pons exhibit greater CMB volume/incidence in the CADASIL group. In CADASIL patients, hot spots of CMBs are identified in the putamen and posteromedial thalamus; hypertension is associated with larger CMB volumes in insula, basal ganglia, and pons. CONCLUSIONS: The spatial distribution of CMBs is differentiable between CADASIL and CAA in lobar regions. In CADASIL patients, hypertension has a region-dependent mediating effect on the CMB volume. KEY POINTS: • The topological distribution of lobar CMBs is differentiable between CADASIL and CAA. • In CADASIL patients, hypertension mediates CMB volume and the mediation is region dependent. • CMB risk mapping allows for voxel-wise exploration of CMB distribution and reveals hot spots in the putamen and posteromedial thalamus in CADASIL.

Plasma soluble TREM2 is associated with white matter lesions independent of amyloid and tau.

Cerebral small vessel disease is one of the most common causes of cognitive decline and stroke. While several lines of evidence have established a relationship between inflammation and cerebrovascular pathology, the mechanistic link has not yet been elucidated. Recent studies suggest activation of immune mediators, including the soluble form of triggering receptor expressed on myeloid cells 2 (TREM2), may be critical regulators. In this study, we compared the plasma levels of soluble TREM2 and its correlations with neuroimaging markers and cerebral amyloid load in 10 patients with Alzheimer's disease and 66 survivors of spontaneous intracerebral haemorrhage with cerebral amyloid angiopathy or hypertensive small vessel disease, two of the most common types of sporadic small vessel disease. We performed brain MRI and 11C-Pittsburgh compound B PET for all participants to evaluate radiological small vessel disease markers and cerebral amyloid burden, and 18F-T807 PET in a subgroup of patients to evaluate cortical tau pathology. Plasma soluble TREM2 levels were comparable between patients with Alzheimer's disease and small vessel disease (P = 0.690). In patients with small vessel disease, plasma soluble TREM2 was significantly associated with white matter hyperintensity volume (P < 0.001), but not with cerebral amyloid load. Among patients with Alzheimer's disease and cerebral amyloid angiopathy, plasma soluble TREM2 was independently associated with a tau-positive scan (P = 0.001) and white matter hyperintensity volume (P = 0.013), but not amyloid load (P = 0.221). Our results indicate plasma soluble TREM2 is associated with white matter hyperintensity independent of amyloid and tau pathology. These findings highlight the potential utility of plasma soluble TREM2 as a strong predictive marker for small vessel disease-related white matter injury and hold clinical implications for targeting the innate immune response when treating this disease.

Arterial Spin Labeling Imaging Assessment of Cerebrovascular Reactivity in Hypertensive Small Vessel Disease.

Objective: Cerebrovascular reactivity (CVR) represents the phenomenon where cerebral vessels dilate or constrict in response to vasoactive stimuli. CVR impairment may contribute to brain injury due to cerebral small vessel disease (SVD). We aimed to determine the CVR in hypertensive intracerebral hemorrhage (ICH) and to identify its vascular dysfunction. Methods: A total of 21 patients with spontaneous hypertensive ICH (strictly deep or mixed deep and lobar hemorrhages, mean age 62.5 ± 11.3 years) and 10 control subjects (mean age 66.1 ± 6.0 years) were enrolled for CVR measurement at least 3 months after the symptomatic ICH event. Each participant underwent a brain MRI study, and CVR was calculated as the cerebral blood flow (CBF) reduction using arterial spin labeling (ASL) between baseline and 10 min after an intravenous dipyridamole injection (0.57 mg/kg). Traditional MRI markers for SVD were also evaluated, including cerebral microbleed, white matter hyperintensity, lacune, and MRI-visible enlarged perivascular space, which were used to determine the total small vessel disease score. Results: Compared to control subjects, hypertensive ICH patients showed reduced CVR in the basal ganglia (CBF reduction 22.4 ± 22.7% vs. 41.7 ± 18.3, p = 0.026), the frontal lobe (15.1 ± 11.9 vs. 26.6 ± 9.9, p = 0.013), and the temporal lobe (14.7 ± 11.1 vs. 26.2 ± 10.0, p = 0.010). These differences remained significant in multivariable models after adjusting for age and sex. Within ICH groups, the CBF reduction in the basal ganglia was significantly correlated with the total small vessel disease score (R = 0.58, p = 0.006), but not with individual MRI markers. Conclusion: Patients with advanced hypertensive SVD demonstrated impaired vasoconstriction after dipyridamole challenge in the basal ganglia and the frontal and temporal lobes. Our findings provide safe approaches for whole-brain CVR mapping in SVD and identify a potential physiological basis for vascular dysfunction in hypertensive SVD.

Surgery for Coagulopathy-Related Intracerebral Hemorrhage: Craniotomy vs. Minimally Invasive Neurosurgery.

Coagulopathy-related intracerebral hemorrhage (ICH) is life-threatening. Recent studies have shown promising results with minimally invasive neurosurgery (MIN) in the reduction of mortality and improvement of functional outcomes, but no published data have recorded the safety and efficacy of MIN for coagulopathy-related ICH. Seventy-five coagulopathy-related ICH patients were retrospectively reviewed to compare the surgical outcomes between craniotomy (n = 52) and MIN (n = 23). Postoperative rebleeding rates, morbidity rates, and mortality at 1 month were analyzed. Postoperative Glasgow Outcome Scale Extended (GOSE) and modified Rankin Scale (mRS) scores at 1 year were assessed for functional outcomes. Morbidity, mortality, and rebleeding rates were all lower in the MIN group than the craniotomy group (8.70% vs. 30.77%, 8.70% vs. 19.23%, and 4.35% vs. 23.08%, respectively). The 1-year GOSE score was significantly higher in the MIN group than the craniotomy group (3.96 ± 1.55 vs. 3.10 ± 1.59, p = 0.027). Multivariable logistic regression analysis also revealed that MIN contributed to improved GOSE (estimate: 0.99650, p = 0.0148) and mRS scores (estimate: -0.72849, p = 0.0427) at 1 year. MIN, with low complication rates and improved long-term functional outcome, is feasible and favorable for coagulopathy-related ICH. This promising result should be validated in a large-scale prospective study.

Centrum Semiovale Perivascular Space and Amyloid Deposition in Spontaneous Intracerebral Hemorrhage.

Background and Purpose: We explored whether high-degree magnetic resonance imaging­visible perivascular spaces in centrum semiovale (CSO) are more prevalent in cerebral amyloid angiopathy (CAA) than hypertensive small vessel disease and their relationship to brain amyloid retention in patients with primary intracerebral hemorrhage (ICH). Methods: One hundred and eight spontaneous ICH patients who underwent magnetic resonance imaging and Pittsburgh compound B were enrolled. Topography and severity of enlarged perivascular spaces were compared between CAA-related ICH (CAA-ICH) and hypertensive small vessel disease­related ICH (non-CAA ICH). Clinical and image characteristics associated with high-degree perivascular spaces were evaluated in univariate and multivariable analyses. Univariate and multivariable models were performed to evaluate associations between the severity of perivascular spaces in CSO and amyloid retention in CAA-ICH and non­CAA-ICH cases. Results: Patients with CAA-ICH (n=29) and non­CAA-ICH (n=79) had similar prevalence of high-degree perivascular spaces in CSO (44.8% versus 36.7%; P=0.507) and in basal ganglia (34.5% versus 51.9%; P=0.131). High-degree perivascular spaces in CSO were independently associated with the presence of lobar microbleed (odds ratio, 3.0 [95% CI, 1.1­8.0]; P=0.032). The amyloid retention was higher in those with high-degree than those with low-degree CSO-perivascular spaces in CAA-ICH (global Pittsburgh compound B standardized uptake value ratio, 1.55 [1.33­1.61] versus 1.13 [1.01­1.48]; P=0.003) but not in non­CAA-ICH. In CAA-ICH, the association between cerebral amyloid retention and the degree of perivascular spaces in CSO remained significant after adjustment for age and lobar microbleed number (P=0.004). Conclusions: Although high-degree magnetic resonance imaging­visible perivascular spaces are equally prevalent between CAA-ICH and non­CAA-ICH in the Asian cohort, the severity of magnetic resonance imaging­visible CSO-perivascular spaces may be an indicator of higher brain amyloid deposition in patients with CAA-ICH.

Amyloid related cerebral microbleed and plasma Aß40 are associated with cognitive decline in Parkinson's disease.

Cerebral microbleeds (MBs) have been found in patients with cognitive decline. We aimed to examine whether MBs are associated with motor or cognitive decline in patients with Parkinson's disease (PD). We enrolled 135 PD patients and 34 healthy controls. All participants underwent brain MRI and plasma biomarker assays, including tau, Aß42, Aß40, and α-synuclein. PD with dementia (PDD) was operationally defined as Mini-Mental State Examination (MMSE) score < 26 and advanced motor stage was defined as Hoehn-Yahr stage ≥ 3 during "on" status. The association between MBs and disease severity was examined using multivariate logistic regression models. More lobar MBs were observed in PD patients than controls (20.7% vs. 3.3%, p = 0.031). PDD patients had more lobar MBs (33.3% vs. 15.6%, p = 0.034), more white matter hyperintensity (p = 0.021) and reduced hippocampal volume (p = 0.001) than PD with normal cognition. The presence of lobar MB (odds ratio = 2.83 [95% confidence interval 1.04-7.70], p = 0.042) and severe white matter hyperintensity (3.29 [1.21-8.96], p = 0.020) was independently associated with PDD after adjusting for vascular risk factors and other confounders. Furthermore, plasma Aß40 levels were associated the MMSE score (p = 0.004) after adjusting for age and sex. Our findings demonstrated that lobar MBs, reduced hippocampal volume, and elevated plasma Aß40 levels are associated with PDD.

Long-Term Vascular Outcomes in Patients With Mixed Location Intracerebral Hemorrhage and Microbleeds.

OBJECTIVE: To determine whether mixed location intracerebral hemorrhages/microbleeds (mixed ICH) is a risk factor for vascular unfavorable outcome compared to cerebral amyloid angiopathy-related ICH (CAA-ICH) or strictly deep hypertensive ICH/microbleeds (HTN-ICH). METHODS: A total of 300 patients with spontaneous ICH were included. Clinical data, neuroimaging markers, and follow-up outcomes (recurrent ICH, ischemic stroke, and vascular death) were compared among mixed ICH (n = 148), CAA-ICH (n = 32), and HTN-ICH (n = 120). The association between follow-up events and neuroimaging markers was explored using multivariable Cox regression models. RESULTS: Patients with mixed ICH were older (65.6 ± 12.1 years vs 58.1 ± 13.3 years, p < 0.001) than patients with HTN-ICH, but younger than patients with CAA-ICH (73.3 ± 13.8 years, p = 0.001). Compared to CAA-ICH, mixed ICH had similar incidence of vascular events (all p > 0.05). Compared to HTN-ICH, mixed ICH is associated with higher ICH recurrence (hazard ratio [HR] 3.0, 95% confidence interval [CI] 1.2-7.7), more ischemic stroke (HR 8.2, 95% CI 1.0-65.8), and vascular composite outcome (HR 3.5, 95% CI 1.5-8.2) after adjustment for age and sex. In patients with mixed ICH, the presence of cortical superficial siderosis (cSS) is associated the development of ICH recurrence (HR 4.8, 95% CI 1.0-23.2), ischemic stroke (HR 8.8, 95% CI 1.7-45.5), and vascular composite outcome (HR 6.2, 95% CI 1.9-20.2). The association between cSS and ischemic stroke (p = 0.01) or vascular composite outcome (p = 0.003) remained significant after further adjustment for other radiologic markers. CONCLUSIONS: Mixed ICH harbors higher risk of unfavorable vascular outcome than HTN-ICH. Presence of cSS in mixed ICH independently predicts vascular event, suggesting the contribution of detrimental effect due to coexisting CAA.

Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy.

Parkinson's disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson's disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson's disease probands with autosomal-dominant Parkinson's disease and 1934 patients with sporadic Parkinson's disease revealed another two variants in UQCRC1 in the probands with familial Parkinson's disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson's disease.

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.