Presence Of Cortical Superficial Siderosis Research Articles

Abstract WMP14: Cerebrospinal Fluid Beta-Amyloid Concentration and MRI Manifestations of Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is associated with reduced cerebrospinal fluid (CSF) levels of the beta-amyloid (Aβ) 40- and 42-amino acid species, thought to reflect the burden of vascular Aβ deposition in the brain. Little is known regarding the association of CSF Aβ reduction with specific MRI manifestations of CAA. Methods: We identified 31 patients with CAA per Boston criteria v2.0 (1 definite, 27 probable, and 3 possible), who underwent CSF sampling for measurement of Aβ42, total tau (t-tau), and phospho-tau (p-tau) as part of their evaluation with ADmark (Athena Diagnostics). We assessed the following MRI manifestations of CAA while blinded to CSF biomarkers: the presence of cortical superficial siderosis (cSS), number of lobar cerebral microbleeds (CMBs), pattern and severity of white matter hyperintensities (WMH), and number of enlarged perivascular spaces in centrum semiovale (CSO-EPVS). Results: Median age of presentation was 69 years (range 56-89). Out of 31 patients, 19 were female (61.3%), 20 (64.5%) presented with cognitive impairment, 9 (29%) with intracerebral hemorrhage, and 2 (6.5%) with transient focal neurologic events. Mean (±SD) CSF Aβ42 concentration in our cohort was 359.3±126.7 pg/ml, substantially reduced relative to that reported in healthy controls. MRI manifestations associated with reduced Aβ42 without altered tau were presence of cSS (310±136 vs. 406±101, p=0.03) and higher burden of CSO-EPVS (307±101 vs. 431±127, p=0.005). Patients presented with cognitive impairment had higher tau levels (t-tau: 551±320 vs. 317±141, p=0.03; p-tau: 75.7±39.8 vs. 49.2±22.4, p=0.05) without altered Aβ42. Similar results were obtained when patients with possible CAA were excluded. Discussion: Our results suggest that presence of cSS and higher burden of CSO-EPVS are associated with lower Aβ42 concentration in CSF, potentially reflecting higher overall burden of vascular Aβ deposition in the brain. We found that higher tau concentrations in CSF are associated with cognitive impairment, presumably reflecting concomitant Alzheimer’s disease pathology. These results help inform interpretation of this clinically accessible test in practice and suggest potential mechanisms for specific CAA-related pathologies.

Influence of Cortical Superficial Siderosis in Patients with Mixed Location Cerebral Microbleeds and Intracerebral Hemorrhage (S36.006)

Influence of Cortical Superficial Siderosis in Patients with Mixed Location Cerebral Microbleeds and Intracerebral Hemorrhage (S36.006)

Mediators of cognitive impairment in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is associated with cognitive decline. CAA has diverse impacts on brain structure and function; however, the brain lesions that mediate the association of CAA with cognition are not understood well. To determine the degree to which CAA neuroimaging biomarkers mediate the association of CAA with cognitive dysfunction. We analyzed cross-sectional data of patients with probable CAA and controls without cognitive impairment from the Functional Assessment of Vascular Reactivity study. Neuropsychological tests were grouped into domains of memory, executive function, and processing speed. Candidate CAA neuroimaging biomarkers were pre-specified based on prior literature, consisting of white matter hyperintensity volume, peak width of skeletonized mean diffusivity (PSMD) on diffusion tensor magnetic resonance imaging (MRI), cerebrovascular reactivity (CVR), cortical thickness, and cortical thickness in a meta-region of interest typically affected by Alzheimer's disease (AD). Cognitive scores and neuroimaging markers were standardized and reported in relation to values in controls. Mediation analysis was used to estimate the total effect of CAA on cognition and the proportion of the total effect that was mediated by neuroimaging biomarkers, controlling for age, sex, and education. There were 131 participants (67 CAA and 64 controls). Mean age was 72.1 ± 7.7 years, and 54.2% were women. As expected, compared to controls, CAA was associated with lower cognition. In mediation analyses, CAA had direct unmediated effects of 48%, 46%, and 52% on all three cognitive domains. The association of CAA with memory was partially mediated by CVR and PSMD, accounting for 18% and 36% of the total effect of CAA. The association of CAA with executive function was partially mediated by PSMD and mean cortical thickness in the AD meta-region of interest (ROI), accounting for 33% and 31% of the total effect of CAA. The association of CAA with processing speed was partially mediated by CVR and PSMD, accounting for 8% and 34% of the total effect of CAA. Among CAA participants, the presence of cortical superficial siderosis was associated with lower processing speed. Altered white matter diffusivity (i.e. PSMD), CVR, and atrophy, taken together, account for about half the effect of CAA on cognition.

Abstract WMP14: White Matter Free Water Drives Diffusion Abnormalities And Correlates With Conventional MRI Markers Of Small Vessel Disease In Cerebral Amyloid Angiopathy

Introduction: Increased extracellular fluid, measured by the free water (FW) diffusion model, was found to be the main contributor to diffusion tensor imaging (DTI) alterations in monogenic and sporadic non-amyloid cerebral small vessel diseases (SVD). We investigated whether the FW component also drives DTI changes in cerebral amyloid angiopathy (CAA) and to what extent it correlates with conventional MRI markers of SVD. Methods: Non-demented probable CAA patients, without symptomatic intracerebral haemorrhage, were recruited from a memory-clinic cohort and underwent structural MRI, including diffusion-weighted imaging. Primary DTI metrics (mean diffusivity [MD] and fractional anisotropy [FA]), FW maps and tissue compartment tensors (tMD, tFA) were computed using a freely available script (https://markvcid.partners.org/). To reduce contamination by cerebrospinal fluid, diffusion metrics were analyzed within the white matter skeleton, using tract-based spatial statics. White matter hyperintensities (WMH) and total brain volume (TBV) were normalized by total intracranial volume. Images were rated for lobar microbleeds count (CMB), perivascular spaces scored in the centrum semiovale (CSO-PVS), and presence of cortical superficial siderosis. Results: Thirty-eight subjects (mean age 72.5 ± 7.4 years; 47.4% female) were included in the analysis. In simple linear regression models, conventional mean MD and FA were more strongly associated with the FW component (β=0.999, p<.001; β=-0.907, p<.001, respectively) than with their respective tissue compartment tensors (β=0.263, p=.111; β=0.659, p<.001, respectively). In multivariable regression analyses, adjusted for age, WMH (β=0.395, p=.002), CMB (β=0.346, p=.003) and CSO-PVS (β=0.496, p<.001) were independently associated with mean FW, whereas TBV was the only independent predictor for tissue compartment metrics (tMD and tFA) (β=0.506, p=.033; β=0.505, p=.040, respectively). Conclusion: FW imaging findings suggest that DTI changes in CAA are mainly driven by increased extracellular fluid rather than disruption of fiber structure. FW content was strongly associated with core SVD MRI markers, which could imply similar underlying pathogenesis.

The role of the hippocampus in mediating cognitive impairment in cerebral amyloid angiopathy

AbstractBackgroundThe interplay between cerebrovascular and Alzheimer’s pathology has an important role in the development of cognitive impairment1. Vascular risk factors and neuroimaging markers of cerebral small vessel disease (CSVD), have well been characterized in patients with Alzheimer’s disease (AD) in the past years2,3. Conversely, few studies asked how hippocampal neurodegeneration, a benchmark of AD, relates to cognition in CSVD patients4.MethodWe set out to investigate the relation between hippocampal neurodegeneration and cognition in a memory clinic cohort of 101 (75.8 ± 6.7 y, 58 F) patients with possible and probable cerebral amyloid angiopathy (CAA), a common CSVD form with defined diagnostic criteria. Linear regression models were used to assess the associations between the volume of hippocampal subfields and cognitive measures. Neuroimaging markers of CSVD were subsequently included in the analyses, to evaluate how they mediate the relation between cognition and hippocampal neurodegeneration.ResultWe found a significant positive association between CA1 volume and cognitive domains (memory: b=0.14, p=0.008; processing speed: b=0.15, p=0.03; language: b=0.14, p=0.03; executive function: b=0.20, p=0.01). CA1 volume was significantly related to memory and executive function, even when accounting for neuroimaging markers of CSVD. Furthermore, presence of cortical superficial siderosis and peak width of skeletonized mean diffusivity (PSMD), a measure of white matter (WM) integrity, were negatively associated with hippocampal and subfields’ volumes.ConclusionThese results suggest that neurodegeneration of CA1 is related to cognitive impairment in CAA patients, and may further support established links between vascular pathology and loss of CA1 integrity and/or overlap of AD pathology in these patients5‐7. Moreover, further studies exploring the relationship between WM and hippocampal integrity may be warranted.

Frailty, MRI, and FDG-PET Measures in an Australian Memory Clinic Cohort

Given that the global population is aging, the number of age-related syndromes, such as frailty, is expected to rise in conjunction. Frailty is characterized by the loss of homeostatic reserve, rendering the individual vulnerable to poor health outcomes. Many biological mechanisms have been proposed to contribute to frailty. However, few studies have assessed the associations between frailty and brain diseases or neuroimaging biomarkers.Aims: The aims of this study were to measure the prevalence of frailty in a memory clinic and to examine associations between frailty and brain changes found on magnetic resonance imaging (MRI) and 18-F deoxyglucose (FDG) positron emission tomography (PET) in memory clinic attendees.Methods: A 54-items Frailty Index was retrospectively assessed for all clinic attendees from 2014. Frailty was defined as FI > 0.25. MR images were analyzed for stroke, cerebral small vessel disease [CSVD, including cerebral microbleeds (CMBs), cortical superficial siderosis (CSS), and white matter hyperintensity (WMH)], and neurodegenerative changes [MRI: mesial temporal atrophy (MTA), FDG-PET: regional hypometabolism], blind to clinical findings.Results: There were 209 clinic attendees in 2014, of whom 121 had MRI performed. The prevalence of frailty (using FI) in the memory clinic in 2014 was 38.3% overall (patients without MRI: 43.2%, patients with MRI 34.7%, p = 0.25). Frailty was associated with presence of deep WMH, increased severity of periventricular WMH, and presence of CSS, but not neurodegeneration markers (MTA atrophy/FDG-PET hypometabolism).Conclusion: The findings support the idea that previously reported associations between frailty and imaging evidence of CSVD in other cohorts are also relevant to the Australian clinic setting. Given that a large proportion of memory clinic attendees are frail, there may be opportunities for interventions to reduce preventable adverse health outcomes, such as falls and fractures, and reduce the prevalence and impact of frailty in this cohort.

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

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). 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. 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. 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.

Migraine With Aura as Early Disease Marker in Hereditary Dutch-Type Cerebral Amyloid Angiopathy.

Background and Purpose- To determine whether migraine, which has often been described as an inaugural manifestation in monogenic cerebrovascular syndromes, is associated with cerebral amyloid pathology, we assessed migraine and its correlation with magnetic resonance imaging markers in Hereditary Dutch-Type Cerebral Amyloid Angiopathy (D-CAA or Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch type). Methods- All D-CAA mutation carriers who visited our clinic between 2012 and 2018 were included. Migraine was diagnosed by an interview and classified according to the International Classification of Headache Disorders. Magnetic resonance imaging scans were scored for intracerebral hemorrhage (ICH) location(s) and presence of cortical superficial siderosis. Kaplan Meier survival analysis was used for age of ICH onset in carriers with and without migraine. Correlation with ICH location(s) and cortical superficial siderosis were calculated with Poisson regression analysis adjusted for confounders. Results- We included 86 D-CAA mutation carriers (57% women, mean age 57 years), 48 (56%) suffered from migraine, all with aura. Prevalence was higher than expected compared with the general population (women, P<0.05; men, P<0.001). Migraine was the inaugural symptom in 77% and an isolated symptom in 35% of the carriers. Carriers with and without migraine did not differ for age of first ICH, cortical superficial siderosis prevalence, or occipital ICH. Time between migraine onset and first ICH was 8.5 years. Aura attacks lasting ≥60 minutes signaled acute ICH in 55%. Conclusions- Migraine with aura is an important, often inaugural, symptom in D-CAA. Aura attacks lasting ≥60 minutes may signal acute ICH in D-CAA. Migraine with aura may be regarded as an early marker of disease in hereditary CAA preceding the occurrence of symptomatic ICH by several years.

Abstract WMP107: Outcomes in Mixed Location Intracerebral Hemorrhage and Microbleeds

Objective: Patients with mixed location intracerebral hemorrhages/microbleeds (Mixed-ICH) have predominantly hypertensive vasculopathy rather than cerebral amyloid angiopathy (CAA), but the long-term outcomes in Mixed-ICH is unknown. In this study, we aimed to determine whether Mixed-ICH is a risk factor for vascular unfavorable outcome compared to CAA-ICH or strictly deep hypertensive intracerebral hemorrhage/microbleeds (HTN-ICH). Methods: 305 consecutive ICH patients were included. Clinical data, neuroimaging markers and follow-up outcomes (recurrent ICH, ischemic stroke and vascular death) were compared between Mixed-ICH (n=151), CAA-ICH (n=33) and HTN-ICH (n=121). The association between follow-up events and neuroimaging markers were explored using multivariable Cox regression models. Results: Mixed-ICH patients were older (65.9±12.4 vs 58.1±13.2, p&lt;0.001) than HTN-ICH, but younger than CAA-ICH patients (73.8 ± 13.9, p=0.001). The survival curves of follow-up outcomes were shown in the Figure. Compared to CAA-ICH, Mixed-ICH has similar incidence of vascular event (all P&gt;0.05). Compared to HTN-ICH, Mixed-ICH is associated with higher ICH recurrence (hazard ratio [HR]=3.0 [1.2-7.7], p=0.021), more ischemic stroke (HR=8.2 [1.0-65.8], p=0.048), and vascular composite outcome (HR=3.5 [1.5-8.2], p=0.003) after adjustment for age and sex. In patients of Mixed-ICH, the presence of cortical superficial siderosis (cSS) is associated the development of ICH recurrence (p=0.048), ischemic stroke (p=0.009), and vascular composite outcome (p=0.008). The association between cSS and vascular composite outcome remains significant after further adjustment for microbleed number, lacune and WMH volume (p=0.019). 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.

Cerebral Cortical Microinfarcts on Magnetic Resonance Imaging and Their Association With Cognition in Cerebral Amyloid Angiopathy.

Background and Purpose- We aimed to explore the association between presence of cerebral cortical microinfarcts (CMIs) on magnetic resonance imaging and other small-vessel disease neuroimaging biomarkers in cerebral amyloid angiopathy (CAA) and to analyze the role of CMIs on individual cognitive domains and dementia conversion. Methods- Participants were recruited from an ongoing longitudinal research cohort of eligible CAA patients between March 2006 and October 2016. A total of 102 cases were included in the analysis that assessed the relationship of cortical CMIs to CAA neuroimaging markers. Ninety-five subjects had neuropsychological tests conducted within 1 month of magnetic resonance imaging scanning. Seventy-five nondemented CAA patients had cognitive evaluation data available during follow-up. Results- Among 102 patients enrolled, 40 patients had CMIs (39%) on magnetic resonance imaging. CMIs were uniformly distributed throughout the cortex without regional predilection ( P=0.971). The presence of CMIs was associated with lower total brain volume (odds ratio, 0.85; 95% CI, 0.74-0.98; P=0.025) and presence of cortical superficial siderosis (odds ratio, 2.66; 95% CI, 1.10-6.39; P=0.029). In 95 subjects with neuropsychological tests, presence of CMIs was associated with impaired executive function (β, -0.23; 95% CI, -0.44 to -0.02; P=0.036) and processing speed (β, -0.24; 95% CI, -0.45 to -0.04; P=0.020). Patients with CMIs had a higher cumulative dementia incidence compared with patients without CMIs ( P=0.043), whereas only baseline total brain volume (hazard ratio, 0.76; 95% CI, 0.62-0.92; P=0.006) independently predicted dementia conversion. Conclusions- Magnetic resonance imaging-detected CMIs in CAA correlated with greater overall disease burden. The presence of CMIs was associated with worse cognitive performance, whereas only total brain atrophy independently predicted dementia conversion.

Atrophy patterns in cerebral amyloid angiopathy with and without cortical superficial siderosis.

To investigate differential atrophy patterns based on the presence of cortical superficial siderosis (cSS) and the role of cSS in predicting amyloid positivity in memory clinic patients fulfilling the diagnostic criteria for probable cerebral amyloid angiopathy (CAA). We retrospectively collected data from 44 cognitively impaired patients with probable CAA who underwent 3-dimensional, T1-weighted MRIs (cSS+, n = 27; cSS-, n = 17). Amyloid-positive patients with Alzheimer disease (AD) (n = 56) and amyloid-negative cognitively normal participants (n = 34) were recruited as controls. Among the patients with CAA who underwent amyloid-PET scans (75.0%), we investigated whether amyloid-negative cases were unevenly distributed based on cSS presentation. APOE genotypes, Mini-Mental State Examination scores, and cortical atrophy pattern along with hippocampal volume were compared across groups. Ten patients with probable CAA presented amyloid negativity and all of them belonged to the cSS- group (58.8%). Compared to the cSS- group, the cSS+ group presented higher APOE ε4 frequency, worse memory dysfunction, and lower hippocampal volume. Compared with cognitively normal participants, the cSS+ group exhibited atrophy in the precuneus, posterior cingulate, parietotemporal, superior frontal, and medial temporal areas, a pattern similar to AD-specific atrophy. The cSS- group exhibited atrophy in the parietotemporal, superior frontal, and precentral regions. Our findings imply that the current version of the Boston criteria may not be sufficient enough to remove non-CAA cases from a cognitively impaired population, especially in the absence of cSS. Patients with probable CAA presenting cSS appear to reflect a CAA phenotype that shares pathologic hallmarks with AD, providing insight into the CAA-to-AD continuum.

Distinctive Clinical Effects of Haemorrhagic Markers in Cerebral Amyloid Angiopathy

Restricted lobar cerebral microbleeds (CMBs) and cortical superficial siderosis (CSS) are the characteristic markers of cerebral amyloid angiopathy (CAA). However, their effects on clinical features has not been evaluated well. The purpose of this study is to investigate the clinical implication of these markers in clinical-radiologically diagnosed CAA. A total of 372 patients with possible or probable CAA who met the modified Boston criteria were recruited in a memory clinic setting. Cortical thickness was measured using surface based methods. Presence of restricted multiple lobar CMBs were independently associated with cortical thinning across the entire cortical regions while presence of CSS was independently associated with cortical thinning primarily in the bilateral frontal region. Presence of restricted multiple lobar CMBs was associated with impairment in all cognitive domains such as attention, language, visuospatial, memory and frontal executive functions while presence of CSS was associated with attention and frontal dysfunction. The relationships of restricted multiple lobar CMBs or CSS with cognitive impairment were partially mediated by thinning in the corresponding cortical regions. Our findings suggested that restricted multiple lobar CMBs and CSS affect distinctive clinical features, providing new insights into potential mechanisms in CAA.

Abstract TP323: Prevalence And Clinical Character Of Cortical Superficial Siderosis In Stroke Patient

Background and purpose: Cortical superficial siderosis (CSS) is a neuroimaging marker of cerebral amyloid angiopathy and has been associated with a high risk for intracerebral hemorrhage. However, CSS in acute stroke patients have not been fully investigated. The aim of this study was to assess the prevalence of CSS in both ischemic and hemorrhagic stroke patients. Furthermore, we aimed to assess the relation between CSS and clinical or radiologic characteristics. Methods: From September 2014 through June 2016, consecutive acute ischemic and hemorrhagic stroke patients who were admitted to our department within 7 days from symptom onset were retrospectively recruited from the prospective registry. CSS was defined as a homogeneous curvilinear signal intensity (black) on T2*-GRE sequences in the superficial layers of the cerebral cortex, within the subarachnoid space, away from at least three sulci of the hematoma with no corresponding signal hyperintensity on FLAIR sequences, to exclude potential hemorrhagic mimics. We analyzed the association between CSS and the topographic distribution of cerebral microbleeds (MBs), white matter lesions plus cardiovascular risk factors. Results: A total of 680 patients (530 ischemic stroke and 150 hemorrhagic stroke; median age 71 years) were enrolled in the present study. CSS was detected in 6 patients (1.1 %) with ischemic stroke and 7 patients (4.7%) with hemorrhagic stroke ( P &lt; 0.0001). CSS are associated with previous stroke ( P = 0.0234), hemorrhagic stroke ( P &lt; 0.0001), white matter lesions ( P = 0.0105), and lobar and non-lobar MBs (both P &lt; 0.0001), but no relationship between age, sex, cardiovascular risk factors and CSS were found. On multivariable logistic regression analysis, high lobar MBs (≥ 2; odds ratio [OR], 74.39; 95% confidence interval [CI], 10.24-1553.25; P &lt; 0.0001) and hemorrhagic stroke (OR, 4.30; 95% CI, 1.12-18.14; P = 0.0336) were independently associated with the presence of CSS. Conclusions: Our results suggest that CSS occurs with high prevalence in hemorrhagic stroke patients and is associated with lobar MBs, while the association between CSS and age, sex and cardiovascular risk factors were not observed.

Abstract WP369: Case-Fatality of Cortical Superficial Siderosis in Intracerebral Hemorrhage

Introduction: Cortical superficial siderosis (CSS) is a neuroimaging biomarker of interest in intracerebral hemorrhage (ICH) and represents hemosiderin deposition in the supratentorial sulci. CSS increases risk for recurrent ICH and is associated with cognitive impairment, but the long-term outcomes of ICH patients with CSS are unknown. We sought to characterize the long-term case-fatality of ICH patients with CSS. Methods: We performed a retrospective convenience study of primary ICH patients who underwent MRI during the index admission. We evaluated each hemisphere for presence of CSS, as well as other SVD markers, and performed Kaplan-Meier analysis to compare the survival curves of those with and without CSS. Vital status was ascertained via chart review and a National Death Index query when necessary. Results: Of 121 patients who underwent an MRI in our cohort, 95 had usable GRE or SWI sequences. Overall CSS prevalence was 11.6% (11/95): 18.2% (10/55) in lobar ICH and 2.5% (1/40) in deep ICH. Univariate predictors of CSS presence included older age (75.6 vs. 63.8, p=.01), larger hematoma volume (10.5mL vs. 4.6, p=.02), and prior ICH (54.5% vs. 10.7%, p=.002). There were no differences between the groups in MBs, EPVS, WMD scores, or DWI lesions. Patients with CSS had a significantly different survival history than those without CSS (log-rank p=.034). Twenty-five percent of the patients with CSS died by 4.4 months after index admission, compared with 45.1 months for those without CSS. The risk of death for the patients with CSS was 2.6 times (95% CI: 1.06-6.41) higher than those without. Four of 11 (36.4%) CSS patients lived at least 4 years after index ICH. Conclusions: Characterization of CSS in ICH patients may improve disease subtyping and clinical trial design. Future studies with larger and more generalizable cohorts are needed to assess how CSS focality vs. dissemination affects case-fatality and whether CSS is an independent predictor of case-fatality.

β-Amyloid in CSF: Biomarker for preclinical cerebral amyloid angiopathy.

To investigate CSF biomarkers in presymptomatic and symptomatic mutation carriers with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), a model for sporadic cerebral amyloid angiopathy, and to determine the earliest deposited form of β-amyloid (Aβ). HCHWA-D mutation carriers and controls were enrolled in the cross-sectional EDAN (Early Diagnosis of Amyloid Angiopathy Network) study. The HCHWA-D group was divided into symptomatic carriers with a previous intracerebral hemorrhage and presymptomatic carriers. CSF concentrations of Aβ40, Aβ42, total tau, and phosphorylated tau181 proteins were compared to those of controls of a similar age. Correlations between CSF biomarkers, MRI markers, and age were investigated with multivariate linear regression analyses. We included 10 symptomatic patients with HCHWA-D (mean age 55 ± 6 years), 5 presymptomatic HCHWA-D carriers (mean age 36 ± 13 years), 31 controls <50 years old (mean age 31 ± 7 years), and 50 controls ≥50 years old (mean age 61 ± 8 years). After correction for age, CSF Aβ40 and Aβ42 were significantly decreased in symptomatic carriers vs controls (median Aβ40 1,386 vs 3,867 ng/L, p < 0.001; median Aβ42 289 vs 839 ng/L, p < 0.001) and in presymptomatic carriers vs controls (median Aβ40 3,501 vs 4,684 ng/L, p = 0.011; median Aβ42 581 vs 1,058 ng/L, p < 0.001). Among mutation carriers, decreasing CSF Aβ40 was associated with higher lobar microbleed count (p = 0.010), increasing white matter hyperintensity volume (p = 0.008), and presence of cortical superficial siderosis (p = 0.02). Decreased levels of CSF Aβ40 and Aβ42 occur before HCHWA-D mutation carriers develop clinical symptoms, implicating vascular deposition of both Aβ species as early steps in cerebral amyloid angiopathy pathogenesis. CSF Aβ40 and Aβ42 may serve as preclinical biomarkers of cerebral amyloid angiopathy pathology.

Association of Key Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease With Hematoma Volume and Expansion in Patients With Lobar and Deep Intracerebral Hemorrhage

Hematoma expansion is an important determinant of outcome in spontaneous intracerebral hemorrhage (ICH) due to small vessel disease (SVD), but the association between the severity of the underlying SVD and the extent of bleeding at the acute phase is unknown to date. To investigate the association between key magnetic resonance imaging (MRI) markers of SVD (as per the Standards for Reporting Vascular Changes on Neuroimaging [STRIVE] guidelines) and hematoma volume and expansion in patients with lobar or deep ICH. Analysis of data collected from 418 consecutive patients admitted with primary lobar or deep ICH to a single tertiary care medical center between January 1, 2000, and October 1, 2012. Data were analyzed on March 4, 2016. Participants were consecutive patients with computed tomographic images allowing ICH volume calculation and MRI allowing imaging markers of SVD assessment. The ICH volumes at baseline and within 48 hours after symptom onset were measured in 418 patients with spontaneous ICH without anticoagulant therapy, and hematoma expansion was calculated. Cerebral microbleeds, cortical superficial siderosis, and white matter hyperintensity volume were assessed on MRI. The associations between these SVD markers and ICH volume, as well as hematoma expansion, were investigated using multivariable models. This study analyzed 254 patients with lobar ICH (mean [SD] age, 75 [11] years and 140 [55.1%] female) and 164 patients with deep ICH (mean [SD] age 67 [14] years and 71 [43.3%] female). The presence of cortical superficial siderosis was an independent variable associated with larger ICH volume in the lobar ICH group (odds ratio per quintile increase in final ICH volume, 1.49; 95% CI, 1.14-1.94; P = .004). In multivariable models, the absence of cerebral microbleeds was associated with larger ICH volume for both the lobar and deep ICH groups (odds ratios per quintile increase in final ICH volume, 1.41; 95% CI, 1.11-1.81; P = .006 and 1.43; 95% CI, 1.04-1.99; P = .03; respectively) and with hematoma expansion in the lobar ICH group (odds ratio, 1.70; 95% CI, 1.07-2.92; P = .04). The white matter hyperintensity volumes were not associated with either hematoma volume or expansion. In patients admitted with primary lobar or deep ICH to a single tertiary care medical center, the presence of cortical superficial siderosis was an independent variable associated with larger lobar ICH volume, and the absence of cerebral microbleeds was associated with larger lobar and deep ICHs. The absence of cerebral microbleeds was independently associated with more frequent hematoma expansion in patients with lobar ICH. We provide an analytical framework for future studies aimed at limiting hematoma expansion.

Cortical Superficial Siderosis and Risk of Bleeding after Thrombolysis for Ischemic Stroke

Background: Cortical superficial siderosis (CSS) is a neuroimaging marker of cerebral amyloid angiopathy and has been associated with a high risk for early subsequent major intracranial hemorrhage (ICH). Therefore, many experts recommend withholding of antithrombotic medication to patients with CSS. In this study, we sought to investigate the prevalence of CSS and the associated risk of ICH in the setting of intravenous thrombolysis (IVT) for ischemic stroke. Methods: We retrospectively searched the medical documentation system of our primary and tertiary care university clinic for all patients with ischemic stroke that received IVT from 2009 to December 2014. All available imaging data were reviewed in a standardized manner and blinded to any clinical data for the presence of CSS and ICH. CSS was defined as linear signal loss along the cerebral cortex on gradient echo T2*-weighted sequences. A stroke neurologist, who was blinded to the neuroimaging data, extracted the corresponding clinical data including follow-up information. Results: We identified 298 patients that received IVT and had undergone brain MRI (mean age 67.6 ± 12.6 years, 59.4% male). Cerebral MRI was performed in 116 patients (38.9%) before and in 182 patients (61.1%) after IVT (median time from stroke symptom onset to MRI: 1 day; range 0-7 days). Only 3 patients (2 females and 1 male aged 90, 76 and 73 years, respectively) had CSS (1%). All of them had a middle cerebral artery (MCA) stroke with a corresponding vessel occlusion. The 76-year-old female patient had extensive CSS and numerous cerebral microbleeds and received another IVT treatment for recurrent MCA stroke 8 months after the first event. After both IVTs, she had clinically asymptomatic small ICH outside the ischemic infarct and distant from CSS. The 2 other patients had only mild to moderate CSS and did not experience any ICH on postthrombolytic imaging. Conclusions: The prevalence of CSS in a clinical cohort of stroke patients that received IVT was low and thus does not appear to pose a substantial risk for symptomatic ICH although this may occur in individual patients. However, such analysis also needs to be extended to the very old stroke patients in whom IVT is increasingly used.