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Background: Cerebral Amyloid Angiopathy (CAA) disease course is highly variable even in hereditary forms. Sex may be a possible modifying factor. We investigated biological sex differences in clinical disease course and magnetic resonance imaging-markers in sporadic (sCAA) and Dutch-type hereditary CAA (D-CAA). Methods: Patients with D-CAA and sCAA were included from hospital and research databases of the Leiden University Medical Center (2012–2020) and Massachusetts General Hospital (1994–2012). Key outcomes were: sex differences in symptomatic intracerebral hemorrhage (sICH) onset, recurrence and survival (analyzed using Kaplan Meier survival and regression analyses), and sex differences in magnetic resonance imaging-markers in D-CAA (explored using scatterplots), and in sCAA (investigated using regression analysis). Results: We included 136 patients with D-CAA (mean age 57 years, 56% women, 64% with previous sICH) and 370 patients with sCAA (mean age 76 years, 51% women, all with previous sICH). Men and women with D-CAA did not differ for sICH onset (median age 54 in men and 56 in women [ P =0.13]). Men with D-CAA had a slightly higher number of sICH compared with women (median 2 versus 1; adjusted RR, 1.5 [95% CI, 1.1–1.9]) and a shorter interval between the first and second sICH (median 1.8 years for men and 3.1 years for women, P =0.02). Men with sCAA had their first sICH at an earlier age (median 75 versus 78 years, respectively, P =0.003) and more lobar microbleeds (median 1 versus 0, P =0.022) compared with women with sCAA. No substantial differences were found in the other magnetic resonance imaging markers. Survival after first sICH was comparable between sexes for D-CAA ( P =0.12) and sCAA ( P =0.23). Conclusions: Men with CAA seem to have an earlier onset (sCAA) and more hemorrhagic disease course (sCAA and D-CAA) compared with women. Future studies are necessary to confirm these findings and determine the underlying role of sex-related factors.

Background: Blood pressure (BP) control represents a crucial intervention to improve long-term outcomes following spontaneous intracerebral hemorrhage (ICH). However, fewer than half of ICH survivors achieve target treatment goals. ICH survivors are also at very high risk for poststroke depression, which may contribute to inadequate BP control. We, therefore, sought to determine whether depressive symptoms after ICH are associated with inadequate BP control. We also investigated whether associations between depression after ICH and BP measurements were mediated by treatment with selective serotonin reuptake inhibitors or norepinephrine-serotonin reuptake inhibitors antidepressants. Methods: We leveraged data from a single-center longitudinal study of ICH conducted at Massachusetts General Hospital (Boston, MA) between 2006 and 2018. We collected data from semiautomated review of electronic health records, baseline and follow-up interviews, and computed tomography imaging. Information on BP measurements, depression diagnoses, antidepressants medication use, and medical visits were collected longitudinally and analyzed using mixed effects models. Primary outcomes included systolic and diastolic BP measurements during long-term follow-up after ICH. Results: We included 1243 consecutive ICH patients without pre-stroke depression history. Of these, 721 (58%) were diagnosed with incident depression over a median follow-up time of 52.8 months (interquartile range, 42.1–60.5). Depression onset was associated with subsequent increase in systolic (+8.3 mm Hg, SE, 2.4 mm Hg, P =0.012) and diastolic (+4.4 mm Hg, SE, 1.2 mm Hg) BP measurements. Resolution of depressive symptoms was associated with subsequent decrease in systolic (−5.9 mm Hg, SE, 1.4 mm Hg, P =0.031) and diastolic (−3.4 mm Hg, SE, 1.1 mm Hg, P =0.041) BP measurements. We also found associations between higher systolic BP measurements and use of selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor antidepressants, independent of whether depression symptoms were active or not (all P Conclusions: ICH survivors displayed increasing BP values after receiving a diagnosis of depression, followed by decreasing values among those experiencing resolution of depressive symptoms. Use of selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor antidepressants was independently associated with higher systolic BP measurements. Clinicians ought to closely monitor BP for ICH survivors being treated for depression, especially using selective serotonin reuptake inhibitor and noradrenaline-serotonin reuptake inhibitor. Future studies will also be required to investigate the mechanisms underlying these associations.

Background: Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease. Methods: In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after ≈4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation. Results: In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level–dependent amplitude ( P =0.011) and prolongation of time to peak ( P P =0.007). Conclusions: Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level–dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage.

Background: Intracerebral hemorrhage (ICH) survivors are at high risk for recurrent stroke and cardiovascular events. Blood pressure (BP) control represents the most potent intervention to lower these risks, but optimal treatment targets in this patient population remain unknown. We sought to determine whether survivors of ICH achieving more intensive BP control than current guideline recommendations (systolic BP Methods: We analyzed data for 1828 survivors of spontaneous ICH from 2 cohort studies. Follow-up BP measurements were recorded 3 and 6 months after ICH, and every 6 months thereafter. Outcomes of interest were major adverse cardiovascular and cerebrovascular events (recurrent ICH, incident ischemic stroke, myocardial infarction), vascular mortality (defined as mortality attributed to recurrent ICH, ischemic stroke, or myocardial infarction), and all-cause mortality. Results: During a median follow-up of 46.2 months, we observed 166 recurrent ICH, 68 ischemic strokes, 69 myocardial infarction, and 429 deaths. Compared with survivors of ICH with systolic BP 120 to 129 mmHg, participants who achieved systolic BP 75 years or with modified Rankin Scale score 4 to 5, systolic BP Conclusions: Targeting systolic BP

Background and Purpose: We explored whether high-degree magnetic resonance imaging–visible 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 disease–related 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 non–CAA-ICH cases. Results: Patients with CAA-ICH (n=29) and non–CAA-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, 1.1–8.0]; 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 [1.33–1.61] versus 1.13 [1.01–1.48]; P =0.003) but not in non–CAA-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 imaging–visible perivascular spaces are equally prevalent between CAA-ICH and non–CAA-ICH in the Asian cohort, the severity of magnetic resonance imaging–visible CSO-perivascular spaces may be an indicator of higher brain amyloid deposition in patients with CAA-ICH.

Background and Purpose— The differentiation between cerebral amyloid angiopathy (CAA) and hypertensive small vessel disease in primary intracerebral hemorrhage is mainly based on hemorrhagic neuroimaging markers in the supratentorial regions, and the cause for cerebellar microbleeds remains unknown. Our aim was to investigate whether superficial cerebellar microbleeds are more likely to be related to CAA rather than hypertensive small vessel disease. Methods— Two hundred seventy-five consecutive patients with intracerebral hemorrhage were retrospectively reviewed from a prospectively maintained hospital-based stroke registry. Eighty-five (33.1%) patients had cerebellar microbleeds and were categorized into superficial (gray matter, vermis), deep (white matter, deep nucleus, cerebellar peduncle), or mixed type based on the location of cerebellar hemorrhagic lesions. Amyloid imaging was obtained using 11C-Pittsburgh Compound B–positron emission tomography in a subgroup of patients. The associations between cerebellar microbleed locations and the type of small vessel disease (CAA versus hypertensive small vessel disease) based on distribution of supratentorial hemorrhagic lesions as well as other magnetic resonance imaging and positron emission tomography markers were analyzed. Results— The presence of cerebellar microbleed was independently associated with supratentorial microbleed and lacunar infarcts (both P P P P =0.03). Of 33 patients assessed by amyloid positron emission tomography, cerebral and cerebellar amyloid load (standardized uptake value ratio) was higher in patients with superficial cerebellar microbleeds compared with deep/mixed cerebellar microbleeds (cerebrum standardized uptake value ratio [reference: cerebellum] 1.33±0.24 versus 1.05±0.09, P P =0.03). Conclusions— Patients with strictly superficial cerebellar microbleeds are associated with a clinicoradiological diagnosis of CAA as well as increased cerebral and cerebellar amyloid deposition on Pittsburgh Compound B–positron emission tomography, suggesting underlying CAA pathology.

Background and Purpose— Hematoma location within the cerebellum may help identify the dominant small vessel disease type (cerebral amyloid angiopathy [CAA] versus nonamyloid small vessel disease). However, it is unknown whether this holds true for cerebral microbleeds (CMBs) within the cerebellum. We tested the hypothesis that cerebellar CMBs restricted to the cortex and vermis (defined as superficial regions) are associated with clinically diagnosed and pathology-verified CAA. Methods— Three hundred and seven consecutive spontaneous intracerebral hemorrhage (ICH) patients with a baseline magnetic resonance imaging that included susceptibility-weighted imaging or angiography were enrolled. Using a topographical template, cerebellar CMB patterns were defined as strictly superficial versus deep (cerebellar gray nuclei and white matter) or mixed (both regions involved). Thirty-six ICH patients with cerebellar CMBs and neuropathology data available were evaluated for the presence of CAA. Results— One hundred and thirty-five (44%) ICH patients had CMBs in the cerebellum. In the patient group with cerebellar CMBs, 85 (63%) showed a superficial pattern, and 50 (37%) had a deep/mixed pattern. Strictly superficial cerebellar CMBs were independently associated with a supratentorial pattern of probable CAA-ICH according to the Boston criteria (odds ratio, 1.6; CI, 1.03–2.5) and deep/mixed cerebellar CMBs with a pattern of deep/mixed ICH (odds ratio, 1.8; CI, 1.2–2.7). Pathologically verified CAA was present in 23 of 24 (96%) patients with superficial cerebellar CMBs versus 3 of 12 (25%) patients with deep/mixed cerebellar CMBs ( P Conclusions— In ICH patients, cerebellar CMBs are relatively common and often restricted to superficial regions. A strictly superficial distribution of cerebellar CMBs is associated with clinically diagnosed and pathologically verified CAA.

Background and Purpose— We investigated cortical superficial siderosis (cSS) progression and its clinical relevance for incident lobar intracerebral hemorrhage (ICH) risk, in probable cerebral amyloid angiopathy presenting with neurological symptoms and without ICH at baseline. Methods— Consecutive patients meeting modified Boston criteria for probable cerebral amyloid angiopathy from a single-center cohort who underwent magnetic resonance imaging (MRI) at baseline and during follow-up were analyzed. cSS progression was assessed by comparison of the baseline and follow-up images. Patients were followed prospectively for incident symptomatic ICH. cSS progression and first-ever ICH risk were investigated in Cox proportional hazard models adjusting for confounders. Results— The cohort included 118 probable cerebral amyloid angiopathy patients: 72 (61%) presented with transient focal neurological episodes and 46 (39%) with cognitive complaints prompting the baseline MRI investigation. Fifty-two patients (44.1%) had cSS at baseline. During a median scan interval of 2.2 years (interquartile range, 1.2–4.4 years) between the baseline (ie, first) MRI and the latest MRI, cSS progression was detected in 33 (28%) patients. In multivariable logistic regression, baseline cSS presence (odds ratio, 4.04; 95% CI, 1.53–10.70; P =0.005), especially disseminated cSS (odds ratio, 9.12; 95% CI, 2.85–29.18; P P =0.017) were independent predictors of cSS progression. For patients without an ICH during the interscan interval (n=105) and subsequent follow-up (median postfinal MRI time, 1.34; interquartile range, 0.3–3 years), cSS progression independently predicted increased symptomatic ICH risk (hazard ratio, 3.76; 95% CI, 1.37–10.35; P =0.010). Conclusions— Our results suggest that cSS evolution may be a useful biomarker for assessing disease progression and ICH risk in cerebral amyloid angiopathy patients and a candidate biomarker for clinical studies and trials.

Background: The mechanisms linking cerebral amyloid angiopathy (CAA) to enlarged perivascular spaces in centrum semiovale (CSO-EPVS) and whether other Alzheimer’s Disease (AD) pathologies might affect CSO-EPVS are unclear. We hypothesized that amyloid but not tau load would independently correlate with CSO-EPVS in CAA. Methods: Fifty prospectively enrolled nondemented probable CAA patients underwent high-resolution structural MRI, Pittsburgh compound B (PiB, for amyloid), and 18 F-flortaucipir (FTP, for tau) PET imaging. Microbleeds (all lobar, LMB) were counted and white matter hyperintensity volume (WMH) was quantified. CSO-EPVS were counted on T 2 -MRI sequence and graded using a previously validated scale (range 0-4). A multivariate ordinal regression model was used to assess the independent associations between CSO-EPVS and mean cortical amyloid as well as tau deposition, after adjusting for relevant covariates. Results: Patients had a mean age of 69.3±7.2. Age, sex, presence of hypertension, intracerebral hemorrhage (ICH), LMB counts, and WMH were not associated with CSO-EPVS grades (p>0.2 for all comparisons). Higher PiB uptake significantly correlated with increased CSO-EPVS (rho=0.45, p=0.001). Higher FTP showed a trend for correlation with CSO-EPVS (rho=0.26, p=0.069). In an ordinal regression model with CSO-EPVS grade as the dependent variable and both amyloid and tau levels included as predictors along with covariates presented above, the association of CSO-EPVS remained significant with higher PiB uptake (β=3.97, 95%CI 1.1-6.8, p=0.007) but not with FTP uptake (p=0.167). Conclusion: Results of this study suggest that CSO-EPVS is independently associated with amyloid but not with tau deposition in CAA. CSO-EPVS was not associated with age or classical vascular risk factors or presence of ICH. Our results support the view that vascular amyloid but not other AD pathologies such as tau might contribute to EPVS in patients with CAA.

Background: Cerebral amyloid angiopathy (CAA) is associated with white matter hyperintensities (WMH) but the physiopathological mechanisms remain unclear. We hypothesized that the relationship between vascular amyloid load and WMH is mediated by vascular dysfunction. Methods: The study cohort included 38 non-demented probable CAA patients who underwent advanced multimodal structural and functional MRI (fMRI) and amyloid PET scans. White matter hyperintensity volume was quantified using FreeSurfer and expressed as a percent of total intracranial volume (pWMHv). Time-to-peak [TTP] of blood oxygen level-dependent [BOLD] response to visual stimulation using fMRI was used as an established measure of vascular dysfunction. Mean cortical Pittsburg Compound B uptake representing amyloid load was calculated. A bootstrapping procedure was used to test the mediation hypothesis adjusting for age, sex, and presence of intracerebral hemorrhage (ICH). Results: Of 38 patients with CAA (mean age 70±7.1, 86.8% male), 25 (65.8%) had ICH, while the remaining 13 patients (34.2%) presented with multiple strictly cortical microbleeds. Higher amyloid load correlated with prolonged TTP response (r=0.373, p=0.021) and higher pWMHv (r=0.337, p=0.039), and prolonged TTP response correlated with higher pWMHv (r=0.485, p=0.002). Amyloid load no longer predicted pWMHv (p=0.254) after controlling for TTP. In the bootstrapping model, TTP response had a significant indirect effect (ab=0.977, 95% CI: 0.15-2.42), showing that the association between amyloid load and pWMHv is mediated by TTP. Discussion: Our findings confirm the hypothesis that the effect of vascular amyloid load on the extent of white matter disease is mediated by vascular dysfunction in patients with CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Background and Purpose: Anticoagulation therapy not only reduces the risk of ischemic stroke in atrial fibrillation (AF) but also predisposes patients to hemorrhagic complications. There is limited knowledge on the risk of first-ever ischemic stroke in patients with AF after extracranial hemorrhage (ECH). Methods: We conducted a retrospective study using the California State Inpatient Database including all nonfederal hospital admissions in California from 2005 to 2011. The exposure variable was hospitalization with a diagnosis of ECH with a previous diagnosis of AF. The outcome variable was a subsequent hospitalization with acute ischemic stroke. We excluded patients with stroke before or at the time of ECH diagnosis. We calculated adjusted hazard ratios for ischemic stroke during follow-up and at 6-month intervals using Cox regression models adjusted for pertinent demographics and comorbidities. In subgroup analyses, subjects were stratified by primary ECH diagnosis, severity/type of ECH, age, CHA 2 DS 2 -VASc score, or the presence/absence of a gastrointestinal or genitourinary cancer. Results: We identified 764 257 patients with AF (mean age 75 years, 49% women) without a documented history of stroke. Of these, 98 647 (13%) had an ECH-associated hospitalization, and 22 748 patients (3%) developed an ischemic stroke during the study period. Compared to patients without ECH, subjects with ECH had ≈15% higher rate of ischemic stroke (overall adjusted hazard ratio, 1.15 [95% CI, 1.11–1.19]). The risk appeared to remain elevated for at least 18 months after the index ECH. In subgroup analyses, the risk was highest in subjects with a primary admission diagnosis of ECH, severe ECH, gastrointestinal-type ECH, with gastrointestinal or genitourinary cancer, and age ≥60 years. Conclusions: Patients with AF hospitalized with ECH may have a slightly elevated risk for future ischemic stroke. Particular consideration should be given to the optimal balance between the benefits and risks of anticoagulation therapy and the use of nonanticoagulant alternatives, such as left atrial appendage closure in this vulnerable population.

Background and Purpose— Magnetic resonance imaging visible perivascular spaces in the centrum semiovale (CSO-PVS) have been associated with cerebral amyloid angiopathy (CAA).We aimed to further confirm this link by evaluating CSO-PVS volume in pathologically-demonstrated sporadic and genetically-demonstrated hereditary forms of the disease. Methods— We studied a retrospective hospital-based cohort consisting of 63 individuals aged >55 having brain magnetic resonance imaging and pathological assessment of CAA (mean age, 73.6±8.5; 46% female), and a separate cohort consisting of 26 carriers, and 28 noncarriers of the hereditary cerebral hemorrhage with amyloidosis–Dutch type (mean age, 46.7±12.8; 61.1% female). CSO-PVS volume was quantified on a single magnetic resonance imaging slice using a computer-assisted segmentation method and expressed as the relative volume of the intracranial volume in that particular slice (CSO-PVS relative volume). We compared CSO-PVS relative volume (1) between subjects with and without the disease in both cohorts; (2) between non-CAA, CAA without hemorrhage, and CAA with hemorrhage cases in the sporadic CAA cohort. All variables reaching P Results— In both sporadic and Dutch cohorts, cases with CAA had significantly higher CSO-PVS relative volume than cases without (median [IQR]: 3.7% [2.5–5.3] versus 1.8% [1.2–2.4], P P =0.007; respectively). In linear regression models, sporadic CAA was associated with higher CSO-PVS relative volume ( P =0.008). In the sporadic CAA cohort, compared with non-CAA cases, CSO-PVS relative volume was higher in both CAA with hemorrhage and without hemorrhage (4.4% [2.6–6.1] and 3% [2.4–3.6] versus 1.8% [1.2–2.4], P P =0.005, respectively). Higher CSO-PVS relative volume was associated with CAA in regression models, both when hemorrhage was present (odds ratio, 2.63; [95% confidence interval, 1.33–5.18]; P =0.005) and absent (odds ratio, 4.55; [95% confidence interval, 0.98–21.04]; P =0.05). Conclusions— Increased CSO-PVS volume is a consistent magnetic resonance imaging marker of cerebrovascular amyloid deposition and a promising diagnostic tool for sporadic CAA without hemorrhagic manifestations.

Background and Purpose— Although the computed tomographic angiography spot sign performs well as a biomarker for hematoma expansion (HE), computed tomographic angiography is not routinely performed in the emergency setting. We developed and validated a score to predict HE-based on noncontrast computed tomography (NCCT) findings in spontaneous acute intracerebral hemorrhage. Methods— After developing the score in a single-center cohort of patients with intracerebral hemorrhage (n=344), we validated it in a large clinical trial population (n=954) and in a multicenter intracerebral hemorrhage cohort (n=241). The following NCCT markers of HE were analyzed: hypodensities, blend sign, hematoma shape and density, and fluid level. HE was defined as hematoma growth >6 mL or >33%. The score was created using the estimates from multivariable logistic regression after final predictors were selected from bootstrap samples. Results— Presence of blend sign (odds ratio, 3.09; 95% confidence interval [CI],1.49–6.40; P =0.002), any intrahematoma hypodensity (odds ratio, 4.54; 95% CI, 2.44–8.43; P P =0.0002) were predictors of HE. A 5-point score was created (BAT score: 1 point for blend sign, 2 points for any hypodensity, and 2 points for timing of NCCT Conclusions— An easy to use 5-point prediction score can identify subjects at high risk of HE with good specificity and accuracy. This tool requires just a baseline NCCT scan and may help select patients with intracerebral hemorrhage for antiexpansion clinical trials.

Despite significant advances in our ability to detect and treat atrial fibrillation (AF), less than half of high embolic risk patients receive oral anticoagulants (OACs).1 The main cause of this problem is the known association between OACs and intracranial hemorrhage (ICH), the latter being the most lethal and disabling condition known to humans, among the relatively common medical emergencies. The last decade saw the development and more recently the Food and Drug Administration (FDA) approval of an endovascular left atrial appendage closure (LAAC) procedure, namely WATCHMAN (Boston Scientific, Plymouth, MN; Figure 1), as a second-line treatment for stroke and systemic embolism prevention in nonvalvular AF (NVAF) without the need for lifelong anticoagulation. Other endovascular and surgical LAAC devices and procedures are currently being developed and tested in clinical trials. The other important advance has been the development of imaging markers that can help stratify the risk of ICH in individual patients. Current AF management guidelines recommend choosing the antithrombotic therapy based on shared decision-making approaches, after discussion of the absolute and relative risks of stroke and bleeding, taking into account the patient’s values and preferences.2 Table 1 and Figures 2 and 3 provide an overview of conditions that are associated with a relatively high ICH risk. In patients with NVAF and any of these high ICH risk conditions, LAAC might be considered for ischemic and hemorrhagic stroke prevention, taking into account the safety and efficacy of the device compared with OAC. View this table: Table 1. Conditions Associated With High Brain Bleeding Risk Figure 1. Select devices and procedures used for left atrial appendage closure (LAAC). A , Left , The WATCHMAN device (Boston Scientific, Plymouth, MN), FDA-approved for stroke prevention in nonvalvular atrial fibrillation through LAAC. Middle , Schematic showing the placement of WATCHMAN device in LAA, note septal puncture. Right , Schematic of …

Background and Purpose— We evaluated whether lacunes in centrum semiovale (lobar lacunes) were associated with cerebral amyloid angiopathy (CAA) markers in an Asian intracerebral hemorrhage (ICH) population. Methods— One hundred ten patients with primary ICH were classified as CAA-ICH (n=24; mean age, 70.9±13.9) or hypertensive ICH (n=86; mean age, 59.3±13.0) according to the presence of strictly lobar (per modified Boston criteria) or strictly deep bleeds (both ICH and cerebral microbleeds), respectively. Lacunes were evaluated in the supratentorial area and classified as lobar or classical deep based on the location. A subgroup of 36 patients also underwent Pittsburgh Compound B positron emission tomography to measure cerebral amyloid deposition and global standardized uptake value ratio were calculated. Results— Lobar lacunes were more frequent in CAA-ICH than hypertensive ICH (29.2 versus 11.6%; P =0.036). In multivariable models, lobar lacunes were associated with lobar cerebral microbleed (odds ratio, 6.8; 95% confidence interval, 1.6–29.9; P =0.011) after adjustment for age, sex, hypertension, and white matter hyperintensity. In 15 CAA-ICH and 21 hypertensive ICH patients with Pittsburgh Compound B positron emission tomography, correlation analyses between lobar lacune counts and global standardized uptake value ratio showed positive association (ρ=0.40; P =0.02) and remained significant after adjustment for age ( r =0.34; P =0.04). Conclusions— Our findings expand on recent work showing that lobar lacunes are more frequent in CAA-ICH than hypertensive ICH. Their independent association with lobar cerebral microbleeds and brain amyloid deposition suggests a relationship with CAA even in an Asian cohort with overall higher hypertensive load.

Background and Purpose- We investigated cortical superficial siderosis (cSS) progression and its clinical relevance for incident lobar intracerebral hemorrhage (ICH) risk, in probable cerebral amyloid angiopathy presenting with neurological symptoms and without ICH at baseline. Methods- Consecutive patients meeting modified Boston criteria for probable cerebral amyloid angiopathy from a single-center cohort who underwent magnetic resonance imaging (MRI) at baseline and during follow-up were analyzed. cSS progression was assessed by comparison of the baseline and follow-up images. Patients were followed prospectively for incident symptomatic ICH. cSS progression and first-ever ICH risk were investigated in Cox proportional hazard models adjusting for confounders. Results- The cohort included 118 probable cerebral amyloid angiopathy patients: 72 (61%) presented with transient focal neurological episodes and 46 (39%) with cognitive complaints prompting the baseline MRI investigation. Fifty-two patients (44.1%) had cSS at baseline. During a median scan interval of 2.2 years (interquartile range, 1.2-4.4 years) between the baseline (ie, first) MRI and the latest MRI, cSS progression was detected in 33 (28%) patients. In multivariable logistic regression, baseline cSS presence (odds ratio, 4.04; 95% CI, 1.53-10.70; P=0.005), especially disseminated cSS (odds ratio, 9.12; 95% CI, 2.85-29.18; P0.0001) and appearance of new lobar microbleeds (odds ratio, 4.24; 95% CI, 1.29-13.9; P=0.017) were independent predictors of cSS progression. For patients without an ICH during the interscan interval (n=105) and subsequent follow-up (median postfinal MRI time, 1.34; interquartile range, 0.3-3 years), cSS progression independently predicted increased symptomatic ICH risk (hazard ratio, 3.76; 95% CI, 1.37-10.35; P=0.010). Conclusions- Our results suggest that cSS evolution may be a useful biomarker for assessing disease progression and ICH risk in cerebral amyloid angiopathy patients and a candidate biomarker for clinical studies and trials.

Introduction: Oral Anticoagulation Therapy (OAT) resumption after ICH is a dilemma due to increased risk of recurrent ICH, particularly after lobar ICH caused by underlying Cerebral Amyloid Angiopathy (CAA). Apolipoprotein E ( APOE ) ε2/ε4 alleles are risk factors for recurrent CAA-related ICH. Hypothesis: APOE genotype predicts lobar ICH recurrence after OAT-ICH. Methods: We enrolled survivors of lobar OAT-ICH in a prospective single-center study to determine whether APOE ε2/ε4: 1) are associated with ICH recurrence following OAT-ICH, using time-to-event analyses; 2) improved prediction of ICH recurrence when added to MRI-based CAA markers (cerebral microbleeds [CMBs], white matter hyperintensities [WMH], expanded peri-vascular spaces [EPVS], and cortical superficial siderosis [CSS]), using Harrell’s C-statistic; 3) could be incorporated in a classification scheme to predict ICH recurrence, as defined by recursive partitioning analysis (RPA). Results: We followed 110 lobar OAT-ICH survivors for a median time of 52.2 months (IQR: 33.5-61.7). We observed 26 recurrent ICH events, corresponding to an annual recurrence rate of 5.7%. APOE ε2/ε4 variants were associated with ICH recurrence following OAT-ICH (ε2: HR 2.14, 95% CI 1.20-3.82; ε4: HR 1.50, 95% CI 1.21-3.47). These associations remained significant after adjusting for anticoagulation status, antiplatelet use, CMBs, WMH, EPVS, and CSS. Inclusion of APOE genotype alongside MRI data resulted in improved predictive ability for ICH recurrence (Harrell’s C: 0.76 vs. 0.68, p=0.034). RPA revealed that APOE ε2/ε4 stratified likelihood of ICH recurrence among otherwise low risk individuals based on MRI data alone (Figure). Conclusions: APOE genotype predicts lCH recurrence following lobar OAT-ICH, and improves predictive performance when added to established neuroimaging markers. APOE-based lobar ICH recurrence prediction warrants further investigation and may affect clinical practice.

Background: Cerebral amyloid angiopathy (CAA) is diagnosed after a lobar intracerebral hemorrhage (L-ICH) but lobar microbleeds (LMB) are increasingly detected on MRIs of patients without L-ICH. We aimed to compare advanced imaging measures of structural brain damage, amyloid load, and cerebrovascular reactivity between CAA patients with L-ICH (CAA-ICH) and those with LMB (LMB-only). Methods: Standard MRI markers (LMB counts, cortical superficial siderosis [cSS], enlarged perivascular spaces [EPVS], white matter hyperintensity [WMH] patterns) and FreeSurfer based advanced volumetric analyses (calculated as percent of total intracranial volume) were obtained in 115 non-demented patients with either CAA-ICH or LMB-only. Pittsburgh compound B PET measures of amyloid deposition and fMRI measures of vascular reactivity (amplitude, time-to-peak, time-to-baseline) were also compared between the 2 groups. Results: LMB-only patients (n=37) presented with transient neurological symptoms or cognitive/gait complaints and stroke/neurodegenerative conditions were ruled out. Age, vascular risk factors, LMB counts, presence of cSS, EPVS counts and WMH patterns were not different between CAA-ICH and LMB-only (Table). Volume of WMH was significantly higher in CAA-ICH as compared to LMB-only patients in univariable and multivariable models (p=0.026). There was no difference in cortical thickness, WM volume, amyloid load/distribution and finally functional MRI markers of vascular reactivity between the two groups (Table). Conclusions: Our results indicate that measures of vascular physiology and amyloid load as well as structural damage of LMB-only patients are not different from CAA-ICH, except a lower WMH load. These data support the view that LMB-only patients represent a non-hemorrhagic stage of the disease and that they can be enrolled in clinical trials aimed at modifying the molecular/physiologic changes to reverse/prevent CAA progression.

Background: Cerebral amyloid angiopathy (CAA) is known for its hemorrhagic manifestations, but ischemic features of the disease are also recognized such as white matter hyperintensities (WMH). We aimed to investigate the interrelationship between two emerging ischemic markers related to CAA: lacunes and cortical microinfarcts (CMI). Methods: CMI were scored on MRIs using high resolution FLAIR, double inversion recovery and MEMPRAGE sequences, in prospectively enrolled patients with CAA. The presence, number, and topography of lacunes (deep vs. subcortical), cerebral microbleeds (CMB), cortical superficial siderosis (cSS), and enlarged perivascular spaces (EPVS) were identified. FreeSurfe r was used for volumetric analyses. The relationship of CMI and lacunes as well as the association of these lesions with other CAA-related markers were analyzed. Results: The cohort consisted of 122 nondemented probable CAA patients (mean age, 69.4±7.6 years, 73% men). Lacunes were present in 31 (25.4%) of the patients and all but 1 were located in subcortical as opposed to deep brain regions. Lacunes were not associated with age, sex, or vascular risk factors. CMI were found in 35 patients (28.7%). CMI were more common in patients with lacunes compared to patients without lacunes (51.6% vs. 20.9%, p=0.002) and this association remained significant in a multivariable model adjusting for age, sex and hypertension (odds ratio: 4.2, 95% CI: 1.75-10, p=0.001). WMH volume, EPVS, WM volume, cortical thickness, and hemorrhagic markers did not differ between patients with or without lacunes (p>0.2 for all comparisons). CMI did not correlate with these markers except showing a positive association with presence/extent of cSS. Conclusion: Lacunes and CMI were common in CAA, and lacunes were more commonly found in subcortical WM as opposed to deep gray structures. Our study shows that CMI are more likely to occur in probable CAA patients with lacunes than without lacunes, suggesting that these two lesion types may be part of a common spectrum of small CAA-related ischemic infarcts. These pathologies did not correlate with markers of more widespread damage, however, suggesting that the mechanism for CAA-related infarcts is distinct from other more widespread effects of CAA.

Background and Purpose— We recently showed that cerebral amyloid angiopathy (CAA) is associated with functionally relevant brain network impairments, in particular affecting posterior white matter connections. Here we examined how these brain network impairments progress over time. Methods— Thirty-three patients with probable CAA underwent multimodal brain magnetic resonance imaging at 2 time points (mean follow-up time: 1.3±0.4 years). Brain networks of the hemisphere free of intracerebral hemorrhages were reconstructed using fiber tractography and graph theory. The global efficiency of the network and mean fractional anisotropies of posterior–posterior, frontal–frontal, and posterior–frontal network connections were calculated. Patients with moderate versus severe CAA were defined based on microbleed count, dichotomized at the median (median=35). Results— Global efficiency of the intracerebral hemorrhage–free hemispheric network declined from baseline to follow-up (−0.008±0.003; P =0.029). The decline in global efficiency was most pronounced for patients with severe CAA (group×time interaction P =0.03). The decline in global network efficiency was associated with worse executive functioning (β=0.46; P =0.03). Examination of subgroups of network connections revealed a decline in fractional anisotropies of posterior–posterior connections at both levels of CAA severity (−0.006±0.002; P =0.017; group×time interaction P =0.16). The fractional anisotropies of posterior–frontal and frontal–frontal connections declined in patients with severe but not moderate CAA (group×time interaction P =0.007 and P =0.005). Associations were independent of change in white matter hyperintensity volume. Conclusions— Brain network impairment in patients with CAA worsens measurably over just 1.3-year follow-up and seem to progress from posterior to frontal connections with increasing disease severity.

Age-related cognitive impairment is arguably the greatest looming threat to aging populations in both the developed and developing world.1 Emerging evidence indicates that cerebral small vessel disease (SVD) is a major contributor to cognitive impairment,2 highlighting the importance of improved understanding of the molecular and physiological mechanisms leading to vascular brain injury. As a result, 2 of the 3 highest priority research areas for the next 5 to 10 years identified by National Institute of Neurological Disorders and Stroke’s (NINDS) Workgroup on Stroke Prevention Research in 2012 were focused on prevention of vascular cognitive impairment (VCI) and imaging biomarkers in stroke prevention.3 This important initiative of NINDS has further accelerated the neuroimaging research in VCI that was blossoming over the preceding 10 years. Novel magnetic resonance imaging (MRI) markers of ischemic and hemorrhagic tissue damage in the brain have been identified, and their associations with the underlying cerebrovascular pathologies and resulting cognitive changes are extensively studied.4 MRI-based studies yielded a large gamut of imaging markers that mediate vascular contributions to dementia. Silent infarcts, lacunes, white matter hyperintensities (WMH) on fluid-attenuated inversion recovery MRI, fractional anisotropy and mean diffusivity changes, and acute punctate infarcts on diffusion weighted MRI are examples of ischemic markers that have been increasingly studied during the past decade.5–7 Cerebral microbleeds (CMB) and cortical superficial siderosis are subtle hemorrhagic lesions visible on T2*-MRI, and they serve as key markers of the most common SVDs that contribute to VCI in elderly.5,8 Enlarged perivascular spaces (EPVS), identified on T1- and T2-weighted MRIs by radiologists for over 2 decades, are emerging as another VCI-related marker, especially because of their association with the type of SVD.5 Functional MRI provided measures of vascular dysfunction and resting-state functional connectivity, whereas diffusion tensor imaging …

See related article, p 1464 The detection and treatment of nonvalvular atrial fibrillation (NVAF) constitute areas of active research yielding novel technologies that result in lively debates among general medicine, cardiology, and neurology specialists. Non–vitamin K antagonist oral anticoagulants (NOAC), approved by Food and Drug Administration (FDA) within the first half of this decade, have been increasingly adopted as first-line agents for stroke prevention in NVAF.1 These medications have shown noninferiority for stroke prevention against warfarin arms with suboptimal international normalized ratio control in patient populations with low mean embolic risk scores for ≈2 years of follow-up. Except ROCKET-AF (Rivaroxaban; The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) that enrolled a large patient population (55%) presenting after an ischemic stroke or transient ischemic attack, the phase III studies of NOACs mostly included primary prevention cohorts (≈80%).2 The mean time in therapeutic range of patients enrolled in warfarin arms of the 3 most commonly used NOACs was in the 55% to 62% range (rivaroxaban, dabigatran, and apixaban). Comparing NOACs to warfarin in that setting suggested equivalent benefit for embolic prevention and a lower risk of intracerebral hemorrhage (ICH) favoring NOACs in patients who were at low ICH risk during study enrollment. Real-world experience with NOACs has been positive to date when used in patient populations similar to their phase III studies, that is, patients with good kidney function, no prior history of ICH, and no perceived high risk for major hemorrhage. A specific reversal agent for dabigatran was FDA approved for use in emergency procedures or in uncontrolled bleeding, and another drug is awaiting approval for the more commonly used Factor Xa inhibitors. These are good news as reversal of anticoagulation can make …

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) is associated with cortical and white matter atrophy. We hypothesized that atrophy in CAA extended into the subcortical gray matter as well and might explain previously observed alterations in subcortical gray matter diffusion-tensor properties. Methods: We compared multimodal MRIs from 80 prospectively enrolled non-demented patients with probable CAA, to two other cohorts: 80 Healthy Controls (HC) and 80 patients with Alzheimer’s Disease (AD) from the AD Neuroimaging Initiative. Validated FreeSurfer algorithms were used to calculate Gray Matter (GMV) and Basal Ganglia Volumes (BGV), expressed as percentage of intracranial volume (ICV). High-resolution diffusion scans were used to calculate the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) within the basal ganglia. A visual basal ganglia atrophy scale was also developed to compare atrophy between 93 patients with CAA-related intracerebral hemorrhage (CAA-ICH) and 93 age-matched patients diagnosed with Hypertensive Arteriopathy and ICH (HTN-ICH). Results: CAA patients (mean age: 70.3 ± 8.5) were age-matched to HC (71.8 ± 3.7) and AD patients (70.4 ± 6.8). Patients with CAA had significantly lower BGV (1.16% ± 0.14) when compared to both HC (1.30% ± 0.13, p Conclusions: Patients with CAA displayed substantial atrophy in the basal ganglia when compared to HC, AD, and HTN-ICH patients. Within the CAA cohort, greater basal ganglia atrophy was independently correlated with greater cortical atrophy and previously observed increases in basal ganglia anisotropy. The mechanisms for and clinical manifestations of CAA-related basal ganglia atrophy remain to be determined.

Background/Purpose: Cross-sectional studies show associations between cerebral amyloid angiopathy (CAA) and cortical as well as white matter atrophy. We hypothesized that CAA patients also have hastened gray and white matter atrophy in longitudinal follow up. Methods: We compared multimodal MRIs from 49 prospectively enrolled non-demented patients with probable CAA (per Boston criteria) scanned at two different time points, to two other longitudinal cohorts: 49 Healthy Controls (HC) and 49 patients with Alzheimer’s Disease (AD) from the AD Neuroimaging Initiative. Validated FreeSurfer algorithms were used to calculate Gray Matter (GMV) and White Matter Volumes (WMV), expressed as percentage of intracranial volume (ICV). Cognitive assessments were done for 34 CAA patients during their baseline and follow up visits, and z scores for executive function, processing speed and memory were calculated. Multivariable models were adjusted for age, sex, presence of hypertension, and baseline variable of interest. Results: Patients with CAA were of similar age (baseline mean age: 71.1) to HC (72.8, p=0.183) but younger than patients with AD (77.3, p Conclusions: Patients with CAA have worse gray matter atrophy than HC as well as worse white matter atrophy than both HC and AD longitudinally, results in line with previous cross-sectional work. The rates of atrophy in CAA also correlated strongly with measures of worsening cognitive function. Our findings support the projected cause-effect relationship between CAA and global brain atrophy leading to cognitive impairment.

Background: Higher load of MRI visible enlarged perivascular spaces in centrum-semiovale (CSO-EPVS) are found in cerebral amyloid angiopathy (CAA), but their association to brain amyloid has been rarely investigated, especially in Asians. We explored whether high degree of CSO-EPVS is associated to other MRI signatures of CAA and its relationship to brain amyloid retention in patients with primary intracerebral hemorrhage (ICH). Methods: 110 patients with either CAA-ICH, strictly lobar ICH and microbleeds (MB) or hypertensive ICH (HTN-ICH), strictly deep-seated ICH/MBs, were included in this study. CSO-EPVS and basal ganglia EPVS (BG-EPVS) were assesd using an established 4-point semiquantitative score. EPVS degree was classified as high (score>2) or low (≤2). We also evaluated MBs, cortical superficial siderosis (cSS), white matter hyperintensities (WMH) and brain atrophy severity on MRIs. Cerebral amyloid deposition was quantified on 11 C-Pittsburgh Compound B (PiB) PETs in 36 patients (15 CAA; 21 HA) as standardized uptake value ratio (SUVR). Results: Patients with CAA-related ICH (n=24) and HTN-ICH (n=86) had similar prevalence of high-degree CSO-EPVS (37.5% and 26.7%, p=0.305) and high-degree BG-EPVS (25% and 18.6%, p=0.489). Patients with high-degree CSO-EPVS were associated with presence of lobar MB (p=0.01) and higher WMH (p=0.008), while patients with high-degree EPVS-BG were associated with older age (p=0.002), higher WMH (p=0.021) and more cortical atrophy (p=0.023). The amyloid burden (global SUVR) was higher in high-degree vs low-degree EPVS-CSO in CAA-ICH (p=0.045), but not in HTN-ICH (p=0.586). On multivariate logistic regression analysis, the degree of EPVS-CSO remains an independent indicator for positive amyloid scan (defined as global SUVR>1.2) even after adjustment for age, WMH, the degree of EPVS-BG and ICH/MBs distribution (Odds ratio 6.2 [1.2-31.6], p=0.029). Conclusion: Although the presence of EPVS-CSO could not directly distinguish CAA-ICH and HTN-ICH in our Asian cohort, high-degree EPVS-CSO was associated with CAA-related MRI markers such as lobar MBs, and higher amyloid load on PiB-PET. The burden of CSO-EPVS can be seen as an indicator of higher brain amyloid deposition in patients with CAA-related ICH.

Background: Patients with intracerebral hemorrhage (ICH) are frequently transferred between hospitals in anticipation of the need for higher level of care than locally available. We aimed to identify factors that are associated with increased resource utilization among patients with ICH transferred to a single academic hospital. Methods: We utilized data on patients with primary ICH at urban academic hospital between 01/01/2005-12/31/2015 from a prospectively collected registry of consecutive patients. Those with trauma, aneurysm, tumor, or other types of secondary ICH were excluded. Disease severity was calculated using the ICH score at time of presentation. The primary outcome (care that may not be available at the sending hospital) was operationally defined as use of either ICU admission or surgical intervention. We used logistic regression to examine predictors of ICU stay or surgical intervention, controlling for age, sex, race/ethnicity, insurance status, anticoagulation use, and past history of stroke or ICH. Results: During the study period, 2008 patients met inclusion criteria, 71% of whom presented as transfers. ICU stay or surgical intervention was required in 887 (44.2%). Patient requiring ICU stay or surgical intervention were younger (mean age 71 vs. 74 years, p65 years (OR 0.38, 95% CI 0.21-0.69), GCS0 (OR 2.23, 95% CI 1.70-2.91). Conclusion: Among this cohort of patients with primary ICH, those with GCS of 15 and ICH score of 0 were less likely to require ICU stay or surgical intervention. These results should be validated in a larger sample but may be valuable for hospitals considering which ICH patients should be transferred to a tertiary care center.

Background: Lacunar infarcts located in centrum-semiovale and lobar regions were more frequent in Caucasians with intracerebral hemorrhage related to cerebral amyloid angiopathy (CAA-ICH) while deep-seated lacunes in ICH related to hypertension (HTN-ICH), but these associations have never been validated in Asian patients. In the present study, we evaluated whether lobar lacunes were associated with core CAA markers such as lobar microbleeds (CMB) and higher amyloid load on 11 C-Pittsburgh Compund B (PiB) PET in an Asian ICH population. Methods: One hundred and ten patients of primary ICH who received MRI scans were classified as CAA-ICH or HTN-ICH according with the presence of strictly lobar or strictly deep bleeds (both ICH and CMBs), respectively. Lacunes were evaluated in the supratentorial area and classified as lobar (when located in CSO, frontal, parietal, insular/subinsular, temporal, and occipital lobes) or deep (when located in thalamus, basal ganglion, internal and external capsule) based on the location. A subgroup of 36 patients also underwent PiB-PET and global standardized uptake value ratio (SUVR) were calculated. Results: There were 24 CAA-ICH (mean age 70.9 ± 13.9) and 86 HTN-ICH (mean age 59.3 ± 13.0). Lobar lacunes were more frequent in CAA-ICH than HTN-ICH (29.2 vs 11.6%, p=0.036). In univariate analysis, lobar lacunes were significantly related to lobar CMB (pr =0.34, p=0.04). Conclusion: Lobar lacunes were more frequent in Asian patients with CAA-related strictly lobar hemorrhages. Their independent association with lobar CMB and brain amyloid deposition suggests a strong relationship with CAA even in an Asian cohort with overall higher hypertensive load.

Background: Previous pathologic reports have suggested that the underlying vasculopathy in cerebellar intracerebral hemorrhage (ICH) patients may be related to the location of the bleed whithin the cerebellum. We sought to determine whether the location of hematoma in the cerebellum (deep and superficial regions) was suggestive of a particular hemorrhage-prone small vessel disease pathology (hypertensive vasculopathy or cerebral amyloid angiopathy, CAA). Methods: Consecutive cerebellar-ICH patients were recruited from January 1998 to January 2016. Based on data from pathologic reports, patients were divided according to the location of the primary cerebellar hematoma (superficial, Figure, panel A-B, blu circles in panel E vs deep, Figure, panel C-D, orange circles in panel E ). Location of cerebral microbleeds (CMB; strictly-lobar, strictly-deep and mixed-CMB) was evaluated on MRI. Results: One-hundred and eight patients (84%) had a deep cerebellar hematoma and 20 (16%) a superficial cerebellar hematoma. Hypertension was more prevalent in deep than in superficial cerebellar-ICH patients (89% vs 65%, respectively; p Conclusions: Our study showed that superficial cerebellar-ICH is related to the presence of strictly lobar-CMB, a pathologically proven marker of CAA. Cerebellar hematoma location may thus help to identify those patients likely to have CAA pathology.

Introduction: Oral Anticoagulation Treatment (OAT) resumption remains an unresolved question in Intracerebral Hemorrhage (ICH) care. Previous studies focused on the effects of OAT resumption on recurrent stroke. Hypothesis: OAT resumption is associated with increased likelihood of functional recovery after ICH, even in the absence of symptomatic stroke recurrence. Methods: We analyzed data for 614 ICH survivors on OAT at time of stroke, who did not experience mortality or recurrent stroke during follow-up, enrolled in three observational studies: 1) the RETRACE study (n=317); 2) a longitudinal ICH study conducted in Boston, USA (n=166); 3) the ERICH study (n=131). We conducted univariable and multivariable analyses of associations between cardioembolic risk (defined by CHA 2 DS 2 -VASc score), OAT resumption, and functional recovery after ICH, defined as ≥ 1 point decrease in modified Rankin Scale (mRS) score at one year post-ICH vs. at discharge. Results: Among 614 participants, 153 (25%) resumed OAT. Individuals resuming OAT differed from those who did not only by higher CHA 2 DS 2 -VASc score (p=0.011). CHA 2 DS 2 -VASc score was associated with decreased likelihood of functional recovery at 1 year after ICH (Odds Ratio [OR] = 0.73 per 1 point increase, 95% Confidence Interval [CI] = 0.62-0.88, p 2 DS 2 -VASc score (OR=2.93, 95% CI = 1.25-4.61, p=0.001). Interaction analyses (Figure) clarified that subjects with higher CHA 2 DS 2 -VASc score benefited more from OAT resumption in terms of functional recovery (OR = 1.69, 95% CI = 1.20-2.38, p=0.003). Conclusions: Increasing cardioembolic risk associated with decreased likelihood of functional recovery after ICH. This effect was mitigated by OAT resumption, with greater benefit seen for subjects at high cardioembolic risk. These findings strongly support exploring recovery outcomes in future studies of OAT-ICH.

Risk and clinical outcome of stroke, as for nearly all complex conditions, is polygenic.1 Discovering influential genetic variants offers the promise of new and personalized treatments that will substantially reduce the devastating effects of stroke on global health. Adequate power to detect multiple genetic risk alleles requires large sample sizes. Although stroke is the second leading cause of death worldwide and a major contributor to adult disability,2 no individual center can collect sufficient samples on its own. Recognizing this challenge, in 2007, stroke researchers from around the world formed the International Stroke Genetics Consortium (ISGC, http://www.strokegenetics.org). The ISGC mission is to identify genetic factors influencing stroke risk, prognosis, and treatment response by studying patients enrolled at centers around the globe. Although there has been notable early success,3–5 much work remains not only to achieve the ultimate goal of personalized medicine in stroke, finding genetic risk alleles, but also, more importantly, to develop comprehensive stroke risk assessments with actionable clinical results.6 Judging from developments in other complex diseases, such as diabetes mellitus and coronary artery disease, sample sizes of the order of 100 000 to 200 000 will be needed to identify the full range of genetic variation involved in stroke. Achieving such sample sizes requires even larger collaboration. We propose a standard methodology for data collection in stroke genetics studies to establish a best practice approach, sharing lessons learned through the ISGC. We outline the appropriate selection of case and control subjects and delineate the phenotypic data to collect, including minimum and preferred data points. Minimum requirements are prerequisites for inclusion in basic stroke genetic studies. Preferred data elements enable centers to participate in a broader variety of collaborations, such as those exploring gene–environment interactions, imaging endophenotypes, such as white matter hyperintensities, and functional …

Introduction: Survivors of Intracerebral Hemorrhage (ICH) are at high risk for developing long-term incident cognitive decline and depression. However, owing largely to limited data on long-term post-ICH depression risk, the degree to which these two forms of post-hemorrhage clinical deterioration overlap is unknown. Hypothesis: post-ICH depression is highly incident, and associated with long-term cognitive decline risk. Methods: We followed longitudinally 695 ICH survivors with no prior history of depression. Exposures of interest included clinical information, known genetic risk factors for ICH / post-ICH dementia (APOE ε2/ε4), and imaging manifestations of cerebral small vessel disease on CT (CT-defined white matter disease [CT-WMD]). We captured outcomes (incident depression and dementia) during follow-up using validated scales administered via telephone every 6 months. Results: A total of 271/695 ICH survivors (40%) developed new-onset mood disorder during a median follow-up time of 49.6 months (Figure). We estimated an incidence rate of 6.9% yearly (95% CI 5.5-8.8%) for post-ICH depression. Independent risk factors for post-ICH depression included lower educational achievements, APOE ε4, and moderate/severe CT-WMD (all p Conclusions: we conducted the first-ever systematic evaluation of long-term post-ICH depression, which affects a large proportion of ICH survivors and shares risk factors (education, APOE genotype, CT-WMD severity) with risk for ICH recurrence and post-ICH dementia. Newly diagnosed depression often signals impending onset of dementia after ICH.

Introduction: Intracerebral hemorrhage (ICH) is more prevalent among African American (AA) and Latino/Hispanic (LH) individuals. While ICH survivors are at high risk for rebleeding, it is unclear whether recurrence risk differs based on race / ethnicity. Hypothesis: We sought to clarify: 1) whether ICH recurrence risk is higher for AA and LH patients; 2) whether this disparity is explained by the most potent ICH risk factors, i.e. hypertension severity and the APOE gene variant ε4. Methods: We conducted a single-center longitudinal study enrolling 738 ICH survivors presenting to a single center from January 2006 to December 2014. Participants had APOE genotype determined at enrollment, and were followed via phone calls and review of medical records. We captured hypertension severity as absolute blood pressure (BP) measures, as well as BP variability (average percent variation during follow-up). We created univariable and multivariable (Cox regression) models to identify risk factors for ICH recurrence. Results: Systolic BP (SBP) was associated with increased ICH recurrence risk ( Hazard Ratio [HR]=1.30, 95% Confidence Interval [CI] 1.02 -1.66, p=0.036), as was SBP variation (HR=1.75 per variation quartile, 95% CI 1.09-2.81, p=0.021). APOE ε4 was also associated with ICH recurrence (HR=1.66, 95% CI 1.10-2.50, p=0.016). After adjusting for BP and APOE ε4, both LH ( HR=1.68, 95% CI 1.01-2.78, p = 0.045 ) and AA ( HR= 2.12, 95% CI 1.14-3.95, p = 0.019 ) patients when at higher risk for ICH recurrence. Both AA and LH patients had a significantly higher systolic BP (SBP) during follow-up (Figure, A); AA individuals also had greater SBP variation during follow up (Figure, B ). Conclusions: AA and LH patients are at higher risk for ICH recurrence, and hypertension severity / APOE ε4 did not fully account for this disparity. Additional studies will be required to further elucidate biological determinants for this health

Background: Patients with Cerebral Amyloid Angiopathy (CAA) have posterior vascular amyloid deposition and lower Amyloid Beta (Aβ) levels when compared to Alzheimer’s Disease (AD). We hypothesized that similar findings would be observed in AD patients with strictly lobar microbleeds (LMB) and/or cortical superficial siderosis (cSS) attributable to CAA [CAA-AD], when compared to AD with no hemorrhagic lesion [NH-AD]. Methods: We reviewed brain MRIs of patients with AD who had T2*-, FLAIR and 3D T1-weighted MRI as well as Florbetapir PET, CSF Aβ-42 and tau levels, and APOE status within the ADNI database. We compared the demographics, quantitative imaging and lab findings of CAA-AD to NH-AD. Results: The CAA-AD (n=51) and NH-AD (n=85) groups were balanced for age, gender and history of hypertension (all p>0.2). The APOE4 was more frequently present in the CAA-AD group (78% vs 60%, p=0.038), no difference for APOE2 (p=0.41). Patients with CAA-AD had higher WMH volume (0.73 vs 0.49 % intracranial volume [ICV], p=0.035) and higher occipital-to-global Florbetapir ratio (0.98 vs 0.94, p=0.02) but similar mean cortical Florbetapir uptake (1.38 vs 1.36, p=0.57), cortical thickness (2.22 vs 2.20 mm, p=0.38), and hippocampal volume (0.37 vs 0.38 % of ICV, p=0.24) when compared to NH-AD. In a multivariable regression model that included all variables above, higher occipital-to-global Florbetapir ratio (p=0.009) and presence of APOE4 (p=0.002) were associated with CAA-AD, higher WMH (p=0.097) showed a trend. In 117 patients with CSF data, CAA-AD (n=46) had lower Aβ-42 (127 vs 140 pg/ml, p=0.038) but similar tau levels (131 vs 136 pg/ml, p=0.68) when compared to NH-AD. Lower Aβ-42 was associated with CAA-AD (p=0.024) in the relevant multivariate regression model. Conclusions: Over one-third of patients with AD displayed subtle hemorrhagic lesions in a CAA-pattern on MRI. When compared to NH-AD, they have higher occipital Florbetapir uptake suggesting vascular amyloid binding and lower CSF Aβ-42 levels that might be related to sequestering of amyloid in cortical vessel walls. These results support the possibility that advanced CAA commonly accompanies clinically diagnosed AD, contributing to dementia pathogenesis and potentially affecting clinical treatment decisions.

Introduction: Intracerebral Hemorrhage (ICH) is a severe manifestation of cerebral small vessel disease, and identifies individuals at high risk for recurrent ICH, ischemic stroke, dementia, late-life depression and gait impairment. Blood pressure (BP) following ICH is strongly associated with risk of these clinical sequelae. Hypothesis: We sought to test whether the most potent genetic risk factors for ICH recurrence, APOE ε2 / ε4, modify the effect of BP. Methods: We prospectively collected demographic and medical data for 608 consecutive ICH survivors, presenting to a single center from January 2006 to December 2013. APOE genotyping was performed on samples obtained via peripheral venous blood draw. Participants were followed longitudinally with periodic BP measurements and evaluation of recurrent ICH / ischemic stroke events. We assessed cognitive and psychiatric outcomes of interest using two validated scales: 1) Telephone Interview for Cognitive Status (TICS); 2) 4-item version of the Geriatric Depression Scale (GDS-4). We generated multivariable Cox models for each outcome, and for overall risk of clinical deterioration (i.e. developing any outcome of interest). Results: APOE ε4 and systolic BP (SBP) interacted to increase risk of ICH recurrence, small vessel ischemic stroke, dementia, and gait impairment after ICH (all p < 0.05). Among patients with average SBP 120-129 mmHg only ε4 carriers were at increased risk for clinical deterioration (Hazard Ratio = 1.67, 95% Confidence Interval 1.06-2.64, p = 0.029). ICH survivors with SBP≥130 mmHg were also at increased risk, with APOE genotype further increasing risk among those with one or more ε4 copies (Figure). Conclusions: APOE ε4 modifies the effect of BP on clinical deterioration risk following ICH, and may identify individuals most likely to benefit from aggressive BP reduction. These data raise the possibility of genetic screening informing hypertension treatment goals in ICH survivors.

Introduction: Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease (SVD). Patients without ICH typically present with transient focal neurological episodes (TFNEs) or cognitive symptoms. We sought to determine if SVD lesion burden differed between CAA patients first presenting with TFNEs versus cognitive symptoms. Methods: A total of 647 patients presenting either to a stroke department (n=205) or an outpatient memory clinic (n=442), were screened for eligibility. Patients meeting modified Boston criteria for probable CAA were included and markers of SVD were quantified including cerebral microbleeds (CMBs), perivascular spaces, cortical superficial siderosis (cSS), and white matter hyperintensities (WMH). Patients were classified according to presentation symptoms (TFNEs vs cognitive). Total CAA-SVD burden was assessed using a validated summary score. Individual neuroimaging markers and total SVD burden were compared between groups using univariable and multivariable models. Results: There were 261 probable CAA patients included. After adjustment for confounders, patients first seen for TFNEs (n=97) demonstrated a higher prevalence of cSS (p Conclusion: We present a large cohort of probable CAA patients without ICH and show that those first evaluated for TFNEs bear a higher burden of structural MRI SVD related damage compared to those first seen for cognitive symptoms. This study sheds light on CAA disease phenotypes, adds to the understanding of CAA clinical expression, and sets the basis for future works investigating CAA prognosis amongst phenotypes.

Introduction: Previous studies showed that Pittsburgh Compound B (PiB) labels vascular amyloid characteristic of cerebral amyloid angiopathy (CAA) on PET scans; PiB is not approved for clinical use, however. Hypothesis: We hypothesized that Florbetapir, an FDA-approved PET tracer, can detect amyloid in CAA and help distinguish CAA-related intracerebral hemorrhage (ICH) from hypertensive ICH (HTN-ICH). Methods: We prospectively enrolled non-demented survivors of primary ICH related to probable CAA (per Boston Criteria, n=10) and HTN-ICH (n=9). All patients underwent Florbetapir-PET, multimodal MRI, and additional PiB-PET for the CAA patients. Amyloid burden was assessed quantitatively using parametric maps and also visually, classified as positive or negative. Spatial correlations between Florbetapir and PiB retention were used to test vascular amyloid binding in CAA. We have tested the diagnostic value of Florbetapir by comparing global and occipital mean Florbetapir retention (standard uptake value ratio, SUVR) as well as Florbetapir positive/negative status between CAA and HTN-ICH groups. Results: The CAA and HTN-ICH groups had similar age (66.9 vs 67.1), sex and white matter hyperintensity volumes (31ml vs 30ml, all p>0.8). Florbetapir uptake and PiB retention strongly correlated in CAA patients both globally within cerebral cortex (r=0.96, p0.8, all p < 0.01). Mean global cortical Florbetapir uptake was significantly higher in CAA than HTN-ICH (SUVR: 1.41±0.16 vs 1.16±0.08, p=0.001) as was mean occipital SUVR (1.44±0.12 vs 1.17±0.08, p Conclusions: Florbetapir, like PiB, appears to label vascular amyloid in patients with CAA-related ICH. Data using the approved Florbetapir binary visual reading method suggest sufficient sensitivity and specificity for diagnostic use in appropriate clinical settings.

Background: Cerebral amyloid angiopathy (CAA), characterized by accumulation of β-amyloid in cortical vessels, is an established cause of hemorrhagic and ischemic brain damage. Although Boston criteria can accurately diagnose CAA in patients who had lobar intracerebral hemorrhage (ICH), its value in asymptomatic older adults is unknown. Objective: We aimed to compare the amyloid load, structural MRI measures and risk factors between asymptomatic subjects who would qualify for a diagnosis of probable CAA based on lobar microbleeds (LMB) and superficial siderosis (SS) to subjects without these MRI findings. Methods: Healthy older adults (n=181) prospectively enrolled in Harvard Aging Brain study had research MRIs and Pittsburgh Compound B (PiB) PET scans. Probable CAA was diagnosed based on presence of 2 or more LMBs or a combination of LMB/SS. Distribution volume ratio (DVR) of PiB-retention, white matter hyperintensity (WMH) and hippocampal volume (HV) were calculated. Demographics, APOE status, risk factors, and imaging markers were compared between subjects with and without probable CAA diagnosed based on LMB/SS. Results: Participants had mean age 74.5±5.8 and 56% were female. Forty-six (25%) subjects had lobar MBs, 11(6%) had deep and 4(2%) cerebellar MBs. The 22 subjects diagnosed with probable CAA had higher occipital DVR (1.35 vs 1.28, p=0.004) and higher WMH (0.51 vs 0.16, p=0.005) when compared to persons without MB. These associations remained significant after adjustment for age and gender. Age, HV, ApoE status and vascular risk factors were similar between probable CAA and no MB/SS subjects (all p>0.2). Conclusions: Probable CAA diagnosis based on presence of lobar MBs and/or SS on MRI of healthy elderly volunteers is associated with other radiologic markers of CAA (posterior amyloid load, WMH) but not with vascular risk factors or markers of Alzheimer’s Disease (HV, ApoE 4). Boston criteria and amyloid imaging thus may allow early diagnosis of CAA even in asymptomatic subjects without ICH or dementia.

Background/Purpose: Cerebral Amyloid Angiopathy (CAA) leads to leukoaraiosis, lacunar infarcts and cortical tissue loss. We hypothesized that CAA is also associated with white matter atrophy (WMA). Methods: We have compared volumetric multimodal MRIs from 72 prospectively enrolled non-demented patients with probable CAA (per Boston criteria), to 3 other well-studied cohorts: 289 Healthy Controls (HC) from the Harvard Aging Brain (HAB) study, 231 HC and 198 patients with AD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Validated FreeSurfer algorithms were used to calculate White Matter Volume (WMV), white matter hyperintensity volume (WMHv), and cortical thickness. Microbleeds (MBs) were counted on SWI-MRI. Measures were obtained from the contralateral hemisphere if intracerebral hemorrhage present. All volumes were corrected for total intracranial volume (ICV), so reported as percent of ICV. Results: The CAA patients were significantly younger (mean age: 70.1) compared to both HC cohorts (ADNI-HC: 76.0, p0.2). Conclusions: Patients with CAA show WMA when compared to older HC and AD. WMA independently correlates with MBs, a marker of CAA severity. Consistent spatial patterns of atrophy especially in posterior regions when compared to both HC and AD [Figure] might represent the “WMA signature of CAA”.

Introduction: Dyslipidemia plays a paradoxical role in some forms of cerebrovascular disease. Unlike its relationship with ischemic stroke, hypercholesterolemia has been associated with reduced risk of intracerebral hemorrhage (ICH). However, serum lipid levels have wide variation coefficients, and point estimates are likely not representative of long-term exposures. Understanding the temporal trends in serum lipid levels and their association with ICH may improve understanding of the biology of dyslipidemia in ICH. We sought to determine the course of temporal variations in total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG) and high-density lipoprotein (HDL) over 48 months before and after primary ICH. Methods: We performed a single-center retrospective longitudinal case-control analysis using cases drawn from an ongoing cohort study of primary ICH and controls drawn from a clinical data registry of patients hospitalized for acute non-cerebral events. Piecewise linear mixed-effects models were used to compare the impact of ICH or hospitalization on lipid trends. Results: 212 ICH cases and 301 control subjects were analyzed. Overall trends in serum TC and LDL levels differed between ICH subjects and non-ICH controls (p Conclusions: Longitudinal serum TC and LDL levels demonstrate decline within 6 months preceding primary ICH, independent of statin or alcohol use. Subjects hospitalized for non-cerebral events did not exhibit this phenomenon. These temporal trends suggest changes in serum TC and LDL levels herald a generalized process that may precipitate ICH occurrence. Further studies are needed to replicate these results and characterize rate of change in serum lipids as a potential biomarker of impending acute cerebral injury.

Introduction: Mechanisms of cortical superficial siderosis (cSS) in cerebral amyloid angiopathy (CAA) are unknown, but might include in situ bleeding from amyloid laden superficial vessels or blood products redistribution from acute lobar intracerebral hemorrhage (ICH). Hypothesis: We aimed to identify factors related to the extent and multifocality of cSS. Methods: We analyzed consecutive CAA-related ICH patients diagnosed with Boston criteria from a prospective cohort. cSS multifocality, was rated for spatially distinct foci involvement and bi-hemispheric distribution on a 0-4 scale (1 point: 1 sulcus or focal immediately adjacent sulci, 2 points: 2 or more non-adjacent sulci OR more than 3 adjacent sulci, in each hemisphere) with excellent interrater reliability (k=0.87). Radiological markers of CAA and ICH characteristics were assessed using quantitative methods or validated visual scales, and their association with cSS multifocality was investigated in multivariable regression. Results: The cohort included 312 CAA patients (53% male; mean age 71.7). cSS was found in 34.6%: unifocal in 42 patients (13.5%), multifocal in 66 (23.1%). Presence and multifocality of cSS were not related with characteristics of the acute ICH such as ICH volume, ICH side or areas of acute subarachnoid blood on initial CT. ICH side did not predict cSS side or multifocality at that side. cSS multifocality was related to the presence of IVH in patients who had a single ICH without microbleeds (MB), but not in patients with multiple hemorrhagic lesions (ICH and/or MBs). In ordinal logistic regression, cSS multifocality was related to lobar microbleeds burden (OR: 1.57; 95%CI: 1.27-1.94; p Conclusion: Extent and multifocality of cSS appear to be markers of CAA severity and independent predictors of ICH recurrence, and can provide insights potential into pathomechanisms.

Introduction: Primary intracerebral hemorrhage (ICH) remains one of the most severe forms of acute cerebrovascular disease. APOE ε2 and ε4 are risk factors for primary ICH, and also involved in regulation of circulating lipid levels. Hypercholesterolemia has been associated with reduced ICH risk. However, the biological mechanisms mediating the roles of APOE and serum lipids on ICH risk remain unclear. Given the pleiotropic relationship between APOE, ICH, and serum lipid levels, we sought to determine the influence of APOE genotype on temporal serum lipid trends before and after ICH. Methods: We performed a single-center retrospective longitudinal cohort analysis using subjects with known APOE genotype drawn from an ongoing cohort study of primary ICH. Serum lipid measurements for total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) collected within 2 years preceding and following index ICH were extracted from electronic medical records (EMR). Piecewise linear mixed-effects random-coefficent models were used to compare APOE allele-specific effects on changes in serum lipid trends in ICH. Results: 124 ICH cases were analyzed. APOE ε4 carriers had significantly greater rates of decline in serum TC and LDL levels within 6 months prior to ICH (TC: -7.30 mg/dL/month, p=0.0035; LDL: -8.44 mg/dL/month, p=0.0001) compared to non-carriers (TC: -3.79 mg/dL/month, p=0.17; LDL: -2.39 mg/dL/month, p=0.55). In contrast, TC and LDL trends for APOE ε2 carriers were not significantly altered within the same time period. APOE genotype had no associations with serum HDL or TG trends. Conclusions: APOE allele status is a strong predictor of subacute serum TC and LDL changes preceding ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. While further studies are needed, our observation that APOE ε4 influences serum lipid trends preceding ICH provides additional insight towards lipid-dependent and lipid-independent APOE-genotype specific effects on stroke risk and suggests that characterization of the metabolic role of APOE is needed to improve understanding of APOE biology in cerebrovascular disease.

Background and Purpose— There is controversy regarding the threshold for treating patients with mild strokes. Physicians often withhold acute treatment in these patients if they perceive the symptoms are not going to be disabling. We tested the appropriateness of this practice by analyzing the relationship between specific neurological deficits in the National Institutes of Health Stroke Scale (NIHSS) score and long-term outcome among patients with a low total NIHSS score. Methods— We performed a secondary analysis on those patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment that presented within 4.5 hours of symptom onset and had a baseline NIHSS score ≤6 (n=194). We performed multivariate logistic regression analyses using very favorable outcome at 3 months as the outcome variable and each of the individual items of the baseline NIHSS examination and syndromic combinations of NIHSS scores as predictors. The analyses were adjusted for potential confounders with and without adjusting for total NIHSS score. Results— Baseline total NIHSS scores were inversely associated with very favorable outcome at 3 months. No individual NIHSS item, or syndromic combination of NIHSS scores, was independently associated with very favorable outcome in a consistent manner after accounting for confounders and collinearity. Conclusions— The types of neurological deficits in the baseline NIHSS are not independent predictors of long-term prognosis for patients with mild stroke. These exploratory findings argue against the practice of withholding reperfusion treatment in patients with mild stroke when the types of baseline NIHSS deficits are perceived to be nondisabling.

Background/Objective: Punctate infarcts (PI) are increasingly seen on DWI of patients with intracerebral hemorrhage (ICH) due to small vessel disease (SVD). We aimed to determine their incidence and potential causes in a large ischemic stroke (IS) cohort that had thorough etiologic workup. Methods: Consecutive patients with MRI-confirmed IS within 72 hours of onset were enrolled. Subjects had either a single high-risk embolic source (cardioembolic or large vessel disease) or no embolic source. PIs were classified by their relationship to the primary infarct as within or outside the same vascular territory. White matter disease burden (WMDB) and microbleed counts were obtained to be used as markers of severity of SVD. Multivariable regression models were constructed to assess the association between PIs and potential etiologies (embolism vs SVD). Results: We analyzed 946 IS patients, mean age 69 +/- 15 years, 46% female. We detected PI (≤5mm) in 269 (28%) subjects, 190 (71%) within the vascular territory of the primary infarct. Large-vessel atherosclerosis (p Conclusions: PIs occurring within the vascular territory of a larger infarct are more likely to have a proximal embolic source, but those occurring outside are more likely related to SVD. Their relatively high incidence and diverse etiologic associations in a cohort of IS patients emphasize the importance of research into their mechanisms.

Background and Purpose— Cerebral amyloid angiopathy (CAA) represents β-amyloid deposition in the small- and medium-sized vessels of the brain and meninges. CAA contributes to altered vessel function and is associated with white matter damage, cognitive impairment, and most salient, hemorrhagic stroke. We used diffusion tensor imaging to evaluate the anatomic distribution of white matter degeneration in participants diagnosed with advanced CAA. Methods— Diffusion tensor imaging was obtained from 11 participants diagnosed with CAA-related intracerebral hemorrhage and 13 matched healthy control participants. Fractional anisotropy (FA) and diffusivity maps were compared using voxel based t test and region-of-interest analyses. Results— FA was reduced in CAA in temporal white matter and in the splenium of the corpus callosum ( P Conclusions— These findings suggest that a pattern of regional brain tissue degeneration is a characteristic feature of advanced CAA.

Background: A post-hoc analysis of the PROGRESS trial suggested that long-term anti-hypertensive therapy prevents intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA). However, the burden of underlying hypertension in patients with CAA is unclear, and it is also unclear whether this hypertensive burden contributes to long-term outcome in survivors of CAA-related ICH. Left ventricle (LV) hypertrophy is a measure of the chronicity and severity of hypertension and could be used to assess hypertensive end-organ damage in patients with CAA. Objective: To test the hypothesis that LV hypertrophy is common in patients with CAA-related ICH and is associated with increased long-term mortality and shorter survival in those patients. Methods: This was a retrospective analysis of a prospectively collected cohort of consecutive patients with primary ICH presenting to a single academic center. We included patients presenting between January/2000 to December/2010, age > 55 years, who received a transthoracic echocardiogram (echo) during follow-up and were diagnosed with definitive, probable or possible CAA according to the Boston criteria. LV mass index (10g/m2) was calculated according to Penn convention. Ninety-day survivors were followed prospectively for long-term mortality or censoring at January/2012. Cox proportional hazards models were used to identify predictors of mortality as time-dependent variables adjusting for potential confounders. Results: Among 211 patients who met inclusion criteria, the mean time to follow-up was 4.28 ± 2.7 years; the median time to echocardiogram was 3 days (IQR:49). The mean age was 75.7 ± 9.1 years; 103 (49%) were male. LV hypertrophy was present in 55 (31.8%) patients and 152 (72%) patients survived more than 90 days. In multivariate analysis, after adjusting for baseline characteristics, LV mass index (10g/m2) was associated with higher long-term mortality (HR: 1.20; 95%CI: 1.01-1.4; p=0.039). On Cox-regression, LV hypertrophy was independently associated with shorter long-term survival (HR 1.91; 95%CI 1.05-3.47; p=0.034). Conclusions: LV hypertrophy is common in patients with CAA-related ICH and is associated with increased risk of subsequent mortality among 90-day survivors.

BACKGROUND/OBJECTIVES: Lobar microbleeds (LMB) are increasingly identified on brain MRI of older adults, suggesting a diagnosis of cerebral amyloid angiopathy (CAA) in the absence of intracerebral hemorrhage (ICH). Identifying the baseline characteristics and risk of future ICH of these subjects is important to understand their prognosis and safety of antithrombotic use in this setting. METHODS: Baseline characteristics (demographics, risk factors, APOE genotype), markers of CAA severity (LMB counts, white matter hyperintensity volume), and finally outcomes during a mean follow up of 4 years (incidence rate of ICH and case-fatality) were compared between 62 CAA patients without and 747 with ICH diagnosed using Boston criteria upon enrollment. The association between antithrombotic use and risk of incident ICH was explored in patients presenting with isolated LMBs after adjusting for covariates listed above. RESULTS: Female gender (52% vs. 37% p=0.023) and hypertension (67% vs. 53% p=0.025) were more common in patients presenting with ICH, other baseline characteristics did not differ. Patients presenting without ICH had more LMBs (median 10 vs. 1 p CONCLUSIONS: Patients presenting with LMBs on MRI have a clinical, genetic, and neuroimaging profile suggestive of severe CAA pathology. They have a considerable risk of incident ICH albeit lower than patients who had a prior lobar ICH. The use of warfarin increases the risk of future ICH in patients with isolated LMBs on MRI.

We review accumulating evidence that cerebrovascular amyloid deposition (cerebral amyloid angiopathy [CAA]) is an independent risk factor for cognitive dysfunction. The two population-based autopsy studies that have analyzed cognitive status during life as a function of CAA have each suggested deleterious effects of CAA on cognition even after controlling for age and Alzheimer disease pathology. We also review data from patients with CAA-related intracerebral hemorrhage (the one form of CAA that can be noninvasively recognized) suggesting associations of CAA with radiographic white matter abnormalities and cognitive impairment. These data highlight the importance of elucidating the effects of vascular amyloid on cerebrovascular function and of developing therapeutic strategies for this potentially widespread form of microvascular cognitive impairment.