Perivascular Spaces Volume in Sporadic and Hereditary (Dutch-Type) Cerebral Amyloid Angiopathy.

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<0.1 in bivariate analyses were entered in logistic regression models. 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<0.0001; 3.8% [0.6-6.2] versus 0.7% [0.4-1.6], 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<0.001 and 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.

Relationship between white matter connectivity loss and cortical thinning in cerebral amyloid angiopathy.

Patients with cerebral amyloid angiopathy (CAA) show loss of white matter connectivity and cortical thinning on MRI, primarily in posterior brain regions. Here we examined whether a potential causal relationship exists between these markers of subcortical and cortical brain injury by examining whether changes in cortical thickness progress in tandem with changes in their underlying connections. Thirty-one patients with probable CAA with brain MRI at two time points were included (follow-up time: 1.3 ± 0.4 years). Brain networks were reconstructed using diffusion MRI-based fiber tractography. Of each network node, we calculated the change in fractional anisotropy-weighted connectivity strength over time and the change in cortical thickness. The association between change in connectivity strength and cortical thickness was assessed with (hierarchical) linear regression models. Our results showed that decline in posterior network connectivity over time was strongly related to thinning of the occipital cortex (ß = 0.65 (0.35-0.94), P < 0.001), but not to thinning of the other posterior or frontal cortices. However, at the level of individual network nodes, we found no association between connectivity strength and cortical thinning of the corresponding node (ß = 0.009 ± 0.04, P = 0.80). Associations were independent of age, sex, and other brain MRI markers of CAA. To conclude, CAA patients with greater progressive loss of posterior white matter connectivity also have greater progression of occipital cortical thinning, but our results do not support a direct causal relationship between them. The association can be better explained by a shared underlying mechanism, which may form a potential target for future treatments. Hum Brain Mapp 38:3723-3731, 2017. © 2017 Wiley Periodicals, Inc.

Cortical Superficial Siderosis in Memory Clinic Patients: Further Evidence for Underlying Cerebral Amyloid Angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with many cases of spontaneous symptomatic lobar intracerebral haemorrhage in older individuals and is emerging as an important contributor to cognitive impairment. Cortical superficial siderosis (cSS) is an increasingly recognized haemorrhagic neuroimaging manifestation of CAA. We sought to investigate its prevalence and its association with underlying CAA among memory clinic patients. METHODS: We included consecutive eligible patients who presented to the out-patient memory clinic at the Massachusetts General Hospital from 2007 to 2010 and had appropriate MRI, including blood-sensitive sequences. We analyzed the prevalence and topography of cSS according to demographic, clinical, APOE and MRI data. RESULTS: Our cohort consisted of 339 memory clinic patients: Alzheimer's disease (n = 86); mild cognitive impairment (n = 162); vascular dementia/mixed dementia (n = 18); other dementia/undetermined (n = 42); and subjective cognitive complains (n = 31). cSS was detected in 10 patients (3%; 95% CI 1.4-5.4): in 7 cases cSS was focal and in 3 cases, it was disseminated. In multivariable logistic regression analysis, the presence of cSS was associated with lobar microbleeds (OR 1.08; 95% CI 1.03-1.13; p = 0.001, per each additional microbleed) and severe white matter hyperintensities (Fazekas score 5-6, OR 4.43; 95% CI 1.21-26.28; p = 0.028) after adjusting for age. These associations were not influenced by the clinical diagnosis. In patients with APOE data, the APOE ε4/ε4 genotype was overrepresented among subjects with vs. without cSS. In the subgroup of patients with probable CAA (n = 68; 9 with cSS) based on the presence of strictly lobar microbleeds, cSS was also associated with a higher prevalence of severe white matter hyperintensities (66.7 vs. 10.2%; p = 0.001), high centrum semiovale perivascular spaces burden (88.9 vs. 52.4%; p = 0.041) and higher counts of lobar microbleeds (median 13; IQR 10-36 vs. median 1; IQR 1-2; p < 0.00001), compared to patients without cSS. CONCLUSIONS: Our data provide further evidence supporting the hypothesis that cSS is a manifestation of advanced CAA in memory clinic populations. Future longitudinal studies should explore any direct effect of cSS on cognition or haemorrhage risk and disease progression.

Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression.

Estimating Total Cerebral Microinfarct Burden From Diffusion-Weighted Imaging.

BACKGROUND AND PURPOSE: Cerebral microinfarcts (CMI) are important contributors to vascular cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. We aim to describe a mathematical method for estimating total number of CMI based on the presence of incidental DWI lesions. METHODS: We reviewed magnetic resonance imaging scans of subjects with cognitive decline, cognitively normal subjects and previously reported subjects with past intracerebral hemorrhage (ICH). Based on temporal and spatial characteristics of DWI lesions, we estimated the annual rate of CMI needed to explain the observed rate of DWI lesion detection in each group. To confirm our estimates, we performed extensive sampling for CMI in the brain of a deceased subject with past lobar ICH who found to have a DWI lesion during life. RESULTS: Clinically silent DWI lesions were present in 13 of 343 (3.8%) cognitively impaired and 10 of 199 (5%) cognitively intact normal non-ICH patients, both lower than the incidence in the past ICH patients (23 of 178; 12.9%; P<0.0006). The predicted annual incidence of CMI ranges from 16 to 1566 for non-ICH and 50 to 5041 for ICH individuals. Histological sampling revealed a total of 60 lesions in 32 sections. Based on previously reported methods, this density of CMI yields an estimated total brain burden maximum likelihood estimate of 9321 CMIs (95% confidence interval, 7255-11 990). CONCLUSIONS: Detecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel-related vascular cognitive impairment.

The characteristics of superficial siderosis and convexity subarachnoid hemorrhage and clinical relevance in suspected cerebral amyloid angiopathy.

BACKGROUND AND AIMS: Systematic studies of superficial siderosis (SS) and convexity subarachnoid hemorrhage (cSAH) in patients with suspected cerebral amyloid angiopathy (CAA) without lobar intracerebral hemorrhage (ICH) are lacking. We sought to determine the potential anatomic correlation between SS/cSAH and transient focal neurological episodes (TFNE) and whether SS/cSAH is predictor of future cerebral hemorrhagic events in these patients. METHODS: We enrolled 90 consecutive patients with suspected CAA (due to the presence of strictly lobar microbleeds (CMBs) and/or SS/cSAH) but without the history of symptomatic lobar ICH who underwent brain MRI including T2*-weighted, diffusion-weighted imaging and fluid-attenuated inversion recovery sequences from an ongoing single center CAA cohort from 1998 to 2012. Evaluation of SS, cSAH and CMBs was performed. Medical records and follow-up information were obtained from prospective databases and medical charts. TFNE was defined according to published criteria and electroencephalogram reports were reviewed. RESULTS: Forty-one patients (46%) presented with SS and/or cSAH. The prevalence of TFNE was significantly higher in those with SS/cSAH (61 vs. 10%; p < 0.001) and anatomically correlated with the location of cSAH, but not SS. The majority of TFNE in patients with SS/cSAH presented with spreading sensory symptoms. Intermittent focal slowing on electroencephalogram was present in the same area as SS/cSAH in 6 patients, but no epileptiform activity was found in any patients. Among those with available clinical follow-up (76/90 patients, 84%), ten patients with SS/cSAH (29%, median time from the scan for all patients with SS/cSAH: 21 months) had a symptomatic cerebral bleeding event on follow up (average time to events: 34 months) compared with only 1 event (2.4%, 25 months from the scan) in patients without SS/​cSAH (time to event: 25 months) (p = 0.001). The location of hemorrhages on follow-up scan was not in the same location of previously noted SS/cSAH in 9 of 10 patients. Follow-up imaging was obtained in 9 of 17 patients with cSAH and showed evidence of SS in the same location as initial cSAH in all these 9 cases. CONCLUSIONS: SS/cSAH is common in patients with suspected CAA without lobar intracerebral hemorrhage and may have a significantly higher risk of future cerebral bleeding events, regardless of the severity of the baseline CMB burden. The findings further highlight a precise anatomical correlation between TFNE and cSAH, but not SS. Distinct from transient ischemic attack or seizure, the majority of TFNE caused by SS/cSAH appear to present with spreading sensory symptoms.

Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage.

INTRODUCTION: The Boston criteria are the basis for a noninvasive diagnosis of cerebral amyloid angiopathy (CAA) in the setting of lobar intracerebral hemorrhage (ICH). We assessed the accuracy of these criteria in individuals with lobar microbleeds (MBs) without ICH. METHODS: We identified individuals aged >55 years having brain magnetic resonance imaging (MRI) and pathological assessment of CAA in a single academic hospital and a community-based population (Framingham Heart Study [FHS]). We determined the positive predictive value (PPV) of the Boston criteria for CAA in both cohorts, using lobar MBs as the only hemorrhagic lesion to fulfill the criteria. RESULTS: We included 102 individuals: 55 from the hospital-based cohort and 47 from FHS (mean age at MRI 74.7 ± 8.5 and 83.4 ± 10.9 years; CAA prevalence 60% and 46.8%; cases with any lobar MB 49% and 21.3%; and cases with ≥2 strictly lobar MBs 29.1% and 8.5%, respectively). PPV of "probable CAA" (≥2 strictly lobar MBs) was 87.5% (95% confidence interval [CI], 60.4-97.8) and 25% (95% CI, 13.2-78) in hospital and general populations, respectively. DISCUSSION: Strictly lobar MBs strongly predict CAA in non-ICH individuals when found in a hospital context. However, their diagnostic accuracy in the general population appears limited.

Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham Heart Study.

BACKGROUND AND PURPOSE: Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB. METHODS: We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [APOE]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed). RESULTS: CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age (P<0.0001) and was higher in men (P<0.001). Hypertension increased risk of any CMB, and in deep and mixed locations (P<0.05), and low total cholesterol and APOE ε4 increased risk of lobar CMB (P<0.05). Statin use increased risk of lobar and mixed location CMB (P<0.05). The latter association was not affected by adjustment for cholesterol levels or concomitant medication use. CONCLUSIONS: We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.

Cerebral amyloid angiopathy burden associated with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study.

OBJECTIVE: We hypothesized that vascular amyloid contributes to chronic brain ischemia, therefore amyloid burden measured by Pittsburgh compound B retention on positron emission tomography (PiB PET) would correlate with the extent of magnetic resonance imaging (MRI) white matter hyperintensities (WMH; or leukoaraiosis) in patients with high vascular amyloid deposition (cerebral amyloid angiopathy [CAA]) but not in patients with high parenchymal amyloid deposition (Alzheimer disease [AD]; mild cognitive impairment [MCI]) or in healthy elderly (HE) subjects. METHODS: Forty-two nondemented CAA patients, 50 HE subjects, and 43 AD/MCI patients had brain MRI and PiB PET. Multivariate linear regression was used to assess the independent association between PiB retention and white matter disease volume, controlling for age, gender, apolipoprotein E genotype, and vascular risk factors within each group. RESULTS: CAA patients were younger than HE and AD subjects (68 ± 10 vs 73.3 ± 7 and 74 ± 7.4, p < 0.01) but had higher amounts of WMH (median = 21 vs 3.2 and 10.8 ml, respectively, p < 0.05 for both comparisons). Global PiB retention and WMH showed strong correlation (rho = 0.52, p < 0.001) in the CAA group but not in HE or AD. These associations did not change in the multivariate models. Lobar microbleed count, another marker of CAA severity, also remained as an independent predictor of WMH volume. INTERPRETATION: Our results indicate that amyloid burden in CAA subjects (with primarily vascular amyloid) but not AD subjects (with primarily parenchymal amyloid) independently correlates with WMH volume. These findings support the idea that vascular amyloid burden directly contributes to chronic cerebral ischemia and highlights the possible utility of amyloid imaging as a marker of CAA severity.

Lobar microbleeds are associated with a decline in executive functioning in older adults.

BACKGROUND: Normal aging is associated with a decline in cognitive abilities, particularly in the domains of psychomotor speed and executive functioning. However, 'aging,' per se, is not a cause of cognitive decline but rather a variable that likely captures multiple accumulating biological changes over time that collectively affect mental abilities. Recent work has focused on the role of cerebrovascular disease as one of the biological changes. In the current study, we examined whether lobar microbleeds - magnetic resonance imaging (MRI) signal voids due to hemosiderin deposits secondary to cerebral amyloid angiopathy - are associated with cognitive decline in normal aging. Previous studies that reported a relationship between the presence of lobar microbleeds and decreased cognitive abilities have been primarily cross-sectional. Here, we used a retrospective longitudinal design to examine whether the presence of lobar microbleeds is associated with the rate of cognitive decline among non-demented older adults. METHODS: Participants came from an ongoing longitudinal community-based aging study, in which subjects are evaluated at 18-24 months intervals and received a full medical, neurological, and neuropsychological examination at each of the follow-up visits. Gradient echo MRI scans were available on 197 non-demented participants (mean age: 84.15 ± 5.02 years). Microbleeds were rated visually on axial view and divided into subcortical (basal ganglia, cerebellum) and lobar (frontal, temporal, parietal, occipital lobe) regions, and confirmed with coronal and sagittal views to exclude artifacts. Cognition was assessed with a neuropsychological battery, providing summary scores for memory, language, executive, and visuospatial abilities. Using general estimating equations (GEE), we compared cognition cross-sectionally between individuals with 2 or more (n = 11) and fewer than 2 (n = 186) lobar microbleeds and examined longitudinal cognitive change beginning 9.47 ± 3.13 years before the MRI scan. RESULTS: Subjects with 2 or more lobar microbleeds had worse executive functioning at the visit closest to the MRI scan (ß = -0.044; p < 0.001) and had a faster decline in executive function over time (ß = -0.072; p = 0.012) than subjects with fewer than 2 lobar microbleeds. The two groups were similar in age at scan date, education, ethnicity, sex distribution, and cognitive performance at first visit. CONCLUSIONS: Lobar microbleeds, a marker of cerebral amyloid angiopathy, are associated with an accelerated rate of executive function decline. The presence of cerebral amyloid angiopathy may be an important source of cognitive decline in aging. Future work should examine how cerebral amyloid angiopathy interacts with neurodegenerative processes, such as Alzheimer's disease.

Functional magnetic resonance imaging detection of vascular reactivity in cerebral amyloid angiopathy.

OBJECTIVE: In addition to its role in hemorrhagic stroke, advanced cerebral amyloid angiopathy (CAA) is also associated with ischemic lesions and vascular cognitive impairment. We used functional magnetic resonance imaging (MRI) techniques to identify CAA-associated vascular dysfunction. METHODS: Functional MRI was performed on 25 nondemented subjects with probable CAA (mean ± standard deviation age, 70.2 ± 7.8 years) and 12 healthy elderly controls (age, 75.3 ± 6.2 years). Parameters measured were reactivity to visual stimulation (quantified as blood oxygen level-dependent [BOLD] response amplitude, time to peak response, and time to return to baseline after stimulus cessation) and resting absolute cerebral blood flow in the visually activated region (measured by arterial spin labeling). RESULTS: CAA subjects demonstrated reduced response amplitude (percentage change in BOLD signal, 0.65 ± 0.28 vs 0.89 ± 0.14; p < 0.01), prolonged time to peak (11.1 ± 5.1 vs 6.4 ± 1.8 seconds; p < 0.001), and prolonged time to baseline (16.5 ± 6.7 vs 11.6 ± 3.1 seconds; p < 0.001) relative to controls. These differences were independent of age, sex, and hypertension in multivariable analysis and were also present in secondary analyses excluding nonresponsive voxels or voxels containing chronic blood products. Within the CAA group, longer time to peak correlated with overall volume of white matter T2 hyperintensity (Pearson correlation, 0.53; p = 0.007). Absolute resting blood flow in visual cortex, in contrast, was essentially identical between the groups (44.0 ± 12.6 vs 45.0 ± 10.0 ml/100 g/min, p = 0.8). INTERPRETATION: Functional MRI identifies robust differences in both amplitude and timing of the response to visual stimulation in advanced CAA. These findings point to potentially powerful approaches for identifying the mechanistic links between vascular amyloid deposits, vascular dysfunction, and CAA-related brain injury.

The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid ß in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484).

Hemostatic proteins and their association with hematoma growth in patients with acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: We tested the hypothesis that proteins of hemostasia could be associated with hematoma growth (HG) in patients with acute intracerebral hemorrhage. METHODS: We prospectively studied patients with spontaneous supratentorial intracerebral hemorrhage within the first 6 hours after the onset of symptoms. HG was defined as an increase > 33% in the volume of hematoma on CT obtained 24 to 72 hours after the onset of symptoms in comparison with the CT obtained at admission. We collected admission and follow-up blood samples. We measured fibrinogen, factor XIII, thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor, plasminogen, α2-antiplasmin, tissue plasminogen activator, d-dimer, thrombomodulin, thrombin-antithrombin complex, and plasmin-antiplasmin complex. RESULTS: We included 90 patients with a mean age of 71 ± 10.8 years; 61% were men. HG was observed in 35 (39%) of the patients. Mean baseline and follow-up protein measurements showed no difference between the groups with and without HG. The analysis of variance showed that factor XIII activity decreased in the non-HG group in the 24 to 72 hours sample, whereas it increased in the HG group (P = 0.001). CONCLUSIONS: Factor XIII was the only measured protein related to HG. The levels at the follow-up sample decreased in the non-HG group and increased in the HG group. Further studies are needed to confirm this association.

White matter atrophy in cerebral amyloid angiopathy.

OBJECTIVE: We postulated that cerebral amyloid angiopathy (CAA) is associated with white matter atrophy (WMA) and that WMA can be related to cognitive changes in CAA. METHODS: White matter volume expressed as percent of intracranial volume (pWMV) of prospectively enrolled patients without dementia diagnosed with probable CAA was compared to age-matched healthy controls (HC) and patients with Alzheimer disease (AD). Cognitive scores were also sought to understand the potential effects of WMA on cognitive function. RESULTS: Patients with CAA (n = 72) had significantly lower pWMV (27.97% ± 2.63) when compared to age-matched HC (n = 72; mean difference [MD], 2.38%; p < 0.0001) and patients with AD (n = 72; MD, 1.57%; p < 0.0001). Differences were most pronounced in the posterior occipital regions in both comparisons. When comparisons were restricted to groups of patients with CAA but no intracerebral hemorrhage (n = 32) or hypertension (n = 32), and age-matched HC and AD, the significant differences were unaltered. Within the CAA cohort, higher age, lobar microbleed counts, and presence of hypertension were associated with lower pWMV (p = 0.0007, p = 0.031, and p = 0.003, respectively). All associations remained independent in multivariable analyses. Within the CAA cohort, higher pWMV independently correlated with better scores of executive function. CONCLUSIONS: Patients with CAA show WMA when compared to age-matched HC and patients with AD. WMA independently correlates with the number of lobar microbleeds, a marker of CAA severity. Consistent spatial patterns of WMA especially in posterior regions might be related to CAA. The association between WMA and measures of executive function suggests that WMA might represent an important mediator of CAA-related neurologic dysfunction.

Change in hemostatic markers after recombinant tissue-type plasminogen activator is not associated with the chance of recanalization.

BACKGROUND AND PURPOSE: We evaluated the association between recombinant tissue-type plasminogen activator recanalization and change in hemostatic markers. METHODS: We studied 40 patients. Recanalization was measured with transcranial Doppler. We evaluated the change in markers of coagulation (fibrinogen) and fibrinolysis (thrombin activatable fibrinolysis inhibitor and alpha(2)-antiplasmin) in patients with ischemic stroke treated with recombinant tissue-type plasminogen activator. Samples were obtained before and 90 minutes after recombinant tissue-type plasminogen activator infusion. RESULTS: The analyses (2-way analysis of variance) showed that the change in the value of each marker did not depend on the vascular patency status. CONCLUSIONS: From a practical point of view, the measurement of these hemostatic markers is probably not useful for predicting recanalization.

Antibodies to AChR, MuSK and VGKC in a patient with myasthenia gravis and Morvan's syndrome.

BACKGROUND: A 46-year-old woman presented to a local hospital with acute respiratory failure and a 2-year progressive history of fatigue, personality changes, increased sweating, dysphagia with substantial weight loss, dysarthria, and intermittent ptosis and diplopia. Neurological examination showed facial weakness, lingual atrophy and bulbar palsy, which necessitated the use of a feeding tube and ventilatory support. Mild limb weakness with severe muscle atrophy and diffuse muscle twitches were observed. The patient had also developed visual hallucinations and persecutory delusions. Her personal and family medical histories were unremarkable. INVESTIGATIONS: Sensory and motor nerve conduction studies, repetitive nerve stimulation, electromyogram, blood-cell counts, general chemistry and metabolic function tests, a CT scan, an [(18)F]fluorodeoxyglucose-PET scan, and tests for serum antibodies to acetylcholine receptors, muscle-specific tyrosine kinase, voltage-gated potassium channels, P/Q-type voltage-gated calcium channels, and paraneoplastic antigens, were carried out. DIAGNOSIS: Myasthenia gravis associated with antibodies to acetylcholine receptor and muscle-specific tyrosine kinase, and Morvan's syndrome associated with antibodies to voltage-gated potassium channels in the absence of thymoma. MANAGEMENT: Combined treatment with prednisone, intravenous immunoglobulin, ciclosporin, and rituximab.

Evolution of cerebral microbleeds after cranial irradiation in medulloblastoma patients.

OBJECTIVE: To characterize the temporal and spatial pattern of cerebral microbleeds (CMBs) after cranial irradiation in patients with medulloblastoma. METHODS: We retrospectively identified patients with medulloblastoma treated with craniospinal irradiation at the Massachusetts General Hospital between 1999 and 2015. Longitudinal MRI including T2*-weighted gradient-recalled echo (GRE) sequences were reviewed, and the prevalence, spatial pattern, and risk factors associated with CMBs were characterized. RESULTS: We identified a total of 27 patients; 5 patients were children (median age 6.3 years) and 22 patients were adults (median age 28.8 years). CMBs were found in 67% (18/27) of patients, who were followed for a median of 4.1 years. Patients with CMBs had longer GRE follow-up time compared to those without CMBs (4.9 vs 1.7 years, p = 0.035). The median latency of the appearance of CMBs was 2.79 years (interquartile range 1.76-4.26). The prevalence of CMBs increased with each year from time of radiation therapy, and the cumulative prevalence was highest in patients age <20 years (100% cumulative prevalence, vs 59% in adult patients treated at age ≥20 years). CMBs were mostly found in lobar distribution and predominately in bilateral occipital lobes. Patients using antithrombotic medications developed CMBs at a significantly higher rate (p = 0.041). CONCLUSIONS: Our data demonstrate a high prevalence of CMBs following cranial irradiation, progressively increasing with each year from time of radiation therapy.

MRI-visible perivascular spaces in cerebral amyloid angiopathy and hypertensive arteriopathy.

OBJECTIVE: To assess MRI-visible enlarged perivascular spaces (EPVS) burden and different topographical patterns (in the centrum semiovale [CSO] and basal ganglia [BG]) in 2 common microangiopathies: cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). METHODS: Consecutive patients with spontaneous intracerebral hemorrhage (ICH) from a prospective MRI cohort were included. Small vessel disease MRI markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and white matter hyperintensities (WMH), were rated. CSO-EPVS/BG-EPVS were assessed on a validated 4-point visual rating scale (0 = no EPVS, 1 = <10, 2 = 11-20, 3 = 21-40, and 4 = >40 EPVS). We tested associations of predefined high-degree (score >2) CSO-EPVS and BG-EPVS with other MRI markers in multivariable logistic regression. We subsequently evaluated associations with CSO-EPVS predominance (i.e., CSO-EPVS > BG-EPVS) and BG-EPVS predominance pattern (i.e., BG-EPVS > CSO-EPVS) in adjusted multinomial logistic regression (reference group, BG-EPVS = CSO-EPVS). RESULTS: We included 315 patients with CAA-ICH and 137 with HA-ICH. High-degree CSO-EPVS prevalence was greater in CAA-related ICH vs HA-related ICH (43.8% vs 17.5%, p < 0.001). In multivariable logistic regression, high-degree CSO-EPVS was associated with lobar CMB (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.10-1.61, p = 0.003) and cSS (OR 2.08, 95% CI 1.30-3.32, p = 0.002). Deep CMBs (OR 2.85, 95% CI 1.75-4.64, p < 0.0001) and higher WMH volume (OR 1.02, 95% CI 1.01-1.04, p = 0.010) were predictors of high-degree BG-EPVS. A CSO-EPVS-predominant pattern was more common in CAA-ICH than in HA-ICH (75.9% vs 39.4%, respectively, p < 0.0001). CSO-PVS predominance was associated with lobar CMB burden and cSS, while BG-EPVS predominance was associated with HA-ICH and WMH volumes. CONCLUSIONS: Different patterns of MRI-visible EPVS provide insights into the dominant underlying microangiopathy type in patients with spontaneous ICH.

Hemorrhage recurrence risk factors in cerebral amyloid angiopathy: Comparative analysis of the overall small vessel disease severity score versus individual neuroimaging markers.

INTRODUCTION: An MRI-based score of total small vessel disease burden (CAA-SVD-Score) in cerebral amyloid angiopathy (CAA) has been demonstrated to correlate with severity of pathologic changes. Evidence suggests that CAA-related intracerebral hemorrhage (ICH) recurrence risk is associated with specific disease imaging manifestations rather than overall severity. We compared the correlation between the CAA-SVD-Score with the risk of recurrent CAA-related lobar ICH versus the predictive role of each of its components. METHODS: Consecutive patients with CAA-related ICH from a single-center prospective cohort were analyzed. Radiological markers of CAA related SVD damage were quantified and categorized according to the CAA-SVD-Score (0-6 points). Subjects were followed prospectively for recurrent symptomatic ICH. Adjusted Cox proportional hazards models were used to investigate associations between the CAA-SVD-Score as well as each of the individual MRI signatures of CAA and the risk of recurrent ICH. RESULTS: In 229 CAA patients with ICH, a total of 56 recurrent ICH events occurred during a median follow-up of 2.8years [IQR 0.9-5.4years, 781 person-years). Higher CAA-SVD-Score (HR=1.26 per additional point, 95%CI [1.04-1.52], p=0.015) and older age were independently associated with higher ICH recurrence risk. Analysis of individual markers of CAA showed that CAA-SVD-Score findings were due to the independent effect of disseminated superficial siderosis (HR for disseminated cSS vs none: 2.89, 95%CI [1.47-5.5], p=0.002) and high degree of perivascular spaces enlargement (RR=3.50-95%CI [1.04-21], p=0.042). CONCLUSION: In lobar CAA-ICH patients, higher CAA-SVD-Score does predict recurrent ICH. Amongst individual elements of the score, superficial siderosis and dilated perivascular spaces are the only markers independently associated with ICH recurrence, contributing to the evidence for distinct CAA phenotypes singled out by neuro-imaging manifestations.

Cortical superficial siderosis multifocality in cerebral amyloid angiopathy: A prospective study.

OBJECTIVE: In order to explore the mechanisms of cortical superficial siderosis (cSS) multifocality and its clinical implications for recurrent intracerebral hemorrhage (ICH) risk in patients with cerebral amyloid angiopathy (CAA), we used a new rating method that we developed specifically to evaluate cSS extent at spatially separated foci. METHODS: Consecutive patients with CAA-related ICH according to Boston criteria from a single-center prospective cohort were analyzed. The new score that assesses cSS multifocality (total range 0-4) showed excellent interrater reliability (k = 0.87). The association of cSS with markers of CAA and acute ICH was investigated. Patients were followed prospectively for recurrent symptomatic ICH. RESULTS: The cohort included 313 patients with CAA. Multifocal cSS prevalence was 21.1%. APOE ε2 allele prevalence was higher in patients with multifocal cSS. In probable/definite CAA, cSS multifocality was independently associated with neuroimaging markers of CAA severity, including lobar microbleeds, but not with acute ICH features, which conversely, were determinants of cSS in possible CAA. During a median follow-up of 2.6 years (interquartile range 0.9-5.1 years), the annual ICH recurrence rates per cSS scores (0-4) were 5%, 6.5%, 13.5%, 16.2%, and 26.9%, respectively. cSS multifocality (presence and spread) was the only independent predictor of increased symptomatic ICH risk (hazard ratio 3.19; 95% confidence interval 1.77-5.75; p < 0.0001). CONCLUSIONS: The multifocality of cSS correlates with disease severity in probable CAA; therefore cSS is likely to be caused by discrete hemorrhagic foci. The new cSS scoring system might be valuable for clinicians in determining annual risk of ICH recurrence.