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Loss of cortical grey matter is a diagnostic marker of many neurodegenerative diseases, and is a key mediator of cognitive impairment. We postulated that cerebral amyloid angiopathy (CAA), characterised by cortical vascular amyloid deposits, is associated with cortical tissue loss independent of parenchymal Alzheimer's disease pathology. We tested this hypothesis in patients with hereditary cerebral haemorrhage with amyloidosis–Dutch type (HCHWA-D), a monogenetic disease with minimal or no concomitant Alzheimer's disease pathology, as well as in patients with sporadic CAA and healthy and Alzheimer's disease controls. In this observational case-control study, we included six groups of participants: patients diagnosed with HCHWA-D using genetic testing; healthy controls age-matched to the HCHWA-D group; patients with probable sporadic CAA without dementia; two independent cohorts of healthy controls age-matched to the CAA group; and patients with Alzheimer's disease age-matched to the CAA group. De-identified (but unmasked) demographic, clinical, radiological, and genetic data were collected at Massachusetts General Hospital (Boston, MA, USA), at Leiden University (Leiden, Netherlands), and at sites contributing to Alzheimer's Disease Neuroimaging Initiative (ADNI). The primary outcome measure was cortical thickness. The correlations between cortical thickness and structural lesions, and blood-oxygen-level-dependent time-to-peak (BOLD-TTP; a physiological measure of vascular dysfunction) were analysed to understand the potential mechanistic link between vascular amyloid and cortical thickness. The radiological variables of interest were quantified using previously validated computer-assisted tools, and all results were visually reviewed to ensure their accuracy. Between March 15, 2006, and Dec 1, 2014, we recruited 369 individuals (26 patients with HCHWA-D and 28 age-matched, healthy controls; 63 patients with sporadic CAA without dementia; two healthy control cohorts with 63 and 126 individuals; and 63 patients with Alzheimer's disease). The 26 patients with HCHWA-D had thinner cortices (2·31 mm [SD 0·18]) than the 28 healthy controls (mean difference −0·112 mm, 95% CI −0·190 to −0·034, p=0·006). The 63 patients with sporadic CAA without dementia had thinner cortices (2·17 mm [SD 0·11]) than the two healthy control cohorts (n=63, mean difference −0·14 mm, 95% CI −0·17 to −0·10, p<0·0001; and n=126, −0·10, −0·13 to −0·06, p<0·0001). All differences remained independent in multivariable analyses. The 63 patients with Alzheimer's disease displayed more severe atrophy than the patients with sporadic CAA (2·1 mm [SD 0·14], difference 0·07 mm, 95% CI 0·11 to 0·02, p=0·005). We found strong associations between cortical thickness and vascular dysfunction in the patients with HCHWA-D (ρ=–0·58, p=0·003) or sporadic CAA (r=–0·4, p=0·015), but not in controls. Vascular dysfunction was identified as a mediator of the effect of hereditary CAA on cortical atrophy, accounting for 63% of the total effect. The appearance of cortical thinning in patients with HCHWA-D indicates that vascular amyloid is an independent contributor to cortical atrophy. These results were reproduced in patients with the more common sporadic CAA. Our findings also suggest that CAA-related cortical atrophy is at least partly mediated by vascular dysfunction. Our results also support the view that small vessel diseases such as CAA can cause cortical atrophy even in the absence of Alzheimer's disease, a conclusion that can help radiologists, neurologists, and other clinicians who diagnose these common geriatric conditions. National Institutes of Health.

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.

The optimal treatment for neurosarcoidosis myelitis is uncertain. We characterize incident neurosarcoidosis myelitis and assess treatment response by MRI and clinical scales. Incident probable or definite neurosarcoidosis myelitis in adults was retrospectively identified from 13 academic medical centers. Cases were analyzed by initial treatment. The primary outcome was T1 post-contrast gadolinium enhancement resolution at 6 months post-treatment. Secondary outcomes were changes in modified Rankin scale (mRS) and Expanded Disability Status Scale (EDSS) from nadir to final follow-up. Two hundred two patients were identified (median diagnosis age: 47 years (IQR 39-55); male: female 1.3:1). Median nadir mRS and EDSS were 2 (IQR 2-3) and 4 (IQR 2.5-6). At initial treatment, 129 (63.9%) received prolonged corticosteroids ≥ 4 weeks (group A ), 36 (17.8%) received corticosteroids < 4 weeks (B ), 21 (10.4%) received corticosteroids plus sarcoidosis-directed immunosuppressant (E), and 16 (7.9%) received corticosteroids plus non-sarcoidosis-directed agents (F). In 167 cases with sufficient imaging, there were no significant differences in contrast enhancement resolution at 6 months (A 27/106 (25.5%), B 9/28 (32.1%), E 5/19 (26.3%), F 5/14 (35.7%); Fisher's exact p = 0.76). There were no significant differences in changes in mRS or EDSS among treatment groups (Kruskal-Wallis p = 0.69 and 0.63, respectively) after median follow-up of 46.5 months (IQR 18-91.3). Different initial immunosuppression strategies did not correlate with MRI contrast enhancement resolution at 6 months or clinical scales (mRS, EDSS). However, conclusions are limited by retrospective design, imbalanced cohorts, and insensitivity of binary MRI outcomes and available clinical scales for treatment response in neurosarcoidosis.

Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid β 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. 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. 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. 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. US National Institutes of Health (R01 AG26484).

The frequency, clinical presentation, radiological features, and prognosis of remote cerebral hematomas (rPH) are not well known. We report our experience in patients treated with intravenous rt-PA. We reviewed our database of consecutive patients treated at our hospital from 1999 to 2008. We used the inclusion/exclusion criteria of the ECASS-2 study from 1999 to 2003, and the criteria of the SITS-MOST study since 2004. A follow-up CT scan was obtained in all of the patients within the first 36 h of treatment. Cerebral hemorrhagic complications were classified as hemorrhagic infarction (HI-1/HI-2) and parenchymal hematoma (PH-1/PH-2). The rPH was defined as any extra-ischemic hemorrhagic lesion observed in the follow-up CT. A favorable outcome was defined as a score 0–1 on the Rankin scale at 3 months. We treated 210 patients (mean age 67.6 ± 12.4 years, 56% were men). The median initial NIHSS score was 14. Patients with rPH ( n  = 7) had a mean age of 72.4 ± 7.5 years and 43% were men. The median initial NIHSS score was 15. Three patients had multifocal rPH; three patients had a single rPH and in one patient the rPH was associated with a PH-2. rPH were lobar in six patients and in brainstem in one patient, symptomatic in five patients and asymptomatic in two patients. The outcome was unfavorable in all of them; four deaths (57%) were recorded. Remote cerebral hemorrhage is an infrequent complication after rt-PA treatment (3.3%), it is usually lobar and symptomatic and has an uniformly unfavorable outcome.

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.

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 (β = -0.044; p < 0.001) and had a faster decline in executive function over time (β = -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.

Objectives The levels of circulating endothelial progenitor cells (EPCs) in ischemic stroke have not been studied extensively and reported results are inconsistent. We aimed to investigate the time course, the prognostic relevance, and the variables associated with EPC counts in patients with ischemic stroke at different time points. Material and methods We studied prospectively 146 consecutive patients with ischemic stroke within the first 48 h from the onset of symptoms (baseline). We evaluated demographic data, classical vascular risk factors, treatment with thrombolysis and statins, stroke etiology, National Institute of Health and Stroke Scale score and outcome (favorable when Rankin scale score 0–2). Blood samples were collected at baseline, at day 7 after stroke (n = 121) and at 3 months (n = 92). The EPC were measured by flow cytometry. Results We included 146 patients with a mean age of 70.8 ± 12.2 years. The circulating EPC levels were higher on day 7 than at baseline or at 3 months (P = 0.045). Pretreatment with statins (odds ratio [OR] 3.11, P = 0.008) and stroke etiology (P = 0.032) were predictive of EPC counts in the baseline sample. EPC counts were not associated with stroke severity or functional outcome in all the patients. However, using multivariate analyses, a better functional outcome was found in patients with higher EPC counts in large‐artery atherosclerosis and small‐vessel disease etiologic subtypes. Conclusions After acute ischemic stroke, circulating EPC counts peaked at day 7. Pretreatment with statins increased the levels of EPC. In patients with large‐artery atherosclerosis and small‐vessel disease subtypes, higher counts were related to better outcome at 3 months. After acute ischemic stroke, circulating endothelial progenitor cell (EPC) counts peaked at day 7. Pretreatment with statins increased the levels of EPC. In patients with large‐artery atherosclerosis and small‐vessel disease subtypes, higher counts were related to better outcome at 3 months.

The influence of statins on the results of intravenous thrombolysis for ischemic stroke is controversial. We studied the risks and benefits of statin pretreatment (SP) in patients treated with intravenous alteplase (t-PA) at our institution, and included our data to a meta-analysis of previous related studies. We reviewed prospectively collected data from consecutive patients with acute ischemic stroke treated with IV rt-PA at our institution over the past 9 years. We compared symptomatic intracranial haemorrhage (SICH), favourable short-term outcome (decrease of ≥4 points on the NIHSS score after 24 h from baseline assessment), favourable long-term outcome (mRS score ≤2 at 3 months) and mortality rates between statin-pretreated (SPP) and nonstatin-pretreated patients (NSPP). We performed a systematic search through MEDLINE/PubMed and Embase datasets to identify similar English language studies. A total of 182 patients were included (mean age 68.3 ± 11.4 years, 54.3% men). There were no significant differences between SPP and NSPP regarding SICH (3.3 vs. 1.7%, p  = 0.47), favourable short-term outcome (44.8 vs 56%, p  = 0.31) and favourable long-term outcome rates (40 vs 44.1%, p  = 0.84). In a meta-analysis of 1,055 patients, SP was neither related to long-term functional outcome nor mortality, but it was a risk factor for SICH (OR 1.99, 95% CI 1.03–3.84, p = 0.04). Statin pretreatment may increase the risk of SICH in patients receiving IV t-PA for ischemic stroke, though it does not influence the 3 months outcome. Prospective studies are needed to confirm this safety concern.