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Background and Objectives: Although left atrial appendage closure (LAAC) is performed in patients with non-valvular atrial fibrillation (NVAF) at increased risk of intracranial haemorrhage (ICH), outcome data are scarce. We assessed the detailed neurological indications for LAAC and outcomes after LAAC in high ICH risk patients., Methods: Study population included consecutive patients with NVAF who underwent LAAC in a single hospital network between January 2015 and October 2021 because of prior ICH or the presence of high ICH risk imaging markers on brain MRI (cerebral microbleeds (CMBs)). Primary safety and efficacy outcome measures were the occurrence of ICH and thromboembolic events, respectively, after LAAC., Results: Among 146 patients with NVAF who underwent LAAC for high ICH risk, 122 had a history of ICH, while 24 presented with high ICH risk imaging markers only. Mean age was 75.7±7.61, 42 (28.8%) were women. Mean CHA 2 DS 2 -VASc score was 5.23±1.52. Of 122 patients with ICH history, 58 (47.5%) had intraparenchymal haemorrhage (IPH), 40 (32.8%) had traumatic ICH (T-ICH) and 18 (14.7%) had non-traumatic subdural haemorrhage. Of 85 patients with brain MRIs including necessary sequences, 43 (50.6%) were related to cerebral amyloid angiopathy and 37 (43.5%) to hypertensive microangiopathy. While 70% of patients were discharged on oral anticoagulants (OAC), 92% were not taking OAC at 1 year. Over 2.12 years mean follow-up, one patient had recurrent non-traumatic IPH (incidence rate (IR) 0.32 per 100 patient-years), five had T-ICH (IR 1.61 per 100 patient-years) and six had an ischaemic stroke (IR 1.94 per 100 patient-years)., Conclusions: Among patients with NVAF at high ICH risk, LAAC demonstrated a low risk of recurrent ICH or ischaemic stroke compared with previously published data. LAAC in high ICH risk populations should be considered in clinical practice per FDA approval and recent guidelines., Competing Interests: Competing interests: Dr. Gurol received research grants from National Institute of Health (NIH, RO1NS11452, NS083711).Dr. Gurol’s hospital received research grants from AVID, Pfizer and Boston Scientific Corporation., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Nonvalvular atrial fibrillation is a common rhythm disorder of middle-aged to older adults that can cause ischemic strokes and systemic embolism. Lifelong use of oral anticoagulants reduces the risk of these ischemic events but increases the risk of major and clinically relevant hemorrhages. These medications also require strict compliance for efficacy, and they have nontrivial failure rates in higher-risk patients. Left atrial appendage closure is a nonpharmacological method to prevent ischemic strokes in atrial fibrillation without the need for lifelong anticoagulant use, but this procedure has the potential for complications and residual embolic events. This workshop of the Roundtable of Academia and Industry for Stroke Prevention discussed future research needed to further decrease the ischemic and hemorrhagic risks among patients with atrial fibrillation. A direct thrombin inhibitor, factor Xa inhibitors, and left atrial appendage closure are FDA-approved approaches whereas factor XIa inhibitors are currently being studied in phase 3 randomized controlled trials for stroke prevention. The benefits, risks, and shortcomings of these treatments and future research required in different high-risk patient populations are reviewed in this consensus statement., Competing Interests: Disclosures Dr Gurol receives research funding from National Institutes of Health. Dr Gurol’s hospital received research grants from Boston Scientific Corporation; research grants from Pfizer Canada Inc; and research grants from Avid Radiopharmaceuticals Inc. Dr Wright reports employment by National Institute of Neurological Disorders and Stroke. Dr Reddy reports compensation from Corvia Medical for consultant services; stock options in Focused Therapeutics; stock options in Heart Repair Technologies (HRT); stock options in Intershunt; stock options in East End Medical; stock options in Medlumics; stock holdings in Nyra Medical; compensation from W. L. Gore & Associates, Inc, for consultant services; compensation from Biotronik, Inc, for consultant services; stock options in Eximo; compensation from Philips for consultant services; stock options in Laminar; compensation from Biostar Ventures for consultant services; stock options in Axon Therapies; stock holdings in Vizaramed; stock options in Keystone Heart; compensation from CardioFocus, Inc, for consultant services; compensation from Biosense Webster, Inc, for consultant services; stock options in Impulse Dynamics (United States), Inc; stock options in Cardiacare. Israel; stock holdings in Affera; stock options in CardioNXT/AFTx; compensation from Cardionomic for consultant services; stock options in Atacor; compensation from Cardiac for consultant services; stock options in Field Medical; stock holdings in SoundCath; stock options in Oracle Health; compensation from AtriAN-Ireland for consultant services; stock options in Anumana; stock options in Acutus Medical, Inc; stock options in EP Frontiers; stock options in Nuvera; stock options in Javelin; stock options in Valcare; stock options in Middlepeak; stock options in Corisma; stock holdings in Surecor, Inc; stock options in Ablacon Inc; stock options in Atrian; stock options in Neutrace; stock options in Backbeat; compensation from Coremap for consultant services; stock options in Biosig; stock options in Dinova-Hangzhou DiNovA EP Technology; stock options in APN Health; compensation from Farapulse-Boston Scientific for consultant services; stock options in Kardium; compensation from Medtronic USA, Inc, for consultant services; compensation from Recor Medical for consultant services; stock options in Sirona Medical; stock holdings in Farapulse-BostonScientific; stock options in Epix Therapeutics; stock options in Aquaheart; stock options in Fire1; stock options in Pulse Biosciences; stock holdings in Manual Surgical Sciences; stock options in Autonomix; compensation from Abbott Vascular for consultant services; compensation from Abbott Vascular for consultant services; stock holdings in Newpace; compensation from Novo Nordisk for consultant services; stock options in EpiEP; compensation from BioTel Heart-Philips for consultant services; compensation from BOSTON SCIENTIFIC CORPORATION for consultant services; stock options in Restore Medical; stock options in EP Dynamics; stock options in LuxMed; stock options in Affera; stock options in Circa Scientific, Inc; stock holdings in Biostar Ventures; stock options in Cardiacare; compensation from Novartis for consultant services; and stock options in Anumana. Dr Merino reports compensation from American Academy of Neurology for other services and compensation from National Institute of Neurological Disorders and Stroke for data and safety monitoring services. Dr Hsu reports compensation from Biosense Webster, Inc, for consultant services; compensation from Abbott Laboratories for consultant services; compensation from Boston Scientific Corporation for consultant services; compensation from Sanofi US Services Inc for consultant services; compensation from Acutus Medical, Inc, for consultant services; compensation from iRhythm Technologies for consultant services; compensation from ZOLL Medical Corporation for consultant services; grants from Biotronik; compensation from Janssen Pharmaceuticals for consultant services; compensation from Pfizer for consultant services; compensation from Medtronic for consultant services; compensation from Biotronik for consultant services; stock options in Vektor Medical; compensation from AltaThera Pharmaceuticals LLC for consultant services; grants from Biosense Webster, Inc; and compensation from Bristol-Myers Squibb for consultant services.

Background and Objectives: Hypertensive cerebral small vessel disease (HTN-cSVD) is the predominant microangiopathy in patients with a combination of lobar and deep cerebral microbleeds (CMBs) and intracerebral hemorrhage (mixed ICH). We tested the hypothesis that cerebral amyloid angiopathy (CAA) is also a contributing microangiopathy in patients with mixed ICH with cortical superficial siderosis (cSS), a marker strongly associated with CAA., Methods: Brain MRIs from a prospective database of consecutive patients with nontraumatic ICH admitted to a referral center were reviewed for the presence of CMBs, cSS, and nonhemorrhagic CAA markers (lobar lacunes, centrum semiovale enlarged perivascular spaces [CSO-EPVS], and multispot white matter hyperintensity [WMH] pattern). The frequencies of CAA markers and left ventricular hypertrophy (LVH), a marker for hypertensive end-organ damage, were compared between patients with mixed ICH with cSS (mixed ICH/cSS[+]) and without cSS (mixed ICH/cSS[-]) in univariate and multivariable models., Results: Of 1,791 patients with ICH, 40 had mixed ICH/cSS(+) and 256 had mixed ICH/cSS(-). LVH was less common in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-) (34% vs 59%, p = 0.01). The frequencies of CAA imaging markers, namely multispot pattern (18% vs 4%, p < 0.01) and severe CSO-EPVS (33% vs 11%, p < 0.01), were higher in patients with mixed ICH/cSS(+) compared with those with mixed ICH/cSS(-). In a logistic regression model, older age (adjusted odds ratio [aOR] 1.04 per year, 95% CI 1.00-1.07, p = 0.04), lack of LVH (aOR 0.41, 95% CI 0.19-0.89, p = 0.02), multispot WMH pattern (aOR 5.25, 95% CI 1.63-16.94, p = 0.01), and severe CSO-EPVS (aOR 4.24, 95% CI 1.78-10.13, p < 0.01) were independently associated with mixed ICH/cSS(+) after further adjustment for hypertension and coronary artery disease. Among ICH survivors, the adjusted hazard ratio of ICH recurrence in patients with mixed ICH/cSS(+) was 4.65 (95% CI 1.38-11.38, p < 0.01) compared with that in patients with mixed ICH/cSS(-)., Discussion: The underlying microangiopathy of mixed ICH/cSS(+) likely includes both HTN-cSVD and CAA, whereas mixed ICH/cSS(-) is likely driven by HTN-cSVD. These imaging-based classifications can be important to stratify ICH risk but warrant confirmation in studies incorporating advanced imaging/pathology., (© 2023 American Academy of Neurology.)

Background: Cerebral Amyloid Angiopathy (CAA) is a cerebral small vessel disease that can lead to microstructural disruption of white matter (WM), which can be measured by the Peak Width of Skeletonized Mean Diffusivity (PSMD). We hypothesized that PSMD measures would be increased in patients with CAA compared to healthy controls (HC), and increased PSMD is associated with lower cognitive scores in patients with CAA., Methods: Eighty-one probable CAA patients without cognitive impairment who were diagnosed with Boston criteria and 23 HCs were included. All subjects underwent an advanced brain MRI with high-resolution diffusion-weighted imaging (DWI). PSMD scores were quantified from a probabilistic skeleton of the WM tracts in the mean diffusivity (MD) image using a combination of fractional anisotropy (FA) and the FSL Tract-Based Spatial Statistics (TBSS) algorithm (www.psmd-marker.com). Within CAA cohort, standardized z-scores of processing speed, executive functioning and memory were obtained., Results: The mean of age and sex were similar between CAA patients (69.6 ± 7.3, 59.3% male) and HCs (70.6 ± 8.5, 56.5% male) ( p = 0.581 and p = 0.814). PSMD was higher in the CAA group [(4.13 ± 0.94) × 10 -4 mm 2 /s] compared to HCs [(3.28 ± 0.51) × 10 -4 mm 2 /s] ( p < 0.001). In a linear regression model corrected for relevant variables, diagnosis of CAA was independently associated with increased PSMD compared to HCs ( ß = 0.45, 95% CI 0.13-0.76, p = 0.006). Within CAA cohort, higher PSMD was associated with lower scores in processing speed ( p < 0.001), executive functioning ( p = 0.004), and memory (0.047). Finally, PSMD outperformed all other MRI markers of CAA by explaining most of the variance in models predicting lower scores in each cognitive domain., Discussion: Peak Width of Skeletonized Mean Diffusivity is increased in CAA, and it is associated with worse cognitive scores supporting the view that disruption of white matter has a significant role in cognitive impairment in CAA. As a robust marker, PSMD can be used in clinical trials or practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Horn, Gokcal, Becker, Das, Schwab, Zanon Zotin, Goldstein, Rosand, Viswanathan, Polimeni, Duering, Greenberg and Gurol.)

Background and Purpose: We evaluate whether non-haemorrhagic imaging markers (NHIM) (white matter hyperintensity patterns, lacunes and enlarged perivascular spaces (EPVS)) can discriminate cerebral amyloid angiopathy (CAA) from hypertensive cerebral small vessel disease (HTN-cSVD) among patients with isolated lobar intracerebral haemorrhage (isolated-LICH)., Methods: In patients with isolated-LICH, four cSVD aetiologic groups were created by incorporating the presence/distribution of NHIM: HTN-cSVD pattern, CAA pattern, mixed NHIM and no NHIM. CAA pattern consisted of patients with any combination of severe centrum semiovale EPVS, lobar lacunes or multiple subcortical spots pattern. HTN-cSVD pattern consisted of any HTN-cSVD markers: severe basal ganglia PVS, deep lacunes or peribasal ganglia white matter hyperintensity pattern. Mixed NHIM consisted of at least one imaging marker from either pattern. Our hypothesis was that patients with HTN-cSVD pattern/mixed NHIM would have a higher frequency of left ventricular hypertrophy (LVH), which is associated with HTN-cSVD., Results: In 261 patients with isolated-LICH, CAA pattern was diagnosed in 93 patients, HTN-cSVD pattern in 53 patients, mixed NHIM in 19 patients and no NHIM in 96 patients. The frequency of LVH was similar among those with HTN-cSVD pattern and mixed NHIM (50% vs 39%, p=0.418) but was more frequent in HTN-cSVD pattern compared with CAA pattern (50% vs 20%, p<0.001). In a regression model, HTN-cSVD pattern (OR: 7.38; 95% CI 2.84 to 19.20) and mixed NHIM (OR: 4.45; 95% CI 1.25 to 15.90) were found to be independently associated with LVH., Conclusion: Among patients with isolated-LICH, NHIM may help differentiate HTN-cSVD from CAA, using LVH as a marker for HTN-cSVD., Competing Interests: Competing interests: ASD reports grants from the Andrew David Heitman Young Investigator Fund. RWR reports grants from the National Institute of Neurological Disorders and Stroke (R25 NS065743). JNG reports research support from National Institutes of Health (NIH), Pfizer, Takeda and Octapharma and consulting support from Alexion, CSL Behring, NControl and Cayuga. MEG receives funding from the NIH (R01NS11452)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: 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., 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)., Competing Interests: Declaration of interests AC reports receiving funding from the Bodossaki Foundation and the Frechette Family Foundation and consulting fees from Imperative Care. MPF reports receiving funding from Biogen and Voyager Therapeutics. Gba reports receiving funding from the Rosetrees Trust, Alzheimer's Research UK, NIHR, and the Stroke Association. CC reports receiving funding from the French Ministry of Health and honoraria from Amgen, and participating in data safety monitoring, advisory, or steering committees for the University of Glasgow, University of Caen, Op2Lysis, AstraZeneca, Bristol Myers Squibb, and Biogen. MD reports receiving funding from Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology and the Vascular Dementia Research Foundation. JH reports receiving funding from the German Research Foundation and German Center for Neurodegenerative Diseases and tissue from Neurobiobank Munich. JL reports serving on a serving on an advisory board for Biogen and Mediaire. LP reports receiving honoraria from Daiichi Sankyo Ireland. FP reports receiving funding from the Alzheimer's Association (AARG-18-561699), participation on an Advisory Board for Roche, and leadership of the CAA Study Group of the Italia Society of Neurology-Dementia and the iCAB International Network. SR reports receiving funding from the German Research Foundation and brain tissue from Neurobiobank Munich. MAR reports receiving funding from the Wellcome Trust. JAS reports receiving funding from the US National Institutes of Health, consulting fees from Alnylam Pharmaceuticals, Apellis Pharmaceuticals, and Avid Radiopharmaceuticals, honoraria from Weil Cornell University, payment for expert testimony from the National Hockey League, support for travel from the US National Institutes for Health, serving on safety monitoring or advisory boards for the Framingham Heart Study, DISCOVERY, University of Kansas, Boston University, and University of California Irvine, and serving in leadership positions for the Alzheimer's Association and Foundation Alzheimer France. CSm reports receiving funding from the Medical Research Council UK. LS reports receiving funding from the Hungarian Academy of Sciences and Ministry for Innovation and Technology of Hungary from the source of the National Research. JMW reports receiving funding from the UK Dementia Research Institute funded by the UK Medical Research Council, Alzheimer's Society, and Alzheimer's Research UK, and a leadership role for the European Stroke Organization SVD Guidelines. FAW reports receiving honoraria from Alexion Pharm. MEG reports receiving funding from Avid Radiopharmaceuticals, Pfizer, and Boston Scientific. AV reports receiving funding from the US National Institutes of Health and consulting fees from Alnylam Pharmaceuticals and Biogen Pharmaceuticals. RA-SS reports receiving funding from the UK Medical Research Council and the Stroke Association. EES reports receiving funding from the Canadian Institutes of Health Research, Brain Canada, and Biogen, and consulting fees from Biogen and Eli Lily. DJW reports receiving consulting fees from Alnylam and Novo Nordisk, honoraria from Bayer and Alexion, participation on a safety monitoring board for the OXHARP study, and serving in leadership for the British Association of Stroke Physicians. SMG reports receiving funding from the US National Institutes of Health, royalties from Up-To-Date, consulting fees from Eli Lily, and serving on data safety monitoring committees for Washington University, Bayer, Biogen, and Roche. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137-2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury.

Background: Although primary intraventricular hemorrhage is frequently due to trauma or vascular lesions, the etiology of idiopathic primary intraventricular hemorrhage (IP-IVH) is not defined., Aims: Herein, we test the hypothesis that cerebral small vessel diseases (cSVD) including hypertensive cSVD (HTN-cSVD) and cerebral amyloid angiopathy are associated with IP-IVH., Methods: Brain magnetic resonance imaging from consecutive patients (January 2011 to September 2019) with non-traumatic intracerebral hemorrhage from a single referral center were reviewed for the presence of HTN-cSVD (defined by strictly deep or mixed-location intracerebral hemorrhage/cerebral microbleeds) and cerebral amyloid angiopathy (applying modified Boston criteria)., Results: Forty-six (4%) out of 1276 patients were identified as having IP-IVH. Among these, the mean age was 74.4 ± 12.2 years and 18 (39%) were females. Forty (87%) had hypertension, and the mean initial blood pressure was 169.2 ± 40.4/88.8 ± 22.2 mmHg. Of the 35 (76%) patients who received a brain magnetic resonance imaging, two (6%) fulfilled the modified Boston criteria for possible cerebral amyloid angiopathy and 10 (29%) for probable cerebral amyloid angiopathy. Probable cerebral amyloid angiopathy was found at a similar frequency when comparing IP-IVH patients to the remaining patients with primary intraparenchymal hemorrhage (P-IPH) (27%, p  = 0.85). Furthermore, imaging evidence for HTN-cSVD was found in 8 (24%) patients with IP-IVH compared to 209 (28%, p  = 0.52) patients with P-IPH., Conclusions: Among IP-IVH patients, cerebral amyloid angiopathy was found in approximately one-third of patients, whereas HTN-cSVD was detected in 23%-both similar rates to P-IPH patients. Our results suggest that both cSVD subtypes may be associated with IP-IVH.

Objective: Recent data suggest that cerebral amyloid angiopathy (CAA) causes haemorrhagic lesions in cerebellar cortex as well as subcortical cerebral atrophy. However, the potential effect of CAA on cerebellar tissue loss and its clinical implications have not been investigated., Methods: Our study included 70 non-demented patients with probable CAA, 70 age-matched healthy controls (HCs) and 70 age-matched patients with Alzheimer's disease (AD). The cerebellum was segmented into percent of cerebellar subcortical volume (pCbll-ScV) and percent of cerebellar cortical volume (pCbll-CV) represented as percent (p) of estimated total intracranial volume. We compared pCbll-ScV and pCbll-CV between patients with CAA, HCs and those with AD. Gait velocity (metres/second) was used to investigate gait function in patients with CAA., Results: Patients with CAA had significantly lower pCbll-ScV compared with both HC (1.49±0.1 vs 1.73±0.2, p<0.001) and AD (1.49±0.1 vs 1.66±0.24, p<0.001) and lower pCbll-CV compared with HCs (6.03±0.5 vs 6.23±0.6, p=0.028). Diagnosis of CAA was independently associated with lower pCbll-ScV compared with HCs (p<0.001) and patients with AD (p<0.001) in separate linear regression models adjusted for age, sex and presence of hypertension. Lower pCbll-ScV was independently associated with worse gait velocity (β=0.736, 95% CI 0.28 to 1.19, p=0.002) in a stepwise linear regression analysis including pCbll-CV along with other relevant variables., Interpretation: Patients with CAA show more subcortical cerebellar atrophy than HC or patients with AD and more cortical cerebellar atrophy than HCs. Reduced pCbll-ScV correlated with lower gait velocity in regression models including other relevant variables. Overall, this study suggests that CAA causes cerebellar injury, which might contribute to gait disturbance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The impact of vascular lesions on cognition is location dependent. Here, we assessed the contribution of small vessel disease lesions in the corpus callosum to vascular cognitive impairment in cerebral amyloid angiopathy, as a model for cerebral small vessel disease. Sixty-five patients with probable cerebral amyloid angiopathy underwent 3T magnetic resonance imaging, including a diffusion tensor imaging scan, and neuropsychological testing. Microstructural white-matter integrity was quantified by fractional anisotropy and mean diffusivity. Z -scores on individual neuropsychological tests were averaged into five cognitive domains: information processing speed, executive functioning, memory, language and visuospatial ability. Corpus callosum lesions were defined as haemorrhagic (microbleeds or larger bleeds) or ischaemic (microinfarcts, larger infarcts and diffuse fluid-attenuated inversion recovery hyperintensities). Associations between corpus callosum lesion presence, microstructural white-matter integrity and cognitive performance were examined with multiple regression models. The prevalence of corpus callosum lesions was confirmed in an independent cohort of memory clinic patients with and without cerebral amyloid angiopathy ( n  = 82). In parallel, we assessed corpus callosum lesions on ex vivo magnetic resonance imaging in cerebral amyloid angiopathy patients ( n  = 19) and controls ( n  = 5) and determined associated tissue abnormalities with histopathology. A total number of 21 corpus callosum lesions was found in 19/65 (29%) cerebral amyloid angiopathy patients. Corpus callosum lesion presence was associated with reduced microstructural white-matter integrity within the corpus callosum and in the whole-brain white matter. Patients with corpus callosum lesions performed significantly worse on all cognitive domains except language, compared with those without corpus callosum lesions after correcting for age, sex, education and time between magnetic resonance imaging and neuropsychological assessment. This association was independent of the presence of intracerebral haemorrhage, whole-brain fractional anisotropy and mean diffusivity, and white-matter hyperintensity volume and brain volume for the domains of information processing speed and executive functioning. In the memory clinic patient cohort, corpus callosum lesions were present in 14/54 (26%) patients with probable and 2/8 (25%) patients with possible cerebral amyloid angiopathy, and in 3/20 (15%) patients without cerebral amyloid angiopathy. In the ex vivo cohort, corpus callosum lesions were present in 10/19 (53%) patients and 2/5 (40%) controls. On histopathology, ischaemic corpus callosum lesions were associated with tissue loss and demyelination, which extended beyond the lesion core. Together, these data suggest that corpus callosum lesions are a frequent finding in cerebral amyloid angiopathy, and that they independently contribute to cognitive impairment through strategic microstructural disruption of white-matter tracts., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To analyze the relationship of lacunes with cortical cerebral microinfarcts (CMIs), to assess their association with vascular dysfunction, and to evaluate their effect on the risk of incident intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA)., Methods: The count and topography of lacunes (deep/lobar), CMIs, and white matter hyperintensity (WMH) volume were retrospectively analyzed in a prospectively enrolled CAA cohort that underwent high-resolution research MRIs. The relationship of lacunes with CMIs and other CAA-related markers including time to peak (TTP) of blood oxygen level-dependent signal, an established measure of vascular dysfunction, was evaluated in multivariate models. Adjusted Cox regression models were used to investigate the relationship between lacunes and incident ICH., Results: The cohort consisted of 122 patients with probable CAA without dementia (mean age, 69.4 ± 7.6 years). Lacunes were present in 31 patients (25.4%); all but one were located in lobar regions. Cortical CMIs were more common in patients with lacunes compared to patients without lacunes (51.6% vs 20.9%, p = 0.002). TTP was not associated with either lacunes or CMIs (both p > 0.2) but longer TTP response independently correlated with higher WMH volume ( p = 0.001). Lacunes were associated with increased ICH risk in univariate and multivariate Cox regression models ( p = 0.048 and p = 0.026, respectively)., Conclusions: Our findings show a high prevalence of lobar lacunes, frequently coexisting with CMIs in CAA, suggesting that these 2 lesion types may be part of a common spectrum of CAA-related infarcts. Lacunes were not related to vascular dysfunction but predicted incident ICH, favoring severe focal vessel involvement rather than global ischemia as their mechanism., (© 2021 American Academy of Neurology.)

Stroke prevention in patients with atrial fibrillation is arguably one of the fastest developing areas in preventive medicine. The increasing use of direct oral anticoagulants and nonpharmacologic methods such as left atrial appendage closure for stroke prevention in these patients has increased clinicians' options for optimal care. Platelet antiaggregants are also commonly used in other ischemic cardiovascular and or cerebrovascular conditions. Long term use of oral anticoagulants for atrial fibrillation is associated with elevated risks of major bleeds including especially brain hemorrhages, which are known to have extremely poor outcomes. Neuroimaging and other biomarkers have been validated to stratify brain hemorrhage risk among older adults. A thorough understanding of these biomarkers is essential for selection of appropriate anticoagulant or left atrial appendage closure for stroke prevention in patients with atrial fibrillation. This article will address advances in the stratification of ischemic and hemorrhagic stroke risk among patients with atrial fibrillation and other conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Essential tremor (ET) is one of the most common movement disorders. Aside from tremor, patients may exhibit other motor features as well as non-motor features, including neuropsychiatric symptoms. The cerebellum and cerebellar connections are thought to play a key role in the pathophysiology of ET. Cognitive and affective disturbances can occur in the context of cerebellar disease. Our aim was to study the prevalence and clinical correlates of alexithymia and its relationship to depression and anxiety in ET patients and control subjects (CS)., Method: We enrolled 100 ET patients and 100 age- and gender-matched CS. The Toronto Alexithymia Scale-20 (TAS-20), the Beck depression inventory-II and the Beck anxiety inventory were administered., Results: Alexithymia levels were significantly higher in ET patients than CS (respective mean TAS-20 scores = 50.63 ± 9.79 vs. 44.05 ± 12.51, p < 0.001).  There were robust associations between alexithymia, depressive symptoms, and anxiety but, after excluding the ET patients and the CS who had moderate or severe depression or who had moderate or severe anxiety, the total alexithymia score remained significantly higher in the ET than the CS group (46.78 ± 9.19 vs. 41.18 ± 11.79, p ≤ 0.01)., Conclusion: This study suggests that prevalence of alexithymia is significantly higher in ET patients. Alexithymia might be another non-motor neuropsychiatric symptom of the disease.  Further studies are needed to confirm and expand upon our findings.

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., (© 2020 American Academy of Neurology.)

Purpose of Review: This review aims to help neurologists managing atrial fibrillation (AF) patients who had an ischemic stroke and/or with intracranial hemorrhage (ICH) markers, therefore at high embolic/hemorrhagic risks., Recent Findings: Implantable loop recorders have substantially improved the accuracy of AF detection. Recent research yielded a set of powerful neuroimaging markers that can stratify ICH risk. Direct oral anticoagulants (DOAC) are easier to use with a lower ICH risk than warfarin in a general AF population. Finally, the FDA-approved left atrial appendage closure (LAAC) with the WATCHMAN device provides an option without the need for life-long anticoagulation. In this review, we introduce the concept of preventing both ischemic and hemorrhagic strokes in AF patients through accurate AF diagnosis and stratification of both embolic and ICH risks. LAAC can be considered in patients at higher hemorrhagic risks while warfarin/DOAC use should be individualized in the majority of AF patients at a low risk of bleeding.

Background: In this study, we assessed 75 patients with myasthenia gravis (MG) for coexistent autoimmune diseases (ADs) and for the characteristic autoantibodies that are associated with the most relevant forms of ADs., Methods: The demographic and clinical characteristics of the patients were recorded. In all patients, thyroid function tests, thyroid autoantibodies, and other autoantibodies were studied. The diagnosis of autoimmune thyroid disease (AITD) was made based on the clinical features, physical examination, and laboratory findings. The diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were made in accordance with the revised criteria of American College of Rheumatology. The presence of other ADs were also recorded which was based on whether or not the patient already had a diagnosis of ADs; or, whether it was detected during the period of the study based on clinical findings and/or laboratory abnormalities., Results: Thirty-nine patients (52%) had autoantibody positivity in their sera. Thyroid autoantibodies and antinuclear antibodies were the main autoantibodies detected. In twenty one of these patients, a diagnosis of AD could not be confirmed. Eighteen patients (24%) had a confirmed diagnosis of a coexisting AD. These ADs included AITD (16%), RA (4%), SLE (2.6%), and Lambert-Eaton myasthenic syndrome (1.3%). In ten patients, the diagnosis of ADs had been established before the development of MG; 8 of the patients included those who were newly diagnosed with ADs in the course of the management of MG., Conclusions: MG has an increased frequency of coexisting ADs. Autoantibodies that are characteristic for ADs can be found in the patients without the presence of any of the clinical findings of ADs. Clinical attention towards the management of ADs is especially needed during the follow-up of patients with MG.