Reorganization of sensory networks after subcortical vestibular infarcts: A longitudinal symptom-related voxel-based morphometry study.

BACKGROUND AND PURPOSE: We aimed to delineate common principles of reorganization after infarcts of the subcortical vestibular circuitry related to the clinical symptomatology. Our hypothesis was that the recovery of specific symptoms is associated with changes in distinct regions within the core vestibular, somatosensory, and visual cortical and subcortical networks. METHODS: We used voxel- and surface-based morphometry to investigate structural reorganization of subcortical and cortical brain areas in 42 patients with a unilateral, subcortical infarct with vestibular and ocular motor deficits in the acute phase. The patients received structural neuroimaging and clinical monitoring twice (acute phase and after 6 months) to detect within-subject changes over time. RESULTS: In patients with vestibular signs such as tilts of the subjective visual vertical (SVV) and ocular torsion in the acute phase, significant volumetric increases in the superficial white matter around the parieto-opercular (retro-)insular vestibular cortex (PIVC) were found at follow-up. In patients with SVV tilts, spontaneous nystagmus, and rotatory vertigo in the acute phase, gray matter volume decreases were located in the cerebellum and the visual cortex bilaterally at follow-up. Patients with saccade pathology demonstrated volumetric decreases in cerebellar, thalamic, and cortical centers for ocular motor control. CONCLUSIONS: The findings support the role of the PIVC as the key hub for vestibular processing and reorganization. The volumetric decreases represent the reciprocal interaction of the vestibular, visual, and ocular motor systems during self-location and egomotion detection. A modulation in vestibular and ocular motor as well as visual networks was induced independently of the vestibular lesion site.

Endovascular stroke treatment in orally anticoagulated patients: an analysis from the German Stroke Registry-Endovascular Treatment.

BACKGROUND: Endovascular treatment (ET) in orally anticoagulated (OAC) patients has not been evaluated in randomized clinical trials and data regarding this issue are sparse. METHODS: We analyzed data from the German Stroke Registry-Endovascular Treatment (GSR-ET; NCT03356392, date of registration: 22 Nov 2017). The primary outcomes were successful reperfusion defined as modified thrombolysis in cerebral infarction (mTICI 2b-3), good outcome at 3 months (modified Rankin scale [mRS] 0-2 or back to baseline), and intracranial hemorrhage (ICH) on follow-up imaging at 24 h analyzed by unadjusted univariate and adjusted binary logistic regression analysis. Additionally, we analyzed mortality at 3 months with adjusted binary logistic regression analysis. RESULTS: Out of 6173 patients, there were 1306 (21.2%) OAC patients, 479 (7.8%) with vitamin K antagonists (VKA) and 827 (13.4%) with non-vitamin K antagonist oral anticoagulation (NOAC). The control group consisted of 4867 (78.8%) non-OAC patients. ET efficacy with the rates of mTICI 2b-3 was similar among the three groups (85.6%, 85.3% vs 84.3%, p = 0.93 and 1). On day 90, good outcome was less frequent in OAC patients (27.8%, 27.9% vs 39.5%, p < 0.005 and < 0.005). OAC status was not associated with ICH at 24 h (NOAC: odd's ratio [OR] 0.89, 95% confidence interval [CI] 0.67-1.20; VKA: OR 1.04, CI 0.75-1.46). Binary logistic regression analysis revealed no influence of OAC status on good outcome at 3 months (NOAC: OR 1.25, CI 0.99-1.59; VKA: OR 1.18, CI 0.89-1.56) and mortality at 3 months (NOAC: OR 1.03, CI 0.81-1.30; VKA: OR 1.04, CI 0.78-1.1.37). CONCLUSIONS: ET can be performed safely and successfully in LVO stroke patients treated with OAC. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov . Unique identifier: NCT03356392.

Regional Associations of Cortical Superficial Siderosis and ß-Amyloid-Positron-Emission-Tomography Positivity in Patients With Cerebral Amyloid Angiopathy.

OBJECTIVE: This is a cross-sectional study to evaluate whether ß-amyloid-(Aß)-PET positivity and cortical superficial siderosis (cSS) in patients with cerebral amyloid angiopathy (CAA) are regionally colocalized. METHODS: Ten patients with probable or possible CAA (73.3 ± 10.9 years, 40% women) underwent MRI examination with a gradient-echo-T2*-weighted-imaging sequence to detect cSS and 18F-florbetaben PET examination to detect fibrillar Aß. In all cortical regions of the Hammers Atlas, cSS positivity (MRI: ITK-SNAP segmentation) and Aß-PET positivity (PET: ≥ mean value + 2 standard deviations of 14 healthy controls) were defined. Regional agreement of cSS- and Aß-PET positivity was evaluated. Aß-PET quantification was compared between cSS-positive and corresponding contralateral cSS-negative atlas regions. Furthermore, the Aß-PET quantification of cSS-positive regions was evaluated in voxels close to cSS and in direct cSS voxels. RESULTS: cSS- and Aß-PET positivity did not indicate similarity of their regional patterns, despite a minor association between the frequency of Aß-positive patients and the frequency of cSS-positive patients within individual regions (r s = 0.277, p = 0.032). However, this association was driven by temporal regions lacking cSS- and Aß-PET positivity. When analyzing all composite brain regions, Aß-PET values in regions close to cSS were significantly higher than in regions directly affected with cSS (p < 0.0001). However, Aß-PET values in regions close to cSS were not different when compared to corresponding contralateral cSS-negative regions (p = 0.603). CONCLUSION: In this cross-sectional study, cSS and Aß-PET positivity did not show regional association in patients with CAA and deserve further exploitation in longitudinal designs. In clinical routine, a specific cross-sectional evaluation of Aß-PET in cSS-positive regions is probably not useful for visual reading of Aß-PETs in patients with CAA.

Colocalization of Tau but Not ß-Amyloid with Cortical Superficial Siderosis in a Case with Probable CAA.

Cortical superficial siderosis (cSS) is a common feature in patients with cerebral amyloid angiopathy (CAA). The correlation between ß-amyloid and/or tau pathology and the occurrence of cSS is unclear. We report on an 80-year-old male patient who was diagnosed with probable CAA according to modified Boston criteria and underwent longitudinal magnetic resonance imaging, amyloid positron emission tomography (PET), and additional tau PET imaging. Amyloid deposition presented predominantly in the contralateral hemisphere not affected by cSS. In contrast, tau deposition was predominantly overlapping with brain regions affected by cSS. Amyloid deposition was not different in the vicinity of cSS whereas tau depositions were elevated in the vicinity of CSS-affected regions compared to non-cSS-affected brain regions. This case of probable CAA suggests that cSS may be associated with a locally elevated tau pathology but not with increased fibrillary amyloid deposition.

[Drug-induced reversible cerebral vasoconstriction syndrome : Ustekinumab as possible trigger?] / Medikamenteninduziertes reversibles zerebrales Vasokonstriktionssyndrom : Ustekinumab als möglicher Auslöser?

The reversible cerebral vasoconstriction syndrome (RCVS) is a common cause of thunderclap headache. Many trigger factors, such as the intake of vasoactive and less commonly immunosuppressive medication have previously been described. This article reports the first case of the occurrence of RCVS after the intake of ustekinumab in a female patient with a history of Crohn's disease.

Prognostic relevance of cortical superficial siderosis in cerebral amyloid angiopathy.

OBJECTIVE: To investigate the prognostic relevance of cortical superficial siderosis (cSS) in patients with cerebral amyloid angiopathy (CAA). METHODS: A total of 302 patients fulfilling clinical and imaging criteria for probable or possible CAA were enrolled into a prospective, multicenter cohort study and followed for 12 months. cSS was assessed on T2*/susceptibility-weighted imaging MRI. The predefined primary composite endpoint was incident stroke or death in patients with cSS compared to those without. Secondary analyses included cerebrovascular events and functional outcome measured by the modified Rankin Scale (mRS). Multiple regression analysis was performed to adjust for possible confounders. RESULTS: cSS prevalence was 40%. The primary endpoint occurred more frequently in patients with cSS (22%, 27/121) compared to those without (8%, 15/181, p = 0.001). Rates of CAA-related incident intracranial hemorrhage were 17% (cSS) and 4% (no cSS, p = 0.0003). The proportion of patients being functionally independent (mRS 0-2) 12 months from baseline were 59% (cSS) and 82% (no cSS, p = 0.00002). Presence of cSS was associated with the primary endpoint (adjusted odds ratio [OR] 1.2, 95% confidence interval [CI] 1.1-1.3, p = 0.0005), incident intracranial hemorrhage (adjusted OR 1.2, 95% CI 1.1-1.3, p = 0.0003), and less favorable outcome as assessed by the mRS (common OR 1.9, 95% CI 1.2-3.1, p = 0.009). Similar results were obtained in analyses restricted to patients with probable CAA and to patients with disseminated cSS (all p < 0.005). CONCLUSIONS: Patients with cSS and suspected CAA are at high risk for CAA-related incident intracranial hemorrhage and poor functional outcome. Both the presence and extent of cSS have prognostic relevance and may influence clinical decision-making.

Early MoCA predicts long-term cognitive and functional outcome and mortality after stroke.

OBJECTIVE: To examine whether the Montreal Cognitive Assessment (MoCA) administered within 7 days after stroke predicts long-term cognitive impairment, functional impairment, and mortality. METHODS: MoCA was administered to 274 patients from 2 prospective hospital-based cohort studies in Germany (n = 125) and France (n = 149). Cognitive and functional outcomes were assessed at 6, 12, and 36 months after stroke by comprehensive neuropsychological testing, the Clinical Dementia Rating (CDR) scale, the modified Rankin Scale (mRS), and Instrumental Activities of Daily Living (IADL) and analyzed with generalized estimating equations. All-cause mortality was investigated by Cox proportional hazard models. Analyses were adjusted for demographic variables, education, vascular risk factors, premorbid cognitive status, and NIH Stroke Scale scores. The additive predictive value of MoCA was examined with receiver operating characteristic curves. RESULTS: In pooled analyses, a baseline MoCA score <26 was associated with cognitive impairment, defined by neuropsychological testing (odds ratio [OR] 5.30, 95% confidence interval [CI] 2.75-10.22) and by CDR score ≥0.5 (OR 2.53, 95% CI 1.53-4.18); functional impairment, defined by mRS score >2 (OR 5.03, 95% CI 2.20-11.51) and by IADL score <8 (OR 2.48, 95% CI 1.40-4.38); and mortality (hazard ratio 7.24, 95% CI 1.99-26.35) across the 3-year follow-up. Patients with MoCA score <26 performed worse across all prespecified cognitive domains (executive function/attention, memory, language, visuospatial ability). MoCA increased the area under the curve for predicting cognitive impairment (neuropsychological testing 0.81 vs 0.72, p = 0.01) and functional impairment (mRS score >2, 0.88 vs 0.84, p = 0.047). CONCLUSION: Early cognitive testing by MoCA predicts long-term cognitive outcome, functional outcome, and mortality after stroke. Our results support routine use of the MoCA in stroke patients.

[New oral anticoagulants (NOAC) in stroke treatment]. / Neue orale Antikoagulantien (NOAK) in der Schlaganfall-Therapie.

Since 2011, new oral anticoagulants (NOAC) can be prescribed for prevention of cardio-embolic ischemic strokes in addition to vitamin K antagonists. NOAC are indicated in patients with non-valvular atrial fibrillation. Although its use is a matter of debate in Germany, the neurological and cardiological societies recommend the use of NOAC over and above vitamin K antagonists due to a better benefit-to-risk ratio attributed to it, especially because of the lower risk of intracranial hemorrhage in NOAC use. A specific antidote is commercially available for the direct thrombin inhibitor dabigatran only. For the factor Xa inhibitors, an antidote is being investigated in clinical trials. To our best knowledge, there are no direct head-to-head studies between the NOACs. Therefore, none of them can be assumed to be superior and the decision for a specific NOAC should be based on the available scientific data from the NOAC trials considering the individual patient's characteristics and comorbidities.

Validation of the Telephone Interview of Cognitive Status and Telephone Montreal Cognitive Assessment Against Detailed Cognitive Testing and Clinical Diagnosis of Mild Cognitive Impairment After Stroke.

BACKGROUND AND PURPOSE: Assessment of cognitive status poststroke is recommended by guidelines but follow-up can often not be done in person. The Telephone Interview of Cognitive Status (TICS) and the Telephone Montreal Cognitive Assessment (T-MoCA) are considered useful screening instruments. Yet, evidence to define optimal cut-offs for mild cognitive impairment (MCI) after stroke is limited. METHODS: We studied 105 patients enrolled in the prospective DEDEMAS study (Determinants of Dementia After Stroke; NCT01334749). Follow-up visits at 6, 12, 36, and 60 months included comprehensive neuropsychological testing and the Clinical Dementia Rating scale, both of which served as reference standards. The original TICS and T-MoCA were obtained in 2 separate telephone interviews each separated from the personal visits by 1 week (1 before and 1 after the visit) with the order of interviews (TICS versus T-MoCA) alternating between subjects. Area under the receiver-operating characteristic curves was determined. RESULTS: Ninety-six patients completed both the face-to-face visits and the 2 interviews. Area under the receiver-operating characteristic curves ranged between 0.76 and 0.83 for TICS and between 0.73 and 0.94 for T-MoCA depending on MCI definition. For multidomain MCI defined by multiple-tests definition derived from comprehensive neuropsychological testing optimal sensitivities and specificities were achieved at cut-offs <36 (TICS) and <18 (T-MoCA). Validity was lower using single-test definition, and cut-offs were higher compared with multiple-test definitions. Using Clinical Dementia Rating as the reference, optimal cut-offs for MCI were <36 (TICS) and approximately 19 (T-MoCA). CONCLUSIONS: Both the TICS and T-MoCA are valid screening tools poststroke, particularly for multidomain MCI using multiple-test definition.

Juvenile Stroke.

BACKGROUND: So-called juvenile stroke, i.e., stroke in a person aged 18 to 55, affects approximately 30 000 persons per year in Germany and is thus an important cause of mortality and permanent morbidity. The spectrum of causes of stroke is broader in this age group than in older patients and is also differently distributed. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed and on current guideline recommendations. RESULTS: Juvenile strokes are often caused by cardiogenic emboli (ca. 25%) and by vascular dissection (ca. 20%). Approximately 10% are due to rare causes such as vasculitis or thrombophilia, 25-50% remain cryptogenic, and 20-30% meet the criteria for an embolic stroke of undetermined source (ESUS). A rational diagnostic algorithm should be applied that is based on the relative frequencies of the potential causes. The acute treatment of ischemic stroke is the same for patients of all ages: the patient must be transferred as soon as possible to a hospital where a vascular recanalization procedure can be performed. From age 40 onward, there is a steep rise in vascular risk factors and therefore also in the resulting macro- and microangiopathy, which lead, in turn, to stroke. Only 40% of patients with juvenile stroke are ever able to return to their original occupation, and approximately one-third remain permanently unable to work. CONCLUSION: The high rates of cryptogenic stroke and ESUS among patients with juvenile stroke indicate that uncertainties remain in the diagnosis and treatment of this entity. The identification of rare causes of juvenile stroke requires a major diagnostic effort. Which diagnostic tests are useful or necessary in which patients is a matter that is currently decided on an individual basis. This is true, above all, of the indication for long-term cardiac monitoring.

Cortical Superficial Siderosis in Different Types of Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Cortical superficial siderosis (cSS) has emerged as a clinically relevant imaging feature of cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is also present in nonamyloid-associated small vessel disease and whether patients with cSS differ in terms of other small vessel disease imaging features. METHODS: Three hundred sixty-four CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, 372 population-based controls, and 100 CAA patients with cSS (fulfilling the modified Boston criteria for possible/probable CAA) were included. cSS and cerebral microbleeds were visually rated on T2*-weighted magnetic resonance imaging. White matter hyperintensities were segmented on fluid-attenauted inversion recovery images, and their spatial distribution was compared between groups using colocalization analysis. Cerebral microbleeds location was determined in an observer-independent way using an atlas in standard space. RESULTS: cSS was absent in CADASIL and present in only 2 population-based controls (0.5%). Cerebral microbleeds were present in 64% of CAA patients with cSS, 34% of patients with CADASIL, and 12% of population-based controls. Among patients with cerebral microbleeds, lobar location was found in 95% of CAA patients with cSS, 48% of CADASIL patients, and 69% of population-based controls. The spatial distribution of white matter hyperintensities was comparable between CAA with cSS and CADASIL as indicated by high colocalization coefficients. CONCLUSIONS: cSS was absent in CADASIL, whereas other small vessel disease imaging features were similar to CAA patients with cSS. Our findings suggest that cSS in combination with other small vessel disease imaging markers is highly indicative of CAA.

Thrombolysis management in thrombectomy patients: Real-life data from German stroke centres.

INTRODUCTION: In randomised clinical trials (RCTs), endovascular thrombectomy (ET) was combined with intravenous thrombolysis (IVT) in the vast majority of patients. We aimed to analyse how German stroke centres manage IVT in patients receiving ET in daily routine. PATIENTS AND METHODS: We performed an online survey among neurologists and neurointerventionalists that included all German University hospitals and a selection of German community hospitals known to perform ET. The survey consisted of 20 questions and was open for reply from 20 December 2016 to 9 January 2017. FINDINGS: Overall, there were 110 replies, 76% (84/110) from neurologists and 20% (22/110) from neurointerventionalists. The majority of participants (75/99, 76%) reported to continue IVT after start of ET. Nine participants (9%) reported to stop IVT as a standard of care before ET and another 15 (15%) reported to stop IVT on a case-by-case basis. Thrombolysis is given intra-arterially in individual cases in 39% (37/99) and as a standard of care in 3% (3/99). Intra-arterial Heparin is given additionally as a standard procedure in 25% (24/96) and in individual cases in 11% (11/96). IVT is omitted even without contraindications before ET in 5% (5/95) as standard procedure and in 14% (13/95) in individual cases. DISCUSSION: We observed a wide heterogeneity with respect to the management of IVT in the context of ET. Evidence from RCTs is not implemented in a large number of cases. CONCLUSION: These findings emphasise a requirement for further education and implementation of standards for the management of intravenous thrombolysis in endovascular treated stroke patients.

Prevalence of Amyloid Positron Emission Tomographic Positivity in Poststroke Mild Cognitive Impairment.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is common after stroke and associated with poor outcome. However, the mechanisms underlying poststroke MCI (PS-MCI) are insufficiently understood. We performed amyloid-ß positron emission tomography (PET) in a prospective cohort of stroke survivors to determine the role of amyloid pathology in PS-MCI. METHODS: We studied 178 consecutive patients enrolled into the prospective DEDEMAS study (Determinants of Dementia After Stroke). Follow-up visits 6 months post stroke included detailed cognitive testing, standardized magnetic resonance imaging, and amyloid-ß imaging using flutemetamol ((18)F) PET. MCI was defined by the modified Petersen criteria. Amyloid-positivity was assessed visually and quantitatively. Fifty-six (31%) patients agreed to undergo PET imaging. RESULTS: Thirty-eight (68%) patients who consented to PET imaging had PS-MCI. Visual assessment revealed amyloid PET positivity in 2 (5%) of the 38 PS-MCI patients and in 2 (11%) of the 18 cognitively healthy stroke survivors. There was no correlation between flutemetamol ((18)F) standardized uptake value ratios and cognitive scores in the 56 patients. PS-MCI patients had significant cognitive impairments on executive function (P<0.01) and memory tests (P<0.01) when compared with cognitively healthy stroke survivors (P<0.01). CONCLUSIONS: The prevalence of amyloid-pathology in patients with PS-MCI is not increased when compared with cognitively healthy stroke survivors and to recent estimates for cognitively healthy elderly subjects. Factors other than amyloid-pathology likely contribute to the development of PS-MCI. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01334749.

Peripheral glucose levels and cognitive outcome after ischemic stroke-Results from the Munich Stroke Cohort.

INTRODUCTION: The relationship between glucose metabolism and stroke outcome is likely to be complex. We examined whether there is a linear or non-linear relationship between glucose measures in the acute phase of stroke and post-stroke cognition, and whether altered glucose metabolism at different time intervals (long- and short-term before stroke, acute phase) is associated with cognitive outcome. PATIENTS AND METHODS: In all, 664 consecutively recruited patients with acute ischemic stroke and without pre-stroke dementia were included in this prospective observational study. Blood samples were taken at admission and fasting on the first morning after stroke. Duration of diabetes was assessed by interview. Cognitive outcome was assessed by the Telephone Interview for Cognitive Status 3 months post-stroke. Dose-response analyses were used to investigate non-linearity. Regression analyses were stratified by diabetes status and adjusted for relevant confounders. RESULTS: Cognitive status was testable in 422 patients (81 with diabetes). There was a non-linear relationship between both admission and fasting glucose levels and cognitive outcome. Lower glucose values were significantly associated with lower Telephone Interview for Cognitive Status scores 3 months post-stroke in patients without diabetes with a similar trend in diabetic patients. There was an inverse association between duration of diabetes and Telephone Interview for Cognitive Status scores (linear regression: -0.10 (95% confidence interval: -0.17 to -0.02) per year increase of diabetes duration), whereas HbA1c was not related to cognitive outcome. Results were supported by sensitivity analyses accounting for attrition. CONCLUSION: Lower glucose levels in the acute phase of stroke are associated with worse cognitive outcome but the relationship is non-linear. Long-term abnormalities in glucose metabolism are also related to poor outcome but this is not the case for shorter term abnormalities. Altered glucose levels at different stages of stroke may affect stroke outcome through different pathways.

Clinical spectrum, underlying etiologies and radiological characteristics of cortical superficial siderosis.

Cortical superficial siderosis (cSS) is an increasingly recognized MR-imaging marker most probably caused by focal convexity subarachnoid hemorrhage (SAH). There is accumulating evidence that cSS represents an important risk factor for subsequent intracranial hemorrhages. Here, we aimed to determine clinical symptoms, underlying etiologies, and radiological characteristics of cSS in a large patient cohort. We performed an electronic database search on all patients who presented between 2002 and 2013 to the university hospital Munich with non-traumatic and non-aneurysmal cSS. T2*-weighted gradient-echo sequences were analyzed regarding localization and extent of cSS as well as of acute SAH, intracerebral hemorrhages (ICH) and microbleeds. Besides, all available clinical, laboratory, imaging and histological data were analyzed. 113 subjects matched the inclusion criteria. The following etiologies for cSS were identified: definite (n = 6; 5 %), probable (n = 75; 66 %), and possible (n = 28; 25 %) cerebral amyloid angiopathy (CAA); reversible cerebral vasoconstriction syndrome: 2 (2 %); central nervous system vasculitis: 1; and hyperperfusion syndrome: 1. Acute ICH was evident in 55 (49 %) cases. Other clinical manifestations were: transient focal neurological episodes (TFNE): 38 (34 %); cognitive impairment: 14 (12 %); generalized seizure: 4 (4 %); and headache: 2 (2 %). Adjusting for age and gender, cognitive impairment was more frequent in disseminated cSS, while TFNE was more often found in focal cSS (p = 0.042). Our data indicate CAA to be the most common etiology of cSS. In absence of symptomatic ICH, patients with focal cSS frequently present with TFNE, while those with disseminated cSS commonly manifest with cognitive impairment.

Acute infarcts cause focal thinning in remote cortex via degeneration of connecting fiber tracts.

OBJECTIVE: To study remote effects distant from acute ischemic infarcts by measuring longitudinal changes of cortical thickness in connected brain regions as well as changes in microstructural integrity in connecting fiber tracts. METHODS: Thirty-two patients (mean age 71 years) underwent a standardized protocol including multimodal MRI and clinical assessment both at stroke onset and 6 months after the event. Cortex connected to acute infarcts was identified by probabilistic diffusion tensor tractography starting from the acute lesion. Changes of cortical thickness were measured using the longitudinal stream of FreeSurfer. Microstructural damage in white matter tracts was assessed by changes of mean diffusivity. RESULTS: We found focal cortical thinning specifically in areas connected to acute infarcts (p < 0.001). Thinning was more pronounced in regions showing a high probability of connectivity to infarcts. Microstructural damage in white matter tracts connecting acute infarcts with distant cortex significantly correlated with thickness changes in that region (ρ = -0.39, p = 0.028). There was no indication of an influence of cavitation status or infarct etiology on the observed changes in cortex and white matter. CONCLUSIONS: These findings identify secondary degeneration of connected white matter tracts and remote cortex as key features of acute ischemic infarcts. Our observations may have implications for the understanding of structural and functional reorganization after stroke.

Cysteine-sparing CADASIL mutations in NOTCH3 show proaggregatory properties in vitro.

BACKGROUND AND PURPOSE: Mutations in NOTCH3 cause cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic cause of stroke and vascular dementia. Misfolding and aggregation of NOTCH3 proteins triggered by cysteine-affecting mutations are considered to be the key disease mechanisms. However, the significance of cysteine-sparing mutations is still debated. METHODS: We studied a family with inherited small vessel disease by standardized medical history, clinical examination, MRI, ultrastructural analysis of skin biopsies, and Sanger sequencing of all NOTCH3 exons. In addition, we performed in vitro characterization of NOTCH3 variants using recombinant protein fragments and a single-particle aggregation assay. RESULTS: We identified a novel cysteine-sparing NOTCH3 mutation (D80G) in 4 family members, which was absent in a healthy sibling. All mutation carriers exhibited a CADASIL typical brain imaging and clinical phenotype, whereas skin biopsy showed inconsistent results. In vitro aggregation behavior of the D80G mutant was similar compared with cysteine-affecting mutations. This was reproduced with cysteine-sparing mutations from previously reported families having a phenotype consistent with CADASIL. CONCLUSIONS: Our findings support the view that cysteine-sparing mutations, such as D80G, might cause CADASIL with a phenotype largely indistinguishable from cysteine mutations. The in vitro aggregation analysis of atypical NOTCH3 mutations offers novel insights into pathomechanisms and might represent a tool for estimating their clinical significance.