Publications by authors named "Hugues Chabriat"

158 Publications

Cognitive impairment in patients with cerebrovascular disease: A white paper from the links between stroke ESO Dementia Committee.

Eur Stroke J 2021 Mar 28;6(1):5-17. Epub 2021 Feb 28.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, the Netherlands.

Purpose: Many daily-life clinical decisions in patients with cerebrovascular disease and cognitive impairment are complex. Evidence-based information sustaining these decisions is frequently lacking. The aim of this paper is to propose a practical clinical approach to cognitive impairments in patients with known cerebrovascular disease.

Methods: The document was produced by the Dementia Committee of the European Stroke Organisation (ESO), based on evidence from the literature where available and on the clinical experience of the Committee members. This paper was endorsed by the ESO.

Findings: Many patients with stroke or other cerebrovascular disease have cognitive impairment, but this is often not recognized. With improvement in acute stroke care, and with the ageing of populations, it is expected that more stroke survivors and more patients with cerebrovascular disease will need adequate management of cognitive impairment of vascular etiology. This document was conceived for the use of and for those clinicians involved in cerebrovascular disease, with specific and practical hints concerning diagnostic tools, cognitive impairment management and decision on some therapeutic options.Discussion and conclusions: It is essential to consider a possible cognitive deterioration in every patient who experiences a stroke. Neuropsychological evaluation should be adapted to the clinical status. Brain imaging is the most informative biomarker concerning prognosis. Treatment should always include adequate secondary prevention.
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http://dx.doi.org/10.1177/23969873211000258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995319PMC
March 2021

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

Lancet Neurol 2021 04 17;20(4):294-303. Epub 2021 Mar 17.

Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.

Methods: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602.

Findings: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models.

Interpretation: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted.

Funding: British Heart Foundation and Stroke Association.
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http://dx.doi.org/10.1016/S1474-4422(21)00024-7DOI Listing
April 2021

Vanishing White Matter Hyperintensities in CADASIL: A Case Report with Insight into Disease Mechanisms.

J Alzheimers Dis 2020 ;78(3):907-910

Université de Paris, Paris, France.

In a woman with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) followed for 15 years, we observed magnetic resonance imaging white matter hyperintensities that vanished in the anterior temporal poles while the brain volume decreased unexpectedly. These imaging changes were transient and detected when the patient was being treated by valproic acid for stabilizing mood disturbances. This intriguing case supports that mechanisms underlying white matter hyperintensities can vary from one brain area to another and that important modifications of water influx into the brain tissue might be involved in some imaging features of CADASIL.
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http://dx.doi.org/10.3233/JAD-201086DOI Listing
January 2020

Modeling the Cognitive Trajectory in CADASIL.

J Alzheimers Dis 2020 ;77(1):291-300

Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, Paris, France.

Background: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition.

Objective: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL.

Methods: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared.

Results: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity.

Conclusion: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies.
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http://dx.doi.org/10.3233/JAD-200310DOI Listing
January 2020

Carotid artery webs in embolic stroke of undetermined source with large intracranial vessel occlusion.

Int J Stroke 2020 Jun 9:1747493020929945. Epub 2020 Jun 9.

Department of Interventional Neuroradiology, Hôpital Lariboisière, University of Paris, Paris, France.

Background: Whether carotid artery web can be considered as a potential source of arterial thromboembolism in ischemic stroke remains uncertain.

Aims: In a large sample of individuals with large intracranial artery occlusion, we compared the prevalence of carotid artery webs between patients with and without embolic stroke of undetermined source.

Methods: In a single-center study of consecutive patients with anterior circulation ischemic stroke referred for mechanical thrombectomy, the presence of carotid artery web was systematically assessed by two independent readers. Thereafter, its prevalence was compared between patients with and without embolic stroke of undetermined source.

Results: Among 466 patients of whom 12% were considered to have had an embolic stroke of undetermined source, ipsilateral carotid artery web was detected in 1.9% (confidence interval 95% = 0.7-3.1). Ipsilateral carotid artery web was more frequent in embolic stroke of undetermined source than in the rest of the sample (10.7% (confidence interval 95% = 2.7-18.7] vs. 0.7% (0-1.5),  < 0.001). This difference remains significant after adjustment for sex, age, and vascular risk factor (odds ratio: 12.5 (2.1-72),  = 0.005) or after exclusion of patients with any other bulb wall thickening ( = 0.025). In contrast, the difference of prevalence of contralateral carotid artery web between the two groups did not reach statistical significance (2.4% vs. 1.9%,  = 0.6).

Conclusions: Our results suggest that the presence of a carotid artery web might be considered as a potential source of large intracranial artery embolism. Longitudinal studies are needed to assess the exact risk of recurrence associated with these lesions.
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http://dx.doi.org/10.1177/1747493020929945DOI Listing
June 2020

Refining endpoints for stroke recovery trials.

Lancet Neurol 2020 05;19(5):381-382

Department of Neurology, Lariboisière Hospital, Paris Diderot University and INSERM U1141, Paris, France.

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http://dx.doi.org/10.1016/S1474-4422(20)30101-0DOI Listing
May 2020

Labbé vein thrombosis.

Neuroradiology 2020 Aug 13;62(8):935-945. Epub 2020 Apr 13.

Department of Neurology, Assistance publique - University Hospitals Lariboisière-St-Louis-Fernand-Widal, APHP - Paris-Diderot University, Paris, France 2, rue Ambroise Paré, 75010, Paris, France.

Purpose: Evaluate the prevalence of Labbé vein thrombosis (LVT) and its liability for the lesions observed in the case of associated ipsilateral transverse sinus thrombosis (TST).

Methods: MRI findings of 58 consecutive patients (≥ 18 years) with acute LVT and TST (group 1) were compared with those of 149 patients with acute TST-no LVT (group 2) observed during the same period.

Results: The prevalence of LVT was 15.2%. Group 1: TST extended to sigmoid sinus in 94.8%, resulting in complete sinuses occlusion. Any lesion was observed in 81% within LV territory: swelling (n = 5, 8.6%), edema (n = 9; 15.5%), non-hemorrhagic Infarct (n = 1; 1.7%), multiple temporal lobe hemorrhages (n = 31; 53.5%), temporal lobe hematoma (n = 13; 22.4%), and pericerebral hemorrhages (n = 28; 50%). The hemorrhagic lesions were not related to dominant TST or to extensive venous thrombosis. There was a prevalence of left TST- LVT (n = 32; 55.2%) and a higher prevalence of hemorrhagic lesions in this subset (59.4%). Risk factors were also associated (p = 0.03). Group 2: the TST resulted in an occlusion of the TS: (i) complete (n = 16; 10.7%); (ii) incomplete (n = 97; 82.8%); and (iii) segmental, involving the TS before (n = 32; 21.5%) or after (n = 10; 6.7%) LV ending within the TS. No parenchymal/pericerebral lesions were associated.

Conclusion: This study shows a strong association between the following: (i) the extent of thrombosis in the TS and the presence of LVT (p < 0.0001), (ii) the concomitance of LVT-TST and the presence of lesions in the LV territory and at the temporo-frontal convexity, (iii) risk factors and group 1 (p = 0.03).
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http://dx.doi.org/10.1007/s00234-020-02396-xDOI Listing
August 2020

Incident cerebral lacunes: A review.

J Cereb Blood Flow Metab 2020 05 3;40(5):909-921. Epub 2020 Mar 3.

Department of Neurology, Groupe Hospitalier Saint-Louis-Lariboisière, Assistance Publique des Hôpitaux de Paris (APHP), Université Denis Diderot and DHU NeuroVasc Sorbonne Paris-Cité (INSERM U1161), Paris, France.

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http://dx.doi.org/10.1177/0271678X20908361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181083PMC
May 2020

Safety and efficacy of GABA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial.

Lancet Neurol 2020 03;19(3):226-233

Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address:

Background: S44819, a selective GABA α5 receptor antagonist, reduces tonic post-ischaemic inhibition of the peri-infarct cortex. S44819 improved stroke recovery in rodents and increased cortical excitability in a transcranial magnetic stimulation study in healthy volunteers. The Randomized Efficacy and Safety Trial of Oral GABA α5 antagonist S44819 after Recent ischemic Event (RESTORE BRAIN) aimed to evaluate the safety and efficacy of S44819 for enhancing clinical recovery of patients with ischaemic stroke.

Methods: RESTORE BRAIN was an international, randomised, double-blind, parallel-group, placebo-controlled, multicentre phase 2 trial that evaluated the safety and efficacy of oral S44189 in patients with recent ischaemic stroke. The study was done in specialised stroke units in 92 actively recruiting centres in 14 countries: ten were European countries (Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, and the UK) and four were non-European countries (Australia, Brazil, Canada, and South Korea). Patients aged 18-85 years with acute ischaemic stroke involving cerebral cortex (National Institute of Health Stroke Scale [NIHSS] score 7-20) without previous disability were eligible for inclusion. Participants were randomly assigned to receive 150 mg S44819 twice a day, 300 mg S44819 twice a day, or placebo twice a day by a balanced, non-adaptive randomisation method with a 1:1:1 ratio. Treatment randomisation and allocation were centralised via the interactive web response system using computer-generated random sequences with a block size of 3. Blinding of treatment was achieved by identical appearance and taste of all sachets. Patients, investigators and individuals involved in the analysis of the trial were masked to group assignment. The primary endpoint was the modified Rankin Scale (mRS) score 90 days from onset of treatment, evaluated by shift analysis (predefined main analysis) or by dichotomised analyses using 0-1 versus 2-6 and 0-2 versus 3-6 cutoffs (predefined secondary analysis). Secondary endpoints were the effects of S44819 on the NIHSS and Montreal Cognitive Assessment (MoCA) scores, time needed to complete parts A and B of the Trail Making Test, and the Barthel index. Efficacy analyses were done on all patients who received at least one dose of treatment and had at least one mRS score taken after day 5 (specifically, on or after day 30). Safety was compared across treatment groups for all patients who received at least one dose of treatment. The study was registered at ClinicalTrials.gov, NCT02877615.

Findings: Between Dec 19, 2016, and Nov 16, 2018, 585 patients were enrolled in the study. Of these, 197 (34%) were randomly assigned to receive 150 mg S44819 twice a day, 195 (33%) to receive 300 mg S44819 twice a day, and 193 (33%) to receive placebo twice a day. 189 (96%) of 197 patients in the 150 mg S44819 group, 188 (96%) of 195 patients in the 300 mg S44819 group, and 191 (99%) patients in the placebo group received at least one dose of treatment and had at least one mRS score taken after day 5, and were included in efficacy analyses. 195 (99%) of 197 patients in the 150 mg S44819 group, 194 (99%) of 195 patients in the 300 mg S44819 group, and 193 (100%) patients in the placebo group received at least one dose of treatment, and were included in safety analyses. The primary endpoint of mRS at day 90 did not differ between each of the two S44819 groups and the placebo group (OR 0·91 [95% CI 0·64-1·31]; p=0·80 for 150 mg S44819 compared with placebo and OR 1·17 [95% CI 0·81-1·67]; p=0·80 for 300 mg S44819 compared with placebo). Likewise, dichotomised mRS scores at day 90 (mRS 0-2 vs 3-6 or mRS 0-1 vs 2-6) did not differ between groups. Secondary endpoints did not reveal any significant group differences. The median NIHSS score at day 90 did not differ between groups (4 [IQR 2-8] in 150 mg S44819 group, 4 [2-7] in 300 mg S44819 group, and 4 [2-6] in placebo group), nor did the number of patients at day 90 with an NIHSS score of up to 5 (95 [61%] of 156 in 150 mg S44819 group, 106 [66%] of 161 in 300 mg S44819 group, and 104 [66%] of 157 in placebo group) versus more than 5 (61 [39%] in 150 mg S44819 group, 55 [34%] in 300 mg S44819 group, and 53 [34%] in placebo group). Likewise, the median MoCA score (22·0 [IQR 17·0-26·0] in 150 mg S44819 group, 23·0 [19·0-26·5] in 300 mg S44819 group, and 22·0 [17·0-26·0] in placebo group), time needed to complete parts A (50 s [IQR 42-68] in 150 mg S44819 group, 49 s [36-63] in 300 mg S44819 group, and 50 s [38-68] in placebo group) and B (107 s [81-144] in 150 mg S44819 group, 121 s [76-159] in 300 mg S44819 group, and 130 s [86-175] in placebo group) of the Trail Making Test, and the Barthel index (90 [IQR 60-100] in 150 mg S44819 group, 90 [70-100] in 300 mg S44819 group, and 90 [70-100] in placebo group) were similar in all groups. Number and type of adverse events were similar between the three groups. There were no drug-related adverse events and no drug-related deaths.

Interpretation: There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans.

Funding: Servier.
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http://dx.doi.org/10.1016/S1474-4422(20)30004-1DOI Listing
March 2020

Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event (RESTORE BRAIN study): a placebo controlled phase II study.

Trials 2020 Feb 3;21(1):136. Epub 2020 Feb 3.

Chair of Vascular Neurology, Dementia and Ageing Research, Department of Neurology, University Hospital Essen, Hufelandstraße 55, 45122, Essen, Germany.

Background: The GABA-α5 receptor antagonist S44819 is a promising candidate to enhance functional recovery after acute ischemic stroke (IS). S44819 is currently evaluated in this indication; RESTORE brain study started in Dec 2016 and was completed in March 2019.

Methods/design: The study is a 3-month international, randomized, double-blind, parallel group, placebo-controlled phase II multicentre study. Patients in 14 countries who suffered an IS leading to a moderate or severe deficit defined by NIHSS score ranging from 7 to 20 and are aged between 18 to 85 years are included between 3 and 8 days after the stroke onset. Approximately 580 patients are to be included. The primary objective of the study is to demonstrate the superiority of at least one of the two doses of S44819 (150 or 300 mg bid) compared to placebo on top of usual care on functional recovery measured with the modified Rankin scale at 3 months. Comparisons between two doses of S44819 and placebo are assessed with ordinal logistic regression evaluating the odds of shifting from one category to the next in the direction of a better outcome at day 90. Secondary objectives include the evaluation of S44819 effects on neurological examination using the National Institute of Health Stroke Scale total score, activities of daily living using the Barthel Index total score, and cognitive performance using the Montreal Cognitive Assessment scale total score and Trail Making Test times. Safety and tolerability of the two doses of S44819 will also be analyzed.

Discussion: The RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS.

Trial Registration: Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event, an international, multi-centre, randomized, double-blind placebo-controlled phase II study. ClinicalTrials.gov, NCT02877615; Eudract 2016-001005-16. Registered 24 August 2016.
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http://dx.doi.org/10.1186/s13063-020-4072-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998064PMC
February 2020

Covert Brain Infarcts: Look at Extra and Intracranial Vessels.

Authors:
Hugues Chabriat

Stroke 2020 01 26;51(1):2-3. Epub 2019 Nov 26.

From the Department of Neurology, Groupe Hospitalier Saint-Louis-Lariboisière, Assistance Publique des Hôpitaux de Paris (APHP), Université Denis Diderot and DHU NeuroVasc Sorbonne Paris-Cité (INSERM U1141), France.

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http://dx.doi.org/10.1161/STROKEAHA.119.027445DOI Listing
January 2020

Artery occlusion independently predicts unfavorable outcome in cervical artery dissection.

Neurology 2020 01 22;94(2):e170-e180. Epub 2019 Nov 22.

From the Department of Neurology and Stroke Center (C.T., G.M.D.M., A. Polymeris, H.G., L.H.B., S.T.E., P.L.), University Hospital Basel and University of Basel; Neurorehabilitation Unit (C.T., H.G., S.T.E.), University of Basel and University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, Basel, Switzerland; Departments of Neurology (C.G.-G., M.K.) and Vascular and Endovascular Surgery (C.G.-G.), Heidelberg University Hospital, Germany; Department of Neurology (B.G.S., U.F., H.S., M.A.), University Hospital Bern; Ospedale San Giovanni (B.G.S.), Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Department of Neurology (S.D.), Bordeaux University Hospital; Inserm U1219 (S.D.), Bordeaux; University of Bordeaux (S.D.), France; Department of Neurology (S.D.), Boston University School of Medicine, MA; Department of Clinical and Experimental Sciences (A.Pezzini.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (J.J.M.), University of Utah, Salt Lake City; Departments of Neurology and Public Health Sciences (A.M.S., B.B.W.), University of Virginia Health System, Charlottesville; Univ-Lille (D.L.), Inserm U1171, CHU Lille, France; Neuro Center (R.B.), Clinic Hirslanden, Zurich, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Centre Hospitalier Universitaire Dijon Bourgogne (Y.B.), EA7460, Pathophysiology and Epidemiology of Cardio-Cerebro-Vascular Diseases, University of Burgundy, Dijon, France; Department of Neurology (H.S.), University Hospital of Zurich, Switzerland; Stroke Theme (V.T.), Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Cerebrovascular Unit Fondazione IRCCS Istituto Neurologico Carlo Besta (A.B.), Milan, Italy; Swiss National Accident Insurance Institution (T.B.), Lucerne, Switzerland; Normandie Université (E.T.), Université Caen Normandie, Inserm U1037, Department of Neurology, CHU Caen Normandie; Department of Neurology (E.T.), CH Sainte-Anne, University Paris Descartes, France; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (H.C.), Lariboisière Hospital, Paris, France; Department of Neurology (T.T.), Sahlgrenska University Hospital; and Department of Clinical Neuroscience Institute for Neuroscience and Physiology (T.T.), Sahlgrenska Academy at University of Gothenburg, Sweden.

Objective: To assess the impact of dissected artery occlusion (DAO) on functional outcome and complications in patients with cervical artery dissection (CeAD).

Methods: We analyzed combined individual patient data from 3 multicenter cohorts of consecutive patients with CeAD (the Cervical Artery Dissection and Ischemic Stroke Patients [CADISP]-Plus consortium dataset). Patients with data on DAO and functional outcome were included. We compared patients with DAO to those without DAO. Primary outcome was favorable functional outcome (i.e., modified Rankin Scale [mRS] score 0-1) measured 3-6 months from baseline. Secondary outcomes included delayed cerebral ischemia, major hemorrhage, recurrent CeAD, and death. We performed univariate and multivariable binary logistic regression analyses and calculated odds ratios (OR) with 95% confidence intervals (CI), with adjustment for potential confounders.

Results: Of 2,148 patients (median age 45 years [interquartile range (IQR) 38-52], 43.6% women), 728 (33.9%) had DAO. Patients with DAO more frequently presented with cerebral ischemia (84.6% vs 58.5%, < 0.001). Patients with DAO were less likely to have favorable outcome when compared to patients without DAO (mRS 0-1: 59.6% vs 80.1%, < 0.001). After adjustment for age, sex, and initial stroke severity, DAO was independently associated with less favorable outcome (mRS 0-1: OR 0.65, CI 0.50-0.84, = 0.001). Delayed cerebral ischemia occurred more frequently in patients with DAO than in patients without DAO (4.5% vs 2.9%, = 0.059).

Conclusion: DAO independently predicts less favorable functional outcome in patients with CeAD. Further research on vessel patency, collateral status and effects of revascularization therapies particularly in patients with DAO is warranted.
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http://dx.doi.org/10.1212/WNL.0000000000008654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988986PMC
January 2020

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Lessons From Neuroimaging.

Stroke 2020 01 22;51(1):21-28. Epub 2019 Nov 22.

From the Department of Neurology and Referral Center for Rare Vascular Diseases of the Brain and Retina (CERVCO), APHP, Lariboisière Hospital, F-75475 Paris, France (E.J., H.C.).

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http://dx.doi.org/10.1161/STROKEAHA.119.024152DOI Listing
January 2020

Global Burden of Small Vessel Disease-Related Brain Changes on MRI Predicts Cognitive and Functional Decline.

Stroke 2020 01 8;51(1):170-178. Epub 2019 Nov 8.

From the Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital (H.J., H.M.L., S. Melkas, T.E.), Finland.

Background and Purpose- Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease-related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods- Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results- The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (<0.001 for global cognitive function, processing speed, executive functions, and memory and <0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on scores strongly predicted cognitive and functional outcomes (<0.001) even above the contribution of the individual brain changes. Conclusions- Global burden of small vessel disease-related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.
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http://dx.doi.org/10.1161/STROKEAHA.119.026170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924941PMC
January 2020

Cerebral Amyloid Angiopathy Related Inflammation With Prominent Meningeal Involvement. A Report of 2 Cases.

Front Neurol 2019 23;10:984. Epub 2019 Sep 23.

APHP, Lariboisière Hospital, Department of Neurology and DHU NeuroVasc Sorbonne Paris Cité, Paris, France.

Cerebral amyloid angiopathy related inflammation (CAA-RI) is a rare form of CAA characterized by subacute encephalitic symptoms (cognitive decline, seizures, focal deficits) associated with extensive and confluent white matter lesions co-localizing with lobar microbleeds on brain MRI. We report two cases of unusual CAA-RI mimicking meningoencephalitis but without typical brain lesions on FLAIR and T2 sequences. These 2 cases may extend the clinical spectrum of CAA-RI by suggesting the possible occurrence of quite purely meningeal forms of CAA-RI.
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http://dx.doi.org/10.3389/fneur.2019.00984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768005PMC
September 2019

Lamotrigine in the Prevention of Migraine With Aura: A Narrative Review.

Headache 2019 09 29;59(8):1187-1197. Epub 2019 Aug 29.

Neurology Department, DHU Neuro-Vasc, Hopital Lariboisière, Paris, France.

Background: Lamotrigine is not recommended in the prevention of migraine in general but some reports suggest that it might be effective for treating specifically migraine with aura (MA). This review aims to summarize the related data from the literature and to better understand this discrepancy.

Methods: All reports from the literature related to the use of lamotrigine in migraine with or without aura published prior to February 2019 found using PUBMED and the 2 keywords "migraine" AND "lamotrigine" were reviewed. Original studies, published in full, systematic reviews, and all case reports were synthetized. We also examined the risk profile, pharmacokinetics, and mode of action of lamotrigine in view of the presumed mechanism of MA.

Results: Lamotrigine was tested in different populations of migraineurs, but previous studies had small sample sizes (n < 35) and might not have been powered enough for detecting a potential benefit of lamotrigine in MA. Accumulating data suggest that the drug can reduce both the frequency and severity of aura symptoms in multiple conditions and is well tolerated.

Conclusion: Lamotrigine appears promising for treating attacks of MA and related clinical manifestations because of its high potential of efficacy, low-risk profile, and cost. Additional studies are needed for testing lamotrigine in patients with MA.
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http://dx.doi.org/10.1111/head.13615DOI Listing
September 2019

Alteration of the Cortex Shape as a Proxy of White Matter Swelling in Severe Cerebral Small Vessel Disease.

Front Neurol 2019 10;10:753. Epub 2019 Jul 10.

Université Paris Diderot, UMR-S 1161 INSERM, Paris, France.

CADASIL is a monogenic small vessel disease characterized by the accumulation of brain tissue lesions of microvascular origin leading to strokes and cognitive deficits. Both cortical and parenchymal alterations have been described using various MRI markers. However, relationships between cortical and subcortical alterations remain largely unexplored. While brain atrophy is a preponderant feature in cerebral small vessel disease, recent results in CADASIL suggest slightly larger brain volumes and increased white matter water content at early stages of the disease by comparison to controls. We hypothesized in this study that increased water content in gyral white matter balances expected brain atrophy. Direct white matter volume computation is challenging in these patients given widespread subcortical alterations. Instead, our approach was that a gyral white matter swelling would translate into a modification of the shape of cortical gyri. Our goal was then to assess the relationship between subcortical lesions and possible alteration of the cortex shape. More specifically, aims of this work were to assess 1) morphometric differences of the cortex shape between CADASIL patients and controls 2) the relationship between the cortex shape and the volume of white matter hyperintensities (WMH), a reflect of white matter alterations. Twenty-one patients at the early stage of the disease and 28 age- and sex-matched controls were included. Cortical surfaces were reconstructed from 3D-T1-weighted images. Folding power assessed from spectral analysis of gyrification and cortical morphometry using curvedness and shape index were computed as proxies of the cortex shape. Influence of segmentation errors were evaluated through the simulation of WMH in controls. As a result, patients had larger folding power and curvedness compared to controls. They also presented lower shape indices both related to sulci and gyri. In patients, the volume of WMH was associated with decreased gyral shape index. These results suggest that the cortex shape of CADASIL patients is different compared to controls and that the enlargement of gyri is related to the extent of white matter alterations. The study of the cortex shape might be another way to evaluate subcortical swelling or atrophy in various neurological disorders.
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http://dx.doi.org/10.3389/fneur.2019.00753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635831PMC
July 2019

Predictors of clinical or cerebral lesion progression in adult moyamoya angiopathy.

Neurology 2019 07 25;93(4):e388-e397. Epub 2019 Jun 25.

From the Referral Center for Rare Vascular Diseases of the Brain and Retina (CERVCO), Department of Neurology and DHU NeuroVasc (D.H., N.I.-A., C.R., O.G., H.C.), Department of Neuroradiology (M.A.L., J.P.G.), and Laboratoire de Génétique Moléculaire (E.T.L.), Hopital Lariboisiére, Department of Nuclear Medicine, Hopital Salpêtrière (M.O.H.), and Service de Biostatistique et Information Médicale, Hôpital Saint Louis (S.C.), Assistance Publique des Hôpitaux de Paris; INSERM U 1161 (D.H., E.T.L., H.C.) and UMR 1153 INSERM (S.C.), Université Paris 7 Diderot (E.T.L., H.C.), Sorbonne Paris Cité; Unité Neurovasculaire (L.C.), Hôpital Pierre-Paul-Riquet, Toulouse; Centre National de Référence de l'AVC de l'Enfant, Hôpital Universitaire Necker-Enfants Malades (M.K.), AP-HP; Sorbonne Paris Cité, Paris; and ECSTRA Team (Épidémiologie Clinique et Statistiques pour la Recherche en Santé) (S.C.), Paris, France.

Objective: To identify independent predictors of clinical or cerebral lesion progression in a large sample of adult patients with moyamoya angiopathy (MMA) prior to decisions regarding revascularization surgery.

Methods: Ninety participants (median age, 37.5 years) were assessed at baseline and followed for a median time of 42.8 months. Incident ischemic and hemorrhagic strokes, death, as well as any incident ischemic and hemorrhagic lesions on MRI were recorded. Multiple demographic, clinical, and cerebral imaging measures at baseline were considered as potential predictors of clinical or cerebral tissue change at follow-up. Data were analyzed based on the Andersen-Gill counting process model, followed by internal validation of the prediction model.

Results: Among multiple potential predictive measures considered in the analysis, Asian origin, a history of TIAs, and a reduction in hemodynamic reserve, as detected by imaging, were found to be significantly associated with an increased risk of combined clinical and imaging events. While the model estimated the risk of clinical or cerebral lesion progression to be approximately 0.5% per year when none of these factors was present, this risk exceeded 20% per year when all factors were present.

Conclusion: A simple combination of demographic, clinical, and cerebral perfusion imaging measures may aid in predicting the risk of incident stroke and cerebral lesion progression in adult patients with MMA. These results may help to improve therapeutic decisions and aid in the design of future trials in adults with this rare condition.
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http://dx.doi.org/10.1212/WNL.0000000000007819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669931PMC
July 2019

Intracranial Extension of Extracranial Vertebral Dissection Is Associated With an Increased Risk of Ischemic Events.

Stroke 2019 08 21;50(8):2231-2233. Epub 2019 Jun 21.

Cognitive Neurology Center, Lariboisière Hospital, Paris, France (E.C.).

Background and Purpose- Intracranial artery dissection can eventually lead to subarachnoid or intracerebral hemorrhage. Little is known about the clinical features and risks associated with extracranial vertebral artery dissection that extends intracranially. The clinical and imaging characteristics of extracranial vertebral artery dissection (eVAD) with (e+iVAD) or without (eVAD) intracranial extension were analyzed. Methods- The frequency of ischemic events, including ischemic strokes and transient ischemic attacks, was compared between e+iVAD and eVAD patients from a monocentric cohort study. Results- Among 328 patients with cervical artery dissection, vertebral artery dissection was diagnosed in 153 individuals. Twenty-nine patients had e+iVAD (19%) and 124 patients had only eVAD (81%). Cardiovascular risk factors did not differ between these 2 groups, but ischemic events were more frequent in patients with e+iVAD than in patients with eVAD (86% versus 48%, P=0.0002). Subarachnoid hemorrhage occurred in 1 patient with e+iVAD and in 9 with eVAD (6% versus 3%, P=0.53). Intracranial extension was an independent factor associated with ischemic stroke at admission (odds ratio, 6.43; 95% CI, -1.96 to 21.08; P=0.002) after adjustment for cardiovascular risk factors and imaging findings. Conclusions- In a large cohort of patients with vertebral artery dissection, intracranial extension of the vessel dissection appears associated with an increased risk of ischemic stroke.
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http://dx.doi.org/10.1161/STROKEAHA.119.025227DOI Listing
August 2019

Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

Lancet Neurol 2019 07 23;18(7):653-665. Epub 2019 May 23.

Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke.

Methods: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602.

Findings: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82-3·29) for intracranial haemorrhage and 1·23 (1·08-1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08-6·72] for intracranial haemorrhage vs 1·47 [1·19-1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36-9·05] vs 1·43 [1·07-1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69-15·81] vs 1·86 [1·23-1·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years).

Interpretation: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden.

Funding: British Heart Foundation and UK Stroke Association.
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http://dx.doi.org/10.1016/S1474-4422(19)30197-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562236PMC
July 2019

Correction: The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant.

Genet Med 2019 Aug;21(8):1895

CADASIL Research Group, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

This Article was originally published under Nature Research's License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the Article have been modified accordingly.
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http://dx.doi.org/10.1038/s41436-018-0306-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608265PMC
August 2019

Increased PKR level in human CADASIL brains.

Virchows Arch 2018 Dec 2;473(6):771-774. Epub 2018 Aug 2.

INSERM U942, Paris, France.

Cerebral autosomal dominant arteriolopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common form of hereditary small vessel disease (SVD) of the brain. Neuronal apoptosis has been demonstrated in the cortex of patients. Whether it is associated with an activation of the pro-apoptotic protein PKR pathway is unknown. Similarly, activation of autophagy in CADASIL has never been explored. Immunostaining of four CADASIL brains previously analyzed for cortical neuronal apoptosis and five control brains for PKR (phosphoPKR) and autophagy (ATG5, LC3II) activation markers. Significant nuclear pPKR staining was observed in CADASIL neurons comparatively to controls (p = 0.001). No difference was observed between patients and controls with autophagy markers. We demonstrated the activation of PKR pathway in CADASIL. This was not associated with a detectable modulation of autophagy. These results open a new field to explore in order to better understand the mechanisms underlying cortical neurons apoptosis.
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http://dx.doi.org/10.1007/s00428-018-2425-yDOI Listing
December 2018

Determinants and outcome of multiple and early recurrent cervical artery dissections.

Neurology 2018 08 1;91(8):e769-e780. Epub 2018 Aug 1.

From the Department of Neuro-oncology (A.C.), Netherlands Cancer Institute/Antoni van Leeuwenhoek; Department of Neurology (A.C.), MC Slotervaart, Amsterdam, the Netherlands; University of Bordeaux (S.S., S.D.); Bordeaux Population Health (S.S., S.D.), INSERM Center U1219, France; Department of Neurology (C.J.V., B.G.-S., H.S., S.J., U.F., M.A.), University Hospital Inselspital and University of Bern; Division of Neuropediatrics (B.G.-S.), San Giovanni Hospital Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Departments of Neurology and Public Health Sciences (A.S., B.B.W.), University of Virginia, Charlottesville; Department of Clinical and Experimental Sciences (A.P.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (M.K., C.G.-G., C.L.), Heidelberg University Hospital, Germany; Normandie Université (E.T.), Unicaen, CHU Caen, Inserm U1237; Université Paris Descartes (E.T.), CH Ste Anne, Inserm U894, Paris, France; Stroke Division (V.T.), Florey Institute for Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (Y.B.), Dijon University Hospital; Department of Neurology (P.R., H.C., M.-G.B.), Lariboisière Hospital, Paris 7 University, DHU Neurovasc Sorbonne Paris Cité, France; Cerebrovascular Unit (A.B.), IRCCS Foundation C. Besta Neurological Institute, Milan, Italy; Suva/Swiss National Accident Insurance Fund (T.B.), Lucerne, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Department of Neurology and Stroke Center (P.A.L., C.T., S.T.E.), Department of Clinical Research, University Hospital and University of Basel, Switzerland; Neurology Clinic (C.L.), Memmingen Hospital, Germany; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (D.L.), Lille University, INSERM U1171, France; NeuroCentre (R.W.B.), Clinic Hirslanden Zürich, Switzerland; Neurorehabilitation Unit (S.T.E.), University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, University of Basel, Switzerland; INSERM 1176 (J.D.), Institut Pasteur de Lille, France; Department of Clinical Neuroscience (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology (T.T.), Sahlgrenska University Hospital, Gothenburg, Sweden; and Department of Neurology-Memory Clinic (S.D.), Bordeaux University Hospital, France.

Objective: To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD).

Methods: We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed.

Results: Of 1,958 patients with CeAD (mean ± SD age 44.3 ± 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) had multiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29-2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34-2.46), family history of stroke (OR 1.55, 95% CI 1.06-2.25), cervical pain (OR 1.36, 95% CI 1.01-1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01-8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients with multiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49-5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD.

Conclusion: Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.
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http://dx.doi.org/10.1212/WNL.0000000000006037DOI Listing
August 2018

Different Types of White Matter Hyperintensities in CADASIL.

Front Neurol 2018 10;9:526. Epub 2018 Jul 10.

UMR-S 1161 INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), white matter hyperintensities (WMH) are considered to result from hypoperfusion. We hypothesized that in fact the burden of WMH results from the combination of several regional populations of WMH with different mechanisms and clinical consequences. To identify regional WMH populations, we used a 4-step approach. First, we used an unsupervised principal component algorithm to determine, without a priori knowledge, the main sources of variation of the global spatial pattern of WMH. Thereafter, to determine whether these sources are likely to include relevant information regarding regional populations of WMH, we tested their relationships with: (1) MRI markers of the disease; (2) the clinical severity assessed by the Mattis Dementia Rating scale (MDRS) (cognitive outcome) and the modified Rankin's score (disability outcome). Finally, through careful interpretation of all the results, we tried to identify different regional populations of WMH. The unsupervised principal component algorithm identified 3 main sources of variation of the global spatial pattern of WMH, which showed significant and sometime inverse relationships with MRI markers and clinical scores. The models predicting clinical severity based on these sources outperformed those evaluating WMH by their volume (MDRS, coefficient of determination of 39.0 vs. 35.3%, = 0.01; modified Rankin's score, 43.7 vs. 38.1%, = 0.001). By carefully interpreting the visual aspect of these sources as well as their relationships with MRI markers and clinical severity, we found strong arguments supporting the existence of different regional populations of WMH. For instance, in multivariate analyses, larger extents of WMH in anterior temporal poles and superior frontal gyri were associated with better outcomes, while larger extents of WMH in pyramidal tracts were associated with worse outcomes, which could not be explained if WMH in these different areas shared the same mechanisms. The results of the present study support the hypothesis that the whole extent of WMH results from a combination of different regional populations of WMH, some of which are associated, for yet undetermined reasons, with milder forms of the disease.
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http://dx.doi.org/10.3389/fneur.2018.00526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048276PMC
July 2018

The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant.

Genet Med 2019 03 22;21(3):676-682. Epub 2018 Jul 22.

CADASIL Research Group, Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Purpose: CADASIL is a small-vessel disease caused by a cysteine-altering pathogenic variant in one of the 34 epidermal growth factor-like repeat (EGFr) domains of the NOTCH3 protein. We recently found that pathogenic variant in EGFr domains 7-34 have an unexpectedly high frequency in the general population (1:300). We hypothesized that EGFr 7-34 pathogenic variant more frequently cause a much milder phenotype, thereby explaining an important part of CADASIL disease variability.

Methods: Age at first stroke, survival and white matter hyperintensity volume were compared between 664 CADASIL patients with either a NOTCH3 EGFr 1-6 pathogenic variant or an EGFr 7-34 pathogenic variant. The frequencies of NOTCH3 EGFr 1-6 and EGFr 7-34 pathogenic variant were compared between individuals in the genome  Aggregation Database and CADASIL patients.

Results: CADASIL patients with an EGFr 1-6 pathogenic variant have a 12-year earlier onset of stroke than those with an EGFr 7-34 pathogenic variant, lower survival, and higher white matter hyperintensity volumes. Among diagnosed CADASIL patients, 70% have an EGFr 1-6 pathogenic variant, whereas EGFr 7-34 pathogenic variant strongly predominate in the population.

Conclusion: NOTCH3 pathogenic variant position is the most important determinant of CADASIL disease severity, with EGFr 7-34 pathogenic variant predisposing to a later onset of stroke and longer survival.
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http://dx.doi.org/10.1038/s41436-018-0088-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752295PMC
March 2019

Altered dynamics of neurovascular coupling in CADASIL.

Ann Clin Transl Neurol 2018 Jul 21;5(7):788-802. Epub 2018 May 21.

Sorbonne Paris Cité Inserm UMR1161 Université Denis Diderot Paris VII Paris France.

Background And Objective: Neurovascular coupling is the complex biological process that underlies use-dependent increases in blood flow in response to neural activation. Neurovascular coupling was investigated at the early stage of CADASIL, a genetic paradigm of ischemic small vessel disease.

Methods: Functional hyperemia and evoked potentials during 20- and 40-sec visual and motor stimulations were monitored simultaneously using arterial spin labeling-functional magnetic resonance imaging (ASL-fMRI) and electroencephalography.

Results: Cortical functional hyperemia differed significantly between 19 patients and 19 healthy individuals, whereas evoked potentials were unaltered. Functional hyperemia dynamics, assessed using the difference in the slope of the response curve between 15 and 30 sec, showed a time-shifted decrease in the response to 40-sec neural stimulations in CADASIL patients. These results were replicated in a second cohort of 10 patients and 10 controls and confirmed in the whole population.

Interpretation: Alterations of neurovascular coupling occur early in CADASIL and can be assessed by ASL-fMRI using a simple marker of vascular dysfunction.
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http://dx.doi.org/10.1002/acn3.574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043774PMC
July 2018

Why Are Only Some Subcortical Ischemic Lesions on Diffusion Magnetic Resonance Imaging Associated With Stroke Symptoms in Small Vessel Disease?

Stroke 2018 08;49(8):1920-1923

From the Department of Neurology, APHP, Lariboisière Hospital, Paris, France (O.O., H.C., E.J.).

Background and Purpose- In cerebral small vessel diseases, small subcortical ischemic lesions (SSIL) on diffusion imaging are responsible for stroke manifestations but can also be occasionally observed in the absence of overt neurological symptoms. We aimed to determine, in a large cohort of young patients with CADASIL (Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic condition leading to SSIL in young patients, the characteristics of SSIL and of surrounding cerebral tissue associated with the presence of stroke symptoms. Methods- Among a cohort of 323 genetically confirmed CADASIL patients who were systematically evaluated every 18 months clinically and with magnetic resonance imaging, we studied all visible SSIL and documented ischemic stroke events with available magnetic resonance imaging data. We used mixed-effect logistic regression models to determine whether the presence of stroke symptoms was associated with age, sex, the volume of SSIL, their location with respect to preexisting white matter hyperintensities and with the load of the different magnetic resonance imaging markers of small vessel disease. Results- We identified 73 SSIL (30 with stroke symptoms and 43 without) in 55 patients. In multivariable models, stroke symptoms were more frequent in male patients (estimate=1.94; SE=0.82; P=0.03) and less frequent when SSIL appeared in contact to preexisting white matter hyperintensities (estimate=-2.12; SE=0.83; P=0.01). Within pyramidal tracts, stroke symptoms were more frequent in patients with extensive white matter hyperintensities (estimate=3.8×10; SE=9.3×10; P<10). Conclusions- Altogether, our results suggest that when SSIL occur, the presence of stroke symptoms may depend on sex and alterations of the surrounding brain tissue rather than on the characteristics of the SSIL itself.
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http://dx.doi.org/10.1161/STROKEAHA.118.021342DOI Listing
August 2018

Distribution of Cerebrospinal Fluid Biomarker Profiles in Patients Explored for Cognitive Disorders.

J Alzheimers Dis 2018 ;64(3):889-897

Background: CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies.

Objective: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders.

Methods: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults.

Results: 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations.

Conclusions: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.
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http://dx.doi.org/10.3233/JAD-180240DOI Listing
July 2019

Optical Coherence Tomography Angiography of Familial Retinal Arteriolar Tortuosity.

Ophthalmic Surg Lasers Imaging Retina 2018 06;49(6):397-401

Background And Objective: To analyze the location of familial retinal arterial tortuosity (fRAT) in the three-dimensional structure of retinal capillaries.

Patients And Methods: Retrospective observational study. Twelve eyes of six patients (two of whom were brothers) were imaged by optical coherence tomography angiography (OCTA). The data from their ocular and systemic examinations were recorded.

Results: OCTA imaging clearly showed increased tortuosity of second- and third-order retinal arteries in all cases, visible in the superficial vascular plexus (SVP) up to the arteriole termination in the capillaries. No change was visible in the deep capillary plexus (DCP).

Conclusions: OCTA shows that fRAT affects all the course of the arterioles up to the capillaries in the SVP. The DCP does not show arteriolar tortuosity because it does not contain arterioles. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:397-401.].
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http://dx.doi.org/10.3928/23258160-20180601-03DOI Listing
June 2018