Publications by authors named "Eric Jouvent"

78 Publications

Brain magnetic resonance imaging lesion load at diagnosis, severity at onset and outcomes in Susac syndrome: A prospective cohort study.

Eur J Neurol 2021 Aug 12. Epub 2021 Aug 12.

Department of Internal Medecine, Hospital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France.

Background: Susac syndrome (SuS) is a rare occlusive microvessel disease of the brain, retina and inner ear. We aimed to determine whether brain lesion load at the acute phase predicts poor outcomes in SuS.

Methods: A prospective national cohort study was conducted from December 2012 to December 2019 in 20 centres in France. Patients included at the principal investigator's center with available brain magnetic resonance imaging (MRI) at diagnosis were analyzed. MRI was reviewed by an experienced neuroradiologist blinded to clinical status. The size, topography and number of hyperintense lesions on diffusion-weighted imaging (DWI-HL) were analyzed at diagnosis and during follow-up. Outcomes involved descriptive characteristics of patients at onset and last follow-up.

Results: Twenty-three patients (38.1 [18.8-56.5] years, 16 females) were prospectively studied. The triad (i.e., brain, eye and ear involvement) was complete at onset in 17 patients. Brain MRI was performed 1.1 (0.1-3.4) months after the first symptom. All patients had DWI-HL at the acute phase. Patients were separated into two groups according to the number of DWI-HL on first MRI: a first group of patients (n=15) displaying low brain lesion load (<50 DWI-HL per patient) and a second group of patients (n=8) displaying high brain lesion load (≥100 DWI-HL). The median follow-up was 57.9 (9.7-98) months. Clinical features, treatment, relapse rate, time to disappearance of DWI-HL, disabilities and professional outcome did not differ according to brain lesion load.

Conclusion: Brain lesion load assessed by DWI at the acute phase is not associated with risks of disability in SuS.
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http://dx.doi.org/10.1111/ene.15062DOI Listing
August 2021

Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Brain 2021 Jul 16. Epub 2021 Jul 16.

AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, France.

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known cerebral small vessel disease genes, including HTRA1, in 3,853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 messenger RNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases (gnomAD v3.1.1 (p = 3.12 x 10-17, OR = 21.9), TOPMed freeze 5 (p = 7.6 x 10-18, OR = 27.1) and 1000 Genomes (p = 1.5 x 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counseling.
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http://dx.doi.org/10.1093/brain/awab271DOI Listing
July 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

Editorial: Cerebral Small Vessel Diseases: From Vessel Alterations to Cortical Parenchymal Injury.

Front Neurol 2020 14;11:92. Epub 2020 Feb 14.

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

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http://dx.doi.org/10.3389/fneur.2020.00092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033488PMC
February 2020

Acute ischemic stroke in adolescents.

Neurology 2020 01 12;94(2):e158-e169. Epub 2019 Dec 12.

From the Stroke Units and Department of Neurology (T.R., N.L., C.D.), Hôpital Bicêtre, Le Kremlin Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris Saclay University; Department of Neurology (Y.B.), University Région Bourgogne, Hôpital de Dijon; Pediatric Neurology Unit (C.B.), Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre; Stroke Units and Department of Neurology (B.L.), Hôpital Foch, Suresnes; Department of Neurology (E.J.), Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris; Department of Neurology (F.P.), Hôpital Andre Mignot, Versailles; Department of Neurology (D.S.), Hôpital Sud Francilien, Evry; Department of Neurology (M.Z.), Hôpital Saint Joseph, Paris; Department of Neurology (S.C.), Hôpital Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris; Department of Neurology (C.L.), Hôpital Sainte Anne, Paris; Interventional Neuroradiology (L.S.), NEURI Centre, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre; French National Health Insurance (P.T.); and Pediatric Neurology Unit (M.K.), Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants malades, France.

Objective: Adolescence represents a transition period between childhood and adulthood, and only limited information exists about stroke characteristics in this population. Our aim was to describe the clinical and neuroradiologic features, etiologies, initial management, and outcome of ischemic stroke in adolescents.

Methods: This retrospective cohort study evaluated all consecutive patients 10 to 18 years with a first-ever ischemic stroke hospitalized between 2007 and 2017 in 10 French academic centers representing a population of ≈10 million. Extracted data from the national database served as validation.

Results: A total of 60 patients were included (53% male, median age 15.2 years). Diagnosis at first medical contact was misevaluated in 36%, more frequently in posterior than anterior circulation strokes (55% vs 20% respectively, odds ratio 4.8, 95% confidence interval 1.41-16.40, = 0.01). Recanalization treatment rate was high (n = 19, 32%): IV thrombolysis (17%), endovascular therapy (11.7%), or both IV and intra-arterial thrombolysis (3.3%); safety was good (only 1 asymptomatic hemorrhagic transformation). Despite thorough etiologic workup, 50% of strokes remained cryptogenic. The most common determined etiologies were cardioembolism (15%), vasculitis and autoimmune disorders (12%, occurring exclusively in female patients), and arterial dissections (10%, exclusively in male patients). Recurrent ischemic cerebrovascular events occurred in 12% (median follow-up 19 months). Recurrence rate was 50% in patients with identified vasculopathy but 0% after cryptogenic stroke. Functional outcome was favorable (Rankin Scale score 0-2 at day 90) in 80% of cases.

Conclusions: Ischemic strokes in adolescents harbor both pediatric and adult features, emphasizing the need for multidisciplinary collaboration in their management. Recanalization treatments appear feasible and safe.
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http://dx.doi.org/10.1212/WNL.0000000000008783DOI Listing
January 2020

Cognitive dysfunction and brain atrophy in Susac syndrome.

J Neurol 2020 Apr 11;267(4):994-1003. Epub 2019 Dec 11.

Department of Internal Medicine, APHP, Bichat Hospital, Paris, France.

Background: Susac syndrome is a very rare cerebral small vessel disease, which can leave patients with cognitive impairment. We aimed at evaluating processing speed slowing, executive dysfunction and apathy and their relationships with whole brain and callosal atrophy.

Methods: Patients with Susac syndrome included in a prospective observational cohort study were evaluated, while clinically steady-state, with standardized brain MRI and a neuropsychological battery specifically designed to capture minimal cognitive alterations in non-disabled young patients. Brain volume and corpus callosum area were measured using 3D-T1 sequences, repeatedly overtime. Relationships between neuropsychological data and brain volumetric measures obtained the same day were tested with linear regression while controlling for sex, age, level of education, scores of depression and of apathy.

Results: Nineteen patients aged 37.5 ± 10.5 years were included. Mean follow-up time was 2.6 ± 1.3 years (5.8 ± 2.2 evaluations). While Montreal Cognitive Assessment scores were 25.1 ± 3.6, processing speed slowing was obvious (Trail Making Test version A: 43.1 ± 16.2 s; version B: 95.5 ± 67.9 s; reaction time: 314.6 ± 79.6 ms). Brain and corpus callosum atrophy was striking. No relationship was found between cognitive performances and brain volume or corpus callosum area.

Conclusion: Patients with Susac syndrome show largely preserved global cognitive functions but important processing speed alterations. Although brain and corpus callosum area atrophy is prominent and evolving, we did not find any relationship with cognitive alterations, questioning the mechanisms underlying cognitive alterations in these patients.

Trial Registration: Clinical Trial Registration-URL: https://www.clinicaltrials.gov Unique Identifier: NCT01481662.
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http://dx.doi.org/10.1007/s00415-019-09664-8DOI Listing
April 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

Brain atrophy in cerebral small vessel diseases: Extent, consequences, technical limitations and perspectives: The HARNESS initiative.

J Cereb Blood Flow Metab 2020 02 20;40(2):231-245. Epub 2019 Nov 20.

Department of Neurology and Referral Center for Rare Vascular Diseases of the Brain and Retina (CERVCO), APHP, Lariboisière Hospital, Paris, DHU NeuroVasc, Univ Paris Diderot, and U1141 INSERM, France.

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http://dx.doi.org/10.1177/0271678X19888967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370623PMC
February 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

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

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

Harmonizing brain magnetic resonance imaging methods for vascular contributions to neurodegeneration.

Alzheimers Dement (Amst) 2019 Dec 26;11:191-204. Epub 2019 Feb 26.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.

Introduction: Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease.

Methods: Surveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis.

Results: A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository.

Conclusions: The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.
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http://dx.doi.org/10.1016/j.dadm.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396326PMC
December 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

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

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

Updates on Prevention of Hemorrhagic and Lacunar Strokes.

J Stroke 2018 May 31;20(2):167-179. Epub 2018 May 31.

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Intracerebral hemorrhage (ICH) and lacunar infarction (LI) are the major acute clinical manifestations of cerebral small vessel diseases (cSVDs). Hypertensive small vessel disease, cerebral amyloid angiopathy, and hereditary causes, such as Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), constitute the three common cSVD categories. Diagnosing the underlying vascular pathology in these patients is important because the risk and types of recurrent strokes show significant differences. Recent advances in our understanding of the cSVD-related radiological markers have improved our ability to stratify ICH risk in individual patients, which helps guide antithrombotic decisions. There are general good-practice measures for stroke prevention in patients with cSVD, such as optimal blood pressure and glycemic control, while individualized measures tailored for particular patients are often needed. Antithrombotic combinations and anticoagulants should be avoided in cSVD treatment, as they increase the risk of potentially fatal ICH without necessarily lowering LI risk in these patients. Even when indicated for a concurrent pathology, such as nonvalvular atrial fibrillation, nonpharmacological approaches should be considered in the presence of cSVD. More data are emerging regarding the presentation, clinical course, and diagnostic markers of hereditary cSVD, allowing accurate diagnosis, and therefore, guiding management of symptomatic patients. When suspicion for asymptomatic hereditary cSVD exists, the pros and cons of prescribing genetic testing should be discussed in detail in the absence of any curative treatment. Recent data regarding diagnosis, risk stratification, and specific preventive approaches for both sporadic and hereditary cSVDs are discussed in this review article.
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http://dx.doi.org/10.5853/jos.2018.00787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007298PMC
May 2018

Validation and Optimization of BIANCA for the Segmentation of Extensive White Matter Hyperintensities.

Neuroinformatics 2018 04;16(2):269-281

University Paris Diderot, Sorbonne Paris Cité, UMR-S 1161 INSERM, F-75205, Paris, France.

White matter hyperintensities (WMH) are a hallmark of small vessel diseases (SVD). Yet, no automated segmentation method is readily and widely used, especially in patients with extensive WMH where lesions are close to the cerebral cortex. BIANCA (Brain Intensity AbNormality Classification Algorithm) is a new fully automated, supervised method for WMH segmentation. In this study, we optimized and compared BIANCA against a reference method with manual editing in a cohort of patients with extensive WMH. This was achieved in two datasets: a clinical protocol with 90 patients having 2-dimensional FLAIR and an advanced protocol with 66 patients having 3-dimensional FLAIR. We first determined simultaneously which input modalities (FLAIR alone or FLAIR + T1) and which training sets were better compared to the reference. Three strategies for the selection of the threshold that is applied to the probabilistic output of BIANCA were then evaluated: chosen at the group level, based on Fazekas score or determined individually. Accuracy of the segmentation was assessed through measures of spatial agreement and volumetric correspondence with respect to reference segmentation. Based on all our tests, we identified multimodal inputs (FLAIR + T1), mixed WMH load training set and individual threshold selection as the best conditions to automatically segment WMH in our cohort. A median Dice similarity index of 0.80 (0.80) and an intraclass correlation coefficient of 0.97 (0.98) were obtained for the clinical (advanced) protocol. However, Bland-Altman plots identified a difference with the reference method that was linearly related to the total burden of WMH. Our results suggest that BIANCA is a reliable and fast segmentation method to extract masks of WMH in patients with extensive lesions.
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http://dx.doi.org/10.1007/s12021-018-9372-2DOI Listing
April 2018

Free water determines diffusion alterations and clinical status in cerebral small vessel disease.

Alzheimers Dement 2018 06 16;14(6):764-774. Epub 2018 Feb 16.

Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.

Introduction: Diffusion tensor imaging detects early tissue alterations in Alzheimer's disease and cerebral small vessel disease (SVD). However, the origin of diffusion alterations in SVD is largely unknown.

Methods: To gain further insight, we applied free water (FW) imaging to patients with genetically defined SVD (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL], n = 57), sporadic SVD (n = 444), and healthy controls (n = 28). We modeled freely diffusing water in the extracellular space (FW) and measures reflecting fiber structure (tissue compartment). We tested associations between these measures and clinical status (processing speed and disability).

Results: Diffusion alterations in SVD were mostly driven by increased FW and less by tissue compartment alterations. Among imaging markers, FW showed the strongest association with clinical status (R up to 34%, P < .0001). Findings were consistent across patients with CADASIL and sporadic SVD.

Discussion: Diffusion alterations and clinical status in SVD are largely determined by extracellular fluid increase rather than alterations of white matter fiber organization.
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http://dx.doi.org/10.1016/j.jalz.2017.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994358PMC
June 2018

Clinical correlates of longitudinal MRI changes in CADASIL.

J Cereb Blood Flow Metab 2019 07 5;39(7):1299-1305. Epub 2018 Feb 5.

1 INSERM, U1161 Paris, France.

Previous studies showed that various types of cerebral lesions, as assessed on MRI, largely contribute to the clinical severity of CADASIL. However, the clinical impact of longitudinal changes of classical markers of small vessel disease on conventional MRI has been only poorly investigated. One hundred sixty NOTCH3 mutation carriers (mean age ± SD, 49.8 ± 10.9 years) were followed over three years. Validated methods were used to determine the percent brain volume change (PBVC), number of incident lacunes, change of volume of white matter hyperintensities and change of number of cerebral microbleeds. Multivariable logistic regression analyses were performed to assess the independent association between changes of these MRI markers and incident clinical events. Mixed-effect multiple linear regression analyses were used to assess their association with changes of clinical scales. Over a mean period of 3.1 ± 0.2 years, incident lacunes are found independently associated with incident stroke and change of Trail Making Test Part B. PBVC is independently associated with all incident events and clinical scale changes except the modified Rankin Scale at three years. Our results suggest that, on conventional MRI, PBVC and the number of incident lacunes are the most sensitive and independent correlates of clinical worsening over three years in CADASIL.
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http://dx.doi.org/10.1177/0271678X18757875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668524PMC
July 2019

Arterial branching and basal ganglia lacunes: A study in pure small vessel disease.

Eur Stroke J 2017 Sep 7;2(3):264-271. Epub 2017 Jul 7.

Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, Scotland.

Introduction: Lacunes are defined morphologically by size and location, but radiological characteristics alone may be unable to distinguish small vessel disease aetiology from alternative mechanisms. We investigated the branching order of arterial vessels associated with basal ganglia lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in order to improve the understanding of their pathogenesis in pure cerebral small vessel disease.

Patients And Methods: Adults with a confirmed diagnosis of CADASIL were included. A pilot study was conducted in a Scottish CADASIL cohort. The Paris-Munich CADASIL cohort was used for independent validation. Lacunes identified on T1-weighted magnetic resonance imaging scans were registered to a standard brain template. A microangiographic template of the basal ganglia vasculature was automatically overlaid onto coronal slices, and raters estimated the vessel branching order related to each lacune.

Results: Of 179 lacunes, 150 (84%) were associated with third-order vessels. In 14 incident lacunes, 11 (79%) were associated with third-order vessels. In the pilot study, lacune volume was significantly lower in lacunes associated with third-order vessels (0.04 ml ± 0.04 ml) compared to second-order vessels (0.48 ± 0.16 ml;  < 0.001).

Discussion: In this study of CADASIL patients, most lacunes were small and associated with third-order vessel disease. This suggests that these are the vessels primarily affected in cerebral small vessel disease. Microangiographic template techniques could be used to further investigate in a general stroke population whether finding large lacunes originating from higher order vessels indicates an alternative cause of stroke.

Conclusion: Lacunes in pure small vessel disease are associated with the smallest vessels in the basal ganglia.
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http://dx.doi.org/10.1177/2396987317718450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454827PMC
September 2017

Cerebral Microbleeds and the Risk of Incident Ischemic Stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy).

Stroke 2017 10 25;48(10):2699-2703. Epub 2017 Aug 25.

From the University Paris Diderot, Sorbonne Paris Cité, INSERM, France (L.P., F.D.G., O.G., H.C., E.J.); Department of Neurology, APHP Lariboisière Hospital, Paris, France (L.P., F.D.G., O.G., H.C., E.J.); DHU NeuroVasc Sorbonne Paris Cité, France (L.P., F.D.G., O.G., H.C., E.J.); Department of Neurology (L.P.) and Laboratory of Functional Neurosciences (L.P.), University Hospital of Amiens, France (L.P.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University, Munich, Germany (M. Duering, M. Dichgans); and Munich Cluster of Systems Neurology, Germany (M. Dichgans).

Background And Purpose: Cerebral microbleeds are associated with an increased risk of intracerebral hemorrhage. Recent data suggest that microbleeds may also predict the risk of incident ischemic stroke. However, these results were observed in elderly individuals undertaking various medications and for whom causes of microbleeds and ischemic stroke may differ. We aimed to test the relationship between the presence of microbleeds and incident stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)-a severe monogenic small vessel disease known to be responsible for both highly prevalent microbleeds and a high incidence of ischemic stroke in young patients.

Methods: We assessed microbleeds on baseline MRI in all 378 patients from the Paris-Munich cohort study. Incident ischemic strokes were recorded during 54 months. Survival analyses were used to test the relationship between microbleeds and incident ischemic stroke.

Results: Three hundred sixty-nine patients (mean age, 51.4±11.4 years) were followed-up during a median time of 39 months (interquartile range, 19 months). The risk of incident ischemic stroke was higher in patients with microbleeds than in patients without (35.8% versus 19.6%, hazard ratio, 1.87; 95% confidence interval, 1.16-3.01; =0.009). These results persisted after adjustment for history of ischemic stroke, age, sex, vascular risk factors, and antiplatelet agents use (hazard ratio, 1.89; 95% confidence interval, 1.10-3.26; =0.02).

Conclusions: The presence of microbleeds is an independent risk marker of incident ischemic stroke in CADASIL, emphasizing the need to carefully interpret MRI data.
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http://dx.doi.org/10.1161/STROKEAHA.117.017839DOI Listing
October 2017

Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease.

J Cereb Blood Flow Metab 2018 09 17;38(9):1391-1417. Epub 2017 Aug 17.

10 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD.
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http://dx.doi.org/10.1177/0271678X17721830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125970PMC
September 2018

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

Stroke 2017 05 31;48(5):1404-1407. Epub 2017 Mar 31.

From the Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Germany (F.A.W., E.B., B.G., M.A., M.D., M.D.); Neurology Unit, Stroke Unit, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy (M.Z.); University Paris Diderot, Sorbonne Paris Cité, UMRS 1161 INSERM, France (E.J., H.C.); Hemorrhagic Stroke Research Program, Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston (A.V.); Department of Neurology, Medical University of Graz, Austria (S.R., R.S.); Klinik für Neurologie, SLK-Kliniken Heilbronn GmbH, Germany (C.O.); and Institut und Poliklinik für Neuroradiologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany (J.L.).

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.
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http://dx.doi.org/10.1161/STROKEAHA.117.016833DOI Listing
May 2017

Focal Macroscopic Cortical Lesions in Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Stroke 2017 05 27;48(5):1408-1411. Epub 2017 Mar 27.

From the Department of Neurology, AP-HP, Lariboisière Hospital, Paris, France (A.L.-I., H.C., E.J.); DHU NeuroVasc Sorbonne Paris Cité, France (A.L.I., F.D.G., H.C., E.J.); UNIACT, NeuroSpin, Gif-sur-Yvette, France (A.L.-I., E.J.); and University Paris Diderot, Sorbonne Paris Cité, UMR-S 1161 INSERM, France (F.D.G., H.C., E.J.).

Background And Purpose: Cortical microinfarcts and secondary cortical degeneration have been demonstrated in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a severe monogenic cerebral small vessel disease. The aim of this study was to determine whether focal macroscopic cortical lesions can be detected using a specific in vivo magnetic resonance imaging approach.

Methods: Three-dimensional T1 magnetic resonance imaging scans were obtained in 28 nondemented nondisabled CADASIL patients and 29 age- and sex-matched controls. The cortical mantle of patients and controls were extracted using Brainvisa by an experienced user and then evaluated during a dedicated reading session by a second reader after removing the white matter to stay blind to the clinical status. Thereafter, confirmed focal macroscopic cortical lesions were characterized using all available imaging data, including 7-T magnetic resonance imaging in some patients.

Results: Three focal macroscopic cortical lesions were confirmed in 3 of 28 patients (11%) but none in controls. All lesions were observed in the close vicinity of severe signal changes in the underlying white matter.

Conclusions: Focal macroscopic cortical lesions can be detected using specific magnetic resonance imaging approaches in CADASIL patients long before the end stage of the disorder. The underlying mechanisms and precise clinical consequences of these cortical changes still need to be determined.
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http://dx.doi.org/10.1161/STROKEAHA.116.015724DOI Listing
May 2017

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects.

BMC Med 2017 02 24;15(1):41. Epub 2017 Feb 24.

Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Viale Bracci 2, 53100, Siena, Italy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients.
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http://dx.doi.org/10.1186/s12916-017-0778-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324276PMC
February 2017

Different types of white matter hyperintensities in CADASIL: Insights from 7-Tesla MRI.

J Cereb Blood Flow Metab 2018 09 27;38(9):1654-1663. Epub 2017 Jan 27.

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

In Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), by contrast to sporadic cerebral small vessel disease related to age and hypertension, white matter hyperintensities (WMH) are frequently observed in the white matter of anterior temporal poles, external capsules, and superior frontal regions. Whether these WMH (specific WMH) differ from those observed in other white matter areas (nonspecific WMH) remains unknown. Twenty patients were scanned to compare specific and nonspecific WMH using high-resolution images and analyses of relaxation times (T1: longitudinal relaxation time and T2*: effective transversal relaxation time). Specific WMH were characterized by significantly longer T1 and T2* (T1: 2309 ± 120 ms versus 2145 ± 138 ms; T2*: 40 ± 5 ms versus 35 ± 5 ms, p < 0.001). These results were not explained by the presence of dilated perivascular spaces found in the close vicinity of specific WMH. They were not either explained by the normal regional variability of T1 and T2* in the white matter nor by systematic imaging artifacts as shown by the study of 17 age- and sex-matched healthy controls. Our results suggest large differences in water content between specific and nonspecific WMH in CADASIL, supporting that mechanisms underlying WMH may differ according to their location.
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http://dx.doi.org/10.1177/0271678X17690164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125962PMC
September 2018

Predictors and Clinical Impact of Incident Lacunes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Stroke 2017 02 29;48(2):283-289. Epub 2016 Dec 29.

From the Department of Neurology, GH Saint-Louis-Lariboisière, Assistance Publique des Hoôpitaux de Paris (APHP), Université Paris Denis Diderot and DHU NeuroVasc Sorbonne Paris-Citeé, Paris, France (F.D.G., E.J., D.H., O.G., H.C.); INSERM UMR 1161, Paris, France (Y.L., F.D.G., E.J., D.H., H.C.); Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China (Y.L.); Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University LMU, Munich, Germany (M. Duering, M. Dichgans); Munich Cluster for Systems Neurology (SyNergy), Munich, Germany (M. Dichgans); and German Center for Neurodegenerative Diseases (DZNE), Munich (M. Dichgans).

Background And Purpose: Previous studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy showed that accumulation of lacunes strongly relate to clinical severity. However, the potential predictors of incident lacunes and their clinical consequences over a short time frame have not been investigated. This study aimed to determine the predictors and clinical impact of such lesions in a large cohort of patients.

Methods: Two hundred and six NOTCH3 mutation carriers (mean age, 49.5±10.6 years) were followed up over 3 years. Incident lacunes were identified using difference imaging from 3-dimensional T1 images. Clinical events and change in different clinical scores such as the Mattis Dementia Rating Scale, Modified Rankin Scale, Barthel index, and time to complete part A and part B of Trail Making Test were recorded. Associations were analyzed with multivariable logistic regression analysis and ANCOVA.

Results: Over a mean period of 3.4±0.7 years, incident lacunes occurred in 51 of 206 patients. Both the number of lacunes (P<0.0001) and systolic blood pressure at baseline (P<0.01) were independent predictors of incident lacunes during follow-up. The results were still significant after excluding patients with systolic blood pressure >140 mm Hg. Incident lacunes were also associated with incident stroke and with change in time to complete Trail Making Test part B, initiation/perseveration subscale of the Mattis Dementia Rating Scale and Barthel Index over the study period.

Conclusions: Systolic blood pressure and the number of prevalent lacunes are independent predictors of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These lesions mainly impact executive performances and functional independence over 3 years.
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http://dx.doi.org/10.1161/STROKEAHA.116.015750DOI Listing
February 2017

Prediction of 3-year clinical course in CADASIL.

Neurology 2016 Oct 30;87(17):1787-1795. Epub 2016 Sep 30.

From UMR-S 1161 INSERM (E.J., F.D.G., D.H., H.C.), Sorbonne Paris Cité, University Paris Diderot; Department of Neurology (E.J., F.D.G., D.H., H.C.), AP-HP, Lariboisière Hospital, Paris; DHU NeuroVasc Sorbonne Paris Cité (E.J., F.D.G., D.H., H.C.); LNAO (E.D., F.H.-S., J.-F.M.), Neurospin, I2BM, CEA, Saclay, France; Institute for Stroke and Dementia Research, Klinikum der Universität München (M. Duering, M. Dichgans), Munich; Munich Cluster for Systems Neurology (SyNergy) (M. Dichgans), Munich; German Center for Neurodegenerative Diseases (DZNE) (M. Dichgans), Munich, Germany; and Department of Neurology (S.R., R.S.), Medical University of Graz, Austria.

Objective: To obtain simple models predicting disease evolution at 3 years for a given patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Methods: Based on data obtained in a prospective study of 236 patients, we built and validated models predicting, at the individual level, 3-year changes in Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (MDRS), Trail Making Test version B (TMTB), and modified Rankin Scale (mRS). These models were based on different sets of predictors obtained at baseline, including either clinical data (epidemiologic data and cardiovascular risk factors) or clinical data and quantitative MRI markers (volume of lacunes [LL], volume of white matter hyperintensities, normalized brain volume [BPF], number of microbleeds). The Bayesian information criterion (BIC) and the coefficient of determination (R) were used to determine models with the highest predictive ability and the lowest numbers of predictors.

Results: We obtained validated models with a demonstrated ability to predict, for a given patient, 3-year changes in MMSE, MDRS, TMTB, and mRS (R on independent samples: 0.22, 0.12, 0.09, and 0.17, respectively). In all cases, the best models according to R and BIC values included only the baseline values of the outcome, of BPF, and of LL. Inclusion of other potential predictors always led to a loss of generalizability.

Conclusions: The prediction of 3-year changes in MMSE, MDRS, TMTB, and mRS for a given patient with CADASIL can be obtained using simple models relying only on the initial values of the considered score, BPF, and LL.
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http://dx.doi.org/10.1212/WNL.0000000000003252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089530PMC
October 2016
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