Characterization of retinal arteries by adaptive optics ophthalmoscopy image analysis.

OBJECTIVE: This paper aims at quantifying biomarkers from the segmentation of retinal arteries in adaptive optics ophthalmoscopy images (AOO). METHODS: The segmentation is based on the combination of deep learning and knowledge-driven deformable models to achieve a precise segmentation of the vessel walls, with a specific attention to bifurcations. Biomarkers (junction coefficient, branching coefficient, wall to lumen ratio (wlr) are derived from the resulting segmentation. RESULTS: reliable and accurate segmentations (mse = 1.75 ± 1.24 pixel) and measurements are obtained, with high reproducibility with respect to images acquisition and users, and without bias. SIGNIFICANCE: In a preliminary clinical study of patients with a genetic small vessel disease, some of them with vascular risk factors, an increased wlr was found in comparison to a control population. CONCLUSION: The wlr estimated in AOO images with our method (AOV, Adaptive Optics Vessel analysis) seems to be a very robust biomarker as long as the wall is well contrasted.

Psychological impact of COVID-19 containment on CADASIL patients.

INTRODUCTION: COVID-19 restrictive containment was responsible for major psychological distress and alteration of quality of life (QoL) in the general population. Their impact in a group of patients having cerebral small vessel disease (SVD) and at high risk of stroke and disability was unknown. OBJECTIVE: We aimed to determine the potential psychological impact of strict containment during the COVID-19 pandemic in a sample of CADASIL patients, a rare SVD caused by NOTCH3 gene mutations. METHODS: Interviews of 135 CADASIL patients were obtained just after the end of the strict containment in France. Depression, QoL and negative subjective experience of the containment were analysed, as well as predictors of posttraumatic and stressor-related manifestations, defined as an Impact Event Scale-Revised score ≥ 24, using multivariable logistic analysis. RESULTS: Only 9% of patients showed a depressive episode. A similar proportion had significant posttraumatic and stressor-related disorder manifestations independently associated only with socio-environment factors, rather than clinical ones: living alone outside a couple (OR 7.86 (1.87-38.32), unemployment (OR 4.73 (1.17-18.70)) and the presence of 2 or more children at home (OR 6.34 (1.35-38.34). CONCLUSION: Psychological impact of the containment was limited in CADASIL patients and did not appear related to the disease status. About 9% of patients presented with significant posttraumatic and stressor-related disorder manifestations which were predicted by living alone, unemployment, or exhaustion related to parental burden.

The Epidermal Growth Factor Domain of the Mutation Does Not Appear to Influence Disease Progression in CADASIL When Brain Volume and Sex Are Taken into Account.

BACKGROUND AND PURPOSE: By studying the evolution of brain volume across the life span in male and female patients, we aimed to understand how sex, brain volume, and the epidermal growth factor repeat domain of the mutation, the 3 major determinants of disability in CADASIL, interact in driving disease evolution. MATERIALS AND METHODS: We used validated methods to model the evolution of normalized brain volume with age in male and female patients using nonparametric regression in a large, monocentric cohort with prospectively collected clinical and high-resolution MR imaging data. We used k-means clustering to test for the presence of different clinical course profiles. RESULTS: We included 229 patients (mean age, 53 [SD, 12] years; 130 women). Brain volume was larger in women (mean size, 1024 [SD, 62] cm3 versus 979 [SD, 50] cm3; P < .001) and decreased regularly. In men, the relationship between brain volume and age unexpectedly suggested an increase in brain volume around midlife. Cluster analyses showed that this finding was related to the presence of a group of older male patients with milder symptoms and larger brain volumes, similar to findings of age-matched women. This group did not show specific epidermal growth factor repeat domain distribution. CONCLUSIONS: Our results demonstrate a detrimental effect of male sex on brain volume throughout life in CADASIL. We identified a subgroup of male patients whose brain volume and clinical outcomes were similar to those of age-matched women. They did not have a specific distribution of the epidermal growth factor repeat domain, suggesting that yet-unidentified predictors may interact with sex and brain volume in driving disease evolution.

Heritable and non-heritable uncommon causes of stroke.

Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.

CADASIL: yesterday, today, tomorrow.

BACKGROUND AND PURPOSE: In 2019, the Brain Prize crowned the discovery of CADASIL in the 1990s and research efforts on this archetypal small vessel disease of the brain over 40 years. METHODS AND RESULTS: The hereditary origin of this arteriolopathy was discovered from a first clinical case and detailed observation of the patient's family. Thereafter, the role of causative mutations within the NOTCH3 gene were identified, allowing the development of a genetic test and then of an animal model of the disease. These crucial steps led to the discovery progressively that CADASIL is the most common genetic cerebral small vessel disease, to describing for the first time the natural history of a cerebral ischaemic small vessel disease from silent cerebral tissue lesions up to severe motor disability and dementia at the end stage, to demonstrating the central role of matrix proteins in its pathophysiology and to opening the door to the discovery of several other genes involved in monogenic cerebral small vessel diseases. DISCUSSION: Today, CADASIL is known to every neurologist, but the disease has not yet revealed all its secrets. A lot of effort is still needed to understand the intimate mechanisms of the disease and the most efficient targets or approaches for the development of efficient therapeutics. The history of CADASIL will be further enriched by multiple ongoing research projects worldwide, at clinical and preclinical level, and will continue to enlighten research in the field of cerebral small vessel disorders.

Imaging of the aging brain and development of MRI signal abnormalities.

Major changes occur at the cerebral level with aging. Cerebral atrophy develops progressively. Multiple lesions related to small-vessel diseases are detected in association with cerebral atrophy including white-matter hyperintensities, lacunes, microbleeds, dilated perivascular spaces and cerebral, including cortex, atrophy. The clinical impact and predictive value of these Imaging makers were examined.

Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology.

BACKGROUND AND PURPOSE: Guidelines on monogenic cerebral small-vessel disease (cSVD) diagnosis and management are lacking. Endorsed by the Stroke and Neurogenetics Panels of the European Academy of Neurology, a group of experts has provided recommendations on selected monogenic cSVDs, i.e. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), autosomal dominant High Temperature Requirement A Serine Peptidase 1 (HTRA1), cathepsin-A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), Fabry disease, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and type IV collagen (COL4)A1/2. METHODS: We followed the Delphi methodology to provide recommendations on several unanswered questions related to monogenic cSVD, including genetic testing, clinical and neuroradiological diagnosis, and management. RESULTS: We have proposed 'red-flag' features suggestive of a monogenic disease. General principles applying to the management of all cSVDs and specific recommendations for the individual forms of monogenic cSVD were agreed by consensus. CONCLUSIONS: The results provide a framework for clinicians involved in the diagnosis and management of monogenic cSVD. Further multicentre observational and treatment studies are still needed to increase the level of evidence supporting our recommendations.

Clinical features related to CSF level of amyloid Aß42 and Aß40 proteins in presence of lobar microbleeds.

In presence of lobar microbleeds, the exact clinical features related to the level of Aß42, Aß40 and to the Aß40/Aß42 ratio in the cerebrospinal fluid (CSF) are poorly known. We analyzed in 28 consecutive patients with such lesions, whose clinical or additional magnetic resonance imaging features are related to these biomarkers. The results showed that the presence of absence of hypertension, the extent or the antero-posterior distribution of white matter hyperintensities, the presence or absence of vascular lesions in the deepest parts of the brain, and the presence of dementia are related to variations of Aß42, Aß40 or of the Aß40/Aß42 ratio in the cerebrospinal fluid.

Leukoencephalopathy with calcifications and cysts (LCC): 5 cases and literature review.

INTRODUCTION: Leukoencephalopathy with calcifications and cysts (LCC) is a rare autosomal recessive cerebral angiomatous-like microangiopathy characterized by diffuse and asymmetric white-matter lesions associated with multiple calcifications and cysts. The disease is caused by SNORD118 mutations. The entire clinical spectrum of LCC is not yet fully determined. MATERIAL AND METHODS: To define the clinical spectrum of LCC, we analyzed data from recently diagnosed cases and from the litterature. Both clinical and imaging features from our five LCC cases harboring compound heterozygous SNORD118 mutations were presented and all cases reported in the litterature reviewed. RESULTS: Ninety-two LCC cases including our five patients were identified. Consanguinity was rare (4%), and 97% of cases were symptomatic. Mean age of first clinical manifestations was 16.1±16.1 years (range 1 month-71 years) and was earlier in men (10.3±14.3 years) than in women (20.2±22.8 years) (P=0.02). The main inaugural symptoms were seizures (36%; mean age at onset: 5.2±9.5 years) and progressive neurological symptoms including ataxia, dystonia and spasticity (26%; 27.8±23.6 years). Intracranial hypertension was less frequently observed (14%), mostly in adults (mean age 31.5±13.2 years). Ischemic or hemorrhagic strokes were inaugural symptoms in two adults (2%). During follow-up, most patients developed progressive extrapyramidal, cerebellar and pyramidal signs (83%), cognitive decline (56%), seizures (37%), intracranial hypertension (30%) or stroke (2%). CONCLUSION: In LCC, the clinical spectrum is largely heterogeneous and the course of the disease appears highly variable in contrast to other hereditary cerebral small vessel diseases.

Can anticoagulation therapy in cerebral venous thrombosis associated with Behçet's disease be stopped without relapse?

There is as yet no consensus on the treatment of cerebral venous thrombosis (CVT) in Behçet's disease, and the place of anticoagulation is also still being debated. This report is of a series of seven patients with Behçet's disease (BD)-associated CVT, for which anticoagulation was stopped, and discusses the possibility of stopping anticoagulation during follow-up while receiving optimal treatment for BD. The diagnosis of BD was established during follow-up, which lasted a median of 120 [range: 60-1490] days after CVT diagnosis. The median duration of anticoagulation therapy was 29.5 months. On stopping anticoagulation, concomitant treatment then included colchicine, steroids and azathioprine, all introduced after BD was diagnosed. With a median follow-up of 25 months after anticoagulation interruption, only one relapse of CVT was observed. No relapse of CVT or other venous thrombosis was observed in the six patients treated by steroids associated with an immunosuppressant or colchicine. Our results emphasize that corticosteroids are essential for the treatment of BD-associated CVT, and that anticoagulant therapy may be safely stopped during follow-up in the presence of optimal BD treatment (steroids alone or with immunosuppressive drugs).

Reaction Time Is Negatively Associated with Corpus Callosum Area in the Early Stages of CADASIL.

BACKGROUND AND PURPOSE: Reaction time was recently recognized as a marker of subtle cognitive and behavioral alterations in the early clinical stages of CADASIL, a monogenic cerebral small-vessel disease. In unselected patients with CADASIL, brain atrophy and lacunes are the main imaging correlates of disease severity, but MR imaging correlates of reaction time in mildly affected patients are unknown. We hypothesized that reaction time is independently associated with the corpus callosum area in the early clinical stages of CADASIL. MATERIALS AND METHODS: Twenty-six patients with CADASIL without dementia (Mini-Mental State Examination score > 24 and no cognitive symptoms) and without disability (modified Rankin Scale score ≤ 1) were compared with 29 age- and sex-matched controls. Corpus callosum area was determined on 3D-T1 MR imaging sequences with validated methodology. Between-group comparisons were performed with t tests or χ2 tests when appropriate. Relationships between reaction time and corpus callosum area were tested using linear regression modeling. RESULTS: Reaction time was significantly related to corpus callosum area in patients (estimate = -7.4 × 103, standard error = 3.3 × 103, P = .03) even after adjustment for age, sex, level of education, and scores of depression and apathy (estimate = -12.2 × 103, standard error = 3.8 × 103, P = .005). No significant relationship was observed in controls. CONCLUSIONS: Corpus callosum area, a simple and robust imaging parameter, appears to be an independent correlate of reaction time at the early clinical stages of CADASIL. Further studies will determine whether corpus callosum area can be used as an outcome in future clinical trials in CADASIL or in more prevalent small-vessel diseases.

Diffusion magnetic resonance imaging in cerebral small vessel disease.

Cerebral small vessel disease (SVD) is frequent in the elderly, and accounts for a wide spectrum of clinical and radiological manifestations. This report summarizes the most important findings obtained using diffusion MRI (DWI) in SVD. With DWI and apparent diffusion coefficient (ADC) maps, recent ischemic lesions can easily be detected after acute stroke in SVD, while even multiple simultaneous lesions may be observed. Microstructural changes are frequent in SVD, with increases in diffusivity and decreases in anisotropy being the most reliable findings observed, mainly in white matter. These tissue changes are associated with clinical severity and especially executive dysfunction. They can also precede the usual MRI markers of SVD, such as white matter hyperintensities, microbleeds and lacunes. Thus, DWI may reveal surrogate markers of SVD progression and offer a better understanding of their underlying mechanisms.

Lower Magnetization Transfer Ratio in the Forceps Minor Is Associated with Poorer Gait Velocity in Older Adults.

BACKGROUND AND PURPOSE: Gait disturbances in the elderly are disabling and a major public health issue but are poorly understood. In this multimodal MR imaging study, we used 2 voxel-based analysis methods to assess the voxelwise relationship of magnetization transfer ratio and white matter hyperintensity location with gait velocity in older adults. MATERIALS AND METHODS: We assessed 230 community-dwelling participants of the Austrian Stroke Prevention Family Study. Every participant underwent 3T MR imaging, including magnetization transfer imaging. Voxel-based magnetization transfer ratio-symptom mapping correlated the white matter magnetization transfer ratio of each voxel with gait velocity. To assess a possible relationship between white matter hyperintensity location and gait velocity, we applied voxel-based lesion-symptom mapping. RESULTS: We found a significant association between the magnetization transfer ratio within the forceps minor and gait velocity (ß = 0.134; 95% CI, 0.011-0.258; P = .033), independent of demographics, general physical performance, vascular risk factors, and brain volume. White matter hyperintensities did not significantly change this association. CONCLUSIONS: Our study provides new evidence for the importance of magnetization transfer ratio changes in gait disturbances at an older age, particularly in the forceps minor. The histopathologic basis of these findings is yet to be determined.

Decreased T1 contrast between gray matter and normal-appearing white matter in CADASIL.

BACKGROUND AND PURPOSE: CADASIL is the most frequent hereditary small-vessel disease of the brain. The clinical impact of various MR imaging markers has been repeatedly studied in this disorder, but alterations of contrast between gray matter and normal-appearing white matter remain unknown. The aim of this study was to evaluate the contrast alterations between gray matter and normal-appearing white matter on T1-weighted images in patients with CADASIL compared with healthy subjects. MATERIALS AND METHODS: Contrast between gray matter and normal-appearing white matter was assessed by using histogram analyses of 3D T1 high-resolution MR imaging in 23 patients with CADASIL at the initial stage of the disease (Mini-Mental State Examination score > 24 and modified Rankin scale score ≤ 1; mean age, 53.5 ± 11.1 years) and 30 age- and sex-matched controls. RESULTS: T1 contrast between gray matter and normal-appearing white matter was significantly reduced in patients compared with age- and sex-matched controls (patients: 1.35 ± 0.08 versus controls: 1.43 ± 0.04, P < 10(-5)). This reduction was mainly driven by a signal decrease in normal-appearing white matter. Contrast loss was strongly related to the volume of white matter hyperintensities. CONCLUSIONS: Conventional 3D T1 imaging shows significant loss of contrast between gray matter and normal-appearing white matter in CADASIL. This probably reflects tissue changes in normal-appearing white matter outside signal abnormalities on T2 or FLAIR sequences. These contrast alterations should be taken into account for image interpretation and postprocessing.

Microvascular retinal abnormalities in acute intracerebral haemorrhage and lacunar infarction.

BACKGROUND: Retinal microvascular changes have been previously associated with cerebral MRI markers of small vessel disease (SVD). Whether retinal changes differ between patient with intracerebral haemorrhage (ICH) and patients with lacunar infarction (LI) caused by small vessel disease has been poorly investigated. OBJECTIVE: The study aims to compare the frequency of retinal changes between patients with LI and patients with ICH at the acute stage of stroke-related SVD. METHODS: Microvascular wall signs (arteriolar occlusion, arteriovenous nicking, focal arterial narrowing) and retinopathy lesions (microanevrysms, cotton wool spots, retinal haemorrhages, hard exudates) were assessed by retinography up to three months after stroke onset. RESULTS: Forty-eight non-diabetic patients with acute stroke-related to SVD (26 LI, 22 ICH) were recruited prospectively in the study. Retinal wall signs (arteriovenous nicking, and focal arterial narrowing) were found in more than three quarters of subjects and most often bilaterally in both groups. Retinopathy lesions (cotton wool spots, retinal haemorrhages) were found more frequently in ICH patients than in LI patients (22.2% vs. 15.4%, 50% vs. 34% respectively, P>0.005). The frequency of bilateral cotton wool spots and of bilateral retinal haemorrhages was significantly higher in ICH patients than in LI patients (12.5% vs. 0%, P=0.012, 41.2% vs. 7.7%, P=0.029 respectively). CONCLUSION: These results confirm the high frequency of microvascular alterations in patients with hypertension-related SVD leading to LI or ICH and suggest that retinal tissue alterations are more frequent in ICH than in LI. Further investigations are needed to investigate the mechanisms underlying this difference.

Results of the PERFORM magnetic resonance imaging study.

The PERFORM MRI Project was an ancillary study of the PERFORM trial. Its aim was to investigate the potential effects of terutroban in patients with atherothrombotic disorders, in comparison to aspirin, on the evolution of magnetic resonance imaging (MRI) lesions after a recent ischemic stroke or transient ischemic attack (TIA). The change in both hypointense and hyperintense lesions on the fluid attenuated inversion recovery (FLAIR) sequence, in the total brain volume and in the hippocampal volume from baseline (M1) to the final visit (M24) was assessed as well as the number of emergent microbleeds. A total of 748 patients had their MRI examination validated both at M1 and M24 during the study. At baseline, the volume of hypointense and hyperintense lesions on FLAIR images, the total brain volume, the hippocampal volume and the number of patients with microbleeds did not differ between the two groups. During follow-up, the mean volumetric increase of lesions hypointense or hyperintense on FLAIR images (from 5 to 8 %), the mean reduction of total brain volume (−0.4 %) and of hippocampal volume (−4 %), did not differ between the two treatment arms. The same parameters analysed ipsilateral to the ischaemic lesion did not differ either between the two groups. In the terutroban group, 16.3 % of patients presented with emergent microbleeds, 10.7 % in the aspirin group; this difference was not significant. In the PERFORM study, the progression of FLAIR lesions, of cerebral or hippocampal atrophy and of microbleeds did not differ between patients treated by terutroban and those treated by aspirin.