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.
CADASIL: yesterday, today, tomorrow Chabriat, H.; Joutel, A.; Tournier‐Lasserve, E. ...
European journal of neurology,
August 2020, Letnik:
27, Številka:
8
Journal Article
Recenzirano
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.
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 (P<0.001 for global cognitive function, processing speed, executive functions, and memory and P<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 Z scores strongly predicted cognitive and functional outcomes (P<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.
Objective To assess the impairment in daily living activities in older people with age related changes in white matter according to the severity of these changes.Design Observational data collection ...and follow-up of a cohort of older people undergoing brain magnetic resonance imaging after non-disabling complaints.Setting 11 European centres.Participants 639 non-disabled older patients (mean age 74.1 (SD 5.0), 45.1% men) in whom brain magnetic resonance imaging showed mild, moderate, or severe age related changes in white matter (Fazekas scale). Magnetic resonance imaging assessment also included cerebral infarcts and atrophy.Main outcome measure Transition from no disability (defined as a score of 0 or 1 on the instrumental activities of daily living scale) to disability (score ≥2) or death over three year follow-up. Secondary outcomes were incident dementia and stroke.Results Over a mean follow-up period of 2.42 years (SD 0.97, median 2.94 years), information on the main outcome was available for 633 patients. The annual rate of transition or death was 10.5%, 15.1%, and 29.5%, respectively, for patients with mild, moderate, or severe age related changes in white matter (Kaplan-Meier log rank test P<0.001). In a Cox model comparing severe with mild changes and adjusted for clinical factors of functional decline, the risk of transition to disability or death was more than twofold higher (hazard ratio 2.36, 95% confidence interval 1.65 to 3.81). The other predictors were age group, history of atrial fibrillation, and complaint of gait disturbances. The effect of severe changes remained significant independently of baseline degree of atrophy and number of infarcts. Incident stroke and dementia only slightly modified this effect.Conclusion The three year results of the LADIS study suggest that in older adults who seek medical attention for non-disabling complaints, severe age related changes in white matter independently and strongly predict rapid global functional decline.
dVRS have been previously associated with aging and cerebrovascular diseases. However, little is known about their prevalence and topographic distribution in the general elderly population.
dVRS were ...evaluated by using high-resolution 3D MR imaging in 1826 subjects enrolled in the 3C-Dijon MR imaging study. On T1-weighted MR imaging, dVRS were detected according to 3D imaging criteria and rated by using 4-level severity scores based in the BG or in the WM. The number and anatomic location of large dVRS (≥3 mm) were recorded.
dVRS were observed in the BG or WM in every subject. The severity of dVRS was significantly associated with higher age in both the BG and WM, whereas sex was related to the severity of dVRS only in the BG. Large dVRS were detected in 33.2% of participants. Status cribrosum was found in 1.3% of participants. dVRS were also highly prevalent within the hippocampus (44.5%) and hypothalamus (11.6%).
dVRS are always detected in the BG or WM in elderly people, and large dVRS are also prevalent. The topographic distribution of dVRS is not uniform within the brain and may depend on anatomic or pathologic characteristics interacting with aging and sex.
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.
To our knowledge, very few MR imaging data have been reported in isolated cortical venous thrombosis (ICoVT). The purpose of this study was to describe MR imaging features, including T2*gradient-echo ...(GE) sequence, in presumed ICoVT.
MR imaging examinations were performed in 8 patients with ICoVT (MR venography was performed in all patients and digital substraction angiography in 4) at the time of diagnosis and during the follow-up at 15 days (4 patients) and at 3 (8 patients), 6 (6 patients), 12 (3 patients), and 18 months (1 patient). We assessed the presence of a magnetic susceptibility effect (MSE) on T2*GE imaging at each site of cerebral venous thrombosis and the presence or absence of a normal flow void and iso-, hypo-, or hyperintense signal intensity on T1, T2, diffusion-weighted imaging (DWI), and fluid-attenuated inversion recovery (FLAIR) images. Parenchymal signal-intensity changes were also assessed on the same sequences.
MSE was detected on T2*GE imaging at the site of a cortical vein in all subjects at the first MR imaging examination. The occluded vein appeared as hyperintense in 3 patients, iso- to slightly hyperintense in 1 on T1, hypointense in 6 on FLAIR images, and as signal-intensity loss on DWI in 3. At follow-up, persisting signal-intensity abnormalities on T2*GE imaging were detected at the venous sites in all patients, whereas signal-intensity changes on T1- and T2-weighted images were no longer present. Parenchymal hyperintensities on FLAIR and DWI (increased apparent diffusion coefficient ADC) were observed in close vicinity to the thrombosis in 6/8 patients. Petechial hemorrhages (n = 3) or hematoma (n = 2) was present on T2*GE imaging in 5/8 patients. During the follow-up, all cerebral tissue signal-intensity changes on T1, T2, and FLAIR images decreased both in volume and intensity. ADC values normalized within the tissue after 3 months in all patients.
On T2*GE imaging, MSE of hemoglobin products within the thrombus was observed both at the early and late phases of ICoVT and appears to be of high diagnostic value compared with the other signal intensity changes detected on standard MR imaging.
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.
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.
Growing evidence suggests that cerebral white-matter changes and depressive symptoms are linked directly along the causal pathway. We investigated whether baseline severity of cerebral white-matter ...changes predict longer-term future depressive outcomes in a community sample of non-disabled older adults.
In the Leukoaraiosis and Disability in the Elderly (LADIS) study, a longitudinal multi-centre pan-European study, 639 older subjects underwent baseline structural magnetic resonance imaging (MRI) and clinical assessments. Baseline severity of white-matter changes was quantified volumetrically. Depressive outcomes were assessed in terms of depressive episodes and depressive symptoms, as measured by the Geriatric Depression Scale (GDS). Subjects were clinically reassessed annually for up to 3 years. Regression models were constructed to determine whether baseline severity of white-matter changes predicted future depressive outcomes, after controlling for confounding factors.
Baseline severity of white-matter changes independently predicted depressive symptoms at both 2 (p<0.001) and 3 years (p=0.015). Similarly, white-matter changes predicted incident depression (p=0.02). Over the study period the population became significantly more disabled (p<0.001). When regression models were adjusted to account for the influence of the prospective variable transition to disability, baseline severity of white-matter changes no longer predicted depressive symptoms at 3 years (p=0.09) or incident depression (p=0.08).
Our results support the vascular depression hypothesis and strongly implicate white-matter changes in the pathogenesis of late-life depression. Furthermore, the findings indicate that, over time, part of the relationship between white-matter changes and depression may be mediated by loss of functional activity.
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