Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts And Leukoencephalopathy Research Articles

SQSTM1 gene as a potential genetic modifier of CADASIL phenotype.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease and is caused by mutations in the NOTCH3 gene. Interestingly, CADASIL patients present a large phenotypic variability even harboring the same pathogenic variant. We describe two CADASIL siblings with a particularly aggressive clinical phenotype characterized by early-onset stroke, gait disturbances and/or dementia, severe emotional dysregulation, and dysexecutive syndrome together with a severe white matter burden on MRI. The genetic analysis revealed the co-occurrence of NOTCH3 (p.Gly420Cys) and SQSTM1 (p.Ser275Phefs*17) pathogenic variants which might worsen the aggressiveness of disease progression in both siblings. Interestingly, to the best of our knowledge, mutations in SQSTM1 gene have never been described in CADASIL patients before. Curiously, both Notch3 and p62 encoded proteins have a key role in the autophagy-lysosomal pathway which is impaired in CADASIL patients. Thus, the contribution of SQSTM1 gene to the clinical heterogeneity of CADASIL patients, in particular for those who develop cognitive impairment or dementia at an early age, is certainly overlooked. Therefore, we advocate expanding the genetic analysis to other genes associated with the phenotype spectrum of CADASIL patients using NGS-customized gene panel.

Apolipoprotein E ε4 Is Associated With the Development of Incident Dementia in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Patients With p.Arg544Cys Mutation.

Background and PurposeTo identify clinical, laboratory, and magnetic resonance imaging (MRI) features in predicting incident stroke and dementia in Korean patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).Materials and MethodsWe enrolled 87 Korean CADASIL patients who had undergone baseline clinical, laboratory, and MRI examinations between March 2012 and February 2015. The primary outcome of this study is the occurrence of stroke and dementia during the study period. The occurrence of incident stroke was confirmed by neuroimaging study, and dementia was defined by the diagnostic and statistical manual of mental disorders, fourth edition, criteria.ResultsOf the 87 patients, 57.5% were men, and the mean age was 63 ± 13 years (range 34–90 years), and 82 patients (94.3%) had p.Arg544Cys mutation. During an average follow-up of 67 months (interquartile range: 53–69 months), incident stroke occurred in 14 of 87 patients (16.1%) and incident dementia in 7 of 70 non-demented patients (10.0%). In adjusted analysis, increased systolic blood pressure was associated with increased risk of incident stroke [for every 10-mmHg increase; hazard ratio, 1.44 (1.02–2.03)]. Apolipoprotein E ε4 genotype was associated with an increased risk of incident dementia [hazard ratio, 10.70 (1.27–89.88)].ConclusionIn this study, apolipoprotein E ε4 genotype was associated with the development of incident dementia, and higher blood pressure was associated with increased risk of incident stroke in CADASIL patients with predominant p.Arg544Cys mutation.

An alternative mechanism of crossed vertical gaze palsy in unilateral mesodiencephalic infarction

Crossed vertical gaze palsy refers to a rare combination of elevation paresis in one eye and depression palsy in the fellow eye. It was once reported in a patient with unilateral infarction involving the mesodiencephalic junction, and was ascribed to selective disruption of the fibers projecting from the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) to the oculomotor nuclear complex. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare cause of ophthalmoplegia and crossed vertical gaze palsy has not been described in this disorder. Our patient with a circumscribed acute infarction involving the left mesodiencephalic junction due to CADASIL showed both upward and downward gaze palsy in both eyes, but more marked depression paresis in the ipsilesional eye and more conspicuous elevation deficit in the contralesional eye, which was consistent with crossed vertical gaze palsy. We provide alternate explanation for this rare phenotype of vertical gaze palsy. Selective disruption of riMLF fibers may cause crossed vertical gaze palsy in unilateral mesodiencephalic lesion.

Coronary microvascular function is impaired in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; OMIM 125310) is a rare inherited disease, caused by NOTCH3 gene mutations. Main clinical manifestations of CADASIL include recurrent subcortical ischemic events, migraine, cognitive impairment and psychiatric disturbances. CADASIL is a systemic microangiopathy and cardiac involvement has been observed in a series of Dutch patients, presenting higher frequency of myocardial infarction compared to non-mutated relatives and general population. In particular, electron microscopic examination of myocardial tissue of a study participant demonstrated CADASIL characteristics. We sought to investigate the relationship between CADASIL and microvascular dysfunction (MVD). Seventeen patients with genetically-confirmed CADASIL, aged <60 years, with ≤1 cardiovascular risk factor (current smoke, diabetes, hypertension, dyslipidemia), recent (<3 months) neurological evaluation with neuropsychological tests and 3 Tesla brain magnetic resonance imaging (MRI) underwent 12-lead ECG, echocardiography, and measurement of maximal myocardial blood flow following Regadenoson infusion (Reg-MBF) by 13NH3positron emission tomography (PET), to investigate the presence of coronary microvascular dysfunction (CMD). Coronary flow reserve (CFR) was defined as Reg-MBF/resting MBF. PET results were compared to those of 15 healthy controls matched for age and sex recruited among a historical cohort of healthy patients. The study was approved by the institutional review board and all the subjects gave informed consent. Mean age was 40±9 years (range 28–57 years); 6 patients (35%) were male. One was a current smoker and 3 ex-smokers; 1 patient was on aspirin, 1 on acetazolamide and 2 on escitalopram, none was taking statins. 12 patients (71%) presented with migraine, 9 (53%) had psychiatric disturbances and 1 (6%) had a previous stroke. Brain MRI showed mild-moderate and severe leukoencephalopathy in 11 (65%) and 5 (29%) patients respectively, lacunes were present in 14 patients and microbleeds in 1; one patient had normal findings. Both Reg-MBF and CFR were blunted in CADASIL patients compared with controls (Reg-MBF 2.46±0.54 versus 3.09±0.44 ml/gr/min respectively, p<0.001; CFR 2.74±0.36 vs. 3.28±0.66, respectively, p<0.01). In 3 male patients (17%), CFR reduction was severe (<2). Segmental Reg-MBF analysis of left ventricular flow showed diffuse hypoperfusion, excluding preferential regional involvement. No correlations were found between Reg-MBF values and neuropsychological performance or cerebral lesion burden, suggesting that neurological and cardiac involvement might be independent in CADASIL. These data represent the first documentation of coronary microvascular involvement in a group of young and mildly symptomatic CADASIL patients, confirming the systemic nature of the disease. This proof of concept study expands our understanding of genetically-driven CMD. Funding Acknowledgement Type of funding source: None

Status epilepticus no convulsivo como manifestación inicial en una familia con arteriopatía autosómica dominante cerebral con infartos subcorticales y leucoencefalopatía (CADASIL)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant small-vessel disease caused by mutations of the NOTCH3 gene. It typically presents with migraine, recurrent brain ischaemia, and cognitive disorders. Seizures rarely present as the initial manifestation, with non-convulsive status epilepticus being even less frequent. We present a series of 3 related patients with this arteriopathy, 2 of whom presented status epilepticus as a manifestation of the disease.

Neuronal densities and vascular pathology in the hippocampal formation in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral small vessel disease. Previous neuroimaging studies have suggested loss of hippocampal volume is a pathway for cognitive impairment in CADASIL. We used unbiased stereological methods to estimate SMI32-positive and total numbers and volumes of neurons in the hippocampal formation of 12 patients with CADASIL and similar age controls (young controls) and older controls. We found densities of SMI32-positive neurons in the entorhinal cortex, layer V, and cornu ammonis CA2 regions were reduced by 26%–50% in patients with CADASIL compared with young controls (p < 0.01), with a decreasing trend observed in older controls in the order of young controls> older controls ≥ CADASIL. These changes were not explained by any hippocampal infarct or vascular pathology or glial changes. Our results suggest notable loss of subsets of projection neurons within the hippocampal formation that may contribute to certain memory deficits in CADASIL, which is purely a vascular disease. It is likely that the severe arteriopathy leads to white matter damage which disconnects cortico-cortical and subcortical-cortical networks including the hippocampal formation.

Insulin-Independent and Dependent Glucose Transporters in Brain Mural Cells in CADASIL

Typical cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the human NOTCH3 gene. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy is characterized by subcortical ischemic strokes due to severe arteriopathy and fibrotic thickening of small vessels. Blood regulating vascular smooth muscle cells (VSMCs) appear as the key target in CADASIL but the pathogenic mechanisms remain unclear. With the hypothesis that brain glucose metabolism is disrupted in VSMCs in CADASIL, we investigated post-mortem tissues and VSMCs derived from CADASIL patients to explore gene expression and protein immunoreactivity of glucose transporters (GLUTs), particularly GLUT4 and GLUT2 using quantitative RT-PCR and immunohistochemical techniques. In vitro cell model analysis indicated that both GLUT4 and -2 gene expression levels were down-regulated in VSMCs derived from CADASIL patients, compared to controls. In vitro studies further indicated that the down regulation of GLUT4 coincided with impaired glucose uptake in VSMCs, which could be partially rescued by insulin treatment. Our observations on reduction in GLUTs in VSMCs are consistent with previous findings of decreased cerebral blood flow and glucose uptake in CADASIL patients. That impaired ability of glucose uptake is rescued by insulin is also consistent with previously reported lower proliferation rates of VSMCs derived from CADASIL subjects. Overall, these observations are consistent with the development of severe cerebral arteriopathy in CADASIL, in which VSMCs are replaced by widespread fibrosis.

Modeling the Cognitive Trajectory in CADASIL.

For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition. We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL. Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared. Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity. These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies.

LIKELIHOOD FOR REACHING EMBRYO TRANSFER FOLLOWING EXCLUSION-BASED NON-DISCLOSURE PREIMPLANTATION GENETIC TESTING FOR MONOGENIC CONDITIONS (PGT-M)

Non-disclosure (ND) preimplantation genetic testing (PGT) for monogenic disorders (PGT-M) via in vitro fertilization (IVF) is an option for individuals at risk for having a late-onset dominant condition. One method involves testing the patient for a familial mutation without disclosing the results, and blinding them to whether their embryos are tested via PGT-M with concurrent PGT for aneuploidy (PGT-A) if they have the mutation, or via PGT-A only if they do not. Exclusion-based testing is an alternate method which does not require the patient’s mutation status to be known. Rather, by determining which of the patient’s chromosome homologs with the gene of interest was inherited from their affected parent, embryos that inherit that copy of the chromosome are excluded from transfer due to the potential risk for inheriting the mutation. Exclusion-based testing eliminates the risk for accidental disclosure of the patient’s mutation status but may exclude unaffected embryos from transfer if the patient does not have the familial mutation. Patients may consider cryopreservation of potentially at-risk embryos in case they pursue testing for themselves at a later time. In this study, we review the likelihood of unaffected and euploid embryo results using exclusion-based ND testing. Retrospective analysis of trophectoderm (TE) biopsy results from IVF patients referred for exclusion-based ND PGT-M with concurrent PGT-A. For each case, a mutation/clinical diagnosis report for the affected relative and samples from the couple and the at-risk patient’s parent(s) were required. TE biopsies were shipped to a lab for genotyping using Illumina Cyto12 SNP-based microarrays with informatics. Twenty-five patients underwent exclusion-based ND PGT-M for 7 disorders (Huntington’s Disease (HD), n=19; Spinocerebellar ataxia (SCA) type 3, n=1; SCA type 6, n=1; Polycystic kidney disease, n=1; Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), n=1; Familial TTR amyloidosis, n=1; Creutzfeldt-Jakob disease, n=1). A total of 273 TE samples from 46 IVF cycles were tested (average of 5.9 embryos/cycle, range 1-21). Average maternal age was 33.1 years (range 26.2–41.9 years). 73.9% (34/46) of cycles had at least one euploid and unaffected embryo. Analysis by maternal age groups indicated that the chance of having at least one euploid and unaffected embryo was 83.3% (5/6) for <30 years, 76.7% (23/30) for 30-34 years, and 60% (6/10) for women ≥35 years. Exclusion-based ND testing avoids the risk of accidental disclosure of a patient’s mutation status, while allowing a relatively high rate of having an embryo for transfer after a single IVF cycle. This information may be useful for counseling patients considering ND exclusion-based PGT-M and discussing the potential need for additional IVF cycles in order to reach transfer, especially for women of advanced maternal age. Although ND exclusion-based testing is most commonly performed for HD, here we demonstrate that this method can be utilized for other dominant late-onset conditions.

Mitochondrial DNA m.3243A>G mutation rarely causes CADASIL-like phenotype

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are 2 monogenic cerebral small vessel diseases sharing several common clinical features including young stroke, migraine, and cognitive dysfunction. The aim of this study was to understand the role of MELAS in patients with CADASIL-like manifestations. We screened 429 unrelated patients with genetically unassigned CADASIL-like syndrome for mitochondrial DNA m.3243A>G mutation. None of them were found to have the mutation. Our finding suggests that m.3243A>G rarely causes CADASIL-like phenotype. It may be not necessary to consider MELAS as a differential diagnosis of CADASIL. Screening m.3243A>G in patients with CADASIL-like phenotype is of limited value.

Intracranial Large Artery Abnormalities and Association With Cerebral Small Vessel Disease in CADASIL.

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited systemic arteriopathy, the classic feature of which is small vessel lesions. Studies on intracranial large arteries in CADASIL are not common. We aim to evaluate intracranial large arteries, describing the characteristics of large arteries in CADASIL and their association with cerebral small vessel associated lesions.Methods: Consecutive CADASIL patients from a single-center prospective cohort were analyzed. Brain magnetic resonance imaging and magnetic resonance angiography were performed to assess the intracranial large arteries and cerebral small vessels associated lesions' neuroimaging.Results: The study included 37 CADASIL patients. Of the patients, 28 of them (75.7%) had intracranial large artery abnormalities. Eighteen (48.6%) had congenital variations such as fenestration, vertebral artery (VA) hypoplasia and agenesis, or common trunk and fetus posterior cerebral artery. Seventeen (45.9%) had acquired anomalies such as arterial stenosis, prolongation, or tortuosity (seven of them had both congenital and acquired anomalies). CADASIL patients with anterior circulation middle cerebral artery (MCA) or internal cerebral artery (ICA) severe stenosis were more likely to have ipsilateral asymmetric white matter hyper-density (WMH) distribution. Patients with posterior circulation VA hypoplasia had a higher prevalence of posterior subcortical zone dominant WMH distribution.Conclusion: CADASIL patients can demonstrate various intracranial large artery abnormalities which might influence the development of microangiopathy. Assessment of great vessels seems essential in CADASIL.

Broad phenotype of cysteine-altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance.

ObjectiveTo determine the small vessel disease spectrum associated with cysteine-altering NOTCH3 variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.MethodsThe exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering NOTCH3 variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry.ResultsWe identified 108 individuals harboring a cysteine-altering NOTCH3 variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor–like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with NOTCH3 variants than in controls (p = 0.006) but lower than in patients with CADASIL with the same variants (p < 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke.ConclusionsAlthough community-dwelling individuals harboring a cysteine-altering NOTCH3 variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that NOTCH3 cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.

A Nationwide Survey and Multicenter Registry-Based Database of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy in Japan.

ObjectivesClinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed.MethodsSubjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire.ResultsBased on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan.ConclusionThis questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.

Effect of Lomerizine Hydrochloride on Preventing Strokes in Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an orphan disease clinically characterized by migraine, recurrent strokes, and dementia. Currently, there are no disease-modifying therapies, and it is difficult to prevent cerebral ischemic events in CADASIL patients by conventional antithrombotic medication. We hypothesized that an antimigraine agent, lomerizine hydrochloride, may prevent strokes in CADASIL patients, based on its effect on increasing cerebral blood flow. This was an open-labeled clinical trial in which 30 adult CADASIL patients received lomerizine at 10 mg/d. Numbers of symptomatic strokes during the 2 years after the start of lomerizine administration were compared with those in the 2 years before its initiation. The effect of lomerizine on preventing strokes was evaluated based on the incidence rate ratio (IR) calculated with the Mantel-Haenszel method. When including all 30 patients (analysis 1), the IR was less than 1 (0.46; 95% confidence interval [CI], 0.19-1.12) but did not reach significance. To evaluate the effect of lomerizine on secondary prevention, subgroups of 15 patients with stroke episodes occurring any time before lomerizine administration (analysis 2) and 10 patients with stroke episodes during the 2 years before lomerizine administration (analysis 3) were analyzed. The IR values were 0.33 (95% CI, 0.12-0.94) in analysis 2 and 0.17 (95% CI, 0.04-0.67) in analysis 3. Our results suggest the effect of lomerizine on preventing secondary stroke in CADASIL patients.

The potential danger of blocking CGRP for treating migraine in CADASIL patients.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease characterised by recurrent ischemic stroke, cognitive decline progressing to dementia, psychiatric disturbances and apathy. More than half of mutation carriers suffer from migraine, most often migraine with aura. Recently, a CADASIL patient was treated with a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor. Monoclonal antibodies targeting the CGRP system have been demonstrated to be safe, well tolerated, and effective in reducing migraine attacks. There is, however, abundant evidence that CGRP is important in maintaining cardiovascular homeostasis under (patho)physiological conditions. CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia and blockage of the system could, therefore, potentially worsen ischemic events. Therefore, we caution against treating patients with small vessel diseases, such as the monogenic disorder CADASIL, with these drugs until relevant safety data and long term follow up results are available. Alternative preventive migraine treatments in CADASIL may be acetazolamide, sodium valproate, lamotrigine, topiramate, verapamil, or flunarizine.

&lt;p&gt;Optical Coherence Tomography Angiography in Neurodegenerative Diseases: A Review&lt;/p&gt;

BackgroundOptical coherence tomography angiography (OCT-A) has emerged as a novel, fast, safe and non-invasive imaging technique of analyzing the retinal and choroidal microvasculature in vivo. OCT-A captures multiple sequential B-scans performed repeatedly over a specific retinal area at high speed, thus enabling the composition of a vascular map with areas of contrast change (high flow zones) and areas of steady contrast (slow or no flow zones). It therefore provides unique insight into the exact retinal or choroidal layer and location at which abnormal blood flow develops. OCTA has evolved into a useful tool for understanding a number of retinal pathologies such as diabetic retinopathy, age-related macular degeneration, central serous chorioretinopathy, vascular occlusions, macular telangiectasia and choroidal neovascular membranes of other causes. OCT-A technology is also increasingly being used in the evaluation of optic disc perfusion and has been suggested as a valuable tool in the early detection of glaucomatous damage and monitoring progression.ObjectiveTo review the existing literature on the applications of optical coherence tomography angiography in neurodegenerative diseases.SummaryA meticulous literature was performed until the present day. Google Scholar, PubMed, Mendeley search engines were used for this purpose. We used 123 published manuscripts as our references. OCT-A has been utilized so far to describe abnormalities in multiple sclerosis (MS), Alzheimer’s disease, arteritic and non-arteritic optic neuropathy (AION and NAION), Leber’s hereditary optic neuropathy (LHON) papilloedema, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), Wolfram syndrome, migraines, lesions of the visual pathway and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). It appears that OCT-A findings correlate quite well with the severity of the aforementioned diseases. However, OCT-A has its own limitations, namely its lack of wide-field view of the peripheral retina and the inaccurate interpretation due to motion artifacts in uncooperative groups of patients (e.g. children). Larger prospective longitudinal studies will need to be conducted in order to eliminate the aforementioned limitations.

Iron leakage owing to blood-brain barrier disruption in small vessel disease CADASIL.

To assess the relationship among iron accumulation, blood-brain barrier (BBB) damage, and cognitive function in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We enrolled 21 patients with NOTCH3 mutations and 21 age-matched healthy controls in this cross-sectional study. All participants underwent global physical and cognitive assessments and brain MRI using voxel-based quantitative susceptibility mapping (QSM; iron deposition measure) and dynamic contrast-enhanced MRI (BBB permeability measure). We compared behavioral and imaging data between the groups and analyzed the correlations in each group. Among 21 NOTCH3 mutation carriers, 10 were symptomatic and 11 asymptomatic. Montreal Cognitive Assessment scores were significantly different among the groups (symptomatic < asymptomatic < control participants). Voxel-based QSM analysis revealed that the symptomatic group had higher QSM values than did the asymptomatic group in the putamen, caudate nucleus, temporal pole, and centrum semiovale. These QSM values were positively correlated with regional BBB permeabilities (putamen: r = 0.57, p = 0.006; caudate nucleus: r = 0.51, p = 0.019; temporal pole: r = 0.48, p = 0.030; centrum semiovale: r = 0.45, p = 0.044) and negatively correlated with Montreal Cognitive Assessment scores (caudate nucleus: r = -0.53, p = 0.012; temporal pole: r = -0.56, p = 0.008). This study showed that cerebral iron burden was associated with regional BBB permeability and cognitive dysfunction in patients with CADASIL, highlighting the potential of these imaging techniques as auxiliary biomarkers to monitor the course of small vessel disease.

Clinical and imaging features of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and cysteine-sparing NOTCH3 mutations.

BackgroundCharacteristics of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and cysteine-sparing NOTCH3 mutations are relatively unknown. This study compared clinical and imaging characteristics between patients with CADASIL and cysteine-sparing NOTCH3 mutations and those with CADASIL and cysteine-involving NOTCH3 mutations.MethodsWe retrospectively reviewed medical records of patients with CADASIL admitted to the Asan Medical Center between September 1999 and September 2017. We compared clinical and brain magnetic resonance imaging (MRI) characteristics based on the presence or absence of cysteine-involving NOTCH3 gene mutations. We compared white matter change frequencies and grades in specific spatial regions between the groups according to age-related white matter change (ARWMC) scores. We evaluated the presence, number, and anatomical distributions of cerebral microbleeds according to the microbleed anatomical rating scale.ResultsWe reviewed data from 79 patients (55 cysteine-involving, 24 cysteine-sparing NOTCH3 mutations). Clinical symptoms and signs did not differ significantly between the groups. The white matter change frequency and ARWMC scores (adjusted for age and stroke risk factors) in the anterior temporal lobes were lower in cysteine-sparing patients than in cysteine-involving patients. Frequencies and grades of the other brain region’s white matter changes and cerebral microbleeds were similar between the groups.ConclusionsPatients with CADASIL and cysteine-sparing NOTCH3 mutations showed less involvement of the anterior temporal lobes in brain MRI than those with CADASIL and cysteine-involving NOTCH3 mutations, although both groups showed similar clinical characteristics.

The INECO Frontal Screening for the Evaluation of Executive Dysfunction in Cerebral Small Vessel Disease: Evidence from Quantitative MRI in a CADASIL Cohort from Colombia.

Executive dysfunction is a predominant cognitive symptom in cerebral small vessel disease (SVD). The Institute of Cognitive Neurology Frontal Screening (IFS) is a well-validated screening tool allowing the rapid assessment of multiple components of executive function in Spanish-speaking individuals. In this study, we examined performance on the IFS in subjects with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited condition leading to the early onset of SVD. We further explored associations between performance on the IFS and magnetic resonance imaging (MRI) markers of SVD. We recruited 24 asymptomatic CADASIL subjects and 23 noncarriers from Colombia. All subjects underwent a research MRI and a neuropsychological evaluation, including the IFS. Structural MRI markers of SVD were quantified in each subject, together with an SVD Sum Score representing the overall burden of cerebrovascular alterations. General linear model, correlation, and receiver operating characteristic curve analyses were used to explore group differences on the IFS and relationships with MRI markers of SVD. CADASIL subjects had a significantly reduced performance on the IFS Total Score. Performance on the IFS correlated with all quantified markers of SVD, except for brain atrophy and perivascular spaces enlargement. Finally, while the IFS Total Score was not able to accurately discriminate between carriers and noncarriers, it showed adequate sensitivity and specificity in detecting the presence of multiple MRI markers of SVD. These results suggest that the IFS may be a useful screening tool to assess executive function and disease severity in the context of SVD.

Intracranial high-resolution vessel wall imaging in CADASIL.

A 64-year-old man with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (heterozygous, c.544C>T; p.Arg182Cys) underwent an intracranial high-resolution black-blood protocoled vessel wall MRI (vwMRI). Intramural patchy gadolinium enhancement in the subcortical and leptomeningeal arteries and veins was noted, consistent with the histopathologic findings of CADASIL (figures 1 and 2).1,2 We hypothesize that vwMRI allowed for an in vivo view of the vasculopathy intrinsic to CADASIL. Pending investigation of larger cohorts, this imaging technique may provide a novel mechanism for understanding CADASIL progression and pathogenesis, as well as potentially serving as a biomarker in future disease modification trials and aiding in the differential diagnosis for interpreting clinicians.