Search

High temperature requirement A1 (HTRA1) is a serine protease playing a modulatory role in various cell processes, particularly in the regulation of transforming growth factor-β (TGF-β) signaling. A deleterious role in late-onset cerebral small vessel diseases (CSVDs) of heterozygous HTRA1 mutations, otherwise causative in homozygosity of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, was recently suggested. However, the pathomechanism of these heterozygous mutations is still undefined. Our aim is to evaluate the expression profile and activity of HTRA1 on TGF-β signaling in fibroblasts from four subjects carrying the HTRA1 heterozygous mutations-p.E42Dfs*173, p.A321T, p.G295R, and p.Q151K. We found a 50% reduction of HTRA1 expression in HTRA1 mutation carriers compared to the control. Moreover, we showed no changes in TGF-β signaling pathway downstream intermediate, Phospho Smad2/3. However, we found overexpression of genes involved in the extracellular matrix formation in two heterozygous HTRA1 carriers. Our results suggest that each heterozygous HTRA1 missense mutation displays a different and peculiar HTRA1 expression pattern and that CSVD phenotype may also result from 50% of HTRA1 expression.

Suppressors of cytokine signaling 1 (SOCS1) protein, a negative regulator of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that mimetics of KIR-SOCS1 can be potent therapeutics in several disorders (e.g., neurological, autoimmune or cardiovascular diseases). In this work, starting from a recently identified cyclic peptidomimetic of KIR-SOCS1, icPS5(Nal1), to optimize the peptide structure and improve its biological activity, we designed novel derivatives, containing crucial amino acids substitutions and/or modifications affecting the ring size. By combining microscale thermophoresis (MST), Circular Dichroism (CD), Nuclear Magnetic Resonance (NMR) and computational studies, we showed that the cycle size plays a key role in the interaction with JAK2 and the substitution of native residues with un-natural building blocks is a valid tool to maintain low-micromolar affinity toward JAK2, greatly increasing their serum stability. These findings contribute to increase the structural knowledge required for the recognition of SOCS1/JAK2 and to progress towards their conversion into more drug-like compounds.

Mutations in POLR3A are characterized by high phenotypic heterogeneity, with manifestations ranging from severe childhood-onset hypomyelinating leukodystrophic syndromes to milder and later-onset gait disorders with central hypomyelination, with or without additional non-neurological signs. Recently, a milder phenotype consisting of late-onset spastic ataxia without hypomyelinating leukodystrophy has been suggested to be specific to the intronic c.1909 + 22G > A mutation in POLR3A. Here, we present 10 patients from 8 unrelated families with POLR3A-related late-onset spastic ataxia, all harboring the c.1909 + 22G > A variant. Most of them showed an ataxic-spastic picture, two a “pure” cerebellar phenotype, and one a “pure” spastic presentation. The non-neurological findings typically associated with POLR3A mutations were absent in all the patients. The main findings on brain MRI were bilateral hyperintensity along the superior cerebellar peduncles on FLAIR sequences, observed in most of the patients, and cerebellar and/or spinal cord atrophy, found in half of the patients. Only one patient exhibited central hypomyelination. The POLR3A mutations present in this cohort were the c.1909 + 22G > A splice site variant found in compound heterozygosity with six additional variants (three missense, two nonsense, one splice) and, in one patient, with a novel large deletion involving exons 14–18. Interestingly, this patient had the most “complex” presentation among those observed in our cohort; it included some neurological and non-neurological features, such as seizures, neurosensory deafness, and lipomas, that have not previously been reported in association with late-onset POLR3A-related disorders, and therefore further expand the phenotype.

Objectives : The Montreal Cognitive Assessment (MoCA) is a cognitive screening test largely employed in vascular cognitive impairment, but there are no data about MoCA longitudinal changes in patients with cerebral small vessel disease (SVD). We aimed to describe changes in MoCA performance in patients with mild cognitive impairment (MCI) and SVD during a 2-year follow-up, and to evaluate their association with transition to major neurocognitive disorder (NCD). Materials and Methods : Within the prospective observational VMCI-Tuscany Study, patients with MCI and SVD underwent a comprehensive clinical, neuropsychological, and functional evaluation at baseline, and after 1 and 2 years. Results : Among the 138 patients (mean age 74.4 ± 6.9 years; males: 57%) who completed the study follow-up, 44 (32%) received a major NCD diagnosis. Baseline MoCA scores (mean±SD) were lower in major NCD patients (20.5 ± 5) than in reverter/stable MCI (22.2 ± 4.3), and the difference approached the statistical threshold of significance (p=.051). The total cohort presented a decrease in MoCA score (mean±SD) of -1.3 ± 4.2 points (-2.6 ± 4.7 in major NCD patients, -0.7 ± 3.9 in reverter/stable MCI). A multivariate logistic model on the predictors of transition from MCI to major NCD, showed MoCA approaching the statistical significance (OR=1.09, 95% CI=1.00–1.19, p=.049). Discussion : In our sample of MCI patients with SVD, longitudinal changes in MoCA performances were consistent with an expected more pronounced deterioration in patients who received a diagnosis of major NCD. MoCA sensitivity to change and predictive utility need to be further explored in VCI studies based on larger samples and longer follow-up periods.

Background Vascular mild cognitive impairment (VMCI) is a potentially transitional state between normal aging and vascular dementia. The presence of macroscopic white matter lesions (WML) of moderate or severe extension on brain MRI is the hallmark of the VMCI. Objective To assess the clinical relevance of the frequency of WML in patients with VMCI independently of total lesion volume (LV). Methods In this multicenter study, we included 110 patients with VMCI (age: 74.3 ± 6.6 years; sex: 60 women). Cognitive assessment was performed with the VMCI-Tuscany Neuropsychological Battery, which allowed to identify four VMCI groups: amnestic single (n = 9) and multi-domain (n = 76), non-amnestic single- (n = 10) and multi-domain (n = 15). Distribution and frequency of WML on MRI FLAIR images were evaluated with lesion probability map (LPM). Voxelwise statistics was performed with nonparametric permutation tests, controlling for age, sex, slice thickness, center, magnetic field strength, total LV and head size (p, Highlights • Vascular mild cognitive impairment (VMCI) has moderate-to-severe white matter lesions (WML). • 110 VMCI patients were assessed by a full neuropsychological battery and a lesion mapping approach on MRI images. • Higher WML frequency along association tracts correlated with worst psychomotor speed and constructional praxis. • Non-amnestic groups of VMCI had higher WML frequency in the frontal WM.

Oculodentodigital dysplasia (ODDD) [MIM 164200] is a rare disorder caused by mutations in the gap junction alpha 1 (GJA1) gene encoding for connexin 43 (Cx43). Typical signs include type III syndactyly, microphtalmia, microdontia, and neurological disturbances. We report a 59-year-old man having clinical symptoms and signs suggestive of ODDD, with some rarely reported features, that is the presence of gross calcifications of basal ganglia and cerebellar nuclei. Mutation analysis of GJA1 gene identified an unreported heterozygous missense mutation [NM_000165.3:c.124 G>C;p.(Glu42Gln)], which may be thought to alter the brain microvessels leading to massive calcifications, as in primary familial brain calcification.

Aims: The DSM-5 introduced the term “major neurocognitive disorders” (NCDs) to replace the previous term “dementia.” However, psychometric and functional definitions of NCDs are missing. We aimed to apply the DSM-5 criteria for diagnosing the transition to NCD to patients with mild cognitive impairment (MCI) and small vessel disease (SVD), and to define clinically significant thresholds for this transition. Methods: The functional and cognitive features of the NCD criteria were evaluated as change from baseline and operationalized according to hierarchically ordered psychometric rules. Results: According to the applied criteria, out of 138 patients, 44 were diagnosed with major NCD (21 with significant cognitive worsening in ≥1 additional cognitive domain), 84 remained stable, and 10 reverted to normal. Single-domain MCI patients were the most likely to revert to normal, and none progressed to major NCD. The amnestic multiple-domain MCI patients had the highest rate of progression to NCD. Conclusion: We provide rules for the DSM-5 criteria for major NCD based on cognitive and functional changes over time, and define psychometric thresholds for clinically significant worsening to be used in longitudinal studies. According to these operationalized criteria, one-third of the MCI patients with SVD progressed to major NCD after 2 years, but only within the multiple-domain subtypes.

SummaryAims Cerebral small vessel disease (SVD) is the leading cause of vascular dementia. Although the most of cases are sporadic, familial monogenic causes have been identified in a growing minority of patients. CADASIL, due to mutations of NOTCH3 gene, is the most common genetic SVD, and CARASIL, linked to HTRA1 gene mutations, is a rare but well known autosomal recessive SVD. Recently, also heterozygous HTRA1 mutations have been described in patients with familial SVD. To detect a genetic cause of familial SVD, we performed mutational analysis of HTRA1 gene in a large cohort of Italian NOTCH3-negative patients. Methods We recruited 142 NOTCH3-negative patients and 160 healthy age-matched controls. Additional control data were obtained from five pathogenicity prediction software. Results Five different HTRA1 heterozygous mutations were detected in nine patients from five unrelated families. Clinical phenotype was typical of SVD, and the onset was presenile. Brain magnetic resonance imaging (MRI) showed a subcortical leukoencephalopathy, with involvement of the external and internal capsule, corpus callosum, and multiple lacunar infarcts. Cerebral microbleeds were also seen, while anterior temporal lobes involvement was not present. Conclusion Our observation further supports the pathogenic role of the heterozygous HTRA1 mutations in familial SVD.

Besides its well known function on bone metabolism, vitamin D role in cerebrovascular pathologies including cerebral small vessel disease has been confirmed by recent meta-analysis. In this study, we measured vitamin D levels in 56 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients (mean age 49.9) with no or minimal disability (modified Ranking Score, mRS ≤2) and in 56 age, sex and seasonality matched healthy controls. History of ischemic events was recorded and cognitive functions were assessed using the Mini-Mental State Examination. White matter hyperintensities on brain T2-weighted magnetic resonance images were classified according to a modified Fazekas scale. Comparison of vitamin D levels between patients and controls showed significant lower values (p

Background and Purpose Intracerebral hemorrhage (ICH) accounts for approximately 10% of stroke cases. Hypertension may play a role in the pathogenesis of ICH that occurs in the basal ganglia, thalamus, pons, and cerebellum, but not in that of lobar ICH. Hypertension contributes to decreased elasticity of arteries, thereby increasing the likelihood of rupture in response to acute elevation in intravascular pressure. This study aimed to evaluate arterial stiffness (using the arterial stiffness index [ASI]) in patients with deep (putaminal and thalamic) ICH in comparison with patients with lobar ICH. Methods We enrolled 64 patients (mean ± SD age: 69.3 ± 10.7 years; 47 men and 17 women) among 73 who referred consecutively to our department for intraparenchymal hemorrhage and underwent brain computed tomography (CT) and cerebral angio-CT. In all the subjects, 24-hour heart rates and blood pressures were monitored. The linear regression slope of diastolic on systolic blood pressure was assumed as a global measure of arterial compliance, and its complement (1 minus the slope), ASI, has been considered as a measure of arterial stiffness. Results In the patients with deep ICH, ASI was significantly higher than in the patients with lobar ICH (0.64 ± 0.19 vs. 0.53 ± 0.17, P = 0.04). Conclusions Our results suggest that in deep ICH, arterial stiffening represents a possible pathogenetic factor that modifies arterial wall properties and contributes to vascular rupture in response to intravascular pressure acute elevation. Therapeutic strategies that reduce arterial stiffness may potentially lower the incidence of deep hemorrhagic stroke.

Cerebral microangiopathies are responsible of a great number of strokes. In the recent years advances in molecular genetics identified several monogenic conditions involving cerebral small vessels and predisposing to ischemic and/or hemorrhagic stroke and diffuse white matter disease leading to vascular dementia. Clinical features and diagnostic clues of these conditions, [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1-related cerebral small vessel diseases, autosomal dominant retinal vasculopathy with cerebral leukodystrophy (AD-RVLC), and Fabry's disease] are here reviewed. Albeit with variable phenotypes and with different defective genes, all these disorders produce arteriopathy and microvascular disintegration with changes in brain functions. Specific diagnostic tools are recommended, genetic analysis being the gold standard for the diagnosis.

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant cerebral white matter degeneration leading to progressive cognitive and motor dysfunction. The peripheral nervous system is generally spared. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R) gene have been shown to be associated with HDLS. Here we report a new case of HDLS, carrying a mutation in CSF1R and manifesting rapidly progressive dementia and peripheral neuropathy.

Adult-onset leukoencephalopathies are clinically and pathologically heterogeneous diseases, characterized by over- lapping clinical and neuroradiological features and a difficult diagnostic process. Nevertheless, knowledge of the metabolic and genetic basis of leukoencephalopathies is constantly increasing. This article provides an overview of currently known leukoen- cephalopathies in adulthood, emphasizing, in addition to the classical forms, their atypical clinical presentations. In particular, we review the clinical spectrum and the molecular pathogenesis of certain adult-onset leukoencephalopathies, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebroretinal microangiopathy with calcifications and cysts (CRMCC), hereditary diffuse leukoencephalopathy with spheroids (HDLS), fragile X-associated tremor/ataxia syn- drome (FXTAS), vanishing white matter disease (VWM), autosomal dominant leukodystrophy due to lamin B1 duplication (ADLD), and vascular leukoencephalopathy mapping to chromosome 20q13.

The objective of the study is to detail clinical and NOTCH3 gene mutational spectrum in a large group of Italian CADASIL patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a familial cerebral small vessels disease caused by mutations in the NOTCH3 gene on 19p13 usually presenting in young or middle adulthood. Characteristic features include migraine, recurrent lacunar stroke, subcortical dementia, mood disturbances and leukoencephalopathy. The disorder is often overlooked and misdiagnosed. CADASIL prevalence and disease burden is still undetermined. We retrospectively reviewed demographic, clinical, and mutational characteristic of all CADASIL patients diagnosed from January 2002 to December 2012 in three referral centers for neurogenetic and cerebrovascular diseases in central Italy. 229 NOTCH3 positive subjects were identified. Mean age at diagnosis was 57.8 ± 14.7 years, and 48.6 ± 17.1 years at first symptom onset. Most frequent clinical symptoms were ischemic events (59 %) and psychiatric disturbances (48 %). The highest percentage of mutations were found on exons 4 and 19 (20.6 and 17.6 % respectively), the remaining being dispersed over the entire EGF-like region of the NOTCH3 gene. 209 patients resided in a circumscribed geographic area which included three regions of the central Italy, yielding a minimum prevalence of 4.1 per 100.000 adult inhabitants. This is the most extensive study on CADASIL in Italy. Clinical phenotype showed several peculiarities in frequency and presentation of the main disease manifestations. Our study enlarges the number of pathogenic NOTCH3 mutations and due to the heterogeneous mutational spectrum observed suggests that full sequencing of exons 2–24 is mandatory for CADASIL screening in the Italian population.

CADASIL is the most prominent inherited form of vascular dementia. The main clinical features include migraine with aura, stroke, mood disturbances, and cognitive decline, with a mid-life (30s-60s) adult onset. Genetic testing is the gold standard for the diagnosis. CADASIL is caused mostly by missense mutations in the NOTCH3 gene, invariably involving a cysteine residue. Only a couple of splice site mutations have been reported. In a few pathologically defined patients, genetic mutations remain unidentified. We report a family with late-onset CADASIL phenotype carrying a novel intronic deletion in the NOTCH3 gene (c.341-26_24delAAC). Transcript analysis revealed a splicing alteration, with the complete intron 3 retention. The insertion was in-frame and encoded an extra 25 amino acids, including 1 cysteine. This is the first report of an aberrant splicing event of the NOTCH3 gene associated with a mutation far away from the canonical splice site. Our finding suggests that the assays used to evaluate splicing should be mandatory in the diagnostic setting of genetically undefined CADASIL cases.

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.