Prevalence of Fabry disease and GLA variants in young patients with acute stroke: The challenge to widen the screening. The Fabry-Stroke Italian Registry.

BACKGROUND: Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes). METHODS: Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18-60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present. RESULTS: Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44-1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03-0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant. CONCLUSION: In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening.

Longitudinal changes in MoCA performances in patients with mild cognitive impairment and small vessel disease. Results from the VMCI-Tuscany Study.

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.

Application of the DSM-5 Criteria for Major Neurocognitive Disorder to Vascular MCI Patients.

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.

Location, number and factors associated with cerebral microbleeds in an Italian-British cohort of CADASIL patients.

BACKGROUND AND PURPOSE: The frequency, clinical correlates, and risk factors of cerebral microbleeds (CMB) in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) are still poorly known. We aimed at determining the location and number of CMB and their relationship with clinical manifestations, vascular risk factors, drugs, and other neuroimaging features in CADASIL patients. METHODS: We collected clinical data by means of a structured proforma and centrally evaluated CMB on magnetic resonance gradient echo sequences applying the Microbleed Anatomical Rating Scale in CADASIL patients seen in 2 referral centers in Italy and United Kingdom. RESULTS: We evaluated 125 patients. CMB were present in 34% of patients and their presence was strongly influenced by the age. Twenty-nine percent of the patients had CMB in deep subcortical location, 22% in a lobar location, and 18% in infratentorial regions. After adjustment for age, factors significantly associated with a higher total number of CMB were hemorrhagic stroke, dementia, urge incontinence, and statins use (this latter not confirmed by multivariate analysis). Infratentorial and deep CMB were associated with dementia and urge incontinence, lobar CMB with hemorrhagic stroke, dementia, and statins use. Unexpectedly, patients with migraine, with or without aura, had a lower total, deep, and lobar number of CMB than patients without migraine. DISCUSSION: CMB formation in CADASIL seems to increase with age. History of hemorrhagic stroke, dementia, urge incontinence, and statins use are associated with a higher number of CMB. However, these findings need to be confirmed by longitudinal studies.

Heterozygous mutations of HTRA1 gene in patients with familial cerebral small vessel disease.

AIMS: 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.

Vitamin D levels in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

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 < 0.05) in no-to-mild CADASIL patients and a higher number of subjects with severe deficiency [25(OH)D <10 ng/ml]. Vitamin D levels did not correlate with vascular risk factors, clinical data or Fazekas score. The role of vitamin D is worth to be further explored in prospective studies.

Circulating Biomarkers in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Patients.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microangiopathy presenting with variable features, including migraine, psychiatric disorders, stroke, and cognitive decline and variable disability. On neuroimaging, CADASIL is characterized by leukoencephalopathy, multiple lacunar infarcts, and microbleeds. Previous studies suggest a possible role of endothelial impairment in the pathogenesis of the disease. METHODS: We assessed plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM) and the blood levels of endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) in 49 CADASIL patients and 49 age-matched controls and their association with clinical/functional and neuroimaging features. RESULTS: In multivariate analysis, CADASIL patients had significantly higher vWF and lower EPC levels. TM levels were similar in the 2 groups. CADASIL patients with a more severe clinical phenotype (history of stroke or dementia) presented lower CPC levels in comparison with patients with a milder phenotype. On correlation analysis, lower CPC levels were associated with worse performances on neuropsychological, motor and functional tests, and with higher lesion load on brain magnetic resonance imaging (degree of leukoencephalopathy and number of lacunar infarcts). CONCLUSIONS: This is the first CADASIL series in which multiple circulating biomarkers have been studied. Our findings support previous studies on the presence and the possible modulating effect of endothelial impairment in the disease. Furthermore, our research data suggest that blood CPCs may be markers of disease severity.

Cerebral microbleeds in patients with mild cognitive impairment and small vessel disease: The Vascular Mild Cognitive Impairment (VMCI)-Tuscany study.

BACKGROUND AND OBJECTIVES: Cerebral microbleeds (CMBs) are a neuroimaging expression of small vessel disease (SVD). We investigated in a cohort of SVD patients with mild cognitive impairment (MCI): 1) the reliability of the Microbleed Anatomical Rating Scale (MARS); 2) the burden and location of CMBs and their association with cognitive performances, independent of other clinical and neuroimaging features. METHODS: Patients underwent clinical, neuropsychological (4 cognitive domains), and MRI assessments. CMBs were assessed by three raters. RESULTS: Out of the 152 patients (57.2% males; mean age±SD: 75.5±6.7years) with gradient-echo (GRE) sequences, 41 (27%) had at least one CMB. Inter-rater agreement for number and location of CMBs ranged from good to very good [multi-rater Fleiss kappa (95%CI): 0.70-0.95]. Lacunar infarcts and some clinical variables (e.g., hypertension and physical activity) were associated with CMBs in specific regions. Total number of CMBs and of those in deep and lobar regions were associated with attention/executive and fluency domains. DISCUSSION: MARS is a reliable instrument to assess CMBs in SVD patients with MCI. Nearly one third of these patients had at least one CMB. Total CMBs burden was associated with attention/executive functions and fluency domains impairment, lacunar infarcts, and with some potentially modifiable risk factors.

White matter microstructural damage and depressive symptoms in patients with mild cognitive impairment and cerebral small vessel disease: the VMCI-Tuscany Study.

BACKGROUND AND PURPOSE: Disruption of cortical-subcortical circuits related to small vessel disease (SVD) may predispose to depression in the elderly. We aimed to determine the independent association between white matter (WM) microstructural damage, evaluated with diffusion tensor imaging (DTI), and depressive symptoms in a cohort of elderly subjects with mild cognitive impairment (MCI) and SVD. METHODS: The vascular mild cognitive impairment (VMCI)-Tuscany Study is an observational multicentric longitudinal study that enrolled patients with MCI and moderate to severe degrees of WM hyperintensities on MRI. Lacunar infarcts, cortical atrophy, medial temporal lobe atrophy, microbleeds, and DTI-derived indices (mean diffusivity, MD and fractional anisotropy, FA) were evaluated on baseline MRI. Geriatric Depression Scale (GDS) (score 0-15) was used to assess depressive symptoms. An extensive neuropsychological battery, Instrumental Activities of Daily Living scale, and the Short Physical Performance Battery were used for cognitive, functional, and motor assessments, respectively. RESULTS: Seventy-six patients (mean age: 75.1 ± 6.8 years) were included. Univariate analyses showed a significant association between GDS score and both DTI-derived indices (MD: r = 0.307, p = 0.007; FA: r = -0.245; p = 0.033). The association remained significant after adjustment for age, WM hyperintensities severity, global cognitive, functional and motor performances, and antidepressant therapy (MD: r = 0.361, p = 0.002; FA: r = -0.277; p = 0.021). CONCLUSIONS: These results outline the presence of an association between WM microstructural damage and depressive symptoms in MCI patients with SVD. This relationship does not seem to be mediated by disability, cognitive, and motor impairment, thus supporting the vascular depression hypothesis.

Operationalizing mild cognitive impairment criteria in small vessel disease: the VMCI-Tuscany Study.

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.

CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients.

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.

White matter microstructural damage in small vessel disease is associated with Montreal cognitive assessment but not with mini mental state examination performances: vascular mild cognitive impairment Tuscany study.

BACKGROUND AND PURPOSE: Montreal Cognitive Assessment (MoCA) has been proposed as a screening tool in vascular cognitive impairment. Diffusion tensor imaging is sensitive to white matter microstructural damage. We investigated if diffusion tensor imaging-derived indices are more strongly associated with performances on MoCA or on the widely used mini mental state examination in patients with mild cognitive impairment and small vessel disease. METHODS: Mild cognitive impairment patients with moderate/severe degrees of white matter hyperintensities on MRI were enrolled. Lacunar infarcts, cortical atrophy, medial temporal lobe atrophy and median values of mean diffusivity and fractional anisotropy of the cerebral white matter were studied and correlated with cognitive tests performances. RESULTS: Seventy-six patients (mean age 75.1±6.8 years, mean years of education 8.0±4.3) were assessed. In univariate analyses, a significant association of both MoCA and mini mental state examination scores with age, education, cortical atrophy, and medial temporal lobe atrophy was found, whereas mean diffusivity and fractional anisotropy were associated with MoCA. In partial correlation analyses, adjusting for all demographic and neuroimaging variables, both mean diffusivity and fractional anisotropy were associated only with MoCA (mean diffusivity: r= -0.275, P=0.023; fractional anisotropy: r=0.246, P=0.043). CONCLUSIONS: In patients with mild cognitive impairment and small vessel disease, diffusion tensor imaging-measured white matter microstructural damage is more related to MoCA than mini mental state examination performances. MoCA is suited for the cognitive screening of patients with small vessel disease.

Inherited leukoencephalopathies with clinical onset in middle and old age.

The currently widespread use of neuroimaging has led neurologists to often face the problem of the differential diagnosis of white matter diseases. There are various forms of leukoencephalopathies (vascular, inflammatory and immunomediated, infectious, metabolic, neoplastic) and sometimes white matter lesions are expression of a genetic disease. While many inherited leukoencephalopathies fall in the child neurologist's interest, others may have a delayed or even a typical onset in the middle or old age. This field is rapidly growing and, in the last few years, many new inherited white matter diseases have been described and genetically defined. A non-delayed recognition of middle and old age inherited leukoencephalopathies appears important to avoid unnecessary tests and therapies in the patient and to possibly anticipate the diagnosis in relatives. The aim of this review is to provide a guide to direct the diagnostic process when facing a patient with a suspicion of an inherited form of leukoencephalopathy and with clinical onset in middle or old age. Based on a MEDLINE search from 1990 to 2013, we identified 24 middle and old age onset inherited leukoencephalopathies and reviewed in this relation the most recent findings focusing on their differential diagnosis. We provide summary tables to use as a check list of clinical and neuroimaging findings that are most commonly associated with these forms of leukoencephalopathies. When present, we reported specific characteristics of single diseases. Several genetic diseases may be suspected in patients with middle or old age and white matter abnormalities. In only few instances, pathognomonic clinical or associated neuroimaging features help identifying a specific disease. Therefore, a comprehensive knowledge of the characteristics of these inherited white matter diseases appears important to improve the diagnostic work-up, optimize the choice of genetic tests, increase the number of diagnosed patients, and stimulate the research interest in this field.

The Florence VAS-COG clinic: a model for the care of patients with cognitive and behavioral disturbances consequent to cerebrovascular diseases.

BACKGROUND AND OBJECTIVE: Services dedicated to patients with cognitive and behavioral consequences of cerebrovascular diseases are not well established. In this paper, we report on the general organization of such a service (the Florence VAS-COG Clinic) after 9 years of activity, updating a previous work related to the first 5 years. METHODS: The Florence VAS-COG clinic, started in 2006, is an outpatient service dedicated to the assessment and follow-up of patients with cerebrovascular diseases and related cognitive, psychiatric, and behavioral disturbances. The staff involved in the clinic is composed of certified neurologists, one neuropsychologist, and neurology residents. The diagnostic protocol includes detailed personal and family history, general and neurologic examinations, and functional, neuropsychological, and neuroimaging assessment. After this work-up, comprehensive diagnoses are made. RESULTS: From January 2006 to March 2014, 600 patients (mean age 67.3 years ± 13.9; 52% females) have been evaluated in the clinic. Cognitive impairment, including mild cognitive impairment and dementia, mainly of vascular origin, was the most common (36.4%) diagnostic category, followed by suspected or confirmed familial micro-angiopathy (35.8%). Compared to the first years of activity, we are now facing the need of augmenting the number of visits due to increasing request and to better implement the multidisciplinarity of the team. Efforts are currently directed towards the definition of management protocols in pharmacological and non-pharmacological strategies. CONCLUSIONS: The establishment of a VAS-COG clinic represents an important step for the appreciation of the patient clinical needs and for the implementation of screening, diagnostic, and treatment options in the field of the neuropsychiatric consequences of cerebrovascular diseases.

Association of the variant Cys139Arg at GRN gene to the clinical spectrum of frontotemporal lobar degeneration.

BACKGROUND: Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer's disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them. OBJECTIVE: Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD. METHODS: The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples. RESULTS: The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein. CONCLUSION: We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD.

Cerebral hemorrhages in CADASIL: report of four cases and a brief review.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease, clinically characterized by migraine, recurrent transient ischemic attacks or strokes, psychiatric disorders and cognitive decline. Strokes are typically ischemic, while hemorrhagic events have been only sporadically described. However, cerebral microbleeds have been found in 31-69% of CADASIL patients. METHODS: We describe four unrelated CADASIL patients who had hemorrhagic strokes. We also briefly review the literature on intracerebral hemorrhage (ICH) in CADASIL. RESULTS: Three patients had a thalamo-capsular hemorrhage (age at onset: 54, 67, 77) and one of these had a second hemispheric cerebellar hemorrhage. Another patient experienced an interpeduncular cistern subarachnoid hemorrhage when he was 39. None of these patients was receiving antiplatelets, anticoagulants or statins at the time of hemorrhage; all were hypertensive. NOTCH3 gene analysis revealed mutations on exons 14, 22 (two patients presenting the same mutation), and 24. MRI signs of previous hemorrhages were present in all these patients. CONCLUSIONS: Hemorrhagic stroke can occur in CADASIL similarly to sporadic cerebral small vessel diseases; this finding expands the phenotype of the disease. A diagnosis of CADASIL should probably be considered also in patients with ICH. These data bear potential implications in terms of need of better control of risk factors, particularly hypertension, and raise relevant questions about the use of antiplatelets as prevention measures in CADASIL patients.

The Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Scale: a screening tool to select patients for NOTCH3 gene analysis.

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) phenotype is highly variable, and, although the full clinical-neuroimaging picture may be suggestive of the disease, no characteristic is pathognomonic. Thus, a genetic test remains the diagnostic gold standard, but because it is costly and time-consuming, a pregenetic screening appears desirable. We aimed at developing the CADASIL scale, a screening tool to be applied in the clinical setting. METHODS: A preliminary scale was created assigning weighted scores to common disease features based on their frequencies obtained in a pooled analysis of selected international CADASIL series. The accuracy of the scale versus the genetic diagnosis was tested with receiver operating characteristic analysis after the application of this scale to 61 CADASIL and 54 NOTCH3-negative patients (no pathogenic mutation on exons 2-23 of the NOTCH3 gene). To improve the scale accuracy, we then developed an ad hoc optimization algorithm to detect the definitive scale. A third group of 39 patients affected by sporadic small-vessel disease was finally included in the algorithm to evaluate the stability of the scale. RESULTS: The cutoff score of the definitive CADASIL scale had a sensitivity of 96.7% and a specificity of 74.2%. This scale was robust to contamination of patients with sporadic small-vessel disease. CONCLUSIONS: The CADASIL scale is a simple and sufficiently accurate screening tool to select patients with a high probability to be affected by the disease and therefore to be subjected to the genetic testing.

Risk and Determinants of Dementia in Patients with Mild Cognitive Impairment and Brain Subcortical Vascular Changes: A Study of Clinical, Neuroimaging, and Biological Markers-The VMCI-Tuscany Study: Rationale, Design, and Methodology.

Dementia is one of the most disabling conditions. Alzheimer's disease and vascular dementia (VaD) are the most frequent causes. Subcortical VaD is consequent to deep-brain small vessel disease (SVD) and is the most frequent form of VaD. Its pathological hallmarks are ischemic white matter changes and lacunar infarcts. Degenerative and vascular changes often coexist, but mechanisms of interaction are incompletely understood. The term mild cognitive impairment defines a transitional state between normal ageing and dementia. Pre-dementia stages of VaD are also acknowledged (vascular mild cognitive impairment, VMCI). Progression relates mostly to the subcortical VaD type, but determinants of such transition are unknown. Variability of phenotypic expression is not fully explained by severity grade of lesions, as depicted by conventional MRI that is not sensitive to microstructural and metabolic alterations. Advanced neuroimaging techniques seem able to achieve this. Beside hypoperfusion, blood-brain-barrier dysfunction has been also demonstrated in subcortical VaD. The aim of the Vascular Mild Cognitive Impairment Tuscany Study is to expand knowledge about determinants of transition from mild cognitive impairment to dementia in patients with cerebral SVD. This paper summarizes the main aims and methodological aspects of this multicenter, ongoing, observational study enrolling patients affected by VMCI with SVD.

Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary experience.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by NOTCH3 mutations. It is characterized by migraine, with or without aura, ischemic events, psychiatric and cognitive disturbances. There is no approved treatment for migraine prophylaxis in CADASIL, but acetazolamide has been anecdotally reported to be effective. We retrospectively reviewed our database of patients with a genetic diagnosis of CADASIL to identify how many of them were treated with acetazolamide for the prophylaxis of migraine. The efficacy and the tolerability of this treatment were checked looking at the clinic reports. Acetazolamide was prescribed in seven patients; the mean duration of treatment was 6 months, and the daily dose ranged from 125 to 500 mg. Three patients had a total and sustained remission, while in two patients a reduction in attacks and an improvement of the headache intensity were recorded. In one of these, acetazolamide was deliberately taken only during the migraine attack and the beneficial effect started 1 h after administration. In two patients, the drug did not produce any beneficial effect. Mild side effects were recorded in two patients. Our preliminary experience expands previous reports and confirms the possible efficacy of acetazolamide in CADASIL migraine. Based on these data, a randomized controlled trial seems worthy to be carried out to test the efficacy and safety of this drug.