Hyperosmolar hyperglycaemic state causing atypical status epilepticus with hippocampal involvement.

Diabetes mellitus may arise abruptly and decompensate suddenly, leading to a hyperglycaemic hyperosmolar state. Coma often ensues, although this usually reverses after the metabolic abnormalities have resolved. Acute symptomatic seizures can also occur in patients who are conscious, although these usually resolve after osmolarity and glycaemia have normalised. We describe an elderly woman who failed to regain vigilance despite prompt treatment; the cause was an unusual non-convulsive status epilepticus arising from the mesial temporal lobe and promoting a progressive and selective hippocampal involvement. During follow-up, her seizures recurred after stopping antiseizure medication and she developed hippocampal sclerosis, although she subsequently became seizure-free with antiseizure medications. Patients who are unresponsive in a hyperglycaemic hyperosmolar state may be having subclinical epileptiform discharges and risk developing permanent brain damage and long-term epilepsy.

Cerebral Cortical Microinfarcts on Magnetic Resonance Imaging and Their Association With Cognition in Cerebral Amyloid Angiopathy.

Background and Purpose- We aimed to explore the association between presence of cerebral cortical microinfarcts (CMIs) on magnetic resonance imaging and other small-vessel disease neuroimaging biomarkers in cerebral amyloid angiopathy (CAA) and to analyze the role of CMIs on individual cognitive domains and dementia conversion. Methods- Participants were recruited from an ongoing longitudinal research cohort of eligible CAA patients between March 2006 and October 2016. A total of 102 cases were included in the analysis that assessed the relationship of cortical CMIs to CAA neuroimaging markers. Ninety-five subjects had neuropsychological tests conducted within 1 month of magnetic resonance imaging scanning. Seventy-five nondemented CAA patients had cognitive evaluation data available during follow-up. Results- Among 102 patients enrolled, 40 patients had CMIs (39%) on magnetic resonance imaging. CMIs were uniformly distributed throughout the cortex without regional predilection ( P=0.971). The presence of CMIs was associated with lower total brain volume (odds ratio, 0.85; 95% CI, 0.74-0.98; P=0.025) and presence of cortical superficial siderosis (odds ratio, 2.66; 95% CI, 1.10-6.39; P=0.029). In 95 subjects with neuropsychological tests, presence of CMIs was associated with impaired executive function (ß, -0.23; 95% CI, -0.44 to -0.02; P=0.036) and processing speed (ß, -0.24; 95% CI, -0.45 to -0.04; P=0.020). Patients with CMIs had a higher cumulative dementia incidence compared with patients without CMIs ( P=0.043), whereas only baseline total brain volume (hazard ratio, 0.76; 95% CI, 0.62-0.92; P=0.006) independently predicted dementia conversion. Conclusions- Magnetic resonance imaging-detected CMIs in CAA correlated with greater overall disease burden. The presence of CMIs was associated with worse cognitive performance, whereas only total brain atrophy independently predicted dementia conversion.

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.

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.

The rehabilitation of attention in patients with mild cognitive impairment and brain subcortical vascular changes using the Attention Process Training-II. The RehAtt Study: rationale, design and methodology.

UNLABELLED: Cerebral small vessel disease (SVD) may cause attentional and executive cognitive deficits. No drug is currently available to improve cognitive performance or to prevent dementia in SVD patients, and cognitive rehabilitation could be a promising approach. We aimed to investigate: (1) the effectiveness of the Attention Process Training-II program in the rehabilitation of patients with mild cognitive impairment (MCI) and SVD; (2) the impact of the induced cognitive improvement on functionality and quality of life; (3) the effect of training on brain activity at rest and the possibility of a training-induced plasticity effect. The RehAtt study is designed as a 3-year prospective, single-blinded, randomized clinical trial. Inclusion criteria were: (1) MCI defined according to Winblad et al. criteria; (2) evidence of impairment across attention neuropsychological tests; (3) evidence on MRI of moderate/severe white matter hyperintensities. All enrolled patients are evaluated at baseline, and after 6 and 12 months, according to an extensive clinical, functional, MRI and neuropsychological protocol. The baseline RehAtt cohort includes 44 patients (66 % males, mean ± SD age and years of education 75.3 ± 6.8 and 8.3 ± 4.3, respectively). After baseline assessment, patients have been randomly assigned to 'attention training' or 'standard care'. Treatments and follow-up visits at 6 months are completed, while follow-up visits at 12 months are ongoing. This study is the first attempt to reduce attention deficits in patients affected by MCI with SVD. The results of this pilot experience will represent an essential background for designing larger multicenter, prospective, double-blinded, randomized and controlled clinical trials. TRIAL REGISTRATION: NCT02033850 (ClinicalTrials.gov Identifier).

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.

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.

Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: a randomized controlled trial.

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. METHODS: In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. RESULTS: The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, -0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. CONCLUSIONS: Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.

Treatment of vascular risk factors in patients with a diagnosis of Alzheimer's disease: a systematic review.

BACKGROUND: Increasing evidence suggests vascular risk factors (VRF) play a role in the pathogenesis of Alzheimer's disease (AD). Epidemiological studies have found associations between VRF and risk of AD. Treating VRF in patients with AD offers a potential treatment option but ineffective treatments should be avoided in this group who are frequently on multiple medications and in whom compliance may be challenging. METHODS: Studies containing information on the treatment of VRF in patients with a diagnosis of AD were identified using a defined search strategy. Randomised controlled trials and observational studies were included. RESULTS: The pre-specified search strategy retrieved 11,992 abstract articles, and 25 papers including those identified on review of reference lists and reviews met the inclusion criteria. Of these, 11 were randomised controlled trials (RCTs) and 14 observational studies. Observational studies suggested that a VRF package and treatment of hypertension and statin therapy may be associated with improved outcome but these studies suffered from potential bias. The few RCTs performed were mostly small with short duration follow-up, and do not provide clear evidence either way. CONCLUSIONS: Observational data raises the possibility that treating VRF could alter the rate of decline in AD. However RCT data are not yet available to support this hypothesis and to alter clinical practice. RCTs in larger numbers of individuals with longer follow-up, ideally in the early stages of AD, are required to address this potentially important treatment question.

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.

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.

The VAS-COG clinic: an out-patient service for patients with cognitive and behavioral consequences of cerebrovascular diseases.

Services dedicated to patients with cognitive and behavioral consequences of cerebrovascular diseases (CVD) are not established. We started an out-patient clinic (the "VAS-COG clinic") to assess patients with psycho-cognitive disturbances related to CVD. The work-up includes a clinical-neuroimaging diagnostic process and the individuation of the best therapeutic strategies as done in patients with neurodegenerative cognitive impairment. We report the results of the first 5 years of activity. Reasons for patient referral were not only cognitive, language, gait, and psychiatric disturbances related to stroke or chronic CVD, but also neuroimaging evidence of vascular encephalopathy and screening for familial microangiopathies. The patients were evaluated with uniformed protocols. From January 2006 to November 2010, we evaluated 403 patients. Of these, 374 (93%; mean age 69.7 years ± 15.0) were considered appropriate for the VAS-COG clinic. The following diagnoses were made: vascular dementia (8.6%), Alzheimer disease (2.1%), mixed dementia (vascular plus degenerative) (4.8%), vascular mild cognitive impairment (MCI) (9.1%), amnesic-MCI (8.0%), mixed-MCI (4.8%), post-stroke depression (2.7%), post-stroke language disturbances (4.5%), subjective memory complaint (1.3%), familiar microangiopathy (31.3%), vascular encephalopathy evidenced by neuroimaging not associated with specific clinical disturbances (15.3%), and other conditions (7.5%). Psycho-cognitive disturbances associated with CVD are heterogeneous. In addition to acute stroke care strategies, long-term assessment of patients with CVD is required. The VAS-COG clinic may represent a model in this regard and might be important for improving the care of patients and offering counseling to their families. The efficacy of this service needs, however, to be proved by successive work.

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.

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.

Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy-Related Inflammation: A Multicenter Prospective Longitudinal Cohort Study.

BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri). METHODS: This was a multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria recruited through the Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease ßiomarkers International Network from January 2013 to March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, gradient recalled echo-T2*, fluid-suppressed T2-weighted (fluid-attenuated inversion recovery), and T1 postgadolinium contrast-enhanced images acquired on 1.5T MRI, was used at the 3-, 6-, 12-, and 24-month follow-up. Centralized reads of MRIs were performed by investigators blinded to clinical, therapeutic, and time-point information. Main outcomes were survival, clinical and radiologic recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri. RESULTS: The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri). Their mean age was 72.9 years; 43.4% were female; 37.1% were APOEε4 carriers; 36.3% had a history of Alzheimer disease; and 33.6% had a history of ICH. A history of ICH and the occurrence of new ICH at follow-up were more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%, p < 0.0001 and 19.3% vs 3.6%, p < 0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% confidence interval [CI] 61.6%-78.5%) and 84.1% (95% CI 76.2%-90.6%) clinically recovered within 3 and 12 months, followed by radiologic recovery in 45.1% (95% CI 36.4%-54.8%) and 77.4% (95% CI 67.7%-85.9%), respectively. After clinicoradiologic resolution of the first-ever episode, 38.3% (95% CI 22.9%-59.2%) had at least 1 recurrence within the following 24 months. Recurrence was more likely if IV high-dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering off (hazard ratio 4.68, 95% CI 1.57-13.93; p = 0.006). DISCUSSION: These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiologic acute manifestations of the disease and the effectiveness of slow oral tapering off after IV corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in ß-amyloid-driven diseases, including treatment-related ARIA in patients with Alzheimer disease exposed to immunotherapy drugs.

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.

Increased arterial stiffness is an independent risk factor for hemorrhagic transformation in ischemic stroke undergoing thrombolysis.

BACKGROUND: Hemorrhagic transformation (HT) is a multifactorial phenomenon and represents a possible complication of ischemic stroke, especially after thrombolytic treatment. Increased arterial stiffness has been associated with intracranial hemorrhage, but there is no evidence of association with HT after thrombolytic therapy. The aim of our study is to investigate a possible link between arterial stiffness and HT occurrence after thrombolytic therapy in patients with ischemic stroke. METHODS: We enrolled 258 patients (135 males, 123 females; mean age: 73±12years) with acute ischemic stroke undergoing intravenous thrombolysis or/and mechanical thrombectomy. All stroke patients underwent neuroimaging examination, 24-h heart rate and blood pressure monitoring and brain CT-scan after 24-72h to evaluate HT occurrence. The linear regression slope of diastolic on systolic blood pressure was obtained and assumed as a global measure of arterial compliance, and its complement (1 minus the slope), named arterial stiffness index (ASI), has been taken as a measure of arterial stiffness. RESULTS: Out of 258, HT occurred in 55 patients. ASI was significantly higher in patients with HT than in patients without HT (0.70±0.12 vs 0.62±0.14, p<0.001). Logistic regression model showed ASI as independent predictors of HT (OR: 1.9, 95% CI: 1.09-3.02, for every 0.2 increase of ASI): in particular, OR was 5.2 (CI: 2.22-12.24) when ASI was >0.71, in comparison with ASI lower than 0.57. CONCLUSIONS: Our results point to arterial stiffness as a novel independent risk factor for HT after ischemic stroke treated with thrombolysis, suggesting a particularly high bleeding risk when ASI is >0.71.

Effect of Attention Training in Mild Cognitive Impairment Patients with Subcortical Vascular Changes: The RehAtt Study.

BACKGROUND AND OBJECTIVE: Mild cognitive impairment (MCI) patients with small vessel disease (SVD) are at high dementia risk. We tested the effects of cognitive rehabilitation in these patients using the Attention Process Training-II (APT-II) program in a single-blinded, randomized clinical trial. METHODS: Patients were randomized to APT-II or standard care and evaluated at baseline, 6, and 12 months with functional, quality of life, cognitive tests, and resting state functional MRI (rsfMRI). RESULTS: Forty-six patients were enrolled and 43 (mean±SD age 75.1±6.8) completed the study. No change was seen in functionality and quality of life between treated and non-treated patients. However, the Rey Auditory-Verbal Learning Test immediate recall showed a significant improvement in treated compared to non-treated group (change score 6 versus 12 months: 1.8±4.9 and -1.4±3.8, p = 0.021; baseline versus 12 months: 3.8±6.1 and 0.2±4.4, p = 0.032). A higher proportion of treated patients had stable/better evaluation compared to non-treated group on Visual search test (6 versus 12 months: 95% versus 71%, p = 0.038) and Rey-Osterrieth Complex Figure copy (6 versus 12 months: 95% versus 67%, p = 0.027). RsfMRI, performed in a subsample, showed that the difference between follow-up and baseline in synchronization of activity in cerebellar areas was significantly greater in treated than in non-treated patients. CONCLUSION: We were unable to show a significant effect in quality of life or functional status in treated patients with MCI and SVD. However, APT-II produces some beneficial effects in focused attention and working memory and seems to increase activity in brain circuits involved in cognitive processes.

Diffusion Tensor Imaging to Map Brain Microstructural Changes in CADASIL.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) is sensitive to brain microstructural changes. The aims of this DTI study were to map voxelwise the spatial distribution of brain microstructural changes in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to investigate any correlation between DTI-derived indices and extension of T2 hyperintensity. METHODS: Eighteen patients with CADASIL and 18 age-, sex-, and education-level-matched healthy controls underwent magnetic resonance imaging at 3 T. Differences in DTI-derived indices (mean diffusivity [MD], fractional anisotropy [FA], axial [AD] and radial [RD] diffusivities, and mode of anisotropy [MO]) of brain white matter (WM) between CADASIL patients and healthy subjects were assessed through tract-based spatial statistics. Then, DTI-derived indices were correlated with the patient's score on the extended Fazekas visual scale of the T2 hyperintensity. RESULTS: When compared to healthy controls, CADASIL patients showed extensive symmetric areas of increased MD/RD and decreased AD/FA/MO that involved almost the entire hemispheric cerebral WM (internal and external capsule, WM of the temporal poles, superior and inferior longitudinal fasciculus, inferior frontal-occipital fasciculus, uncinate fasciculus, cingulum, forceps major and minor, corticospinal tracts, and thalamic radiations), thalami, and corpus callosum. Additional areas of increased RD were observed in pons, midbrain, cerebellar peduncles, and cerebellar WM. Only FA was negatively correlated with extended Fazekas visual score. CONCLUSIONS: Our results indicate that brain damage in CADASIL is associated with extensive microstructural changes implying impairment of intra- and inter-hemispheric cerebral, thalamocortical, and cerebrocerebellar connections. Severity of microstructural changes correlates with extension of T2 hyperintensity.