Discovering the Italian phenotype of cerebral amyloid angiopathy (CAA): the SENECA project.

Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.

Carotid artery stenting in patients with acute coronary syndrome: a possible primary therapy for symptomatic carotid stenosis.

PURPOSE: To report the results of carotid artery stenting (CAS) in symptomatic patients (stroke/transient ischemic attack) after recent percutaneous transluminal coronary angioplasty (PTCA) for acute coronary syndrome (ACS). METHODS: Between January 2009 and July 2011, 28 consecutive patients (18 women; mean age 66 years, range 42-82) underwent protected CAS for symptomatic carotid stenosis following recent PTCA that included bare or drug-eluting stents requiring uninterrupted dual antiplatelet therapy. Primary technical success, neurological complications, major adverse cardiovascular events, and death were evaluated at 30 days and over midterm follow-up. RESULTS: Technical success was 96%; 1 patient suffered a nonfatal major stroke (3.5% 30-day stroke rate) during the procedure. During a median 21.6-month follow-up, 4 (14%) patients died of myocardial infarction (all diabetic smokers with ejection fractions <40%), but there were no new neurological events. Estimated survival was 89.3% at 2 years. Further coronary interventions were performed in 2 diabetic patients with a body mass index >34 kg/m(2). CONCLUSION: This preliminary experience demonstrated that CAS is a reasonable, safe, and effective treatment for patients with symptomatic carotid artery stenosis who were recently treated with coronary stents requiring uninterrupted dual antiplatelet therapy.

Coexistence of Amyotrophic Lateral Sclerosis and Alzheimer's Disease: Case Report and Review of the Literature.

We describe a case of amyotrophic lateral sclerosis (ALS) associated with Alzheimer's disease (AD) and review the literature about the coexistence of the two entities, highlighting the following: mean age at onset is 63.8 years, with slight female predominance; ALS tends to manifest after cognitive impairment and often begins in the bulbar region; average disease duration is 3 years; cognitive phenotype is mostly amnestic; the pattern of brain involvement is, in most cases, consistent with AD. Our case and the reviewed ones suggest that patients with ALS and dementia lacking unequivocal features of FTD should undergo additional examinations in order to recognize AD.

Novel Twinkle (PEO1) gene mutations in mendelian progressive external ophthalmoplegia.

Multiple deletions of mitochondrial DNA (mtDNA) are associated with different mitochondrial disorders inherited as autosomal dominant and recessive traits. Causative mutations have been found in five genes, mainly involved in mtDNA replication and stability. They include POLG1, the gene encoding the catalytic subunit of mtDNA polymerase (pol gamma), POLG2 encoding its accessory subunit, ANT1 coding the adenine nucleotide translocator and PEO1 which codes for Twinkle, the mitochondrial helicase. Finally OPA1 missense mutations are involved in phenotypes presenting optic atrophy as a major feature.To define the relative contribution of POLG1, POLG2, ANT1 and PEO1 genes to the mtDNA multiple deletion syndromes, we analysed them in a cohort of 67 probands showing accumulation of multiple mtDNA deletions in muscle. The patients were predominantly affected with a mitochondrial myopathy with or without progressive external ophthalmoplegia (PEO). Genetic analysis revealed that 1) PEO1 has a major role in determining familial PEO, since it accounts for 26.8% of familial cases, followed by ANT1 (14.6%) and POLG1 (9.8%); 2) no mutations in any of the known genes were found in 53.7% of probands of this series. Six novel missense mutations contributing to the mutational load of PEO1 gene (p.R334P, p.W315S, p. S426N, p.W474S, p.F478I, p.E479K) were associated with an adult onset PEO phenotype.

Impact of obstructive sleep apnea on cardiac organ damage in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Both obstructive sleep apnea (OSA) and cardiac organ damage have a crucial role in acute ischemic stroke. Our aim is to explore the relationship between OSA and cardiac organ damage in acute stroke patients. METHODS: A total of 130 consecutive patients with acute ischemic stroke were enrolled. Patients underwent full multichannel 24-h polysomnography for evaluation of OSA and echocardiography to evaluate left ventricle (LV) mass index (LV mass/BSA, LV mass/height), thickness of interventricular septum (IVS) and posterior wall (LVPW), LV ejection fraction and left atrium enlargement. Information on occurrence of arterial hypertension and its treatment before stroke was obtained from patients' history. RESULTS: 61.9% (70) of patients, mostly men (67.1%), with acute stroke had OSA (AHI > 10). Patients with acute stroke and OSA showed a significant increase (P < 0.05) of LV mass index, IVS and LVPW thickness and a significant left atrial enlargement as compared with patients without OSA. LV ejection fraction was not significantly different in stroke patients with and without OSA and was within normal limits. No relationship was found among cardiac alterations, occurrence of OSA and history of hypertension. CONCLUSION: Acute stroke patients with OSA had higher LV mass and showed greater left atrial enlargement than patients without OSA. This study confirms the high prevalence of OSA in stroke patients, suggesting also an association between OSA and cardiac target organ damage. Our finding of structural LV abnormalities in acute stroke patients with OSA suggests a potential role of OSA as contributing factor in determining both cerebrovascular and cardiac damage, even in absence of clear link with a history of blood pressure elevation.

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

The THRombolysis and STatins (THRaST) study.

OBJECTIVE: To assess the impact on stroke outcome of statin use in the acute phase after IV thrombolysis. METHODS: Multicenter study on prospectively collected data of 2,072 stroke patients treated with IV thrombolysis. Outcome measures of efficacy were neurologic improvement (NIH Stroke Scale [NIHSS] ≤ 4 points from baseline or NIHSS = 0) and major neurologic improvement (NIHSS ≤ 8 points from baseline or NIHSS = 0) at 7 days and favorable (modified Rankin Scale [mRS] ≤ 2) and excellent functional outcome (mRS ≤ 1) at 3 months. Outcome measures of safety were 7-day neurologic deterioration (NIHSS ≥ 4 points from baseline or death), symptomatic intracerebral hemorrhage type 2 with NIHSS ≥ 4 points from baseline or death within 36 hours, and 3-month death. RESULTS: Adjusted multivariate analysis showed that statin use in the acute phase was associated with neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.26-2.25; p < 0.001), major neurologic improvement (OR 1.43, 95% CI 1.11-1.85; p = 0.006), favorable functional outcome (OR 1.63, 95% CI 1.18-2.26; p = 0.003), and a reduced risk of neurologic deterioration (OR: 0.31, 95% CI 0.19-0.53; p < 0.001) and death (OR 0.48, 95% CI 0.28-0.82; p = 0.007). CONCLUSION: Statin use in the acute phase of stroke after IV thrombolysis may positively influence short- and long-term outcome.

NOTCH3 gene mutations in subjects clinically suspected of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations involving loss or gain of a cysteine residue in the NOTCH3 gene. A cluster of mutations around exons 3 and 4 was originally reported. Identification of pathogenic mutation is important for diagnostic confirmation of the disease, however genetic counselling and testing of relatives at risk is critical in mutation carriers. METHODS: Mutation analysis of the NOTCH3 gene was performed through direct sequencing in 140 patients with clinical suspicion of CADASIL. Patients underwent genetic counselling pre and post testing. The 2-23 exons containing all EGF-like domains were screened. RESULTS: 14 familial forms of the disease have been identified with 14 different causative mutations in exons 2, 3, 4, 5, 7, 10, 14, 19, 20 and 22 of the NOTCH3 gene; no pathogenetic mutations have been identified in exons 6 and 8; several genetic variations both in coding as well as in intronic regions were identified too. CONCLUSIONS: Our data confirm the importance of screening the whole EGF-like domains region of NOTCH3 gene for the molecular diagnosis of CADASIL among the Italian population too. Moreover genetic variants different from loss or gain of a cysteine residue are identified and presented.