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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.

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.

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.

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.

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.

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: The insulin-like growth factor-1 (IGF-1) signaling system is regulated by many factors which interact in regulating the bioavailability of IGF-I. In this context, little information is available on free IGF-1, the bioactive form of IGF-1, in amyotrophic lateral sclerosis (ALS)., Methods: We investigated the endogenous expression of IGF-1, and two related binding proteins (IGF-binding proteins, IGFBP-2 and BP-3) in serum and cerebrospinal fluid (CSF) of 54 sporadic ALS (sALS) patients. Twenty-five healthy individuals and 25 with other neurological diseases (OND) were used as controls. Total and free IGF-1, and IGFBP-3 levels were detected by immunoradiometric assay (IRMA); IGFBP-2 levels were determined by radioimmunoassay (RIA)., Results: Total and free IGF-1, IGFBP-2 and BP-3 serum levels were not significantly different between patients and controls, although in sALS patients free IGF-1 was negatively correlated with ALS-Functional Rating Scale-revised (ALS-FRS-R) score (r = -0.4; P = 0.046) and forced vital capacity (FVC) (r = -0.55; P < 0.04). In CSF, free IGF-1 was significantly increased in sALS patients compared with OND (P < 0.0001)., Conclusions: Though in the serum we did not find significant differences amongst the three groups, IGF-1 bioavailability, represented by the free IGF-1 levels, correlated with disease severity. In the CSF, the significant increment of the free fraction of IGF-1 suggests an up-regulation of the IGF-1 system in the intrathecal compartment of sALS patients. Since IGF-1 is a trophic factor for different tissues, we speculate that high levels of the free IGF-1 in sALS might reflect a physiological defensive mechanism promoted in response to neural degeneration and/or muscle atrophy.

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.

The present study aims to demonstrate that errors when writing are more common than expected in patients affected by primary lateral sclerosis (PLS) with severe dysarthria or complete mutism, independent of spasticity. Sixteen patients meeting Pringle's et al. [34] criteria for PLS underwent standard neuropsychological tasks and evaluation of writing. We assessed writing abilities in spelling through dictation in which a set of words, non-words and short phrases were presented orally and by composing words using a set of preformed letters. Finally, a written copying task was performed with the same words. Relative to controls, PLS patients made a greater number of spelling errors in all writing conditions, but not in copy task. The error types included: omissions, transpositions, insertions and letter substitutions. These were equally distributed on the writing task and the composition of words with a set of preformed letters. This pattern of performance is consistent with a spelling impairment. The results are consistent with the concept that written production is critically dependent on the subvocal articulatory mechanism of rehearsal, perhaps at the level of retaining the sequence of graphemes in a graphemic buffer. In PLS patients a disturbance in rehearsal opportunity may affect the correct sequencing/assembly of an orthographic representation in the written process.

Mitochondrial disorders are human genetic diseases with extremely variable clinical and genetic features. To better define them, we made a genotype-phenotype correlation in a series of 207 affected patients, and we examined most of them with six laboratory examinations (serum CK and basal lactate levels, EMG, cardiac and EEG studies, neuroradiology). We found that, depending on the genetic abnormality, hyperckemia occurs most often with either chronic progressive external ophthalmoplegia (CPEO) and ptosis or with limb weakness. Myopathic EMGs are more common than limb weakness, except in patients with A8344G mutations. Peripheral neuropathy, when present, is always axonal. About 80% of patients with A3243G and A8344G mutations have high basal lactate levels, whereas pure CPEO is never associated with increased lactate levels. Cardiac abnormalities mostly consist of conduction defects. Abnormalities on CT or MRI of the brain are relatively common in A3243G mutations independently of the clinical phenotype. Patients with multiple mtDNA deletions are somehow "protected" against the development of abnormalities with any of the tests. We conclude that, despite the phenotypic heterogeneity of mitochondrial disorders, correlation of clinical features and laboratory findings may give the clinician important clues to the genetic defect, allowing earlier diagnosis and counselling.

Aim and Method: To verify whether muscle necrosis in critically ill patients could be due to an inflammatory process, we tested muscle biopsies from five intensive care patients with different inflammation-specific immunocytochemical markers (antibodies anti-class I major histocompatibility complex products (class I MHCP or HLA I), membrane attack complex (MAC), T lymphocytes helper-inducer (CD4), cytotoxic (CD8) and pan-B-lymphocytes)., Results: In three patients muscle biopsy showed class I MHCP positivity on the surface membrane of several groups of fibres, mainly perifascicular, and scattered microvascular deposits of MAC. In the other two patients muscle biopsy did not show class I MHCP and MAC positivity., Conclusion: Our results suggest that inflammation may be a component of muscle damage in some critically ill patients.

Two patients were treated with treatment-resistant polymyositis with intravenous immunoglobulin over four days at a dose of 0.4 g/kg/day. Clinical recovery followed within two months. Serum creatine kinase (CK) activity decreased to normal, and a clear improvement in muscle strength was observed. One patient showed neither clinical relapses nor increase in serum CK activity after 20 months. The other showed a mild increase in serum CK activity after 24 months and was successfully retreated with intravenous immunoglobulin. There were no significant adverse side effects.

Muscle glucose-6-phosphate dehydrogenase (G6PD) deficiency is described in four clinically heterogeneous patients: an athlete who developed myoglobinuria after physical exercise; a 7-year-old, mildly mentally retarded boy, who had episodes of dark urine and high creatine kinase; and two brothers of Sardinian origin, the elder showing moderate exercise intolerance. Histochemical and biochemical studies showed a lack of G6PD activity in muscle biopsy specimens as well as in erythrocytes. G6PD characterization in erythrocytes classified these mutant enzymes as Mediterranean variant in all the patients. The deficiency was confirmed in the patients' myotubes and skin fibroblasts, where residual activity was present. Electrophoretic studies in tissue culture extracts showed that the residual muscle enzyme migrated as a single electrophoretic band like normal human muscle G6PD.

We report biochemical, immunological, and morphological findings in a patient with fatal Kearns-Sayre syndrome. Histochemical and biochemical findings from muscle biopsy specimens obtained 7 years apart documented the disease's evolution from a mild mitochondrial disorder affecting a small proportion of muscle fibers to a severe disorder affecting a large proportion of muscle fibers. Cytochrome c oxidase activity in muscle declined profoundly as the disease progressed, although the level of enzyme protein was normal, as shown by immunochemical techniques. Other organs were severely affected by the disease. Examination of postmortem tissue showed spongiosis in the frontal cortex, diffuse loss of Purkinje cells in the cerebellum, liver steatosis, and heart fibrosis with mitochondrial abnormalities. Cytochrome c oxidase activity was only slightly reduced in these organs.

Histochemical, biochemical and immunologic analysis of cytochrome c oxidase (COX) in skeletal muscle, heart and kidney during human fetal development was performed. COX histochemical activity was present only in few muscle fibres from the 11th to the 20th week of gestation. At the same developmental stage intrafusal muscle fibres, heart and kidney already showed strong activity. At the 28th week of gestation muscular COX activity was present in about 90% of the fibres. Tissue biochemical analysis confirmed these histochemical findings. Histochemical and biochemical findings compared to the immunocytochemical results and ELISA indicate that COX activity parallels the progressive synthesis of the enzyme in each tissue.

Calcium (Ca2+) is mainly bound to anionic phospholipids and to sialic acid at the cell surface. We studied the ultrastructural localization of these Ca2+ binding sites in normal human muscle fibers, using Polymyxin B as a marker for anionic phospholipids and the lectin Limulus Polyphemus as a probe for sialic acid. We found that anionic phospholipids have a patchy distribution along the muscle sarcolemma, with a preferential localization at the I band level and at the junction between the I and A band. Sialic acid has an uniform distribution along the muscle plasma membrane and basal lamina. Our observations suggest that the plasma membrane, basal lamina, and transverse tubular system play an important role in providing the negative charge of the human muscle cell surface and that these structures may be involved in the binding of calcium.