Neurology

Smith-Magenis syndrome (SMS), a neurodevelopmental disorder characterized by dysmorphic features, intellectual disability (ID), and sleep disturbances, results from a 17p11.2 microdeletion or a mutation in the RAI1 gene. We performed exome sequencing on 6 patients with SMS-like phenotypes but without chromosomal abnormalities or RAI1 variants. We identified pathogenic de novo variants in two cases, a nonsense variant in IQSEC2 and a missense variant in the SAND domain of DEAF1, and candidate de novo missense variants in an additional two cases. One candidate variant was located in an alpha helix of Necdin (NDN), phased to the paternally inherited allele. NDN is maternally imprinted within the 15q11.2 Prader-Willi Syndrome (PWS) region. This can help clarify NDN's role in the PWS phenotype. No definitive pathogenic gene variants were detected in the remaining SMS-like cases, but we report our findings for future comparison. This study provides information about the inheritance pa...

Niemann-Pick Disease, type C1 (NPC1) is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI) of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. We hypothesize that cerebellar volume, fractional anisotropy (FA) and mean diffusivity (MD) negatively correlate with NIH NPC neurological severity score (NNSS) and motor severity subscores. Magnetic resonance imaging (MRI) was obtained for thirty-nine NPC1 subjects, ages 1-21.9 years (mean = 11.1, SD = 6.1). Using an atlas-based automated approach, the cerebellum of each patient was measured for FA, MD and volume. Additionally, each patient was given an NNSS. Decreased cerebellar FA and volume, and elevated MD correlate with higher NNSS. The cognition subscore and motor subscores for eye movement, ambulation, speech, swallowing, and fine motor skills were also statistically significant. Microstructural disorganization negatively correlated with motor severity in subjects. Additionally, Miglustat therapy correlated with lower severity scores across ranges of FA, MD and volume in all regions except the inferior peduncle, where a paradoxical effect was observed at high FA values. These findings suggest that DTI is a promising prognostication tool.

Congenital disorders of glycosylation (CDGs) are disorders of abnormal protein glycosylation that affect multiple organ systems. Because most CDGs have been described in only a few individuals, our understanding of the associated phenotypes and the mechanisms of individual survival are limited. In the process of studying two siblings, aged 6 and 11 years, with MOGS-CDG and biallelic MOGS (mannosyl-oligosaccharide glucosidase) mutations (GenBank: NM_006302.2; c.[65C>A; 329G>A] p.[Ala22Glu; Arg110His]; c.[370C>T] p.[Gln124*]), we noted that their survival was much longer than the previous report of MOGS-CDG, in a child who died at 74 days of age. Upon mutation analysis, we detected multiple MOGS genotypes including wild-type alleles in their cultured fibroblast and peripheral blood DNA. Further analysis of DNA from cultured fibroblasts of six individuals with compound heterozygous mutations of PMM2 (PMM2-CDG), MPI (MPI-CDG), ALG3 (ALG3-CDG), ALG12 (ALG12-CDG), DPAGT1 (DPAGT1-CDG), and ALG1 (ALG1-CDG) also identified multiple genotypes including wild-type alleles for each. Droplet digital PCR showed a ratio of nearly 1:1 wild-type to mutant alleles for most, but not all, mutations. This suggests that mitotic recombination contributes to the survival and the variable expressivity of individuals with compound heterozygous CDGs. This also provides an explanation for prior observations of a reduced frequency of homozygous mutations and might contribute to increased levels of residual enzyme activity in cultured fibroblasts of individuals with MPI-and PMM2-CDGs.

Purpose In the chronic phase after mild traumatic brain injury (mTBI), microhaemorrhages are frequently detected on magnetic resonance imaging (MRI). It is however unclear whether microhaemorrhages are associated with functional outcome and which MRI sequence is most appropriate to address this association. We aimed to determine the association between microhaemorrhages and functional outcome in the chronic posttraumatic phase after injury with the most suitable MRI sequence to address this association. Methods One hundred twenty-seven patients classified with mTBI admitted to the outpatient clinic from 2008 to 2015 for persisting posttraumatic complaints were stratified according to the presence of MRI abnormalities (n = 63 (MRI+ group) and n = 64 without abnormalities (MRI-group)). For the detection of microhaemorrhages, susceptibility-weighted imaging (SWI) and T2* gradient recalled echo (T2*GRE) were used. The relation between the functional outcome (dichotomized Glasgow Outcome Scale Extended scores) and the number and localization of microhaemorrhages was analysed using binary logistic regression. Results SWI detected twice as many microhaemorrhages compared to T2*GRE: 341 vs. 179. Lesions were predominantly present in the frontal and temporal lobes. Unfavourable outcome was present in 67% of the MRI+ group with a significant association of total number of microhaemorrhages in the temporal cortical area on SWI (OR 0.43 (0.21-0.90) p = 0.02), with an explained variance of 44%. The number of microhaemorrhages was not correlated with the number of posttraumatic complaints. Conclusion An unfavourable outcome in the chronic posttraumatic phase is associated with the presence and number of microhaemorrhages in the temporal cortical area. SWI is preferably used to detect these microhaemorrhages. Keywords Mild traumatic brain injury . MRI . Microhaemorrhages . Functional outcome . SWI and T2*GRE * J. van der Naalt j.van.

Objective: To investigate brain b-amyloid binding in subjects with Down syndrome (DS) using [ 18 F] florbetaben PET imaging. Methods: Thirty-nine subjects with DS (46.3 6 4.7 years) were assessed with [ 18 F]florbetaben PET imaging. Three blinded independent readers assessed the scans to provide a visual analysis. The primary quantitative imaging outcome was a standardized uptake value ratio (SUVR) obtained for 6 brain regions. Cognitive status was evaluated using the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). Results: [ 18 F]Florbetaben uptake was correlated with age (p , 0.0001, R 2 5 0.39); 90% of scans in subjects with DS aged 50 years or older (SUVR 5 1.62 6 0.26), 53% in those aged 45 to 49 years (SUVR 5 1.43 6 0.16), and 7% in those aged 40 to 45 years (SUVR 5 1.27 6 0.11) were visually assessed as positive. Visual and quantitative assessments were highly related (x 2 5 11.3823, p 5 0.0007; Cohen k 5 0.58). Only 2 of 34 participants were considered to have dementia by the DSQIID. Conclusions: Brain b-amyloid binding, as measured by [ 18 F]florbetaben, increases with age in DS. Subjects with DS who have no evidence of dementia demonstrate brain b-amyloid binding in vivo, suggesting that [ 18 F]florbetaben PET imaging may detect b-amyloid in this at-risk population.

Prolonged exposure to nitrous oxide produces a recognized neurologic syndrome. We report clinical and electrophysiologic studies of nervous system involvement in a 25-year-old student who abused nitrous oxide. He developed signs of a sensorimotor polyneuropathy and of myelopathy. Routine blood studies, CSF examination, and myelogram were normal. Clinical electrophysiologic studies were performed serially. Nerve conduction studies demonstrated reduced amplitude and slowed sensory potentials, and mildly prolonged late responses. Sensory evoked potentials revealed prolonged latency of scalpevoked potentials from tibial nerve stimulation with normal median nerve values. The foveal visual evoked potential was delayed in the right eye, with normal visual acuity, funduscopic examination, and spatial contrast sensitivity. Repeat electrophysiologic studies demonstrated improvement. Nitrous oxide produces multifocal reversible dysfunction within the nervous system similar to that described in patients with vitamin B,, deficiency.

“Frontotemporal dementia” (FTD) is a clinical syndrome characterized by the focal involvement of the frontal and/or temporal lobes. FTD has three clinical phenotypes: the behavioral variant and two linguistic subtypes, namely, non-fluent/agrammatic primary progressive aphasia (PPA-NF/A) and semantic PPA (PPA-S). FTD is the second most common cause of dementia in individuals under the age of 65 years. This article presents recommendations for the diagnosis of FTD in the Brazilian scenario, considering the three levels of complexity of the health system: primary health care, secondary and tertiary levels. Diagnostic guidelines are proposed, including cognitive testing, behavioral and language assessments, laboratory tests, and neuroimaging.

he results of recent carotid artery stenting (CAS) vs carotid endarterectomy (CEA) randomized studies (CREST, 1 SPACE, 2 EVA3S, 3 and ICSS 4 ) have created conflict among surgical and endovascular communities over which procedure is preferred for secondary stroke prevention for symptomatic carotid stenosis. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) established CEA as the gold standard for surgical treatment in the early 1990s. Carotid stenting has been held to the high standard of CEA, and in order to present a viable alternative surgical therapy, it must be effective at preventing strokes, durable, and safe, with complication rates comparable to CEA. Carotid stenting is a clinically effective procedure. CREST, SPACE, and EVA3S showed equivalent annual stroke rates for the 2 treatments in symptomatic patients after the initial 30

Background and ObjectivesDeclines in stroke admission, IV thrombolysis (IVT), and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the effect of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), IVT, and mechanical thrombectomy over a 1-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020).MethodsWe conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, IVT treatments, and mechanical thrombectomy procedures. Diagnoses were identified by theirICD-10codes or ...

Background It has been reported that acute stroke services were compromised during COVID-19 due to various pandemic-related issues. We aimed to investigate these changes by recruiting centers from different countries. Methods Eight countries participated in this cross-sectional, observational, retrospective study by providing data from their stroke data base. We compared 1 year before to 1 year during COVID-19 as regards onset to door (OTD), door to needle (DTN), door to groin (DTG), duration of hospital stay, National Institute of Health Stroke Scale (NIHSS) at baseline, 24 h, and at discharge as well as modified Rankin score (mRS) on discharge and at 3 months follow-up. Results During the pandemic year, there was a reduction in the number of patients, median age was significantly lower, admission NIHSS was higher, hemorrhagic stroke increased, and OTD and DTG showed no difference, while DTN time was longer, rtPA administration was decreased, thrombectomy was more frequent, and hos...

Stroke is the second leading cause of death and the most common cause of adult disabilities among elderlies. It involves a complex series of mechanisms among which, excitotoxicity is of great importance. Also, miRNAs appear to play role in post-stroke excitotoxicity, and changes in their transcriptome occur right after cerebral ischemia. Recent data indicate that specific miRNAs such as miRNA-223, miRNA-181, miRNA-125a, miRNA-125b, miRNA-1000, miRNA-132 and miRNA-124a regulate glutamate neurotransmission and excitotoxicity during stroke. However, limitations such as poor in vivo stability, side effects and inappropriate biodistribution in miRNAbased therapies still exist and should be overcome before clinical application. Thence, investigation of the effect of application of these miRNAs after the onset of ischemia is a pivotal step for manipulating these miRNAs in clinical use. Given this, present review concentrates on miRNAs roles in post-ischemic stroke excitotoxicity.

OBJECTIVE: To analyze the clinical pharmacist interventions performed during the review of prescription orders of the Adult Intensive Care, Cardiologic Intensive Care, and Clinical Cardiology Units of a large tertiary teaching hospital in Brazil. METHODS: The analysis took place daily with the following parameters: dose, rate of administration, presentation and/or dosage form, presence of inappropriate/unnecessary drugs, necessity of additional medication, more proper alternative therapies, presence of relevant drug interactions, inconsistencies in prescription orders, physical-chemical incompatibilities/solution stability. From this evaluation, the drug therapy problems were classified, as well as the resulting clinical interventions. RESULTS: During the study, a total of 6,438 drug orders were assessed and 933 interventions were performed. The most prevalent drug therapy problems involved ranitidine (28.44%), enoxaparin (13.76%), and meropenem (8.26%). The acceptability of the int...

1 Care este rolul kinetoterapiei în recuperarea funcțională?
2 Ce este recuperarea funcțională?
3 Care sunt etapele planului de kinetoterapiei?
3.1 Observații preliminare și evaluarea stării pacientului
3.2 Screeningul durerii în etapa preliminară a kinetoterapiei
3.3 Evaluarea stilului de viață
3.4 Evaluarea și testarea reflexelor
3.5 Stabilirea obiectivelor
3.6 Elaborarea unui plan terapeutic
4 Resurse și suport pentru pacienți
5 Concluzii
6 Referințe

In view of upcoming clinical trials, quantitative molecular markers accessible in peripheral blood are of critical importance as prognostic or pharmacodynamic markers in genetic neurodegenerative diseases such as Spinocerebellar Ataxia Type 3 (SCA3), in particular for signaling target engagement. In this pilot study, we focused on the quantification of ataxin-3, the protein altered in SCA3, in human peripheral blood mononuclear cells (PBMCs) acquired from preataxic and ataxic SCA3 mutation carriers as well as healthy controls, as a molecular marker directly related to SCA3 pathophysiology. We established two different highly sensitive TR-FRET-based immunoassays to measure the protein levels of either total full-length, non-expanded and expanded, ataxin-3 or specifically polyQ-expanded ataxin-3. In PBMCs, a clear discrimination between SCA3 mutation carrier and controls were seen measuring polyQ-expanded ataxin-3 protein level. Additionally, polyQ-expanded ataxin-3 protein levels cor...

Objective-Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia (ADCA) of which the mutation causing the disease has recently been characterised as an expanded CAG trinucleotide repeat in the gene coding for the 1A -subunit of the voltage dependent calcium channel. The aim was to further characterise the SCA6 phenotype Methods-The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadic cerebellar ataxia and the CAG repeat length of the expanded allele was correlated with the disease phenotype. Results-Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Disease onset ranged from 30 to 71 years of age and was significantly later than in other forms of ADCA. Age at onset correlated inversely with repeat length. The SCA6 phenotype comprises predominantly cerebellar signs in concordance with isolated cerebellar atrophy on MRI. Non-cerebellar systems were only mildly aVected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAG repeat length. Conclusions-This study provides the first detailed characterisation of the SCA6 phenotype. Clinical features apart from cerebellar signs were highly variable in patients with SCA6. By comparison with SCA1, SCA2, and SCA3 no clinical or electrophysiological finding was specific for SCA6. Therefore, the molecular defect cannot be predicted from clinical investigations. In Germany, SCA6 accounts for about 13% of families with ADCA. However, up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadic disease due to late manifestation in apparently healthy parents. Genetic testing is therefore recommended for the SCA6 mutation also in patients with putative sporadic ataxia.

Background: Hereditary spastic paraplegias (HSP) are clinically and genetically highly heterogeneous. Recently two novel genes, SPG11(spatacsin) and SPG15 (spastizin), associated with autosomal recessive HSP (AR-HSP) were identified. Clinically, both are characterized by complicated HSP and a rather similar phenotype consisting of early onset spastic paraplegia, cognitive deficits, thin corpus callosum (TCC), peripheral neuropathy and mild cerebellar ataxia. Objective: To compare the frequency of SPG11 and SPG15 in patients with early onset complicated HSP and to further characterize the phenotype of SPG11 and SPG15. Results: A sample of 36 index patients with early onset complicated HSP and a family history compatible with autosomal recessive inheritance was collected and screened for mutations in SPG11 and SPG15. Overall frequency of SPG11 was 14% (5 out of 36) but was considerably higher in patients with TCC (42%). One single patient with mental retardation and thinning of the corpus callosum was compound heterozygous for two novel SPG15 mutations. Additionally, several new polymorphisms and sequence variants of unknown significance have been identified in the SPG15 gene. Conclusions: TCC seems to be the best phenotypic predictor for SPG11 as well as SPG15. No clinical features could discriminate between SPG11 and SPG15. Therefore priority of genetic testing should be driven by mutation frequency that appears to be substantially higher in SPG11 than in SPG15.

Immunomodulating factors have been shown to play a role in the pathogenesis of Parkinson's disease (PD) by biochemical methods. In order to investigate functionally important genes of the tumor necrosis factor alpha (TNFα) pathway we studied the frequency of DNA polymorphisms in the interleukin 6 (IL6), the TNFα, and the TNFα receptor 1 (TNFR1) genes in 264 sporadic German PD patients and in 183 age and sex matched German healthy controls. Analyzing the TNFα-308 polymorphism we found heterozygous individuals carrying alleles 1 and 2 more frequently in patients with a relative risk of 1.56 (p ϭ 0.046, p c ϭ 0.13, χ 2 ϭ 3.98). In contrast, the frequency of the B/2 haplotype described by the TNFR1Ϫ609 and TNFRIϩ36 polymorphisms was significantly decreased in our PD patients group (p ϭ 0.0097, p c ϭ 0.048, χ 2 ϭ 6.69) with a relative risk reduced to 0.52. Our results suggest an involvement of immunomodulating factors in the pathogenesis of sporadic PD as revealed by a molecular genetic approach.

Monoclonal IgM anti-myelin-associated glycoprotein (MAG) antibody-related peripheral neuropathy (anti-MAG neuropathy) is predominantly a demyelinating sensory neuropathy with ataxia and distal paresthesia. The clinical course of anti-MAG neuropathy is usually slowly progressive making difficult the identification of clear criteria to start a specific treatment. Although no consensus treatment is yet available, a rituximab-based regimen targeting the B-cell clone producing the monoclonal IgM may be proposed, alone or in combination with alkylating agents or purine analogs. However, in some rare cases, an acute and severe neurological deterioration can occur in few days leading to a rapid loss of autonomy. In these cases, a treatment rapidly removing the monoclonal IgM from the circulation might be useful before initiating a specific therapy. We report successful treatment with plasma exchanges (PE) in four patients presenting with acute neurological deterioration. PE allowed a dramatic and rapid neurological improvement in all patients. PE are safe and may be useful at the initial management of these cases of anti-MAG neuropathy.

Background and purpose: Careful counseling through the diagnostic process and adequate postdiagnostic support in patients with mild cognitive impairment (MCI) is important. Previous studies have indicated heterogeneity in practice and the need for guidance for clinicians. Methods: A joint European Academy of Neurology/European Alzheimer's Disease Consortium panel of dementia specialists was appointed. Through online meetings and emails, positions were developed regarding disclosing a syndrome diagnosis of MCI, preand postbiomarker sampling counseling, and postdiagnostic support. Results: Prior to diagnostic evaluation, motives and wishes of the patient should be sought. Diagnostic disclosure should be carried out by a dementia specialist taking the ethical principles of "the right to know" versus "the wish not to know" into account. Disclosure should be accompanied by written information and a follow-up plan. It should be made clear that MCI is not dementia. Prebiomarker counseling should always be carried out if biomarker sampling is considered and postbiomarker counseling if sampling is carried out. A dementia specialist knowledgeable about biomarkers should inform about pros and cons, including alternatives, to enable an autonomous and informed decision. Postbiomarker counseling will depend in part on the results of biomarkers. Follow-up should be considered for all patients with MCI and include brain-healthy advice and possibly treatment for specific underlying causes. Advice on advance directives may be relevant. Conclusions: Guidance to clinicians on various aspects of the diagnostic process in patients with MCI is presented here as position statements. Further studies are needed to enable more evidence-based and standardized recommendations in the future.

Background: Recurrent ischemic stroke (IS) increases the risk of cognitive decline. To lower the risk of recurrent IS, secondary prevention is essential. Objective: Our aim was to compare post-discharge secondary IS prevention and its maintenance up to 3 years after first IS in patients with and without Alzheimer's disease and other dementia disorders. Methods: Prospective open-cohort study 2007-2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who experienced an IS (n = 1410; 332 [23.5%] with Alzheimer's disease) were compared with matched non-dementia IS patients (n = 7150). We analyzed antiplatelet, anticoagulant, blood pressure lowering, and statin treatment as planned medication initiation at discharge and actual dispensation of medications at first, second, and third year post-stroke. Results: At discharge, planned initiation of medication was higher in patients with dementia compared to non-dementia patients for antiplatelets (OR with 95% CI for fully adjusted models 1. 23 [1.02-1.48]) and lower for blood pressure lowering medication (BPLM; 0.57 [0.49-0.67]), statins (0.57 [0.50-0.66]), and anticoagulants (in patients with atrial fibrillation -AF; 0.41 [0.32-0.53]). When analysis for antiplatelets was stratified according to the presence of AF, ORs for receiving

Brain-derived tau secreted into CSF and blood consists of different N-terminal and mid-domain fragments, which may have a differential temporal course and thus, biomarker potential across the Alzheimer’s disease continuum or in other neurological diseases. While current clinically validated total tau assays target mid-domain epitopes, comparison of these assays with new biomarkers targeting N-terminal epitopes using the same analytical platform may be important to increase the understanding of tau pathophysiology. We developed three total tau immunoassays targeting specific N-terminal (NTA and NTB total tau) or mid-region (MR total tau) epitopes, using single molecule array technology. After analytical validation, the diagnostic performance of these biomarkers was evaluated in CSF and compared with the Innotest total tau (and as proof of concept, with N-p-tau181 and N-p-tau217) in three clinical cohorts (n = 342 total). The cohorts included participants across the Alzheimer’s diseas...

Background and purposeDementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow‐up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia.MethodsA systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated.ResultsSystematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulan...

Background: Alzheimer's disease (AD)-related pathology is frequently found in patients with dementia with Lewy bodies (DLB). However, it is unknown how amyloid-β and tau-related pathologies influence neurodegeneration in DLB. Understanding the mechanisms underlying brain atrophy in DLB can improve our knowledge about disease progression, differential diagnosis, drug development and testing of anti-amyloid and anti-tau therapies in DLB. Objectives: We aimed at investigating the combined effect of CSF amyloid-β42, phosphorylated tau and total tau on regional brain atrophy in DLB in the European DLB (E-DLB) cohort. Methods: 86 probable DLB patients from the E-DLB cohort with CSF and MRI data were included. Random forest was used to analyze the association of CSF biomarkers (predictors) with visual rating scales for medial temporal lobe atrophy (MTA), posterior atrophy (PA) and global cortical atrophy scale-frontal subscale (GCA-F) (outcomes), including age, sex, education and disease duration as extra predictors. Results: DLB patients with abnormal MTA scores had abnormal CSF Aβ42, shorter disease duration and older age. DLB patients with abnormal PA scores had abnormal levels of CSF Aβ42 and p-tau, older age, lower education and shorter disease duration. Abnormal GCA-F scores were associated with lower education, male sex, and older age, but not with any AD-related CSF biomarker. Conclusions: This study shows preliminary data on the potential combined effect of amyloid-β and tau-related

ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/...

Neurodegenerative diseases are one of the most important contributors to morbidity and mortality in the elderly. In Europe, over 14 million people are currently living with dementia, at a cost of over 400 billion EUR annually. Recent advances in diagnostics and approval for new pharmaceutical treatments for Alzheimer's disease (AD), the most common etiology of dementia, heralds the beginning of precision medicine in this field. However, their implementation will challenge an already over-burdened healthcare systems. There is a need for innovative digital solutions that can drive the related clinical pathways and optimize and personalize care delivery. Public-private partnerships are ideal vehicles to tackle these challenges. Here we describe the Innovative Health Initiative (IHI) public-private partnership project PROMINENT that has been initiated by connecting leading dementia researchers, medical professionals, dementia patients and their care partners with the latest innovative health technologies using a precision medicine based digital platform. The project builds upon the knowledge and already implemented digital tools from several collaborative initiatives that address new models for early detection, diagnosis, and monitoring of AD and other neurodegenerative disorders. The project aims to provide support to improvement efforts to each aspect of the care pathway including diagnosis, prognosis, treatment, and data collection for real world evidence and cost effectiveness studies. Ultimately the PROMINENT project is expected to lead to cost-effective care and improved health outcomes.

Background Cerebral small vessel disease (CSVD) and metabolic syndrome were separately associated with cognitive impairment and depression. However, whether metabolic syndrome adds to cognitive impairment and depression in patients who already have CSVD remained unanswered. Objective The aim of our study was to investigate the association of metabolic syndrome with cognitive impairment and depression in patients with CSVD who have lacunar lesions or white matter hyperintensities. Methods This prospective cohort study was conducted at Neurology Clinic, Clinical Center, Kragujevac, Serbia. Main outcomes of the study were cognitive assessment, and assessment of depression among hospitalized patients with or without CSVD. Results The study included 74 inpatients, 25 of them having lacunary infarctions, 24 with the white matter hyperintensities, and 25 control patients without CSVD. The CSVD was accompanied by impairment of cognition and depression, the patients with lacunary lesions bei...

Thrombosis of veins and venous sinus (CVT) is the rare cerebral vascular disorder which makes less than 1% of all strokes. Thrombosis of veins and venous sinuses is picturesquely called “мајоr neurological forger” since it is characterized by very varied clinical picture. Among the various causes of CVT, which can be of infective or non-infective nature, the congenital hyper coagulations especially stand out, diagnosis is based on highly sophisticated diagnostic tests.We present the case of a female patient, 36 years old, who was hospitalized at the Clinic for Neurology in Clinical Center because of the diffuse headache she had for the last few days, with milder right-sided hemiparesis and one generalized tonic-clonic epileptic seizure. With nuclear magnetic resonance (MR/2D venography) the thrombosis of the upper and lower sagittal sinuses is confirmed. By appropriate laboratory tests, as well as by confirmatory immunological and genetic analyses, the impact of the most of the fact...

The extent to which a substance in the circulation gains access to the CNS needs to be determined for potential neuropharmaceuticals as well as for drug candidates with primary targets in the periphery. Characteristics of the in vivo methods, ranging from classical pharmacokinetic techniques (intravenous administration and tissue sampling) over brain perfusions to microdialysis and imaging techniques, are highlighted. In vivo measurements remain unmatched with respect to sensitivity and for the characterization of carrier-mediated uptake, receptor-mediated transport, and active efflux. Isolated microvessels are valuable tools for molecular characterization of transporters. Endothelial cell culture models of the bloodbrain barrier (BBB) are pursued as in vitro systems suitable for screening procedures. Recent applications of conditionally im-mortalized cell lines indicate that a particular weakness of culture models because of downregulation of BBB-specific transporter systems can be overcome. In silico approaches are being developed with the goal of predicting brain uptake from molecular structure at early stages of drug development. Currently, the predictive capability is limited to passive, diffusional uptake and predominantly relies on few molecular descriptors related to lipophilicity, hydrogen bonding capacity, charge, and molecular weight. A caveat with most present strategies is their reliance on surrogates of BBB transport, like CNS activity/ inactivity or brain-to-blood partitioning rather than actual BBB permeability data.

Background: Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disease. It is a neuromuscular disorder caused by degenerative of lower motor neurons and occasionally bulbar neurons leading to progressive limb paralysis and muscular atrophy. The SMN1 gene is recognized as a SMA causing gene while NAIP has been characterized as a modifying factor for the clinical severity and age at disease onset in SMA patients (SMA subtypes). The relationship between NAIP deletion and type of SMA remains to be clarified; we investigated this gene alteration in all types of SMA patients. Methods: Molecular analysis was performed on fifty patients with a clinical diagnosis of SMA in Khuzestan province. In addition to common PCR-RFLP analysis for exon 7 and 8 of SMN1 gene, as an internal control we analysed NAIP deletion with PCR of exon 5 of this gene in a multiplex PCR with exon 13 of it. Results: Homozygous-deletion frequency rate for the telomeric copy of SMN (SMN1) exon 7 in all types (type I, II, Ш) of SMA was approximately 90% and the frequency of deletion in exon 7 and 8 together in all types estimated about 70%. Moreover NAIP gene was deleted in about 60% of these patients and this shows deletion in 91% of type I SMA patients. The correlation between NAIP-deletion and SMN1 mutation showed a high frequency rate. Conclusion: In this study, high frequency of NAIP gene deletion in all type of disease shows the importance role of it in disease pathogenesis. High frequency of NAIP deletion in SMA type I, also shows the importance of the gene in type and severity of disease so it may be a modifier factor in severity of disease.

The link between neuroinflammation and neurogenesis is an area of intensive research in contemporary neuroscience. The burgeoning amount of evidence accumulated over the past decade has been incredible, and now there remains the figuring out of minutia to give us a more complete picture of what individual, synergistic, and antagonistic events are occurring between neurogenesis and neuroinflammation. An intricate study of the inflammatory microenvironment influenced by the presence of the various inflammatory components like cytokines, chemokines, and immune cells is essential for: 1) understanding how neurogenesis can be affected in such a specialized niche and 2) applying the knowledge gained for the treatment of cognitive and/or motor deficits arising from inflammation-associated diseases like stroke, traumatic brain injury, Alzheimer's disease, and Parkinson's disease. This review is written to provide the reader with up-to-date information explaining how these inflammatory components are effecting changes on neurogenesis.

Objective: To examine the association between retinopathy and cognitive decline or brain lesions and volumes in older women. Methods: This study included 511 women aged 65 and older who were simultaneously enrolled in the Women's Health Initiative Memory Study and the Sight Examination Study. In this analysis, we examined the link between retinopathy, assessed using fundus photography (2000-2002), cognitive performance over time assessed by the modified Mini-Mental State Examination (3MSE) (1996-2007), and white matter hyperintensities and lacunar infarcts in the basal ganglia. Results: Presence of retinopathy was associated with poorer 3MSE scores (mean difference ϭ 1.01, SE: 0.43) (p ϭ 0.019) over a 10-year follow-up period and greater ischemic volumes in the total brain (47% larger, p ϭ 0.04) and the parietal lobe (68% larger, p ϭ 0.01) but not with measures of regional brain atrophy. The correspondence we found between retinopathy and cognitive impairment, along with larger ischemic lesion volumes, strengthens existing evidence that retinopathy as a marker of small vessel disease is a risk factor for cerebrovascular disease that may influence cognitive performance and related brain changes. Retinopathy may be useful as a clinical tool if it can be shown to be an early marker related to neurologic outcomes. Neurology ® 2012;78:942-949 GLOSSARY 3MSE ϭ modified Mini-Mental State Examination; AMD ϭ age-related macular degeneration; CEE ϭ conjugated equine estrogen;

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Sever...

Alzheimer's disease (AD) is characterized by progressive cognitive decline associated with a featured neuropathology (neuritic plaques and neurofibrillary tangles). Several studies have implicated oxidative damage to DNA, DNA repair, and altered cell-cycle regulation in addition to cell death in AD post-mitotic neurons. However, there is a lack of studies that systematically assess those biological processes in patients with AD neuropathology but with no evidence of cognitive impairment. We evaluated markers of oxidative DNA damage (8-OHdG, H2AX), DNA repair (p53, BRCA1, PTEN), and cellcycle (Cdk1, Cdk4, Cdk5, Cyclin B1, Cyclin D1, p27 Kip1 , phospho-Rb and E2F1) through immunohistochemistry and cell death through TUNEL in autopsy hippocampal tissue samples arrayed in a tissue microarray (TMA) composed of three groups: I) ''clinical-pathological AD'' (CP-AD) -subjects with neuropathological AD (Braak$IV and CERAD = B or C) and clinical dementia (CDR$2, IQCODE.3.8); II) ''pathological AD'' (P-AD) -subjects with neuropathological AD (Braak$IV and CERAD = B or C) and without cognitive impairment (CDR 0, IQCODE,3.2); and III) ''normal aging'' (N) -subjects without neuropathological AD (Braak#II and CERAD 0 or A) and with normal cognitive function (CDR 0, IQCODE,3.2). Our results show that high levels of oxidative DNA damage are present in all groups. However, significant reductions in DNA repair and cell-cycle inhibition markers and increases in cell-cycle progression and cell death markers in subjects with CP-AD were detected when compared to both P-AD and N groups, whereas there were no significant differences in the studied markers between P-AD individuals and N subjects. This study indicates that, even in the setting of pathological AD, healthy cognition may be associated with a preserved repair to DNA damage, cell-cycle regulation, and cell death in post-mitotic neurons.

1 Cauzele și tratamentul amneziei
2 Care sunt cauzele amneziei?
2.1 Cauze organice ale amneziei
2.2 Cauze determinate de unele intervenții medicale
2.3 Cauze psihoemoționale corelate cu stilul de viață
3 Resurse și suport pentru pacienți
4 Cum se diagnostichează amnezia?
4.1 Istoricul pacientului și analiza simptomelor
4.2 Examinarea fizică
4.3 Examinarea neurologică
4.4 Teste cognitive și de memorie
4.5 Evaluare psihologică
4.6 Teste de laborator
4.7 Studii imagistice și testări specializate
4.8 Stabilirea diagnosticului diferențial
5 Tratamentul amneziei
6 Concluzii
7 Referințe

1 Afecțiuni neurologice tratate cu toxina botulinică
2 Ce este toxina botulinică?
3 Ce alte aplicații clinice are toxina botulinică?
4 Resurse și suport pentru pacienți
5 Care sunt tipurile de toxină botulinică recomandate în reabilitarea neurologică?
6 În ce constă tratamentul cu toxină botulinică al afecțiunilor neurologice?
6.1 Consultație specializată
6.2 Evaluarea tipului de tratament
6.3 Tratamentul propriu zis
7 După cât timp apar rezultatele tratamentului cu toxină botulinică?
8 Care sunt efectele secundare ale tratamentului cu toxină botulinică?
9 Concluzii
10 Referințe

Objective: To explore the relation between venous disease and idiopathic intracranial hypertension. Background: Optic nerve sheath fenestration and ventricular shunting are the classic methods when medical treatment has failed. Idiopathic intracranial hypertension is caused by venous sinus obstruction in an unknown percentage of cases. Recently, endoluminal venous sinus stenting was proposed as an alternative treatment. Ten consecutive patients with refractory idiopathic intracranial hypertension underwent examination with direct retrograde cerebral venography and manometry to characterize the morphologic features and venous pressures in their cerebral venous sinus. All patients demonstrated morphologic obstruction of the venous lateral sinuses. The CSF pressure was measured in all patients. The CSF pressure on lumbar puncture ranged from 27 to 45 mm Hg with normal composition. All patients had headache, and visual acuity loss was noted in eight patients. Funduscopic examination demonstrated papilledema for all patients. All patients had stenting of the venous sinuses. Intrasinus pressures were recorded before and after the procedure and correlated with clinical outcome. Intrasinus pressures were invariably reduced by stenting. For headache, six patients were rendered asymptomatic, two were improved, and two were unchanged after venous sinus stenting for a mean (Ϯ SD) follow-up of 17 Ϯ 10.1 months (range 6 to 36 months). Papilledema disappeared in all patients. In all cases, CSF pressure was normalized at 3-month follow-up. In all patients, direct retrograde cerebral venography or multidetector row CT angiography was performed at 6-month follow-up and demonstrated the absence of stent thrombosis.

Background: Frontotemporal dementia (FTD) is recognised as a clinically and morphologically heterogeneous group of interrelated neurodegenerative conditions. One of the subtypes within this disease spectrum is the behavioural variant FTD (bvFTD). This is known to be a varied disorder with a mixture of tau-positive and taunegative underlying pathologies. The other subtypes include semantic dementia (SD), which generally exhibits taunegative pathology, and progressive non-fluent aphasia (PNFA), which is usually tau-positive. As the clinical presentation of these subtypes may overlap, a specific diagnosis can be difficult to attain and today no specific biomarker can predict the underlying pathology. Neurofilament light chain protein (NFL), a cytoskeletal constituent of intermediate filaments, is thought to reflect neuronal and axonal death when appearing in the cerebrospinal fluid (CSF). NFL has been shown to be elevated in CSF in patients with FTD compared with AD and controls. Our hypothesis was that the levels of NFL also differ between the subtypes of FTD and may indicate the underlying pathological subtype. Methods: We retrospectively analysed data from previous CSF analyses in 34 FTD cases (23 bvFTD, seven SD, four PNFA), 20 AD cases, and 26 healthy controls. A separate group of 10 neuropathologically verified and subtyped FTD cases (seven tau-negative, three tau-positive) were also analysed. Result: NFL levels were significantly higher in FTD compared with both AD (p<0.001) and controls (p<0.001). The NFL levels of SD and bvFTD were significantly higher (p<0.001) compared with AD. The biomarker profiles of PNFA and AD were similar. In the neuropathologically verified FTD cases, NFL was higher in the tau-negative than in the tau-positive cases (exact p=0.017). The marked NFL elevation in some but not all FTD cases is likely to reflect the different underlying pathologies. The highest NFL values found in the SD group as well as in the neuropathologically verified taunegative cases may be of subtype diagnostic value, if corroborated in larger patient cohorts. In bvFTD, a mixture of tau-positive and tau-negative underlying pathologies could possibly explain the intermediate NFL values.

We studied 12 patients with spasmodic dyephonia (SD) and 12 healthy control subjects. The patients, who had no symptomatic involvement of the eyes, were evaluated for increased excitability of blink reflexes, which is characteristic of blepharoepasm and generalized dyetonia. We measured symptom severity from aound spectrograms of five sentences, including sentence production time, number of pitch phonatory breaka, and percentage of aperiodic phonation. We evoked blink reflexes by electrical and mechanical stimulation, and asaeseed excitability by obtaining excitability recovery curves and responses to trains of stimuli. Patients and controls differed from each other in test R2 amplitude attenuation acroes all intervale from 150 to 1,OOO msec to electrical and mechanical stimulation. Our results indicate that patients with SD have increaaed excitability of blink reflexes, which suggests that the dystonia involves not only the larynx but also other anatomical structures.