Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis.

OBJECTIVES: Cerebrospinal fluid (CSF) from some patients with amyotrophic lateral sclerosis (ALS) has been demonstrated to significantly reduce the neuronal viability of primary cell cultures of motor neurons. We aimed to study the potential clinical consequences associated with the cytotoxicity of CSF in a cohort of patients with ALS. METHODS: We collected CSF from thirty-one patients with ALS. We analysed cytotoxicity by incubating it into the primary cultures of motor cortex neurons. Neural viability was quantified after 24 hours using the colorimetric MTT reduction assay. All patients were followed up from the moment of diagnosis to death, and a complete evaluation during disease progression and survival was performed, including gastrostomy and respiratory assistance. RESULTS: Twenty-one patients (67.7%) presented a cytotoxic CSF. There were no significant differences between patients with and without cytotoxicity regarding mean time from symptom onset to the diagnosis, from the diagnosis to death, from the diagnosis to respiratory assistance with BIPAP, from diagnosis to gastrostomy and from the onset of symptoms to death. In Cox regression analysis, bulbar onset, but not cytotoxicity, gender or age at onset, was associated with a lower risk of survival. CONCLUSIONS: Cerebrospinal fluid cytotoxicity was not associated with differential survival rates. This suggests that the presence of cytotoxicity in CSF, measured through neuronal viability in primary cultures of motor cortex neurons, could reflect different mechanisms of the disease, but it does not predict disease outcome.

A pilot study of a new method of cognitive stimulation using abacus arithmetic in healthy and cognitively impaired elderly subjects. / Estudio piloto de un nuevo método de estimulación aritmética empleando el ábaco en ancianos sanos y con trastorno cognitivo.

BACKGROUND: This study explores the applicability of a cognitive stimulation method based on abacus arithmetic in elderly people with and without cognitive impairment. METHODS: This observational and prospective pilot study was performed in 2 hospitals. The study assessed the applicability of a programme of arithmetic training developed for use in the elderly population. The primary endpoint was an evaluation of the stimulation programme, in terms of usability, satisfaction, and participation, in healthy elderly controls and elderly patients with mild cognitive impairment or Alzheimer disease. Secondary endpoints were family satisfaction, caregiver burden, and the behaviour and cognition of patients. RESULTS: Usability, satisfaction, and degree of participation were high. The Mini-Mental State Examination showed significant changes (23.1±4.8 before the intervention vs 24.9±4.2 afterwards, P=.002); there were no changes on the Trail Making Test parts A and B, Yesavage Geriatric Depression scale, and Zarit caregiver burden scale. CONCLUSIONS: The study suggests that cognitive stimulation with abacus arithmetic may be used in elderly people with and without cognitive impairment. Further studies will be needed to evaluate the efficacy of this kind of programmes.

Topography of primitive reflexes in dementia: an F-18 fluorodeoxyglucose positron emission tomography study.

BACKGROUND AND PURPOSE: Although primitive reflexes (PRs) are inhibited during the first years of childhood, they may reappear with brain injury. PRs have been linked to frontal lobe dysfunction, but their precise topography has not yet been defined. The purpose of this study was to map which regions of the brain display a reduced glucose metabolism in patients with cognitive impairment and PRs. METHODS: A prospective study was conducted to evaluate PRs in a group of patients assessed due to suspected cognitive decline. Neurological and neuropsychological examinations and (18) F-fluorodeoxyglucose positron emission tomography fused with computerized tomography were performed. Voxel-based brain mapping analysis by means of statistical parametric mapping was used to compare patients with and without PRs. RESULTS: The study included 99 patients (33 diagnosed with Alzheimer's disease, 33 on the frontotemporal dementia spectrum and 33 with other diagnoses). Mean age was 71 ± 9.7 years; time since symptom onset was 3.6 ± 2.9 years. At least one PR was observed in 43 cases (43.4% of the whole sample; 48.5% in the Alzheimer disease group, 63.6% in frontotemporal dementia and 18.2% in the group with other diagnoses). The group of patients with PRs exhibited a decreased cerebral metabolism in the bilateral superior frontal gyri (Brodmann area 6), bilateral putamina and thalami. CONCLUSIONS: The presence of PRs was associated with hypometabolism at the superior frontal gyrus and putamen. This suggests that dysfunction in the corticostriatal motor circuit (supplementary motor area-putamen-thalamus) may constitute the anatomical basis of the recurrence of PRs.

Biomarkers: a new approach to behavioural variant frontotemporal dementia.

INTRODUCTION: Lobar frontotemporal degeneration (FTLD) encompasses a group of molecular disease defined by the deposition of an abnormal protein in the central nervous system. Behavioural variant frontotemporal dementia (bvFTD) is the most frequent clinical presentation of FTLD. The past two decades of research have contributed to a better understanding of this entity, which may be the first manifestation in many different neurodegenerative disorders. DEVELOPMENT: We reviewed correlations between clinical, pathological, and genetic findings and the main disease biomarkers of FTLD, with particular interest in bvFTD. Anatomical pathology findings in FTLD are heterogeneous and the syndrome is not associated with any one specific histopathological type. Promising available biomarkers include structural and functional neuroimaging techniques and biochemical and genetic biomarkers. Disease-modifying drugs designed for specific molecular targets that are implicated in FTLD pathogenesis are being developed. CONCLUSIONS: BvFTD is a frequent cause of dementia. Of all the clinical variants of FTLD, behavioural variant is the one in which establishing a correlation between clinical and pathological signs is the most problematic. A biomarker evaluation may help predict the underlying pathology; this approach, in conjunction with the development of disease-modifying drugs, offers new therapeutic possibilities.

Study of outpatient neurological care in the Region of Madrid: The impact of implementing free choice of hospital.

INTRODUCTION: A new model permitting free choice of hospital has been introduced in the Region of Madrid. This may result in changes in how outpatient neurological care is provided and managed. The purpose of this study is to analyse initial visits to a general neurology department in the Region of Madrid and record the health district corresponding to each patient's residence. METHODS: Observational and prospective study of a cohort of patients making initial outpatient visits to a neurology department between 16 September 2013 and 16 January 2014. RESULTS: The study included 1109 patients (63.8% women, mean age 55.2±20.5). The most frequent diagnostic groups were periodic headache, cognitive disorders, and neuromuscular diseases. Non-neurological diseases were diagnosed in 1.1% of the cases. The mean time of delay was 7.2±5.1 days. Residents within the hospital's health district made up 73.8% of the total, while 26.2% chose a hospital outside of the health district corresponding to their residences. In the latter group, 59.5% made the choice based on the level of care offered, while 39.7% changed hospitals due to shorter times to consultation. The patients who came from another health district were younger (50.7 vs 57.3, P<.0001) and had a lower rate of discharges on the first visit (16.4% vs 30.1%, P<.0001). CONCLUSION: The model of free choice of hospital delivers significant changes in healthcare management and organisation. Reasons given for choosing another hospital are more ample experience and shorter delays with respect to the home district hospital. Management of patients from outside the health district is associated with greater complexity.

Validation of the Spanish version of Addenbrooke's Cognitive Examination III for diagnosing dementia.

INTRODUCTION: Addenbrooke's Cognitive Examination is a screening test used to diagnose dementia. The third edition of this test (ACE-III) was recently developed. The aim of this study was to translate and validate the ACE-III in Spanish. METHODS: The ACE-III was translated and adapted to Spanish. It was then administered to a group of healthy subjects as well as a group of patients with different types of mild dementia treated in 2 hospitals in Spain. RESULTS: Internal reliability (Cronbach's alpha = 0.927), inter-rater reliability (intraclass correlation coefficient = 0.976) and test-retest reliability (kappa 0.995) were excellent. Age (r = -0.512) and education (r = 0.659) showed a significant correlation with total test scores. The diagnostic accuracy of ACE-III was higher than that of the Mini-Mental State Examination, particularly for the group with the highest educational level. Researchers obtained normative data and cut-off points for the diagnosis of dementia. CONCLUSIONS: The Spanish version of the ACE-III is a reliable and valid test for diagnosing dementia. Its diagnostic accuracy is high, especially in patients with a higher level of education.

Suboptimal interventional conditions for the occlusion of ruptured intracranial aneurysms do not increase periprocedural complications and poor clinical outcomes.

BACKGROUND AND OBJECTIVE: Occluding a ruptured intracranial aneurysm as early as possible may entail certain periprocedural conditions that compromise the outcome. The aim of the present study was to evaluate the effectiveness, safety, and clinical outcome of endovascular coiling procedures performed on an emergency basis under potentially suboptimal conditions, and to compare results with those from scheduled procedures under potentially optimal conditions. METHODS: Interventions performed on 66 SAH patients were retrospectively analysed by classifying them into two groups: under emergency (within three hours from diagnosis or during non-standard working hours) or scheduled conditions. A binary logistic regression analysis was also performed to identify characteristics associated with poor outcomes. RESULTS: No differences in effectiveness, periprocedural complications, or clinical outcomes were found between the two groups. Rebleeding was detected in 4.8 % of the emergency interventions and 2.2 % of the scheduled interventions. Multivariate analysis identified age and Hunt and Hess grade, but no conditions of treatment, as the factors associated to poor outcome. CONCLUSION: Suboptimal interventional conditions for occluding ruptured intracranial aneurysms, such as performing procedures outside of standard working hours or within three hours of diagnosis, do not result in increased periprocedural complications and poor clinical outcomes compared with scheduled procedures under potentially optimal conditions. These results suggest the need for treatment to be provided as soon as possible.

Behavioural variant frontotemporal dementia: clinical and therapeutic approaches.

INTRODUCTION: Behavioural variant frontotemporal dementia (bvFTD) is the most frequent presentation in the clinical spectrum of frontotemporal dementia (FTD) and it is characterised by progressive changes in personality and conduct. Major breakthroughs in molecular biology and genetics made during the last two decades have lent us a better understanding of this syndrome, which may be the first manifestation in many different neurodegenerative diseases. DEVELOPMENT: We reviewed the main epidemiological, clinical, diagnostic and therapeutic aspects of bvFTD. Most cases manifest sporadically and the average age of onset is 58 years. Current criteria for bvFTD propose three levels of diagnostic certainty: possible, probable, and definite. Clinical diagnosis is based on a detailed medical history provided by family members and caregivers, in conjunction with neuropsychological testing. Treatments which have been used in bvFDT to date are all symptomatic and their effectiveness is debatable. New drugs designed for specific molecular targets that are implicated in frontotemporal lobar degeneration are being developed. CONCLUSIONS: BvFDT is a frequent cause of dementia. It is a non-specific syndrome associated with heterogeneous histopathological and biomolecular findings. The definition of clinical subtypes complemented by biomarker identification may help predict the underlying pathology. This knowledge, along with the development of drugs designed for molecular targets, will offer new treatment possibilities.

Large artery occlusion diagnosed by computed tomography angiography in acute ischaemic stroke: frequency, predictive factors, and safety.

INTRODUCTION: Demonstrating artery occlusion in ischaemic stroke has gained importance due to the increasing availability of endovascular therapies. This study evaluates the frequency of artery occlusion, its associated factors, and complications following the use of CT-angiography in acute stroke. METHODS: We retrospectively analysed a cohort of patients who suffered acute ischaemic stroke between July and-December 2011. RESULTS: We included 157 patients (mean age, 74±11; mean NIHSS score, 5 [2-13]). Of that total, 56.7% of the patients were admitted to hospital during the first 8hours. CT-angiography was performed in 71 cases (45.2%); arterial large-vessel occlusion was detected in 37 (52.1%) of these cases, and the most frequent site was M1 (40%). Univariate analysis showed that the NIHSS score (17 vs 7, P<.001) and atrial fibrillation (64% vs 32%, P=.006) were associated with artery occlusion. A logistic regression analysis was performed subsequently, confirming these associations. There were no cases of contrast-induced nephropathy. Door-to-needle time for intravenous thrombolysis was 61.2±24.5minutes in patients who underwent CT-angiography, and 53.5±34.3minutes in those who did not (P=.495). CONCLUSIONS: Arterial occlusions are seen in 23.6% of patients, especially in those who are admitted during the first few hours. NIHSS score serves as a useful predictive factor.

Murine experimental models of amyotrophic lateral sclerosis: an update.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose aetiology is unknown. It is characterised by upper and lower motor neuron degeneration. Approximately 90% of cases of ALS are sporadic, whereas the other 10% are familial. Regardless of whether the case is familial o sporadic, patients will develop progressive weakness, muscle atrophy with spasticity, and muscle contractures. Life expectancy of these patients is generally 2 to 5 years after diagnosis. DEVELOPMENT: In vivo models have helped to clarify the aetiology and pathogenesis of ALS, as well as the mechanisms of the disease. However, as these mechanisms are not yet fully understood, experimental models are essential to the continued study of the pathogenesis of ALS, as well as in the search for possible therapeutic targets. Although 90% of cases are sporadic, most of the models used to study ALS pathogenesis are based on genetic mutations associated with the familial form of the disease; the pathogenesis of sporadic ALS remains unknown. Therefore, it would be critical to establish models based on the sporadic form. CONCLUSIONS: This article reviews the main genetic and sporadic experimental models used in the study of this disease, focusing on those that have been developed using rodents.

Primary progressive aphasia: from syndrome to disease.

INTRODUCTION: Primary progressive aphasia (PPA) is a clinical syndrome characterised by a progressive decline in language and speech of neurodegenerative origin. Major breakthroughs made in recent years have lent us a better understanding of this syndrome, which may be the first manifestation of any of a number of neurodegenerative diseases. DEVELOPMENT: We reviewed the main aspects of PPA epidemiology, clinical manifestations, diagnosis, aetiology and treatment. Most cases manifest sporadically and the typical age of onset is between 50 and 70 years. Three clinically distinct variants have been described: nonfluent or agrammatic PPA, semantic PPA and logopenic PPA. Each of these variants tends to be associated with specific histopathological findings, but clinical diagnostic methods are imperfect predictors of underlying pathology. Anatomical and functional neuroimaging can provide useful biomarkers. Several treatments have been proposed, and while no clear benefits have been demonstrated, acetylcholinesterase inhibitors may be useful, especially in the logopenic variant. CONCLUSIONS: PPA is an emerging syndrome which may be more prevalent than we might expect. It was previously listed as part of the frontotemporal dementia spectrum, and it is also related to Alzheimer disease. Clinical diagnosis, complemented by a biomarker evaluation, may predict the underlying pathology, which in turn will improve treatment possibilities.

What happens to medical articles submitted in Spanish that are not accepted for publication?

INTRODUCTION: The fate of manuscripts submitted and subsequently rejected by Spanish-language journals is unknown. The present study was designed to determine whether or not articles submitted to Neurología are published following rejection, and if so, where. METHODS: We searched Medline in late April 2012 and also analysed all manuscripts rejected by Neurología between October 2004 and April 2012 according to that journal's two databases. In that period, 1277 articles were submitted to the journal. RESULTS: Of the 271 manuscripts rejected by Neurología, 54 articles (19.9%) were published in other journals. Neurology journals published 31 of the manuscripts (57.4%); 43 manuscripts (79.6%) appeared in Spanish-language journals. Of the rejected manuscripts, 24.1% of the originals, 8.3% of the letters to the editor, 28.9% of the case reports, 22.6% of the reviews and 6.3% of the images were published. Authors with three previously published articles on the same topic managed to publish their manuscripts in 34% of the cases, compared to only 11.8% of authors with fewer published articles (P < .0001). Of the total manuscripts rejected between 2004 and 2010, 24.8% were eventually published. The median time lapse between article submission and publication was 13 months (range, 2-59 months). CONCLUSION: Manuscripts rejected by Neurología are often published in other journals, but this scenario is not as common as in English-language journals. In the case of Neurología, the editor's decision to reject an article is more significant than it would be in an English-language journal because the author will have fewer additional possibilities of having the manuscript published.

Exonic variants of the P2RX7 gene in familial multiple sclerosis.

INTRODUCTION: Several studies have analysed the presence of P2RX7 variants in patients with MS, reporting diverging results. METHODS: Our study analyses P2RX7 variants detected through whole-exome sequencing (WES). RESULTS: We analysed P2RX7, P2RX4, and CAMKK2 gene variants detected by whole-exome sequencing in all living members (n = 127) of 21 families including at least 2 individuals with multiple sclerosis. P2RX7 gene polymorphisms previously associated with autoimmune disease. Although no differences were observed between individuals with and without multiple sclerosis, we found greater polymorphism of gain-of-function variants of P2RX7 in families with individuals with multiple sclerosis than in the general population. Copresence of gain-of-function and loss-of-function variants was not observed to reduce the risk of presenting the disease. Three families displayed heterozygous gain-of-function SNPs in patients with multiple sclerosis but not in healthy individuals. We were unable to determine the impact of copresence of P2RX4 and CAMKK2 variants with P2RX7 variants, or the potential effect of the different haplotypes described in the gene. No clinical correlations with other autoimmune diseases were observed in our cohort. CONCLUSIONS: Our results support the hypothesis that the disease is polygenic and point to a previously unknown mechanism of genetic predisposition to familial forms of multiple sclerosis. P2RX7 gene activity can be modified, which suggests the possibility of preventive pharmacological treatments for families including patients with familial multiple sclerosis.

Variant rs4149584 (R92Q) of the TNFRSF1A gene in patients with familial multiple sclerosis.

INTRODUCTION: Genomic studies have identified numerous genetic variants associated with susceptibility to multiple sclerosis (MS); however, each one explains only a small percentage of the risk of developing the disease. These variants are located in genes involved in specific pathways, which supports the hypothesis that the risk of developing MS may be linked to alterations in these pathways, rather than in specific genes. We analyzed the role of the TNFRSF1A gene, which encodes one of the TNF-α receptors involved in a signaling pathway previously linked to autoimmune disease. METHODS: We included 138 individuals from 23 families including at least 2 members with MS, and analyzed the presence of exonic variants of TNFRSF1A through whole-exome sequencing. We also conducted a functional study to analyze the pathogenic mechanism of variant rs4149584 (-g.6442643C > G, NM_001065.4:c.362 G > A, R92Q) by plasmid transfection into human oligodendroglioma (HOG) cells, which behave like oligodendrocyte lineage cells; protein labeling was used to locate the protein within cells. We also analyzed the ability of transfected HOG cells to proliferate and differentiate into oligodendrocytes. RESULTS: Variant rs4149584 was found in 2 patients with MS (3.85%), one patient with another autoimmune disease (7.6%), and in 5 unaffected individuals (7.46%). The 2 patients with MS and variant rs4149584 were homozygous carriers and belonged to the same family, whereas the remaining individuals presented the variant in heterozygosis. The study of HOG cells transfected with the mutation showed that the protein does not reach the cell membrane, but rather accumulates in the cytoplasm, particularly in the endoplasmic reticulum and near the nucleus; this suggests that, in the cells presenting the mutation, TNFRSF1 does not act as a transmembrane protein, which may alter its signaling pathway. The study of cell proliferation and differentiation found that transfected cells continue to be able to differentiate into oligodendrocytes and are probably still capable of producing myelin, although they present a lower rate of proliferation than wild-type cells. CONCLUSIONS: Variant rs4149584 is associated with risk of developing MS. We analyzed its functional role in oligodendrocyte lineage cells and found an association with MS in homozygous carriers. However, the associated molecular alterations do not influence the differentiation into oligodendrocytes; we were therefore unable to confirm whether this variant alone is pathogenic in MS, at least in heterozygosis.