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Background and purpose: No previous study has assessed the frequency and clinical– radiological characteristics of patients with diabetes mellitus (DM) and acute onset non-choreic and nonballistic movements. We conducted a prospective study to investigate the spectrum of acute onset movement disorders in DM.Methods: We recruited all the patients with acute onset movement disorders and hyper-glycemia who attended the wards of three hospitals in West Bengal, India from August 2014 to July 2021.Results: Among the 59 patients (mean age = 55.4± 14.3 years, 52.5% men) who were included, 41 (69.5%) had choreic or ballistic movements, and 18 (30.5%) had nonchoreic and nonballistic movements. Ballism was the most common movement disorder (n= 18, 30.5%), followed by pure chorea (n= 15, 25.4%), choreoathetosis (n= 8, 13.6%), tremor (n= 5, 8.5%), hemifacial spasm (n= 3, 5.1%), parkinsonism (n= 3, 5.1%), myoclonus (n= 3, 5.1%), dystonia (n= 2, 3.4%), and restless leg syndrome (n= 2, 3.4%). The mean duration of DM was 9.8 ± 11.4 years (89.8% of the patients had type 2 DM). Nonketotic hypergly-cemia was frequently (76.3%) detected. The majority (55.9%) had no magnetic resonance imaging (MRI) changes; the remaining showed striatal hyperintensity. Eight patients with MRI changes exhibited discordance with sidedness of movements. Most of the patients (76.3%) recovered completely.Conclusions: This is the largest clinical series depicting the clinical–radiological spectrum of acute onset movement disorders in DM. Of note was that almost one third of patients had nonchoreic and nonballistic movements. Our findings highlight the importance of a capillary blood glucose measurement in patients with acute or subacute onset movement disorders, irrespective of their past glycemic status.

BACKGROUND Specific cognitive alterations could be one of the predictors that lead to the complex activities of daily living (CADL) impairment in mild cognitive impairment (MCI) and, hence, help to explain the continuum between MCI and dementia. OBJECTIVE We aimed to reevaluate the existing uncertainty regarding the impact of memory and executive functions on CADL in patients with MCI. METHODS Caregivers of 161 patients with amnestic multi-domain MCI and of 150 patients with incipient Alzheimer's disease as well as 100 age-, sex-, and education-matched controls, completed the Interview for Deterioration in Daily Living Activities in Dementia, a suitable instrument for the description and discrimination of CADL. In addition, all patients and controls were assessed with a neuropsychological battery to measure explicit memory and executive functions performance. RESULTS Multiple regression analyses showed that in the group of patients with amnestic multi-domain MCI, 67.4% of the variability of the CADL impairment was explained by worse performance on executive functions tests (p

ObjectiveTo report 3 patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who developed generalized myoclonus.MethodsPatient data were obtained from medical records from the University Hospital “12 de Octubre,” Madrid, Spain.ResultsThree patients (2 men and 1 woman, aged 63–88 years) presented with mild hypersomnia and generalized myoclonus following the onset of the so-called inflammatory phase of coronavirus disease 2019 (COVID-19). All of them had presented previously with anosmia. Myoclonus was generalized with both positive and negative jerks, predominantly involving the facial, trapezius, sternocleidomastoid, and upper extremities muscles. These myoclonic jerks occurred spontaneously and were extremely sensitive to multisensory stimuli (auditive and tactile) or voluntary movements, with an exaggerated startle response. Other causes of myoclonus were ruled out, and none of the patients had undergone respiratory arrest or significant prolonged hypoxia. All of them improved, at least partially, with immunotherapy.ConclusionsOur 3 cases highlight the occurrence of myoclonus during the COVID-19 pandemic as a post- or para-infectious immune-mediated disorder. However, we cannot rule out that SARS-CoV-2 may spread transneuronally to first- and second-order structures connected with the olfactory bulb. Further investigation is required to clarify the full clinical spectrum of neurologic symptoms and optimal treatment.

[Abstract] Objective The pathogenesis of orthostatic tremor (OT) is unknown. We investigated OT‐related white matter changes and their correlations with scores from a neuropsychological testing battery. Methods Diffusion tensor imaging measures were compared between 14 OT patients and 14 age‐ and education‐matched healthy controls, using whole‐brain tract‐based spatial statistics analysis. Correlations between altered diffusion metrics and cognitive performance in OT group were assessed. Results In all cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language), OT patients’ cognitive performance was significantly worse than that of healthy controls. OT patients demonstrated altered diffusivity metrics not only in the posterior lobe of the cerebellum (left cerebellar lobule VI) and in its efferent cerebellar fibers (left superior cerebellar peduncle), but also in medial lemniscus bilaterally (pontine tegmentum), anterior limb of the internal capsule bilaterally, right posterior limb of the internal capsule, left anterior corona radiata, right insula, and the splenium of corpus callosum. No relationship was found between diffusion measures and disease duration in OT patients. Diffusion white matter changes, mainly those located in right anterior limb of the internal capsule, were correlated with poor performance on tests of executive function, visuospatial ability, verbal memory, and visual memory in OT patients. Interpretation White matter changes were preferentially located in the cerebellum, its efferent pathways, as well as in the pontine tegmentum and key components of the frontal–thalamic–cerebellar circuit. Further work needs to be done to understand the evolution of these white matter changes and their functional consequences. National Institutes of Health; R01 NS39422 National Institutes of Health; R01 NS094607 National Institutes of Health; R01 NS085136 National Institutes of Health; R01 NS073872 National Institutes of Health; R01 NS088257 European Commission. Grant Number: ICT‐2011‐287739 Ministerio de Ecnomía y Competitividad; RTC‐2015‐3967‐1 Spanish Health Research Agency; FIS PI12/01602 Spanish Health Research Agency; FIS PI16/00451 Ministerio de Ecnomía y Competitividad; DPI‐2015‐68664‐C4‐1‐R

Background and purpose The unanticipated detection by magnetic resonance imaging (MRI) in the brain of asymptomatic subjects of white matter lesions suggestive of multiple sclerosis (MS) has been named radiologically isolated syndrome (RIS). As the difference between early MS [i.e. clinically isolated syndrome (CIS)] and RIS is the occurrence of a clinical event, it is logical to improve detection of the subclinical form without interfering with MRI as there are radiological diagnostic criteria for that. Our objective was to use machine-learning classification methods to identify morphometric measures that help to discriminate patients with RIS from those with CIS. Methods We used a multimodal 3-T MRI approach by combining MRI biomarkers (cortical thickness, cortical and subcortical grey matter volume, and white matter integrity) of a cohort of 17 patients with RIS and 17 patients with CIS for single-subject level classification. Results The best proposed models to predict the diagnosis of CIS and RIS were based on the Naive Bayes, Bagging and Multilayer Perceptron classifiers using only three features: the left rostral middle frontal gyrus volume and the fractional anisotropy values in the right amygdala and right lingual gyrus. The Naive Bayes obtained the highest accuracy [overall classification, 0.765; area under the receiver operating characteristic (AUROC), 0.782]. Conclusions A machine-learning approach applied to multimodal MRI data may differentiate between the earliest clinical expressions of MS (CIS and RIS) with an accuracy of 78%.

Movement disorders are extremely rare in acute disseminated encephalomyelitis (ADEM) and in the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. We herein report a 34-years-old previously healthy woman who presented with a febrile illness and a constellation of movement disorders (predominantly myoclonus) followed by encephalopathy. After exclusion of common infectious, autoimmune and paraneoplastic etiologies, she was diagnosed to have COVID-19 induced ADEM, which responded to intravenous methylprednisolone and intravenous immunoglobulin. Our case adds to the tally of cases of post-SARS-CoV-2 infection related movement disorders and to the exceedingly rare list of cases in which movement disorders preceded ADEM., Graphical abstract Unlabelled Image

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis. Both movement disorders and neuropsychiatric manifestations are considered core features of anti-NMDAR encephalitis. Strong clinical suspicion, along with NMDAR antibody positivity in paired sample of serum and cerebrospinal fluid, with supportive MRI changes clinch diagnosis in majority. We herein report a case of a middle-aged woman with subacute behavioral abnormalities, which were so severe that forced her to attempt suicide. Hemichorea and dystonia, which appeared later in course, are not previously reported movement disorders in combination in anti-NMDAR encephalitis. Further, magnetic resonance imaging showed bilateral thalamic hyperintensities with diffusion restriction, which are in turn not described in this entity. After amalgamation of history, especially the presence of neuropsychiatric symptoms, clinical features, physical examination, and investigations, the diagnosis of anti-NMDAR encephalitis could be established. Our case not only highlights that the combination of hemichorea and dystonia can be features of anti-NMDAR encephalitis, but adds novelty by bilateral symmetric thalamic changes., Graphical abstract Unlabelled Image, Highlights • Subacute onset behavioral abnormalities along with complex movement disorders warrants investigations to exclude anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. • The combination of hemichorea with dystonia can be features of anti-NMDAR encephalitis. • Bilateral symmetric thalamic changes can be observed in anti-NMDAR encephalitis.

Aim To report on the impact of COVID-19 on a brain damage unit. Methods We reviewed the records of all patients admitted to our brain damage unit. The study included all the significant clinical events from the first positive qualitative real-time reverse-transcriptase–polymerase-chain-reaction assay (April 8th, 2020) for SARS-CoV-2 to the day all patients tested negative (June 8th, 2020). Results Of the 20 patients (14 men) (age 57.7 ± 14.9; 2–71 months after brain damage; all with a modified Rankin scale score > 4), 16 tested positive for SARS-CoV-2 and remained positive for a mean of 32.3 days (ranging from 26 to 61). One patient died from COVID-19, while 12 patients were asymptomatic and three suffered mild pneumonia without acute respiratory distress syndrome. All patients received prophylactic subcutaneous heparin. Intravenous methylprednisolone was prescribed for three patients with bilateral pneumonia with excellent results. Conclusions Most positive cases (93.7%) were not severe. The good outcome was most likely due to the use of prophylactic anticoagulation therapy, the early use of methylprednisolone for pneumonia and the previously reported immunosuppression amid patients with brain damage. This study hopes to encourage further study into brain damage immunity.

Background : Spinal cord complications associated with coronavirus infectious disease of 2019 (COVID-19) are being widely reported. The purpose of this systematic review was to summarize so far available pieces of evidence documenting de novo novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) mediated spinal cord demyelinating diseases. Indeed, the spinal demyelinating disorders that have been reported in those patients who have suffered from COVID-19 rather than on the people already living with diagnosed or undiagnosed primary demyelinating disorders. Methods : We used the existing PRISMA consensus statement. Data were collected from PubMed, NIH Litcovid, EMBASE and Cochrane library databases, as well as Pre-print servers (medRxiv, bioRxiv, and pre-preints.org), until September 10, 2020, using pre-specified searching strategies. Results : The 21 selected articles were all case reports and included 11 (52%) men and 10 (48%) women. The mean age was of 46.7 ± 18.0. The neurological manifestations included weakness, sensory deficit, autonomic dysfunction and ataxia. In most cases, elevated cerebrospinal fluid protein as well as lymphocytic pleocytosis were found. SARS-CoV-2 was detected in five (24%) patients, meanwhile in 13 (62%) patients, the testing was negative. Testing was not performed in two cases and, in one, data were unavailable. Nearly half of the cases (N = 9) were associated with isolated long extensive transverse myelitis (LETM), whereas a combination of both LETM and patchy involvement was found in two. Only five patients had isolated short segment involvement and two patchy involvement. Furthermore, concomitant demyelination of both brain and spine was reported in six patients. Concerning the prognosis, most of the patients improved and the mortality rate was low (N = 2, Conclusion : Spinal cord demyelination should be added to the plethora of immune mediated neurologic complications associated with COVID-19.

Objective The association between higher education and increased mortality in Alzheimer's disease (AD) is controversial. Further it is unknown whether education predicts survival in all dementia subtypes. We assessed mortality rates and death causes of persons with dementia compared to participants without dementia. Methods Participants derive from the Neurological Disorders in Central Spain, a prospective population- based cohort study of older adults. We compared 269 persons with dementia to 2944 participants without dementia. We carried out Cox regression models to predict the risk of mortality dependent on the educational attainment adjusting for covariates. Reasons of death were obtained from the National Population Register. Results During a median follow-up of 5.4 years, 400 individuals died (171 with dementia, 229 without dementia). Among the participants with dementia, those with higher educational attainment had an increased risk of death than those with lower education; the adjusted hazard ratio (HRa) was 1.40 (95% confidence interval [CI], 1.01 to 1.94). When the analysis was restricted to patients with AD the HRa increased to 1.51 (95% CI = 1.01-2.24). By contrast, educational attainment was not associated with increased mortality among participants without dementia (HRa = 0.92, 95% CI = 0.71-1.20, p = 0.55), whereas education did not influence mortality in QD. Conclusion Our findings suggest that high educational attainment is associated with increased mortality risk in people with dementia. This observation implies that neuropathology is more advanced in patients with higher education at any level of clinical severity, leading these individuals to an earlier death after diagnosis.

Objective. We propose, design and test a novel thin-film multichannel electrode that can be used for both recording from and stimulating a muscle in acute implants. Approach. The system is built on a substrate of polyimide and contains 12 recording and three stimulation sites made of platinum. The structure is 420 μm wide, 20 μm thick and embeds the recording and stimulation contacts on the two sides of the polyimide over an approximate length of 2 cm. We show representative applications in healthy individuals as well as tremor patients. The designed system was tested by a psychometric characterization of the stimulation contacts in six tremor patients and three healthy individuals determining the perception threshold and current limit as well as the success rate in discriminating elicited sensations (electrotactile feedback). Also, we investigated the possibility of using the intramuscular electrode for reducing tremor in one patient by electrical stimulation delivered with timing based on the electromyographic activity recorded with the same electrode. Main results. In the tremor patients, the current corresponding to the perception threshold and the current limit were 0.7 ± 0.2 and 1.4 ± 0.7 mA for the wrist flexor muscles and 0.4 ± 0.2 and 1.5 ± 0.7 mA for the extensors. In one patient, closed-loop stimulation resulted in a decrease of the tremor power >50%. In healthy individuals the perception threshold and current limits were 0.9 ± 0.6 and 2.1 ± 0.6 mA for the extensor carpi radialis muscle. The subjects could distinguish four or six stimulation patterns (two or three stimulation sites × two stimulation current amplitudes) with true positive rate >80% (two subjects) and >60% (one subject), respectively. Significance. The proposed electrode provides a compact multichannel interface for recording electromyogram and delivering electrical stimulation in applications such as neuroprostheses for tremor suppression and closed-loop myoelectric prostheses., This study was financed by the European Projects EXTEND (H2020-ICT-23-2017-779982) and NeuroTREMOR (FP7-ICT-2011-7-287739). The funding agency was not involved in the collection, analyses, and interpretation of data or writing and publication of this article.

Wearable technology used in Parkinson's disease (PD) research has become an increasing focus of interest in this field. Our group assessed the feasibility, clinical correlation, reliability, and acceptance of smartwatches in order to quantify arm resting tremors in PD patients. An Android application on a smartwatch was used to obtain raw data from the smartwatch's gyroscopes. Twenty-two PD patients were consecutively recruited and followed for 1 year. Arm rest tremors were video filmed and scored by two independent raters using the motor subscale of the Unified Parkinson's Disease Rating Scale (UPDRS-III). The tremor intensity parameter was defined by the root mean square of the angular speed measured by the smartwatch at the wrist. Sixty-four smartwatch evaluations were completed. The Spearman coefficient among the mean of the resting tremor (UPDRS-III) scores and smartwatch measurements for tremor intensity was 0.81 (p, This work was supported by the Ministerio de Economía y Competitividad, Gobierno de España [RTC-2015-3967-1, “NetMD - Plataforma para el seguimiento de Trastornos del Movimiento”].

Orthostatic tremor (OT) is an extremely rare, misdiagnosed, and underdiagnosed disorder affecting adults in midlife. There is debate as to whether it is a different condition or a variant of essential tremor (ET), or even, if both conditions coexist. Our objective was to use data mining classification methods, using magnetic resonance imaging (MRI)-derived brain volume and cortical thickness data, to identify morphometric measures that help to discriminate OT patients from those with ET. Methods: MRI-derived brain volume and cortical thickness were obtained from 14 OT patients and 15 age-, sex-, and education-matched ET patients. Feature selection and machine learning methods were subsequently applied. Results: Four MRI features alone distinguished the two, OT from ET, with 100% diagnostic accuracy. More specifically, left thalamus proper volume (normalized by the total intracranial volume), right superior parietal volume, right superior parietal thickness, and right inferior parietal roughness (i.e., the standard deviation of cortical thickness) were shown to play a key role in OT and ET characterization. Finally, the left caudal anterior cingulate thickness and the left caudal middle frontal roughness allowed us to separate with 100% diagnostic accuracy subgroups of OT patients (primary and those with mild parkinsonian signs). Conclusions: A data mining approach applied to MRI-derived brain volume and cortical thickness data may differentiate between these two types of tremor with an accuracy of 100%. Our results suggest that OT and ET are distinct conditions., This research was supported by FEDER funds. Benito‐León is supported by the National Institutes of Health, Bethesda, MD, USA (NINDS #R01 NS39422), European Commission (grant ICT‐2011‐287739, NeuroTREMOR), the Ministry of Economy and Competitiveness (grant RTC‐2015‐3967‐1, NetMD – platform for the tracking of movement disorder), and the Spanish Health Research Agency (grant FIS PI12/01602 and grant FIS PI16/00451). Romero is supported by the European Commission (grant ICT‐2011‐287739, NeuroTREMOR) and the Spanish Ministry of Economy and Competitiveness (grant DPI‐2015‐68664‐C4‐1‐R, NeuroMOD). Louis has received research support from the National Institutes of Health: NINDS #R01 NS094607 (principal investigator), NINDS #R01 NS085136 (principal investigator), NINDS #R01 NS073872 (principal investigator), NINDS #R01 NS085136 (principal investigator), and NINDS #R01 NS088257 (principal investigator). He has also received support from the Claire O'Neil Essential Tremor Research Fund (Yale University). Sánchez‐Ferro is supported by the Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid and the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007‐2013). Serrano is supported by RoboCity2030‐DIH‐CM Madrid Robotics Digital Innovation Hub (“Robótica aplicada a la mejora de la calidad de vida de los ciudadanos. fase IV”; S2018/NMT‐4331), funded by “Programas de Actividades I + D en la Comunidad de Madrid” and cofunded by Structural Funds of the European Commission. We acknowledge the neuropsychologist Verónica Puertas‐Martín, for her assistance with the project.

Alzheimer disease (AD) mortality risk in a large cohort of subjects treated or not with non-steroidal anti-inflammatory drugs (NSAIDs) is unknown. Our objective was to determine whether NSAIDs use is associated with decreased risk of AD mortality. In this prospective, population-based study (Neurological Disorders in Central Spain [NEDICES]) of 5,072 people without AD (aged 65 years and older), sociodemographic, comorbidity factors, and current medications were recorded at baseline. Community-dwelling older adults were followed for a median of 12.7 years, after which the death certificates of deceased participants were examined. 2,672 (52.7%) of 5,072 participants died, including 504 (18.9%) NSAIDs users and 2,168 (81.1%) non-users. Of the 2,672 deceased participants, 113 (4.2%) had AD as a cause of death (8 [1.6%] among NSAIDs users and 105 [4.8%] among non-users, chi-square = 10.70, p = 0.001). In an unadjusted Cox model, risk of AD mortality was decreased in NSAIDs users (hazard ratio [HR] for AD mortality = 0.35, 95% confidence interval [CI] 0.17–0.72, p = 0.004) when compared to non-users. After adjusting for numerous demographic factors and co-morbidities, the HR for AD mortality in NSAIDs users was 0.29, 95% CI 0.12–0.73, p = 0.009. Stratified analyses showed a significantly decreased risk of AD mortality with aspirin, whereas non-aspirin NSAIDs only showed a statistical trend toward significance in the adjusted Cox regression models. NSAIDs use was associated with 71% decreased risk of AD mortality in older adults. Our results support the hypothesis that NSAIDs use is a protective factor of developing AD.

Opsoclonus is an ocular motility disorder characterized by spontaneous, arrhythmic conjugate saccades of varying amplitude occurring in all directions of gaze without normal intersaccadic interval. Etiological spectrum of opsoclonus encompasses paraneoplastic and neoplastic conditions, infectious and para-infectious encephalitis, autoimmune, metabolic and toxic encephalopathies, drugs, motor neuron diseases, multiple sclerosis and rarely neuromyelitis optica spectrum disorder (NMOSD). Opsoclonus has never been reported as a presenting manifestation heralding NMOSD. We herein report a previously healthy 37-year-old Asian Indian woman who presented with oscillopsia and opsoclonus, followed, 12 h later, by right-sided hemiparesis, right-sided appendicular ataxia, and left-sided lower motor neuron type facial palsy and dysarthria. Brain magnetic resonance imaging revealed hyperintense lesions in brainstem and thalamus in T2-weighted and fluid attenuated inversion recovery-weighted images, quite suggestive of NMOSD. Serum and cerebrospinal fluid samples were positive for anti-aquaporin-4 antibodies, which clinched the diagnosis of seropositive NMOSD. After completion of a course of intravenous methylprednisolone 1 g/day for 5 days, her opsoclonus disappeared completely. There was significant improvement in her speech and weakness within the first week of therapy and no objective deficit after day 20 of admission. After one-and-a-half-year follow-up, the patient was maintaining well on rituximab as secondary prophylaxis without any further attack. Our case highlights that isolated opsoclonus can be the presenting feature of NMOSD.

Objective: Although the cerebello-thalamo-cortical network has often been suggested to be of importance in the pathogenesis of essential tremor (ET), the origins of tremorgenic activity in this disease are not fully understood. We used a combination of cortical thickness imaging and neurophysiological studies to analyze whether the severity of tremor was associated with anatomical changes in the brain in ET patients. Methods: Magnetic resonance imaging (MRI) and a neurophysiological assessment were performed in 13 nondemented ET patients. High field structural brain MRI images acquired in a 3T scanner and analyses of cortical thickness and surface were carried out. Cortical reconstruction and volumetric segmentation was performed with the FreeSurfer image analysis software. We used high-density surface electromyography (hdEMG) and inertial measurement units (IMUs) to quantify the tremor severity in upper extrimities of patients. In particular, advanced computer tool was used to reliably identify discharge patterns of individual motor units from surface hdEMG and quantify motor unit synchronization. Results: We found significant association between increased motor unit synchronization (i.e., more severe tremor) and cortical changes (i.e., atrophy) in widespread cerebral cortical areas, including the left medial orbitofrontal cortex, left isthmus of the cingulate gyrus, right paracentral lobule, right lingual gyrus, as well as reduced left supramarginal gyrus (inferior parietal cortex), right isthmus of the cingulate gyrus, left thalamus, and left amygdala volumes. Interpretation: Given that most of these brain areas are involved in controlling movement sequencing, ET tremor could be the result of an involuntary activation of a program of motor behavior used in the genesis of voluntary repetitive movements., This work was funded by FEDER grant ; National Institutes of Health grant ; NINDS grants R01 NS39422;, R01 NS094607;, R01 NS085136;, R01 NS073872;, and R01 NS088257; European Commission grant ICT‐2011‐287739; Ministry of Economy and Competitiveness grant RTC‐2015‐3967‐1; Spanish Health Research Agency grants FIS PI12/01602; and FIS PI16/00451; Spanish Ministry of Economy and Competitiveness grants DPI‐2015‐68664‐C4‐1‐R; and DPI2015‐72638‐EXP; Claire O'Neil Essential Tremor Research grant ; Slovenian Research Agency grant J2‐7357.

There remains much to learn about the changes in cortical anatomy that are associated with tremor severity in Parkinson's disease (PD). For this reason, we used a combination of structural neuroimaging to measure cortical thickness and neurophysiological studies to analyze whether PD tremor was associated with cortex integrity. Magnetic resonance imaging and neurophysiological assessment were performed in 13 nondemented PD patients (9 women, 69.2%) with a clearly tremor-dominant phenotype. Cortical reconstruction and volumetric segmentation were performed with the Freesurfer image analysis software. Assessment of tremor was performed by means of high-density surface electromyography (hdEMG) and inertial measurement units (IMUs). Individual motor unit discharge patterns were identified from surface hdEMG and tremor metrics quantifying motor unit synchronization from IMUs. Increased motor unit synchronization (i.e., more severe tremor) was associated with cortical changes (i.e., atrophy) in wide-spread cortical areas, including caudal middle frontal regions bilaterally (dorsal premotor cortices), left inferior parietal lobe (posterior parietal cortex), left lateral orbitofrontal cortex, cingulate cortex bilaterally, left posterior and transverse temporal cortex, and left occipital lobe, as well as reduced left middle temporal volume. Given that the majority of these areas are involved in controlling movement sequencing, our results support Albert's classic hypothesis that PD tremor may be the result of an involuntary activation of a program of motor behavior used in the genesis of rapid voluntary alternating movements.

Early separation of mild cognitive impairment (MCI) from normal aging and mild cases of dementia remains a challenge, especially in the general population. We aimed to analyze the diagnostic accuracy of a brief neuropsychological battery (BNB) in dementia and MCI cases from the Neurological Disorders in Central Spain (NEDICES) population-based cohort study. We screened 3,891 participants into dementia and non-dementia groups using a two-phase procedure: screening (MMSE-37 and Pfeffer-11) and clinical diagnosis by specialists (DSM-IV criteria). We selected subsequently a subsample of dementia (nA¢Â€ÂŠ=A¢Â€ÂŠ98), MCI (nA¢Â€ÂŠ=A¢Â€ÂŠ71), and cognitively healthy (nA¢Â€ÂŠ=A¢Â€ÂŠ123) participants matched in socio-demographic characteristics. The clinical validity of each test of the BNB was determined by the area under the ROC curve. We determined the best combination of tests to classify individuals into the diagnostic groups by logistic regression analyses. The results indicated that dementia and MCI groups could be best discriminated from the healthy control group on the basis of their scores on the semantic verbal fluency and delayed recall subtests of the BNB. As for discriminating the MCI group from the dementia group, immediate recall tasks (stories and pictures) yielded the highest level of accuracy. Probably the most interesting finding is that the verbal fluency task consistently allowed discrimination among the diagnostic groups. Overall, subtests of the BNB are more accurate in differentiating dementia patients than MCI patients from healthy controls. In this population-based sample, a more fine-grained discrimination that includes MCI patients should follow a systematic subtest-wise analysis and decision.

Background An association between head trauma and essential tremor (ET) has not been formally assessed. Our purpose was to assess the association between serious head trauma and ET. Methods History of head trauma was assessed in 274 ET cases and 3201 controls in the Neurological Disorders in Central Spain (NEDICES) study, a population-based study in central Spain. Head trauma was defined as serious only if the subject reported that the trauma resulted in loss of consciousness, hospitalization, or a visit to the emergency department. Results Thirty-two (11.7%) of 274 ET cases vs. 260 (8.1%) of 3201 controls reported a history of serious head trauma (p = 0.04). In an adjusted logistic regression analysis, participants who reported serious head trauma were 52% more likely to have ET (odds ratio [OR] 1.52; 95% confidence interval [CI] 1.02–2.27, p = 0.04). The odds of ET increased with increasing age of head trauma: adjusted ORs = 1.23 (95% CI 0.43–3.46, p = 0.70) for serious head trauma that occurred before age 18 years, adjusted OR = 1.49 (95% CI 0.62–3.55, p = 0.37) for serious head trauma between ages 18 to 39 years, and adjusted OR = 1.61 (95% CI 1.00–2.57, p = 0.04) for serious head trauma at age 40 years or older. Conclusions Our study suggests that serious head trauma, especially when it occurs after 40 years, is associated with increased odds of ET. Additional studies are needed to reproduce this novel finding.

Background Essential tremor (ET), a highly-prevalent, progressive, aging-associated neurological disease, poses a significant public health challenge. Aside from its associated motor features, the disease affects cognition in some patients, mood, and morale, and has been associated with increased risk of mortality in the elderly. Studies have not investigated the relationship between self-rated health and risk of ET. We determined whether baseline poor self-rated health was associated with increased risk of incident ET. Methods In this prospective, population-based study of people ≥65 years of age, subjects were evaluated at baseline and 3 years later. At baseline, subjects were asked to rate their health using a single-item health question. Hazard ratios (HR) of ET according to baseline self-rated health (very good, good, fair, poor, and very poor) were estimated with Cox models. Results The 3853 subjects had a median follow-up duration of 3.2 years. There were 82 incident ET cases. Compared to subjects who rated their health as good or very good, the risk of ET was increased for subjects who rated their health as fair (HR = 1.69, p = 0.03), and for subjects who rated their health as poor or very poor (HR = 2.12, p = 0.02). In a fully adjusted model, the risk remained increased for subjects who rated their health as poor or very poor (HR = 2.34, p = 0.01). Conclusions Subjects rating their health as poor/very poor at baseline were at increased risk of incident ET at follow-up. Premotor and/or early motor symptoms of ET could negatively influence self-perceptions of health status.

Objective. This research aims to determine whether residence (rural vs. urban) at different life stages (childhood, adulthood, and late life) is associated with increased risk of incident dementia in a population-based cohort of older Spaniards. Methods. In this prospective study, 2,711 participants aged 65 years and older were assessed at baseline and 3 years later. All cases of incident dementia were diagnosed using DSM-IV criteria. The relationship between residence and the relative risk of dementia was analysed using Cox's regression models. Demographics, comorbidity index, consumption (tobacco / alcohol) and doubtful dementia diagnosis were considered as possible confounders. Results. At the three-year follow-up, 91 cases of dementia were detected. Lower education and occupational attainment were associated with a higher incidence of dementia three years later. Rural residence in adulthood was associated with a significantly higher risk of dementia at the follow-up. Childhood rural residence revealed a marked trend for risk of dementia (p = 0.08), but it was nonsignificant in later life. The risk of dementia was considerably higher for the rural/low-education group than for the urban/high-education group, for both childhood and adulthood residence. Finally, people from areas with the lowest socio- economic status Arevalo (rural, blue-collar) and Margaritas (urban, blue-collar) showed higher risk of dementia than people from Lista (urban, mixed white/blue collar). Conclusion. In this cohort, early and mid-life stages rural residence was a risk factor for dementia, but not later-life rural residence. The rural residence effect was noticeably higher in people with a lower educational level.

Background Multiple sclerosis (MS) patients have high rates of complications and disability, including cognitive impairment, that often, impact on caregivers' emotional health. Clarification may help identify improved supportive strategies for both caregivers and patients. Objective We aimed to analyse whether MS domain-specific cognitive impairment can influence the severity of psychiatric symptoms of MS caregivers. Methods Patients with definite MS (n = 63) and their corresponding caregivers (n = 63) were recruited. In addition, 59 matched controls were enrolled for establishing normative cognitive data. Each patient underwent a complete neuropsychological testing for cognitive impairment and thorough clinical assessment, including data of disability status (EDSS), affective and emotional symptoms (depression, anxiety, anger) and fatigue. Psychiatric symptoms of the caregivers were assessed with the Beck Anxiety Inventory (BAI) and the Beck Depression Inventory (BDI). Results In logistic regression analyses, even after controlling for other MS-related symptoms, cognitive deficits, namely impairment on Symbol Digit Modalities Test (OR = 8.03, 95% CI = 1.27–25.33, p = 0.027) and on the Paced Auditory Serial Addition Test (OR = 6.86, 95% CI = 1.07–21.97, p = 0.042), were significant and independent predictors of more severe caregivers' depressive symptoms. Conclusions Information processing speed impairment is independently associated with more severe depressive symptoms of caregivers of MS patients, thereby reflecting a further deterioration of family setting.

The influence of education and oral word-reading ability on cognitive performance was examined in a sample of 1510 nondemented elders differing in socioeconomic status (SES) from three Spanish communities.All individuals were enrolled in the Neurological Disorders in Central Spain, a population-based epidemiological study in central Spain. They completed a detailed demographic survey and a short standardized neuropsychological battery assessing psychomotor speed, attention, language, and memory. The Word Accentuation Test (WAT) was used as measure of oral reading ability. The influence of education and oral reading on cognitive performance was determined by multiple linear regression models, first controlling for demographics (age and sex), and subsequently for the WAT score and education. The contribution of socioeconomic conditions was addressed by stratifying the sample into groups of high and low SES.The WAT showed a significant independent effect on cognitive scores, generally greater than that predicted by demographics. The higher predictive power of oral word reading on cognitive scores compared to education was consistent across the three communities. Although the variance explained by WAT was very similar in areas with diverse SES (low vs. high), WAT scores accounted for slightly more variance in naming and memory tasks in low SES areas. In contrast, the variance explained by WAT was higher for verbal fluency and the Trail-Making Test in areas with high SES.Oral word-reading ability predicts cognitive performance better than years of education across individuals with different SES. The influence of WAT may be modulated by SES and cognitive task properties.

Background: Little information is available on the potential association between polypharmacy and risk of mortality. Objective: To determine in a population-based study whether polypharmacy is associated with increased risk of mortality in elderly persons. Methods: In this population-based, prospective study of 5,052 people aged 65 years and older (Neurological Disorders in Central Spain), current medications were recorded. Cox proportional hazards models, adjusted for sociodemographics and comorbidity factors, were used to assess the risk of death up to 13.3 years later, comparing the polypharmacy group (≥6 drugs) to those who were taking 1-5 drugs and those in a nonmedicated group (0 drugs). Results: Out of 5,052 participants, 2,550 (50.5%) died over a median follow-up of 6.5 years, including 361 (28.8%) deaths among 931 nonmedicated participants, 1,946 (51.4%) deaths among 3,787 participants taking 1-5 drugs daily, and 243 (72.8%) among 334 participants on polypharmacy. In an unadjusted Cox model, risk of mortality was increased in participants on polypharmacy [hazard ratio (HR) = 2.78, 95% confidence interval [CI]: 2.36-3.27, p < 0.001) and in those taking between 1 and 5 drugs (HR = 1.47, 95% CI: 1.31-1.64, p < 0.001) versus those who were nonmedicated (reference group). In a Cox model that adjusted for a variety of demographic factors and comorbidities, HR remained increased in participants on polypharmacy (HR = 1.83, 95% CI: 1.51-2.21, p < 0.001). Conclusion: This study provides evidence that polypharmacy is associated with increased risk of mortality in elderly people. The extent to which polypharmacy is the proximate cause rather than a marker of this increase risk remains to be determined.

Background Despite growing evidence showing an association between Parkinson's disease (PD) and diabetes, epidemiological studies have shown conflicting results. Aims of the study To evaluate the association between PD and diabetes and the impact of diabetes duration in this association in an elderly (≥65 years) Spanish population. Methods Data for this cross-sectional population-based analysis were obtained from NEDICES study. Subjects were identified from census list. Diagnosis of PD was confirmed by neurological examination. Diabetes was defined by self-report, being on antidiabetic medication or diagnosis on medical records. Logistic regression analysis adjusted by potential confounders was performed to estimate the association between both conditions and also after dividing patients into short-duration (

Essential tremor (ET) is one of the most prevalent movement disorders. Being that it is a common disorder, its diagnosis is considered routine. However, misdiagnoses may occur regularly. Over the past decade, several studies have identified brain morphometric changes in ET, but these changes remain poorly understood. Here, we tested the informativeness of measuring cortical thickness for the purposes of ET diagnosis, applying feature selection and machine learning methods to a study sample of 18 patients with ET and 18 age- and sex-matched healthy control subjects. We found that cortical thickness features alone distinguished the two, ET from controls, with 81% diagnostic accuracy. More specifically, roughness (i.e., the standard deviation of cortical thickness) of the right inferior parietal and right fusiform areas was shown to play a key role in ET characterization. Moreover, these features allowed us to identify subgroups of ET patients as well as healthy subjects at risk for ET. Since treatment of tremors is disease specific, accurate and early diagnosis plays an important role in tremor management. Supporting the clinical diagnosis with novel computer approaches based on the objective evaluation of neuroimage data, like the one presented here, may represent a significant step in this direction. post-print 1720 KB

BACKGROUND: Sense of Coherence (SOC) is defined as a tendency to perceive life experiences as comprehensible, manageable and meaningful. The construct is split in three major domains: Comprehensibility, Manageability, and Meaningfulness. SOC has been associated with successful coping strategies in the face of illness and traumatic events and is a predictor of self-reported and objective health in a variety of contexts. In the present study we aim to evaluate the association of SOC with disability and dependence in Spanish elders. METHODS: A total of 377 participants aged 75 years or over from nine locations across Spain participated in the study (Mean age: 80.9 years; 65.3% women). SOC levels were considered independent variables in two ordinal logistic models on disability and dependence, respectively. Disability was established with the World health Organization-Disability Assessment Schedule 2.0 (36-item version), while dependence was measured with the Extended Katz Index on personal and instrumental activities of daily living. The models included personal (sex, age, social contacts, availability of an intimate confidant), environmental (municipality size, access to social resources) and health-related covariates (morbidity). RESULTS: High Meaningfulness was a strong protective factor against both disability (Odds Ratio [OR] = 0.50; 95% Confidence Interval [CI] = 0.29-0.87) and dependence (OR = 0.33; 95% CI = 0.19-0.58) while moderate and high Comprehensibility was protective for disability (OR = 0.40; 95% CI = 0.22-0.70 and OR = 0.39; 95%CI = 0.21-0.74), but not for dependence. Easy access to social and health resources was also highly protective against both disability and dependence. CONCLUSIONS: Our results are consistent with the view that high levels of SOC are protective against disability and dependence in the elderly. Elderly individuals with limited access to social and health resources and with low SOC may be a group at risk for dependence and disability in Spain. This project was partially funded by a research contract in support of the project “Epidemiological Study of Dementia in Spain” signed by the Pfizer Foundation and Carlos III Institute of Health. The funding agency had no influence in the scientific process including study design, data collection, data analysis, interpretation of results, and writing of the manuscript. Sí

Background: There is evidence of the presence of a disturbed pattern of anger in multiple sclerosis (MS). Emotion changes, including anger, are thought to influence health-related quality of life (HRQoL). However, although deleterious consequences of anger on physical health have been well reported, there are no studies that have analysed the effects of anger on the HRQoL in patients with MS. Our purpose was to assess the extent to which anger impacts on the HRQoL of a cohort of MS patients. Methods: One hundred and fifty-seven consecutive MS patients were enrolled in the study. Participants were administered affective trait measures (Beck Depression Inventory, Beck Anxiety Inventory) and anger measures (the Spanish adapted version of the State-Trait Anger Expression Inventory-2). HRQoL was quantified using the Functional Assessment of MS. Results: Linear regression analyses revealed that even after controlling for socio-demographic and clinical variables, higher levels of anger expression-in (tendency to handle anger by keeping it inside) independently predicted worse overall HRQoL of MS patients (β = −0.15, p = 0.04). We further found that this relationship was moderated by gender, showing that anger expression-in is a more influential predictor of the HRQoL in women with MS. Conclusion: The present study provides evidence that anger negatively affects the HRQoL of MS patients. Our results may have implications for those involved in treating emotional complications of MS and especially regarding psychotherapeutic interventions to improve HRQoL of MS patients.

Previous studies have shown that Alzheimer's disease (AD) is associated with a reduced risk of cancer. However, most studies exclude those with undiagnosed dementia. The only way to overcome this methodological issue is to examine all the participants or to screen the population for symptoms of dementia with a validated instrument and confirm any suspected dementia patients with a clinical examination (i.e., a two-phase investigation method). We used this methodology to estimate whether cancer-specific mortality is associated with AD and other types of dementia in a prospective population-based study (NEDICES) involving 5,278 elderly people. Community-dwelling subjects with and without dementia were identified and followed for a median of 12.5 years, after which the death certificates of those who deceased were examined. A total of 1,976 (47.1%) died, including 277 who had possible or probable AD and 126 with non-AD dementia. Cancer was reported significantly less often in those with possible or probable AD (5.8%) or non-AD dementia (6.3%) than in those without dementia (26.5%). In an unadjusted Cox model, hazard ratio (HR) of cancer-specific mortality in participants with AD = 0.45 (p = 0.002) and HR in participants with non-AD dementia = 0.62 (p = 0.179) when compared to the non-demented group. In a Cox model that adjusted for a variety of demographic factors and co-morbidities, HRs of cancer-specific mortality in participants with AD = 0.50 (p = 0.028) and 0.97 (p = 0.942) in non-AD dementia. This study provides further evidence of an inverse association between cancer and AD.

Previous studies have shown that dementia is frequently omitted as a cause of death from the death certificate in patients with long-standing dementia. However, most studies exclude those undiagnosed dementia sufferers in the population. In order to overcome this problem, it is necessary to examine all the participants or to screen the population for symptoms of dementia and confirm the diagnosis with a clinical examination (two-phase approach). We used this latter methodology to estimate the proportion of reporting of dementia on death certificates in a prospective population-based study (NEDICES), involving 4,197 elderly people. Community-dwelling subjects with and without dementia were identified and followed during a median of 12.5 years, after which the death certificates of those who deceased were examined. A total of 1,976 (47.1%) died (403 subjects with dementia). Dementia was rarely reported as the primary cause of death, even in known cases of dementia (20.8%). Indeed it was reported in only 13.3% of those with mild dementia and 24.3% of those with moderate or severe dementia; in 24.9% of those with possible or probable Alzheimer's disease; and in 11.9% of those with non-Alzheimer dementia. In a stepwise multiple logistic regression analysis with the dependent variable being presence or absence of dementia on the death certificate, the significant associated independent variables were age at death, severity of dementia, and etiology of dementia. We conclude that reporting of dementia on death certificates remains poor. This suggests a lack of awareness of the importance of dementia as a cause of death.

We analyzed the allelic and genotypic frequencies of the glutathione-S-transferase P1 (GSTP1) rs1695 single nucleotide polymorphism (SNP) in 290 patients with multiple sclerosis (MS) and in 310 healthy controls. We found no significant association between the rs1695 variant and MS. Among MS patients, there was no relationship between the rs1695 variant and either gender, clinical type of MS or the age of onset of MS. These results suggest that the GSTP1 rs1695 polymorphism is not a risk factor for MS.

A recent genome-wide association study and other replication studies have suggested that the rs3794087 single nucleotide polymorphism in the solute carrier family 1 - glial affinity glutamate transporter-member 2 (SLC1A2) gene is associated with an increased risk for essential tremor (ET), and a replication study in an Asian cohort has shown a decreased risk for ET associated with the rs3794087T allele. We tried to replicate this association in a White Spanish population.We analyzed the distribution of allelic and genotypic frequencies of rs3794087 in 202 patients with familial ET and 308 healthy controls using a TaqMan-based quantitative PCR assay.Genotypic and allelic frequencies of rs3794087 did not differ significantly between patients with ET and controls and were unrelated with the age at onset of tremor or sex.Our study suggests that SLC1A2 rs3794087 is not associated with the risk for developing familial ET in the Spanish population, thus subtracting relevance to SLC1A2 rs3794087 as a risk biomarker for ET.

Optical coherence tomography is a simple, high-resolution technique to quantify the thickness of retinal nerve fiber layer (RNFL). Previous studies have shown that degenerative changes occur in optic nerve fibers and are manifested as thinning of RNLF in patients with Alzheimer's disease (AD). However, there are no studies on the thickness of the RNLF in other types of dementia, such as dementia with Lewy bodies and dementia associated with Parkinson's disease. In this study, patients fulfilling diagnostic for AD (n = 10), dementia with Lewy bodies (n = 10), dementia associated with Parkinson's disease (n = 10), and cognitively normal age-matched controls (n = 10) underwent optical coherence tomography examinations to measure RNLF thickness. There was a significant decrease in RNLF thickness in each type of dementia compared to the control group (Mann-Whitney test, all p < 0.001). Although patients with dementia with Lewy bodies may have a greater thinning than both patients with AD and dementia associated with Parkinson's disease, the differences were statistically nonsignificant (Kruskal-Wallis test, p = 0.525). The thickness of the RNLF correlated significantly (p < 0.001) with both the Mini-Mental State Examination and the Mattis Dementia Rating Scale scores in all types of dementia; that is to say, the greater the cognitive deterioration, the greater the reduction of thickness of the RNLF. The findings from this study show that retinal involvement measured by optical coherence tomography may also be present in non-AD dementias.

Background Environmental correlates for essential tremor (ET) are largely unexplored. The search for such environmental factors has involved the study of a number of neurotoxins. Harmane (1-methyl-9H-pyrido[3,4- b ]indole) is a potent tremor-producing toxin. In two prior case–control studies in New York, we demonstrated that blood harmane concentration was elevated in ET patients vs. controls, and especially in familial ET cases. These findings, however, have been derived from a study of cases ascertained through a single tertiary referral center in New York. Objective Our objective was to determine whether blood harmane concentrations are elevated in familial and sporadic ET cases, ascertained from central Spain, compared to controls without ET. Methods Blood harmane concentrations were quantified by a well-established high performance liquid chromatography method. Results The median harmane concentrations were: 2.09 g −10 /ml (138 controls), 2.41 g −10 /ml (68 sporadic ET), and 2.90 g −10 /ml (62 familial ET). In an unadjusted logistic regression analysis, log blood harmane concentration was not significantly associated with diagnosis (familial ET vs. control): odds ratio = 1.56, p = 0.26. In a logistic regression analysis that adjusted for evaluation start time, which was an important confounding variable, the odds ratio increased to 2.35, p = 0.049. Conclusions Blood harmane levels were slightly elevated in a group of familial ET cases compared to a group of controls in Spain. These data seem to further extend our observations from New York to a second cohort of ET cases in Spain. This neurotoxin continues to be a source of interest for future confirmatory research.

Background: The biomedical and psychosocial mechanisms underlying the relationship between self-rated health (SRH) and mortality in elderly individuals remain unclear. Objective: To assess the association between different measurements of subjective health (global, age-comparative, and time-comparative SRH) and cause-specific mortality. Methods: Neurological Disorders in Central Spain (NEDICES) is a prospective population-based survey of the prevalence and incidence of major age-associated conditions. Data on demographic and health-related variables were collected from 5,278 subjects (≥65 years) in the baseline questionnaire. Thirteen-year mortality and cause of death were obtained from the National Death Registry. Adjusted hazard ratios (aHR) for SRH and all-cause and cause-specific mortality were estimated by Cox proportional hazard models. Results: At baseline, 4,958 participants (93.9%) answered the SRH questionnaire. At the end of follow-up, 2,468 (49.8%) participants had died, of whom 723 (29.2%) died from cardiovascular diseases, 609 (24.7%) from cancer, and 359 (14.5%) from respiratory diseases. Global SRH independently predicted all-cause mortality (aHR for ‘poor or very poor' vs. ‘very good' category: 1.39; 95% confidence interval (CI): 1.15-1.69). Analysis of cause-specific mortality revealed that global SRH was an independent predictor for death due to respiratory diseases (aHR for ‘poor or very poor' vs. ‘very good' category: 2.61; 95% CI: 1.55-4.39), whereas age-comparative SRH exhibited a gradient effect on the risk of death due to stroke. Time-comparative SRH provided small additional predictive value. Conclusions: The predictive ability of SRH for mortality largely differs according to the specific cause of death, with the strongest associations found for respiratory disease and stroke mortality.

BACKGROUND Several reports found a relationship between increased serum lead levels and the risk for essential tremor (ET), especially in carriers of the minor allele of the single nucleotide polymorphism (SNP) rs1800435 in the aminolevulinate dehydratase (ALAD) gene, which is involved in the synthesis of haem groups. Our group reported decreased risk for ET in carriers of the minor alleles of the rs2071746 and rs1051308 SNPs in the haem-oxygenases 1 and 2 (HMOX1 and HMOX2), respectively, involved in haem metabolism. We analysed whether ALAD rs1800435 alone and their interactions with the four common SNPs in the HMOX1 and HMOX2 genes are associated with the risk for ET. MATERIALS AND METHODS We analysed the genotype and allele variants frequencies of ALAD rs1800435 in 202 patients with familial ET and 218 healthy controls using a TaqMan method. We also analysed the role of the interaction between ALAD rs1800435 and the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363 and HMOX2 rs1051308 with the risk of developing ET. RESULTS The frequencies of genotype and allelic variants of ALAD rs1800435 did not differ significantly between patients with ET and controls, and were not influenced by gender. Subjects carrying the ALAD rs1800435CC genotype (wild-type) and the HMOX2 rs1051308GG genotype or the HMOX2 rs1051308G allele had significantly decreased risk for ET. CONCLUSIONS These results suggest that the ALAD rs1800435 SNP is not related with the risk for ET, but its interaction with the HMOX2 rs1051308 SNP could be weakly associated with the risk for this disease.

The pathogenesis of orthostatic tremor (OT) remains unclear, although some evidence points to dysfunction in the brainstem or cerebellum. We used single voxel proton magnetic resonance spectroscopy (1H-MRS) (3 T) to investigate whether neurochemical changes underlie abnormal cerebellar or cortical function in OT. Fourteen OT patients and 14 healthy controls underwent 1H-MRS studies with voxels placed in midparietal gray matter and cerebellum (vermis and central white matter). Spectral analysis was analyzed using the software package LCModel (version 6.3). The absolute metabolite concentrations and ratios of total N-acetylaspartate + N-acetylaspartyl glutamate (NAA), choline-containing compounds, myoinositol, and glutamate + glutamine to creatine were calculated. In midparietal gray matter spectra, we found a significant decrease in the absolute concentration of NAA in OT patients versus healthy controls (7.76 ± 0.25 vs 8.11 ± 0.45, P = 0.017). A similar decrease in NAA was seen in the cerebellar vermis (7.33 ± 0.61 vs 8.55 ± 1.54, P = 0.014) and cerebellar white matter (8.54 ± 0.79 vs 9.95 ± 1.57, P = 0.010). No differences in the other metabolites or their ratios were observed. Reductions in both cerebral cortical and cerebellar NAA suggest that there is neuronal damage or loss in OT, raising the intriguing question as to whether OT is a neurodegenerative disease. Along with clinical history and electrophysio0logical examination, 1H-MRS could serve as a useful diagnostic aid for OT.

To date, it remains largely unknown whether there is in radiologically isolated syndrome (RIS) brain damage beyond visible T2 white matter lesions. We used single- voxel proton magnetic resonance spectroscopy and diffusion tensor imaging (3 T MRI) to analyze normal-appearing brain tissue regions in 18 RIS patients and 18 matched healthy controls. T2-hyperintense lesion volumes and structural brain volumes were also measured. The absolute metabolite concentrations and ratios of total N-acetylaspartate+N-acetylaspartyl glutamate (NAA), choline-containing compounds, myoinositol, and glutamine-glutamate complex to creatine were calculated. Spectral analysis was performed by LCModel. Voxelwise morphometry analysis was performed to localize regions of brain tissue showing significant changes of fractional anisotropy or mean diffusivity. Compared with healthy controls, RIS patients did not show any significant differences in either the absolute concentration of NAA or NAA/Cr ratio in mid-parietal gray matter. A trend toward lower NAA concentrations (–3.35%) was observed among RIS patients with high risk for conversion to multiple sclerosis. No differences in the other metabolites or their ratios were observed. RIS patients showed lower fractional anisotropy only in clusters overlapping lesional areas, namely in the cingulate gyrus bilaterally and the frontal lobe subgyral bilaterally (P

To analyse the sentences due to loss of chance that were passed by the Contentious-Administrative Court (i.e., in public medicine), in which both the origin of the disease to be treated and the damages were neurological.We analysed the 90 sentences concerning neurological conditions that referred to the concept of loss of chance that were passed in Spain from 2003 (year of the first sentence) until May 2014.Of the 90 sentences, 52 (57.8%) were passed due to diagnostic error and 30 (33.3%), due to inadequate treatment. 72 (80.0%) of the sentences were passed from 2009 onwards, which equates to more than a 300% increase with respect to the 18 (20.0%) issued in the first six years of the study (from 2003 to 2008). Most of the patients (66.7%) were men, and a 61.1% presented sequelae. Hypoxic-ischaemic encephalopathy (14.4%) and spinal cord disorders (14.4%) were the most common conditions to lead to sentencing.The litigant activity due to loss of chance in neurological disease in the Spanish public healthcare system has significantly increased in the last few years. The sentences were mainly passed because of diagnostic error or inadequate treatment.

The loss of chance in healthcare has been forcibly introduced in the adjudications pronounced in recent years. Our objective was to analyse the verdicts of guilt resulting from the loss of chance ordered by the Contentious-Administrative Court (i.e., in the public healthcare system), in which both the origin of the disease to be treated and the sequelae were oncological processes.We analysed 137 cancer-related court judgments from the Contentious-Administrative Court, which referred to the concept of loss of chance, issued in Spain up to May 2014.Of the 137 sentences, 119 (86.9%), were pronounced due to diagnostic error and 14 (10.2%) due to inadequate treatment. Since 2010, 100 sentences have been passed (73.0%), representing an increase of more than 170% with respect to the 37 (27.0%) ordered in the first six years of the study (from 2004 to 2009). Most of the patients (68.6%) died, predominantly from breast cancer and gynaecological cancer (24.1%), and gastrointestinal cancers (21.1%). These malignancies were the ones most often involved in the sentences.The litigant activity due to loss of chance in oncological processes in the public health care has significantly increased in the last years. The judgments were mainly given because of diagnostic error or inadequate treatment.

The 37-item version of the Mini-Mental State Examination (MMSE-37) is an extended version of the original test for individuals with low education, which was adapted for different cultures. Despite its favorable psychometric properties, there is a lack of normative data for this instrument. We provide normative data for the MMSE-37 stratified by age, sex, and education in a large population-based cohort of older Spanish adults. The sample consisted of 3,777 participants without dementia (age range: 65-97 years) from different socioeconomic areas of central Spain. Normative data are presented in percentile ranks and divided into nine overlapping age tables with different midpoints, using the overlapping cell procedure. A hierarchical regression was performed to evaluate the effects of sociodemographic variables on MMSE-37 performance. Results showed that age, sex, and education affect test score. The norms presented herein are important for the correct interpretation of MMSE-37 scores when assessing older adults in Spain.

Introduction Evidence suggests that the cerebellum could play a role in the pathophysiology of orthostatic tremor. The link between orthostatic tremor and the cerebellum is of interest, especially in light of the role the cerebellum plays in cognition, and it raises the possibility that orthostatic tremor patients could have cognitive deficits consistent with cerebellar dysfunction. Our aim was to examine whether orthostatic tremor patients had cognitive deficits and distinct personality profiles when compared with matched controls. Methods Sixteen consecutive orthostatic tremor patients (65.7 ± 13.3 years) and 32 healthy matched controls underwent a neuropsychological battery and the Personality Assessment Inventory. In linear regression models, the dependent variable was each one of the neuropsychological test scores or the Personality Assessment Inventory subscales and the independent variable was orthostatic tremor vs. control. Results Adjusted for age in years, sex, years of education, comorbidity index, current smoker, and depressive symptoms, diagnosis (orthostatic tremor vs. healthy control) was associated with poor performance on tests of executive function, visuospatial ability, verbal memory, visual memory, and language tests, and on a number of the Personality Assessment Inventory subscales (somatic concerns, anxiety related disorders, depression, and antisocial features). Older-onset OT (> 60 years) patients had poorer scores on cognitive and personality testing compared with their younger-onset OT counterparts. Conclusion Orthostatic tremor patients have deficits in specific aspects of neuropsychological functioning, particularly those thought to rely on the integrity of the prefrontal cortex, which suggests involvement of frontocerebellar circuits. Cognitive impairment and personality disturbances could be disease-associated nonmotor manifestations of orthostatic tremor. pre-print 426 KB

Background A variety of symptoms may precede the classical motor features of Parkinson disease (PD). However, it is not known whether cognitive dysfunction precedes the motor phase of PD. We examined whether patients with incident PD had had global cognitive function disturbances three years prior to diagnosis when compared with matched controls in a cohort of community-dwelling subjects. Methods All participants were age 65 years or older (median 76 years) and were enrolled in the Neurological Disorders in Central Spain (NEDICES) study in central Spain. We identified all participants with incident PD (N = 23), diagnosed in the follow-up examination (1997–1998), who had performed an expanded 37-item version of the Mini-Mental State Examination (37-MMSE) at the baseline evaluation (1994–1995). These 23 were 1:4 matched to 92 controls. Results Baseline 37-MMSE scores were 27.9 ± 4.9 (28) in PD patients and 28.7 ± 6.5 (31) in controls (p = 0.212). There were no patient–control differences in orientation, immediate recall, attention and calculation, memory recall, language, or visuospatial copying. In analyses that adjusted for several possible confounding factors, there were no case–control differences. Conclusions In this population-based sample, patients with incident PD did not have evidence of significant global cognitive function disturbances three years prior to their diagnosis when compared with matched controls. Our data suggest that global cognitive dysfunction does not precede the diagnosis of PD.

To evaluate the mortality, thirteen years after the baseline wave (1994), of participants suffering dementia in the Neurological Disorders in Central Spain (NEDICES) Cohort Study, we conducted a population-based cohort study in the elderly (65 years and more) with 5,278 screened participants at baseline. Mortality has been evaluated by means of the National Death Registry of Spain at 1-5-2007, 13 years after enrolment. Cox's proportional hazards regression models were used to evaluate the hazard of death according to dementia severity and type, adjusting for potential covariates (gender, age, level of education, and co-morbidity). Survival was estimated using Kaplan-Meier method. Of the 5,278 participants screened at baseline, 306 had dementia. Mortality at 13 years was: 275 deaths (89.9%) in dementia subjects; and 2,426 (49.0%) in subjects without dementia. Mortality was higher and statistically significant in dementia subjects. The degree of dementia (DSM-III-R) correlated with the risk of mortality, from mild (HR = 2.23; CI: 1.77-2.82) to moderate (HR =3.10; CI: 2.47-3.89) and severe dementia (HR = 4.98; CI: 3.85-6.44). Survival was similar in Alzheimer's disease and vascular dementia. Factors associated with higher mortality in Cox proportional hazard models were older age, male gender, and comorbidity. Using Population Attributable risk (PAR%), dementia was related to 11.3% of all deaths. Dementia intensity increases the mortality risk at ten years in the NEDICES Study as in other cohort studies. Age, gender, and co-morbidity are associated with higher mortality in dementia patients. Almost one third of deaths in persons over 85 years-old could be attributable to dementia.

Objective To develop and test the first specific instrument for assessing caregiver health-related quality of life (HRQOL) in multiple sclerosis (MS) (CAREQOL-MS). Study Design and Setting Questionnaire items were derived from a literature review and the views of patients, caregivers, and experts. Instrument was reduced after the analyses of caregivers' interviews and experts' opinions. CAREQOL-MS psychometric properties were assessed in 276 MS caregivers. Results The final version consisted of 24 items (four subscales) and was free of floor or ceiling effects. For subscales, the Cronbach's alpha coefficient ranged from 0.75 to 0.90. The item-total correlation was 0.62–0.74 for subscale I (physical burden/global health); 0.56–0.74 for subscale II (social impact); 0.52–0.62 for subscale III (emotional impact); and 0.58–0.65 for subscale IV (need of help/emotional reactions). The intraclass correlation coefficient (0.96 for the total score; 0.75–0.95 for subscales) suggested satisfactory reproducibility. Association was close between CAREQOL-MS subscales and the Zarit burden interview and moderate with short form 36 mental/physical components. CAREQOL-MS subscales scores significantly increased (worse HRQOL) with increasing caregivers' age and Expanded Disability Status Scale. The standard error of the measurement ranged from 0.91 to 2.43 for subscales. Conclusions Our results provided initial evidence of the usefulness and satisfactory psychometric properties of the CAREQOL-MS.

Mild cognitive impairment (MCI) is often considered to be a transitional stage between normal aging and dementia. Frontal-executive dysfunction, memory impairments, and dementia have been associated with essential tremor (ET). Yet the association between MCI and ET has only been examined in one prior study. We determined whether ET is associated with MCI. We identified all persons with MCI and ET in a dementia-free, population-based study in central Spain (NEDICES). MCI was diagnosed using consensus criteria of the International Working Group on MCI. Forty-two (20.3%) of 207 ET cases had MCI versus 399 (16.1%) of 2,472 non-ET subjects (controls) (odds ratio [OR] = 1.32, 95% Confidence Interval [CI] = 0.93 to 1.89, p = 0.12). In a model that adjusted for age, gender, educational level, smoking, hearing impairment, depressive symptoms or antidepressant use, and use of a medication that could potentially affect cognitive function, the OR was 1.28, 95% CI = 0.88 to 1.84, p = 0.19. In an adjusted model, ET cases with tremor onset after age 65 were 57% more likely to have MCI than controls (OR = 1.57, 95% CI = 1.03 to 2.38, p = 0.03), whereas ET cases with tremor onset prior to age 65 and controls were equally likely to have MCI (OR = 0.73, 95% CI = 0.34 to 1.57, p = 0.43). In this study, older-onset ET was associated with MCI. This finding supports the hypothesis that cognitive disturbances are one of the core non-motor symptoms of ET.

Objective To evaluate whether memory impairment detected in the three-word delayed recall task of the Mini-Mental State Examination (MMSE) increases the risk of mortality. Methods The NEDICES (Neurological Diseases in Central Spain) cohort study, is a population census-based study, aimed at detecting age-associated neurological diseases in people aged 65 and over, living in one rural and two urban communities in central Spain. Participants with dementia or without MMSE evaluation at baseline were excluded. Mortality was evaluated 10.67 years after enrolment. Cox's proportional hazards regression models were used to evaluate the hazard of death according to performance in the three-word delayed recall task included in the MMSE (score 0–3), adjusting for potential covariates (sex, age, level of education, and comorbidity). Survival was estimated using Kaplan–Meier method. Results The final study population comprised 3778 non-demented elderly subjects. After adjusting for confounding covariates, mortality was 52% greater in persons with the lowest memory score (0) vs. persons with the highest score (3). Hazard ratios (HR) showed a tendency to an increase in mortality from the highest to the lowest memory score, which was statistically significant for the groups with none (HR = 1.52; CI = 1.27–1.80) or one (HR = 1.24; CI = 1.04–1.48) word recall. Older age, male sex, and comorbidity were also associated with mortality, but level of education was not. Conclusions Memory impairment in the three-word delayed free recall, a very simple task used by physicians worldwide, increases the risk of mortality at 10 years in non-demented elderly. Copyright © 2010 John Wiley & Sons, Ltd.

Background: To describe the design of the baseline assessment of an epidemiological study of elderly persons living in Salamanca, central-western Spain: the Neurological Diseases in Salamanca (NEDISA) study. We assessed the epidemiology of stroke, cognitive disorders, essential tremor (ET), Parkinson’s disease (PD) and restless legs syndrome. Methods: In phase 1 (February 1 to May 31, 2007), 4 neurologists and 2 trained general physicians examined and performed phlebotomy on all participants. In phase 2 (June 1, 2007, to June 1, 2008), the participants were reexamined and had a complete neuropsychological assessment. Neuroimaging was performed in participants with cognitive disorders, ET and PD. Results: The registered study population consisted of 1,077 individuals, but 45 people were ineligible (address change, refusals or death), leaving a final sample of 1,032 (95.8%). The main demographic data on the 1,032 participants (408 men, 624 women) are provided. Conclusions: Most of the registered study population was enrolled, and this may have been due to the close relationship between NEDISA researchers and the general physicians in the area of study. The NEDISA study will likely improve our knowledge of prevalence rates of the neurological diseases chosen for study as well as the set of risk factors that predispose individuals in Spain to these disorders.

Background: Mild hand tremor occurs in most normal adults. There are no surveys of the prevalence or clinical correlates of such tremor among children. Methods: A cross-sectional study of tics, tremor and other neurological disorders was conducted in Spanish children; thus, 819 schoolchildren in Burgos, Spain, drew Archimedes spirals with each hand. Tremor in spirals was rated (0–2) by a blinded neurologist and an overall tremor rating (0–4) was assigned. Results: The mean age was 10.9 ± 3.1 years. A tremor rating of 1 (mild tremor) was present in either hand in 424 (51.7%) children, and in both hands in 88 (10.7%) children. Higher tremor ratings were very uncommon. The overall tremor rating was higher in boys than girls (1.31 ± 0.41 vs. 1.22 ± 0.34, p = 0.002) and correlated weakly yet significantly with age (ρ = 0.09, p = 0.01). Within subjects, the left hand spiral rating was greater than the right (p < 0.001). Conclusions: In this cross-sectional study of 819 Spanish schoolchildren, mild tremor was commonly observed. As in adults, males had more tremor than females, tremor scores increased with age, and tremor scores were higher in the left than right arm, demonstrating that these clinical correlations seem to be more broadly generalizable to children. The functional significance of tremor in children, particularly as it relates to handwriting proficiency, deserves additional scrutiny.

There is currently a need to develop tools to identify patients with mild AD and mild cognitive impairment (MCI). We determined the validity and reliability of a brief, easily administered cognitive screening battery consisting of fusion of two well-known brief tests (Mini-Mental Status Examination [MMSE] and Clock Drawing Test [CDT]) (Mini-clock) to differentiate between patients with mild AD, MCI, and healthy control subjects. 66 consecutive patients with mild AD, 21 with MCI, and 66 healthy controls seen in a memory clinic setting were compared. Receiver operating characteristic (ROC) curve analysis was used to calculate the cut-off value permitting discrimination between mild AD, MCI, and healthy control subjects. Interrater and test-retest reliability were also assessed. Mean cognitive scores for patients with AD, MCI, and control subjects on all two individual tests were significantly different (for each, p < 0.001). The mean area under the ROC curve for Mini-clock was higher than that obtained with MMSE or CDT in differentiating mild AD from controls (0.973 vs. 0.952 and 0.881, respectively) and MCI from controls (0.855 vs. 0.821 and 0.779, respectively). Test-retest reliability for the Mini-clock was 0.99, meanwhile interrater reliability was 0.87. The mean time to complete the test for all subjects was 8 min and 50 s. The Mini-clock is highly sensitive and specific in the detection of mild AD and reasonably accurate when attempting to separate MCI from health controls. It has a high interrater and test-retest reliability, can be quickly administered, and does not require major training.