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Objective An intriguing electrophysiological feature of patients with Huntington’s disease (HD) is the delayed latency and decreased amplitude of somatosensory long-latency evoked potentials (LLeps). We investigated whether such dysfunction was associated with delayed conscious perception of the sensory stimulus. Methods Sixteen HD patients and 16 control subjects faced a computer screen showing the Libet’s clock ( Libet et al., 1983 ). In Rest trials, subjects had to memorize the position of the clock handle at perception of either electrical or thermal stimuli (AW). In React, additionally, they were asked to make a fist with their right hand, in a simple reaction time task (SRT). LLseps were recorded from Cz in both conditions. Results LLeps negative peak latency (N2) and SRT were abnormally delayed in patients in all conditions. AW was only abnormally prolonged in the React condition but the time difference between AW and the negative peak of the LLeps was not different in the two groups. There was a significant negative correlation between SRT and AW or LLeps amplitude in patients but not in healthy subjects. Conclusion Our HD patients did not show abnormalities in conscious perception of sensory stimuli but their LLeps abnormalities were more marked when they had to react. This is compatible with failure to detect stimulus salience rather than with a cognitive defect. Significance HD patients at early stages of the disease have preserved subjective perception of sensation but faulty sensorimotor integration.

The presence of non-motor symptoms in Huntington's disease (HD) has not been systematically assessed so far. Our objective was to know their prevalence and to compare it with a cohort of patients with Parkinson's disease (PD).Participants were consecutively recruited from our outpatient clinic. They were assessed through the motor part of the Unified Huntington's Disease Rating Scale, the motor part of the Unified Parkinson's Disease Rating Scale, the total functional capacity scale and the PD non-motor symptoms questionnaire.We enrolled 123 participants: 53 HD, 45 PD and 25 healthy controls (HC). Non-motor symptoms were significantly more prevalent in HD patients than in HC. The most frequent non-motor symptoms in HD, involving more than 50% of patients, were attentional deficits, apathy, dysphagia, memory complaints, depression falls, insomnia and urinary urgency. The total score of non-motor symptoms correlated with disease duration, total functional capacity and disease stage. HD scored significantly higher than PD in 11 items (dysphagia, constipation, bowel incontinence, faecal tenesmus, weight loss, memory, apathy, attention, falls, nightmares, delusions) and in four domains (cognitive, hallucinations and delusions, digestive and cardiovascular). PD did not score significantly higher than HD in any domain.HD patients have a high prevalence of non-motor symptoms, which is even higher than in PD, and correlates with disease progression.

Background: Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. Objectives: To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. Methods: Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. Results: We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. Conclusions: The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders. Keywords: Apathy, Diffusion MRI, Huntington's disease, Individual differences, Neurodegeneration, White matter microstructure

A cognitive stimulating lifestyle has been observed to confer cognitive benefits in multiple neurodegenerative diseases. However, the underlying neurobiological basis of this phenomenon remains unclear. Huntington's disease can provide a suitable model to study the effects and neural mechanisms of cognitive engagement in neurodegeneration. In this study, we investigate the effect of lifestyle factors such as education, occupation and engagement in cognitive activities in Huntington's disease gene carriers on cognitive performance and age of onset as well as the underlying neural changes sustaining these effects, measured by magnetic resonance imaging. Specifically, we analyzed both gray matter volume and the strength of connectivity of the executive control resting-state network. High levels of cognitive engagement were significantly associated with more preserved executive functions, a delay in the appearance of symptoms, reduced volume loss of the left precuneus and the bilateral caudate and a modulation of connectivity strength of anterior cingulate cortex and left angular gyrus with the executive control network. These findings suggest that a cognitively stimulating lifestyle may promote brain maintenance by modulating the executive control resting-state network and conferring protection against neurodegeneration, which results in a delayed onset of symptoms and improved performance in executive functions.

A prospective, observational multicenter study was carried out assessing neuropsychiatric symptoms in a sample of 117 subjects in order to validate the Spanish version of the Problem Behaviors Assessment-Short (PBA-s). The psychometric properties of this version were analyzed. Inter- and intra-rater reliability were good: the mean weighted Cohen’s kappa was 0.90 for severity scores and 0.93 for frequency scores. Four factors accounting for 56% of the total variance were identified after an exploratory factor analysis: apathy, irritability, depression, and perseveration. The PBA-s correlates strongly with the Neuropsychiatric Inventory, demonstrating its accuracy for assessing neuropsychiatric symptoms in patients with Huntington’s disease.

Objective In Parkinson's disease (PD), effects on behavior and cognition of levodopa/carbidopa intestinal gel (LCIG) and subthalamic stimulation (STN-DBS) and their practical consequences remain controversial. This study was designed to analyze the possible effects of these therapies on cognition and behavior after 1 year follow-up. Methods This was an open-label, nonrandomized prospective study for pre- and postintervention analyses. Twenty-four patients were considered eligible to be candidates for complex therapies such as STN-DBS or LCIG; 23 patients treated with standard medication were included as controls. Several cognitive, behavioral, and motor scales were administered before and at 6 and 12 months after the intervention. Results Patients treated with LCIG experienced significant improvement in specific neuropsychological functions when compared with patients receiving STN-DBS and conventional medical treatment after 1 year from the onset of the intervention. In this study, no significant cognitive or behavioral changes occurred in patients treated with subthalamic stimulation when compared to patients receiving conventional medical treatment at 1 year follow-up. Conclusions Patients treated with LCIG may significantly improve some specific neuropsychological functions when compared with patients receiving STN-DBS and with patients receiving conventional medical treatment after 1 year from the intervention; there are not significant cognitive or behavioral changes in patients treated with STN-DBS when compared to PD patients receiving conventional medical treatment after 1 year from the intervention. The outcomes showed in the study can help to the selection of the appropriate candidates for STN-DBS and LCIG.

STUDY OBJECTIVES To measure the sleep spindle characteristics in patients with unilateral thalamic stroke. DESIGN A prospective study of patients with thalamic stroke and age-matched healthy controls. SETTING Department of Neurology of a University Hospital. PARTICIPANTS Thirteen patients (mean age: 67 years, SD: 13,44) with an isolated, unilateral acute thalamic stroke and 18 healthy age-matched volunteers. INTERVENTIONS A polysomnogram recording from 14 scalp EEG electrodes performed during 2 consecutive nights, the second or third week after the stroke. Only the sleep of the second night was analyzed. MEASUREMENTS AND RESULTS Sleep spindles were counted during two separate 10-minute epochs of stage II. Spindles appearing synchronously in both sides with similar amplitude were called "bilateral." Spindles with twice the amplitude in one side than the other were "right" or "left-side predominant". There were 8 patients with posterolateral, 3 with global and 2 with anterior lesions. Eight were right and 5 left-sided. The number of spindles was similar in patients (39.8 +/- 23.4 in 20 minutes) than controls (26.07 +/- 29.07; p=0.173). Spindles with a centroparietal (34%) and centroparieto-occipital localization (22%) were the most frequent. In controls approximately 66% of the spindles had a bilateral and symmetric distribution over the scalp, 23% of the spindles were predominantly left-sided and 5% were predominantly right-sided. In patients, bilateral spindles decreased (p

Background: Basic issues regarding factors influencing progressive supranuclear palsy (PSP) patient caregiver burden remain unresolved, including whether and how disease severity and duration influence caregiver burden. Objective: To examine the relation between PSP patient caregiver burden and disease severity, describe the time course of caregiver burden in relation to disease progression, and identify the contribution of other factors (e.g., patient memory and behavioral problems, caregiver gender) to caregiver burden. Methods: Mail survey of 180 caregivers of PSP patients (living at home and cared for by nonprofessionals) who were members of the Society for Progressive Supranuclear Palsy. The survey included the Burden Interview, an instrument measuring caregiver burden by inquiring how they feel about different aspects and demands of caregiving. Results: Caregiver burden was related to both PSP disease severity ( r = 0.40) and disability/need for assistance ( r = 0.43). The relation between burden and disease duration was nonlinear, following the same time course as disease severity; the burden increased during the first 18 months postdiagnosis and leveled off thereafter. Women reported more burden than men (caregiver sex Δ r 2 = 0.05), even after controlling for disease severity and duration (Δ r 2 = 0.22) and patient gender (Δ r 2 r 2 = 0.09), and aggressiveness (Δ r 2 = 0.02). Conclusion: Burden in PSP is related to disease severity, disease duration, and caregiver gender (even after controlling for patient9s memory, patient depression, and aggression).

Many studies have demonstrated a strong association between the presence of one or two epsilon 4 alleles and Alzheimer's disease (AD), although few data are available on the apolipoprotein E (APOE) epsilon 4 frequencies at the preclinical stages of AD. Thus, with a view to determining whether APOE genotyping could be useful in the early detection of AD, we determined the Apoe allele frequencies in patients with memory complaints without dementia (age-related memory decline, ARMD). We found an APOE epsilon 4 allele frequency of 0.315 in the ARMD group, similar to 0.293 in the AD group, in contrast to 0.057 in the control group. Significant differences (t=-2.91, df=25, p=0.008) were found between the Alzheimer's Disease Assessment Scale (ADAS) total scores in the ARMD patients with at least one epsilon 4 allele (mean=24.2) compared with the ARMD patients without the epsilon 4 allele (mean=14.7). Our results suggest that the patients with memory complaints, a high ADAS score, and the presence of one or two APOE-4 alleles could be at high risk for developing AD. Thus, we propose that genotyping in conjunction with the ADAS scale may prove useful as diagnostic markers of AD in the presymptomatic stages.

Background Autosomal dominant early-onset Alzheimer disease is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in thePSEN1gene, whereas mutations in theAPPandPSEN2genes are rare. Objective To describe a novel mutation in thePSEN2gene associated with early-onset autosomal dominant Alzheimer disease. Patients and Methods The proband was a 49-year-old individual who displayed progressive dementia beginning at age 45 years. One of the parents and one of the grandparents had developed dementia at ages 64 years and 60 years, respectively, and 1 sibling had mild cognitive impairment. Some family members also had Tourette syndrome. Mutation analysis of theAPP,PSEN1,PSEN2,and tau (TAU) genes was performed. Apolipoprotein E (APOE) was also genotyped. Results We found a missense mutation at codon 430 of thePSEN2gene that predicts a threonine-to-methionine substitution. This mutation was detected in the affected individuals and in 1 cognitively healthy sibling. The mutation was absent in 260 control chromosomes. The normal amino acid was conserved in the human and mousePSEN1and mousePSEN2homologues. No influence of theAPOEgenotype was observed. Conclusions We have found a novel mutation in thePSEN2gene in a family with early-onset Alzheimer disease. The variation in the age at onset confirms thatPSEN2mutations are associated with variable clinical expression.

The Mini-Mental State (MMS) is a brief structured test of cognitive function. The purpose of this study was to adapt and normalise MMS for the Spanish population. The test was administered to 450 subjects (253 control volunteers, 86 mild memory/cognitive impairment without dementia subjects - CIWD and 111 Alzheimer's Disease patients - AD). A cross-sectional statistical study in a population stratified by age and education was conducted. A more accurate diagnosis is provided by scores that have been adjusted for age and level of education. The recommended cut-off in our study was 24/25 (non-demented above 24). The adaptation and normalisation of MMS provides the Spanish population with a highly valuable screening tool.

Reduced uptake of 123I- metaiodobenzylguanidine (MIBG) on cardiac gammagraphy and impaired odor identification are markers of neurodegenerative diseases with Lewy bodies (LB) as a pathological hallmark, such as idiopathic Parkinson’s disease (IPD). LRRK2 patients present with a clinical syndrome indistinguishable from IPD, but LB have not been found in some cases. Patients with such mutations could behave differently than patients with IPD with respect to MIBG cardiac uptake and olfaction. We studied 14 LRRK2 patients, 14 IPD patients matched by age, gender, disease duration and severity, and 13 age and gender matched control subjects. Olfaction was analyzed through the University of Pennsylvania Smell Identification Test (UPSIT). MIBG cardiac uptake was evaluated through the H/M ratio. The late H/M was 1.44 ± 0.31 for LRRK2 patients, 1.19 ± 0.15 for PD patients, and 1.67 ± 0.16 for control subjects. LRRK2 patients presented lower but not statistically significant MIBG cardiac uptake than controls (p = 0.08) and significant higher uptake than PD patients (p = 0.04). UPSIT mean scores were 21.5 ± 7.3 for LRRK2 patients, 18.7 ± 6.2 for IPD patients and 29.7 ± 5.7 for control subjects. UPSIT score was lower in both LRRK2 and PD than in controls. In LRRK2 patients a positive correlation was found between myocardial MIBG uptake and UPSIT scores, (R = 0.801, p

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices – fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences. Keywords: Linked ICA, Data fusion, Huntington's disease, Neurodegeneration, Clinical profiles, Structural MRI

Background The most accurate knowledge about progressive supranuclear palsy (PSP) comes from small sample studies that preclude precise estimation of the proportion of PSP patients affected with various symptoms and the examination of factors predicting survival time. Objectiue To describe the course of PSP in a large clinically diagnosed sample of PSP patients and to identify factors predicting survival time. Methods We surveyed the caregivers of 318 living and 119 deceased patients with progressive supranuclear palsy. The main outcome measures were a principal symptom severity questionnaire and a signs and symptoms questionnaire. Results The estimated age of PSP symptom onset depends critically on how symptom onset is defined, with estimates differing by as much as 1.5 years. Men and women were represented equally (51.6% versus 48.4%) in the living sample, but men formed 61.8% of the deceased sample. Men were diagnosed later than women following symptom onset (33.4 versus 24.1 months) and died earlier following the diagnosis (37.0 versus 47.6 months). Motor and visual symptoms appeared first, followed by emotional and personality problems, cognitive impairment, and sleep changes. Whereas motor symptoms eventually affected almost every patient, emotionallpersonality and cognitive symptoms did not. The early onset, presence of falls, slowness, and inability to move eyes downward early in the development of the disease predicted survival time. Conclusion PSP is a rapidly progressive disease dominated by motor symptoms, and it affects men more frequently than women.