Measuring the functional impact of cognitive impairment in Huntington's disease

Acord transformatiu CRUE-CSICBackground: Patients with Huntington's disease (HD) exhibit a variable predominance of cognitive, behavioral and motor symptoms. A specific instrument focusing on the impact of cognitive impairment in HD over functional capacity is lacking. Objective: To address the need for a brief and specifically developed HD questionnaire able to capture functional aspects suspected to be sensitive to cognitive impairment. Methods: We developed and validated the "Huntington's Disease-Cognitive Functional Rating Scale" (HD-CFRS) in 78 symptomatic carriers of the Huntington's disease mutation. We also administered the HD-CFRS to a knowledgeable informant to measure the level of agreement. To explore the association between HD-CFRS scores and participants' cognitive status, we administered objective measures of cognition. Participants were classified as cognitively preserved (HD-NC), as having mild cognitive impairment (HD-MCI), or as having dementia (HD-Dem). Results: The HD-CFRS showed concurrent validity and internal consistency in the three groups. HD carriers and informants in the HD-NC group obtained similar HD-CFRS scores. However, in patients with mild cognitive impairment and dementia, informers reported greater functional impairment than HD participants. The HD-CFRS total score showed strong correlations with measures assessing cognition. Conclusions: These findings support the utility of the HD-CFRS as a brief and reliable instrument to measure functional defects associated with cognitive impairment in HD. We believe this questionnaire could be a useful tool both for clinical practice and research

Neuroanatomical and Functional Correlates of Cognitive and Affective Empathy in Young Healthy Adults

Neural substrates of empathy are mainly investigated through task-related functional MRI. However, the functional neural mechanisms at rest underlying the empathic response have been poorly studied. We aimed to investigate neuroanatomical and functional substrates of cognitive and affective empathy. The self-reported empathy questionnaire Cognitive and Affective Empathy Test (TECA), T1 and T2∗-weighted 3-Tesla MRI were obtained from 22 healthy young females (mean age: 19.6 ± 2.4) and 20 males (mean age: 22.5 ± 4.4). Groups of low and high empathy were established for each scale. FreeSurfer v6.0 was used to estimate cortical thickness and to automatically segment the subcortical structures. FSL v5.0.10 was used to compare resting-state connectivity differences between empathy groups in six defined regions: the orbitofrontal, cingulate, and insular cortices, and the amygdala, hippocampus, and thalamus using a non-parametric permutation approach. The high empathy group in the Perspective Taking subscale (cognitive empathy) had greater thickness in the left orbitofrontal and ventrolateral frontal cortices, bilateral anterior cingulate, superior frontal, and occipital regions. Within the affective empathy scales, subjects with high Empathic Distress had higher thalamic volumes than the low-empathy group. Regarding resting-state connectivity analyses, low-empathy individuals in the Empathic Happiness scale had increased connectivity between the orbitofrontal cortex and the anterior cingulate when compared with the high-empathy group. In conclusion, from a structural point of view, there is a clear dissociation between the brain correlates of affective and cognitive factors of empathy. Neocortical correlates were found for the cognitive empathy dimension, whereas affective empathy is related to lower volumes in subcortical structures. Functionally, affective empathy is linked to connectivity between the orbital and cingulate cortices

Neuroanatomical and functional correlates of cognitive and affective empathy in young healthy adults

Neural substrates of empathy are mainly investigated through task-related functional MRI. However, the functional neural mechanisms at rest underlying the empathic response have been poorly studied. We aimed to investigate neuroanatomical and functional substrates of cognitive and affective empathy. The self-reported empathy questionnaire Cognitive and Affective Empathy Test (TECA), T1 and T2∗-weighted 3-Tesla MRI were obtained from 22 healthy young females (mean age: 19.6 ± 2.4) and 20 males (mean age: 22.5 ± 4.4). Groups of low and high empathy were established for each scale. FreeSurfer v6.0 was used to estimate cortical thickness and to automatically segment the subcortical structures. FSL v5.0.10 was used to compare resting-state connectivity differences between empathy groups in six defined regions: the orbitofrontal, cingulate, and insular cortices, and the amygdala, hippocampus, and thalamus using a non-parametric permutation approach. The high empathy group in the Perspective Taking subscale (cognitive empathy) had greater thickness in the left orbitofrontal and ventrolateral frontal cortices, bilateral anterior cingulate, superior frontal, and occipital regions. Within the affective empathy scales, subjects with high Empathic Distress had higher thalamic volumes than the low-empathy group. Regarding resting-state connectivity analyses, low-empathy individuals in the Empathic Happiness scale had increased connectivity between the orbitofrontal cortex and the anterior cingulate when compared with the high-empathy group. In conclusion, from a structural point of view, there is a clear dissociation between the brain correlates of affective and cognitive factors of empathy. Neocortical correlates were found for the cognitive empathy dimension, whereas affective empathy is related to lower volumes in subcortical structures. Functionally, affective empathy is linked to connectivity between the orbital and cingulate cortices

A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson's Disease

Altres ajuts: CERCA; CIBERNED; La Marató de TV3 (2014/U/477, 20142910); Fondo Europeo de Desarrollo Regional (FEDER).Background: Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence. Objective: We studied the effects of safinamide on apathy in PD. Methods: Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented PD on stable dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of change, and safety and tolerability measures. Results: In total, 30 participants (active treatment = 15; placebo = 15; 80% showing clinically significant apathetic symptoms according to the AS) were enrolled, and included in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance [p = 0.059] mediated by a more marked decrease in AS score with safinamide (−7.5 ± 6.9) than with placebo (−2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant positive change in the AS score between 12-week and 24-week [p = 0.001] only in the active group. No significant or trend changes were found for any of the secondary outcome variables. Adverse events were few and only mild in both treatment groups. Conclusions: Safinamide was safe and well-tolerated, but failed to provide evidence of improved apathy. The positive trend observed in the post-hoc analyses deserves to be studied in depth in larger studies. Trial Registration: EudraCT 2017-003254-17

Measuring cognitive impairment and monitoring cognitive decline in Huntington's disease:a comparison of assessment instruments

Background Progressive cognitive decline is an inevitable feature of Huntington’s disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. Methods We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. Results The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. Conclusion The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia

Clinical and structural brain correlates of hypomimia in early-stage Parkinson's disease

Altres ajuts: acord transformatiu CRUE-CSICBackground and purpose: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. Methods: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. Results: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (β = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. Conclusion: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Correlats neuroanatòmics i diferències de gènere en l’empatia cognitiva i afectiva en una mostra de joves sans

Introducció: L’estudi de l’empatia des de la neurociència i la neuroimatge funcional ha suggerit l’existència de dos circuits diferents: el de l’empatia afectiva i el de l’empatia cognitiva. Ara bé, els correlats neuroanatòmics de l’empatia no són ben coneguts ni hi ha un consens en la literatura en si existeixen diferències de gènere. L’actual treball pretén explorar les diferències de gènere en les diferents escales d’un test d’empatia validat en població espanyola i investigar les diferències neuroanatòmiques entre persones amb alta i baixa empatia. Mètodes: Es varen analitzar imatges per ressonància magnètica potenciades en T1 adquirides amb un aparell de 3-tesla i el Test d’Empatia Cognitiva i Afectiva (TECA) en una mostra de 42 adults sans (22 dones i 20 homes) emparellats per edat, anys d’educació, nivell educatiu, ocupació i estimació de quocient d’intel·ligència. Es va utilitzar un model lineal general amb les dades de gruix cortical per fer comparacions entre grups d’empatia Alta (A) i Mitjana-Baixa (MB). Es van realitzar també correlacions i comparacions grupals amb les parcel·lacions corticals i segmentacions subcorticals. Resultats: En 4 de les 5 escales del test d’empatia es van trobar diferències de gènere. No obstant, no hi havia diferències entre la proporció d’homes i dones entre els grups d’empatia A o MB. En l’escala d’Adopció de Perspectives, el grup d’empatia A tenia un major gruix cortical respecte al de MB en el còrtex prefrontal, el lòbul parietal inferior i en regions occipitals. Les puntuacions en les escales d’empatia cognitiva van correlacionar amb regions frontals i temporals. No es van trobar correlacions ni diferències significatives en cap estructura subcortical excepte en el tàlem dret que tenia major volum en el grup d’empatia A en l’escala d’Estrès Empàtic. Conclusions: El còrtex orbitofrontal i el cingulat són estructures relacionades amb l’empatia cognitiva. El processament empàtic no és diferent entre homes i dones.Background: From a neuroscientific and functional neuroimaging approach, the study of empathy has suggested the existence of two different networks in the empathy construct: the affective empathy and the cognitive empathy. However, neuroanatomic correlates of empathy are not entirely known and there’s no consensus in literature about the existence of gender differences. Current work, aims to explore gender differences in a Spanish validated empathy test scales and to investigate neuroanatomic differences between high empathy and low empathy subjects. Methods: T1-weighted 3-tesla MRI and the Affective Empathy and Cognitive Test (TECA) were analysed in a sample of 42 healthy adults (22 women and 20 men) matched by age, years of education, level of education, occupation and intelligence quotient estimation. A general linear model with cortical thickness data was used to compare the High empathy group (H) and the Medium-Low group (ML). Group comparisons and correlations were also assessed with cortical parcellations and subcortical segmentations. Results: Gender differences were found in 4 out of 5 empathy test scales. However, there were no significant differences between the proportion of men and women in the empathy groups H or ML. In the Perspective Taking scale, the H empathy group showed increased cortical thickness related to the ML empathy group in the prefrontal cortex, the inferior parietal lobule and in occipital regions. Scores from cognitive empathy scales correlated with frontal and temporal regions. No correlations or significant differences were found in any subcortical structure except for the right thalamus that had an increased volume in the H empathy group in the Empathic Stress scale. Conclusions: The orbitofrontal and cingulate cortices are brain structures related to cognitive empathy. Gender was not a key variable in the empathic response