Structural brain correlates of dementia in Huntington's disease

Altres ajuts: The present study was partially funded by the "Human Biology Project Grant" of the Huntington's Disease Society of America (USA).Huntington's disease (HD) is a fatal genetic neurodegenerative disorder with no effective treatment currently available. Progressive basal ganglia and whole-brain atrophy and concurrent cognitive deterioration are prototypical aspects of HD. However, the specific patterns of brain atrophy underlying cognitive impairment of different severity in HD are poorly understood. The aim of this study was to investigate the specific structural brain correlates of major cognitive deficits in HD and to explore its association with neuropsychological indicators. Thirty-five symptomatic early-to-mild HD patients and 15 healthy controls (HC) with available T1-MRI imaging were included in this study. In this cross-sectional study, HD patients were classified as patients with (HD-Dem) and without (HD-ND) major cognitive impairment in the range of dementia. This classification was based on previously validated PD-CRS cutoff scores for HD. Differences in brain atrophy across groups were studied by means of grey-matter volume voxel-based morphometry (GMV-VBM) and cortical thickness (Cth). Voxelwise and vertexwise general linear models were used to assess the group comparisons, controlling for the effects of age, sex, education, CAG repeat length and severity of motor symptoms. Clusters surviving p < 0.05 and family-wise error (FWE) correction were considered statistically significant. In order to characterize the impact on cognitive performance of the observed brain differences across groups, GMV and Cth values in the set of significant regions were computed and correlated with specific neuropsychological tests. All groups had similar sociodemographic profiles, and the HD groups did not significantly differ in terms of CAG repeat length. Compared to HC, both HD groups exhibited significant atrophy in multiple subcortical and parietal brain regions. However, compared to HC and HD-ND groups, HD-Dem patients showed a more prominent pattern of reduced GMV and cortical thinning. Importantly, this thinning was restricted to regions of the parietal-temporal and occipital cortices. Furthermore, these brain alterations were further associated with poorer cognitive performance in tasks assessing frontal-executive and attention domains as well as memory, language and constructional abilities. Major cognitive impairment in the range of dementia in HD is associated with brain and cognitive alterations exceeding the prototypical frontal-executive deficits commonly recognized in HD. The observed posterior-cortical damage identified by MRI and its association with memory, language, and visuoconstructive dysfunction suggest a strong involvement of extra-striatal atrophy in the onset of severe cognitive dysfunction in HD patients. Critically, major cognitive impairment in this sample was not associated with CAG repeat length, age or education. This finding could support a possible involvement of additional neuropathological mechanisms aggravating cognitive deterioration in HD

Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease

Malaltia de Parkinson; Cognició; Estil de vidaEnfermedad de Parkinson; Cognición; Estilo de vidaParkinson Disease; Cognition; Life StyleBackground: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. Methods: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. Results: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). Conclusions: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD.Fundación Curemos el Parkinson (https:// curem oselp arkin son. org/) covered the expenses derived from hiring a CRO and from carrying out complementary tests

Structure and Dynamics of Large-Scale Cognitive Networks in Huntington's Disease

Altres ajuts: La Marató de TV3 (20142910).Background: Huntington's disease is a neurodegenerative disorder characterized by clinical alterations in the motor, behavioral, and cognitive domains. However, the structure and disruptions to large-scale brain cognitive networks have not yet been established. Objective: We aimed to profile changes in large-scale cognitive networks in premanifest and symptomatic patients with Huntington's disease. Methods: We prospectively recruited premanifest and symptomatic Huntington's disease mutation carriers as well as healthy controls. Clinical and sociodemographic data were obtained from all participants, and resting-state functional connectivity data, using both time-averaged and dynamic functional connectivity, was acquired from whole-brain and cognitively oriented brain parcellations. Results: A total of 64 gene mutation carriers and 23 healthy controls were included; 21 patients with Huntington's disease were classified as premanifest and 43 as symptomatic Huntington's disease. Compared with healthy controls, patients with Huntington's disease showed decreased network connectivity within the posterior hubs of the default-mode network and the medial prefrontal cortex, changes that correlated with cognitive (t = 2.25, P = 0.01) and disease burden scores (t = −2.42, P = 0.009). The salience network showed decreased functional connectivity between insular and supramarginal cortices and also correlated with cognitive (t = 2.11, P = 0.02) and disease burden scores (t = −2.35, P = 0.01). Dynamic analyses showed that network variability was decreased for default-central executive networks, a feature already present in premanifest mutation carriers (dynamic factor 8, P = 0.02). Conclusions: Huntington's disease shows an early and widespread disruption of large-scale cognitive networks. Importantly, these changes are related to cognitive and disease burden scores, and novel dynamic functional analyses uncovered subtler network changes even in the premanifest stages

Clinical manifestations of intermediate allele carriers in Huntington disease

OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. METHODS: We assessed a cohort of participants at risk with &lt;36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington\u27s Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (&lt;27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. RESULTS: Of 12,190 participants, 657 (5.38%) with &lt;36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p = 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p = 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p = 0.002). CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. CLINICALTRIALSGOV IDENTIFIER: NCT01590589

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

Association Between Insulin‐Like Growth Factor‐1 and Social Cognition in Huntington's Disease

Insulin-like growth factor 1 (IGF-1) seems to be involved in the neural circuits associated with social cognition and brain structure.Study funded by Gerencia Regional de Salud de Castilla y Leon (Sacyl GRS 1768/A/18)

Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease

Background: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. Methods: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. Results: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). Conclusions: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD

Correlatos neuronales y neuropsicológicos de las alteraciones cognitivas y conductuales en las fases prodrómica e inicial de la enfermedad de Huntington

El caràcter minoritari de la malaltia de Huntington ha suposat, en comparació a altres processos neurodegeneratius més freqüents, un desajustat i lent avanç en la comprensió dels mecanismes neuropatològics responsables de la malaltia i en la identificació i descripció detallada dels fenotips clínics que la caracteritzen . Històricament, les manifestacions clíniques de la malaltia de Huntington, han estat preferentment atribuïdes a la característica atròfia subcortical que presenten tots els pacients. En correspondència amb aquesta atròfia dels ganglis basals, des del punt de vista neuropsicològic, la malaltia de Huntington ha estat considerada un paradigma de demència subcortical amb un perfil neurocognitiu frontal-disexecutiu caracteritzat per alentiment cognitiu, disfunció executiva, apatia i canvis de personalitat. El desenvolupament d'estudis observacionals de caràcter multicèntric i internacional, ha permès al llarg dels últims 15 anys, aprofundir de manera notable en el coneixement de la malaltia gràcies a l'seguiment de grans cohorts de persones afectades. Aquests estudis han il·lustrat que, des d'etapes primerenques de la malaltia i fins i tot durant la fase asimptomàtica, alguns dels canvis neuropatològics més evidents s'estenen més enllà dels ganglis basals i afecten extensos territoris corticals, principalment en àrees parieto-occipitals i temporals. En paral·lel a aquestes troballes, els treballs que han explorat la correspondència de les anomalies cerebrals amb les manifestacions clíniques de la malaltia, han revelat que les alteracions cognitives desborden àmpliament el perfil disexecutiva i que l'alteració de múltiples dominis i processos il·lustren un fenotip cognitiu bastant més complex i divers a l'inicialment descrit. Tot i això, queden moltes incògnites per resoldre. Actualment sabem que canvis cognitius i conductuals subtils, objectivables a través del rendiment en determinades tasques, poden posar-se de manifest fins a 15 anys abans que les primeres manifestacions motores siguin evidents. Això ha suposat que la comunitat científica dedicada a la malaltia hagi centrat importants esforços a explorar les variables cognitives que caracteritzen la malaltia i que prediuen la seva progressió, així com la manera en què podem capturar de manera eficient les primeres manifestacions preclíniques. També sabem, que independentment de la càrrega genètica de la malaltia, hi ha una notable variabilitat tant en l'edat d'inici com en la forma i en el curs que adquireix la malaltia al llarg de la seva evolució. Ampliar el nostre camp de visió més enllà dels ganglis basals ha contribuït a desvetllar un conjunt d'elements encara difícils d'encaixar amb precisió en el conjunt de la malaltia, però que reafirmen la necessitat d'aprofundir en l'estudi dels seus mecanismes causals. Seguim sense comprendre clarament: 1) perquè la malaltia es comporta de diferent manera en persones la càrrega genètica i edat és la mateixa; 2) quin paper tenen alguns dels canvis cerebrals més subtils i primerencs que esdevenen en el curs de la malaltia; 3) quin és el patró de neurodegeneració cerebral associat a determinades manifestacions neuropsiquiàtriques amb la limitació que això comporta per als plantejaments terapèutics; 4) quin és el perfil neurocognitiu concret de les formes greus de deteriorament cognitiu en la malaltia, ni com podem mesurar aquests perfils en les seves formes lleus i greus ni, 5) quin sigui el patró neurodegeneratiu que presenten els pacients que desenvolupen demència. Els objectius d'aquesta tesi, com posen de manifest els treballs publicats que la conformen, s'han dirigit a la recerca d'algunes respostes per a aquestes incògnites que suposin avenços concrets per al coneixement i el maneig clínic d'aquesta devastadora malaltia.El carácter minoritario de la enfermedad de Huntington ha supuesto, en comparación a otros procesos neurodegenerativos más frecuentes, un desajustado y lento avance en la comprensión de los mecanismos neuropatológicos responsables de la enfermedad y en la identificación y descripción pormenorizada de los fenotipos clínicos que la caracterizan. Históricamente, las manifestaciones clínicas de la enfermedad de Huntington, han sido preferentemente atribuidas a la característica atrofia subcortical que presentan todos los pacientes. En correspondencia con esta atrofia de los ganglios basales, desde el punto de vista neuropsicológico, la enfermedad de Huntington ha sido considerada un paradigma de demencia subcortical con un perfil neurocognitivo frontal-disejecutivo caracterizado por enlentecimiento cognitivo, disfunción ejecutiva, apatía y cambios de personalidad. El desarrollo de estudios observacionales de carácter multicéntrico e internacional, ha permitido a lo largo de los últimos 15 años, ahondar de manera notable en el conocimiento de la enfermedad gracias al seguimiento de grandes cohortes de personas afectadas. Estos estudios han ilustrado que, desde etapas tempranas de la enfermedad e incluso durante la fase asintomática, algunos de los cambios neuropatológicos más evidentes se extienden más allá de los ganglios basales y afectan a extensos territorios corticales, principalmente en áreas parieto-occipitales y temporales. Los objetivos de esta tesis, como ponen de manifiesto los trabajos publicados que la conforman, se han dirigido a la búsqueda de algunas respuestas para estas incógnitas que supongan avances concretos para el conocimiento y el manejo clínico de esta devastadora enfermedad.The minority nature of Huntington's disease has meant, in comparison to other more frequent neurodegenerative processes, an imbalanced and slow progress in the understanding of the neuropathological mechanisms responsible for the disease and in the identification and detailed description of the clinical phenotypes that characterize it. Historically, the clinical manifestations of Huntington's disease have been preferentially attributed to the characteristic subcortical atrophy that all patients present. In correspondence with this atrophy of the basal ganglia, from the neuropsychological point of view, Huntington's disease has been considered a paradigm of subcortical dementia with a frontal-dysexecutive neurocognitive profile characterized by cognitive slowing, executive dysfunction, apathy and personality changes. Over the last 15 years, the development of multicenter and international observational studies has made it possible to significantly deepen our knowledge of the disease thanks to the follow-up of large cohorts of affected people. These studies have illustrated that, from the early stages of the disease and even during the asymptomatic phase, some of the most obvious neuropathological changes extend beyond the basal ganglia and affect extensive cortical territories, mainly in parieto-occipital and temporal areas. Parallel to these findings, studies that have explored the correspondence of brain abnormalities with the clinical manifestations of the disease have revealed that cognitive disturbances go far beyond the dysexecutive profile and that the alteration of multiple domains and processes illustrate a fairly cognitive phenotype more complex and diverse than initially described. Despite this, many unknowns remain to be resolved. We now know that subtle cognitive and behavioral changes, observable through performance in certain tasks, can become apparent up to 15 years before the first motor manifestations are evident. This has meant that the scientific community dedicated to the disease has focused important efforts on exploring the cognitive variables that characterize the disease and that predict its progression, as well as the way in which we can efficiently capture the first preclinical manifestations. We also know that regardless of the genetic load of the disease, there is a notable variability both in the age of onset and in the form and course that the disease acquires throughout its evolution. Expanding our field of vision beyond the basal ganglia has contributed to uncovering a set of elements that are still difficult to fit precisely into the disease as a whole, but which reaffirm the need to deepen the study of its causal mechanisms. We still do not clearly understand: 1) why the disease behaves differently in people whose genetic makeup and age is the same; 2) what role do some of the most subtle and early brain changes that occur in the course of the disease have; 3) what is the pattern of brain neurodegeneration associated with certain neuropsychiatric manifestations with the limitation that this entails for therapeutic approaches; 4) what is the specific neurocognitive profile of severe forms of cognitive impairment in the disease, or how can we measure these profiles in their mild and severe forms, or 5) what is the neurodegenerative pattern that patients who develop dementia present. The objectives of this thesis, as evidenced by the published works that comprise it, have been aimed at finding some answers to these unknowns that represent concrete advances in the knowledge and clinical management of this devastating disease.Universitat Autònoma de Barcelona. Programa de Doctorat en Medicin

Neuropsicología de la percepción humana del tiempo

La percepción del tiempo juega un papel central dentro del conjunto de procesos que rigen la construcción de la realidad que experimentamos. A pesar de ser un fenómeno cotidiano, seguimos sin disponer de un modelo que lo explique en su totalidad. Pero tanto las aproximaciones basadas en modelos neurocognitivos como el estudio de la función normal y alterada del sistema nervioso nos han permitido conceptualizar y entender muchos de los mecanismos necesarios para que el ser humano sea capaz de experimentar, estimar y comprender el tiempo. En este trabajo se desarrollan de manera unificada algunos de los modelos neurocognitivos esenciales para comprender los procesos que rigen la percepción del tiempo, se describe la arquitectura neuronal implicada en la percepción del tiempo y los procesos que de ella dependen y, finalmente, se revisa la fenomenología más compleja o atípica con la que las alteraciones de la percepción del tiempo se pueden presentar en un contexto clínico

Early Gray Matter Volume Loss in MAPT H1H1 de Novo PD Patients: A Possible Association With Cognitive Decline

The MAPT H1 haplotype has been identified as a predictor of cognitive decline in Parkinson's disease (PD). However, its underlying pathological mechanisms have not been fully established. In this work, using a cohort of 120 de novo PD patients with preserved cognition from the Parkinson's Progression Markers Initiative (PPMI) database, we found that patients who were homozygous for MAPT H1 had less gray matter volume (GMV) and greater 1-year GMV loss than patients without this genetic profile. Importantly, these changes were associated with a longitudinal worsening of cognitive indicators. Our findings suggest that early GMV loss in MAPT H1H1 PD patients increases their risk to develop cognitive decline