Downregulation of ERK1/2 activity by CaMKII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer’s disease patients

11 páginas, 9 figuras, 2 tablas -- PAGS nros. 1090-1100Previously, we reported a Ca2+/calmodulin (CaM)-dependent impairment of apoptosis induced by serum deprivation in Alzheimer’s disease (AD) lymphoblasts. These cell lines showed downregulation of extracellular signal-regulated kinase (ERK)1/2 activity and elevated content of p21 compared with control cells. The aim of this study was to delineate the molecular mechanism underlying the distinct regulation of p21 content in AD cells. Quantitative reverse transcription polymerase chain reaction analysis demonstrated increased p21 messenger RNA (mRNA) levels in AD cells. The ERK1/2 inhibitor, PD98059, prevented death of control cells and enhanced p21 mRNA and protein levels. The CaM antagonist, calmidazolium, and the CaMKII inhibitor, KN-62, normalized the survival pattern of AD lymphoblasts by augmenting ERK1/2 activation and reducing p21 mRNA and protein levels. Upregulation of p21 transcription in AD cells appears to be the consequence of increased activity of forkhead box O3a (FOXO3a) as the result of diminished ERK1/2-mediated phosphorylation of this transcription factor, which in turn facilitates its nuclear accumulation. Murine double minute 2 (MDM2) protein levels were decreased in AD cells relative to control lymphoblasts, suggesting an impairment of FOXO3a degradationThis work has been supported by grants from Ministerio de Economía y Competitividad (SAF2007-624505, SAF2011-28603) and Fundación Ramón Areces to A.M.-R. N.E. holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

Under reporting of Parkinson’s disease on death certificates: a population-based study (NEDICES)

Background Parkinson's disease is frequently omitted as a cause of death from death certificates. A limitation of previous studies that attempted to assess the validity of death certificates is that population-dwelling cases, with milder, undiagnosed Parkinson's disease were likely excluded. As a result, those studies likely overestimated the validity of death certificates because they did not include these milder cases. We assessed the validity of death certificates in a prospective population-based study (NEDICES), which includes previously undiagnosed Parkinson's disease cases detected during the assessment. Methods 3926 community-dwelling elderly subjects with and without Parkinson's disease were followed during a median of 12.6 years, after which the death certificates of those who died were examined. We calculated the proportion of cases of clinically diagnosed Parkinson's disease for whom a diagnosis of Parkinson's disease was certified as the basic cause of death on death certificates. Results 1791 (45.6%) of the 3926 participants died over a median follow-up of 7.1 years, including 82 (73.9%) deaths among 111 participants with Parkinson's disease. Parkinson's disease was rarely certified as the basic cause of death (14.6%). Gender, disease stage and the period during which the study was conducted (i.e., 1994 to 2007) did not influence the likelihood that Parkinson's disease would be reported. Conclusions Our findings reinforce the notion that the reporting of Parkinson's disease on death certificates remains poor. This suggests a lack of awareness of the importance of Parkinson's disease as a cause of death.pre-print261 K

Medical, environmental and personal factors of disability in the elderly in Spain: a screening survey based on the International Classification of Functioning

Malalties cròniques; Demència; Avaluació de la discapacitatEnfermedades crónicas; Demencia; Evaluación de la discapacidadChronic diseases; Dementia; Disability evaluationObjectives: The International Classification of Functioning, Disability and Health (ICF) advocates a multifactorial and multifaceted conceptualization of disability. The objective of this study was to ascertain major medical, environmental and personal determinants of severe/extreme disability among the elderly population in Spain. The assessment scheme was consistent with the ICF model of disability.Methods: Nine populations contributed probabilistic or geographically-defined samples following a two-phase screening design. The Mini-Mental State Examination and the 12-item version of the World Health Organization-Disability Assessment Schedule, 2(nd) ed. (WHO-DAS II), were used as cognitive and disability screening tools, respectively. Positively screened individuals underwent clinical work-up for dementia and were administered the 36-item version of the WHO-DAS II to estimate ICF disability levels. We used logistic regression for the purposes of data combination, adjusted for age and sex in all analyses. Results: The sample was composed of 503 participants aged ≥ 75 years. Alzheimeŕs disease and depression were highly predictive of severe/extreme disability (OR: 17.40, 3.71). Good access to social services was strongly associated with a low level or absence of disability (OR: 0.05 to 0.18). Very difficult access to services and having dementia or another psychiatric disorder were associated with an increase in disability (OR: 66.06). There was also a significant interaction effect between access to services and neurological disorders (OR: 12.74).Conclusions: Disability is highly prevalent among the Spanish elderly and is influenced by medical, social and personal factors. Disability could potentially be reduced by ensuring access to social services, preventing dementia and stroke, and treating depression.This project, led by J. de Pedro-Cuesta, was supported by thePfizer Foundation and by the RECSP C03-09, CIEN C03-06 and CIBERNED and CIBERSAM research network

Altered functional connectivity in essential tremor

Essential tremor (ET) has been associated with a spectrum of clinical features, with both motor and nonmotor elements, including cognitive deficits. We employed resting-state functional magnetic resonance imaging (fMRI) to assess whether brain networks that might be involved in the pathogenesis of nonmotor manifestations associated with ET are altered, and the relationship between abnormal connectivity and ET severity and neuropsychological function. Resting-state fMRI data in 23 ET patients (12 women and 11 men) and 22 healthy controls (HC) (12 women and 10 men) were analyzed using independent component analysis, in combination with a ‘‘dualregression’’ technique, to identify the group differences of resting-state networks (RSNs) (default mode network [DMN] and executive, frontoparietal, sensorimotor, cerebellar, auditory/language, and visual networks). All participants underwent a neuropsychological and neuroimaging session, where resting-state data were collected. Relative to HC, ET patients showed increased connectivity in RSNs involved in cognitive processes (DMN and frontoparietal networks) and decreased connectivity in the cerebellum and visual networks. Changes in network integrity were associated not only with ET severity (DMN) and ET duration (DMN and left frontoparietal network), but also with cognitive ability.Moreover, in at least 3 networks (DMN and frontoparietal networks), increased connectivity was associated with worse performance on different cognitive domains (attention, executive function, visuospatial ability, verbal memory, visual memory, and language) and depressive symptoms. Further, in the visual network, decreased connectivity was associated with worse performance on visuospatial ability. ET was associated with abnormal brain connectivity in major RSNs that might be involved in both motor and nonmotor symptoms

Tremor severity in Parkinson’s disease and cortical changes of areas controlling movement sequencing: a preliminary study.

. 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 was 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 were defined. Increased motor unit synchronization (i.e., more severe tremor) was associated with cortical changes (i.e., atrophy) in dorsal premotor cortices, left 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.pre-print670 K

Essential tremor severity and anatomical changes in brain areas controlling movement sequencing.

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.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.post-print432 K

Practical application of brief cognitive tests

RESUMEN Introducción.- Los test cognitivos breves (TCB) pueden ayudar a detectar el deterioro cognitivo (DC) en el ámbito asistencial. Se han desarrollado y/o validado varios TCB en nuestro país, pero no existen recomendaciones específicas para su uso. Desarrollo.- Revisión de estudios de rendimiento diagnóstico llevados a cabo en España con TCB que requieran menos de 20 minutos. Recomendaciones de uso consensuadas por expertos sobre la base de las características de los TCB y de los estudios disponibles. Conclusión.- El Fototest, el Memory Impairment Screen (MIS) y el Mini-Mental State Examination (MMSE) son las opciones más recomendables para el primer nivel asistencial, pudiendo añadirse otros test (Test del Reloj [TR], test de fluidez verbal [TFV]) en caso de resultado negativo y queja o sospecha persistente (aproximación escalonada). En el segundo nivel asistencial es conveniente una evaluación sistemática de las distintas áreas cognitivas, que puede llevarse a cabo con instrumentos como el Montreal Cognitive Assessment, MMSE, Rowland Universal Dementia Assessment o Addenbrooke's Cognitive Examination, o bien mediante el uso escalonado o combinado de herramientas más simples (TR, TFV, Fototest, MIS, Test de Alteración de la Memoria, Eurotest). El uso asociado de cuestionarios cumplimentados por un informador (CCI) aporta valor añadido a los TCB en la detección del DC. La elección de los instrumentos vendrá condicionada por las características del paciente, la experiencia del clínico y el tiempo disponible. Los TCB y CCI deben reforzar -pero nunca suplantar- el juicio clínico, la comunicación con el paciente y el diálogo interprofesional

A protective personal factor against disability and dependence in the elderly: an ordinal regression analysis with nine geographically-defined samples from Spain

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

Aplicación práctica de los test cognitivos breves

Introducción.- Los test cognitivos breves (TCB) pueden ayudar a detectar el deterioro cognitivo (DC) en el ámbito asistencial. Se han desarrollado y/o validado varios TCB en nuestro país, pero no existen recomendaciones específicas para su uso. Desarrollo.- Revisión de estudios de rendimiento diagnóstico llevados a cabo en España con TCB que requieran menos de 20 minutos. Recomendaciones de uso consensuadas por expertos sobre la base de las características de los TCB y de los estudios disponibles. Conclusión.- El Fototest, el Memory Impairment Screen (MIS) y el Mini-Mental State Examination (MMSE) son las opciones más recomendables para el primer nivel asistencial, pudiendo añadirse otros test (Test del Reloj [TR], test de fluidez verbal [TFV]) en caso de resultado negativo y queja o sospecha persistente (aproximación escalonada). En el segundo nivel asistencial es conveniente una evaluación sistemática de las distintas áreas cognitivas, que puede llevarse a cabo con instrumentos como el Montreal Cognitive Assessment, MMSE, Rowland Universal Dementia Assessment o Addenbrooke's Cognitive Examination, o bien mediante el uso escalonado o combinado de herramientas más simples (TR, TFV, Fototest, MIS, Test de Alteración de la Memoria, Eurotest). El uso asociado de cuestionarios cumplimentados por un informador (CCI) aporta valor añadido a los TCB en la detección del DC. La elección de los instrumentos vendrá condicionada por las características del paciente, la experiencia del clínico y el tiempo disponible. Los TCB y CCI deben reforzar -pero nunca suplantar- el juicio clínico, la comunicación con el paciente y el diálogo interprofesional