Demencia frontotemporal por mutaciones en el gen de la progranulina. Aspectos clínicos y moleculares

177 p.La demencia frontotemporal (DFT) comprende un grupo de enfermedades neurodegenerativas, clínica y neuropatológicamente heterogéneo, que se agrupan por la afectación predominante de los lóbulos frontal y temporal del cerebro, con síntomas de alteración progresiva de la conducta, la personalidad y el lenguaje, y con relativa preservación de la memoria. La DFT tiene un importante componente genético y se encuentra una historia familiar positiva entre un 25-50% de los casos. En el año 2006 se describieron mutaciones en el gen de la progranulina (GRN), en el cromosoma 17q21-22, en pacientes con DFT familiar con neuropatología consistente en inclusiones tau-negativas y ubiquitin-positivas. Más adelante se describió que el componente principal de estas inclusiones patológicas era la proteína TAR DNA-binding protein 43 (TDP-43). En el año 2008 se identificó la mutación c.709-1G>A en GRN en una serie de familias de origen vasco.El trabajo presentado en esta tesis se divide en cinco estudios, cuyo objetivo principal es la caracterización clínica de los pacientes con DFT portadores de la mutación c.709-1G>A en GRN y el estudio de los portadores asintomáticos de la mutación, para detectar la posible existencia de cambios neuropsicológicos o de neuroimagen previos al inicio de síntomas clínicos. El primer estudio analiza el fenotipo clínico de 21 pacientes con la mutación c.709-1G>A en GRN. Los pacientes mostraron un fenotipo variable, tanto en la edad de inicio como en los síntomas de presentación. La demencia frontotemporal variante conductual (DFTvc) y la afasia progresiva no fluente (APNF) fueron los síndromes de presentación más frecuentes. Un porcentaje alto de pacientes desarrollaron un síndrome corticobasal como diagnóstico secundario. El objetivo del segundo estudio era determinar si determinadas variantes genéticas modificaban la edad de inicio de la enfermedad en nuestra serie de 21 pacientes con la mutación c.709-1G>A en GRN. Se incluyeron las siguientes variables genéticas: polimorfismos rs5848 y rs9897526 en GRN, APOE, el haplotipo del gen de la proteína tau asociada a microtúbulos (MAPT) y el polimorfismo del codón 129 en el gen de la proteína priónica (PRNP). Encontramos una asociación entre el polimorfismo del codón 129 de PRNP y la edad de inicio de la enfermedad, de forma que los portadores homocigotos MM presentaban una edad de inicio media 8.5 años menor que los pacientes portadores de al menos una valina en su codón 129 de PRNP (MV o VV). El tercer estudio es un estudio transversal que compara la evaluación neuropsicológica de una muestra de 13 portadores presintomáticos de la mutación c.709-1G>A en GRN con la de 19 familiares no portadores. Los portadores presintomáticos de la mutación c.709-1G>A en GRN presentaron unas puntuaciones significativamente peores que los sujetos no portadores en pruebas de atención, flexibilidad mental y lenguaje, sugiriendo la existencia de una fase prodrómica que precede al inicio de los síntomas de DFT. El cuarto estudio analiza la neuroimagen estructural mediante comparación del grosor cortical en 13 portadores de la mutación c.709-1G>A en GRN frente a un grupo de 13 sujetos sanos pareados por edad y sexo. Los portadores asintomáticos mostraron un menor grosor cortical asociado a la edad en diferentes zonas del lóbulo temporal. Además, el grosor cortical se correlacionaba con puntuaciones en diferentes pruebas neuropsicológicas (Trail Making Test A y B y Test de Denominación de Boston). El menor grosor cortical en portadores presintomáticos en el córtex temporal lateral sugiere un efecto precoz y específico de la enfermedad en estas áreas.Por último, el quinto estudio tenía como objetivo evaluar la influencia de la variante p.A152T en MAPT en el fenotipo clínico y neuropatológico de las familias vascas portadoras de la mutación c.709-1G>A en GRN. El grupo de pacientes con ambas alteraciones genéticas (GRN+/p.A152T+) presentaba unas características clínicas similar al grupo que solamente presentaba la mutación en GRN (GRN+/p.A152T-). Se analizaron siete autopsias cerebrales (6 GRN+/p.A152T+ y 1 GRN+/p.A152T-), y todas presentaban, además de los hallazgos característicos de las mutaciones en GRN (DLFT-TDP tipo A), inclusiones tau patológicas en grado leve a moderado, no acompañadas de patología ¿-amiloide, excepto en dos casos en que coexistía enfermedad de Alzheimer. Se especula que la variante p.A152T en MAPT en portadores de la mutación c.709-1G>A en GRN podría conferir una mayor predisposición a presentar patología tau cerebral asociada

Utility of the MoCA for cognitive impairment screening in long-term psychosis patients

Cognitive impairment is a key feature in patients with psychotic disorders. The Montreal Cognitive Assessment (MoCA) is a brief tool that has been shown to be effective in identifying mild cognitive impairment and early dementia. This study explores the usefulness of this instrument to detect cognitive impairment in long-term psychotic disorders. One hundred-forty stabilized patients were re-evaluated more than 15 years after a First Episode of Psychosis (FEP). Patients were psychopathologically assessed, and the MoCA test and MATRICS Consensus Cognitive Battery (MCCB) were administered. Two cut-off scores for cognitive impairment using the MCCB were applied (T score <40 and < 30). Concurrent validation was found between the total scores of the MoCA and MCCB. We also found significant associations between 5 out of 7 MoCA subtests (visuospatial-executive, attention, language, abstraction and delayed recall) and MCCB subtests but not for the naming and orientation MoCA subtests. Receiver operating characteristic (ROC) analysis suggested a <25 cut-off for cognitive impairment instead of the original <26. Our results suggest that the MoCA test is a useful screening instrument for assessing cognitive impairment in psychotic patients and has some advantages over other available instruments, such as its ease-of-use and short administration time

Trends in socioeconomic inequalities in mortality in small areas of 33 Spanish cities

Background: In Spain, several ecological studies have analyzed trends in socioeconomic inequalities in mortality from all causes in urban areas over time. However, the results of these studies are quite heterogeneous finding, in general, that inequalities decreased, or remained stable. Therefore, the objectives of this study are: (1) to identify trends in geographical inequalities in all-cause mortality in the census tracts of 33 Spanish cities between the two periods 1996–1998 and 2005–2007; (2) to analyse trends in the relationship between these geographical inequalities and socioeconomic deprivation; and (3) to obtain an overall measure which summarises the relationship found in each one of the cities and to analyse its variation over time. Methods: Ecological study of trends with 2 cross-sectional cuts, corresponding to two periods of analysis: 1996–1998 and 2005–2007. Units of analysis were census tracts of the 33 Spanish cities. A deprivation index calculated for each census tracts in all cities was included as a covariate. A Bayesian hierarchical model was used to estimate smoothed Standardized Mortality Ratios (sSMR) by each census tract and period. The geographical distribution of these sSMR was represented using maps of septiles. In addition, two different Bayesian hierarchical models were used to measure the association between all-cause mortality and the deprivation index in each city and period, and by sex: (1) including the association as a fixed effect for each city; (2) including the association as random effects. In both models the data spatial structure can be controlled within each city. The association in each city was measured using relative risks (RR) and their 95 % credible intervals (95 % CI). Results: For most cities and in both sexes, mortality rates decline over time. For women, the mortality and deprivation patterns are similar in the first period, while in the second they are different for most cities. For men, RRs remain stable over time in 29 cities, in 3 diminish and in 1 increase. For women, in 30 cities, a non-significant change over time in RR is observed. However, in 4 cities RR diminishes. In overall terms, inequalities decrease (with a probability of 0.9) in both men (RR = 1.13, 95 % CI = 1.12–1.15 in the 1st period; RR = 1.11, 95 % CI = 1.09–1.13 in the 2nd period) and women (RR = 1.07, 95 % CI = 1.05–1.08 in the 1st period; RR = 1.04, 95 % CI = 1.02–1.06 in the 2nd period). Conclusions: In the future, it is important to conduct further trend studies, allowing to monitoring trends in socioeconomic inequalities in mortality and to identify (among other things) temporal factors that may influence these inequalities.This article was partially funded by Plan Nacional de I + D + I 2008–2011 and Instituto de Salud Carlos III (ISCIII) –Subdirección General de Evaluación y Fomento de la Investigación- (Award numbers: PI081488, PI081978, PI080367, PI08/1017, PI080330, P08/0142, PI081785, PI080662, PI081713, PI081058, PI081340, PI080803, PI126/08), Fundación Canaria de Investigación Sanitaria FUNCIS 84/07 and by CIBER Epidemiología y Salud Pública (CIBERESP)

Link between cognitive polygenic risk scores and clinical progression after a first-psychotic episode

Background Clinical intervention in early stages of psychotic disorders is crucial for the prevention of severe symptomatology trajectories and poor outcomes. Genetic variability is studied as a promising modulator of prognosis, thus novel approaches considering the polygenic nature of these complex phenotypes are required to unravel the mechanisms underlying the early progression of the disorder. Methods The sample comprised of 233 first-episode psychosis (FEP) subjects with clinical and cognitive data assessed periodically for a 2-year period and 150 matched controls. Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, education attainment and cognitive performance were used to assess the genetic risk of FEP and to characterize their association with premorbid, baseline and progression of clinical and cognitive status. Results Schizophrenia, bipolar disorder and cognitive performance PRSs were associated with an increased risk of FEP [false discovery rate (FDR) ⩽ 0.027]. In FEP patients, increased cognitive PRSs were found for FEP patients with more cognitive reserve (FDR ⩽ 0.037). PRSs reflecting a genetic liability for improved cognition were associated with a better course of symptoms, functionality and working memory (FDR ⩽ 0.039). Moreover, the PRS of depression was associated with a worse trajectory of the executive function and the general cognitive status (FDR ⩽ 0.001). Conclusions Our study provides novel evidence of the polygenic bases of psychosis and its clinical manifestation in its first stage. The consistent effect of cognitive PRSs on the early clinical progression suggests that the mechanisms underlying the psychotic episode and its severity could be partially independent

Relationship between cognition and age at onset of first-episode psychosis: comparative study between adolescents, young adults, and adults

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed with FEP and classified them as having an early onset (EOS), youth onset (YOS), or adult onset (AOS) based on age limits of = 25 years (N = 116), respectively. Socio-demographic and clinical variables included age at baseline, gender, socio-economic status, antipsychotic medication, DSM-IV diagnoses assessed by clinical semi-structured interview, psychotic symptom severity, and age at onset. Neuropsychological assessment included six cognitive domains: premorbid intelligence, working memory, processing speed, verbal memory, sustained attention, and executive functioning. The EOS group had lower scores than the YOS or AOS groups in global cognition, executive functioning, and sustained attention. Although the scores in the YOS group were intermediate to those in the EOS and AOS groups for most cognitive factors, no statistically significant differences were detected between the YOS and AOS groups. Age at onset results in specific patterns of cognitive interference. Of note, impairment appears to be greater with EOS samples than with either YOS or AOS samples. A longitudinal study with a larger sample size is needed to confirm our findings

Trends in socioeconomic inequalities in preventable mortality in urban areas of 33 Spanish cities, 1996–2007 (MEDEA project)

Background: Preventable mortality is a good indicator of possible problems to be investigated in the primary prevention chain, making it also a useful tool with which to evaluate health policies particularly public health policies. This study describes inequalities in preventable avoidable mortality in relation to socioeconomic status in small urban areas of thirty three Spanish cities, and analyses their evolution over the course of the periods 1996–2001 and 2002–2007. Methods: We analysed census tracts and all deaths occurring in the population residing in these cities from 1996 to 2007 were taken into account. The causes included in the study were lung cancer, cirrhosis, AIDS/HIV, motor vehicle traffic accidents injuries, suicide and homicide. The census tracts were classified into three groups, according their socioeconomic level. To analyse inequalities in mortality risks between the highest and lowest socioeconomic levels and over different periods, for each city and separating by sex, Poisson regression were used. Results: Preventable avoidable mortality made a significant contribution to general mortality (around 7.5%, higher among men), having decreased over time in men (12.7 in 1996–2001 and 10.9 in 2002–2007), though not so clearly among women (3.3% in 1996–2001 and 2.9% in 2002–2007). It has been observed in men that the risks of death are higher in areas of greater deprivation, and that these excesses have not modified over time. The result in women is different and differences in mortality risks by socioeconomic level could not be established in many cities. Conclusions: Preventable mortality decreased between the 1996–2001 and 2002–2007 periods, more markedly in men than in women. There were socioeconomic inequalities in mortality in most cities analysed, associating a higher risk of death with higher levels of deprivation. Inequalities have remained over the two periods analysed. This study makes it possible to identify those areas where excess preventable mortality was associated with more deprived zones. It is in these deprived zones where actions to reduce and monitor health inequalities should be put into place. Primary healthcare may play an important role in this process.This work was partly supported by the FIS-FEDER projects PI080330, PI081713, PI081978, PI0463/2010, PI081017, PI081785, PI081058, PI080142, and the FUNDACIÓN CAJAMURCIA project FFIS/CM10/27

Relapse, cognitive reserve, and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study

Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition and CR may broaden our understanding of the course of the disease. We aimed to determine whether relapse was associated with cognitive impairment, controlling for the effects of CR. Ninety-nine patients with a remitted first episode of schizophrenia or schizophreniform disorder were administered a set of neuropsychological tests to assess premorbid IQ, attention, processing speed, working memory, verbal and visual memory, executive functions and social cognition. They were followed up for 3 years (n=53) or until they relapsed (n=46). Personal and familial CR was estimated from a principal component analysis of the premorbid information gathered. Linear mixed-effects models were applied to analyse the effect of time and relapse on cognitive function, with CR as covariate. Patients who relapsed and had higher personal CR showed less deterioration in attention, whereas those with higher CR (personal and familial CR) who did not relapse showed better performance in processing speed and visual memory. Taken together, CR seems to ameliorate the negative effects of relapse on attention performance and shows a positive effect on processing speed and visual memory in those patients who did not relapse. Our results add evidence for the protective effect of CR over the course of the illness

Opposite cannabis-cognition associations in psychotic patients depending on family history

The objective of this study is to investigate cognitive performance in a first-episode psychosis sample, when stratifying the interaction by cannabis use and familial or non-familial psychosis. Hierarchical-regression models were used to analyse this association in a sample of 268 first-episode psychosis patients and 237 controls. We found that cannabis use was associated with worse working memory, regardless of family history. However, cannabis use was clearly associated with worse cognitive performance in patients with no family history of psychosis, in cognitive domains including verbal memory, executive function and global cognitive index, whereas cannabis users with a family history of psychosis performed better in these domains. The main finding of the study is that there is an interaction between cannabis use and a family history of psychosis in the areas of verbal memory, executive function and global cognition: that is, cannabis use is associated with a better performance in patients with a family history of psychosis and a worse performance in those with no family history of psychosis. In order to confirm this hypothesis, future research should explore the actual expression of the endocannabinoid system in patients with and without a family history of psychosis

Gene co-expression architecture in peripheral blood in a cohort of remitted first-episode schizophrenia patients

A better understanding of schizophrenia subtypes is necessary to stratify the patients according to clinical attributes. To explore the genomic architecture of schizophrenia symptomatology, we analyzed blood co-expression modules and their association with clinical data from patients in remission after a first episode of schizophrenia. In total, 91 participants of the 2EPS project were included. Gene expression was assessed using the Clariom S Human Array. Weighted-gene co-expression network analysis (WGCNA) was applied to identify modules of co-expressed genes and to test its correlation with global functioning, clinical symptomatology, and premorbid adjustment. Among the 25 modules identified, six modules were significantly correlated with clinical data. These modules could be clustered in two groups according to their correlation with clinical data. Hub genes in each group showing overlap with risk genes for schizophrenia were enriched in biological processes related to metabolic processes, regulation of gene expression, cellular localization and protein transport, immune processes, and neurotrophin pathways. Our results indicate that modules with significant associations with clinical data showed overlap with gene sets previously identified in differential gene-expression analysis in brain, indicating that peripheral tissues could reveal pathogenic mechanisms. Hub genes involved in these modules revealed multiple signaling pathways previously related to schizophrenia, which may represent the complex interplay in the pathological mechanisms behind the disease. These genes could represent potential targets for the development of peripheral biomarkers underlying illness traits in clinical remission stages after a first episode of schizophrenia