Efecte de la variabilitat genètica de DDR1 en la matèria blanca cerebral i en la velocitat de processament en pacients amb un trastorn de l'espectre de l'esquizofrènia i altres psicosis

El nostre grup de recerca va observar una relació entre el gen del receptor domini de la discoidina 1 (DDR1) amb la mielinització i amb l’esquizofrènia. En aquest treball vam estudiar si les variants rs1264323 i rs2267641 de DDR1 s’associaven al diagnòstic de trastorn de l’espectre de l’esquizofrènia i altres psicosis (TEEAP) en altres mostres i també si s’associaven amb una disminució de la integritat de la matèria blanca i a la velocitat de processament (VP) cognitiu. 1) Vam realitzar una revisió bibliogràfica sistemàtica sobre el paper de DDR1 en el sistema nerviós central. 2) Es va replicar l’estudi d’associació cas-control entre TEEAP i el genotip DDR1 i es va observar una combinació genotípica (rs1264323AA-rs2267641AC/CC) de risc. 3) Es va explorar la relació entre els single nucleotide polymorphism (SNPs) de DDR1 i la VP en una mostra de TEEAP, trobant que els pacients amb el genotip rs2267641CC, comparat amb els AA i AC, presentaven una disminució de la VP. 4) En explorar la relació entre SNPs de DDR1 i la VP en dues mostres independents de pacients en primeres fases de la psicosi vam trobar que la combinació genotípica de risc s’associava a un increment de la VP en els pacients però no en els controls sans. 5) En un subgrup de pacients amb TEEAP mitjançant neuroimatge per diffusion tensor imaging, vam observar que els portadors del genotip rs1264323AA presentaven una disminució de la anisotropia fraccional en regions de la matèria blanca associades a una disminució de la VP. Els resultats confirmen la interacció entre variants del tipus SNP del DDR1 i el risc de presentar un TEEAP, i suggereixen que s’associen a alteracions de la microestructura de la mielina que a la vegada s’associen a la VP.Nuestro grupo de investigación observó una relación entre el gen del receptor dominio de la discoidina 1 (DDR1) con la mielinización y la esquizofrenia. En este trabajo estudiamos si las variantes rs1264323 y rs2267641 de DDR1 se asociaban al diagnóstico de trastorno del espectro de la esquizofrenia y otras psicosis (TEEOP) en otras muestras y también si se asociaban a una disminución de la integridad de la sustancia blanca y a la velocidad de procesamiento (VP) cognitivo. 1) Realizamos una revisión bibliográfica sistemática sobre el papel de DDR1 en el sistema nervioso central. 2) Se replicó el estudio de asociación caso-control entre TEEOP y el genotipo DDR1 y se observó una combinación genotípica (rs1264323AA-rs2267641AC/CC) de riesgo. 3) Se exploró la relación entre los single nucleotide polymorphisms (SNPs) de DDR1 y la VP en una muestra de TEEOP, encontrando que los pacientes con el genotipo rs2267641CC, comparado con los AA y AC, presentaban una disminución de la VP. 4) Al explorar la relación entre SNPs de DDR1 y la VP en dos muestras independientes de pacientes en primeras fases de la psicosis encontramos que la combinación genotípica de riesgo se asociaba a un incremento de la VP en los pacientes pero no en los controles sanos. 5) En un subgrupo de pacientes con TEEOP a través de neuroimagen por diffusion tensor imaging, observamos que los portadores del genotipo rs1264323AA presentaban una disminución de la anisotropía fraccional en regiones de la sustancia blanca asociadas a una disminución de la VP. Los resultados confirman la interacción entre variantes del tipo SNP del DDR1 y el riesgo de presentar un TEEOP, y sugieren que se asocian a alteraciones de la microestructura de la mielina que su vez se asocian a la VP.Our research group observed that the discoidin domain receptor 1 (DDR1) gene is linked to myelination and schizophrenia. In this work we studied whether the rs1264323 and rs2267641 DDR1 variants were associated with the diagnosis of schizophrenia spectrum and other psychotic disorders (SSOPD) in other samples and also whether they were associated with a decrease in the integrity of white matter and cognitive processing speed (PS). 1) We conducted a systematic literature review on the role of DDR1 in the central nervous system. 2) The case-control association study between SSOPD and the DDR1 genotype was replicated and a genotypic combination (rs1264323AA-rs2267641AC/CC) of risk was observed. 3) The relation between DDR1 single nucleotide polymorphisms (SNPs) and PS was explored in a SSOPD sample, finding that patients with rs2267641CC genotype, compared to AA and AC, had a decreased PS. 4) By exploring the relation between DDR1 SNPs and PS in two independent samples of patients in the early phases of psychosis, we found that the genotypic combination of risk was associated with an increase in PS in patients but not in controls. 5) In a subgroup of patients with SSOPD using neuroimaging by diffusion tensor imaging, we observed that carriers of the rs1264323AA genotype showed a decrease in fractional anisotropy in white matter regions associated with a decrease in PS. The results confirm the interaction between SNP-type variants of DDR1 and the risk of developing a SSOPD, and suggest that they are associated with alterations in myelin microstructure that are in turn associated with PS

Functional MRI in FMR1 premutation carriers: a cross-sectional study of neurodegeneration and neurodevelopment

Expansion of the CGG repeat region of the FMR1 gene from less than 45 repeats to between 55 and 200 repeats is known as the FMR1 premutation. Carriers of the FMR1 premutation may develop a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS), which involves progressive symptoms of tremor, ataxia and cognitive decline. Evidence also suggests that premutation carriers experience other psychiatric difficulties throughout their lifespan. The present study aimed to investigate and delineate neurodegenerative and neurodevelopmental aspects of the premutation utilising primarily fMRI, clinical assessments and molecular measurements in 17 premutation carrier participants and 17 age-matched control participants, aged between 20 and 70 years. The functional imaging protocol included a motor task and an emotional processing task. A battery of clinical and neuropsychological tests outside of the scanner and blood-based measurements of FMR1 CGG repeat length, FMRP levels and FMR1 mRNA levels were also carried out. In the motor task, premutation carriers demonstrated significantly less cerebellar activation than controls during sequential versus random finger tapping (FWEcorr<0.001). In addition, there was a significant age by group interaction in the hippocampus, inferior parietal cortex and temporal cortex originating from a more negative relationship between brain activation and age in the carrier group compared to the controls (FWEcorr<0.001). Quantative real-time PCR analysis revealed that mean age-matched FMR1 mRNA levels display a trend towards being higher in carriers and clinical testing of motor skills additionally showed significantly worse tremor and co-ordination scores in non-FXTAS carriers. No significant associations were seen between these measurements and neuroimaging data. During the emotional processing task, carriers exhibited significantly lower activation compared to controls (FWEcorr<0.001) at the bilateral superior parietal lobe, bilateral Brodmann Area (BA) 17 (V1), right intraparietal area and right BA18 (V2) when comparing high arousal and low arousal conditions. Group by age interaction analyses indicated no significant between group differences at a whole brain level. Clinical assessment revealed that carriers displayed significantly worse symptoms of obsessive-compulsiveness, anxiety, global severity of psychiatric symptoms, facial emotion recognition and autistic traits compared to controls and FMRP levels were comparable between groups. No significant associations were seen between these measurements and neuroimaging data. Here, we present for the first time functional imaging-based evidence for early movement-related neurodegeneration in Fragile X premutation carriers. These changes pre-exist the diagnosis of FXTAS and are greatest in older carriers suggesting that they may be indicative of FXTAS vulnerability. Additionally, we show significantly altered emotional processing at neuropsychological, clinical and functional neuroimaging levels in carriers compared to controls, which appear to display stability over age. Overall, we present new evidence in keeping with possible neurodegenerative and neurodevelopmental traits in FMR1 premutation carriers