title: Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease.
abstract: The dual syndrome hypothesis for cognitive impairment in Parkinson's disease (PD) establishes a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to these syndromes although the exact contribution is still controversial. The study's objective was to investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in the dual syndromes. We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients. The degree of dopaminergic depletion was investigated with [123I]FP-CIT SPECTs and the presence of dementia was ascertained with a long-term review based on established criteria. The association between genetic and imaging parameters was studied with linear regression, and the relationship with dementia onset with Cox regression. We found that APOE2 allele (Pput = 0.002; Pcau = 0.01), the minor allele 'G' in SNCA polymorphism (Pput = 0.02; Pcau = 0.006) and GBA deleterious variants in (Pput = 0.01; Pcau = 0.001) had a detrimental effect on striatal [123I]FP-CIT uptake in PD. Conversely, Met/Met carriers in COMT polymorphism had increased caudate uptake (Pcau = 0.03). The development of dementia was influenced by APOE4 allele (HR = 1.90; P = 0.03) and GBA deleterious variants (HR = 2.44; P = 0.01). Finally, we observed no role of MAPT locus in any of the syndromes. As a conclusion, APOE2, SNCA, COMT and GBA influence frontostriatal dysfunction whereas APOE4 and GBA influence the development of dementia, suggesting a double-edged role of GBA. The dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Huertas
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Jesús
authors.affiliation: Servicio de Medicina Nuclear. UDIM. Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: García-Gómez
authors.affiliation: Servicio de Medicina Nuclear. UDIM. Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Lojo
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Bernal-Bernal
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Bonilla-Toribio
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Martín-Rodriguez
authors.affiliation: Servicio de Medicina Nuclear. UDIM. Hospital Universitario Virgen del Rocío, Seville, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: García-Solís
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Gómez-Garre
authors.affiliation: Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Mir
mesh_terms: D000368:Aged; D003342:Corpus Striatum / Q000503:physiopathology*; D003704:Dementia / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D011110:Polymorphism, Genetic; D015899:Tomography, Emission-Computed, Single-Photon