title: FOXP2, APOE, and PRNP: new modulators in primary progressive aphasia.
abstract: Primary progressive aphasia (PPA) is a heterogeneous disorder characterized by progressive language impairment. Polymorphisms within forkhead box P2 gene (FOXP2) gene have been associated with speech and language impairment. Apolipoprotein E (APOE) genotype and PRNP 129 codon status have been demonstrated to increase the risk of PPA, but with contrasting results. In the present study, we have evaluated the impact of FOXP2, APOE and PRNP genetic variations as risk factors and/or disease-modulators in PPA. 94 PPA patients and 200 age-matched healthy controls were considered and FOXP2 polymorphisms (rs1456031, rs17137124), APOE genotype, and PRNP codon 129 polymorphism analyzed. In 34 PPA patients, SPECT imaging data were analyzed by Statistical Parametric Mapping (SPM8). Genetic distributions and allele frequencies of FOXP2 and PRNP polymorphisms did not differ between groups while APOE ε4 was more represented in PPA as compared to controls. PPA patients carrying at-risk FOXP2 polymorphisms (rs1456031 and/or rs17137124) showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus and the right cingulated gyrus compared to non-carriers (p < 0.005). PPA patients carrying at least one ε4 allele had greater hypoperfusion in orbitofrontal regions (superior frontal gyrus and orbital gyrus) as compared to non-carriers ε4 (p < 0.005). PRNP codon 129 homozigosity correlated with left frontotemporal hypoperfusion (p < 0.005). Genetic variations within FOXP2, APOE, and PRNP modulate PPA disease, leading to a specific regional hypoperfusion according to different molecular pathways. APOE ε4 is overrepresented in PPA, thus likely acting as genetic risk factor on disease development.
authors: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
authors: Enrico
authors: E
authors: Premi
authors: Andrea
authors: A
authors: Pilotto
authors: Antonella
authors: A
authors: Alberici
authors: Alice
authors: A
authors: Papetti
authors: Silvana
authors: S
authors: Archetti
authors: Davide
authors: D
authors: Seripa
authors: Antonio
authors: A
authors: Daniele
authors: Carlo
authors: C
authors: Masullo
authors: Valentina
authors: V
authors: Garibotto
authors: Barbara
authors: B
authors: Paghera
authors: Federico
authors: F
authors: Caobelli
authors: Alessandro
authors: A
authors: Padovani
authors: Barbara
authors: B
authors: Borroni
mesh_terms: D000368:Aged; D018888:Aphasia, Primary Progressive / Q000000981:diagnostic imaging / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000502:physiology*; D016022:Case-Control Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072002:Prion Proteins; D011328:Prions / Q000502:physiology*; D011877:Radionuclide Imaging
chemical_list: D053327:Apolipoprotein E4; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions