FOXP2, APOE, and PRNP: New Modulators in Primary Progressive Aphasia

Article type: Research Article

Authors: Premi, Enrico^{a; 1} | Pilotto, Andrea^{a; 1} | Alberici, Antonella^a | Papetti, Alice^a | Archetti, Silvana^b | Seripa, Davide^c | Daniele, Antonio^d | Masullo, Carlo^d | Garibotto, Valentina^e | Paghera, Barbara^f | Caobelli, Federico^f | Padovani, Alessandro^a | Borroni, Barbara^{a; *}

Affiliations: [a] Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy | [b] Laboratories of Biotechnology, Brescia Hospital, Brescia, Italy | [c] Department of Medical Sciences, Istituto Di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy | [d] Neuropsychology Unit, Catholic University, Rome, Italy | [e] Department of Medical Imaging, Geneva University Hospital, Geneva, Switzerland | [f] Nuclear Medicine Unit, University of Brescia, Brescia, Italy

Correspondence: [*] Correspondence to: Barbara Borroni, MD, Neurology Unit, University of Brescia, Piazza Spedali Civili 1, 25125 Brescia, Italy. E-mail: [email protected].

Note: [1] These authors equally contributed to this work.

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.

Keywords: Apolipoprotein E ε4, FOXP2, primary progressive aphasia, progressive non-fluent aphasia, PRNP, semantic dementia, SPECT, statistical parametric mapping

DOI: 10.3233/JAD-2011-111541

Journal: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 941-950, 2012