Linguistic, Anatomic/Metabolic and Biologic Characterisation of the Three Main Variants of Primary Progressive Aphasia : Towards the Rationale for Drug Trials and Specific Language Rehabilitations

Rationale Primary progressive aphasia (PPA) is an umbrella term which identifies a group of neurodegenerative diseases characterized by language deficits. By definition, language disorders are isolated for at least two years; subsequently the disease extends to other cognitive areas leading to a global dementia. Usually PPA affects relatively young patients between 50 and 65 years of age. The outcome is fatal after 10 to 15 years. No treatment is currently available. Three variants of PPA have been described: progressive nonfluent aphasia (PNFA), fluent PPA or semantic dementia (SD), and logopenic progressive aphasia (LPA). These variants are characterized by differences in the nature of the language deficits, the patterns of brain atrophy and the underlying pathology, comprising Alzheimer's pathology in about 30% of patients with PPA . In spite of the growing interest, the cognitive, anatomic and biologic characterization of the 3 PPA variants remains incomplete and the available data derive from studies on small patient samples. However, such a three-fold characterisation is essential in order to provide the rationale for therapeutic interventions comprising both specific rehabilitation of language and pharmacological treatments. In particular, the pharmacological approach crucially depends on a better knowledge of the underlying histopathology (e.g., the existence of Alzheimer pathology), as well as on the understanding of the damaged neural networks that may provide evidence for the implication of specific neurotransmitters. Our aim is to address these issues through exploring a large population of patients with PPA associating psycholinguistic tools, cutting-edge techniques of neuroimaging, CSF biomarker analyses and genetic screening. The study will provide a cross-sectional and longitudinal assessment of PPA patients involving 17 memory centres qualified in the domain of PPA.

Main objective Providing an comprehensive characterisation of the 3 PPA variants through a cross-sectional and longitudinal approach investigating 1) the cognitive features (psycholinguistic), 2) the anatomic/metabolic substrates (structural MRI, DTI-based tractography, functional connectivity - resting state, 18FDG-PET), and 3) the biologic aspects (CSF biomarkers [amyloid-β and tau], genetic screening for mutations in the progranulin gene, apolipoprotein E genotyping).

Secondary objectives

1. Identification of prognostic markers (linguistic, anatomical/metabolic, biologic) for each PPA variant. 2) Identification of predictive markers (linguistic, neuroimaging) for the underlying histopathology (correlation analyses among linguistic, imaging, CSF and genetic markers). 3) Validation of the diagnostic criteria of semantic dementia to distinguish the fluent/semantic variant of PPA and forms with multimodal disorders of semantics (verbal and visual).

Perspectives Providing the rationale for drug trials and for specific language rehabilitations.