Aphasia Primary Progressive Clinical Trial
Official title:
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
Primary progressive aphasias (PPA) represent a challenging group of degenerative language
diseases that has led to growing interest in the scientific and medical community. However, a
full-blown cognitive/linguistic, anatomic and biologic characterization of the three main
variants remains incomplete given that the available data derive from relatively small
patient samples. Such a three-fold characterisation will be an major milestone with the
prospective of providing the rationale for therapeutic interventions comprising specific
rehabilitations protocols and pharmacological trials.
The present study addresses theses issues in the three PPA main variants through a
cross-sectional and longitudinal investigation exploring 1) cognitive/linguistic features, 2)
anatomic/metabolic specifications (MRI-VBM, MRI-fiber tracking, functional connectivity - MRI
resting state, PET), and 3) biologic aspects (CSF biomarkers, genetic screening).
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.
Methodology One hundred twenty-five PPA patients and 40 healthy age-matched controls will be
included in the study. Patients will be recruited from a national network including the
"national center of reference for rare dementias" and 10 associated "Centers of competence" ,
as well as six additional hospitals, all experienced in the domain of PPA.
Study design: The duration of the study will be three years (18 months inclusion, 18 months
exploration). Participants will be assessed at inclusion (M0), at 9 months (M9) and at 18
months (M18). The explorations will be subdivided into 3 work packages, each coordinated by a
supervisor. 1) Cognitive work package (M0, M9, M18): A) Neuropsychological and language
testing using standardized and internationally validated batteries; B) Neuropsychological
battery specially conceived to explore verbal and visual semantics (validation of the new
diagnostic criteria of semantic dementia; secondary objective N° 3); C) Language assessment
using specifically targeted paradigms based on psycholinguistic models. Imaging work package
(M0, M18): A) MRI and MRI-based tractography to detect and quantify cortical atrophy, the
involvement of white matter tracts and to study the functional connectivity (resting state
fMRI); B) 18FDG-PET to study metabolic defects of the cortex and the basal ganglia. 3)
Biologic work package (M0; no controls): Lumbar puncture for the analysis of biomarkers in
the CSF (amyloid-β, tau); B) genetic analyses on peripheral blood: quantification of plasma
progranulin and (according to the results) screening for mutations of the progranulin gene;
apolipoprotein E genotyping.
Statistics. Cross-sectional analyses for inter-group comparisons (PPA groups, healthy
controls) and longitudinal analyses for inter-group and intra-group comparisons (M0, M9,
M18).
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT04623125 -
Spaced Retrieval as Treatment for Aphasia
|
N/A |