MedicalResearch.com Interview with:
Miguel A. Santos–Santos, MD
Department of Neurology, Memory and Aging Center
University of California San Francisco
Autonomous University of Barcelona, Cerdanyola del Valles, Spain
MedicalResearch.com: What is the background for this study?
Response: Primary progressive aphasia (PPA) is a clinically and pathologically heterogeneous (generally Frontotemporal lobar degeneration [FTLD, generally tau or tdp proteinopathies] or Alzheimer’s disease [AD] pathology) condition in which language impairment is the predominant cause of functional impairment during the initial phases of disease. Classification of PPA cases into clinical-anatomical phenotypes is of great importance because they are linked to different prevalence of underlying pathology and prediction of this pathology during life is of critical importance due to the proximity of molecule-specific therapies. The 2011 international consensus diagnostic criteria established a classification scheme for the three most common variants (the semantic [svPPA], non-fluent/agrammatic [nfvPPA], and logopenic [lvPPA]) of PPA and represent a collective effort to increase comparability between studies and improve the reliability of clinicopathologic correlations compared to the previous semantic dementia and progressive non-fluent aphasia criteria included in the 1998 consensus FTLD clinical diagnostic criteria. Since their publication, a few studies have reported amyloid imaging and pathological results in PPA, however most of these studies are retrospective in nature and the prevalence of FTLD and Alzheimer’s disease pathological findings or biomarkers in each variant has been inconsistent across the literature, therefore prospective validation with biomarker and autopsy data remains scarce and highly necessary.
MedicalResearch.com: What are the main findings?
Response: We studied amyloid brain imaging and autopsy results in one of the largest prospectively studied cohorts of PPA patients to test the hypothesis that classification according to the current criteria will result in groups with largely homogeneous biomarker features.
We found that, out of 89 individuals that met root PPA diagnostic criteria, 24/28 (86%) semantic variant PPA and 28/31 (90%) non fluent/agrammatic variant PPA were amyloid PET negative, whereas 25/26 (96%) of logopenic variant and 3/4 (75%) PPA with mixed phenotype were positive. The amyloid positive svPPA and nfvPPA cases with available autopsy data (2/4 and 2/3 respectively) all had a primary Frontotemporal lobar degeneration (FTLD) and secondary Alzheimer’s disease pathological diagnoses.
MedicalResearch.com: What should readers take away from your report?
Response: Classification according to current criteria PPA variant was highly predictive of Alzheimer’s disease biomarker status, with lvPPA being associated with PIB deposition in over 95% of our patients with sporadic PPA.
Furthermore, we found that most cases with typical svPPA and nfvPPA and an unexpected positive amyloid scan had mixed FTLD and AD pathology. These results suggest that typical clinical and MRI findings in svPPA and nfvPPA variants are highly predictive of the presence of FTLD pathology, even in the face of discordant molecular AD biomarker results.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: This work points towards several important unanswered questions that are interesting lines for future research.
The first is the identification of reliable biomarkers that could aid in the in-vivo prediction of atypical underlying pathologies in each of the PPA variants, in particular the differentiation of nfvPPA cases with underlying tau vs tdp proteinopathy is critical.
Another important question is if mixed and genetic PPA cases present with consistent clinical-pathologic associations. Finally, how to determine the clinical relevance of specific pathological deposits, even if they are not considered the primary pathological cause of disease (as happened in the amyloid positive svPPA and nfvPPA cases in our cohort), is a challenge of maximal relevance to the field of neurodegenerative disease.
Santos-Santos MA, Rabinovici GD, Iaccarino L, Ayakta N, Tammewar G, Lobach I, Henry ML, Hubbard I, Mandelli ML, Spinelli E, Miller ZA, Pressman PS, O’Neil JP, Ghosh P, Lazaris A, Meyer M, Watson C, Yoon SJ, Rosen HJ, Grinberg L, Seeley WW, Miller BL, Jagust WJ, Gorno-Tempini ML. Rates of Amyloid Imaging Positivity in Patients With Primary Progressive Aphasia. JAMA Neurol. Published online January 08, 2018. doi:10.1001/jamaneurol.2017.4309
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