Clinical dimensions along the progressive nonfluent variant primary progressive aphasia spectrum
Authors: Illán-Gala Ignacio , Lorca-Puls Diego L. , Ezzes Zoe , Deleon Jessica , Miller Zachary A. , Rubio-Guerra Sara , Santos-Santos Miguel , Gómez-Andrés David , Grinberg Lea T. , Spina Salvatore , Kramer Joel H. , Wauters Lisa , Henry Maya L. , Miller Bruce L. , Seeley William W. , Mandelli Maria Luisa , Gorno-Tempini Maria Luisa 
Published: April 2023

It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum traditionally termed nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analyzed speech, language, and disease severity features in a comprehensive cohort of patients with a progressive motor speech impairment and/or agrammatism to ascertain any evidence of the existence of naturally occurring, non-overlapping syndromic entities (e.g., PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with etiologic/prognostic value could be identified. We included 98 participants with progressive motor speech impairment and/or agrammatism, with 43 having an autopsy-confirmed neuropathological diagnosis. Speech pathologists assessed motor speech features indicative of dysarthria and apraxia of speech (AOS). Quantitative expressive/receptive agrammatism measures were obtained and compared with healthy controls. Baseline and longitudinal disease severity was evaluated using the Clinical Dementia Rating sum-of-boxes (CDR-SB). We investigated the data’s clustering tendency to form robust symptom clusters and employed principal component analysis to extract data-driven latent clinical dimensions (LCD). The longitudinal CDR-SB change was estimated utilizing linear mixed-effects models. Of the participants included in this study, 91 conformed to previously reported clinical profiles (69 with AOS and agrammatism, 18 PPAOS, and 4 PAA). The remaining seven participants were characterized by nonfluent speech and dysarthria without apraxia of speech or agrammatism. No baseline clinical features differentiated between FTLD neuropathological subgroups. Critically, the Hopkins statistic dismissed the presence of non-overlapping syndromic clusters in the entire sample (.45 with values near 0.5 indicating random data). Three data-driven components accounted for 71% of the variance ([i] severity-agrammatism, [ii] prominent AOS, and [iii] prominent dysarthria). The component typified by prominent dysarthria was more specific to patients with Progressive Supranuclear Palsy (4/5 [80%] participants with autopsy in this group had PSP), while the severity-agrammatism component predicted a faster CDR-SB increase. Higher dysarthria severity, reduced words per minute, and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression (as measured by the CDR-SB score). Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum strongly predictive of underlying Frontotemporal Lobar Degeneration (FTLD, 66% 4R tauopathy, 16% Pick’s disease, 9.3% FTLD TDP type A, and 12% other pathologies). While highlighting the graded distinctions (rather than sharp boundaries) that characterize the nfvPPA spectrum may be useful for establishing early clinical rehabilitation strategies, novel clinical and biological markers are needed to improve clinical-pathological correlations.