Clinical dimensions along the progressive nonfluent variant primary progressive aphasia spectrum

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the NIH and the Alzheimer's Association ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Institutional Review Board of UCSF and was conducted following the Declaration of Helsinki. All participants gave their written informed consent to participate in the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The conditions of our ethics approval do not permit the public archiving of anonymized study data. Data requests can be submitted here: https://memory.ucsf.edu/research-trials/professional/open-science. Following a UCSF-regulated procedure, access will be granted to designated individuals in line with ethical guidelines on reusing sensitive data. This would require the submission of a Material Transfer Agreement. Commercial use will not be approved.