Clinical dimensions along the non-fluent variant primary progressive aphasia spectrum

Abstract

Apraxia of speech; Corticobasal degeneration; Primary progressive aphasia

Apraxia del habla; Degeneración corticobasal; Afasia primaria progresiva

Apràxia de la parla; Degeneració corticobasal; Afàsia primària progressiva

It is debated whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) belong to the same clinical spectrum, traditionally termed non-fluent/agrammatic variant primary progressive aphasia (nfvPPA), or exist as two completely distinct syndromic entities with specific pathologic/prognostic correlates. We analysed speech, language and disease severity features in a comprehensive cohort of patients with progressive motor speech impairment and/or agrammatism to ascertain evidence of naturally occurring, clinically meaningful non-overlapping syndromic entities (e.g. PPAOS and PAA) in our data. We also assessed if data-driven latent clinical dimensions with aetiologic/prognostic value could be identified. We included 98 participants, 43 of whom had 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 and cluster stability 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 using linear mixed-effects models. Of the participants included in this study, 93 conformed to previously reported clinical profiles (75 with AOS and agrammatism, 12 PPAOS and six PAA). The remaining five participants were characterized by non-fluent speech, executive dysfunction and dysarthria without apraxia of speech or frank agrammatism. No baseline clinical features differentiated between frontotemporal lobar degeneration neuropathological subgroups. The Hopkins statistic demonstrated a low cluster tendency in the entire sample (0.45 with values near 0.5 indicating random data). Cluster stability analyses showed that only two robust subgroups (differing in agrammatism, executive dysfunction and overall disease severity) could be identified. Three data-driven components accounted for 71% of the variance [(i) severity-agrammatism; (ii) prominent AOS; and (iii) prominent dysarthria]. None of these data-driven LCDs allowed an accurate prediction of neuropathology. The severity-agrammatism component was an independent predictor of a faster CDR-SB increase in all the participants. Higher dysarthria severity, reduced words per minute and expressive and receptive agrammatism severity at baseline independently predicted accelerated disease progression. Our findings indicate that PPAOS and PAA, rather than exist as completely distinct syndromic entities, constitute a clinical continuum. In our cohort, splitting the nfvPPA spectrum into separate clinical phenotypes did not improve clinical-pathological correlations, stressing the need for new biological markers and consensus regarding updated terminology and clinical classification.

I.I.-G. is a senior Atlantic Fellow for Equity in Brain Health at the Global Brain Health Institute (GBHI), and receives funding from the GBHI, the Alzheimer’s Association, and the Alzheimer Society (GBHI ALZ UK-21-720973 and AACSF-21-850193). I.I.-G. was also supported by the Juan Rodés Contract (JR20/0018) and PI21/00791 from Instituto de Salud Carlos III. D.L.L-P. is supported with funding from the Chilean National Agency for Research and Development (ANID SUBVENCIÓN A LA INSTALACIÓN EN LA ACADEMIA 85220006). D.L.L-P. was also supported by a postdoctoral fellowship from the Chilean National Agency for Research and Development (ANID BECAS-CHILE 74200073). This work was supported by the National Institutes of Health (L.T.G., NIA K24 AG053435; S.S., K08AG052648; M.L.H., NIDCD R01DC016291; A.L.B., NS092089, R01AG038791, U19AG063911; H.J.R., AG045333, AG056749, AG032306, AG045390; B.L.M., NIA P50 AG023501, NIA P01 AG019724; M.L.G-T., NINDS R01 NS050915, NIDCD K24 DC015544, NIA U01 AG052943). The UCSF Neurodegenerative Disease Brain Bank receives funding support from NIH grants P30 AG062422, P01 AG019724, U01 AG057195, and U19 AG063911, as well as the Rainwater Charitable Foundation and the Bluefield Project to Cure FTD.