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

Abstract

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.

Keywords: apraxia of speech; corticobasal degeneration; dysarthria; magnetic resonance imaging; primary progressive aphasia; progressive supranuclear palsy.

Figure 1

Frequency of main clinical features. Frequency of main clinical features in the 98 participants included in this study. Venn diagram illustrating the overlap between motor speech impairment, agrammatism (either expressive or receptive) and reduced speech fluency (A), apraxia of speech, dysarthria, expressive and receptive agrammatism, and reduced speech fluency (words per minute, WPM) (B). Only one participant was not found to have impaired performance according to the thresholds defined in this study in any of the main clinical features included in this figure. This participant was diagnosed with non-fluent/agrammatic variant primary progressive aphasia (nfvPPA) because the treating physician noted mild expressive agrammatism.

Figure 2

Clustered heat map of all participants. The clustered heat map illustrates the lack of robust clinical clusters within the nfvPPA-spectrum. The first unlabelled column relates to the neuropathological data of each participant [pink = no autopsy available; red = corticobasal degeneration (CBD); dark blue = progressive supranuclear palsy (PSP); green = Pick’s disease; light blue = frontotemporal lobar degeneration characterized by phosphorylated 43-kDa TAR DNA-binding protein inclusions (FTLD-TDP) type A; purple = other pathologies]. Each labelled column represents its corresponding clinical feature, and each row represents a participant. The scores for all clinical features have been scaled to allow their comparison. The participants and the variables have been ordered based on similarity, as illustrated by dendrograms on the top (variables) and left (participants). CDR-SB = Clinical Dementia Rating Sum of Boxes; CYCLE = Curtiss Yamada Comprehensive Language Evaluation; DKEFS = Delis-Kaplan Executive Function Scale; MSE = motor speech evaluation; SALT = Systematic Analysis of Language Transcripts.

Figure 3

Characterization of latent clinical dimensions derived from principal component analysis. In all panels, the x- and y-axes represent one of the three latent clinical dimensions (or ‘clinical components’) derived from principal component analysis (PCA). The percentage of variance explained by each component is shown in parentheses. In A and B, the value at the x- and y-axes represent the standardized coefficient (relative weight) of the components derived from PCA (higher values indicating a more substantial contribution to a given component). Each variable included in the PCA is represented by an arrow whose orthogonal projection to the x- and the y-axes indicates its standardized coefficient for the corresponding component. (A) The relative contribution of each variable to Component 1 (characterized by agrammatism, reduced verbal fluency and higher disease severity) and Component 2 (represented by prominent apraxia of speech and less disease severity and executive dysfunction). (B) The relative contribution of each variable to Component 2 and Component 3 (characterized by prominent dysarthria with less apraxia of speech). (C and D) The individual loadings for each component (lower individual loadings representing more impaired performance). Each participant’s neuropathological diagnosis (if available) is shown in the legend of C and D. For each neuropathological category, the centroid of the ellipse encompassing each group is represented by the biggest symbol. Notably, the distribution of individual loadings did not reveal clusters of participants but rather a widespread distribution. (C and D) The x- and y-axes represent the individual loading for one of the three components derived from PCA in C and D. CDR-SB = Clinical Dementia Rating sum-of-boxes; CYCLE = Curtiss Yamada Comprehensive Language Evaluation; DKEFS = Delis-Kaplan Executive Function Scale; FTLD-TDP type A = frontotemporal lobar degeneration characterized by phosphorylated 43-kDa TAR DNA-binding protein inclusions; LCD = latent clinical dimension; MSE = motor speech evaluation; SALT = Systematic Analysis of Language Transcripts.

Figure 4

Neuropathological correlates of data-driven latent clinical dimensions. Subject-specific loading for each latent clinical component was available in 90 participants from the total sample and 36 participants with neuropathological diagnoses. D1 = latent clinical dimension 1; D2 = latent clinical dimension 2; D3 = latent clinical dimension 3.

Figure 5

Baseline predictors of faster longitudinal decline. (A) Spaghetti plot representing longitudinal data. (B–D) CDR-SB estimates were obtained from linear mixed-effects models as a function of individual loading for Components 1, 2 and 3. For illustrative purposes, we show the CDR-SB estimates for each tercile. Error bars represent 95% confidence intervals and lower values for each latent clinical component represent more impaired performance. D1 = component 1; D2 = component 2; D3 = component 3; CDR-SB = Clinical Dementia Rating Sum of Boxes.