Neural basis of speech and grammar symptoms in non-fluent variant primary progressive aphasia spectrum - PubMed (original) (raw)

. 2024 Feb 1;147(2):607-626.

doi: 10.1093/brain/awad327.

Andrea Gajardo-Vidal 1 3 4, Maria Luisa Mandelli 1, Ignacio Illán-Gala 5 6 7, Zoe Ezzes 1, Lisa D Wauters 1 8, Giovanni Battistella 1 9, Rian Bogley 1, Buddhika Ratnasiri 1, Abigail E Licata 1, Petronilla Battista 1 7 10, Adolfo M García 7 11 12, Boon Lead Tee 1 7, Sladjana Lukic 1 13, Adam L Boxer 1, Howard J Rosen 1, William W Seeley 1 14, Lea T Grinberg 1 7 14, Salvatore Spina 1, Bruce L Miller 1 7, Zachary A Miller 1, Maya L Henry 8 15, Nina F Dronkers 16 17, Maria Luisa Gorno-Tempini 1

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Neural basis of speech and grammar symptoms in non-fluent variant primary progressive aphasia spectrum

Diego L Lorca-Puls et al. Brain. 2024.

Abstract

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative syndrome primarily defined by the presence of apraxia of speech (AoS) and/or expressive agrammatism. In addition, many patients exhibit dysarthria and/or receptive agrammatism. This leads to substantial phenotypic variation within the speech-language domain across individuals and time, in terms of both the specific combination of symptoms as well as their severity. How to resolve such phenotypic heterogeneity in nfvPPA is a matter of debate. 'Splitting' views propose separate clinical entities: 'primary progressive apraxia of speech' when AoS occurs in the absence of expressive agrammatism, 'progressive agrammatic aphasia' (PAA) in the opposite case, and 'AOS + PAA' when mixed motor speech and language symptoms are clearly present. While therapeutic interventions typically vary depending on the predominant symptom (e.g. AoS versus expressive agrammatism), the existence of behavioural, anatomical and pathological overlap across these phenotypes argues against drawing such clear-cut boundaries. In the current study, we contribute to this debate by mapping behaviour to brain in a large, prospective cohort of well characterized patients with nfvPPA (n = 104). We sought to advance scientific understanding of nfvPPA and the neural basis of speech-language by uncovering where in the brain the degree of MRI-based atrophy is associated with inter-patient variability in the presence and severity of AoS, dysarthria, expressive agrammatism or receptive agrammatism. Our cross-sectional examination of brain-behaviour relationships revealed three main observations. First, we found that the neural correlates of AoS and expressive agrammatism in nfvPPA lie side by side in the left posterior inferior frontal lobe, explaining their behavioural dissociation/association in previous reports. Second, we identified a 'left-right' and 'ventral-dorsal' neuroanatomical distinction between AoS versus dysarthria, highlighting (i) that dysarthria, but not AoS, is significantly influenced by tissue loss in right-hemisphere motor-speech regions; and (ii) that, within the left hemisphere, dysarthria and AoS map onto dorsally versus ventrally located motor-speech regions, respectively. Third, we confirmed that, within the large-scale grammar network, left frontal tissue loss is preferentially involved in expressive agrammatism and left temporal tissue loss in receptive agrammatism. Our findings thus contribute to define the function and location of the epicentres within the large-scale neural networks vulnerable to neurodegenerative changes in nfvPPA. We propose that nfvPPA be redefined as an umbrella term subsuming a spectrum of speech and/or language phenotypes that are closely linked by the underlying neuroanatomy and neuropathology.

Keywords: agrammatic; articulation; lesion-symptom; sentence comprehension; sentence production; syntactic.

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Conflict of interest statement

The authors report no competing interests.

Figures

Figure 1

Figure 1

Distribution of neuropathological subtypes across distinct clinical presentations of nfvPPA. The figure illustrates the overlap, in terms of underlying neuropathology, between different speech-language phenotypes subsumed under the umbrella term ‘nfvPPA’. Apart from an increased frequency of PSP pathology in patients with dominant dysarthria (DD group), no other clinico-pathological correlations were observed [disregarding the progressive agrammatic aphasia (PAA) group which comprised one case only]. The vast majority of patients (28/33 = 85%) exhibited FTLD-tau (PSP, CBD, PiD, and unclassifiable 4R-tau) as primary neuropathology. AD = Alzheimer’s disease; AOS = apraxia of speech; CBD = corticobasal degeneration; FTLD = frontotemporal lobar degeneration; nfvPPA = non-fluent/agrammatic variant of primary progressive aphasia; PiD = Pick’s disease; PSP = progressive supranuclear palsy; PPAOS = primary progressive apraxia of speech; TDP-A = transactive response DNA-binding protein 43 kD type A.

Figure 2

Figure 2

Atrophy frequency map of 104 patients with nfvPPA. The figure shows the distribution of tissue loss across the brain, with the colour scale depicting the percentage of patients with atrophy at each given voxel in sagittal slices. nfvPPA = non-fluent/agrammatic variant of primary progressive aphasia.

Figure 3

Figure 3

Patterns of brain tissue loss associated with impaired motor speech in nfvPPA. (A) Apraxia of speech effect from VBM Analysis 1. (B) Dysarthria effect from VBM Analysis 1. Images are shown in neurological orientation. nfvPPA = non-fluent/agrammatic variant of primary progressive aphasia; VBM = voxel-based morphometry.

Figure 4

Figure 4

3D volume rendering of thresholded statistical maps. The figure illustrates the relative location of the neural substrates of apraxia of speech (AoS) and dysarthria (both from VBM Analysis 1), as well as expressive (Ex) and receptive (Re) agrammatism (from VBM Analyses 2b and 3b, respectively). There was a confined area of overlap between the effects of AoS and expressive agrammatism within the deep left frontal operculum. L = left hemisphere; R = right hemisphere; VBM = voxel-based morphometry.

Figure 5

Figure 5

Patterns of brain tissue loss associated with agrammatism in nfvPPA. (A) Expressive agrammatism effect from VBM Analysis 2a. (B) Expressive agrammatism effect from VBM Analysis 2b (i.e. co-varying out variance unrelated to morphosyntactic encoding). (C) Receptive agrammatism effect from VBM Analysis 3a. (D) Receptive agrammatism effect from VBM Analysis 3b (i.e. co-varying out variance unrelated to morphosyntactic decoding). Images are shown in neurological orientation. nfvPPA = non-fluent/agrammatic variant of primary progressive aphasia; VBM = voxel-based morphometry.

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References

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