Handedness and language learning disability differentially distribute in progressive aphasia variants

Abstract

Primary progressive aphasia is a neurodegenerative clinical syndrome that presents in adulthood with an isolated, progressive language disorder. Three main clinical/anatomical variants have been described, each associated with distinctive pathology. A high frequency of neurodevelopmental learning disability in primary progressive aphasia has been reported. Because the disorder is heterogeneous with different patterns of cognitive, anatomical and biological involvement, we sought to identify whether learning disability had a predilection for one or more of the primary progressive aphasia subtypes. We screened the University of California San Francisco Memory and Aging Center's primary progressive aphasia cohort (n = 198) for history of language-related learning disability as well as hand preference, which has associations with learning disability. The study included logopenic (n = 48), non-fluent (n = 54) and semantic (n = 96) variant primary progressive aphasias. We investigated whether the presence of learning disability or non-right-handedness was associated with differential effects on demographic, neuropsychological and neuroimaging features of primary progressive aphasia. We showed that a high frequency of learning disability was present only in the logopenic group (χ(2) = 15.17, P < 0.001) and (χ(2) = 11.51, P < 0.001) compared with semantic and non-fluent populations. In this group, learning disability was associated with earlier onset of disease, more isolated language symptoms, and more focal pattern of left posterior temporoparietal atrophy. Non-right-handedness was instead over-represented in the semantic group, at nearly twice the prevalence of the general population (χ(2) = 6.34, P = 0.01). Within semantic variant primary progressive aphasia the right-handed and non-right-handed cohorts appeared homogeneous on imaging, cognitive profile, and structural analysis of brain symmetry. Lastly, the non-fluent group showed no increase in learning disability or non-right-handedness. Logopenic variant primary progressive aphasia and developmental dyslexia both manifest with phonological disturbances and posterior temporal involvement. Learning disability might confer vulnerability of this network to early-onset, focal Alzheimer's pathology. Left-handedness has been described as a proxy for atypical brain hemispheric lateralization. As non-right-handedness was increased only in the semantic group, anomalous lateralization mechanisms might instead be related to frontotemporal lobar degeneration with abnormal TARDBP. Taken together, this study suggests that neurodevelopmental signatures impart differential trajectories towards neurodegenerative disease.

Keywords: Alzheimer’s disease; case control study; dementia aphasia; frontotemporal dementia; risk factors in epidemiology.

Figures

Figure 1

Pattern of atrophy in patients with PPA variants versus controls. Statistical parametric maps show patterns of grey matter atrophy in logopenic variant PPA (lvPPA; n = 24), non-fluent variant PPA (nfvPPA; n = 40) and semantic variant PPA (svPPA; n = 58) compared with their relative healthy control groups matched for age, gender, scan and sample size. Voxel-based morphometry results are thresholded at a family-wise error rate of P < 0.001. FEW = familywise error rate.

Figure 2

Distribution of learning disability in PPA. Estimated rates of dyslexia are 5–10% of the general population, the dashed line above represents the demarcation for an estimated 10% rate. LD = learning disability; lvPPA = logopenic variant PPA; nfvPPA = non-fluent variant PPA; svPPA = semantic variant PPA.

Figure 3

Distribution of hand preference in PPA. Expected rates of non-right-handedness are 8–10% of the general population, the dashed line above represents the demarcation for an expected 10% rate. lvPPA = logopenic variant PPA; nfvPPA = non-fluent variant PPA; nRH = non-right-handed; RH = right-handed; svPPA = semantic variant PPA.

Figure 4

Pattern of atrophy in learning disability and non-learning disability in patients with logopenic variant PPA versus controls. Statistical parametric maps show patterns of grey matter atrophy in non-learning disabled (n = 18) and learning disabled (n = 6) patients with logopenic variant PPA (lvPPA) compared with their relative healthy control groups matched for age, gender, handedness, scan and sample size. Voxel-based morphometry results are thresholded at a family-wise error rate of P < 0.001. LD = learning disabled; nLD = non-learning disabled.

Figure 5

Planum temporale volumes and laterality index distribution in right-handed and non-right-handed healthy controls and right-handed and non-right-handed patients with semantic variant PPA. (A) Laterality index of planum temporale for each cohort. The laterality index between right-handed healthy controls and non-right-handed healthy controls showed a significant difference (P = 0.002), whereas there was no difference between right-handed patients with semantic variant PPA and non-right-handed patients with semantic variant PPA. (B) Statistical parametric maps show grey matter leftward asymmetries in the area of the superior temporal gyrus correspondent to the planum temporale (x = −44; y = −34; z = 18) in right-handed healthy controls with a family-wise error rate threshold of P < 0.05.