Progression of language decline and cortical atrophy in subtypes of primary progressive aphasia

Abstract

Objectives: To examine the longitudinal course of primary progressive aphasia (PPA) over a 2-year period and to offer quantitative ranges of expected change that could be used to guide the design and evaluation of therapeutic intervention trials.

Methods: Regional changes of cortical thickness and whole-brain cortical volume loss as well as neuropsychological language performance were assessed at baseline and 2 years later in 13 rigorously characterized patients who fulfilled research criteria for logopenic, agrammatic, and semantic PPA subtypes (6 PPA-L, 3 PPA-G, and 4 PPA-S).

Results: There was substantial progression of clinical deficits and cortical atrophy over 2 years. Neuropsychological language performance patterns lost the sharp distinctions that differentiated one PPA variant from another. Nonetheless, the subtype-specific differential impairment of word comprehension vs grammatical processing was largely maintained. Peak atrophy sites spread beyond the initial distinctive locations that characterized each of the 3 subtypes and displayed a more convergent distribution encompassing all 3 major components of the language network: the inferior frontal gyrus, the temporoparietal junction, and lateral temporal cortex. Despite the progression, overall peak atrophy remained lateralized to the left hemisphere.

Conclusions: The results suggest that the unique features, which sharply differentiate the PPA variants at the early to middle stages, may lose their distinctiveness as the degeneration becomes more severe. Given the substantial atrophy over 2 years, PPA clinical trials may require fewer patients and shorter study durations than Alzheimer disease trials to detect significant therapeutic effects.

Figures

Figure 1. Distribution of cortical thinning on the lateral pial surface for each primary progressive aphasia variant compared to a cognitively healthy control group

False discovery rate was set at 0.01 and the flame scale displays significance as a log(10) p value. ATC = anterior temporal cortex; DFC = dorsal frontal cortex; IFG = inferior frontal gyrus; LH = left hemisphere; LTC = lateral temporal cortex; PPA-G = agrammatic primary progressive aphasia subtype; PPA-L = logopenic primary progressive aphasia subtype; PPA-S = semantic primary progressive aphasia subtype; RH = right hemisphere; TPC = temporoparietal cortex; VFC = ventral frontal cortex.

Figure 2. Progression of cortical thinning in the left hemisphere by subtype

Areas of significant cortical thinning in the left hemisphere at baseline (green) and 2 years later (blue) for each of the primary progressive aphasia variants. ATC = anterior temporal cortex; DFC = dorsal frontal cortex; IFG = inferior frontal gyrus; LTC = lateral temporal cortex; PPA-G = agrammatic primary progressive aphasia subtype; PPA-L = logopenic primary progressive aphasia subtype; PPA-S = semantic primary progressive aphasia subtype; TPC = temporoparietal cortex.