Longitudinal changes in brains of patients with fluent primary progressive aphasia
Introduction
Primary progressive aphasia (PPA) is a rare type of dementia, belonging to neurodegenerative disorders with an onset between 60 and 70 years of age. It was first described by Mesulam (1982). The predominant impairment is in the language domain. During the course of PPA, other cognitive deficits can emerge after about 2 years, but aphasia remains the most severe impairment (Mesulam, 2001) and finally results in mutism (Gorno-Tempini et al., 2004). Because of its circumscribed deficit with relative slow progression of linguistic symptoms, PPA may reveal especially in its early phase, compensatory mechanisms of structure–function interrelation. Detecting the relationship between cognitive, neurofunctional, and neuroanatomical parameters in PPA may thus improve our understanding of the plasticity of the brain under pathological conditions. Consequently, this knowledge may help formulate a more general model which extends to other degenerative diseases and which may be the ground to understand the role of neurofunctional changes e.g. in other types of dementia.
In the literature, several attempts have been made to classify subtypes of PPA according to their predominant aphasic symptoms, e.g. syntactic/agrammatic deficits vs. semantic or phonological retrieval problems (e.g. Sonty et al., 2003). The most widely agreed-upon distinction pertains to (at least) one non-fluent/agrammatic type and one fluent type with word finding difficulties. Some authors (e.g. Snowden, Neary, & Mann, 1996; Neary et al., 1998; Hodges, Patterson, Oxbury, & Funnell, 1992) further distinguish between this fluent PPA variant and semantic dementia (SD): Whereas in SD, semantic memory loss is generally evident in verbal as well as non-verbal tasks, patients with fluent PPA only have circumscribed deficits in lexical semantics but are unimpaired in non-verbal semantic tasks. The distinct symptoms in subtypes of PPA are associated with different patterns of atrophy in frontal (non-fluent PPA) vs. temporal (fluent PPA) cortices (e.g. Mesulam et al., 2009). Often atrophy emerges in parallel with hypoperfusion (Perneczky, Diehl-Schmid, Pohl, Drzezga, & Kurz, 2007). Gorno-Tempini et al. (2011) have recently published a new guideline for the classification of PPA in non-fluent/agrammatic, semantic, and logopenic PPA.
The underlying neurofunctional mechanism of progression of aphasic symptoms in PPA remains largely unknown. Cross-sectional studies of cerebral blood flow showed differences between PPA patients in different stages of progression; however, these differences intermingled with regional perfusion changes in healthy aging subjects (Meinzer et al., 2009). Evidence for a reduced structural and functional connectivity in brains of PPA patients likewise rely on cross-sectional rather than longitudinal data (Oliveira et al., 2011, Sonty et al., 2007). In order to distinguish pathological changes from normal age-related changes, longitudinal examinations are mandatory (e.g. Rogalski et al., 2011), which should cover short time intervals. In addition, such studies are capable of disclosing the course of pathological changes in the individual patient, a necessary prerequisite towards personalised therapy (e.g. Dressel et al., 2010).
The present study was designed to address longitudinal changes in language performance and underlying neurofunctional changes in PPA. Over the course of 1 year, fluent (logopenic) PPA patients and matched controls were repeatedly examined at intervals of 6 months (time point T1: 0 months; time point T2: 6 months; time point T3: 12 months). In this study, we employed a lexical decision task including a battery of words and pseudowords. This lexical decision task, which was performed during fMRI scanning, tested for skills of receptive language processing, and avoided problems with expressive language in later stages of the disease. The “lexicality effect” (pseudowords vs. words), a well-established indicator of visual-lexical processing (Binder et al., 2005, Carreiras et al., 2007) was used to investigate lexical processing in fluent PPA. Based on findings in the literature, the following hypotheses were tested: (1) Considering that atrophy is often associated with hypoperfusion (Acosta-Cabronero et al., 2011, Perneczky et al., 2007) indicating reduced neuronal activity (Hughes, Nestor, Hodges, & Rowe, 2011), we tested the hypothesis that brains of PPA patients show hypoperfusion (and hence, reduced BOLD signal) relative to controls, which becomes more pronounced over time. (2) During aging (Meinzer et al., 2009) as well as in aphasic patients after stroke (e.g. Saur et al., 2006), an additional recruitment of right-hemispheric regions was observed for language processing. In this context we asked the question about comparable effects during disease progression. (3) Finally, we examined whether the differences in functional activations found in the aforementioned experiments were associated with local structural changes. To this end, relative changes of the activation clusters found in the fMRI experiments were computed by means of longitudinal deformation field morphometry (Pieperhoff et al., 2008).
Section snippets
Participants
Four fluent logopenic PPA patients1 (mean age ± SD: 65.8 ± 7.0 years; 2 women; all right-handed according to the Edinburgh Inventory by Oldfield, 1971) and four matched control subjects (66.5 ± 6.5 years; 2 women) were examined repeatedly on three occasions over the course of 1 year. The details about the individual patients and control subjects are provided in Table 1. The
Performance during lexical decisions
Response accuracy in the lexical decision task was at ceiling for both groups in all examinations. Consequently, there were no significant differences between PPA patients and controls at any examination (T1: Mann–Whitney U = 1.0; p = 0.057; T2: Mann–Whitney U = 4.5; p = 0.343; T3: Mann–Whitney U = 4.5; p = 0.343; all p-values not significant at thresholds uncorrected for multiple comparisons). In particular, the initial trend for a group difference disappeared at later examinations. However, there was
Activation differences between PPA patients and controls at T1
The comparison of PPA patients and control subjects at the initial examination (T1) revealed that PPA patients had higher amplitudes for the lexicality effect than controls in the right posterior middle temporal gyrus (pMTG), extending into posterior superior temporal gyrus, and in right inferior parietal lobule. A second maximum was found in the right occipital lobe (for details see Table 2 and Fig. 2a). Reversely, controls had higher amplitudes for the lexicality effect than PPA patients in
Discussion
The present fMRI study sought to elucidate neurofunctional changes in the course of fluent PPA by means of a longitudinal approach involving short between-test intervals. Investigating four PPA patients and the same number of matched control subjects for three times over the course of 1 year, we provide fine-grained quantitative data of neuronal responses and their temporal dynamics in brains of patients with PPA.
Conclusion
The present study demonstrates unique neurofunctional changes in PPA when examined longitudinally and at short between-examination intervals. The data show that the loci of neurofunctional dynamics also show progressive atrophy. Interestingly, longitudinal activation increase for lexical processing, rather than decrease, was observed in brain regions increasingly affected by neurodegeneration, hinting at a compensatory mechanism. Moreover, our study shows that right-hemispheric involvement in
Acknowledgments
We wish to thank Yosef Grodzinsky for inspiring discussions about the different facets of PPA. Moreover, we are grateful for support by the Department of Neurology at RWTH Aachen University. This project was supported by a JARA – Translational Brain Medicine grant to MG and SH, and the “Stiftung für Altersforschung”, Heinrich-Heine-University, Düsseldorf, Germany (Grant to MS). The project underlying this report “Helmholtz Alliance for Mental Health in an Ageing Society” (HelMA, HA-215) was
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