This study investigated thinning pattern along the entire brain cortical surface in LPA patients. The results showed that LPA group had overall perspective of pronounced cortical thinning in more areas on the left than right hemisphere compared to control group, especially in the area around left TPJ including MTG, SG, ITG and LOC. This finding is consistent with the previous ones, which demonstrated that the area of peak cortical atrophy in LPA patients extended on the left temporal cortex and TPJ, while the temporal pole and medial temporal cortex were spared (6-9).
Apart from that typical imaging feature, we demonstrated the whole-hemispheric overall cortical thickness to be lower in LPA than in control group, regardless of the younger age and the slightly greater brain volume. Most parcellated cortical areas also tended to be thinner in LPA group (Figure 1). In addition, the TMSE score was shown to have significant positive correlations with the whole-hemispheric overall cortical thickness. This may reflect the nature of neurodegenerative disorder which every single neuron is vulnerable. Yet, the mechanism how LPA patients had a distinct character of peak atrophy in the language area of the dominant hemisphere, in spite of common neuropathological substrate as AD, remains unresolved (3).
Interestingly, our analyses revealed that bilateral middle frontal gyri (MFG) and left SFG are significantly thinner in LPA patients comparing to control subjects. These clusters in the frontal regions were considerably large, especially on the left hemisphere which the clusters placed in both caudal and rostral parts of MFG. To our knowledge, frontal lobe involvement has been rarely described causing disorders in LPA patients. This finding, however, is quite consistent with some previous studies of cortical thickness in LPA patients reported the relative cortical thinning in the left frontal region (8, 19). Regarding the language function of this frontal region, there was a study correlated the cortical thickness to language processing denoted that MFG and speech fluency were related (11). This study also remarked that reduction of fluency such as impaired utterance and disrupted chain of spoken or written language can be seen in many language or speech disorders including non-fluent/agrammatic variant of PPA (nfvPPA, PPA-G), apraxia of speech and even LPA. Additionally, there was a report of some LPA patients presenting with word-finding difficulty and poor verbal fluency despite nearly normal naming ability (3). Therefore, the involvement of MFG, the region responsible for verbal fluency, may alternatively underlie the classical symptom in some clinically diagnosed LPA patients. In other words, our analyses indicated that the classical symptoms of LPA, including failures in word retrieval and sentence repetition, are underlaid by abnormalities in the TPJ area or alternatively in the MFG. This finding may emphasize the complexity of neural substrate in association with language disorder, as a defect in the different steps of language processing potentially leads to an apparently identical phenotype of LPA. This inference implicates clinical practice as it reminds that an absolute decision on anatomical localization from a single clinical presentation of language disorder is not necessarily correct. For the LPA patients, further explorations regarding disease progression, prognosis, response to treatment, and even neuropathology in association with pattern of cortical thinning would have clinical benefits as well.
To discuss further, many Thai noun words are “noun phrases”, which are composed of several simple words (20). For example, the word “driver” in Thai language is literally expressed as “man-drive-car”. Ordering of words in the noun phrase must also be in a correct sequence. As MFG is involved in sequential word ordering process (21), the thinning of MFG is thus possibly an exceptional feature in Thai LPA patients.
Other significant thinner regions and clusters in LPA group located in bilateral PHG, ECs and TPs. Involvement of the PHG and ECs may reflect the underlying AD neuropathology in majority of LPA patients (22). As for TPs involvement, prominent atrophy of the left anterior temporal lobe and left TP has been known as a common pattern in semantic variant of PPA (svPPA, PPA-S) (7). Although to a lesser extent, right anterior temporal region was also reported to be consistently atrophied in svPPA patients (23). Thus, our finding regarding the thinning of TPs reflects that LPA manifestation possibly represents a prodromal stage of svPPA in some patients. This hypothesis is in accordance with the natural history of PPA syndrome, which the distinctive features of each PPA variant at early stage usually loss their uniqueness as the disease progresses to late stage, i.e. the progression trajectory (3, 24, 25).
Our finding about the alternative area of prominent cortical thinning in LPA patients is considered to be a strength in this study. The main limitation is the diagnosis of LPA, which was based on clinical diagnostic criteria combined with information from structural brain MRI. The use of functional imaging and biomarkers would possibly lead to the more accurate diagnosis. A between-group comparison by functional brain imaging technique, additional to structural MRI, would also strengthen the study result. These were unfortunately limited due to resource constraints. Besides, the present study lacks the information regarding formal linguistic tests in LPA patients as the Thai version of such tests have not been validated and primary language of all the patients is Thai. The TMSE, which had been validated and was used in our study, may not be the best assessment tool for patients with linguistic problem. Because good language capacity is required to complete tasks in several sections of the TMSE, i.e. not specific to the language section (26). This was reflected in our results, which showed that LPA patients had significantly lower performance in both language and non-language sections of the TMSE.
Regarding the demographic data, proportion of male patient and age of the participants were markedly higher in LPA group. These occurred due to limitations in our resources, i.e. we were not able perform brain MRI in perfectly healthy and well-matched control individuals. The difference in proportion of sex, however, should not seriously confound our result since cortical areas known to be thicker in woman than in man locate in parietal and temporal regions of the right cerebral hemisphere (27). Regarding the difference in age of participants, one may argue this potentially confounds the results since brain atrophy relates to aging process (28). However, it is unlikely that this difference would significantly change our results as we demonstrated that the brain volume of the two groups were comparable. In fact, this difference in age should bias our result into the opposite direction because the control group was the one that were significantly older. In addition, we demonstrated that age and sex had no significant relationship to overall cortical thickness in our participants. Lastly, the present work is a single-centered study containing small numbers of LPA patients as we had to strictly follow the diagnostic criteria to avoid misdiagnosis. Also, there is a substantial difference in the number of participants between the groups. We recruited more participants in the control group in order to increase reliability of our analyses.