Familial language network vulnerability in primary progressive aphasia

Abstract

ObjectiveTo investigate evidence of the potential role of early cortical vulnerability in the development of primary progressive aphasia (PPA).MethodA woman with a diagnosis of PPA and her 9 adult siblings, 7 with developmental language disabilities, underwent neuropsychological testing, structural MRI, and resting-state fMRI. Whole-exome sequencing was conducted for genes associated with dyslexia or with neurodegenerative dementia.ResultsThe siblings demonstrated lower verbal than nonverbal cognitive test scores in a developmental dyslexia pattern. On structural MRI, although the siblings did not differ from controls in total brain volume, the left hemisphere language area volume was significantly smaller than the right. Furthermore, cortical connectivity between the left superior temporal area, previously identified as the region of peak atrophy in the proband early in the course of illness, and adjacent language network components, including the planum temporale, was decreased in the siblings. No distinctive genetic signatures were identified.ConclusionThis report further supports the hypothesis that at least some cases of PPA may be based on a familial language network vulnerability that interferes with the acquisition of language in some members and that makes the language network a locus of least resistance to the effects of an independently late-arising neurodegenerative disease in others. This association offers a conceptual model to explain why identical neurodegenerative diseases may selectively target the language network in some individuals while targeting networks that regulate memory or behavior in others. The genetic basis for this vulnerability remains to be determined.

Primary Progressive Aphasia: Toward a Pathophysiological Synthesis

“…However, there is not complete concordance between phenotype and pathology: svPPA can more rarely be caused by tau or Alzheimer pathologies [22, 37•, 40]; nfvPPA is sometimes caused by Alzheimer's disease, or TDP-43 (type A or B) [22, 37•, 41, 42]; lvPPA has been associated with dementia with Lewy bodies [43] and TDP-43 (type A) [41]; and an lvPPA-like phenotype has been consistently identified in people with mutations in the progranulin gene [44,45]. Emerging evidence suggests that specific language network vulnerabilities caused by genetic, developmental, and/or lifestyle factors may determine why some people develop a PPA phenotype in the context of a specific proteinopathy [27,46,47]. Age at onset may also influence phenotypic expression [48].…”

Investigation of the Association Between History of Learning Disabilities and Primary Progressive Aphasia in Brazilian Portuguese Speakers

“…PPA is a disease centered on language disorders, and, therefore, it is possible that some risk factors are dependent on the language spoken by the subject. Our results may indicate that the behavior and development of the disease may be different in speakers of other languages than English since most of the studies produced so far focused on native English speakers ( 7 , 9 , 11 , 16 , 17 ). Other possibility is that, at the time when the generation of people investigated in this study was in school, the knowledge of learning disabilities among education and health professionals was scarce, and such conditions were not investigated, much less diagnosed.…”

“…Learning disabilities have been treated as a potential risk factor in the development of PPA. There is evidence indicating that the history of learning disabilities, such as dyslexia, is significantly higher in patients with PPA and their first-degree relatives than in healthy controls or in patients with the behavioral variant of FTD or with AD ( 7 , 9 , 11 , 15 – 17 ).…”

Symptom-led staging for primary progressive aphasia

“…Following patients through to post-mortem would allow for relation of clinical symptoms to underlying neuropathology, and genetic cohorts, whilst rare, represent a unique and important opportunity to unpack the very earliest stages of disease (i.e., the putative ‘stage 0’). Application and interpretation of staging would be enhanced by more clinical and demographic detail concerning, factors that modulate the expression of PPA such as developmental dyslexia and educational attainment 11, 76 .…”