Primary progressive aphasia and the language network: The 2013 H. Houston Merritt Lecture

OBJECTIVE:Review of clinical and biological features of primary progressive aphasia (PPA). RESULTS AND CONCLUSIONS:The PPA syndrome arises when language-dominant (usually left) hemisphere becomes the principal target of neurodegeneration. Depending on the distribution of neuronal loss within the language network, agrammatic (PPA-G), logopenic (PPA-L), and semantic (PPA-S) subtypes are identified. The most common underlying neuropathology is frontotemporal degeneration with tauopathy in PPA-G, frontotemporal degeneration with TDP-43 proteinopathy in PPA-S, and Alzheimer pathology in PPA-L. When Alzheimer pathology is detected, the neurofibrillary tangles show lower entorhinal-to-neocortical ratios and greater leftward asymmetry in PPA than in the typical amnestic dementia of Alzheimer disease. The ε4 allele of APOE, a major risk factor for Alzheimer pathology in amnestic dementias, is not a risk factor for Alzheimer pathology in PPA. These observations indicate that Alzheimer disease has biological variants with distinct patterns of lesion distribution and perhaps also molecular background. The selective vulnerability of the language network in PPA is likely to reflect complex interactions between factors that determine the type of histopathology, on one hand, and those that influence the resilience of the language network, on the other. A history of learning disability, including dyslexia, is emerging as one of the potential factors in this second group of determinants. Patient care in PPA should be individualized so that speech therapy can address the specific type of language impairment while pharmacologic therapy is directed to the underlying disease process.