Distinctive pathological mechanisms involved in primary progressive aphasias Cristian E. Leyton a, b, c, * ,1 , Anna K. Britton d,1 , John R. Hodges b, c, e , Glenda M. Halliday b, e , Jillian J. Kril d a Faculty of Health Sciences, The University of Sydney, Lidcombe, New South Wales, Australia b Neuroscience Research Australia, Randwick, New South Wales, Australia c ARC Centre of Excellence in Cognition and its Disorders, Sydney, New South Wales, Australia d Department of Pathology, Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia e School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia article info Article history: Received 7 August 2015 Received in revised form 16 October 2015 Accepted 17 October 2015 Available online 26 October 2015 Keywords: Primary progressive aphasia Quantitative pathology Alzheimer’s disease Frontotemporal dementia Semantic variant Logopenic variant Nonfluent/agrammatic variant abstract Primary progressive aphasia (PPA) comprises a heterogeneous group of neurodegenerative conditions that can be classified in three cliniconeuroanatomic syndromes. Limited information exists, however, about patterns of neuropathologic spreading and microscopic changes underpinning each syndrome. We performed an analysis of a longitudinal in vivo cohort and a postmortem PPA cohort to investigate neurodegeneration over time and to quantify microscopic changes in key language brain areas. The longitudinal analyses demonstrated distinctive patterns of topological extension of brain atrophy. Although semantic variant (sv-PPA) showed an eccentric pattern, nonfluent and/or agrammatic (nfv-PPA) and logopenic (lv-PPA) variants showed additional multifocal extension. The quantitative pathology showed that sv-PPA had neuronal loss and thinning in BA 38, whereas nfv-PPA showed thinning in BA 44/45 and evidence of microscopic involvement in BA 40/22. Although lv-PPA showed neuronal loss focused on BA 40/22, imaging results demonstrated widespread left-sided brain atrophy. These analyses provide an account of the pathologic process whereby each variant has stereotypical patterns of brain atrophy extension, which is largely determined by the specific pathologic type. Ó 2016 Elsevier Inc. All rights reserved. 1. Introduction It is well established that the language network can be selectively targeted by neurodegeneration and causes progressive, albeit cir- cumscribed, language deterioration (Mesulam, 1982). This condi- tion, formally known as primary progressive aphasia (PPA) (Mesulam, 2001), can be caused by different pathologies, each of which tends to exhibit specific patterns of linguistic deficits and a characteristic distribution of brain atrophy. Based on the presence of core language and speech deficits, current international consensus criteria propose three clinical variants: semantic (sv-PPA), nonfluent and/or agrammatic (nfv-PPA), and logopenic (lv-PPA) (Gorno- Tempini et al., 2011). Cases with semantic variant display marked anomia and difficulties in recognizing words, objects, people, and tunes, deficits attributed to degradation of semantic representations (Hodges et al., 2010; Hsieh et al., 2011). By contrast, cases with nfv- PPA show preservation of semantic knowledge but effortful speech, loss of prosody, and articulatory errors, all of which result from disruption of motor planning or speech execution (Croot et al., 2012; Josephs et al., 2013b) or, alternatively, present with morpho- syntactical deficits and omission of function words leading to agrammatism and oversimplification of language output (Wilson et al., 2010a, 2010b). In contrast to the other variants, logopenic variant (lv-PPA) cases display relative preservation of semantic representations and motor aspects of speech, but instead they show marked word-finding difficulties, anomia and striking difficulties in sentence repetition (Gorno-Tempini et al., 2004, 2008). Evidence from neuroimaging studies implicates distinct left hemispheric brain regions as responsible for the core language deficits in each of the variants of PPA. In sv-PPA, the temporal pole (BA 38) is strongly correlated with semantic processing (Mesulam et al., 2009; Mummery et al., 2000). Reduced speech fluency in nfv-PPA is correlated with cortical thinning in the left inferior frontal cortex (BA 44/45) (Gunawardena et al., 2010; Sapolsky et al., 2010; Wilson et al., 2010a, 2013b). The deficits of impaired naming and reduced sentence repetition in lv-PPA have been correlated with cortical thinning in the supramarginal gyrus (BA 40) and su- perior temporal gyrus (BA 22), respectively (Leyton et al., 2012). In * Corresponding author at: Faculty of Health Sciences, The University of Sydney, 75 East St. Libcombe, NSW 2141, Australia. Tel.: þ61 2 9351 2222; fax: þ61 2 9351 9173. E-mail address: cristian.leyton@sydney.edu.au (C.E. Leyton). 1 These authors contributed equally to this work. Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging 0197-4580/$ e see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2015.10.017 Neurobiology of Aging 38 (2016) 82e92