Cortical degeneration associated with phonologic and semantic language impairments in AD J.A. Harasty, PhD; G.M. Halliday, PhD; J. Xuereb, MD; K. Croot, PhD; H. Bennett, MSc; and J.R. Hodges, MD Article abstract—Objective: To compare the pattern of cortical degeneration associated with different language deficits in cases of AD. Methods: Cases for detailed neuropathologic analysis (Patients 1 and 2) were selected because of their detailed clinical and neuropsychological assessments of language dysfunction in AD. Patient 1 had severe phonologic impairment with relatively preserved semantic aspects of language. Patient 2 had severe semantic language impairment with relatively preserved phonologic skills. The tissue volume of cortical regions associated with speech and language function was measured using standardized three-dimensional techniques. Neuronal areal fraction was also measured from histologic tissue samples. The degree of volume atrophy and neuronal loss was calculated in comparison to control measures (n = 10 men and 11 women). Measurements more than 2 SD from controls were considered abnormal. Results: Both AD cases had significant degeneration of the superior temporal gyrus and area 37. Cortical language regions affected only in Patient 1 included the anterior and posterior insula and part of Broca’s area. In contrast, Patient 2 had a greater degree of degeneration in the temporal gyri and their white matter connections with the hippocampal/entorhinal complex. Conclusions: Variable patterns of neurodegeneration underlie the clinical differences observed in patients with AD. Disconnection within the temporal lobe appears associated with semantic language difficulties, whereas disconnection of the anterior and posterior language areas appears associated with phonologic and grammatical impairment. NEUROLOGY 2001;56:944 –950 Neuropsychological models of language production suggest that a number of levels of cognitive process- ing occur before the final output of speech. These include a semantic level, at which the meaning of the intended utterance is organized, a phonologic level involving retrieval of the sound structure of the re- quired words from memory, and a level of articula- tory organization and motor planning. Recent data suggest that the anterior insula may be involved in coordinating the final speech articulation and that damage to this area leads to a disorder known as “apraxia of speech.” 1 By contrast, the regions critical for phonologic processing remain more controversial; the planum temporale is implicated in receptive pho- nologic processing, 2 but the cortical regions critical for phonologic output processing disturbances have not been studied in detail. The progressive and sequential nature of linguis- tic deterioration in patients with AD and other neu- rodegenerative disorders suggests a gradual loss of the neural networks underlying language function. This linguistic disruption can be remarkably selec- tive, as exemplified by the syndrome of semantic de- mentia (progressive fluent aphasia), in which is seen severe semantic disruption with relative preserva- tion of the phonologic and syntactic systems, and the mirror image of this syndrome—progressive nonflu- ent aphasia—in which semantic aspects are pre- served in the face of severe and progressive disruption of the phonologic and syntactic components. 3 To understand which specific areas of the brain relate to different linguistic deficits, modern stereo- logic anatomic techniques need to be applied post- mortem to the brains of subjects for whom comprehensive, prospective neuropsychological data are available. Presented here is a quantitation of neuronal loss in the cortex of two patients, one with nonfluent, progressive aphasia secondary to patho- logically confirmed AD, 4 and the other with a more typical semantic presentation of AD. The quantita- tive results from neuropsychological and linguistic testing are related to a detailed analysis of neuronal loss and neuropathology. From the Prince of Wales Medical Research Institute (Drs. Harasty and Halliday), Randwick; Faculty of Medicine (Dr. Harasty), University of New South Wales; Centre for Education and Research on Aging (H. Bennett), Concord Hospital, and the School of Communication Sciences and Disorders (Dr. Croot), University of Sydney, Australia; the Cambridge Brain Bank Laboratory (Dr. Xuereb), Department of Pathology, and the MRC Cognition and Brain Sciences Unit (Dr. Hodges), University of Cambridge, England. Supported by the National Health and Medical Research Council of Australia (NHMRC) and the Medical Research Council of Britain (MRC), Faculty of Medicine, UNSW and the Prince of Wales Medical Research Institute. Received October 4, 1999. Accepted in final form December 11, 2000. Address correspondence and reprint requests to Dr. J. Harasty, Prince of Wales Medical Research Institute, Randwick, Sydney, Australia 2031; e-mail: J.Harasty@unsw.edu.au 944 Copyright © 2001 by AAN Enterprises, Inc.