Axonal Injury within Language Network in Primary Progressive Aphasia Marco Catani, MD, 1,2 Massimo Piccirilli, MD, 3 Antonio Cherubini, MD, PhD, 2 Roberto Tarducci, PhD, 4 Tiziana Sciarma, MD, 3 Gianni Gobbi, PhD, 4 GianPiero Pelliccioli, MD, 5 Stefania Maria Petrillo, PhD, 3 Umberto Senin, MD, 2 and Patrizia Mecocci, MD, PhD 2 Primary progressive aphasia (PPA) is characterized by an isolated progressive impairment of word use and compre- hension reflecting the distribution of pathological processes within the left hemisphere. We used proton magnetic resonance spectroscopy (1H-MRS) to study in vivo the integrity of axonal fibers connecting perisylvian language areas in 11 patients with PPA, 11 subjects with Alzheimer’s disease, and 22 controls. Brain metabolites (N-acetylaspartate, myoinositol, choline, creatine) were measured bilaterally within a volume of interest located in the central portion of the superior longitudinal fasciculus, a long associative bundle connecting Broca’s area with Wernicke’s area, and other language regions of the temporal lobe. In the PPA group, there was an asymmetrical N-acetylaspartate to creatine ratio reduction compared with Alzheimer’s disease and controls, with greater changes on the left side. The myoinositol to creatine ratio was increased in the PPA group bilaterally compared with controls. The choline to creatine ratio did not differ among the three groups. These results indicate an asymmetrical focal axonal injury within the language network in PPA. The marked difference in the distribution of N-acetylaspartate to creatine between PPA and Alzheimer’s disease suggests that proton magnetic resonance spectroscopy may help to differentiate between these two conditions. Ann Neurol 2003;53:242–247 In 1982, Mesulam reported six patients with “slowly progressive language dysfunction without generalized dementia,” accompanied by focal atrophy of the left perisylvian region. 1 Termed primary progressive aphasia (PPA), it was considered to be a focal cerebral degen- eration restricted to language areas. Since the initial re- port, more than 100 similar cases have been published and diagnostic criteria proposed. 2–4 Impairments of use of language are also a common early manifestation of Alzheimer’s disease (AD) and making a differential diagnosis between PPA and cases of AD with language deficits can be difficult on clinical grounds alone. Neuroimaging techniques have been used to study brain changes in PPA. With magnetic resonance imag- ing, patients typically show atrophic changes in the left hemisphere, but up to 50% of imaging studies either are normal or indicate nonspecific generalized cortical atrophy. 3,5– 8 Positron emission tomography and single-photon emission computed tomography studies report predominant left hemisphere changes in 70% of patients, but bilateral perfusion deficits also have been reported. 3,6,7,9 –14 Note that asymmetrical atrophy and regions of hypoperfusion also have been reported from AD cases. 15,16 Hence, conventional neuroimaging does not generate findings that are specific for PPA, and dif- ferentiation from cases of AD remains difficult. To the best of our knowledge, no magnetic reso- nance spectroscopy studies have been published on PPA. Proton magnetic resonance spectroscopy ( 1 H- MRS) is a valuable tool for the in vivo assessment of several biochemical compounds in the brain, such as N-acetylaspartate, myoinositol, choline, and creatine. Most N-acetylaspartate is located within neurons, and a reduction in N-acetylaspartate content can reflect neu- ronal and axonal dysfunction or loss. 17 Myoinositol is a precursor of the inositol polyphosphate messenger sys- tem and is located mainly within glial cells. 18 Several putative roles have been proposed for this molecule: as a marker of glial cells, cellular osmoregulator, second messenger, and detoxifying molecule. 19 Myoinositol concentration increases have been considered to repre- sent an early marker of metabolic dysfunction. 20 The choline resonance reflects the contribution of several cytosolic choline-containing compounds. The creatine signal usually is used as an internal reference standard From the 1 Institute of Psychiatry, London, United Kingdom; 2 In- stitute of Gerontology and Geriatrics and 3 Unit of Cognitive Reha- bilitation, University of Perugia; and Departments of 4 Physics and 5 Neuroradiology, Perugia, Italy. Received May 29, 2002, and in revised form Oct 10. Accepted for publication Oct 10, 2002. Published online Dec 8, 2002, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.10445 Address correspondence to Dr Catani, Section of Old Age Psychia- try, Institute of Psychiatry, London SE5 8AF, United Kingdom. E-mail: spjumrc@iop.kcl.ac.uk 242 © 2002 Wiley-Liss, Inc.