ORIGINAL ARTICLE Global brain atrophy and corticospinal tract alterations in ALS, as investigated by voxel-based morphometry of 3-D MRI JAN KASSUBEK, ALEXANDER UNRATH, HANS-JU ¨ RGEN HUPPERTZ*, DOROTHE ´ E LULE ´ , THOMAS ETHOFER, ANNE-DORTE SPERFELD & ALBERT C. LUDOLPH Department of Neurology, University of Ulm, Ulm, and *Epilepsy Centre, University of Freiburg, Freiburg, Germany Abstract In ALS, advanced magnetic resonance imaging (MRI) techniques are increasingly used to investigate the underlying pathology. In this study, the technique of voxel-based morphometry (VBM) was applied to 3-D MRI data in ALS patients to localize regional grey and white matter changes. Twenty-two ALS patients (mean age 58¡9 years) with clinically definite ALS by revised El Escorial criteria were studied. None of the patients had any signs of associated frontotemporal dementia. High-resolution 3-D MRI data sets of the whole brain, collected on a 1.5 T scanner, were analysed by statistical parametric mapping (SPM) and VBM in comparison to an age-matched normal data base consisting of 22 healthy volunteers (mean age 59¡11 years), for grey matter and white matter segments separately. Global brain atrophy was assessed by calculation of brain parenchymal fractions (BPF). In ALS patients, BPF were significantly reduced compared to controls (p50.0003), indicating global brain atrophy. Regional decreases of grey matter density were found in the ALS patients at corrected pv0.01 in the right-hemispheric primary motor cortex (area of the highest Z-score) and in the left medial frontal gyrus. Furthermore, regional white matter alterations were observed along the corticospinal tracts bilaterally and in multiple smaller areas including corpus callosum, cerebellum, frontal and occipital subcortical regions. Besides considerable global atrophy in ALS, the topography of ALS-associated cerebral morphological changes could be mapped using VBM, in particular white matter signal changes along the bilateral corticospinal tracts, but also in extra-motor areas. VBM might be a potential tool to visualize disease progression in future longitudinal studies. Key words: Amyotrophic lateral sclerosis, corticospinal tract, dementia, magnetic resonance imaging, motor neuron disease, voxel-based morphometry Introduction It had long been the predominant view that, in motor neuron disease, neuroimaging is used princi- pally to rule out diagnostic alternatives. In most ALS patients, routine magnetic resonance imaging (MRI) of the brain shows no pathological findings, and abnormalities such as signal hyperintensities of the corticospinal tracts (CST) are non-specific (1) and have been reported only in single cases (2) or by use of certain pulse sequences such as fluid-attenuated inversion recovery (FLAIR) (3,4). Advanced MRI techniques, however, such as magnetic resonance spectroscopy (5), functional MRI, diffusion weighted imaging or magnetization transfer imaging are increasingly used to investigate anatomical and functional changes in ALS (6,7). All these novel imaging modalities have contributed important new aspects to the understanding of ALS pathogenesis. As a further important approach, in vivo investiga- tions of regional cerebral volume alterations using computational MRI analyses are highly useful in order to demonstrate the topography of ALS- associated changes. By visual evaluation of conven- tional MRI, regional atrophy (e.g. of the precentral cortex) is only very inconsistently reported (1,6) but might be recognized by computer-assisted imaging. One previous volumetric MRI investigation in ALS demonstrated grey matter loss in frontal areas, but not in the precentral gyrus (8). In addition to changes in motor areas, the involvement of extra- motor neurodegeneration is important to investigate since it is beyond all doubt that ALS is a multisystem disease with considerable biological heterogeneity (9). In particular, frontotemporal dementia (FTD) Correspondence: J. Kassubek, Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany. Fax: 49 731 1771202. E-mail: jan.kassubek@medizin.uni-ulm.de (Received 22 September 2004; accepted 8 April 2005) Amyotrophic Lateral Sclerosis. 2005; 6: 213–220 ISSN 1466-0822 print/ISSN 1471-180X online # 2005 Taylor & Francis DOI: 10.1080/14660820510038538