Global cerebral atrophy in early stages of Huntington’s disease: quantitative MRI study Jan Kassubek, CA G. Bernhard Landwehrmeyer, Daniel Ecker, Freimut D. Juengling, 1 Rainer Muche, 2 Sabine Schuller, 3 Adolf Weindl 3 and Alexander Peinemann 3 Departments of Neurology; 2 Biometrics and Medical Documentation, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany; 1 Department of Nuclear Medicine, University of Bern, Switzerland; 3 Department of Neurology, Technical University of Munich, Germany CA Corresponding Author: jan.kassubek@medizin.uni-ulm.de Received 16 September 2003; accepted 24 October 2003 DOI: 10.1097/01.wnr.0000107527.38715.ef Global brain atrophy was determined in 70 patients su¡ering from Huntington’s disease (HD) and 70 healthy controls, using brain par- enchymal fractions calculated from 3D MRI data in a standardized procedure. In HD patients, brain parenchymal fractions were sig- ni¢cantly reduced compared to controls in all age groups; the phy- siological decline with age was less pronounced in HD. However, brain parenchymal fraction values did not allow the prediction of clinical impairment (as assessed by clinical scores). Global brain parenchyma reduction seems to be an early or even constitutional feature of HD, but clinical symptoms appear to re£ect regional rather than global atrophy. Overall, MRI-based brain volume quan- ti¢cation correlated with clinical scores clari¢es the functional im- pact of morphological brain alterations. NeuroReport 15:363^365  c 2004 Lippincott Williams & Wilkins. Key words: Aging; Atrophy; Brain parenchymal fraction; Huntington’s disease; Magnetic resonance imaging; Neurodegenerative disease INTRODUCTION Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease in which onset of clinical symptoms usually occurs during midlife. At autopsy, the brains of HD patients are, as a rule, globally smaller than normal [1]. In an MRI study using a region-of-interest-based interactive analysis technique in a sample of 18 patients, only a slight reduction of the cerebral exterior volumes to 95% of normal was reported [2]. However, in this and other studies MRI brain volume changes were not normalized to compensate for differences in skull sizes [3]. The highly automated and standardized measure of brain parenchymal fraction (BPF) [4], defined by the proportion of brain parenchymal volume to total intracranial volume, allows for a size-normalized quantification of brain volumes and was shown to be of use as a biological marker of global cerebral atrophy in neurodegenerative disorders [5]. BPF values of a sizable cohort of normal controls stratified for age enabled the derivation of age-dependent reference values for direct comparison to pathology [6]. In the present study, volume-rendering MRI data were analyzed with respect to BPF in a large cohort of HD patients to investigate whether patients in early stages of HD show a reduction of global cerebral volumes. PATIENTS AND METHODS All data are given as arithmetic mean 7 s.d. Seventy patients suffering from genetically confirmed HD were included in the study (mean age 44.0 7 10.0 years, range 18–66; 35 men, 35 women). The mean number of cytosine- adenosine-guanosine (CAG) repeats in the mutant allele was 44.4 7 3.3. All patients were in early clinical stages I and II [7]. The mean disease duration, assessed as interval between onset of motor symptoms and imaging, was 5.1 7 3.7 years. The mean subscore for motor function from the Unified HD Rating Scale (UHDRS) was 17 7 11.4; the mean Total Functional Capacity score (TFC) was 12 7 1.4. As a normal data base, 70 healthy subjects were investigated (mean age 42.7 7 15.8 years, range 21–76; male/female ratio 42/27). All control subjects were normal on standard neurological examination; none had a history of neurologi- cal or psychiatric disorders or other medical conditions. The study was approved by the Ethics Committee of the University of Ulm, and all HD patients and healthy subjects gave written informed consent according to institutional guidelines. For patients and controls, high-resolution volume-rendering datasets of the whole head were collected on a 1.5 T clinical MRI scanner (Magnetom Vision, Siemens, Erlangen, Germany). T1-weighted 3D datasets were ac- quired using a magnetization-prepared rapid-acquisition gradient echo sequence (MP-RAGE) with the following parameters: repetition time 9.7 ms; time to echo 3.93 ms; flip angle 151; matrix size 256  256 mm 2 ; voxel size 1  1  1 mm 3 . The brain parenchymal fractions were calculated from the 3D MRI data according to a largely automated standard protocol described previously [5]. For data processing, the fully automatical algorithms were used as implemented in the Statistical Parametric Mapping software (SPM99, Well- come Department of Imaging Neuroscience Group, London, BRAIN IMAGING NEUROREPORT 0959-4965  c Lippincott Williams & Wilkins Vol 15 No 2 9 February 2004 363 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.