Cerebellum DOI 10.1007/s12311-014-0555-6

ORIGINAL PAPER

Increased Catabolic State in Spinocerebellar Ataxia Type 1 Patients Anja Mähler & Jochen Steiniger & Matthias Endres & Friedemann Paul & Michael Boschmann & Sarah Doss

# Springer Science+Business Media New York 2014

Abstract Autosomal dominant spinocerebellar ataxia type 1 (SCA1) is a genetic movement disorder with neuronal loss in the cerebellum, brainstem, and other cerebral regions. The course of SCA1 is accompanied with progressive weight loss and amyotrophia—the causes for that remain, however, unclear. We tested the hypothesis that an imbalance between energy intake and expenditure contributes to weight loss in SCA1 patients. Anthropometric measures, energy intake (food records), and resting (calorimetry) and free-living (accelerometry) energy expenditure were determined in 10 patients with genetically proven SCA1 and 10 healthy controls closely matched for age, sex, and body composition. At rest, energy expenditure per kilogram fat-free mass was 22 % and fat oxidation rate 28 % higher in patients vs. controls Electronic supplementary material The online version of this article (doi:10.1007/s12311-014-0555-6) contains supplementary material, which is available to authorized users. A. Mähler (*) : J. Steiniger : F. Paul : M. Boschmann Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Centrum für Molekulare Medizin, Lindenberger Weg 80, 13125 Berlin, Germany e-mail: [email protected] A. Mähler : M. Endres : F. Paul : S. Doss Excellence Cluster NeuroCure, Charité Universitätsmedizin, Berlin, Germany M. Endres : S. Doss Department of Neurology, Charité Universitätsmedizin, Berlin, Germany M. Endres Center for Stroke Research, Charité Universitätsmedizin, Berlin, Germany F. Paul Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité Universitätsmedizin, Berlin, Germany

indicating an increased catabolic state. Under free-living conditions, total energy expenditure and daily step counts were significantly lower in patients vs. controls. However, most patients were able to maintain energy intake and expenditure in a balanced state. Resting energy expenditure, fat oxidation, and activity energy expenditure per step count are higher, whereas 24-h total energy expenditure is lower in SCA1 patients vs. healthy controls. An altered autonomic nervous system activity, gait ataxia, and a decreased physical activity might contribute to this outcome. Keywords Spinocerebellar ataxia . Energy expenditure . Energy balance . Calorimetry . Accelerometry

Introduction Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominantly inherited neurodegenerative disorder caused by an instable cytosine-adenine-guanine (CAG) repeat extension mutation of variable length in the ATXN1 gene on chromosome 6p23. The resulting mutated ataxin-1 protein contains a prolonged polyglutamine chain with a tendency to aggregate in the nuclei of cerebellar Purkinje cells and brainstem neurons and is associated with progressive neuronal cell death in these areas. A longer CAG repeat correlates with earlier disease onset and faster progression [1, 2]. The highly variable phenotype of SCA1 includes disturbed motor coordination (gait ataxia), slurred speech, dysphagia, spasticity, extrapyramidal movements (dystonia, chorea), cerebellar oculomotor disturbances and ophthalmoparesis, retinal nerve fiber loss, saccade slowing, and cognitive impairment at late disease stage [3, 4]. Symptoms based on non-neuronal tissue dysfunction have been rarely evaluated. There is limited clinical evidence for amyotrophia and weight loss within disease course of SCA1 and SCA3 [5, 6].

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Body weight maintenance requires energy balance, i.e., energy (food) intake should meet energy expenditure (resting energy expenditure (REE), diet-induced thermogenesis, and physical activity). The major component of energy expenditure is REE, which depends mainly on lean (fat-free) body mass, gender, and age [7]. REE can be predicted by equations, for example, the one by Harris and Benedict [8]. However, these equations are derived from healthy subjects and might not be applicable for patients suffering from diseases which might affect energy metabolism. Energy expenditure can be assessed by indirect calorimetry—still one of the most accurate methods used in clinical settings [9]. REE can be measured, for example, in a metabolic chamber at a comfortable temperature with a subject that has fasted overnight and is awake but resting [7]. It is known from other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) that weight loss can be relevant for disease prognosis and that early countermeasures can improve patient’s quality of life [10]. Like SCA1, HD comprises a trinucleotide repeat expansion disorder based on a prolonged polyglutamine chain in a mutated protein huntingtin. Weight loss in HD patients might be due to a negative energy balance that is not primarily caused by dysphagia-related difficulties in food (energy) intake but originates from the genetic disease pathology [11]. In this study, we investigated genetically proven SCA1 patients and healthy controls, closely matched for age, sex, and body composition, with respect to anthropometric measures, and energy intake and expenditure both at rest and under free-living conditions. We tested the hypothesis that an imbalance in energy intake and expenditure contributes to weight loss in SCA1 patients.

The study was approved by the institutional review board of Charité University Medicine Berlin and conducted in accordance with the Declaration of Helsinki (59th WMA General Assembly, 2008). All participants gave written informed consent. Anthropometry All measurements were performed after a 12-h overnight fast. Body weight, height, and waist circumference were determined in a standardized fashion. Body composition (fat and fat-free mass) was obtained from body weight and body volume measured by air-displacement plethysmography (ADP, BOD POD, Life Measurement, Inc., Concord, CA). In addition, body fat was estimated from skinfold thicknesses measured at four sites (triceps, biceps, subscapular, and suprailiac) by using the Lange Skinfold Caliper (Beta Technology Inc., Cambridge, MD). All participants were measured by the same investigator. The average of three skinfold measurements at each site was used to calculate the sum of four skinfolds. From this, body fat was calculated using the equations of Durnin and Womersley [13]. Systemic Metabolic Measures

Subjects and Methods

In blood samples drawn from a large antecubital vein, plasma/ serum concentrations of glucose, HbA1c, insulin, low- and high-density lipoproteins, triglycerides, and thyroidstimulating hormone were measured according to international standards. Homeostasis model assessment of insulin resistance (HOMA-IR) is a surrogate marker of insulin sensitivity in humans which ranks individuals similarly to the glucose clamp technique. HOMA score (fasting serum insulin [μU/ml]× fasting plasma glucose [mmol/l]/22.5) gives an estimate of insulin sensitivity with high scores denoting low insulin sensitivity (insulin resistance) [14].

Subjects

Resting Energy Expenditure

We prospectively recruited 10 SCA1 patients from the ataxia clinic and assessed them by careful clinical examination. Inclusion criteria were 18–75 years of age and genetically diagnosed SCA1. Exclusion criteria were bedriddenness, lack of ability to communicate, and degenerative or inflammatory diseases of the central nervous system, apart from SCA1, as well as known endocrine/metabolic diseases such as diabetes mellitus. Some patients presented with mild dysphagia that did not restrict food intake. CAG repeats and scale for assessment and rating of ataxia (SARA) scores [12] were available. On the study day, SARA scores were reevaluated for all patients by the same physician. We also identified 10 healthy controls closely matched for age, sex, and body mass index and composition, respectively.

All subjects were asked to refrain from caffeine- and alcoholcontaining beverages on the day preceding the measurement and from smoking on the study day itself. Carbon dioxide production (VCO2) and oxygen consumption (VO2) were measured by open-circuit indirect calorimetry in a metabolic chamber. This chamber is a comfortable, airtight room (width 2.5 m, depth 2.0 m, height 2.2 m) which is constantly supplied with fresh air [15]. The room is equipped with a comfortable arm chair, table, entertainment center, cycle ergometer, toilet, air condition, air lock, and two cameras for monitoring the subject. VCO2 and VO2 measurements were started at first for air equilibration (30 min) and then for calculating subject’s REE while being seated in the arm chair (40 min). During this time, subject’s movements were recorded by three passive

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infrared sensors (PIRS) inside the chamber (one in front and two above the subject). VCO2 and VO2 were used to calculate REE and respiratory quotient (RQ=VCO2/VO2). The RQ can be used to assess changes in carbohydrate and fat oxidation rates. REE and substrate oxidation rates were calculated according to the equations proposed by Ferrannini [16]. Total Energy Intake and Expenditure For four consecutive days (two work and weekend days, respectively), participants recorded their dietary intake and wore a SenseWear Armband (SWA; BodyMedia Inc, Pittsburgh, PA, USA). The 4-day food records were analyzed for macro- and micronutrient content using Optidiet (V5.0.2.010, GOE, Linden, Germany), a professional analysis software that is based on nutritional content of food as provided by the German Nutrient Database [17]. The SWA worn on the upper arm (triceps, mid-humerus point) measured two-axis accelerometry, heat flux, skin temperature, near body temperature, and galvanic skin response from which proprietary algorithms estimated subject’s energy expenditure using sex, age, height, and weight as variables [18]. From this, total energy expenditure (TEE), metabolic equivalent of task (MET), step count, and sleep duration were given by the manufacture’s software. MET is a widely used physiological concept considered to be a simple procedure for expressing energy cost of physical activities as a multiple of REE [19]. Data Analysis Statistical analyses and graphics were performed with GraphPad Prism (version 5.01). Group differences (SCA1 vs. controls) were compared by non-parametric MannWhitney U tests. Association between variables was assessed by using non-parametric Spearman’s rank correlation coefficients (rs). Percent variability of one variable accounted for by the other was determined by squaring rs and multiplying by 100. A P value

Increased catabolic state in spinocerebellar ataxia type 1 patients.

Autosomal dominant spinocerebellar ataxia type 1 (SCA1) is a genetic movement disorder with neuronal loss in the cerebellum, brainstem, and other cere...
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