The Human Globus Pallidus In Huntington’s Disease: Characterization of volumetric changes, pallidal neuron loss and cell morphology in association with pathological grade and symptom-type

Abstract

THE HUMAN GLOBUS PALLIDUS IN HUNTINGTON’S DISEASE: CHARACTERIZATION OF VOLUMETRIC CHANGES, PALLIDAL NEURON LOSS AND CELL MORPHOLOGY IN ASSOCIATION WITH PATHOLOGICAL GRADE AND SYMPTOM-TYPE Malvindar Singh-Bains, Virginia Hogg, Beth Synek, Lynette Tippett, Henry Waldvogel, Richard Faull Abstract. Introduction: In Huntington’s disease (HD) numerous studies have documented the patterns of cell loss in the striatum. However, there are no studies using design-based stereology to assess the impact of HD on a principle target of striatal outfl ow, the globus pallidus (GP). Objectives: To characterize regional volume, pallidal neuron loss and morphological changes in both segments of the HD human globus pallidus using design-based stereology; and explore the relationships between these data and HD striatal neuropathological grade, and clinical symptomatology. Methods: In the present double-blind study, 8 HD and 8 normal cases were analysed using the optical fractionator to measure the volume of the globus pallidus, and quantify pallidal neurons. Pallidal neurons were identifi ed on Nisslstained sections, with external (GPe) and internal (GPi) boundaries delineated with enkephalin and substance-P immunoreactivity. The cross sectional areas of parvalbuminpositive pallidal neurons were measured using the isotropic nucleator. Pathology and symptomatology data of HD cases were collected, with reference to the Quantitative Neurological Exam (QNE) and Unifi ed Huntington’s Disease Rating Scale (UHDRS). Results: Stereological analysis reveals the HD GPe reduces to more than half the normal volume, with quantifi cation showing >60% pallidal neuron loss. The HD GPi volume is also reduced, to a smaller degree compared to the GPe, with minor cell loss (20%). Morphometric analysis show that HD GPe pallidal neurons were 35% smaller compared to normal, with no changes in the GPi. Changes in regional volume and cell loss were shown to relate to striatal pathology grades, with greater volume reduction and cell loss corresponding with increased grades. Preliminary analysis shows that there is a strong correlation between HD GPe volumes and both QNE/UHDRS motor impairment score severity, but not with chorea. Conclusion: This study highlights that the GPe is more vulnerable to HD than the GPi, consistent with neurochemical studies showing that enkephalinergic striatal-GPe fi bres degenerate in advance of substance-P striatal-GPi fi bres. In particular, our studies show that GPe atrophy is related to HD clinical symptom-type, with regional atrophy showing a strong correlation with the severity of motor impairment, but not with chorea. Support: Health Research Council of New Zealand; Neurological Foundation of New Zealand; The University of Auckland.