Basal ganglia disorders are a heterogeneous group of clinical syndromes with a common anatomic locus within the basal ganglia. To account for the variety of clinical manifestations associated with insults to various parts of the basal ganglia we propose a model in which specific types of basal ganglia disorders are associated with changes in the function of subpopulations of striatal projection neurons. This model is based on a synthesis of experimental animal and post-mortem human anatomic and neurochemical data. Hyperkinetic disorders, which are characterized by an excess of abnormal movements, are postulated to result from the selective impairment of striatal neurons projecting to the lateral globus pallidus. Hypokinetic disorders, such as Parkinson's disease, are hypothesized to result from a complex series of changes in the activity of striatal projection neuron subpopulations resulting in an increase in basal ganglia output. This model suggests that the activity of subpopulations of striatal projection neurons is differentially regulated by striatal afferents and that different striatal projection neuron subpopulations may mediate different aspects of motor control.

Huntington disease (HD) is characterized by the loss of striatal projection neurons, which constitute the vast majority of striatal neurons. To determine whether there is differential loss among different populations of striatal projection neurons, the integrity of the axon terminal plexuses arising from the different populations of substance P-containing and enkephalin-containing striatal projection neurons was studied in striatal target areas by immunohistochemistry. Analysis of 17 HD specimens indicated that in early and middle stages of HD, enkephalin-containing neurons projecting to the external segment of the globus pallidus were much more affected than substance P-containing neurons projecting to the internal pallidal segment. Furthermore, substance P-containing neurons projecting to the substantia nigra pars reticulata were more affected than those projecting to the substantia nigra pars compacta. At the most advanced stages of the disease, projections to all striatal target areas were depleted, with the exception of some apparent sparing of the striatal projection to the substantia nigra pars compacta. These findings may explain some of the clinical manifestations and pharmacology of HD. They also may aid in identifying the neural defect underlying HD and provide additional data with which to evaluate current models of HD pathogenesis.Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by choreiform movements, cognitive decline, and personality disturbance (1). The underlying genetic defect in HD is unknown, but the gene has been localized to the short arm of chromosome 4 (2). The histopathology of HD reveals cell loss and astrogliosis in several brain areas, with the most prominent alterations occurring in the striatum (3-5). Although the pathogenetic mechanism of this process is unknown, endogenous "excitotoxins" have been proposed as the mechanism of cell death (6-8). Recent findings indicate that striatal neurons are not uniformly affected in HD and that somatostatin-neuropeptide Y-containing interneurons and cholinergic interneurons are relatively spared (8, 9). Striatal interneurons, however, constitute only a small fraction of the total number of striatal neurons, and it has not been possible to correlate the preservation of interneuron populations with the clinical features of HD.The great majority of striatal neurons are projection neurons, which are heterogeneous in terms of their projection targets and in terms of the neuropeptides they contain (10, 11). These neurons show the earliest evidence of abnormality and are progressively depleted in HD (4, 12). Previous studies, however, have not resolved whether all populations of striatal projection neurons are equally affected in HD. The identification ofthe putative populations of striatal projection neurons that are earliest and most severely affected in HD, however, could provide valuable clues regarding the basis of striatal cell death in HD. To determine whether some populations of striatal proje...

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The Unified Huntington's Disease Rating Scale (UHDRS) was developed as a clinical rating scale to assess four domains of clinical performance and capacity in HD: motor function, cognitive function, behavioral abnormalities, and functional capacity. We assessed the internal consistency and the intercorrelations for the four domains and examined changes in ratings over time. We also performed an interrater reliability study of the motor assessment. We found there was a high degree of internal consistency within each of the domains of the UHDRS and that there were significant intercorrelations between the domains of the UHDRS, with the exception of the total behavioral score. There was an excellent degree of interrater reliability for the motor scores. Our limited longitudinal database indicates that the UHDRS may be useful for tracking changes in the clinical features of HD over time. The UHDRS assesses relevant clinical features of HD and appears to be appropriate for repeated administration during clinical studies.

We compared the number of CAG repeats, the age at death, and the severity of neuropathology in 89 Huntington's disease brains. We found a linear correlation between the CAG repeat number and the quotient of the degree of atrophy in the striatum (the brain region most severely affected in Huntington's disease) divided by age at death, with an intercept at 35.5 repeats. The largest CAG repeat length, therefore, at which no pathology is expected to develop is 35.5. These results imply that striatal damage in Huntington's disease is almost entirely a linear function of the length of the polyglutamine stretch beyond 35.5 glutamines multiplied by the age of the patient. Thus, it is predicted that the pathological process develops linearly from birth. Analysis of other measures of striatal function could test this hypothesis and might determine when treatment for CAG repeat diseases should start.

Loss of neurotransmitter receptors, especially glutamate and dopamine receptors, is one of the pathologic hallmarks of brains of patients with Huntington disease (HD). Transgenic mice that express exon 1 of an abnormal human HD gene (line R6͞2) develop neurologic symptoms at 9-11 weeks of age through an unknown mechanism. Analysis of glutamate receptors (GluRs) in symptomatic 12-week-old R6͞2 mice revealed decreases compared with age-matched littermate controls in the type 1 metabotropic GluR (mGluR1), mGluR2, mGluR3, but not the mGluR5 subtype of G protein-linked mGluR, as determined by

The anatomical distributions and affinity states of dopamine D1 and D2 receptors were compared in the rat central nervous system using quantitative autoradiography. [3H]SCH23390 and [3H]spiperone (in the presence of 100 nM mianserin) were used to label the D1 and D2 receptors, respectively. The densities of D1 and D2 receptors displayed a positive correlation among 21 brain regions (Pearson correlation coefficient, r = 0.80, P less than 0.001). The affinity states for the D1 and D2 receptors were found to be quite different from each other, and different from the results obtained by others using homogenate preparations. Both the D1 and D2 receptors were best modeled using a two-state model. In the absence of exogenous guanine nucleotides and using the nonselective agonist dopamine as the competitor, the D1 receptor was primarily in a low affinity agonist state (RH = 21 +/- 6%), whereas the D2 receptor was primarily in the high affinity agonist state (RH = 77 +/- 3%). In the presence of 10 microM guanylyl-imidodiphosphate or guanosine-5'-O-(2-thiophosphate) both the D1 and the D2 receptor were completely in a low affinity agonist state (RL = 100%). These affinity states were found both in the nucleus accumbens and olfactory tubercle using dopamine as the competitor and in the striatum using selective D1 or D2 agonists as competitors. Receptor occupancy of the D2 receptor with either an agonist or antagonist did not alter the affinity states of the D1 receptor, and conversely, receptor occupancy of the D1 receptor did not alter the affinity states of the D2 receptor. The correlation between densities of D1 and D2 receptors provides an anatomical framework for evaluating behavioral and electrophysiological evidence of an interaction between the two dopamine receptor subtypes. This interaction does not appear to be due to a sharing or coupling of G-proteins in such a way that binding to one dopamine receptor subtype alters the affinity state of the other receptor subtype. The differences between dopamine receptor distributions described by labeled agonists and antagonists may be due in part to differences in their affinity states. The low proportion of high affinity state D1 receptors may explain some of the difficulties in assigning specific behavioral roles to the D1 receptor.

Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15-20 years and, at present, there is no effective treatment. The mutation in patients with Huntington's disease is an expanded CAG/polyglutamine repeat in huntingtin, a protein of unknown function with a relative molecular mass of 350,000 (M(r) 350K). The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset. The molecular pathways mediating the neuropathology of Huntington's disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine repeat develop a progressive syndrome with many of the characteristics of human Huntington's disease. Here we demonstrate evidence of caspase-1 activation in the brains of mice and humans with the disease. In this transgenic mouse model of Huntington's disease, expression of a dominant-negative caspase-1 mutant extends survival and delays the appearance of neuronal inclusions, neurotransmitter receptor alterations and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of the disease. In addition, we demonstrate that intracerebroventricular administration of a caspase inhibitor delays disease progression and mortality in the mouse model of Huntington's disease.