The early articles of Alzheimer and Dunlap and the more recent one of Vonsattel and DiFiglia contain the most authoritative descriptions of the microscopic changes. The latter authors have graded the disease into early, moderately advanced, and far advanced stages. In 5 early but genetically verified cases, no striatal lesion was found, which suggests that the first clinical manifestations are based on a biochemical or infrastructural change. This view is supported by the observation that Huntington patients studied with PET show a characteristic decrease in glucose metabolism in the caudate nuclei, which precedes the volumetric loss of tissue (Hayden et al). The striatal degeneration begins in the medial part of the caudate nucleus and spreads, tending to spare the nucleus accumbens. Of the 6 cell types in the striatum (a differentiation based on size, dendritic arborizations, spines, and axon trajectories), the smaller neurons are affected before the larger ones. Loss of dendrites of the small spiny neurons has been an early finding, while the large cells are relatively preserved and exhibit no special alterations.
The anterior parts of the putamen and caudate are more affected than the posterior parts. Some observers have noted changes in the globus pallidus, subthalamic nucleus, red nucleus, cerebellum, and in the pars reticulata of the substantia nigra. In the cerebral cortex, there is slight neuronal loss in layers 3, 5, and 6, with replacement gliosis. Cases are reported with typical striatal lesions but normal cortices in which only chorea had been present during late life. Several neuropathologists have observed marked cell loss and gliosis in the subthalamic nuclei in Huntington-affected children or young adults with chorea and behavior disorders. However, Hadzi and colleagues have determined that the pathologic changes in the striatum and the cortex evolve differently and have separate relationships to the CAG repeat length.
Genetics and mechanism of disease As mentioned above, there is a general relationship between the number of CAG repeats and the age of onset of symptoms. It has been found that it is the longer sequence on either of the 2 alleles that determines the age of onset, the size of the expansion of the normal allele exerting no influence (Lee et al, 2012). Earlier onset in successive generations (anticipation) is well described in the early writings on the subject and is now known to be attributable to increasing lengths of the CAG repeat sequence.
From the molecular perspective, the pathogenesis of this disease is a direct, but still poorly understood, consequence of the aforementioned expansion of the polyglutamine region of huntingtin. It has been shown that the mutant huntingtin protein aggregates in the nuclei of neurons. Moreover, the protein accumulates preferentially in cells of the striatum and parts of the cortex affected in Huntington disease. Evidence, particularly that given by Wetz (cited in the review by Bates), suggests that these aggregates may be toxic to neurons, either directly or in their protofibrillary (unaggregated) form. The situation is, however, likely to be more complex, as the bulk of huntingtin deposition is found in cortical neurons, whereas the neuronal loss is predominantly striatal. One theory supports the concept that the polyglutamine complex renders certain cell types unduly sensitive to glutamate-mediated excitotoxicity. Two mechanisms have been proposed based on an interruption of protein transcription by the binding of mutant huntingtin to transcription proteins or that mitochondrial dysfunction occurs directly or through the same transcriptional mechanism, as summarized by Greenamyre. Because polyglutamine expansions are implicated in several neurodegenerative diseases (reviewed in corresponding sections of this chapter), treatments that block their effects on cellular function may be broadly effective in several degenerative diseases.