Other neurodegenerative diseases

Last updated on Friday, April 17 2009 by gliageek

Huntington Disease (HD) is inherited as an autosomal dominant disease with full penetrance. It occurs worldwide with an overall prevalence of 10 per 100,000 population (similar to the prevalence of ALS), although high regional concentrations are found due to large individual kindreds. Clinically, HD is characterized by cognitive and affective abnormalities with a choreoathetoid movement disorder. Defining the precise onset of illness often is difficult, and age at diagnosis can range from infancy to beyond the eighth decade. Nevertheless, estimates of age of onset generally show a normal distribution with a mean value of about 39 years. Estimates of survival range from 10 to 25 years, but there is considerable variability. The HD gene has been shown to be an unstable trinucleotide repeat (CAG) sequence on the short arm of chromosome 4. Normal individuals have 6 to 34 repeats, while HD patients have 40 or more repeats. Juvenile onset HD generally demonstrates the greatest number of repeats, while late-onset HD shows the fewest. In addition, longer trinucleotide repeat length is associated with a faster rate of deterioration and greater pathologic severity.

In established HD, neuroimaging shows bilateral atrophy of the corpus striatum with ventricular enlargement, especially anteriorly. In late cases, neocortical atrophy may also be appreciated. In the early stages of the disease, neuroirnaging studies can appear normal.

The characteristic histopathologic changes in the corpus striatum involve loss of the medium spiny (by Golgi impregnation) neurons containing GABA/substance P and GABA/enkephalin, projecting to the globus pallidus and pars reticulata of the substantia nigra. Ubiquitin immunostaining reveals nuclear aggregates of ubiquinated huntintin in the nuclei of striatal and neocortical neurons, but not in other regions of the brain.

In the early stages of HD, when chorea is most prominent, there is selective loss of inhibitory, enkephalin-containing striatal neurons projecting to the lateral globus pallidus (LGP). Increased LGP activity leads to loss of subthalamic nucleus derived excitatory drive to the medial globus pallidus and pars reticulata of the substantia nigra with consequent disinhibition of thalamocortical projections. This disinhibited thalamocortical pathway is felt to be responsible for the choreoathetosis of Huntington's disease. The degree of neuronal loss from the corpus stratum (as reflected in the profile of the caudate nucleus relative to the lateral ventricle) parallels the degree of neurologic dysfunction, as follows:

Pathologic Grade    Caudate Profile Neurologic Disability
1                                Normal                 Assisted ambulation
2                        Less convex             Minimal ambulation
3                                Flat                          Wheelchair-bound
4                                Concave                   Bed-ridden

Further reading:

La Spada AR. Getting a handle on Huntington's disease: silencing neurodegeneration. Nat Med. 2009 Mar;15(3):252-3.

Paulsen JS. Functional imaging in Huntington's disease. Exp Neurol. 2009 Apr;216(2):272-7.

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