Huntington's Disease

Pathophysiology

HD is associated with progressive degeneration of neurons in certain regions of the brain and the presence of astrocytes that accumulate due to destruction of nearby neurons (gliosis). These neurodegenerative changes primarily occur within the caudate nuclei and the putamen, substructures of the basal ganglia that are collectively known as the striatum. (The basal ganglia consist of specialized nerve cell clusters deep within the brain that organize motor behavior. Major substructures of the basal ganglia include the caudate nuclei, the putamen, and the globus pallidus as well as other cell groups.) HD is also characterized by associated neuronal degeneration within the temporal and frontal lobes of the cerebral cortex. This part of the brain is responsible for integrating higher mental functioning, movements, and sensations.

The degenerative changes in HD primarily affect certain nerve cells of the striatum known as medium-sized "spiny" neurons, which are named for their size and appearance and project into the globus pallidus and substantia nigra. These highly specialized "spiny" neurons secrete gamma-aminobutyric acid (GABA), a neurotransmitter that inhibits the release of neurotransmitters from other nerve cells. One theory suggests that selective loss of these specialized cells results in decreased inhibition (i.e., increased activity) of the thalamus. Therefore the thalamus increases its output to certain regions of the brain's cerebral cortex. This may lead to the disorganized, excessive (hyperkinetic) movement patterns of chorea.

• Some studies demonstrate reduced uptake of the neurotransmitter dopamine within the striatum, potentially playing a role in causing the choreic movements associated with HD.
• Several investigations indicate that impaired energy metabolism (mitochondrial dysfunction) may result in excessive or prolonged activation (excitotoxicity) by neurotransmitters, such as glutamate or N-methyl-D-aspartate (NMDA). This may cause damage to and loss of nerve cells (apoptosis). (For more on apoptosis, see "Mutant huntingtin protein and intracellular abnormalities.")
• Evidence suggests that the formation of toxic compounds known as oxygen-free radicals may contribute to striatal cell injury. An imbalance between free radical production and elimination results in an increasing accumulation of these toxins in certain tissues. Eventually, this causes damage and impaired functioning of affected cells. Many researchers theorize that free radicals may play some role in the loss of neurons associated with many neurodegenerative diseases.

In patients with HD, positron emission tomography (PET) scanning has shown decreased glucose and oxygen metabolism within the caudate nuclei early in the course of the disease. These findings occur in patients with other neurodegenerative diseases associated with chorea. This lends support to the theory that disturbances in the metabolism of certain neurotransmitters and heightened sensitivity of particular neuroreceptors may contribute to the symptoms associated with HD.