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By John Brokars

June 12, 2002 | Neurodegenerative and psychiatric disorders account for more hospitalizations and long-term care than nearly all other disorders combined. Age is a risk factor, and that means the problem will only grow worse, as the number of people over the age of 65 is expected to double by 2025. The most prominent CNS disorders are Alzheimer's, Parkinson's, and Huntington's diseases.

Alzheimer's disease — the most common form of dementia — presently affects about 4 million Americans, and that number is expected to reach 14 million by 2025. The disease is typically fatal, with patients living about eight to 10 years after its onset. In Alzheimer's, there is a marked loss of cells that produce the neuroactive chemical acetylcholine (Ach) for higher brain function. Deposits of a protein called beta amyloid collect on the outside of neurons that once produced Ach. The dementia that gradually follows generally includes progressive memory loss, personality change, and a marked decline in thinking and reasoning. Psychiatric features such as paranoia, delusions, depression, and agitation may also occur.

Companies such as EnVivo are focusing research on genes that produce the beta amyloid plaques on Ach-producing neurons. Presently, there are three drugs on the market that help relieve Ach-related Alzheimer's symptoms: First Horizon's Cognex, Pfizer's Aricept, and Novartis' Exelon. Common side effects include nausea and vomiting, and improvement of function is minimal.

Huntington's and Parkinson's diseases, meanwhile, are generally understood as disorders of either extreme excess or lack of the neurotransmitter dopamine. At the central part of the brain, groups of cells called the basal nuclei control the body's movement. Dopamine is a key signal in the pathway of these interdependent groups of brain cells. The excess (Huntington's) or deficit (Parkinson's) of dopamine in the basal nuclei causes downstream movement disorders — either too much or too little brain excitation.

Genetic factors are a key element in the onset of these diseases and the focus of much drug research. In Parkinson's, there is a consistent accumulation of alpha synuclein plaques on a specific subset of the basal nuclei called the substantia nigra. Hereditary mutations in the alpha synuclein gene itself have been documented in families on rare occasion.

Unlike Alzheimer's and Parkinson's, all cases of Huntington's disease are hereditary. The disease is known for the increasingly wild and violent involuntary movements it produces, with the typical age of onset between 35 and 50. The disease affects 30,000 people in the United States; another 150,000 are at risk. An estimated half-million people suffer from this disease worldwide.

Parkinson's disease affects about 1.5 million people in the United States and 12 million worldwide. There are drugs available to treat its symptoms, such as leva-dopa, a synthetic precursor to dopamine. Leva-dopa has dramatically improved the outcome for patients, but because its effects diminish over time, it is not a long-term solution. The newest class of drugs help perpetuate the persistence of dopamine in the brain. Examples include catechol-o-methyl-transferase (COMT) inhibitors, which prevent degradation of leva-dopa (Tasmar, for example), and dopamine agonist (such as Mirapex).

Lewis Sudarsky, a neurologist at Brigham and Women's Hospital, points to a "paradigm shift in thinking" during the past two years by treating Parkinson's with drugs that not only relieve disease symptoms, but also protect the brain cells of the basal nuclei vulnerable to the alpha synuclein plaques. Surgical techniques are available, but most are still experimental. Deep brain implants similar to pacemakers in the heart are also a promising treatment for the future.

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