ScienceWeek

MEDICAL BIOLOGY: ON PARKINSON DISEASE

The following points are made by A.H Schapira and W. Olanow (J. Am. Med. Assoc. 2004 291:358):

1) Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease, having an incidence of approximately 1 in 200 and a lifetime risk of 1 in 45. Approximately 1 million people have PD in the US, and the prevalence is predicted to increase dramatically in the coming decades due to the aging of the population.(1) Parkinson disease is responsible for significant morbidity and increased mortality among those with the disease and causes substantial social and economic hardship for patients, caregivers, and society.

2) The cardinal clinical features of PD are resting tremor, rigidity, and bradykinesia (i.e., motor slowing). Pathologically, the disease is characterized by a specific loss of dopamine neurons in the substantia nigra pars compacta (SNc), with intracellular proteinaceous inclusions or Lewy bodies, and a reduction in striatal dopamine. In the early stages of the disease, symptoms are relatively well controlled with levodopa and other dopaminergic agents. However, over time the majority of patients experience levodopa-related motor complications and the disease relentlessly progresses with the development of features such as freezing, falling, autonomic dysfunction, and dementia that do not adequately respond to dopamine replacement therapies.(1) Thus, despite advances in modern therapy, patients with PD continue to experience unacceptable disability. The main challenge facing those involved in the management of patients with PD is the development of a neuroprotective therapy that can be administered early in the course of the disease and slow, stop, or reverse disease progression.

3) Recent studies have drawn attention to the potential for certain drugs to provide neuroprotective benefits in PD. These results have attracted considerable attention and debate. At the heart of this controversy is the issue of determining whether the clinical and imaging end points that have been used in these trials do in fact measure disease progression.

4) In summary: Parkinson disease is an age-related neurodegenerative disease that affects approximately 1 million persons in the US. Current therapies provide effective control of symptoms, particularly in the early stages of the disease, but most patients develop motor complications with long-term treatment, and the disease is characterized by development of symptoms such as postural instability, falling, and dementia that are not adequately controlled with existing medications. Accordingly, neuroprotective therapy that might slow, stop, or reverse disease progression is urgently needed. While many agents appear to be promising based on laboratory studies, selecting clinical end points for clinical trials that are not confounded by symptomatic effects of the study intervention has been difficult. More recently, neuroimaging end points have been used as biomarkers of disease progression, but again there are concerns that they may be influenced by regulatory effects of the drugs used.(2-5)

References (abridged):

1. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology. 2001;56(suppl 5):S1-S88

2. Goetz C, Koller WC, Poewe O, et al. Management of Parkinson's disease: an evidence-based review. Mov Disord. 2002;17(suppl 4):S1-S166

3. Warner TT, Schapira AH. Genetic and environmental factors in the cause of Parkinson's disease. Ann Neurol. 2003;53(suppl 3):S16-S25

4. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: an etiologic study. JAMA. 1999;281:341-346

5. Olanow CW, ed, Schapira AH, ed, Agid Y, ed. Neuroprotection for Parkinson's disease: prospects and promises. Ann Neurol. 2003;53(suppl 3):S1-S2

J. Am. Med. Assoc. http://www.jama.com

--------------------------------

Notes:

Parkinson's disease (also called Parkinson disease) is a slowly progressive degenerative central nervous system disorder characterized by decreased movement, muscular rigidity, resting tremor, and postural instability. The disease was first described by James Parkinson in 1817 and is now known to be associated with degeneration of one or more specific regions of the brain (dopaminergic neuron groups) and resultant loss of neural connections (projections) from these groups to several important brain centers. Dopaminergic neurons are nerve cells that use *dopamine as a *neurotransmitter substance. Dopamine is found in several major areas of the brain, and it is the degeneration of so-called dopamine neurons that is apparently involved in Parkinson's disease.

One must distinguish "parkinsonism" from Parkinson's disease. Parkinsonism is a syndrome (a complex of symptoms; in this context, a complex of various movement symptoms) that may be caused by Parkinson's disease, but which may also be caused by infectious, vascular, pharmacological, toxic, metabolic, structural, and various degenerative disorders. In other words, not every individual with parkinsonism has Parkinson's disease. The major differentiating characteristic is the response to the drug "*levodopa", which is converted by the body into dopamine. Individuals with parkinsonism who respond to levodopa treatment receive a diagnosis of Parkinson's disease. At the present time, Parkinson's disease is the 4th most common neurodegenerative disease of the elderly. It affects approximately 1 percent of people older than 65 years, and 0.4 percent of people between 40 and 65 years.

The disease has an early-onset form (age =< 50 years), and a childhood form (juvenile Parkinson's disease), but most cases are adult onset, with incidence increasing markedly past age 50 years.

The causes of Parkinson's disease are largely unknown, but there is evidence that the disease has a genetic component. In a few large families with early onset Parkinson's disease or juvenile Parkinson's disease, the disease is transmitted as an autosomal dominant or recessive trait resulting from mutations in the genes encoding the proteins alpha-synuclein and parkin, respectively. However, in the majority of families affected by Parkinson's disease, the disease appears to skip generations, irrespective of the age of onset. Therefore, this disease is considered a complex, multifactorial disease resulting from interaction between one or more genes and the environment.

Terms:

dopamine: Dopamine is an important neurotransmitter in the human brain, and it has been implicated in several serious behavioral pathologies. There is a dopamine hypothesis of depression, a dopamine hypothesis of schizophrenia, and dopamine has also been implicated in the reinforcing effects of psychostimulant drugs of abuse such as cocaine and amphetamine.

neurotransmitter substance: Neurotransmitters are chemical substances released at the terminals of nerve axons in response to the propagation of an impulse to the end of that axon. The neurotransmitter substance diffuses into the synapse, the junction between the presynaptic nerve ending and the postsynaptic neuron, and at the membrane of the postsynaptic neuron the transmitter substance interacts with a receptor. Depending on the type of receptor, the result may be an excitatory or an inhibitory effect on the postsynaptic nerve cell.

levodopa: (L-dopa) The biologically active form of "dopa", which is converted into dopamine. Dopamine = 3,4-dihydroxyphenylethylamine. Dopa = 3,4-dihydroxypheynylalanine.

ScienceWeek http://scienceweek.com