Rather than beginning in the substantia nigra and moving into the cerebellar regions, nerve damage may begin in the dorsal motor nucleus of the vagal nerve and progress upward into the midbrain, killing neurons all along its path. Constipation, cardiac denervation, and rapid eye movement sleep disorder are some of the conditions that may appear as the march of cell death continues, Dr. Yoshikuni Mizuno said at the conference
“Parkinson's probably starts in the peripheral portions of the vagal nerve,” said Dr. Mizuno, director of the Research Institute for Diseases of Old Age at Juntendo University, Tokyo. “When the neurons die, their content is expelled into the extraneural space in the medulla oblongata.” Other nerve terminals pick up this intracellular debris and die as well, expelling their own contents as damage progresses. “Eventually, this reaches the substantia nigra and the higher cerebellar neurons. This, I believe, is the model for the spread of Parkinson's.”
Constipation can be one of the first symptoms, occurring when Lewy body lesions first appear on the vagal nerve's dorsal motor nucleus. This is generally 15-20 years before the onset of motor symptoms, Dr. Mizuno said.
The Honolulu Heart Program study clearly showed the association between Parkinson's disease and constipation. The study followed almost 7,000 men. Over an average of 12 years, 96 developed Parkinson's disease. In a multivariate analysis, men who had fewer than one bowel movement per day were four times more likely to develop the disease than were men with two or more bowel movements per day (Neurology 2001;57:456-62).
“I think most of these patients already had Parkinson's before the onset of motor symptoms,” he said.
As cell death proceeds along the nerve, it can affect cardiac innervation. Cardiac scintigraphy with the imaging agent iodine-123 metaiodobenzylguanidine (MIBG) highlights norepinephrine transport cells in the normal heart. “In patients with Parkinson's and dementia with Lewy bodies, you don't see this, because of the loss of postganglionic parasympathetic nerve fibers,” Dr. Mizuno said. “In Alzheimer's, as well as in progressive supranuclear palsy and multisystem atrophy, you do have nice visualization of these fibers, and this is a very useful test for differentiating Lewy body disorders from these other diseases.”
His own studies suggest that MIBG cardiac uptake may parallel the progression of Parkinson's disease. About half of patients with stage 1 disease show reduced uptake, but “there is much more markedly diminished cardiac MIBG uptake in those with stage 2 disease or higher,” Dr. Mizuno said.
Disordered sleep can occur when cell damage advances to the pons – about 10 years before motor symptoms are apparent. “Half of the patients with idiopathic REM sleep disorder will go on to develop Parkinson's disease,” he said.
As nerve damage progresses further, the olfactory bulb may be affected. Hyposmia affects most (80%) Parkinson's patients, but about 40% report a decline in olfactory function before the onset of motor symptoms. “The interval between hyposmia and motor symptom onset is about 5 years,” Dr. Mizuno said.
The characteristic motor symptoms appear only when most of the dopaminergic neurons in the substantia nigra have died. If the damage progresses further, the cortex may be affected, leading to dementia.
“If you compare clinical and lab findings in Parkinson's disease dementia and dementia with Lewy bodies, you will notice a lot of similarities: constipation, loss of smell, executive dysfunction, fluctuating cognition, and visuospatial dysfunction,” Dr. Mizuno said. “The only difference between the two is the presentation of initial symptoms. If motor symptoms appear first, we call it Parkinson's disease, while if dementia is the initial symptom, we call it dementia with Lewy bodies.”