Lewy body pathology is found in the brains of 10 to 30% of older adults without any parkinsonian motor symptoms and is called incidental Lewy body disease (ILBD). Research suggests that ILBD may represent a ‘preclinical’ stage of Parkinson’s disease (PD) that occurs before symptoms develop. However, researchers have yet to establish a clear understanding of the relationship between the presence of Lewy body pathology and the dysfunction of neurons and cell loss.
Researchers theorized that if ILBD is an early stage of Parkinson’s disease, neurons in the areas of the brain affected earliest in Parkinson’s disease would display some type of dysfunction in ILBD. Comparing brain tissue of 63 autopsied individuals with PD (13), ILBD (33) and normal controls (17), researchers examined neurons in the main dopamine producing area of the brain, the substantia nigra. They looked for reduced production of an enzyme called tyrosine hydroxylas (TH), which is involved in dopamine production.
It is thought that Lewy body pathology normally progressed in a fairly typical, stepwise progression through the brain and spinal cord. The stages of progression described by Heiko Braak and colleagues are now referred to as Braak PD stages. In Parkinson’s disease, Braak PD stages 1-3 are considered preclinical and Lewy bodies are not found in the substantia nigra until stage 3. Braak PD stages 4-6 represent the phases where symptoms appear and progressively worsen in most patients. Interestingly, some people can have widespread Lewy body pathology without any symptoms. Why some people have symptoms from Lewy body pathology and others don’t is the subject of ongoing research.
In this study, the researchers hypothesized that if Lewy body pathology was the real problem in PD, then patients who died with Braak PD stage 1-2 pathology (meaning no Lewy bodies are seen in the substantia nigra), would have no evidence of neuronal dysfunction or loss in the substantia nigra. Neuron counting was done in the substantia nigra to determine the density of neurons. Lower density suggests that neurons were dying. Individuals with Parkinson’s disease had the lowest levels of neuronal density in the substantia nigra, followed by those with ILBD and normal controls had the highest levels. However, contrary to their hypotheses, density appeared to be independent of the regional distribution of Lewy body pathology in ILBD. Even in patients with Braak PD stage 1-2, there was evidence of neuronal loss in the substantia nigra.
These results provided some evidence that ILBD may be an intermediate stage between normal controls and Parkinson’s disease, but that there may be some additional factors that influence which individuals develop Parkinson’s symptoms and those who do not.
Neuron dysfunction was assessed by determining whether the neurons of the substantia nigra were producing TH. In particular, the investigators looked for neurons that were not producing TH (termed TH negative neurons), which they believed suggested that the neuron was not healthy. They found that the percentage of TH negative neurons were lowest in normal subjects, intermediate in PD cases and highest in ILBD cases. In addition, similarly to what they found regarding loss of neurons, the percentage of TH negative neurons was not associated with Lewy body burden in the substantia nigra.
Of special interest, ILBD cases with Braak PD stages 1 and 2 already demonstrated neuronal dysfunction. To the authors knowledge, this is the first time that neurodegeneration was demonstrated in this particular, vulnerable group of neurons before Lewy body pathology was formed. This raises serious questions about what was actually causing the neuronal dysfunction and death observed, and suggests that it is not due to Lewy bodies.
Compared to the PD cases, the percentage of TH negative cases was higher in ILBD. This suggests that those dysfunctional neurons may be struggling to survive in ILBD and may have died by end-stage PD. This is supported by the lower density of nigral neurons in PD compared with all Braak PD stages of ILBD. This raises the possibility that at these early stages, these vulnerable ‘sick’ neurons might be treated with therapies to reverse the neurodegenerative process and save them from dying.
In conclusion, this study suggests that the loss of dopamine-producing neurons in the substantia nigra precedes accumulation of Lewy body pathology. Further research is needed to truly understand how these neurons are dying and to develop therapies to halt the disease progression in these early ‘pre-clinical’ stages.
This study was published in Neurology in December, 2012. Senior author, John E. Duda, MD, is a member of the LBDA’s Scientific Advisory Council.