A pair of clinical researchers from the Department of Clinical Neurosciences and Mental Health, Faculty of Medicine at the University of Porto, in Porto, Portugal have written a scholarly article that refines and defines how the varying symptoms presented by people with PARKINSON’S DISEASE can be assessed and understood.  They make a convincing argument that a “leap in concepts and a shift in research” is needed to enable therapeutic advances toward early treatment with specific neuroprotective agents for each unique presentation of symptoms.

In the past, PARKINSON’S DISEASE was thought to be caused by a loss of dopaminergic neurons in the substantia nigra.  Positive diagnosis was delayed until motor symptoms were obvious and depended on the patient’s response to the ‘gold standard’, that is if the patient’s symptoms responded to levodopa.  Positive response meant a diagnosis of PARKINSON’S, no response meant PARKINSONISM.  Although patients had positive motor improvement responses to dopamine replacement, the results were only temporarily palliative; progression of the disease and the development of non-motor symptoms could not be halted.  Many non-motor symptoms such as Rapid Eye Movement Sleep Disorder, loss of sense of smell, cognitive changes and mood problems may be present years before the motor symptoms present, and they involve neurological systems other than the dopamine system of the substantia nigra.  These non-motor symptoms may well be precursors to the disease process, and appropriate treatments for them could delay or even halt the development of the motor symptoms.

Studies of the genetics of PARKINSON’S DISEASE have found only a few examples of heritable forms of the disease.  But studies of those same genes have yielded further information of the specific roles each of those genes play in modifying or affecting various cellular processes that occur in the development of the disease.  The alpha-synuclein gene (SNCA) when mutated, causes aggregations of alpha-synuclein but also has interactions with the PARK genes, with the LRRK2 or the GBA genes. The results of those various and individual interactions contribute significant differences in their presentation in the clinical and neuropathological features of the disease.

Post mortem examinations have shown that patients whose motor symptoms presented early and who had a good response to levodopa but then had a more rapid decline, including dementias, had mutations in the SNCA genes.  Patients who had a slower progression of motor symptoms but had more dystonia or tremors usually carried LRRK2 mutations. GBA mutations were found in brains of patients who had early onset with both sides of the body equally affected and also more pronounced neuropsychiatric issues, such as symptoms often being found in Alzheimer’s disease patients. Another unique mutation in the VPS35 gene causes motor complications that get a significant benefit from dopamine replacement and no diminishment of cognitive function.  PARK2 carriers had a slower progression of symptoms and responded well to dopamine replacement, but frequently were prone to develop dyskinesias. Dementia was rare in these cases and synucleinopathy was not found in post mortem examinations; however, much deterioration of the substantia nigra was seen.

The above descriptions show that many share multiple symptoms with PARKINSON’S DISEASE, but also demonstrate many differences in clinical presentation, imaging and other neuropathological features.  While they may share a common response to dopamine replacement, they may, indeed, be manifestations of other similar but different diseases.  There currently are no reliable biomarkers that can accurately predict the onset of the disease or distinguish one form from another, or even monitor its progression.  Given the differing symptom presentations, genetics and pathological findings, it is likely that PARKINSON’S DISEASE is not a single disease, but an umbrella that covers multiple, but similar diseases.

Monteiro, A., Massano, J. Parkinson’s disease cluster:  the wind of change; Open Access Publication ; 24 March 2014



Review by Marcia McCall


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