March 14, 2024 | Scientists from a trio of countries are calling for a new, more comprehensive way of classifying Parkinson’s disease for diagnostic research purposes that considers an individual’s biology. The disorder might thereby be detected before patients have any symptoms, as is now the case for cancer and diabetes, according to Ron Postuma, M.D., a clinician-scientist at The Neuro (Montreal Neurological Institute-Hospital) of McGill University.
The biological classification, called SynNeurGe, is a three-component system that looks at the presence or absence of pathological alpha-synuclein (a-synuclein) in tissues or cerebrospinal fluid (CSF), evidence of neurodegeneration in the brain, and documentation of genetic mutations that cause or strongly predispose one to Parkinson's disease. Details about the biological classification criteria are available in a recently published article in The Lancet Neurology (DOI: 10.1016/S1474-4422(23)00404-0).
“Traditionally people come to us with a tremor or slowness of movement and stiffness, and we’d do a diagnostic evaluation and then say they had Parkinson’s,” Postuma says. But major changes in the field of Parkinson’s research over the past 20 years have triggered new ways of thinking about the complex progressive neurodegenerative disease.
For starters, Parkinson’s is “almost always” associated with abnormal deposits of a-synuclein in the brain that are present for a long time prior to diagnosis and the buildup appears to start in areas outside the motor and dopamine systems that have always been used to classify the disease, he says. On a practical level, new diagnostic techniques have been developed to pick up the synucleinopathy in CSF and tissue biopsies.
This is, so far, a conceptual shift for research purposes, he stresses. A similar process has already happened with Alzheimer’s disease where researchers look for changes in the brain rather than the clinical symptoms that inevitably follow.
“I see Parkinson’s patients four times a week, and I don’t diagnose the disease any differently yet,” says Postuma. “But there is a change coming in the way we think about neurological diseases; these are not just clinical syndromes anymore.”
It is widely believed that a-synuclein plays at least a partial causative role in Parkinson’s disease—not the synuclein itself but probably aggregates of it, Postuma says. “For example, if you are born with a large excess of normal a-synuclein, you are guaranteed to get Parkinson’s disease.”
Neural damage, or at least dysfunction, also occurs across multiple areas of the brain. “This may be, but not necessarily, caused by abnormal aggregation or buildup of the protein,” he says. “However, the definition does not make any assumptions in this regard.”
The neurodegeneration of Parkinson’s most commonly starts in the olfactory areas, with patients experiencing a loss of smell an average of 20 years before they get the disease, Postuma adds. The bladder and especially the bowel are often also affected. Constipation is a frequent early symptom. And then there are the sleep disruptions. Strikingly, almost everyone who gets REM sleep behavior disorder ends up with Parkinson’s or related conditions 15 years later, he reports.
Parkinson’s-associated cognitive changes, if dominant, can result in dementia with Lewy bodies that is somewhat like having Parkinson’s and Alzheimer’s disease at the same time, says Postuma. Anxiety, depression, and changes in motivation are likewise commonly seen symptoms and often happen before the dopamine system is even touched. Dysfunction of the dopamine system is how Parkinson’s disease is currently diagnosed, which may be relatively late in the disease.
The number of genetic mutations associated with Parkinson’s disease changes every year. Two, namely glucocerebrosidase (GBA) and leucine rich repeat kinase 2 (LRRK2), are the commonest, he says. Dozens of others have been tied to increased risk thanks to genome-wide association studies. Additionally, a series of less-common genes are rare causes of a Parkinson’s-like disease. The a-synuclein (SNCA) gene is the most common normal variant gene, says Postuma. Inflammatory genes and lysosomal genes are another common group of important genes. SynNeurGe lists 10 or 11 genes that are either fully penetrant, guaranteeing disease development, or serve as a moderate or strong risk factor, he adds.
The proposed new model for classifying Parkinson’s is an initiative of two researchers, Günter U. Höglinger, M.D. (Germany), and Anthony E. Lang, M.D., (Canada), says Postuma, who was involved in initial efforts by the global Movement Disorders Society to define the disorder. A decade ago, he helped write the diagnostic criteria for early phases of the disease called prodromal Parkinson’s.
The Michael J. Fox Foundation has also created a system which incorporates biology into the classification of Parkinson’s, Postuma points out. Both groups coincidentally started working on this at around the same time. An article from the foundation appeared in the same publication and issue as the one penned by Postuma and his colleagues and offers a more restrictive definition, which uses a single pathway to diagnose disease.
Neither view comes from an official body, meaning a group like the International Parkinson’s and Movement Disorders Society, European Academy of Neurology, or American Academy of Neurology will need to be leading the charge on adoption of the most appropriate model with a unifying consensus statement.
The end game here is to change scientific thought on Parkinson’s, so treatments can be delivered before the disease is advanced, and hopefully on a personalized individual basis rather than lumping everyone together just because they have common signs of the clinical syndrome, Postuma says. He is confident that this is the way to move the needle on therapeutics for the neurodegenerative disorder, which is how historic progress has been made over the last few years with Alzheimer’s disease.