Subtyping Parkinson’s disease at diagnosis may predict disease course and survival, providing both doctors and patients with a more accurate prognosis, a study suggests.
The study, “Prognosis and Neuropathologic Correlation of Clinical Subtypes of Parkinson Disease,” was published in JAMA Neurology.
Parkinson’s disease is characterized by clinical diversity, and many attempts have been made to identify distinct clinical syndromic patterns. The presence of not only motor but also non-motor symptoms is increasingly being used to categorize the disease into different clinical subtypes.
However, “classification of patients with [Parkinson’s disease] is purely based on data association and may not reflect underlying [physiological processes associated with disease] driving clinical heterogeneity,” the researchers wrote.
Although very little is known about the correlation between brain tissue molecular/cellular changes and Parkinson’s subtypes, some studies suggest that motor severity, cognitive impairment, autonomic dysfunction — when the nerves of the system that controls basic bodily functions are damaged — and rapid eye movement (REM) sleep behavior disorder need to be taken into consideration during clinical subtyping. (REM is a sleep stage in which the eyes move rapidly in various directions.)
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Moreover, the predictive value of Parkinson’s-related subtype classification remains to be confirmed.
For this purpose, investigators from the University College London Queen Square Institute of Neurology gathered life-course clinical and brain tissue analysis data and correlated it with Parkinson’s disease subtypes.
They analyzed the clinical records of 111 Parkinson’s patients, 60.4% of whom were men, who were regularly assessed throughout their disease and had their diagnosis confirmed by autopsy.
According to the severity of their motor symptoms, REM sleep behavior disorder, cognitive performance, and autonomic function at diagnosis, the patients were classified into three subtypes: mild-motor predominant (meaning they had mild motor and non-motor symptoms), diffuse malignant (severe symptoms), or intermediate (where they did not meet the criteria for the other two subtypes).
Researchers calculated the time it took patients to achieve specific disease milestones (recurrent falls, wheelchair dependence, dementia, and care home placement) and compared them between subtypes. They also assessed time from diagnosis to death.
In addition, post-mortem analysis of brain tissue was performed to assess the severity and distribution patterns of Lewy bodies — abnormal deposits of alpha-synuclein protein — and Alzheimer’s disease-related tissue changes.
Of the 111 participants, 54 were classified as mild-motor predominant, 39 as intermediate, and 18 as diffuse malignant.
Patients with the mild-motor predominant subtype were significantly younger at diagnosis, had a better response to levodopa, and received a higher levodopa equivalent dose. In contrast, those with the diffuse malignant subtype were older, had a poorer response to levodopa, and were more frequently misdiagnosed as having an atypical parkinsonian syndrome during their lifetime.
Age at diagnosis was significantly different across Parkinson’s subtypes: mild-motor predominant — 58.2 years, intermediate — 65 years, and diffuse malignant — 70.3 years.
Patients’ ages at diagnosis were also associated with faster disease progression and reduced survival: The later they were diagnosed, the faster the disease progressed.
All Parkinson’s subtypes showed different rates of deterioration, “with the diffuse malignant subtype reaching all prognostic milestones earlier in the disease course and having the shortest survival,” according to the researchers.
Additionally, all subtypes “reached advanced stages, with 105 of 111 patients (94.6%) reaching at least one disease milestone,” they said.
Brain tissue analysis revealed distinct progression rates of Lewy body and Alzheimer’s disease-related pathologies, which were found to be associated with age at death. However, there were no significant differences across subtypes regarding severity of Lewy pathology.
“Clinical subtyping of [Parkinson’s disease] … is feasible in clinical practice and provides accurate long-term estimation of disease progression and survival. Different pathologies with differing rates of progression are important determinants of clinical subtypes, and age at diagnosis should be included in future subtype classification systems,” the researchers concluded.