Striking baseline difference in REM sleep behavior symptoms

Two neuroanatomically-defined biotypes of early Parkinson’s disease (PD) were identified in a longitudinal study of Parkinson’s Progression Markers Initiative (PPMI) data.

The biotypes differed in symptomatology at presentation before treatment and progressed at different rates, reported Jianfeng Feng, PhD, of Fudan University in Shanghai, China, and coauthors, in Neurology.

The researchers used a deformation-based morphometry (DBM) approach to identify neuroanatomical features that correlated with Unified Parkinson Disease Rating Scale (UPDRS) scores.

“To summarize, biotype 1 had higher baseline MDS-UPDRS I, worse baseline sleep problems and autonomic dysfunction, and faster progression of most motor symptoms, cognitive impairment, and activities of daily living, compared to biotype 2,” they wrote.

“The most striking baseline difference was the much higher REM Sleep Behavior Disorder screening questionnaire score in biotype 1,” they said.

“Severity and rate of disease progression are an important issue in PD therapeutics, and identifying progression biotypes of PD at diagnosis using neuroanatomical patterns may be one way to address heterogeneity in PD,” Feng and co-authors added.

The two biotypes were similar in age, sex, education, and symptom duration among 314 Parkinson’s patients. Biotype 1 (n=114) had lower subcortical volumes than healthy controls, with pronounced differences in nearly the whole brain. Volumes in their motor, cognitive, and emotion-related areas — including putamen, caudate, pallidum, lingual gyrus, temporal cortex, insula, amygdala, hippocampus and orbital frontal cortex — also were significantly lower. These patients had more severe baseline motor impairment, autonomic dysfunction, and much worse REM sleep behavior symptoms, and more rapid decline in clinical domains and in dopamine functional neuroimaging with SPECT.

Biotype 2 (n=200) had subcortical brain volumes larger than healthy controls in the brainstem, putamen, caudate, occipital lobe, lingual gyrus, olfactory, posterior cingulate cortex, and white matter.

“Larger subcortical volume may attenuate the negative impact of PD pathology during disease progression, suggesting that subcortical brain morphological differences may support the maintenance of function despite progressing pathology,” observed Guillaume Lamotte, MD, MSca, of Georgetown University in Washington, D.C., and Benjamin Becker, PhD, of the University of Electronic Science and Technology of China in Chengdu, in an accompanying editorial.

“However, using brain volume as sole proxy for brain reserve has limitations. It does not detail the biological substrate of brain reserve, and subtle individual differences in brain reserve may not be captured by a volumetric measure,” they continued.

“Nevertheless, the present study provides important insights into the feasibility of deriving brain-based subtypes of PD characterized by distinguishable behavioral and progression profiles and emphasizes that future research should focus on biomarker driven subgroups,” they wrote.

Neurodegeneration early in Parkinson’s is prominently subcortical, and brain volume may be proportionate to brain reserve, helping preserve the integrity of large-scale networks. Prior work has shown that subcortical volume loss reflects disease severity in PD, including cognitive impairment.

Recent interest in PD subtypes that embrace considerable clinical heterogeneity and can focus clinical trials and treatment has given rise to approaches that combine traditional motor with important non-motor features. Another approach involves identifying neuroanatomical patterns.

DBM considers a participant’s brain in relation to a generated, population-based template and defines what change is necessary to bring the spatial anatomy of the patient to conform with the reference. The nonlinear transformations required to match individual brains to the reference allow computation of voxel-wise volume, and the technique has been shown to detect changes in early PD.

The authors correlated clinical findings with structural MRI DBM analysis for 457 people (314 patients with early PD and 143 healthy controls) identified through the PPMI. Mean age was 61, 34% were female, and average follow-up was 5 years. Disease duration was about 7 years on average. Mean baseline UPDRS scores for parts I, II, and III were 5.6, 6.9, and 20.7, respectively.

Clinically, biotype 1 patients had significantly lower subcortical volumes; baseline worse mentation, behavior, mood, and REM sleep behavior disorder symptoms and a tendency more severe cognitive impairment; more severe autonomic dysfunction; greater progression in MDS-UPDRS scores (except tremor score); and more rapid progression of difficulties with activities of daily living than biotype 2 patients.

“Biotype 2 patients had larger subcortical volume (higher DBM values) than controls on average, suggesting they may contain more cells (including increasing the ability to support maintenance of function despite declines in brain volume). Accordingly, biotype 2 patients had a slower disease progression rate,” Feng and co-authors noted.

“In contrast, biotype 1 patients had less brain reserve, and did not compensate as well as PD progressed over time, resulting in a faster disease progression rate. Indeed, there was evidence that this was already the case at the time of presentation, given the worse symptom severity in several domains,” they added.

Limitations of the study include overlap in clinical scores at the individual level, and “the implication of the findings in a clinical setting remains limited,” the editorialists wrote. “Brain based-biotypes determined by advanced neurocomputational approaches are only as good as data they are made from and validation of the biotypes in another cohort will be important,” they noted.

  1. Two neuroanatomically-defined biotypes of early Parkinson’s disease (PD) were identified in a longitudinal study of Parkinson’s Progression Markers Initiative (PPMI) data.

  2. The two PD biotypes differed in symptomatology at presentation before treatment and progressed at different rates. The most striking baseline difference was the much higher REM Sleep Behavior Disorder screening questionnaire score in biotype 1.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study is sponsored by the Michael J. Fox Foundation for Parkinson’s Research.

Feng is supported by the 111 Project, the key project of Shanghai Science & Technology, National Key R&D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, and ZJLab.

The editorialists reported no disclosures relevant to the manuscript.

Cat ID: 37

Topic ID: 82,37,730,37,192,925