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Prognosis and Neuropathologic Correlation of Clinical Subtypes of Parkinson Disease
Open accessAbstract
Importance: Clinical subtyping of Parkinson disease at diagnosis is useful in estimating disease course and survival. Severity and rate of progression of neuropathologies are important determinants of clinical Parkinson subtypes. Objective: To provide longitudinal clinical disease-course data and neuropathologic correlation for newly proposed Parkinson disease subtypes. Design, Setting, and Participants: Retrospective cohort study of consecutive patients with autopsy-confirmed Parkinson disease who were regularly seen throughout their disease course by hospital specialists in the United Kingdom and donated their brain at death to the Queen Square Brain Bank between January 2009 and December 2017. Patients with additional neuropathologic diagnoses, monogenic forms of parkinsonism, or insufficiently detailed clinical information were excluded. Based on severity of motor symptoms, rapid eye movement sleep behavior disorder, and autonomic and cognitive function at diagnosis, patients were classified adapting a subtyping classification into mild-motor predominant, intermediate, or diffuse malignant subtypes. Main Outcomes and Measures: Time from diagnosis to disease milestones (recurrent falls, wheelchair dependence, dementia, and care home placement) and death were compared between subtypes, and their risk was estimated using Cox hazard regression models. Severity and distribution of Lewy pathology and Alzheimer disease-related pathology were assessed using staging systems. Results: From a total of 146 patients, 111 patients were included (67 men [60.4%]; mean [SD] age at diagnosis, 62.5 [11.5] years). The diffuse malignant subtype had earlier development of milestones and reduced survival. Cox proportional hazard regression showed an increased adjusted risk of any disease milestone (hazard ratio, 10.90; 95% CI, 5.51-21.58; P < .001) and death (hazard ratio, 3.65; 95% CI, 1.98-6.75; P < .001) in the diffuse malignant group. Age at diagnosis was the only additional variable with statistical significance (adjusted hazard ratio for death, 1.14; 95% CI, 1.11-1.17; P <.001). Staging of Lewy pathology and Alzheimer disease-related pathology did not differ between subtypes, although they showed different rates of progression, and the latter was associated with age at death. Conclusions and Relevance: Parkinson clinical subtypes at diagnosis may estimate disease course and survival, which may be useful in providing a more accurate prognosis in individual patients in clinical practice and helping to stratify subgroups in clinical trials. Different severity and progression of neuropathologies are important determinants of Parkinson subtypes, and age at diagnosis should be included in future subtype classifications.
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“One barrier to the clinical implementation of passive digital biomarkers, however, has been the lack of computing resources for storing and automatically processing and analyzing the large amount of data collected from passive digital tools that continuously monitor behavior over long periods of time.120”
From Review of Artificial Intelligence for Clinical Use in Alzheimer's Disease and Related Dementias (2026) · cites this paper as [120]
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Staging of brain pathology related to sporadic Parkinson’s disease
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Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium
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Systematic review of levodopa dose equivalency reporting in Parkinson's disease
Tomlinson, C. L., Stowe, R. L., Patel, S., Rick, C., Gray, R. G., & Clarke, C. E. (2010) · Movement Disorders · doi:10.1002/mds.23429 · Cited by 4,310
Phases of Aβ-deposition in the human brain and its relevance for the development of AD
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The Parkinson Progression Marker Initiative (PPMI)
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Self-citationClinical criteria for subtyping Parkinson’s disease: biomarkers and longitudinal progression
Fereshtehnejad, S., Zeighami, Y., Dagher, A., & Postuma, R. B. (2017) · Brain · doi:10.1093/brain/awx118 · Cited by 619
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Armstrong, M. J., & Okun, M. S. (2020) · JAMA · doi:10.1001/jama.2019.22360 · Cited by 2,924
Challenges in the diagnosis of Parkinson's disease
Tolosa, E., Garrido, A., Scholz, S. W., & Poewe, W. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00030-2 · Cited by 1,874
Parkinson’s disease: etiopathogenesis and treatment
Jankovic, J. J., & Tan, E. K. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2019-322338 · Cited by 1,273
The genetic architecture of Parkinson's disease
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Metadata
- Authors
- De Pablo-Fernández, E., Lees, A. J., Holton, J. L., & Warner, T. T.
- Affiliations
- Reta Lila Weston Institute of Neurological Studies, University College London Queen Square Institute of Neurology, London, England
- National Hospital for Neurology and Neurosurgery (GB)
- Corresponding author
- Warner, Thomas T.
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-04-01
- Volume
- 76
- Issue
- 4
- Pages
- 470
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC6459129
- OpenAlex
- W2909700430
- Cited by
- 332
- References
- 31
- Citations by year
- 2026: 23 · 2025: 53 · 2024: 45 · 2023: 42 · 2022: 46 · 2021: 39 · 2020: 63 · 2019: 20
- FWCI
- 28.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Medical Research Council (MR/L023784/2, MR/L023784/1)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Deep Brain Stimulation and Movement Disorders
- Keywords
- Parkinson's disease, clinical subtypes, prognosis, disease progression, survival, Lewy body pathology, rapid eye movement sleep behavior disorder, dementia, wheelchair dependence, nursing home admission, age at death, autonomic dysfunction, cognitive function, brain donation
- MeSH terms
- Aged, Autonomic Nervous System Diseases, Autopsy, Brain, Female, Humans, Male, Middle Aged, Parkinson Disease, Prognosis, Retrospective Studies, Severity of Illness Index, Survival Rate, Proportional Hazards Models, Lewy Bodies, Neurofibrillary Tangles, Age of Onset, Disease Progression, REM Sleep Behavior Disorder, Plaque, Amyloid, Cognitive Dysfunction
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