Many advances in understanding the pathophysiology of Parkinson disease (PD) have been based on research addressing its motor symptoms and phenotypes. Various data-driven clinical phenotyping studies supported by neuropathological and in vivo neuroimaging data suggest the existence of distinct non-motor endophenotypes of PD even at diagnosis, a concept further strengthened by the predominantly non-motor spectrum of symptoms in prodromal PD. Preclinical and clinical studies support early dysfunction of noradrenergic transmission in both the CNS and peripheral nervous system circuits in patients with PD that results in a specific cluster of non-motor symptoms, including rapid eye movement sleep behaviour disorder, pain, anxiety and dysautonomia (particularly orthostatic hypotension and urinary dysfunction). Cluster analyses of large independent cohorts of patients with PD and phenotype-focused studies have confirmed the existence of a noradrenergic subtype of PD, which had been previously postulated but not fully characterized. This Review discusses the translational work that unravelled the clinical and neuropathological processes underpinning the noradrenergic PD subtype. Although some overlap with other PD subtypes is inevitable as the disease progresses, recognition of noradrenergic PD as a distinct early disease subtype represents an important advance towards the delivery of personalized medicine for patients with PD.
Parkinson disease (PD) is a phenotypically heterogeneous, multisystem condition that affects the CNS and peripheral nervous system as well as multiple neurotransmitters, rather than a single ‘disease’.
PD can present at diagnosis with motor-predominant and non-motor-predominant symptoms.
Neuropathological studies, neuroimaging findings and data from animal models suggest that PD with specific non-motor-predominant symptoms is driven by noradrenergic dysfunction in the CNS and peripheral nervous system.
Cluster analyses and clinical phenotyping studies confirm the association between PD with specific non-motor-predominant symptoms and noradrenergic dysfunction.
The noradrenergic phenotype of PD includes key features of rapid eye movement sleep behaviour disorder and dysautonomia (including orthostatic hypotension and/or urinary dysfunction), pain and anxiety.
Formal identification of the noradrenergic phenotype as a clinical subtype of PD would help to define its natural history and promote the development of subtype-specific personalized treatment.
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The views expressed are those of the authors and not necessarily those of the UK National Health Service (NHS), National Institutes of Health Research (NIHR) or the Department of Health. The authors acknowledge the support of the International Parkinson and Movement Disorder Society Non-Motor PD Study Group, the NIHR London South Clinical Research Network and the NIHR Biomedical Research Centre. The authors’ independent collaborative research is part funded by the NIHR Biomedical Research Centre at South London, Maudsley NHS Foundation Trust and King’s College London. P.S. is supported by the John and Lucille Van Geest Foundation. K.R.C. is supported by NIHR Biomedical Research Centre at South London, Maudsley NHS Foundation Trust and King’s College London and the Parkinson Foundation, USA.
K.R.C. declares that he has received honoraria for advisory board membership from 4D Pharma, AbbVie, Acadia, Britannia, Global kinetics (GKC), Lobsor, Profile Pharma, Roche, Scion, Stada, Synovion, Therevance, UCB and Zambon; speaker’s honoraria for lectures from AbbVie, Bial, Boeringer Ingelheim, Britannia, Kyowa Kirin, Novartis, SK Pharma, UCB, and Zambon; investigator initiated research grants from AbbVie, Bial; Britannia, UCB, Global Kinetics; and academic grant funding from EU Horizon 2020, Parkinson’s UK, Wellcome Trust, Kirby Laing Foundation and the Medical Research Council; royalty payments or license fees from Oxford University Press, and Cambridge University Press, MAPI institute (King’s Parkinson Disease Pain Scale (KPPS) and Parkinson Disease Sleep Scale 2 (PDSS-2)); and payment for expert testimony from the General Medical Council unrelated to the submitted work. V.L. declares that she has received grants and/or honoraria for speaker-related activities from Abbvie, Bial, Britannia Pharmaceuticals, Invisio, Profile and UCB unrelated to the submitted work. P.S. declares that he has received honoraria for advisory board membership from AbbVie, Kyowa Kirin and Takeda; honoraria for lectures from AbbVie and Zambon; and academic grants from, Lexa International/Nordstjernan, Michael J. Fox Foundation, Stockholm City Council and Wallenberg Clinical Scholarship unrelated to the submitted work. The other authors declare no competing interests.
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Ray Chaudhuri, K., Leta, V., Bannister, K. et al. The noradrenergic subtype of Parkinson disease: from animal models to clinical practice. Nat Rev Neurol 19, 333–345 (2023). https://doi.org/10.1038/s41582-023-00802-5