Prodromal Parkinson disease subtypes — key to understanding heterogeneity

Berg, Daniela; Borghammer, Per; Fereshtehnejad, Seyed‐Mohammad; Heinzel, Sebastian; Horsager, Jacob; Schaeffer, Eva; Postuma, Ronald B.

doi:10.1038/s41582-021-00486-9

Cited by 241 publications

(226 citation statements)

References 152 publications

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“…DOPAL-treated rats had evidence of baroreflex dysfunction, orthostatic hypotension, and time-dependent associated changes in αS monomers/trimers. The data suggest the plausibility of "body-first" subtype of PD that features autonomic abnormalities [138].…”

Section: Dopal-protein Interactions With Emphasis On Alpha-synucleinmentioning

confidence: 77%

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Don’t Know

Goldstein¹

2021

Preprint

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3,4-dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (S), a major component of Lewy bodies. DOPAL potently oligomerizes S, and S oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intra-neuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with S, and vice versa, are poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intra-neuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

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Section: Dopal-protein Interactions With Emphasis On Alpha-synucleinmentioning

confidence: 77%

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Don’t Know

Goldstein¹

2021

Preprint

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Section: Studying the Heterogeneity Of Pre-diagnostic Parkinson's Disease In Population-based Studiesmentioning

confidence: 99%

“…Heterogeneity in the prodromal phase of PD is currently understudied (12,96). A recent review article has highlighted the importance of acknowledging heterogeneity in prodromal PD for early disease recognition and targeted neuroprotective interventions (96). Several subtypes in the prodromal phase were mentioned in this review, including RBD subtypes, brainfirst and body-first subtypes, genetic subtypes and biological subtypes.…”

Section: Studying the Heterogeneity Of Pre-diagnostic Parkinson's Disease In Population-based Studiesmentioning

confidence: 99%

“…With regards to differences in RBD subtypes, RBD in the prodromal phase seems to predispose to a more malignant PD subtype, especially regarding non-motor symptoms (97)(98)(99). The brain-first vs. body-first subtypes, suggesting that αsynuclein pathology originates either in the brain itself or in the autonomic nervous system, might explain the difference in the sequence of the occurrence of symptoms in the prodromal phase (96,100,101). These subtypes of prodromal PD require further investigation in longitudinal studies (96).…”

Section: Studying the Heterogeneity Of Pre-diagnostic Parkinson's Disease In Population-based Studiesmentioning

confidence: 99%

“…The brain-first vs. body-first subtypes, suggesting that αsynuclein pathology originates either in the brain itself or in the autonomic nervous system, might explain the difference in the sequence of the occurrence of symptoms in the prodromal phase (96,100,101). These subtypes of prodromal PD require further investigation in longitudinal studies (96). Recognition of these different subtypes in the prodromal phase is important, but acknowledging heterogeneity in basic patient characteristics, for instance by sex and ethnicity, is also essential (6,47).…”

Section: Studying the Heterogeneity Of Pre-diagnostic Parkinson's Disease In Population-based Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Probing the Pre-diagnostic Phase of Parkinson's Disease in Population-Based Studies

Dommershuijsen

Ikram

2021

Front. Neurol.

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Parkinson's disease covers a wide spectrum of symptoms, ranging from early non-motor symptoms to the characteristic bradykinesia, tremor and rigidity. Although differences in the symptomatology of Parkinson's disease are increasingly recognized, there is still a lack of insight into the heterogeneity of the pre-diagnostic phase of Parkinson's disease. In this perspective, we highlight three aspects regarding the role of population-based studies in providing new insights into the heterogeneity of pre-diagnostic Parkinson's disease. First we describe several specific advantages of population-based cohort studies, including the design which overcomes some common biases, the broad data collection and the high external validity. Second, we draw a parallel with the field of Alzheimer's disease to provide future directions to uncover the heterogeneity of pre-diagnostic Parkinson's disease. Finally, we anticipate on the emergence of prevention and disease-modification trials and the potential role of population-based studies herein. In the coming years, bridging gaps between study designs will be essential to make vital advances in elucidating the heterogeneity of pre-diagnostic Parkinson's disease.

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Functional Impairment Preceding Parkinson Disease Diagnosis—What’s in a Prodrome?

Bledsoe

Shukla

2023

JAMA Neurol

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clinical observations and our current-growing but still incomplete-knowledge about the factors that contribute to disability accumulation suggest that we should revisit our traditional categorization of MS into relapsing and progressive courses. These previously devised clinical phenotypes have served their purpose in defining populations of patients that are most likely to be responsive to existing diseasemodifying treatments. As we are moving toward developing treatments to help prevent disability accumulation, a more personalized understanding of a given patient's disability status is needed to help guide individualized treatment decisions. This new approach should be based on the comprehensive characterization of the different constituents of the disease process using advanced laboratory and imaging methods together with more granular, comprehensive, and meaningful digital measures of the functional consequences of MS.

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Prodromal Parkinson disease subtypes — key to understanding heterogeneity

Cited by 241 publications

References 152 publications

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Don’t Know

The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Don’t Know

Probing the Pre-diagnostic Phase of Parkinson's Disease in Population-Based Studies

Functional Impairment Preceding Parkinson Disease Diagnosis—What’s in a Prodrome?

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