The Logic and Pitfalls of Parkinson's Disease as “Brain‐First” Versus “<scp>Body‐First</scp>” Subtypes

Fearon, Conor; Lang, Anthony E.; Espay, Alberto J.

doi:10.1002/mds.28493

Cited by 31 publications

(15 citation statements)

References 41 publications

(78 reference statements)

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“…Overall, results are similar to other studies and differences for select organ systems may reflect methodologic differences. These timing data also indirectly relate to pathogenesis models of PD such as the hypothetical body‐first (eg, gut and nose‐first Braak hypothesis)/brain‐first dichotomous model of synucleinopathy propagation 21‐23 . Although speculative when based on symptom timing, onset times do not always show a gut/nasal‐first progression or dichotomy in subgroup time course data.…”

Section: Discussionmentioning

confidence: 99%

“…These timing data also indirectly relate to pathogenesis models of PD such as the hypothetical body-first (eg, gut and nose-first Braak hypothesis)/brain-first dichotomous model of synucleinopathy propagation. [21][22][23] Although speculative when based on symptom timing, onset times do not always show a gut/nasal-first progression or dichotomy in subgroup time course data. Future subgroup analysis is needed to more definitively compare symptomatology to models of synucleinopathy propagation.…”

Section: Discussionmentioning

confidence: 99%

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Onset of Skin, Gut, and Genitourinary Prodromal Parkinson's Disease: A Study of 1.5 Million Veterans

et al. 2021

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Background Prodromal Parkinson's disease of skin, genitourinary, and gastrointestinal systems offers a unique window for understanding early disease pathogenesis and developing disease modifying treatments. However, prior studies are limited by incomplete timing information, small sample size, and lack of adjustment for known confounders. Verifying prodromal timing and identifying new disorders in these accessible organs is critically important given their broad use. Objective We aimed to measure onset timing for gastrointestinal, genitourinary, and skin disorders in a large, nationwide clinically characterized cohort of 1.5 million participants. Methods Patients with Parkinson's disease (n = 303,693) were identified using diagnostic codes in the medical records database of the United States Veterans Affairs healthcare system and were compared 4:1 with matched controls. Disorder prevalence and estimated onset times were assessed for 20 years preceding diagnosis. Results The earliest significantly increased prodromal disorders were gastroesophageal reflux, sexual dysfunction, and esophageal dyskinesia at 17, 16, and 15 years before diagnosis. Estimated onset times for each disorder occurred 5.5 ± 3.4 years before the first measured increase. The earliest estimated onset times were smell/taste, upper gastrointestinal tract, and sexual dysfunction at 20.9, 20.6, and 20.1 years before diagnosis. Onset times for constipation and urinary dysfunction were notably longer by 7 and 9 years compared to prior studies in sleep disorder patients. Dermatophytosis and prostatic hypertrophy were identified as new high prevalence prodromal disorders. Conclusions Gastrointestinal, genitourinary, and skin disorders manifest decades before diagnosis of Parkinson's disease, reiterating their potential as sites for developing early diagnostic testing and understanding pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Onset of Skin, Gut, and Genitourinary Prodromal Parkinson's Disease: A Study of 1.5 Million Veterans

et al. 2021

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“…Parkinson’s disease (PD) was originally described in 1817 by British physician James Parkinson in “Essay on the Shaking Palsy” 1 . PD pathology includes a loss of dopamine neurons in the substantia nigra pars compacta (SNc) 2 – 4 . Braak postulated that an unknown pathogen in the gut or nasal cavity could initiate the dopamine cell loss in sporadic PD through either the vagus nerve or olfactory tract 2 .…”

Section: What Is Disease Modification In Parkinson’s Disease?mentioning

confidence: 99%

“…Consistent with this postulate, a molecular alteration noted in sporadic PD, misfolded and aggregated α-synuclein (αS), may exhibit prion-like capability with the capability to cross synapses and spread within both the enteric and central nervous systems 3 , 5 . The complexity of PD origins, however, has been underscored by recent discussions of brain versus gut first etiology, molecular biomarkers, involvement of αS, phenotypic characteristics (such as unilateral vs bilateral, or tremor predominant vs akinetic-rigid vs postural instability, and gait disturbance), and genotyping 3 , 4 , 6 , 7 . These various biomarkers and characteristics may eventually be useful for surgery triage.…”

Section: What Is Disease Modification In Parkinson’s Disease?mentioning

confidence: 99%

Comparative efficacy of surgical approaches to disease modification in Parkinson disease

Rahimpour

Zhang

Vitek

et al. 2022

npj Parkinsons Dis.

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Parkinson’s disease (PD) may optimally be treated with a disease-modifying therapy to slow progression. We compare data underlying surgical approaches proposed to impart disease modification in PD: (1) cell transplantation therapy with stem cell-derived dopaminergic neurons to replace damaged cells; (2) clinical trials of growth factors to promote survival of existing dopaminergic neurons; (3) subthalamic nucleus deep brain stimulation early in the course of PD; and (4) abdominal vagotomy to lower risk of potential disease spread from gut to brain. Though targeted to engage potential mechanisms of PD these surgical approaches remain experimental, indicating the difficulty in translating therapeutic concepts into clinical practice. The choice of outcome measures to assess disease modification separate from the symptomatic benefit will be critical to evaluate the effect of the disease-modifying intervention on long-term disease burden, including imaging studies and clinical rating scales, i.e., Unified Parkinson Disease Rating Scale. Therapeutic interventions will require long follow-up times (i.e., 5–10 years) to analyze disease modification compared to symptomatic treatments. The promise of invasive, surgical treatments to achieve disease modification through mechanistic approaches has been constrained by the reality of translating these concepts into effective clinical trials.

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“…This proposed dichotomy stems from research indicating that some individuals with PD develop RBD before motor symptoms ( Boeve, 2010 ), while others do not develop RBD at all, or for whom motor symptoms precede RBD ( Olson et al, 2000 ). The dichotomization has received criticism given the complexity and diversity of PD ( Fearon et al, 2021 ); however, despite the dichotomy proposed, this does not preclude the possibility that these progression types could occur simultaneously ( Horsager et al, 2020 ). Indeed, Horsager et al (2020) state as much, outlining that the two main proposed phenotypes may not capture all phenotypic variations and that parkinsonism and RBD may arise simultaneously in cases.…”

Section: Introductionmentioning

confidence: 99%

To the Gut Microbiome and Beyond: The Brain-First or Body-First Hypothesis in Parkinson’s Disease

et al. 2022

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There is continued debate regarding Parkinson’s disease etiology and whether it originates in the brain or begins in the gut. Recently, evidence has been provided for both, with Parkinson’s disease onset presenting as either a “body-first” or “brain-first” progression. Most research indicates those with Parkinson’s disease have an altered gut microbiome compared to controls. However, some studies do not report gut microbiome differences, potentially due to the brain or body-first progression type. Based on the etiology of each proposed progression, individuals with the body-first progression may exhibit altered gut microbiomes, i.e., where short-chain fatty acid producing bacteria are reduced, while the brain-first progression may not. Future microbiome research should consider this hypothesis and investigate whether gut microbiome differences exist between each type of progression. This may further elucidate the impact of the gut microbiome in Parkinson’s disease and show how it may not be homogenous across individuals with Parkinson’s disease.

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The Logic and Pitfalls of Parkinson's Disease as “Brain‐First” Versus “Body‐First” Subtypes

Cited by 31 publications

References 41 publications

Onset of Skin, Gut, and Genitourinary Prodromal Parkinson's Disease: A Study of 1.5 Million Veterans

Onset of Skin, Gut, and Genitourinary Prodromal Parkinson's Disease: A Study of 1.5 Million Veterans

Comparative efficacy of surgical approaches to disease modification in Parkinson disease

To the Gut Microbiome and Beyond: The Brain-First or Body-First Hypothesis in Parkinson’s Disease

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