Study of Axial and Cognitive Symptoms and Biomarkers of Neurodegeneration in Brain-first and Body-first PD

Official title

Study of the Progression of Axial and Cognitive Symptoms and Biomarkers of Neurodegeneration in Patients With Parkinson's Disease Divided Into Brain-first and Body-first Phenotypes

Overview

This observational study aims to systematically characterize a cohort of patients with early-stage Parkinson's disease (PD) attending the Movement Disorders Center of AUSL-IRCCS Reggio Emilia, Italy. PD is the second most common neurodegenerative disorder, affecting about 1% of individuals over 60 years of age. The project will explore clinical and biological differences between the recently proposed "Brain-First" and "Body-First" phenotypes of PD. Patients will undergo detailed clinical evaluation, neuroimaging, and biomarker assessments (including neurodegeneration and neuroinflammation markers). Particular attention will be given to the progression of axial and cognitive symptoms, which represent major contributors to disability. Findings from this study are expected to improve early patient stratification, clarify disease mechanisms, and support the development of precision medicine strategies and future disease-modifying therapies.

Detailed description

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting up to 1% of individuals over the age of 60. While treatment remains symptomatic and no disease-modifying therapies are currently available, increasing research efforts are focusing on precision medicine approaches and the identification of disease subtypes that may guide prognosis and therapy.

Historically, PD patients have been classified according to motor (tremor-dominant, akinetic-rigid, axial) and non-motor features (sleep disturbances, autonomic dysfunction, mood disorders, fatigue, pain, weight loss, cognitive impairment). Genetic classifications have also been introduced, with approximately 10-15% of patients carrying mutations such as GBA or LRRK2, which are associated with earlier onset and potentially more aggressive disease.

In the early 2000s, Braak and colleagues proposed a neuropathological staging system in which α-synuclein pathology progresses in a stereotypical pattern from peripheral to central structures. More recent clinical and pathological evidence, however, has challenged this model and led to the proposal of two distinct subtypes: Brain-First and Body-First. In Brain-First PD, pathology begins in the central nervous system and spreads to the autonomic system; in Body-First PD, pathology originates in peripheral structures such as the enteric nervous system, propagating rostrally to involve the brain. REM sleep behavior disorder (RBD) has emerged as a clinical marker of the Body-First subtype.

This study will systematically characterize patients with early-stage PD, combining detailed clinical evaluation with instrumental assessments including neuroimaging and blood-based biomarkers. In particular, the project will investigate whether Brain-First and Body-First phenotypes differ in terms of:

* Clinical progression (with focus on axial and cognitive symptoms). * Neurodegeneration biomarkers, including neurofilament light chain. * Neuroinflammation markers, such as immune responses to α-synuclein, interferon-gamma, and interleukin-5.

The overarching goal is to identify biological and clinical markers that distinguish PD subtypes, improve early stratification, and support the development of targeted, disease-modifying therapies.

Interventions

• Other Clinical assessments
  standardized neurological examination, motor and non-motor symptom scales, cognitive testing, and autonomic symptom questionnaires.
• Other Phenotypic classification
  patients will be stratified into Brain-First and Body-First phenotypes based on the presence of RBD and instrumental findings.

Primary outcome measures

• Assessment of the progression of axial symptoms [Time frame: baseline, 12, 24, 36,48, 60 months]
• Risk of falling in the two subgroups, brain-first and body-first [Time frame: baseline, 12, 24, 36,48, 60 months]
• Risk of falling in the two subgroups, brain-first and body-first [Time frame: baseline, 12, 24, 36,48, 60 months]
• Assessment of the progression of axial symptoms [Time frame: baseline, 12, 24, 36,48, 60 months]

Secondary outcome measures (4)

• Assessment of disease progression [Time frame: baseline, 12, 24, 36,48, 60 months]
• Assessment of the progression of neurodegeneration and inflammatory biomarkers (neurofilaments, interferon-γ, cell-mediated anti-α-synuclein responses). [Time frame: baseline, 12, 24, 36,48, 60 months]
• Brain MRI: analysis of differences in qualitative and quantitative parameters extrapolated at diagnosis. [Time frame: 24 months]
• Baseline Assessment of Nigrostriatal and Myocardial Denervation. [Time frame: 24 months]

Eligibility criteria

Inclusion criteria

• Patients diagnosed with PD according to the MDS Clinical Diagnostic Criteria for Parkinson's Disease divided into brain-first and body-first phenotypes, based on the presence or absence of a REM sleep behavior disorder diagnosed using ambulatory polysomnography methods according to the criteria of the International Classification of Sleep Disorders (ICSD-3) criteria and on data from SPECT with DATSCAN and myocardial innervation scintigraphy \[123I-MIBG\].
• Free and informed consent expressed by the participant.
• At least 18 years of age.

Exclusion criteria

• Inability to express free and informed consent.
• Patient with a doubtful diagnosis.
• Participant under 18 years of age.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Italy · 1 center

• Azienda USL IRCCS di Reggio Emilia — Reggio Emilia

Publications

• Piancino MG, Farina D, Talpone F, Merlo A, Bracco P. Muscular activation during reverse and non-reverse chewing cycles in unilateral posterior crossbite. Eur J Oral Sci. 2009 Apr;117(2):122-8. doi: 10.1111/j.1600-0722.2008.00601.x. PMID 19320720
• Cavallieri F, Gessani A, Merlo A, Campanini I, Budriesi C, Fioravanti V, Di Rauso G, Feletti A, Damiano B, Scaltriti S, Guagnano N, Bardi E, Corni MG, Antonelli F, Cavalleri F, Molinari MA, Contardi S, Menozzi E, Puzzolante A, Vannozzi G, Bergamini E, Pavesi G, Fraix V, Meoni S, Fraternali A, Versari A, Lusuardi M, Biagini G, Pinto S, Moro E, Valzania F. Interplay between speech and gait variables PMID 36971736
• Merlo A, Zemp D, Zanda E, Rocchi S, Meroni F, Tettamanti M, Recchia A, Lucca U, Quadri P. Postural stability and history of falls in cognitively able older adults: the Canton Ticino study. Gait Posture. 2012 Sep;36(4):662-6. doi: 10.1016/j.gaitpost.2012.06.016. Epub 2012 Jul 24. PMID 22832469
• Horsager J, Knudsen K, Sommerauer M. Clinical and imaging evidence of brain-first and body-first Parkinson's disease. Neurobiol Dis. 2022 Mar;164:105626. doi: 10.1016/j.nbd.2022.105626. Epub 2022 Jan 11. PMID 35031485
• Horsager J, Andersen KB, Knudsen K, Skjaerbaek C, Fedorova TD, Okkels N, Schaeffer E, Bonkat SK, Geday J, Otto M, Sommerauer M, Danielsen EH, Bech E, Kraft J, Munk OL, Hansen SD, Pavese N, Goder R, Brooks DJ, Berg D, Borghammer P. Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study. Brain. 2020 Oct 1;143(10):3077-3088. doi: 10.1093/brain/awaa238. PMID 32830221
• Bohnen NI, Postuma RB. Body-first versus brain-first biological subtyping of Parkinson's disease. Brain. 2020 Oct 1;143(10):2871-2873. doi: 10.1093/brain/awaa293. PMID 33103732

Identifiers

NCT: NCT07187843 · 350/2024/OSS/AUSLRE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗