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

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

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.

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.

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.