Clinical trial NCT06156917: Evaluation of Autonomic, Imaging and Genetic Markers for Parkinson-related Dementia : Longitudinal Assessment of a PD Cohort.
Official title: Evaluation of Autonomic, Imaging and Genetic Markers for Parkinson-related Dementia : Longitudinal Assessment of a PD Cohort.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Parkinson Disease
Lead sponsor: IRCCS San Raffaele
Sponsor class: OTHER
First posted: 2023-12-05
Enrollment: 100
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: This project provides the opportunity to collect and characterize a large cohort of PD patients to be studied prospectively.

We will evaluate whether dlfferences In the measured variables exist between patients who will develop dementia (primary endpoint) within the observatlon time frame and those who will remain free from cognitive impairment at follow-up. We will compare PD patients who reach this endpoint before 10 years from disease onset to those who by that tlme remain cognitively preserved.

Brief summary: Neuropathologically, Parkinson disease (PD) is characterized by the accumulation of intra-neuronal protein aggregates (Lewy bodies and Lewy neurites). It is believed that altered rt-synuclein protein handling plays a key role in the etiopathogenesis of PD, because it is the principal component of Lewy pathology. Recent evidence now suggests the possibility that a-synuclein is a prion-like protein and that PD is a prion-like disease. Some studies have suggested that environmental toxins promote the release of a-synuclein by enter- ic neurons and that released enteric a-synuclein is taken up by presynaptic sympathetic neurites and retro- gradely transported to the soma, where it accumulates, thus mediating the progression of PD pathology. These data indicate the precocity of autonomic nervous system involvement with reference to further spread of a-synuclein pathology. We have evidence from a previous study that the vagal preganglionic pro- jections to the gut express a-synuclein, thus providing a candidate a-synuclein-expressing pathway for the retrograde transport of pathogens to the central nervous system. Cardiovascular autonomic dysfunction explores the reactivity of sympathetic and parasympathetic pathways to a predefined set of tests, allowing to quantify the degree of dysfunction in each of the two components of the autonomic nervous system.

Mutations in the GBA gene influence the risk for dementia in PD 21; this effect of GBA is not synergistic with that of increasing age. Heterozygous GBA mutations are considered an important risk factor for PD and dementia, possibly causing a wider protein accumulation in the brain. In vitro models of alpha-synuclein aggregation have provided evidence for co-localization with mutant GBA . It has been proposed that a gain of function mechanism operates in patients with PD carrying GBA gene mutations, whereby mutant G8A promotes alpha-synuclein aggregation, accelerating Lewy body formation and neuronal loss.

Each of the selected variables provides a unique window to ascertain the association between PD patho- physiology and the risk of related dementia. Our hypothesis is that PD patients who develop incident dementia will have a number of statistically different abnormalities that will be evidenced as individual predictors and will also be assembled into a predictive algorithm. This project addresses a key issue in Parkinson disease, a progressive neurodegenerative condition, related to the assessment of variables associated to the development of dementia. The project is focused on dementia as a significant and important clinical milestone that constitutes the main cause of non-reversible functional impairment in PD patients.


Eligibility criteria: Inclusion Criteria:

* Diagnosis of "clinically established PD" based on the MDS clinical diagnostic criteria.

Age at disease onset will be between 40 and 70.

Exclusion Criteria:

* severe autonomic dysfunction (as defined in red flag 5a and 5b) will be an exclusion criterion Previous deep brain stimulation is an exclusion criterion.

Primary outcomes:
measure: correlation of dysautonomia with incident dementia associated to PD
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Milano
country: Italy
facility: Irccs San Raffaele
state: Italia
Study officials:
References: