Non Motor Symptoms in Glucocerebrosidase-related Parkinson's Disease

Official title

Prospective and Controlled Glucocerebrosidase-related Parkinson's Disease Evaluation of Non Motor Symptoms (PROGENS-PD)

Overview

The goal of this observational study is to describe non motor symptoms in a prospective study of patients with Parkinson's disease associated to glucocerebrosidase (GBA-PD) mutations. The main questions it aims to answer are: * Do GBA-PD patients have a greater burden of non motor symptoms? * How do these non motor symptoms evolve during a prospective follow up of two years? * Are these non motor symptoms different from those that affect Parkinson's disease patients without glucocerebrosidase mutations (non GBA-PD), in prevalence, severity and type? * Do these non motor symptoms correlate with objective measures such as posturography or speed reaction tests? * Is there a test or combination of tests that can predict the appearance of early or severe non motor symptoms? For this reason researchers will compare the GBA-PD group of patients with a group of non mutated GBA Parkinson disease. Participants will undergo a neurological and neuropsychological evaluation with different tests in subsequent visits for a total of 2 years.

Detailed description

Parkinson's disease is the second most prevalent neurodegenerative disorder worldwide. Up to date, the main risk factor for its development is carrying an heterozygous mutation in glucocerebrosidase gene (GBA). GBA codifies for a GC-ase protein that takes part in lysosomal function. The homozygous mutation of this gene gives rise to Gaucher disease, which is a lysosomal disorder. This gene has also been associated with Lewy body dementia.

The presence of an heterozygous mutation in GBA in Parkinson's disease can be found in up to 5-15% of the patients, depending on age and ethnicity. It has been described that those patients carrying the mutation can have an earlier debut of the disease.

According to non motor symptoms, patients are prone to develop earlier and more severe motor symptoms. This has been studied specially in cognitive impairment but also dysautonomia, impulse control disorder and others.

In relation to cognitive impairment these patients usually develop an earlier and more severe affection, reaching dementia states earlier in the disease. Some studies have described a worsening in cognitive function in GBA mutated patients after deep brain stimulation (DBS) to treat parkinsonian symptoms. This prevents patients from being candidates to therapies such as DBS.

For this reason, the investigators consider it important to make a proper description of non motor symptoms in GBA mutated parkinsonian patients, since this finding can help to delineate the prognosis and choose individualized treatments, regarding the suggested differences with other Parkinson's disease patients.

It is an observational prospective cohort study. Participants will be collected from a subgroup of patients that have agreed to undertake a genetic test including a panel of genes associated to Parkinson's disease.

According to the results, patients will be subdivided in two groups according to their genetic status:

* GBA heterozygous mutations * Absence of genetic mutations

These patients will undergo neurologic evaluations, neuropsychological evaluations and self-administered evaluations. There will be no intervention.

The pharmacologic and other type of treatment assessments will be conducted during their regular follow up with their neurologist.

These visits will be repeated every 6 months for a total of 2 years. Total of 5 visits for each patient.

Interventions

• Other Tests on non motor symptoms
  Neurological, neuropsychological and self-administered tests on non motor symptoms, including posturography and speed reaction times.

Primary outcome measures

• Change in non motor symptoms scale from baseline to 2 years [Time frame: 2 years]
• Change in non motor symptoms scale from baseline to 6 months [Time frame: 6 months]
• Change in non motor symptoms scale from 6 months to 1 year [Time frame: 6 months]
• Change in non motor symptoms scale from 12 months to 18 months [Time frame: 6 months]
• Change in non motor symptoms scale from 18 months to 24 months [Time frame: 6 months]

Secondary outcome measures (12)

• Change in Montreal Cognitive Assessment scale from baseline to 2 years [Time frame: 2 years]
• Change in Montreal Cognitive Assessment scale from baseline to 6 months [Time frame: 6 months]
• Change in Montreal Cognitive Assessment scale from 6 months to 12 months [Time frame: 6 months]
• Change in Montreal Cognitive Assessment scale from12 months to 18 months [Time frame: 6 months]
• Change in Montreal Cognitive Assessment scale from18 months to 24 months [Time frame: 6 months]
• Change in Parkinson's disease cognitive rating scale from baseline to 24 months [Time frame: 2 years]
• Change in Parkinson's disease cognitive rating scale from baseline to 6 months [Time frame: 6 months]
• Change in Parkinson's disease cognitive rating scale from 6 months to 12 months [Time frame: 6 months]
• Change in Parkinson's disease cognitive rating scale from 12 months to 18 months [Time frame: 6 months]
• Change in Parkinson's disease cognitive rating scale from 18 months to 24 months [Time frame: 6 months]
• Change in Line Orientation Judgement scale from baseline to 24 months [Time frame: 2 years]
• Change in Line Orientation Judgement scale from baseline to 6 months [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Aged over 18 years old.
• Fulfill Parkinson's disease criteria of Movement Disorder Society 2015.
• Parkinson's disease symptoms began before they were 70 and/or Parkinson's disease family history.
• Underwent a genetic test of Parkinson's disease related genes.
• Heterozygous mutation of glucocerebrosidase gene (only cases).
• Absence of mutation in the Parkinson's disease genetic test (only controls).

Exclusion criteria

• Suspicion of atypical parkinsonism.
• Personal history of other neurodegenerative disorders such as Alzheimer's disease.
• Personal history of significant cerebrovascular damage, intracraneal lessions or important craneoencephalic trauma.
• Deep brain stimulation treatment for Parkinson's disease.
• Moderate or severe dementia that precludes from performing the tests.

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

Spain · 2 centers

• Universidad Francisco de Vitoria — Pozuelo de Alarcón
• Hospital Universitario La Princesa — Madrid

Publications

• Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira PMID 19846850
• Barkhuizen M, Anderson DG, Grobler AF. Advances in GBA-associated Parkinson's disease--Pathology, presentation and therapies. Neurochem Int. 2016 Feb;93:6-25. doi: 10.1016/j.neuint.2015.12.004. Epub 2015 Dec 30. PMID 26743617
• Brockmann K, Srulijes K, Pflederer S, Hauser AK, Schulte C, Maetzler W, Gasser T, Berg D. GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study. Mov Disord. 2015 Mar;30(3):407-11. doi: 10.1002/mds.26071. Epub 2014 Dec 1. PMID 25448271
• Leocadi M, Canu E, Donzuso G, Stojkovic T, Basaia S, Kresojevic N, Stankovic I, Sarasso E, Piramide N, Tomic A, Markovic V, Petrovic I, Stefanova E, Kostic VS, Filippi M, Agosta F. Longitudinal clinical, cognitive, and neuroanatomical changes over 5 years in GBA-positive Parkinson's disease patients. J Neurol. 2022 Mar;269(3):1485-1500. doi: 10.1007/s00415-021-10713-4. Epub 2021 Jul 23. PMID 34297177
• Swan M, Doan N, Ortega RA, Barrett M, Nichols W, Ozelius L, Soto-Valencia J, Boschung S, Deik A, Sarva H, Cabassa J, Johannes B, Raymond D, Marder K, Giladi N, Miravite J, Severt W, Sachdev R, Shanker V, Bressman S, Saunders-Pullman R. Neuropsychiatric characteristics of GBA-associated Parkinson disease. J Neurol Sci. 2016 Nov 15;370:63-69. doi: 10.1016/j.jns.2016.08.059. Epub 2016 Aug 30. PMID 27772789
• Malek N, Weil RS, Bresner C, Lawton MA, Grosset KA, Tan M, Bajaj N, Barker RA, Burn DJ, Foltynie T, Hardy J, Wood NW, Ben-Shlomo Y, Williams NW, Grosset DG, Morris HR; PRoBaND clinical consortium. Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study. J Neurol Neurosurg Psychiatry. 2018 Jul;89(7):702-709. doi: 10.1136/jnnp-2017-317348. Epub 2018 Jan 29 PMID 29378790
• Ren J, Zhou G, Wang Y, Zhang R, Guo Z, Zhou H, Zheng H, Sun Y, Ma C, Lu M, Liu W. Association of GBA genotype with motor and cognitive decline in Chinese Parkinson's disease patients. Front Aging Neurosci. 2023 Feb 10;15:1091919. doi: 10.3389/fnagi.2023.1091919. eCollection 2023. PMID 36845659

Identifiers

NCT: NCT06451419 · 5564

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗