Clinical trial NCT06451419: 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)
Study type: OBSERVATIONAL
Overall status: ENROLLING_BY_INVITATION
Conditions: Parkinson Disease
Keywords: glucocerebrosidase heterozygous mutation
non motor symptoms
neuropsychology
posturography
Lead sponsor: Universidad Francisco de Vitoria
Sponsor class: OTHER
Collaborators: name: Fundación de Investigación Biomédica - Hospital Universitario de La Princesa
First posted: 2024-06-11
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Parkinson's disease patients whose symptoms began before they were 70 and/or those who had Parkinson's disease family history and underwent a genetic test including the following Parkinson's disease related genes: ADCY5, ANO, APOE, APP, ATP1A3, ATP9A, C19orf12, CHCHD2, CNEP1R1, COX20, CTDNEP1, DCTN1, DNAJC13, DNAJC6, ELOVO7, FJ47, FBXO7, GAK, GBA, GCDH, GCH1, GNAL, GNE, GRN, HPCA, KCTD17, KMT2B, LPIN1, LPIN2, LPIN3, LRRK2, MAPT, MCCC1, MCOLN1, NPC1, PANK2, PARK7, PDE8B, PDGFB PIN, PDGFR, PDGFR PLA2G, POLG, PRRKN, PRRKA, PSEN1, PSEN2, RAB12, RAB39B, SGCE excepto exón NM_001099401 exón 10, SLC19A3, SLC20A2, SLC30A10, SLC39A14, SLC6A3, SNCA, SNCB, SYN-1, SYNJ1, TA, TH1 TOR1A, VAC14, VPS13C (hotspot exones 11, 3, 4, 61 y 9), VPS35, XPR1 and agreed to participate in the study.

Brief summary: 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.

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.

Primary outcomes:
measure: Change in non motor symptoms scale from baseline to 2 years
timeFrame: 2 years
measure: Change in non motor symptoms scale from baseline to 6 months
timeFrame: 6 months
measure: Change in non motor symptoms scale from 6 months to 1 year
timeFrame: 6 months
measure: Change in non motor symptoms scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in non motor symptoms scale from 18 months to 24 months
timeFrame: 6 months
Secondary outcomes:
measure: Change in Montreal Cognitive Assessment scale from baseline to 2 years
timeFrame: 2 years
measure: Change in Montreal Cognitive Assessment scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Montreal Cognitive Assessment scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Montreal Cognitive Assessment scale from12 months to 18 months
timeFrame: 6 months
measure: Change in Montreal Cognitive Assessment scale from18 months to 24 months
timeFrame: 6 months
measure: Change in Parkinson's disease cognitive rating scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Parkinson's disease cognitive rating scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Parkinson's disease cognitive rating scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Parkinson's disease cognitive rating scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Parkinson's disease cognitive rating scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Line Orientation Judgement scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Line Orientation Judgement scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Line Orientation Judgement scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Line Orientation Judgement scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Line Orientation Judgement scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Rey figure from baseline to 24 months
timeFrame: 2 years
measure: Change in Rey figure from baseline to 6 months
timeFrame: 6 months
measure: Change in Rey figure from 6 months to 12 months
timeFrame: 6 months
measure: Change in Rey figure from 12 months to 18 months
timeFrame: 6 months
measure: Change in Rey figure from 18 months to 24 months
timeFrame: 6 months
measure: Change in Weschler Memory test from baseline to 24 months
timeFrame: 2 years
measure: Change in Weschler Memory test from baseline to 6 months
timeFrame: 6 months
measure: Change in Weschler Memory test from 6 months to 12 months
timeFrame: 6 months
measure: Change in Weschler Memory test from 12 months to 18 months
timeFrame: 6 months
measure: Change in Weschler Memory test from 18 months to 24 months
timeFrame: 6 months
measure: Change in Stroop test from baseline to 24 months
timeFrame: 2 years
measure: Change in Stroop test from baseline to 6 months
timeFrame: 6 months
measure: Change in Stroop test from 6 months to 12 months
timeFrame: 6 months
measure: Change in Stroop test from 12 months to 18 months
timeFrame: 6 months
measure: Change in Stroop test from 18 months to 24 months
timeFrame: 6 months
measure: Change in Trail Making Test A from baseline to 24 months
timeFrame: 2 years
measure: Change in Trail Making Test B from baseline to 24 months
timeFrame: 2 years
measure: Change in Trail Making Test A from baseline to 6 months
timeFrame: 6 months
measure: Change in Trail Making Test B from baseline to 6 months
timeFrame: 6 months
measure: Change in Trail Making Test A from 6 months to 12 months
timeFrame: 6 months
measure: Change in Trail Making Test B from 6 months to 12 months
timeFrame: 6 months
measure: Change in Trail Making Test A from 12 months to 18 months
timeFrame: 6 months
measure: Change in Trail Making Test B from 12 months to 18 months
timeFrame: 6 months
measure: Change in Trail Making Test A from 18 months to 24 months
timeFrame: 6 months
measure: Change in Trail Making Test B from 18 months to 24 months
timeFrame: 6 months
measure: Change in Questionnaire for impulsive-compulsive disorders in Parkinson's disease (QUIP-RS) from baseline to 2 years
timeFrame: 2 years
measure: Change in Questionnaire for impulsive-compulsive disorders in Parkinson's disease (QUIP-RS) from baseline to 6 months
timeFrame: 6 months
measure: Change in Questionnaire for impulsive-compulsive disorders in Parkinson's disease (QUIP-RS) from 6 months to 12 months
timeFrame: 6 months
measure: Change in Questionnaire for impulsive-compulsive disorders in Parkinson's disease (QUIP-RS) from 12 months to 18 months
timeFrame: 6 months
measure: Change in Questionnaire for impulsive-compulsive disorders in Parkinson's disease (QUIP-RS) from 18 months to 24 months
timeFrame: 6 months
measure: Change in Neuropsychiatric inventory from baseline to 2 years
timeFrame: 2 years
measure: Change in Neuropsychiatric inventory from baseline to 6 months
timeFrame: 6 months
measure: Change in Neuropsychiatric inventory from 6 months to 12 months
timeFrame: 6 months
measure: Change in Neuropsychiatric inventory from 12 months to 18 months
timeFrame: 6 months
measure: Change in Neuropsychiatric inventory from 18 months to 24 months
timeFrame: 6 months
measure: Change in Apathy Evaluation Scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Apathy Evaluation Scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Apathy Evaluation Scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Apathy Evaluation Scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Apathy Evaluation Scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Beck Depression Inventory from baseline to 24 months
timeFrame: 2 years
measure: Change in Beck Depression Inventory from baseline to 6 months
timeFrame: 6 months
measure: Change in Beck Depression Inventory from 6 months to 12 months
timeFrame: 6 months
measure: Change in Beck Depression Inventory from 12 months to 18 months
timeFrame: 6 months
measure: Change in Beck Depression Inventory from 18 months to 24 months
timeFrame: 6 months
measure: Change in Stai-trait Anxiety Inventory from baseline to 24 months
timeFrame: 2 years
measure: Change in Stai-trait Anxiety Inventory from baseline to 6 months
timeFrame: 6 months
measure: Change in Stai-trait Anxiety Inventory from 6 months to 12 months
timeFrame: 6 months
measure: Change in Stai-trait Anxiety Inventory from 12 months to 18 months
timeFrame: 6 months
measure: Change in Stai-trait Anxiety Inventory from 18 months to 24 months
timeFrame: 6 months
measure: Change in Parkinson's disease sleep scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Parkinson's disease sleep scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Parkinson's disease sleep scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Parkinson's disease sleep scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Parkinson's disease sleep scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire from baseline to 24 months
timeFrame: 2 years
measure: Change in REM Sleep Behavior Disorder Screening Questionnaire from baseline to 6 months
timeFrame: 6 months
measure: Change in REM Sleep Behavior Disorder Screening Questionnaire from to 6 months to 12 months
timeFrame: 6 months
measure: Change in REM Sleep Behavior Disorder Screening Questionnaire from to 12 months to 18 months
timeFrame: 6 months
measure: Change in REM Sleep Behavior Disorder Screening Questionnaire from to 18 months to 24 months
timeFrame: 6 months
measure: Change in Epworth Sleepiness Scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Epworth Sleepiness Scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Epworth Sleepiness Scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Epworth Sleepiness Scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Epworth Sleepiness Scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Restless Legs Syndrome Rating Scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Restless Legs Syndrome Rating Scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Restless Legs Syndrome Rating Scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Restless Legs Syndrome Rating Scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Restless Legs Syndrome Rating Scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Berg balance scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Berg balance scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Berg balance scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Berg balance scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Berg balance scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in limits of stability from baseline to 24 months
timeFrame: 2 years
measure: Change in limits of stability from baseline to 6 months
timeFrame: 6 months
measure: Change in limits of stability from 6 months to 12 months
timeFrame: 6 months
measure: Change in limits of stability from 12 months to 18 months
timeFrame: 6 months
measure: Change in limits of stability from 18 months to 24 months
timeFrame: 6 months
measure: Change in speed reaction test from baseline to 24 months
timeFrame: 2 years
measure: Change in speed reaction test from baseline to 6 months
timeFrame: 6 months
measure: Change in speed reaction test from 6 months to 12 months
timeFrame: 6 months
measure: Change in speed reaction test from 12 months to 18 months
timeFrame: 6 months
measure: Change in speed reaction test from 18 months to 24 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part II scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part II from baseline to 6 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part II from 6 months to 12 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part II from 12 months to 18 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part II from 18 months to 24 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part III scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part III scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part III scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part III scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part III scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part IV scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part IV scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part IV scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale pary IV scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Movement Disorder's Society- Unified Parkinson's Disease Rating Scale part IV scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Hoehn and Yahr scale from baseline to 24 months
timeFrame: 2 years
measure: Change in Hoehn and Yahr scale from baseline to 6 months
timeFrame: 6 months
measure: Change in Hoehn and Yahr scale from 6 months to 12 months
timeFrame: 6 months
measure: Change in Hoehn and Yahr scale from 12 months to 18 months
timeFrame: 6 months
measure: Change in Hoehn and Yahr scale from 18 months to 24 months
timeFrame: 6 months
measure: Change in Parkinson's disease Questionnaire-39 from baseline to 24 months
timeFrame: 2 years
measure: Change in Parkinson's disease Questionnaire-39 from baseline to 6 months
timeFrame: 6 months
measure: Change in Parkinson's disease Questionnaire-39 from 6 months to 12 months
timeFrame: 6 months
measure: Change in Parkinson's disease Questionnaire-39 from 12 months to 18 months
timeFrame: 6 months
measure: Change in Parkinson's disease Questionnaire-39 from 18 months to 24 months
timeFrame: 6 months
measure: Change in number of Parkinson's disease treatments from baseline to 24 months
timeFrame: 2 years
measure: Change in number of Parkinson's disease treatments from baseline to 6 months
timeFrame: 6 months
measure: Change in number of Parkinson's disease treatments from 6 months to 12 months
timeFrame: 6 months
measure: Change in number of Parkinson's disease treatments from 12 to 18 months
timeFrame: 6 months
measure: Change in number of Parkinson's disease treatments from 18 to 24 months
timeFrame: 6 months
Other outcomes:
Locations:
city: Pozuelo De Alarcón
country: Spain
facility: Universidad Francisco de Vitoria
state: Madrid
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
Study officials:
affiliation: Hospital Universitario La Princesa
name: Inés Muro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universidad Francisco de Vitoria
name: Juan P Romero, PhD
role: STUDY_DIRECTOR
affiliation: Hospital Universitario La Princesa
name: Lydia López, MD
role: STUDY_CHAIR
References:
citation: 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 C, Ottman R, Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22;361(17):1651-61. doi: 10.1056/NEJMoa0901281.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.