Predictive and Diagnostic Value of Tau and Beta-amyloid Markers in the Dementia of Parkinson's Disease

NCT02243982 | Completed Early Phase 1

• 1 other identifier: PI1080236
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

The PET tracer Fluoro-ethyl-methyl-amino-naphthyl-ethylidene-malononitrile (\[F18\]-FDDNP) has a specific affinity for lesions containing tau protein and beta-amyloid The study consists of two phases

• In a first transversal phase, 8 neurologically unimpaired controls, 15 patients with PD and no dementia (PDND) and 8 with PD and dementia (PDD) will undergo lumbar puncture for study of tau, phospho-tau and beta-amyloid levels in cerebrospinal fluid (CSF), as well as positron emission tomography (PET) with (\[F18\]-FDDNP. Concentration of CSF markers and both the degree and topography of FDDNP-PET uptake will be compared among groups, along with correlation analysis between CSF and PET findings.
• During the second phase (18 months follow-up), the PDND patients will undergo the same procedures, and cognitive changes including incident dementia will be assessed. The correlation between cognitive impairment and neurochemical and neuroimaging changes will be established to determine the predictive value of these markers. Since the pathological lesions observed in Alzheimer disease (AD) are common in the PD and the concentrations of tau and beta-amyloid are altered in AD and PET with \[F18\]-FDDNP is able to separate patients with AD and cognitive impairment from controls, we hypothesized that:
• \- Patients with PD will show a biomarkers profile similar to the AD (decreased levels of beta-amyloid and increased phospho-tau and tau) in CSF, and an abnormal uptake of \[F18\]-FDDNP PET compared to PDND patients and controls.
• -The distribution of cortical \[F18\]-FDDNP in the PD will be different from the AD and similar to dementia with Lewy bodies, predominantly in posterior cortical areas.
• PDND patients will show a \[F18\]-FDDNP PET uptake and levels of protein markers in CSF intermediate between controls and patients with PD.
• -In the subsequent follow-up, PDND patients will show cognitive impairment correlate to changes in the levels of protein markers in CSF and uptake of PET with \[F18\]-FDDNP
• \- The predictive value for the development of dementia in PD of specific patterns of PET uptake and CSF proteins profile will be established.

Conditions

Parkinson's Disease; Parkinson-Dementia Syndrome

Keywords

Parkinson, dementia, FDDNP, tau, beta-amyloid

Outcome Measures

Primary Outcomes (1)

• Relative Volume of Distribution of [F18]-FDDNP in non-demented patients with Parkinson's disease (PDND), demented patients with Parkinson's disease (PDD) and controls.

  To asses the \[F18\]-FDDNP PET uptake in non-demented patients with Parkinson's disease (PDND), demented patients with Parkinson's disease (PDD) and controls.

  Baseline assessment

Secondary Outcomes (2)

• Concentration ( pg/mL) of beta-amyloid, tau and phospho-tau in cerebrospinal fluid (CSF) of non-demented patients with Parkinson's disease (PDND), demented patients with Parkinson's disease (PDD) and controls.

  Baseline assessment

• Number of patients without dementia at baseline that switch to dementia at 18 months follow-up

  18 months

Study Arms (1)

[F18]-FDDNP

EXPERIMENTAL

2-(1-{6-\[(2-\[fluorine-18\]fluoroethyl)(methyl)amino\]-2-naphthyl}-ethylidene)malononitrile. Radiopharmaceutical tracer

Other: [F18]-FDDNP

Interventions

[F18]-FDDNP OTHER

radiopharmaceutical tracer, intravenous, single dose, of 360+/- 20 megabecquerel

Also known as: 2-(1-{6-[(2-[fluorine-18]fluoroethyl)(methyl)amino]-2-naphthyl}-ethylidene)malononitrile

[F18]-FDDNP

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 60 years old;
• Diagnose of PD probable or definite according to criteria of the United Kingdom Parkinson's Disease Society Brain Bank;
• The Hoehn \& Yahr stage of the disease between 3 and 5 in off state;
• Diagnose of dementia established according to the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the diagnostic guidelines for dementia of the Movement Disorders Society (MDS);
• The score of the Mini-Mental State Examination of Folstein (MMSE) \<24;
• The score on the Mattis Dementia Rating Scale (MDRS) \<136.
• Male or female ≥ 60 years old;
• Diagnose of PD probable or definite according to criteria of the United Kingdom Parkinson's Disease Society Brain Bank;
• The Hoehn \& Yahr stage of the disease between 3 and 5 in OFF state;
• The score of the Mini-Mental State Examination of Folstein (MMSE) ≥24;
• The score on the Mattis Dementia Rating Scale (MDRS) ≥136.
• Male or female ≥ 60 years old;
• No known diagnosis of neuropsychiatric diseases
• The score of the Mini-Mental State Examination of Folstein (MMSE) ≥24;
• The score on the Mattis Dementia Rating Scale (MDRS) ≥136.

You may not qualify if:

• The subject is pregnant or breastfeeding;
• The subject has a history of drug abuse or alcohol;
• The subject has developed dementia in the first year of parkinsonism or before than parkinsonism;
• The subject meets criteria for vascular dementia;
• The subject has symptoms suggestive of other types of parkinsonism (multi-system atrophy cortico-basal, supra-nuclear palsy progressive degeneration) or degenerative dementia (fronto-temporal dementia);
• The subject has a moderate or severe renal functional impairment (serum creatinine\> 1.5 mg / dL);
• The subject has a moderate or severe hepatic impairment (bilirubin\> 2 times the upper limit of normal, transaminases\> 3 times the upper limit of normal);
• The subject presents structural abnormalities in basal ganglia or cortical level on magnetic resonance imaging or computerized tomography;
• The subject has participated in a clinical study with an investigational drug product within 30 days prior to screening and / or radiopharmaceutical in a minimum period of 5 radioactive half-lives prior to screening;
• Occupational exposure to radiation\> 15 milliSievert (mSv) / year
• The subject has received treatment with non-steroidal anti-inflammatory drugs during the 30-day period before the PET scan
• The subject has allergy to the investigational product or any of its components;
• The subject has a clinically active, serious disease with a reduced life expectancy;
• The subject is claustrophobic / a.
• The subject has received in the last 364 days a dose of ionizing radiation that coupled with the study dose exceeds 10 mSv

Sponsors & Collaborators

• Fundacion Clinic per a la Recerca Biomédica: lead

Study Sites (1)

Hospital Clinic

Barcelona, Barcelona, 08036, Spain

Location

Related Publications (16)

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• Aarsland D, Perry R, Brown A, Larsen JP, Ballard C. Neuropathology of dementia in Parkinson's disease: a prospective, community-based study. Ann Neurol. 2005 Nov;58(5):773-6. doi: 10.1002/ana.20635.

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• Lashley T, Holton JL, Gray E, Kirkham K, O'Sullivan SS, Hilbig A, Wood NW, Lees AJ, Revesz T. Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson's disease patients. Acta Neuropathol. 2008 Apr;115(4):417-25. doi: 10.1007/s00401-007-0336-0. Epub 2008 Jan 8.

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• Jellinger KA, Wenning GK, Seppi K. Predictors of survival in dementia with lewy bodies and Parkinson dementia. Neurodegener Dis. 2007;4(6):428-30. doi: 10.1159/000107703. Epub 2007 Oct 9.

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• Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol. 2003 Oct;2(10):605-13. doi: 10.1016/s1474-4422(03)00530-1.

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• Jansen Steur E, Vermes I, de Vos RA. Cerebrospinal-fluid tau protein and aspartate aminotransferase in Parkinson's disease. Lancet. 1998 Apr 11;351(9109):1105-6. doi: 10.1016/s0140-6736(05)79387-9. No abstract available.

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• Mollenhauer B, Trenkwalder C, von Ahsen N, Bibl M, Steinacker P, Brechlin P, Schindehuette J, Poser S, Wiltfang J, Otto M. Beta-amlyoid 1-42 and tau-protein in cerebrospinal fluid of patients with Parkinson's disease dementia. Dement Geriatr Cogn Disord. 2006;22(3):200-8. doi: 10.1159/000094871. Epub 2006 Aug 7.

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• Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006 Mar;59(3):512-9. doi: 10.1002/ana.20730.

  PMID: 16372280 BACKGROUND

• Maetzler W, Reimold M, Liepelt I, Solbach C, Leyhe T, Schweitzer K, Eschweiler GW, Mittelbronn M, Gaenslen A, Uebele M, Reischl G, Gasser T, Machulla HJ, Bares R, Berg D. [11C]PIB binding in Parkinson's disease dementia. Neuroimage. 2008 Feb 1;39(3):1027-33. doi: 10.1016/j.neuroimage.2007.09.072. Epub 2007 Oct 22.

  PMID: 18035558 BACKGROUND

• Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, Cole GM, Small GW, Huang SC, Barrio JR. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease. J Neurosci. 2001 Dec 15;21(24):RC189. doi: 10.1523/JNEUROSCI.21-24-j0004.2001.

  PMID: 11734604 BACKGROUND

• Shoghi-Jadid K, Small GW, Agdeppa ED, Kepe V, Ercoli LM, Siddarth P, Read S, Satyamurthy N, Petric A, Huang SC, Barrio JR. Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. Am J Geriatr Psychiatry. 2002 Jan-Feb;10(1):24-35.

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• Smid LM, Vovko TD, Popovic M, Petric A, Kepe V, Barrio JR, Vidmar G, Bresjanac M. The 2,6-disubstituted naphthalene derivative FDDNP labeling reliably predicts Congo red birefringence of protein deposits in brain sections of selected human neurodegenerative diseases. Brain Pathol. 2006 Apr;16(2):124-30. doi: 10.1111/j.1750-3639.2006.00006.x.

  PMID: 16768752 BACKGROUND

• Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ, Lavretsky H, Burggren AC, Cole GM, Vinters HV, Thompson PM, Huang SC, Satyamurthy N, Phelps ME, Barrio JR. PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006 Dec 21;355(25):2652-63. doi: 10.1056/NEJMoa054625.

  PMID: 17182990 BACKGROUND

• Kepe V, Huang SC, Small GW, Satyamurthy N, Barrio JR. Visualizing pathology deposits in the living brain of patients with Alzheimer's disease. Methods Enzymol. 2006;412:144-60. doi: 10.1016/S0076-6879(06)12010-8.

  PMID: 17046657 BACKGROUND

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  PMID: 8784228 BACKGROUND

• Buongiorno M, Antonelli F, Compta Y, Fernandez Y, Pavia J, Lomena F, Rios J, Ramirez I, Garcia JR, Soler M, Camara A, Fernandez M, Basora M, Salazar F, Sanchez-Etayo G, Valldeoriola F, Barrio JR, Marti MJ. Cross-Sectional and Longitudinal Cognitive Correlates of FDDNP PET and CSF Amyloid-beta and Tau in Parkinson's Disease1. J Alzheimers Dis. 2017;55(3):1261-1272. doi: 10.3233/JAD-160698.

  PMID: 27814297 DERIVED

MeSH Terms

Conditions

Parkinson Disease; Progressive supranuclear palsy atypical; Dementia; Pick Disease of the Brain; Plaque, Amyloid

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Maria Jose Martí, Md, PhD

  Fundació per a la Recerca Biomedica

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: August 13, 2014
• First Posted: September 18, 2014
• Study Start: March 1, 2010
• Primary Completion: June 1, 2011
• Study Completion: December 1, 2012
• Last Updated: September 18, 2014

Record last verified: 2009-12

Locations

ES (1)