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

Parkinson's Disease Clinical Trial

Official title:

Predictive and Diagnostic Value of Tau and Beta-amyloid Markers in Cerebrospinal Fluid and Positron Emission Tomography in the Dementia of Parkinson's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02243982
• Other study ID #: PI1080236
• Status: Completed
• Phase: Phase 0
• First received: August 13, 2014
• Last updated: September 16, 2014
• Start date: March 2010
• Est. completion date: December 2012

Study information

• Verified date: December 2009
• Source: Fundacion Clinic per a la Recerca Biomédica
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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:

1. - 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.

2. -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.

3. PDND patients will show a [F18]-FDDNP PET uptake and levels of protein markers in CSF intermediate between controls and patients with PD.

4. -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

5. - The predictive value for the development of dementia in PD of specific patterns of PET uptake and CSF proteins profile will be established.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: December 2012
• Est. primary completion date: June 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

Inclusion Criteria PDD

• 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.

Inclusion criteria PDND:

• 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.

Inclusion criteria Controls:

• 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.

Exclusion Criteria:

• 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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Dementia
• Parkinson Disease
• Parkinson's Disease
• Parkinson-Dementia Syndrome
• Supranuclear Palsy, Progressive

Intervention

Other:
• [F18]-FDDNP
radiopharmaceutical tracer, intravenous, single dose, of 360+/- 20 megabecquerel

Locations

Country	Name	City	State
Spain	Hospital Clinic	Barcelona

Sponsors (1)

Lead Sponsor	Collaborator
Fundacion Clinic per a la Recerca Biomédica

Country where clinical trial is conducted

Spain, 

References & Publications (15)

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. — View Citation

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. — View Citation

Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol. 2003 Oct;2(10):605-13. Review. — View Citation

Caballol N, Martí MJ, Tolosa E. Cognitive dysfunction and dementia in Parkinson disease. Mov Disord. 2007 Sep;22 Suppl 17:S358-66. doi: 10.1002/mds.21677. Review. — View Citation

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. — View Citation

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. — View Citation

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

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. Review. — View Citation

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. — View Citation

Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996 Sep;16(5):834-40. — View Citation

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. Epub 2007 Oct 22. — View Citation

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. Epub 2006 Aug 7. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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.	Enzyme linked immunosorbent assay (ELISA) method will be used to assess the concentration of the biomarkers in the CSF.	Baseline assessment	No
Secondary	Number of patients without dementia at baseline that switch to dementia at 18 months follow-up	PDND group will be followed-up at 18 months to assess the number of patient that develops dementia, using the criteria of Diagnostic and Statistical Manual of Mental Disorders version IV.	18 months	No