Brain Changes by Rivastigmine According to Butyrylcholinesterase Alleles

Alzheimer's Disease Clinical Trial

Official title:

Differences of Functional Changes in Brain by Rivastigmine According to Butyrylcholinesterase Alleles in Alzheimer's Disease Patients(Rivastigmine, Imaging, and BuChE in AD: RIBA)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02063269
• Other study ID #: CENA713DKR15T
• Status: Active, not recruiting
• Phase: N/A
• First received: February 12, 2014
• Last updated: May 12, 2015
• Start date: February 2014
• Est. completion date: June 2017

Study information

• Verified date: May 2015
• Source: Seoul National University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Korea: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Butyrylcholinesterase (BuChE) activity is increasing in Alzheimer Disease (AD) process (Lane et al., 2006). BuChE wild type has stronger butyrylcholine esterase activity than BuChE K variant allele and this strong activity can affect AD brain negatively by choline depletion. Rivastigmine has unique dual action - acetylcholine esterase inhibition and butyrylcholine esterase inhibition. Therefore, rivastigmine can lower serum butyrylcholine esterase activity and delay functional decrease of Fluorodeoxyglucose positron emission tomography (FDG PET) images in AD patients with BuChE wild type allele by strong BuChE inhibition.

It suggests that rivastigmine can affect brain function differently by BuChE genotype in AD. Therefore, we will try to find the different changes of serum butyrylcholine esterase activity by ELISA and functional and structural changes of brain between BuChE wild type and K-variant type by FDG PET and MRI pre and post images after 12 month use of rivastigmine.

1. Primary objective:

1. the mean changes of Standardized Uptake Values (SUVmean) in PET imaging

2. the mean changes of serum BuChE activity between BuChE wild type and K-variant type.

2. Secondary objectives:

1. the mean changes of cortical thickness in brain MRI

2. the cognitive changes in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)

3. the cognitive changes in Mini-Mental State Exam (MMSE)

4. the daily function changes by Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)

5. the behavioural changes by Caregiver-Administered Neuropsychiatric Inventory (NPI)

6. the disease severity changes by Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) between BuChE wild type and K-variant type.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 70
• Est. completion date: June 2017
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 55 Years to 80 Years

Eligibility

Inclusion Criteria:

• Clinical diagnosis of Alzheimer's Disease (NINCD-ADRDA and MMSE between 10 ~26)

• Who didn't take Cholinesterase Inhibitor on liver within 3 months

Exclusion Criteria:

• diagnosed with diseases other than AD that affect brain atrophy according to Brain MRI

• Diagnosed with diseases other than AD which affect cognitive functions (i.g. Schizophrenia, Major Depression, Mental Retardation, encephalopathy, etc.)

• Didn't suspect of drug or alcohol addictions within last decade

• Unable to participate the study due to poor sight and hearing

• Who aren't suitable to participate according to the researchers' judgement

Study Design

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Drug:
• Rivastigmine
9-18mg/rivastigmine for 52 weeks

Locations

Country	Name	City	State
Korea, Republic of	Seoul Metropolitan Government Seoul National University Boramae Medical Center	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Seoul National University Hospital	Novartis Korea Ltd.

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (15)

Ames A 3rd. CNS energy metabolism as related to function. Brain Res Brain Res Rev. 2000 Nov;34(1-2):42-68. Review. — View Citation

Blesa R, Bullock R, He Y, Bergman H, Gambina G, Meyer J, Rapatz G, Nagel J, Lane R. Effect of butyrylcholinesterase genotype on the response to rivastigmine or donepezil in younger patients with Alzheimer's disease. Pharmacogenet Genomics. 2006 Nov;16(11):771-4. — View Citation

Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 1976 Dec 25;2(8000):1403. — View Citation

Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007 Sep;8(9):700-11. Review. — View Citation

Holmes C, Ballard C, Lehmann D, David Smith A, Beaumont H, Day IN, Nadeem Khan M, Lovestone S, McCulley M, Morris CM, Munoz DG, O'Brien K, Russ C, Del Ser T, Warden D. Rate of progression of cognitive decline in Alzheimer's disease: effect of butyrylcholinesterase K gene variation. J Neurol Neurosurg Psychiatry. 2005 May;76(5):640-3. — View Citation

Jagust WJ, Bandy D, Chen K, Foster NL, Landau SM, Mathis CA, Price JC, Reiman EM, Skovronsky D, Koeppe RA; Alzheimer's Disease Neuroimaging Initiative. The Alzheimer's Disease Neuroimaging Initiative positron emission tomography core. Alzheimers Dement. 2010 May;6(3):221-9. doi: 10.1016/j.jalz.2010.03.003. — View Citation

Ki CS, Na DL, Kim JW, Kim HJ, Kim DK, Yoon BK. No association between the genes for butyrylcholinesterase K variant and apolipoprotein E4 in late-onset Alzheimer's disease. Am J Med Genet. 1999 Apr 16;88(2):113-5. — View Citation

Kim KW, Jhoo JH, Lee JH, Lee KU, Lee DY, Youn JC, Youn JY, Woo JI. Neither the butyrylcholinesterase K variant nor transferrin C2 variant confers a risk for Alzheimer's disease in Koreans. J Neural Transm (Vienna). 2001;108(10):1159-66. — View Citation

Kimura N, Kumamoto T, Masuda T, Hanaoka T, Okazaki T, Arakawa R. Evaluation of the regional cerebral blood flow changes during long-term donepezil therapy in patients with Alzheimer's disease using 3DSRT. J Neuroimaging. 2012 Jul;22(3):299-304. doi: 10.1111/j.1552-6569.2011.00612.x. Epub 2011 Jun 23. — View Citation

Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol. 2006 Feb;9(1):101-24. Epub 2005 Aug 5. Review. — View Citation

Levy JA, Parasuraman R, Greenwood PM, Dukoff R, Sunderland T. Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease. Neuropsychology. 2000 Apr;14(2):288-98. — View Citation

Nobili F, Koulibaly M, Vitali P, Migneco O, Mariani G, Ebmeier K, Pupi A, Robert PH, Rodriguez G, Darcourt J. Brain perfusion follow-up in Alzheimer's patients during treatment with acetylcholinesterase inhibitors. J Nucl Med. 2002 Aug;43(8):983-90. — View Citation

O'Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, Ford GA, O'Brien JT, Swan AG, Fairbairn AF, Wesnes K, del Ser T, Edwardson JA, Morris CM, McKeith IG. Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics. 2003 Apr;13(4):231-9. — View Citation

Poirier J. Evidence that the clinical effects of cholinesterase inhibitors are related to potency and targeting of action. Int J Clin Pract Suppl. 2002 Jun;(127):6-19. Review. — View Citation

Silverman JM, Ciresi G, Smith CJ, Marin DB, Schnaider-Beeri M. Variability of familial risk of Alzheimer disease across the late life span. Arch Gen Psychiatry. 2005 May;62(5):565-73. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	the mean changes of Standardized Uptake Values (SUVmean) in PET imaging	Unit: mg/100g/min	screening and 52weeks (2 times)	No
Primary	the mean changes of serum BuChE activity between BuChE wild type and K-variant type	unit of umil ACSCh/h/mg	screening and 52weeks (2 times)	No
Secondary	the mean changes of cortical thickness in brain MRI	unit of mm	screening and 52weeks (2 times)	No
Secondary	the cognitive changes in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)	unit in points	screening, 26, and 52 weeks (3 times)	No
Secondary	the cognitive changes in Mini-Mental State Exam (MMSE)	unit in points	screening, 26, and 52 weeks (3 times)	No
Secondary	the daily function changes by Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)	unit in points	screening, 26, and 52 weeks (3 times)	No
Secondary	the behavioural changes by Caregiver-Administered Neuropsychiatric Inventory (NPI)	unit in points	screening, 26, and 52 weeks (3 times)	No
Secondary	the disease severity changes by Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) between BuChE wild type and K-variant type	unit in points	screening, 26, and 52 weeks (3 times)	No