Brain Changes by Rivastigmine According to Butyrylcholinesterase Alleles

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

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.

Study Overview

• Status: Unknown
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Rivastigmine

• Study Type: Interventional
• Enrollment (Anticipated): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 156-707
    • Seoul Metropolitan Government Seoul National University Boramae Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rivastigmine	Drug: Rivastigmine; 9-18mg/rivastigmine for 52 weeks; Other Names: Exelon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the mean changes of Standardized Uptake Values (SUVmean) in PET imaging	Unit: mg/100g/min	screening and 52weeks (2 times)
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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the mean changes of cortical thickness in brain MRI	unit of mm	screening and 52weeks (2 times)
the cognitive changes in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog)	unit in points	screening, 26, and 52 weeks (3 times)
the cognitive changes in Mini-Mental State Exam (MMSE)	unit in points	screening, 26, and 52 weeks (3 times)
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)
the behavioural changes by Caregiver-Administered Neuropsychiatric Inventory (NPI)	unit in points	screening, 26, and 52 weeks (3 times)
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)

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Collaborators: Novartis Korea Ltd.

Publications and helpful links

General Publications

• Ames A 3rd. CNS energy metabolism as related to function. Brain Res Brain Res Rev. 2000 Nov;34(1-2):42-68. doi: 10.1016/s0165-0173(00)00038-2.
• 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. doi: 10.1097/01.fpc.0000220573.05714.ac.
• Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer's disease. Lancet. 1976 Dec 25;2(8000):1403. doi: 10.1016/s0140-6736(76)91936-x. No abstract available.
• Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007 Sep;8(9):700-11. doi: 10.1038/nrn2201.
• 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. doi: 10.1136/jnnp.2004.039321.
• 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.
• Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol. 2006 Feb;9(1):101-24. doi: 10.1017/S1461145705005833. Epub 2005 Aug 5.
• 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. doi: 10.1037//0894-4105.14.2.288.
• 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.
• 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. doi: 10.1097/00008571-200304000-00008.
• 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.
• 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. doi: 10.1001/archpsyc.62.5.565.
• 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. doi: 10.1002/(sici)1096-8628(19990416)88:23.0.co;2-3.
• 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. doi: 10.1007/s007020170005.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (ANTICIPATED): June 1, 2017
• Study Completion (ANTICIPATED): June 1, 2017

Study Registration Dates

• First Submitted: February 12, 2014
• First Submitted That Met QC Criteria: February 13, 2014
• First Posted (ESTIMATE): February 14, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): May 14, 2015
• Last Update Submitted That Met QC Criteria: May 12, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: rivastigmine, butyrylcholinesterase, MRI, PET
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Neuroprotective Agents; Protective Agents; Cholinesterase Inhibitors; Rivastigmine
• Other Study ID Numbers: CENA713DKR15T