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| Principal Investigator | |
| Principal Investigator's Name: | KEUN YOU KIM |
| Institution: | Yonsei University College of Medicine / Severance Hospital |
| Department: | Psychiatry |
| Country: | |
| Proposed Analysis: | 1. Study Title Clusterin and irisin as level in dementia and diabetes using ADNI data 2. Background and purpose of study Alzheimer’s disease (AD) is known to be multifactorial disease(1). The close relationship between AD and diabetes mellitus (DM), the most common metabolic disorder, has already been proven through many epidemiological and biological studies(2, 3). Insulin resistance is known to be involved in both diseases and play an important role in aggravating core AD pathologies such as amyloid beta and tau, as well as a key pathogenetic mechanism of DM(4). Clusterin, also known as apolipoprotein J, is lipoprotein diffusely distributed in brain and other peripheral tissue(5). Peripheral circulating clusterin level has been suggested as a potential biomarker for AD diagnosis and increasing peripheral clustering level is closely related to the degree of brain cortical atrophy(6-8). Recently, a significant increase in clusterin levels has been reported in various metabolic diseases such as DM, coronary artery disease, and obesity, and it is carefully reported as a marker capable of representing insulin resistance(9-11). The increasing level of clusterin in not only in AD but also various metabolic diseases may suggest that it may be directly involved in the relationship between DM and AD as a mediator representing insulin resistance. Irisin, exercise-induced myokine which is cleaved from the transmembrane receptor fibronectin type III domain containing 5 (FNDC5) in skeletal muscle, was at first identified as the mediator of the favoring effect of physical exercise on obesity and diabetes mellitus (DM) through stimulating adipocyte browning and thermogenesis(12). It was also revealed that, in the opposite direction of clusterin, irisin could play an important role as a link between the brain and peripheral tissues since irisin protected neuroinflammation and synaptic loss in AD mice via expressing brain-derived neurotrophic factor (BDNF)(13, 14). Irisin was also found in the human brain and recent studies reported that people with high cerebrospinal fluid (CSF) irisin level showed good cognitive function and low AD pathology(13, 15). However, so far, there are very few studies that have measured clusterin or irisin by simultaneously considering both DM and AD. Recently, our research team revealed that clusterin may have a role in linking DM with AD as a potential mediator(16); but the relationship between clusterin and AD pathology is still unknown. In addition, there are no longitudinal studies investigating how the increased level of initial clusterin or irisin level in the nondemented people with metabolic disease affects the onset or prognosis of AD. Using ADNI data, we would like to determine how clusterin or irisin levels in plasma and CSF change in DM and AD patients, respectively, and the longitudinal change of the relationship between these biomarkers and AD pathology or brain images. 3. Target number of participants Participants diagnosed with Normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) between 55 and 90 years of age from January 1, 2004 to December 31, 2008 in ADNI data. Among those who meet the selection criteria, it is estimated that about 800 people are eligible. 4. Inclusion/exclusion criteria A. Inclusion criteria i. Adults aged between 55 – 90 ii. GDS (Geriatric Depression Scale) less than 6 iii. Visual and auditory acuity adequate for neuropsychological testing iv. Completed six grades of education or has a good work history (to exclude mental retardation) B. Exclusion criteria i. Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions; Participants with multiple lacunes or lacunes in a critical memory structure are exclude ii. Residence in skilled nursing facility iii. Clinically significant abnormalities in B12, or TFTs that might interfere with the study iv. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body v. Major depression, bipolar disorder as described in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) within the past 1 year vi. Currently treated with medication for obsessive-compulsive disorder or attention deficit disorder vii. History of schizophrenia viii. History of alcohol or substance abuse or dependence within the past 2 years 5. Study design and method A. Primary outcome i. Interaction of clusterin or irisin with DM or AD ii. Conversion rate from NC or MCI to AD differed by baseline clusterin or irisin concentration iii. AD conversion rate of DM patient group (with NC or MCI) according to baseline clusterin or irisin concentration B. Secondary outcome i. The relationship between clusterin or irisin concentration and brain structural changes on MRI (Both cross-sectional and longitudinal change) ii. The relationship between clusterin or irisin concentration and amyloid beta or tau pathologic change on MRI (Both cross-sectional and longitudinal change) 6. Statistical analysis A. Analysis will be conducted using SPSS or R and the difference in biomarkers (clusterin or irisin) for each disease of AD and DM can be checked using one-way ANOVA. The interaction effect of DM and biomarkers will be measured by using two-way ANOVA. The mediating or moderating effect of biomarkers on the relationship between DM and AD will be investigated using regression analysis. The correlation between clinical indicators and biomarker level will be analyzed through Pearson's correlation. B. Longitudinal changes of AD pathology and cognitive function according to biomarkers will be worked through repeated measure ANOVA or linear mixed model analysis. 7. References 1. Holtzman DM, Morris JC, Goate AM. Alzheimer's disease: the challenge of the second century. Sci Transl Med. 2011;3(77):77sr1. 2. Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Archives of neurology. 2009;66(3):300-5. 3. Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology. 2005;65(4):545-51. 4. Talbot K, Wang H-Y, Kazi H, Han L-Y, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. The Journal of Clinical Investigation. 2012;122(4):1316-38. 5. Calero M, Tokuda T, Rostagno A, Kumar A, Zlokovic B, Frangione B, et al. Functional and structural properties of lipid-associated apolipoprotein J (clusterin). Biochem J. 1999;344 Pt 2(Pt 2):375-83. 6. Thambisetty M, An Y, Kinsey A, Koka D, Saleem M, Guntert A, et al. Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment. Neuroimage. 2012;59(1):212-7. 7. Thambisetty M, Simmons A, Velayudhan L, Hye A, Campbell J, Zhang Y, et al. Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry. 2010;67(7):739-48. 8. Lacour A, Espinosa A, Louwersheimer E, Heilmann S, Hernandez I, Wolfsgruber S, et al. Genome-wide significant risk factors for Alzheimer's disease: role in progression to dementia due to Alzheimer's disease among subjects with mild cognitive impairment. Mol Psychiatry. 2017;22(1):153-60. 9. Mackness B, Hunt R, Durrington Paul N, Mackness Michael I. Increased Immunolocalization of Paraoxonase, Clusterin, and Apolipoprotein A-I in the Human Artery Wall With the Progression of Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17(7):1233-8. 10. Ishikawa Y, Akasaka Y, Ishii T, Komiyama K, Masuda S, Asuwa N. Distribution and synthesis of apolipoprotein J in the atherosclerotic aorta. Arterioscler Thromb Vasc Biol. 1998;18. 11. Trougakos IP, Poulakou M, Stathatos M, Chalikia A, Melidonis A, Gonos ES. Serum levels of the senescence biomarker clusterin/apolipoprotein J increase significantly in diabetes type II and during development of coronary heart disease or at myocardial infarction. Exp Gerontol. 2002;37(10-11):1175-87. 12. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-8. 13. Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nature medicine. 2019;25(1):165-75. 14. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell metabolism. 2013;18(5):649-59. 15. Lourenco MV, Ribeiro FC, Sudo FK, Drummond C, Assunção N, Vanderborght B, et al. Cerebrospinal fluid irisin correlates with amyloid‐β, BDNF, and cognition in Alzheimer's disease. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. 2020;12(1):e12034. 16. Ha J, Moon MK, Kim H, Park M, Cho SY, Lee J, et al. Plasma Clusterin as a Potential Link Between Diabetes and Alzheimer Disease. J Clin Endocrinol Metab. 2020;105(9). |
| Additional Investigators |
