Abstract
In the present study, we examined whether neuropsychiatric symptoms were correlated with plasma brain-derived neurotrophic factor (BDNF) levels as a state marker or were associated with the BDNF polymorphism Val66Met in patients with amnestic mild cognitive impairment (A-MCI) or Alzheimer disease (AD). One hundred and seventy-six outpatients with AD (n = 129) or A-MCI (n = 47) were selected and their plasma BDNF concentrations measured. Next, we investigated the correlation between the plasma BDNF level and the Behavioral Pathology in Alzheimer Disease (Behave-AD) subscale scores, which reflect neuropsychiatric symptoms. We also compared the plasma BDNF level and the Behave-AD subscale scores among the BDNF Val66Met genotypic groups. Among the seven Behave-AD subscale scores, aggressiveness was positively correlated with the plasma BDNF level (ρ = 0.237, P < 0.005), but did not differ significantly among the three BDNF Val66Met genotypic groups. The Behave-AD total and other subscale scores did not differ significantly among the BDNF Val66Met genotypic groups and were not associated with the plasma BDNF level. Moreover, the plasma BDNF level did not differ significantly among the three BDNF Val66Met genotypic groups or between patients with A-MCI and those with AD. The plasma BDNF level was robustly correlated with aggressiveness, implying that the plasma BDNF level might be useful as a behavioral state marker in patients with AD or A-MCI.
Similar content being viewed by others
References
Akatsu H, Yamagata HD, Kawamata J, Kamino K, Takeda M, Yamamoto T, Miki T, Tooyama I, Shimohama S, Kosaka K (2006) Variations in the BDNF gene in autopsy-confirmed Alzheimer’s disease and dementia with Lewy bodies in Japan. Dement Geriatr Cogn Disord 22(3):216–222
Angelucci F, Spalletta G, di Iulio F, Ciaramella A, Salani F, Colantoni L, Varsi AE, Gianni W, Sancesario G, Caltagirone C, Bossù P (2010) Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are characterized by increased BDNF serum levels. Curr Alzheimer Res 7(1):15–20
Borroni B, Archetti S, Costanzi C, Grassi M, Ferrari M, Radeghieri A, Caimi L, Caltagirone C, Di Luca M, Padovani A, ITINAD Working Group (2009) Role of BDNF Val66Met functional polymorphism in Alzheimer’s disease-related depression. Neurobiol Aging 30(9):1406–1412
Bruen PD, McGeown WJ, Shanks MF, Venneri A (2008) Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain 131(Pt9):2455–2463. doi:10.1093/brain/awn151
Brunoni AR, Lopes M, Fregni F (2008) A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 11(8):1169–1180. doi:10.1017/S1461145708009309
Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, Lee FS (2004) Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24(18):4401–4411
Christensen R, Marcussen AB, Wörtwein G, Knudsen GM, Aznar S (2008) Abeta (1-42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5-HT(2A) levels. Exp Neurol 210(1):164–171
Cross AJ, Crow TJ, Ferrier IN, Johnson JA (1986) The selectivity of the reduction of serotonin S2 receptors in Alzheimer-type dementia. Neurobiol Aging 7(1):3–7
Diniz BS, Teixeira AL (2011) Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. Neuromolecular Med. 13(4):217–222. doi:10.1007/s12017-011-8154-x
Dubois B, Slachevsky A, Litvan I, Pillon B (2000) The FAB: a frontal assessment battery at bedside. Neurology 55(11):1621–1626
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B, Weinberger DR (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112(2):257–269
Folstein MF, Folstein SE, McHugh PR (1975) “Mini-Mental State”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198
Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, Izzo G, Gattaz WF (2010) Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry 11(6):774–780. doi:10.3109/15622971003797241
Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J, Sun B, Tandon NN (2002) Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 87(4):728–734
Gunstad J, Benitez A, Smith J, Glickman E, Spitznagel MB, Alexander T, Juvancic-Heltzel J, Murray L (2008) Serum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults. J Geriatr Psychiatry Neurol 21(3):166–170. doi:10.1177/0891988708316860
Huang R, Huang J, Cathcart H, Smith S, Poduslo SE (2007) Genetic variants in brain-derived neurotrophic factor associated with Alzheimer’s disease. J Med Genet 44(2):e66
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry 140:566–572
Iga J, Ueno S, Yamauchi K, Numata S, Tayoshi-Shibuya S, Kinouchi S, Nakataki M, Song H, Hokoishi K, Tanabe H, Sano A, Ohmori T (2007) The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients. Am J Med Genet B Neuropsychiatr Genet 144B:1003–1006
Ito W, Chehab M, Thakur S, Li J, Morozov A (2011) BDNF-restricted knockout mice as an animal model for aggression. Genes Brain Behav 10(3):365–374. doi:10.1111/j.1601-183X.2010.00676.x
Klein AB, Williamson R, Santini MA, Clemmensen C, Ettrup A, Rios M, Knudsen GM, Aznar S (2011) Blood BDNF concentrations reflect brain-tissue BDNF levels across species. Int J Neuropsychopharmacol 14(3):347–353. doi:10.1017/S1461145710000738
Kobayashi N, Nagata T, Shinagawa S, Oka N, Shimada K, Shimizu A, Tatebayashi Y, Yamada H, Nakayama K, Kondo K (2013) Increase in the IgG avidity index due to herpes simplex virus type 1 reactivation and its relationship with cognitive function in amnestic mild cognitive impairment and Alzheimer’s disease. Biochem Biophys Res Commun 430(3):907–911. doi:10.1016/j.bbrc.2012.12.054
Lanctôt KL, Herrmann N, Eryavec G, van Reekum R, Reed K, Naranjo CA (2002) Central serotonergic activity is related to the aggressive behaviors of Alzheimer’s disease. Neuropsychopharmacology 27(4):646–654
Lang UE, Günther L, Scheuch K, Klein J, Eckhart S, Hellweg R, Danker-Hopfe H, Oehler J (2009) Higher BDNF concentrations in the hippocampus and cortex of an aggressive mouse strain. Behav Brain Res 197(1):246–249. doi:10.1016/j.bbr.2008.08.025
Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, Bartels M, Buchkremer G, Schott K (2006) Stage-dependent BDNF serum concentrations in Alzheimer’s disease. J Neural Transm. 113(9):1217–1224
Lee BC, Choi IG, Kim YK, Ham BJ, Yang BH, Roh S, Choi J, Lee JS, Oh DY, Chai YG (2009) Relation between plasma brain-derived neurotrophic factors and nerve growth factor in the male patients with alcohol dependence. Alcohol 43(4):265–269
Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, Wihler C, Koliatsos VE, Tessarollo L (1999) Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci USA 96(26):15239–15244
Matsumoto N, Ikeda M, Fukuhara R, Shinagawa S, Ishikawa T, Mori T, Toyota Y, Matsumoto T, Adachi H, Hirono N, Tanabe H (2007) Caregiver burden associated with behavioral and psychological symptoms of dementia in elderly people in the local community. Dement Geriatr Cogn Disord 23(4):219–224
Matsushita S, Arai H, Matsui T, Yuzuriha T, Urakami K, Masaki T, Higuchi S (2005) Brain-derived neurotrophic factor gene polymorphisms and Alzheimer’s disease. J Neural Transm 112(5):703–711
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34(7):939–944
Murman DL, Chen Q, Powell MC, Kuo SB, Bradley CJ, Colenda CC (2002) The incremental direct costs associated with behavioral symptoms in AD. Neurology 59(11):1721–1729
Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15(3):331–337. doi:10.1038/nm.1912
Nagata T, Shinagawa S, Ochiai Y, Kada H, Kasahara H, Nukariya K, Nakayama K (2010) Relationship of frontal lobe dysfunction and aberrant motor behaviors in patients with Alzheimer’s disease. Int Psychogeriatr 22(3):463–469. doi:10.1017/S1041610209991323
Nagata T, Shinagawa S, Nukariya K, Yamada H, Nakayama K (2012) Association between BDNF polymorphism (Val66Met) and executive function in patients with amnestic mild cognitive impairment or mild Alzheimer disease. Dement Geriatr Cogn Disord 33(4):266–272. doi:10.1159/000339358
O’Bryant SE, Hobson V, Hall JR, Waring SC, Chan W, Massman P, Lacritz L, Cullum CM, Diaz-Arrastia R, Texas Alzheimer’s Research Consortium (2009) Brain-derived neurotrophic factor levels in Alzheimer’s disease. J Alzheimers Dis. 17(2):337–341. doi:10.3233/JAD-2009-1051
O’Bryant SE, Hobson VL, Hall JR, Barber RC, Zhang S, Johnson L, Diaz-Arrastia R, Texas Alzheimer’s Research Consortium (2011) Serum brain-derived neurotrophic factor levels are specifically associated with memory performance among Alzheimer’s disease cases. Dement Geriatr Cogn Disord 31(1):31–36. doi:10.1159/000321980
Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winbland B (2001) Current concepts in mild cognitive impairment. Arch Neurol 58(12):1985–1992
Piccinni A, Marazziti D, Catena M, Domenici L, Del Debbio A, Bianchi C, Mannari C, Martini C, Da Pozzo E, Schiavi E, Mariotti A, Roncaglia I, Palla A, Consoli G, Giovannini L, Massimetti G, Dell’Osso L (2008) Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments. J Affect Disord 105(1–3):279–283
Reisberg B, Borenstein J, Salob SP, Ferris SH, Franssen E, Georgotas A (1987) Behavioral symptoms in Alzheimer’s disease: phenomenology and treatment. J Clin Psychiatry 48(Suppl):9–15
Rosenberg PB, Mielke MM, Appleby BS, Oh ES, Geda YE, Lyketsos CG (2013) The association of neuropsychiatric symptoms in MCI with incident dementia and Alzheimer disease. Am J Geriatr Psychiatry 21(7):685–695. doi:10.1016/j.jagp.2013.01.006
Schroeter ML, Stein T, Maslowski N, Neumann J (2009) Neural correlates of Alzheimer’s disease and mild cognitive impairment: a systematic and quantitative meta-analysis involving 1351 patients. Neuroimage 47(4):1196–1206. doi:10.1016/j.neuroimage.2009.05.037
Sen S, Duman R, Sanacora G (2008) Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 64(6):527–532. doi:10.1016/j.biopsych.2008.05.005
Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, Blennow K, Soares H, Simon A, Lewczuk P, Dean R, Siemers E, Potter W, Lee VM, Trojanowski JQ (2009) Alzheimer’s disease neuroimaging initiative. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 65(4):403–413. doi:10.1002/ana.21610
Shibata N, Ohnuma T, Kuerban B, Komatsu M, Arai H (2011) Genetic association between ghrelin polymorphisms and Alzheimer’s disease in a Japanese population. Dement Geriatr Cogn Disord 32(3):178–181. doi:10.1159/000333075
Shin SJ, Yoon HE, Chung S, Kim YG, Kim DJ (2012) Plasma brain-derived neurotrophic factor in hemodialysis patients. Int J Med Sci. 9(9):772–777. doi:10.7150/ijms.5063
Teng E, Lu PH, Cummings JL (2007) Neuropsychiatric symptoms are associated with progression from mild cognitive impairment to Alzheimer’s disease. Dement Geriatr Cogn Disord 24(4):253–259
Terracciano A, Piras MG, Lobina M, Mulas A, Meirelles O, Sutin AR, Chan W, Sanna S, Uda M, Crisponi L, Schlessinger D (2011) Genetics of serum BDNF: Meta-analysis of the Val66Met and genome-wide association study. World J Biol Psychiatry. doi:10.3109/15622975.2011.616533
Vaidya VA, Marek GJ, Aghajanian GK, Duman RS (1997) 5-HT2A receptor-mediated regulation of brain-derived neurotrophic factor mRNA in the hippocampus and the neocortex. J Neurosci 17(8):2785–2795
Vermeiren Y, Le Bastard N, Van Hemelrijck A, Drinkenburg WH, Engelborghs S, De Deyn PP (2012) Behavioral correlates of cerebrospinal fluid amino acid and biogenic amine neurotransmitter alterations in dementia. Alzheimer Dement. doi:10.1016/j.jalz.2012.06.010
Voineskos AN, Lerch JP, Felsky D, Shaikh S, Rajji TK, Miranda D, Lobaugh NJ, Mulsant BH, Pollock BG, Kennedy JL (2011) The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. Arch Gen Psychiatry 68(2):198–206. doi:10.1001/archgenpsychiatry.2010.194
Yu H, Zhang Z, Shi Y, Bai F, Xie C, Qian Y, Yuan Y, Deng L (2008) Association study of the decreased serum BDNF concentrations in amnestic mild cognitive impairment and the Val66Met polymorphism in Chinese Han. J Clin Psychiatry 69(7):1104–1111
Zarros ACh, Kalopita KS, Tsakiris ST (2005) Serotoninergic impairment and aggressive behavior in Alzheimer’s disease. Acta Neurobiol Exp (Wars) 65(3):277–286
Zhang XY, da Chen C, Xiu MH, Haile CN, Luo X, Xu K, Zhang HP, Zuo L, Zhang Z, Zhang X, Kosten TA, Kosten TR (2012) Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls. Hum Genet 131(7):1187–1195. doi:10.1007/s00439-012-1150-x
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nagata, T., Kobayashi, N., Shinagawa, S. et al. Plasma BDNF levels are correlated with aggressiveness in patients with amnestic mild cognitive impairment or Alzheimer disease. J Neural Transm 121, 433–441 (2014). https://doi.org/10.1007/s00702-013-1121-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-013-1121-y