Abstract
Dementia is an ever-expanding problem facing an ageing society. Currently, there is a sharp paucity of treatment strategies. It has long been known that sex hormones, namely 17β-estradiol and testosterone, possess neuroprotective- and cognitive-enhancing qualities. However, certain lacunae in the knowledge underlying their molecular mechanisms have delayed their use as treatment strategies in dementia. With recent advancements in pharmacology and molecular biology, especially in the development of safer selective oestrogen receptor modulators and the recent discovery of the small-molecule brain-derived neurotrophic factor receptor agonist, 7,8-dihydroxyflavone, the exploitation of these signalling pathways for clinical use has become possible. This review aims to adumbrate the evidence and hurdles underscoring the use of sex hormones in the treatment of dementia as well as discussing some direction that is required to advance the translation of evidence into practise.
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Aguero-Torres H, Fratiglioni L, Guo Z, Viitanen M, Winblad B (1998) Prognostic factors in very old demented adults: a seven-year follow-up from a population-based survey in Stockholm. J Am Geriatr Soc 46(4):444–452
Aguirre CC, Baudry M (2009) Progesterone reverses 17beta-estradiol-mediated neuroprotection and BDNF induction in cultured hippocampal slices. Eur J Neurosci 29(3):447–454. doi:10.1111/j.1460-9568.2008.06591.x
Allen KM, Purves-Tyson TD, Fung SJ, Shannon Weickert C (2015) The effect of adolescent testosterone on hippocampal BDNF and TrkB mRNA expression: relationship with cell proliferation. BMC Neurosci 16:4. doi:10.1186/s12868-015-0142-x
Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, et al. (1999) Gender differences in the incidence of AD and vascular dementia: the EURODEM Studies. EURODEM Incidence Research Group. Neurology 53(9):1992–1997
Asthana S, Baker LD, Craft S, Stanczyk FZ, Veith RC, Raskind MA, Plymate SR (2001) High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 57(4):605–612
Bachman DL, Wolf PA, Linn R, Knoefel JE, Cobb J, Belanger A, et al. (1992) Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study. Neurology 42(1):115–119
Bachman DL, Wolf PA, Linn RT, Knoefel JE, Cobb JL, Belanger AJ, et al. (1993) Incidence of dementia and probable Alzheimer’s disease in a general population: the Framingham Study. Neurology 43(3 Pt 1):515–519
Baldereschi M, Di Carlo A, Lepore V, Bracco L, Maggi S, Grigoletto F, et al. (1998) Estrogen-replacement therapy and Alzheimer’s disease in the Italian Longitudinal Study on Aging. Neurology 50(4):996–1002
Barde YA, Edgar D, Thoenen H (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J 1(5):549–553
Barrett-Connor E, Goodman-Gruen D, Patay B (1999) Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 84(10):3681–3685. doi:10.1210/jcem.84.10.6086
Begliuomini S, Casarosa E, Pluchino N, Lenzi E, Centofanti M, Freschi L, et al. (2007) Influence of endogenous and exogenous sex hormones on plasma brain-derived neurotrophic factor. Hum Reprod 22(4):995–1002. doi:10.1093/humrep/del479
Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, et al. (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A 105(7):2711–2716. doi:10.1073/pnas.0711863105
Bosse KE, Maina FK, Birbeck JA, France MM, Roberts JJ, Colombo ML, Mathews TA (2012) Aberrant striatal dopamine transmitter dynamics in brain-derived neurotrophic factor-deficient mice. J Neurochem 120(3):385–395. doi:10.1111/j.1471-4159.2011.07531.x
Bourque M, Morissette M, Di Paolo T (2014) Raloxifene activates G protein-coupled estrogen receptor 1/Akt signaling to protect dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice. Neurobiol Aging 35(10):2347–2356. doi:10.1016/j.neurobiolaging.2014.03.017
Bozdagi O, Rich E, Tronel S, Sadahiro M, Patterson K, Shapiro ML, et al. (2008) The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism. J Neurosci 28(39):9857–9869. doi:10.1523/JNEUROSCI.3145-08.2008
Brann DW, Dhandapani K, Wakade C, Mahesh VB, Khan MM (2007) Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 72(5):381–405. doi:10.1016/j.steroids.2007.02.003
Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88(9):1337–1342
Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3(3):186–191. doi:10.1016/j.jalz.2007.04.381
Buchman AS, Yu L, Boyle PA, Schneider JA, De Jager PL, Bennett DA (2016) Higher brain BDNF gene expression is associated with slower cognitive decline in older adults. Neurology 86(8):735–741. doi:10.1212/WNL.0000000000002387
Buchman VL, Davies AM (1993) Different neurotrophins are expressed and act in a developmental sequence to promote the survival of embryonic sensory neurons. Development 118(3):989–1001
Burns A (2009) Another nail in the coffin of the cognitive paradigm of dementia. Br J Psychiatry 194(3):199–200. doi:10.1192/bjp.bp.108.058537
Burns A, Iliffe S (2009) Dementia. BMJ 338:b75. doi:10.1136/bmj.b75
Carcaillon L, Brailly-Tabard S, Ancelin ML, Tzourio C, Foubert-Samier A, Dartigues JF, et al. (2014) Low testosterone and the risk of dementia in elderly men: impact of age and education. Alzheimers Dement 10(5 Suppl):S306–S314. doi:10.1016/j.jalz.2013.06.006
Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM (2014) 7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss. PLoS One 9(3):e91453. doi:10.1371/journal.pone.0091453
Chan JP, Cordeira J, Calderon GA, Iyer LK, Rios M (2008) Depletion of central BDNF in mice impedes terminal differentiation of new granule neurons in the adult hippocampus. Mol Cell Neurosci 39(3):372–383. doi:10.1016/j.mcn.2008.07.017
Chang H, Park H, Lee HS, Cheong J, Kang H (2015) Status of treatment for dementia patients who visited hospital as the first visit. Arch Gerontol Geriatr 60(3):453–456. doi:10.1016/j.archger.2015.01.018
Chen C, Li XH, Zhang S, Tu Y, Wang YM, Sun HT (2014) 7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction. Rejuvenation Res 17(3):249–254. doi:10.1089/rej.2013.1519
Cherrier MM, Anderson K, Shofer J, Millard S, Matsumoto AM (2015) Testosterone treatment of men with mild cognitive impairment and low testosterone levels. Am J Alzheimers Dis Other Demen 30(4):421–430. doi:10.1177/1533317514556874
Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, et al. (2001) Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 57(1):80–88
Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, et al. (2005a) The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 64(2):290–296. doi:10.1212/01.WNL.0000149639.25136.CA
Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, et al. (2005b) Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64(12):2063–2068. doi:10.1212/01.WNL.0000165995.98986.F1
Cherrier MM, Plymate S, Mohan S, Asthana S, Matsumoto AM, Bremner W, et al. (2004) Relationship between testosterone supplementation and insulin-like growth factor-I levels and cognition in healthy older men. Psychoneuroendocrinology 29(1):65–82
Chu LW, Tam S, Lee PW, Wong RL, Yik PY, Tsui W, et al. (2008) Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol 68(4):589–598. doi:10.1111/j.1365-2265.2007.03094.x
Chu LW, Tam S, Wong RL, Yik PY, Song Y, Cheung BM, et al. (2010) Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men. J Alzheimers Dis 21(4):1335–1345
Cikla U, Chanana V, Kintner DB, Udho E, Eickhoff J, Sun W, et al. (2016) ERalpha signaling is required for TrkB-mediated hippocampal neuroprotection in female neonatal mice after hypoxic ischemic encephalopathy(1,2,3). eNeuro 3(1). doi:10.1523/ENEURO.0025-15.2015
Coelho FG, Vital TM, Stein AM, Arantes FJ, Rueda AV, Camarini R, et al. (2014) Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer’s disease. J Alzheimers Dis 39(2):401–408. doi:10.3233/JAD-131073
Cohen-Cory S, Kidane AH, Shirkey NJ, Marshak S (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 70(5):271–288. doi:10.1002/dneu.20774
Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M (1997) Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Brain Res Mol Brain Res 49(1–2):71–81
Cummings SR, Duong T, Kenyon E, Cauley JA, Whitehead M, Krueger KA (2002) Serum estradiol level and risk of breast cancer during treatment with raloxifene. JAMA 287(2):216–220
Devi L, Ohno M (2012) 7,8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 37(2):434–444. doi:10.1038/npp.2011.191
Di Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, et al. (2002) Incidence of dementia, Alzheimer’s disease, and vascular dementia in Italy. The ILSA Study. J Am Geriatr Soc 50(1):41–48
Du X, Hill RA (2015) 7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders. Neurochem Int 89:170–180. doi:10.1016/j.neuint.2015.07.021
Edland SD, Rocca WA, Petersen RC, Cha RH, Kokmen E (2002) Dementia and Alzheimer disease incidence rates do not vary by sex in Rochester, Minn. Arch Neurol 59(10):1589–1593
Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, et al. (2011) Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A 108(7):3017–3022. doi:10.1073/pnas.1015950108
Ernfors P, Lee KF, Jaenisch R (1994) Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature 368(6467):147–150. doi:10.1038/368147a0
Espeland MA, Rapp SR, Shumaker SA, Brunner R, Manson JE, Sherwin BB, et al. (2004) Conjugated equine estrogens and global cognitive function in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291(24):2959–2968. doi:10.1001/jama.291.24.2959
Fanaei H, Karimian SM, Sadeghipour HR, Hassanzade G, Kasaeian A, Attari F, et al. (2014) Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. Brain Res 1558:74–83. doi:10.1016/j.brainres.2014.02.028
Ferguson JM (2001) SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry 3(1):22–27
Fischer B, Gleason C, Asthana S (2014) Effects of hormone therapy on cognition and mood. Fertil Steril 101(4):898–904. doi:10.1016/j.fertnstert.2014.02.025
Forlenza OV, Diniz BS, Teixeira AL, Radanovic M, Talib LL, Rocha NP, Gattaz WF (2015) Lower cerebrospinal fluid concentration of brain-derived neurotrophic factor predicts progression from mild cognitive impairment to Alzheimer’s disease. Neuromol Med 17(3):326–332. doi:10.1007/s12017-015-8361-y
Fratiglioni L, Viitanen M, von Strauss E, Tontodonati V, Herlitz A, Winblad B (1997) Very old women at highest risk of dementia and Alzheimer’s disease: incidence data from the Kungsholmen Project, Stockholm. Neurology 48(1):132–138
Ganguli M, Dodge HH, Chen P, Belle S, DeKosky ST (2000) Ten-year incidence of dementia in a rural elderly US community population: the MoVIES Project. Neurology 54(5):1109–1116
Gao S, Hendrie HC, Hall KS, Hui S (1998) The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry 55(9):809–815
Garcia-Mesa Y, Pareja-Galeano H, Bonet-Costa V, Revilla S, Gomez-Cabrera MC, Gambini J, et al. (2014) Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms. Psychoneuroendocrinology 45:154–166. doi:10.1016/j.psyneuen.2014.03.021
Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, et al. (2006) Mild cognitive impairment. Lancet 367(9518):1262–1270. doi:10.1016/S0140-6736(06)68542-5
Gold SM, Chalifoux S, Giesser BS, Voskuhl RR (2008) Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone. J Neuroinflammation 5:32. doi:10.1186/1742-2094-5-32
Goldberg NR, Caesar J, Park A, Sedgh S, Finogenov G, Masliah E, et al. (2015) Neural stem cells rescue cognitive and motor dysfunction in a transgenic model of dementia with Lewy bodies through a BDNF-dependent mechanism. Stem Cell Reports 5(5):791–804. doi:10.1016/j.stemcr.2015.09.008
Grech A, Breck J, Heidelbaugh J (2014) Adverse effects of testosterone replacement therapy: an update on the evidence and controversy. Ther Adv Drug Saf 5(5):190–200. doi:10.1177/2042098614548680
Hamshere ML, Holmans PA, Avramopoulos D, Bassett SS, Blacker D, Bertram L, et al. (2007) Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer’s disease. Hum Mol Genet 16(22):2703–2712. doi:10.1093/hmg/ddm224
Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 86(2):724–731. doi:10.1210/jcem.86.2.7219
Hebert LE, Scherr PA, McCann JJ, Beckett LA, Evans DA (2001) Is the risk of developing Alzheimer’s disease greater for women than for men? Am J Epidemiol 153(2):132–136
Henderson VW (2014) Alzheimer’s disease: review of hormone therapy trials and implications for treatment and prevention after menopause. J Steroid Biochem Mol Biol 142:99–106. doi:10.1016/j.jsbmb.2013.05.010
Henderson VW, Ala T, Sainani KL, Bernstein AL, Stephenson BS, Rosen AC, Farlow MR (2015) Raloxifene for women with Alzheimer disease: a randomized controlled pilot trial. Neurology 85(22):1937–1944. doi:10.1212/WNL.0000000000002171
Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG (1994) Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol 51(9):896–900
Hock C, Heese K, Hulette C, Rosenberg C, Otten U (2000) Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol 57(6):846–851
Hogervorst E, Williams J, Budge M, Barnetson L, Combrinck M, Smith AD (2001) Serum total testosterone is lower in men with Alzheimer’s disease. Neuro Endocrinol Lett 22(3):163–168
Hourani L, Williams J, Bray R, Kandel D (2015) Gender differences in the expression of PTSD symptoms among active duty military personnel. J Anxiety Disord 29:101–108. doi:10.1016/j.janxdis.2014.11.007
Hsiao YH, Hung HC, Chen SH, Gean PW (2014) Social interaction rescues memory deficit in an animal model of Alzheimer’s disease by increasing BDNF-dependent hippocampal neurogenesis. J Neurosci 34(49):16207–16219. doi:10.1523/JNEUROSCI.0747-14.2014
Hsu B, Cumming RG, Waite LM, Blyth FM, Naganathan V, Le Couteur DG, et al. (2015) Longitudinal relationships between reproductive hormones and cognitive decline in older men: the Concord Health and Ageing in Men Project. J Clin Endocrinol Metab 100(6):2223–2230. doi:10.1210/jc.2015-1016
Huang EJ, Reichardt LF (2001) Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 24:677–736. doi:10.1146/annurev.neuro.24.1.677
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280(7):605–613
Inagaki T, Begum T, Reza F, Horibe S, Inaba M, Yoshimura Y, Komatsu Y (2008) Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons. Neurosci Res 61(2):192–200. doi:10.1016/j.neures.2008.02.006
Jacobsen DE, Melis RJ, Verhaar HJ, Olde Rikkert MG (2012) Raloxifene and tibolone in elderly women: a randomized, double-blind, double-dummy, placebo-controlled trial. J Am Med Dir Assoc 13(2):189 . doi:10.1016/j.jamda.2011.05.005e181-187
Jacobsen DE, Samson MM, Emmelot-Vonk MH, Verhaar HJ (2010) Raloxifene improves verbal memory in late postmenopausal women: a randomized, double-blind, placebo-controlled trial. Menopause 17(2):309–314. doi:10.1097/gme.0b013e3181bd54df
Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, et al. (2010) A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci U S A 107(6):2687–2692. doi:10.1073/pnas.0913572107
Kang L, Li S, Xing Z, Li J, Su Y, Fan P, et al. (2014) Dihydrotestosterone treatment delays the conversion from mild cognitive impairment to Alzheimer’s disease in SAMP8 mice. Horm Behav 65(5):505–515. doi:10.1016/j.yhbeh.2014.03.017
Katoh-Semba R, Asano T, Ueda H, Morishita R, Takeuchi IK, Inaguma Y, Kato K (2002) Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. FASEB J 16(10):1328–1330. doi:10.1096/fj.02-0143fje
Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A (2000) Age-specific incidence rates of Alzheimer’s disease: the Baltimore Longitudinal Study of Aging. Neurology 54(11):2072–2077
Kenny AM, Fabregas G, Song C, Biskup B, Bellantonio S (2004) Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. J Gerontol A Biol Sci Med Sci 59(1):75–78
Klotz L (2015) Testosterone therapy and prostate cancer—safety concerns are well founded. Nat Rev Urol 12(1):48–54. doi:10.1038/nrurol.2014.338
Kozisek ME, Middlemas D, Bylund DB (2008) Brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B in the mechanism of action of antidepressant therapies. Pharmacol Ther 117(1):30–51. doi:10.1016/j.pharmthera.2007.07.001
Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, et al. (2002) Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 59(11):1737–1746
Larson EB, Shadlen MF, Wang L, McCormick WC, Bowen JD, Teri L, Kukull WA (2004) Survival after initial diagnosis of Alzheimer disease. Ann Intern Med 140(7):501–509
Launer LJ, Andersen K, Dewey ME, Letenneur L, Ott A, Amaducci LA, et al. (1999) Rates and risk factors for dementia and Alzheimer’s disease: results from EURODEM pooled analyses. EURODEM Incidence Research Group and Work Groups. European Studies of Dementia. Neurology 52(1):78–84
LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2001) Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA 285(11):1489–1499
Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82(6):1367–1375
Lee JG, Shin BS, You YS, Kim JE, Yoon SW, Jeon DW, et al. (2009) Decreased serum brain-derived neurotrophic factor levels in elderly Korean with dementia. Psychiatry Investig 6(4):299–305. doi:10.4306/pi.2009.6.4.299
Leifke E, Gorenoi V, Wichers C, Von Zur Muhlen A, Von Buren E, Brabant G (2000) Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort. Clin Endocrinol 53(6):689–695
Letenneur L, Gilleron V, Commenges D, Helmer C, Orgogozo JM, Dartigues JF (1999) Are sex and educational level independent predictors of dementia and Alzheimer’s disease? Incidence data from the PAQUID project. J Neurol Neurosurg Psychiatry 66(2):177–183
Leyhe T, Eschweiler GW, Stransky E, Gasser T, Annas P, Basun H, Laske C (2009) Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s disease. J Alzheimers Dis 16(3):649–656. doi:10.3233/JAD-2009-1004
Lin Y, Lu X, Dong J, He X, Yan T, Liang H, et al. (2015) Involuntary, forced and voluntary exercises equally attenuate neurocognitive deficits in vascular dementia by the BDNF-pCREB mediated pathway. Neurochem Res 40(9):1839–1848. doi:10.1007/s11064-015-1673-3
Lindsay RM, Thoenen H, Barde YA (1985) Placode and neural crest-derived sensory neurons are responsive at early developmental stages to brain-derived neurotrophic factor. Dev Biol 112(2):319–328
Liu X, Zhang J, Sun D, Fan Y, Zhou H, Fu B (2014) Effects of fluoxetine on brain-derived neurotrophic factor serum concentration and cognition in patients with vascular dementia. Clin Interv Aging 9:411–418. doi:10.2147/CIA.S58830
Lu PH, Masterman DA, Mulnard R, Cotman C, Miller B, Yaffe K, et al. (2006) Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol 63(2):177–185. doi:10.1001/archneur.63.2.nct50002
Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, et al. (1999) Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 96(26):15239–15244
MacLennan AH, Henderson VW, Paine BJ, Mathias J, Ramsay EN, Ryan P, et al. (2006) Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study. Menopause 13(1):28–36. doi:10.1097/01.gme.0000191204.38664.61
Maki PM (2013) Critical window hypothesis of hormone therapy and cognition: a scientific update on clinical studies. Menopause 20(6):695–709. doi:10.1097/GME.0b013e3182960cf8
Malberg JE, Blendy JA (2005) Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci 26(12):631–638. doi:10.1016/j.tips.2005.10.005
Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. (2013) Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA 310(13):1353–1368. doi:10.1001/jama.2013.278040
Martin DM, Wittert G, Burns NR, Haren MT, Sugarman R (2007) Testosterone and cognitive function in ageing men: data from the Florey Adelaide Male Ageing Study (FAMAS). Maturitas 57(2):182–194. doi:10.1016/j.maturitas.2006.12.007
McCarrey AC, Resnick SM (2015) Postmenopausal hormone therapy and cognition. Horm Behav 74:167–172. doi:10.1016/j.yhbeh.2015.04.018
Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L (2002) Incidence of AD may decline in the early 90s for men, later for women: the Cache County study. Neurology 58(2):209–218
Mitlak BH, Cohen FJ (1999) Selective estrogen receptor modulators: a look ahead. Drugs 57(5):653–663
Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM (2004) Free testosterone and risk for Alzheimer disease in older men. Neurology 62(2):188–193
Morse JK, Wiegand SJ, Anderson K, You Y, Cai N, Carnahan J, et al. (1993) Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection. J Neurosci 13(10):4146–4156
Muller M, Aleman A, Grobbee DE, de Haan EH, van der Schouw YT (2005) Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level? Neurology 64(5):866–871. doi:10.1212/01.WNL.0000153072.54068.E3
Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, et al. (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
Nickelsen T, Lufkin EG, Riggs BL, Cox DA, Crook TH (1999) Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology 24(1):115–128
Ohman H, Savikko N, Strandberg TE, Pitkala KH (2014) Effect of physical exercise on cognitive performance in older adults with mild cognitive impairment or dementia: a systematic review. Dement Geriatr Cogn Disord 38(5–6):347–365. doi:10.1159/000365388
Ottem EN, Bailey DJ, Jordan CL, Breedlove SM (2013) With a little help from my friends: androgens tap BDNF signaling pathways to alter neural circuits. Neuroscience 239:124–138. doi:10.1016/j.neuroscience.2012.12.019
Pardridge WM (2007) Blood-brain barrier delivery. Drug Discov Today 12(1–2):54–61. doi:10.1016/j.drudis.2006.10.013
Pardridge WM, Wu D, Sakane T (1998) Combined use of carboxyl-directed protein pegylation and vector-mediated blood-brain barrier drug delivery system optimizes brain uptake of brain-derived neurotrophic factor following intravenous administration. Pharm Res 15(4):576–582
Park H, Poo MM (2013) Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14(1):7–23. doi:10.1038/nrn3379
Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21(17):6706–6717
Perry RT, Wiener H, Harrell LE, Blacker D, Tanzi RE, Bertram L, et al. (2007) Follow-up mapping supports the evidence for linkage in the candidate region at 9q22 in the NIMH Alzheimer’s disease Genetics Initiative cohort. Am J Med Genet B Neuropsychiatr Genet 144B(2):220–227. doi:10.1002/ajmg.b.30433
Podfigurna-Stopa A, Casarosa E, Luisi M, Czyzyk A, Meczekalski B, Genazzani AR (2013) Decreased plasma concentrations of brain-derived neurotrophic factor (BDNF) in patients with functional hypothalamic amenorrhea. Gynecol Endocrinol 29(9):817–820. doi:10.3109/09513590.2013.813472
Poduslo JF, Curran GL (1996) Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res 36(2):280–286
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9(1):63–75 . doi:10.1016/j.jalz.2012.11.007e62
Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, et al. (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289(20):2663–2672. doi:10.1001/jama.289.20.2663
Rasika S, Alvarez-Buylla A, Nottebohm F (1999) BDNF mediates the effects of testosterone on the survival of new neurons in an adult brain. Neuron 22(1):53–62
Riggs BL, Hartmann LC (2003) Selective estrogen-receptor modulators—mechanisms of action and application to clinical practice. N Engl J Med 348(7):618–629. doi:10.1056/NEJMra022219
Rizzi L, Rosset I, Roriz-Cruz M (2014) Global epidemiology of dementia: Alzheimer’s and vascular types. Biomed Res Int 2014:908915. doi:10.1155/2014/908915
Roberts RO, Knopman DS, Mielke MM, Cha RH, Pankratz VS, Christianson TJ, et al. (2014) Higher risk of progression to dementia in mild cognitive impairment cases who revert to normal. Neurology 82(4):317–325. doi:10.1212/WNL.0000000000000055
Rosario ER, Chang L, Head EH, Stanczyk FZ, Pike CJ (2011) Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease. Neurobiol Aging 32(4):604–613. doi:10.1016/j.neurobiolaging.2009.04.008
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288(3):321–333
Rzemieniec J, Litwa E, Wnuk A, Lason W, Golas A, Krzeptowski W, Kajta M (2015) Neuroprotective action of raloxifene against hypoxia-induced damage in mouse hippocampal cells depends on ERalpha but not ERbeta or GPR30 signalling. J Steroid Biochem Mol Biol 146:26–37. doi:10.1016/j.jsbmb.2014.05.005
Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, et al. (2014) Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med 275(3):251–283. doi:10.1111/joim.12191
Shao H, Breitner JC, Whitmer RA, Wang J, Hayden K, Wengreen H, et al. (2012) Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology 79(18):1846–1852. doi:10.1212/WNL.0b013e318271f823
Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, et al. (2004) Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291(24):2947–2958. doi:10.1001/jama.291.24.2947
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, et al. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289(20):2651–2662. doi:10.1001/jama.289.20.2651
Singh M, Meyer EM, Millard WJ, Simpkins JW (1994) Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats. Brain Res 644(2):305–312
Singh M, Meyer EM, Simpkins JW (1995) The effect of ovariectomy and estradiol replacement on brain-derived neurotrophic factor messenger ribonucleic acid expression in cortical and hippocampal brain regions of female Sprague-Dawley rats. Endocrinology 136(5):2320–2324. doi:10.1210/endo.136.5.7720680
Singh M, Setalo G Jr, Guan X, Warren M, Toran-Allerand CD (1999) Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci 19(4):1179–1188
Sohrabji F, Miranda RC, Toran-Allerand CD (1995) Identification of a putative estrogen response element in the gene encoding brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92(24):11110–11114
Stassen HH, Angst J, Delini-Stula A (1997) Delayed onset of action of antidepressant drugs? Survey of recent results. Eur Psychiatry 12(4):166–176. doi:10.1016/S0924-9338(97)89100-6
Tan RS, Pu SJ (2003) A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male 6(1):13–17
Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319(5870):1683–1687. doi:10.1126/science.1152864
Tschanz JT, Corcoran CD, Schwartz S, Treiber K, Green RC, Norton MC, et al. (2011) Progression of cognitive, functional, and neuropsychiatric symptom domains in a population cohort with Alzheimer dementia: the Cache County Dementia Progression study. Am J Geriatr Psychiatry 19(6):532–542. doi:10.1097/JGP.0b013e3181faec23
Tsolaki M, Grammaticos P, Karanasou C, Balaris V, Kapoukranidou D, Kalpidis I, et al. (2005) Serum estradiol, progesterone, testosterone, FSH and LH levels in postmenopausal women with Alzheimer’s dementia. Hell J Nucl Med 8(1):39–42
Uher R, Farmer A, Henigsberg N, Rietschel M, Mors O, Maier W, et al. (2009) Adverse reactions to antidepressants. Br J Psychiatry 195(3):202–210. doi:10.1192/bjp.bp.108.061960
Uluc K, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D, et al. (2013) TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia. CNS Neurol Disord Drug Targets 12(3):360–370
Verdile G, Laws SM, Henley D, Ames D, Bush AI, Ellis KA, et al. (2014) Associations between gonadotropins, testosterone and beta amyloid in men at risk of Alzheimer’s disease. Mol Psychiatry 19(1):69–75. doi:10.1038/mp.2012.147
Verhovshek T, Cai Y, Osborne MC, Sengelaub DR (2010) Androgen regulates brain-derived neurotrophic factor in spinal motoneurons and their target musculature. Endocrinology 151(1):253–261. doi:10.1210/en.2009-1036
Wahjoepramono EJ, Asih PR, Aniwiyanti V, Taddei K, Dhaliwal SS, Fuller SJ, et al. (2016) The effects of testosterone supplementation on cognitive functioning in older men. CNS Neurol Disord Drug Targets 15(3):337–343
Watanabe T, Koba S, Kawamura M, Itokawa M, Idei T, Nakagawa Y, et al. (2004) Small dense low-density lipoprotein and carotid atherosclerosis in relation to vascular dementia. Metabolism 53(4):476–482
Weinstein G, Beiser AS, Choi SH, Preis SR, Chen TC, Vorgas D, et al. (2014) Serum brain-derived neurotrophic factor and the risk for dementia: the Framingham Heart Study. JAMA Neurol 71(1):55–61. doi:10.1001/jamaneurol.2013.4781
Wharton W, Baker LD, Gleason CE, Dowling M, Barnet JH, Johnson S, et al. (2011) Short-term hormone therapy with transdermal estradiol improves cognition for postmenopausal women with Alzheimer’s disease: results of a randomized controlled trial. J Alzheimers Dis 26(3):495–505. doi:10.3233/JAD-2011-110341
Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, et al. (2005) Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci 8(8):1069–1077. doi:10.1038/nn1510
Wright MA, Ribera AB (2010) Brain-derived neurotrophic factor mediates non-cell-autonomous regulation of sensory neuron position and identity. J Neurosci 30(43):14513–14521. doi:10.1523/JNEUROSCI.4025-10.2010
Wu YC, Du X, van den Buuse M, Hill RA (2014) Sex differences in the adolescent developmental trajectory of parvalbumin interneurons in the hippocampus: a role for estradiol. Psychoneuroendocrinology 45:167–178. doi:10.1016/j.psyneuen.2014.03.016
Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, et al. (2005) Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry 162(4):683–690. doi:10.1176/appi.ajp.162.4.683
Yaffe K, Krueger K, Sarkar S, Grady D, Barrett-Connor E, Cox DA, Nickelsen T (2001) Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 344(16):1207–1213. doi:10.1056/NEJM200104193441604
Yaffe K, Vittinghoff E, Ensrud KE, Johnson KC, Diem S, Hanes V, Grady D (2006) Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life. Arch Neurol 63(7):945–950. doi:10.1001/archneur.63.7.945
Yamada K, Nabeshima T (2003) Brain-derived neurotrophic factor/TrkB signaling in memory processes. J Pharmacol Sci 91(4):267–270
Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, et al. (1995) Incidence and risk factors of vascular dementia and Alzheimer’s disease in a defined elderly Japanese population: the Hisayama Study. Neurology 45(6):1161–1168
Young LA, Neiss MB, Samuels MH, Roselli CE, Janowsky JS (2010) Cognition is not modified by large but temporary changes in sex hormones in men. J Clin Endocrinol Metab 95(1):280–288. doi:10.1210/jc.2009-1346
Yue X, Lu M, Lancaster T, Cao P, Honda S, Staufenbiel M, et al. (2005) Brain estrogen deficiency accelerates Abeta plaque formation in an Alzheimer’s disease animal model. Proc Natl Acad Sci U S A 102(52):19198–19203. doi:10.1073/pnas.0505203102
Zhang QG, Wang RM, Scott E, Han D, Dong Y, Tu JY, et al. (2013) Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause. Brain 136(Pt 5):1432–1445. doi:10.1093/brain/awt046
Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, et al. (2014) 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 39(3):638–650. doi:10.1038/npp.2013.243
Zhou J, Zhang H, Cohen RS, Pandey SC (2005) Effects of estrogen treatment on expression of brain-derived neurotrophic factor and cAMP response element-binding protein expression and phosphorylation in rat amygdaloid and hippocampal structures. Neuroendocrinology 81(5):294–310. doi:10.1159/000088448
Zigova T, Pencea V, Wiegand SJ, Luskin MB (1998) Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci 11(4):234–245. doi:10.1006/mcne.1998.0684
Acknowledgments
XD is supported by the NHMRC-ARC Dementia Research Development Fellowship (1109959). RH was supported by a NHMRC postdoctoral fellowship and, subsequently, a Career Development Fellowship. We would also like to acknowledge the operational infrastructure support from the State Government of Victoria.
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Du, X., Hill, R.A. The Potential of Gonadal Hormone Signalling Pathways as Therapeutics for Dementia. J Mol Neurosci 60, 336–348 (2016). https://doi.org/10.1007/s12031-016-0813-9
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DOI: https://doi.org/10.1007/s12031-016-0813-9