Neuropsychiatric disturbances in Alzheimer’s disease: What have we learned from neuropathological studies?

Current Alzheimer Research

Volumn 13, Issue 10, 2016, Pages 1145-1164

  Van Dam, Debby ^a,b   Vermeiren, Yannick ^a,b   Dekker, Alain D ^a,b   Naudé, Petrus J W ^a,b   De Deyn, Peter P ^a,b,c  

^a UNIVERSITY OF ANTWERP   (Belgium)

^b UNIVERSITY MEDICAL CENTER GRONINGEN   (Netherlands)

^c Hospital Network Antwerp ZNA Middelheim and Hoge Beuken   (Belgium)

Author keywords

Aggression; Amyloid; Depression; Neurofibrillary tangles; Neuronal loss; Neurotransmitter; Psychosis

Indexed keywords

ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; COPPER ZINC SUPEROXIDE DISMUTASE; POLYGLUTAMINE; PRESENILIN 1; PROTEIN AGGREGATE; TATA BINDING PROTEIN; TAU PROTEIN; UBIQUITINATED PROTEIN;

AGGRESSION; AGITATION; ALLOCORTEX; ALZHEIMER DISEASE; AMYLOID PLAQUE; AMYOTROPHIC LATERAL SCLEROSIS; ANXIETY; APATHY; BEHAVIOR; BRAIN REGION; CELL LOSS; CIRCADIAN RHYTHM; DEPRESSION; DOPAMINERGIC SYSTEM; EXECUTIVE FUNCTION; HUMAN; MEDIAL TEMPORAL LOBE; MENTAL DISEASE; MONOAMINERGIC SYSTEM; NEOCORTEX; NERVE CELL NETWORK; NERVE DEGENERATION; NERVE TRACT; NERVOUS SYSTEM INFLAMMATION; NEUROBIOLOGY; NEUROFIBRILLARY TANGLE; NEUROPSYCHIATRY; NEUROTRANSMISSION; NONHUMAN; PATHOPHYSIOLOGY; PHOBIA; PRIORITY JOURNAL; PSYCHOSIS; REVIEW; SENILE PLAQUE; SLEEP DISORDER; SYNAPSE; VASCULAR AMYLOIDOSIS; WHITE MATTER; BRAIN; CAREGIVER; COGNITION DISORDERS; COMPLICATION; ENCEPHALITIS; METABOLISM; PATHOLOGY; PSYCHOLOGY;

ALZHEIMER DISEASE; BEHAVIORAL SYMPTOMS; BRAIN; CAREGIVERS; COGNITION DISORDERS; ENCEPHALITIS; HUMANS;

EID: 84986879605     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/1567205013666160502123607     Document Type: Review

References (280)

1. Graham NL, Emery T, Hodges JR. Distinctive cognitive profiles in Alzheimer's disease and subcortical vascular dementia. J Neurol Neurosurg Psychiatry 75: 61-71 (2004).
2. Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, et al. Neuropsychiatric symptoms in Alzheimer's disease: past progress and anticipation of the future. Alzheimers Dement 9: 602-8 (2013).
3. Reisberg B, Borenstein J, Salob SP, Ferris SH, Franssen E, Georgotas A. Behavioral symptoms in Alzheimer’s disease: Phenomenology and treatment. J Clin Psychiatry 48: 9-15 (1987).
4. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 44: 2308-14 (1994).
5. Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer’s disease. Neurology 46: 130-5 (1996).
6. Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 48: S10-6 (1997).
7. Lyketsos CG, Carrillo MC, Ryan MJ, Khachaturian AS, Trzepacz P, Amatniek J, et al. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimers Dement 7: 532-9 (2011).
8. Finkel SI, Costa e Silva J, Cohen G, Miller S, Sartorius N. Behavioral and psychological signs and symptoms of dementia: a consensus statement on current knowledge and implications for research and treatment. Int Psychogeriatr 8: 497-500 (1996).
9. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, De-Kosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. JAMA 288: 1475-83 (2002).
10. Okura T, Plassman BL, Steffens DC, Llewellyn DJ, Potter GG, Langa KM. Neuropsychiatric symptoms and the risk of institutionalization and death: the aging, demographics, and memory study. J Am Geriatr Soc 59: 473-81 (2011).
11. Gonzalez-Salvador MT, Arango C, Lyketsos CG, Barba AC. The stress and psychological morbidity of the Alzheimer patient caregiver. Int J Geriatr Psychiatry 14: 701-10 (1999).
12. Emanuel JE, Lopez OL, Houck PR, Becker JT, Weamer EA, Demichele-Sweet MA, et al. Trajectory of cognitive decline as a predictor of psychosis in early Alzheimer disease in the cardiovascular health study. Am J Geriatr Psychiatry 19: 160-8 (2011).
13. Douglas A, Letts L, Richardson J. A systematic review of accidental injury from fire, wandering and medication self-administration errors for older adults with and without dementia. Arch Gerontol Geriatr 52: e1-10 (2011).
14. Herrmann N, Lanctot KL, Sambrook R, Lesnikova N, Hebert R, McCracken P, et al. The contribution of neuropsychiatric symptoms to the cost of dementia care. Int J Geriatr Psychiatry 21: 972-6 (2006).
15. American Psychiatric Association. DSM-V: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Association 2013.
16. Gauthier S, Cummings J, Ballard C, Brodaty H, Grossberg G, Robert P, et al. Management of behavioral problems in Alzheimer’s disease. Int Psychogeriatr 22: 346-72 (2010).
17. Van Dam D, De Deyn PP. Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 5: 956-70 (2006).
18. Van Dam D, De Deyn PP. Animal models in the drug discovery pipeline for Alzheimer's disease. Br J Pharmacol 164: 1285-300 (2011).
19. Lansbury PT Jr. In pursuit of the molecular structure of amyloid plaque: new technology provides unexpected and critical information. Biochemistry 31: 6865-70 (1992).
20. Pearson HA, Peers C. Physiological roles for amyloid beta peptides. J Physiol 575: 5-10 (2006).
21. Parihar MS, Brewer GJ. Amyloid-beta as a modulator of synaptic plasticity. J Alzheimers Dis 22: 741-63 (2010).
22. Harper JD, Wong SS, Lieber CM, Lansbury PT. Observation of metastable Abeta amyloid protofibrils by atomic force microscopy. Chem Biol 4: 119-25 (1997).
23. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95: 6448-53 (1998).
24. Roher AE, Lowenson JD, Clarke S, Wolkow C, Wang R, Cotter RJ, et al. Structural alterations in the peptide backbone of betaamyloid core protein may account for its deposition and stability in Alzheimer's disease. J Biol Chem 268: 3072-83 (1993).
25. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13: 45-53 (1994).
26. Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT. Neuropathological alterations in Alzheimer disease. Cold Spring Harb Perspect Med 1: a006189 (2011).
27. Selkoe DJ. Alzheimer's disease. Cold Spring Harb Perspect Biol 3: a004457 (2011).
28. Cruz L, Urbanc B, Buldyrev SV, Christie R, Gomez-Isla T, Havlin S, et al. Aggregation and disaggregation of senile plaques in Alzheimer disease. Proc Natl Acad Sci USA 94: 7612-6 (1997).
29. Thal DR, Walter J, Saido TC, Fandrich M. Neuropathology and biochemistry of Abeta and its aggregates in Alzheimer's disease. Acta Neuropathol 129: 167-82 (2015).
30. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27: 796-807 (2007).
31. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349: 704-6 (1991).
32. Tandon A, Rogaeva E, Mullan M, St George-Hyslop PH. Molecular genetics of Alzheimer's disease: the role of beta-amyloid and the presenilins. Curr Opin Neurol 13: 377-84 (2000).
33. Vilatela MEA, Lopez-Lopez M, Yeseas-Gomez P. Genetics of Alzheimer's Disease. Arch Med Res 43: 622-31 (2012).
34. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet 368: 387-403 (2006).
35. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297: 353-6 (2002).
36. Teipel SJ, Hampel H. Neuroanatomy of Down syndrome in vivo: a model of preclinical Alzheimer's disease. Behav Genet 36: 405-415 (2006).
37. Zigman WB, Lott IT. Alzheimer’s Disease in Down Syndrome: Neurobiology and Risk. Ment Retard Dev Disabil Res Rev 13: 237-46 (2007).
38. Zigman WB. Atypical aging in down syndrome. Dev Disabil Res Rev 18: 51-67 (2013).
39. Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D, Tybulewicz VL, et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci 16(9): 564-74 (2015).
40. Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ 178: 548-56 (2008).
41. Holtzman DM, Bales KR, Tenkova T, Fagan AM, Parsadanian M, Sartorius LJ, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 97: 2892-7 (2000).
42. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 9: 119-28 (2010).
43. Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron 17: 1005-13 (1996).
44. Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383: 710-3 (1996).
45. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393: 702-5 (1998).
46. Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293: 1487-91 (2001).
47. Oliver C, Crayton L, Holland A, Hall S, Bradbury J. A four year prospective study of age-related cognitive change in adults with Down's syndrome. Psychol Med 28:1365-77 (1998).
48. Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology 42: 631-9 (1992).
49. Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10: 698-712 (2011).
50. Wisniewski KE, Wisniewski HM, Wen GY. ccurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 17: 278-82 (1985).
51. Lott IT, Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurol 9: 623-33 (2010).
52. Jucker M, Walker LC. Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70: 532-40 (2011).
53. Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW. The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1: 103-16 (1991).
54. Braak H, Braak E. Neuropathological stageing of Alzheimerrelated changes. Acta Neuropathol 82: 239-59 (1991).
55. Thal DR, Rub U, Orantes M, Braak H. Phases of Aβ deposition in the human brainn and its relevance for the development of AD. Neurology 58: 1791-800 (2002).
56. Montine TJ, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Dickson DW, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol 123: 1-11 (2012).
57. Love S, Saitoh T, Quijada S, Cole GM, Terry RD. Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropath Exp Neurol 47: 393-405 (1988).
58. Perl DP. Neuropathology of Alzheimer's disease. Mt Sinai J Med New 77: 32-42 (2010).
59. Mesulam MM, Asuncion MM. Cholinesterases within neurofibrillary tangles related to age and Alzheimer's disease. Ann Neurol 22: 223-8 (1987).
60. Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739: 198-210 (2005).
61. Braak E, Griffing K, Arai K, Bohl J, Bratzke H, Braak H. Neuropathology of Alzheimer's disease: what is new since A. Alzheimer? Eur Arch Psychiatry Clin Neurosci 249: 14-22 (1999).
62. Braak E, Braak H, Mandelkow EM. A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87: 554-67 (1994).
63. Villemagne VL, Okamura N. In vivo tau imaging: obstacles and progress. Alzheimers Dement 10: S254-S64 (2014).
64. Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC. Tau imaging: early progress and future directions. Lancet Neurol 14: 114-24 (2015).
65. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4: 49-60 (2003).
66. Hamilton RL. Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry. Brain Pathol 10: 378-84 (2000).
67. Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, et al. The Lewy body variant of Alzheimer’s disease: a clinical and pathologic entity. Neurology 40: 1-8 (1990).
68. Olichney JM, Galasko D, Salmon DP, Hofstetter CR, Hansen LA, Katzman R, et al. Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 51: 351-7 (1998).
69. Marsh SE, Blurton-Jones M. Examining the mechanisms that link b-amyloid and a-synuclein pathologies. Alzheimers Res Ther 4: 11 (2012).
70. Resende R, Marques SC, Ferreiro E, Simoes I, Oliveira CR, Pereira CM. Effect of α-synuclein on amyloid β-induced toxicity: relevance to Lewy body variant of Alzheimer disease. Neurochem Res 38: 797-806 (2013).
71. Cummings CJ, Zoghbi HY. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum Mol Genet 9: 909-16 (2000).
72. Fujigasaki H, Martin JJ, De Deyn PP, Camuzat A, Deffond D, Stevanin G, et al. CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia. Brain 124: 1939-47 (2001).
73. Reid SJ, van Roon-Mom WM, Wood PC, Rees MI, Owen MJ, Faull RL, et al. TBP, a polyglutamine tract containing protein, accumulates in Alzheimer's disease. Brain Res Mol Brain Res 125: 120-8 (2004).
74. Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, et al. Aggregation and motor neuron toxicity of an ALSlinked SOD1 mutant independent from wild-type SOD1. Science 281: 1851-4 (1998).
75. Choi J, Rees HD, Weintraub ST, Levey AI, Chin LS, Li L. Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol Chem 280: 11648-55 (2005).
76. Atkin G, Paulson H. Ubiquitin pathways in neurodegenerative disease. Front Mol Neurosci 7: 63 (2014).
77. Perry G, Friedman R, Shaw G, Chau V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc Natl Acad Sci USA 84: 3033-36 (1987).
78. Upadhya SC, Hegde AN. Role of the ubiquitin proteasome system in Alzheimer's disease. BMC Biochem 8: S12 (2007).
79. Riederer BM, Leuba G, Vernay A, Riederer IM. The role of the ubiquitin proteasome system in Alzheimer's disease. Exp Biol Med (Maywood) 236: 268-76 (2011).
80. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130-3 (2006).
81. Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, et al. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology 70: 1850-7 (2008).
82. Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, et al. Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67: 555-64 (2008).
83. Kadokura A, Yamazaki T, Lemere CA, Takatama M, Okamoto K. Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology. Neuropathology 29: 566-73 (2009).
84. Herman AM, Khandelwal PJ, Stanczyk BB, Rebeck GW, Moussa CE. β-amyloid triggers ALS-associated TDP-43 pathology in AD models. Brain Res 1386: 191-9 (2011).
85. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 21: 383-421 (2000).
86. Hensley K. Neuroinflammation in Alzheimer's disease: mechanisms, pathologic consequences, and potential for therapeutic manipulation. J Alzheimers Dis 21: 1-14 (2010).
87. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 14: 388-405 (2015).
88. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 91: 461-553 (2011).
89. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE. CD14 and Toll-like receptors 2 and 4 are required for fibrillar Aβ-stimulated microglial activation. J Neurosci 29: 11982-92 (2009).
90. Hong S, Ostaszewski BL, Yang T, O'Malley TT, Jin M, Yanagisawa K, et al. Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82: 308-19 (2014).
91. Beauquis J, Vinuesa A, Pomilio C, Pavia P, Galvan V, Saravia F. Neuronal and glial alterations, increased anxiety, and cognitive impairment before hippocampal amyloid deposition in PDAPP mice, model of Alzheimer's disease. Hippocampus 24: 257-69 (2014).
92. Mrak RE, Sheng JG, Griffin WS. Glial cytokines in Alzheimer's disease: review and pathogenic implications. Hum Pathol 26: 816-23 (1995).
93. Akiyama H, Kawamata T, Yamada T, Tooyama I, Ishii T, McGeer PL. Expression of intercellular adhesion molecule (ICAM)-1 by a subset of astrocytes in Alzheimer disease and some other degenerative neurological disorders. Acta Neuropathol (Berlin) 85: 628-34 (1993).
94. Savarin-Vuaillat C, Ransohoff RM. Chemokines and chemokine receptors in neurological disease: raise, retain, or reduce? Neurotherapeutics 4: 590-601 (2007).
95. Rohn TT. The role of caspases in Alzheimer's disease; potential novel therapeutic opportunities. Apoptosis 15: 1403-9 (2010).
96. Montine TJ, Sidell KR, Crews BC, Markesbery WR, Marnett LJ, Roberts LJ 2nd, et al. Elevated CSF prostaglandin E2 levels in patients with probable AD. Neurology 53: 1495-98 (1999).
97. Strohmeyer R, Ramirez M, Cole GJ, Mueller K, Rogers J. Association of factor H of the alternative pathway of complement with agrin and complement receptor 3 in the Alzheimer's disease brain. J Neuroimmunol 131: 135-46 (2002).
98. Vodovotz Y, Lucia MS, Flanders KC, Chesler L, Xie QW, Smith TW, et al. Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease. J Exp Med 184: 1425-33 (1996).
99. Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat Rev Neurosci 5: 347-60 (2004).
100. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol 119: 7-35 (2010).
101. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O. Neuroinflammation and psychiatric illness. J Neuroinflamm 10: 43 (2013).
102. Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer’s disease. J Neuroimmunol 24: 173-82 (1989).
103. Pike CJ, Cummings BJ, Cotman CW. Early association of reactive astrocytes with senile plaques in Alzheimer’s disease. Exp Neurol 132: 172-9 (1995).
104. Serrano-Pozo A, Mielke ML, Gomez-Isla T, Betensky RA, Growdon JH, Frosch MP, et al. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179: 1373-84 (2011).
105. Bozyczko-Coyne D, O'Kane TM, Wu ZL, Dobrzanski P, Murthy S, Vaught JL, Scott RW. CEP-1347/KT-7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Abeta-induced cortical neuron apoptosis. J Neurochem 77: 849-63 (2001).
106. Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R, et al. Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci 21: 7551-60 (2001).
107. Canevari L, Abramov A, Duchen M. Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochem Res 29: 637-50 (2004).
108. Donev R, Kolev M, Millet B, Thome J. Neuronal death in Alzheimer’s disease and therapeutic opportunities. J Cell Mol Med 13: 4329-48 (2009).
109. Morishima-Kawashima M, Oshima N, Ogata H, Yamaguchi H, Yoshimura M, Sugihara S, et al. Effect of apolipoprotein E allele epsilon4 on the initial phase of amyloid beta-protein accumulation in the human brain. Am J Pathol 157: 2093-9 (2000).
110. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, et al. Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol 155: 853-62 (1999).
111. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20: 4050-8 (2000).
112. DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27: 457-64 (1990).
113. Scheff SW, DeKosky ST, Price DA. Quantative assessment of cortical synaptic density in Alzheimer’s disease. Neurobiol Aging 11: 29-37 (1990).
114. Masliah E, Terry R. The role of synaptic pathology in the mechanisms of dementia in Alzheimer’s disease. Clin Neurosci 1: 192-8 (1994).
115. Gonatas NK. Neocortical synapses in a presenile dementia. J Neuropath Exp Neurol 26: 150-1 (1967).
116. Baloyannis SJ. Dendritic pathology in Alzheimer's disease. J Neurol Sci 283: 153-7 (2009).
117. Falke E, Nissanov J, Mitchel TW, Bennet DA, Trojanowski JO, Arnold SE. Subiculum dendritic arborization in Alzheimer's disease correlates with neurofibrillary tangle density. Am J Pathol 163: 1615-31 (2006).
118. Baloyannis SJ, Costa V, Mauroudis I, Psaroulis D, Manolides SL, Manolides LS. Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological and morphometric estimation by Golgi technique and electron microscopy. Acta Otolaryngol 127: 351-4 (1953).
119. Paula-Barbosa MM, Cardoso RM, Guimaraes ML, Cruz C. Dendritic degeneration and regrowth in the cerebral cortex of patients with Alzheimer's disease. J Neurol Sci 45: 129-34 (1980).
120. Baloyannis SJ, Manolides SL, Manolides LS. Dendritic and spinal pathology in the acoustic cortex in Alzheimer's disease: morphological estimation in Golgi technique and electron microscopy. Acta Otolaryngol 131: 610-2 (2011).
121. Mavroudis IA, Fotiou DF, Manani MG, Njaou SN, Frangou D, Costa VG, et al. Dendritic pathology and spinal loss in the visual cortex in Alzheimer's disease: a Golgi study in pathology. Int J Neurosci 121: 347-54 (2011).
122. Kummer MP, Heneka MT. Truncated and modified amyloid-beta species. Alzheimers Res Ther 6: 28 (2014).
123. Alexander GE, Crutcher MD, DeLong MR. Basal gangliathalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions. Prog Brain Res 85: 119-46 (1990).
124. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 50: 873-80 (1993).
125. Mesulam MM. From sensation to cognition. Brain 121: 1013-52 (1998).
126. Trillo L, Das D, Hsieh W, Medina B, Moghadam S, Lin B, et al. Ascending monoaminergic systems alterations in Alzheimer’s disease. Translating basic science into clinical care. Neurosci Biobehav Rev 37: 1363-79 (2013).
127. Geschwind N, Kaplan E. A human cerebral deconnection syndrome. A preliminary report. Neurology 12: 675-85 (1962).
128. Catani M, Dell'acqua F, Thiebaut de Schotten M. A revised limbic system model for memory, emotion and behavior. Neurosci Biobehav Rev 37: 1724-37 (2013).
129. Fuxe K, Dahlstrom A, Hoistad M, Marcellino D, Jansson A, Rivera A, et al. From the Golgi-Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: wiring and volume transmission. Brain Res Rev 55: 17-54 (2007).
130. Sluimer JD, van der Flier WM, Karas GB, Fox NC, Scheltens P, Barkhof F, et al. Wholebrain atrophy rate and cognitive decline: longitudinal MR study of memory clinic patients. Radiology 248: 590-8 (2008).
131. Chan D, Janssen JC, Whitwell JL, Watt HC, Jenkins R, Frost C, et al. Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study. Lancet 362: 1121-2 (2003).
132. Thompson PM, Hayashi KM, de Zubicaray G, Janke AL, Rose SE, Semple J, et al. Dynamics of gray matter loss in Alzheimer's disease. J Neurosci 23: 994-1005 (2003).
133. Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN, et al. Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study. Lancet Neurol 5: 828-34 (2006).
134. Singh V, Chertkow H, Lerch JP, Evans AC, Dorr AE, Kabani NJ. Spatial patterns of cortical thinning in mild cognitive impairment and Alzheimer's disease. Brain 129: 2885-93 (2006).
135. McDonald CR, McEvoy LK, Gharapetian L, Fennema-Notestine C, Hagler DJ Jr, Holland D, et al. for the Alzheimer's Disease Neuroimaging Initiative. Regional rates of neocortical atrophy from normal aging to early Alzheimer disease. Neurology 73: 457-65 (2009).
136. Lopez OL, Zivkovic S, Smith G, Becker JT, Meltzer CC, DeKosky ST. Psychiatric symptoms associated with cortical-subcortical dysfunction in Alzheimer's disease. J Neuropsychiatr Clin Neurosci 13: 56-60 (2001).
137. Ball SL, Holland AJ, Watson PC, Huppert FA. Theoretical exploration of the neural bases of behavioural disinhibition, apathy and executive dysfunction in preclinical Alzheimer's disease in people with Down's syndrome: potential involvement of multiple frontalsubcortical neuronal circuits. J Intellect Disabil Res 54: 320-36 (2010).
138. Peavy GM, Salmon DP, Edland SD, Tam S, Hansen LA, Masliah E, et al. Neuropsychiatric features of frontal lobe dysfunction in autopsy-confirmed patients with lewy bodies and "pure" Alzheimer disease. Am J Geriatr Psychiatry 21: 509-19 (2013).
139. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42: 85-94 (1997).
140. Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25: 7709-17 (2005).
141. Broyd SJ, Demanuele C, Debener S, Helps SK, James CJ, Sonuga-Barke EJ. Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev 33: 279-96 (2009).
142. Zhou J, Greicius MD, Gennatas ED, Growdon ME, Jang JY, Rabinovici GD, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain 133: 1352-67 (2010).
143. Oh H, Mormino EC, Madison C, Hayenga A, Smiljic A, Jagust WJ. β-Amyloid affects frontal and posterior brain networks in normal aging. Neuroimage 54: 1887-95 (2011)
144. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 66: 137-47 (1999).
145. Wenk GL. Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 64: 7-10 (2003).
146. Parvizi J, van Hoesen GW, Damasio A. The selective vulnerability of brainstem nuclei to Alzheimer’s disease. Ann Neurol 49: 53-66 (2001).
147. Starkstein SE, Mizrahi R. Depression in Alzheimer's disease. Expert Rev Neurother 6: 887-95 (2006).
148. Van der Mussele S, Bekelaar K, Le Bastard N, Vermeiren Y, Saerens J, Somers N, et al. Prevalence and associated behavioral symptoms of depression in mild cognitive impairment and dementia due to Alzheimer's disease. Int J Geriatr Psychiatry 28: 947-58 (2013).
149. Kessing LV. Depression and the risk for dementia. Curr Opin Psychiatry 25: 457-61 (2012).
150. Ballmaier M, Sowell ER, Thompson PM, Kumar A, Narr KL, Lavretsky H, et al. Mapping brain size and cortical gray matter changes in elderly depression. Biol Psychiatry 55: 382-9 (2004).
151. Campbell S, Marriott M, Nahmias C, MacQueen GM. Lower hippocampal volume in patients suffering from depression: a metaanalysis. Am J Psychiatry 161: 598-607 (2004).
152. Egger K, Schocke M, Weiss E, Auffinger S, Esterhammer R, Goebel G, et al. Pattern of brain atrophy in elderly patients with depression revealed by voxel-based morphometry. Psychiatr Res 164: 237-44 (2008).
153. Lee GJ, Lu PH, Hua X, Lee S, Wu S, Nguyen K, et al. Depressive symptoms in mild cognitive impairment predict greater atrophy in Alzheimer's disease-related regions. Biol Psychiatry 71: 814-21 (2012).
154. Zahodne LB, Gongvatana A, Cohen RA, Ott BR, Tremont G, for the Alzheimer's Disease Neuroimaging Initiative. Are apathy and depression independently associated with longitudinal trajectories of cortical atrophy in mild cognitive impairment? Am J Geriatr Psychiatry 21: 1098-106 (2013).
155. Royall DR, Palmer RF. Alzheimer's disease pathology does not mediate the association between depressive symptoms and subsequent cognitive decline. Alzheimers Dement 9: 318-25 (2013).
156. Royall DR, Palmer RF, Vidoni ED, Honea RA. The default mode network may be the key substrate of depressive symptom-related cognitive changes. J Alzheimers Dis 34: 547-59 (2013).
157. Wu D, Yuan Y, Bai F, You J, Li L, Zhang Z. Abnormal functional connectivity of the default mode network in remitted late-onset depression. J Affect Disord 147: 277-87 (2013).
158. Munro CE, Donovan NJ, Guercio BJ, Wigman SE, Schultz AP, Amariglio RE, et al. Neuropsychiatric Symptoms and Functional Connectivity in Mild Cognitive Impairment. J Alzheimers Dis 46: 727-35 (2015).
159. Rapp MA, Schnaider-Beeri M, Grossman HT, Sano M, Perl DP, Purohit DP, et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry 63: 161-7 (2006).
160. Klatka LA, Louis ED, Schiffer RB. Psychiatric features in diffuse Lewy body disease: a clinicopathologic study using Alzheimer’s disease and Parkinson’s disease comparison groups. Neurology 47: 1148-52 (1996).
161. Papka M, Rubio A, Schiffer RB, Cox C. Lewy body disease: can we diagnose it? J Neuropsychiatr Clin Neurosci 10: 405-12 (1998).
162. Ballard C, Holmes C, McKeith I, Neill D, O’Brien J, Cairns N, et al. Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatry 156: 1039-45 (1999).
163. Fritze F, Ehrt U, Hortobagyi I, Ballard C, Aarsland D. Depressive symptoms in Alzheimer’s disease and Lewy body dementia: a oneyear follow-up study. Dement Geriatr Cogn Disord 32: 143-9 (2011).
164. Lopez OL, Hamilton RL, Becker JT, Wisniewski S, Kaufer DI, DeKosky ST. Severity of cognitive impairment and the clinical diagnosis of AD with Lewy bodies. Neurology 54: 1780-7 (2000).
165. Lopez OL, Becker JT, Sweet RA, Martin-Sanchez FJ, Hamilton RL. Lewy bodies in the amygdala increase risk for major depression in subjects with Alzheimer disease. Neurology 67: 660-5 (2006).
166. Drevets WC. Neuroimaging abnormalities in the amygdala in mood disorders. Ann N Y Acad Sci 985: 420-44 (2003).
167. Smith MC, Mallory M, Hansen LA, Ge N, Masliah E. Fragmentation of the neuronal cytoskeleton in the Lewy body variant of Alzheimer’s disease. NeuroReport 6: 673-9 (1995).
168. Uversky VN. Alpha-synuclein misfolding and neurodegenerative diseases. Curr Protein Pept Sci 9: 507-40 (2008).
169. Chan-Palay V, Asan E. Alterations in catecholamine neurons of the locus coeruleus in senile dementia of the Alzheimer type and in Parkinson's disease with and without dementia and depression. J Comp Neurol 287: 373-92 (1989).
170. Forstl H, Burns A, Luthert P, Cairns N, Lantos P, Levy R. Clinical and neuropathological correlates of depression in Alzheimer's disease. Psychol Med 22: 877-84 (1992).
171. Zubenko GS, Moossy J, Kopp U. Neurochemical correlates of major depression in primary dementia. Arch Neurol 47: 209-14 (1990).
172. Vermeiren Y, Van Dam D, Aerts T, Engelborghs S, De Deyn PP. Monoaminergic neurotransmitter alterations in postmortem brain regions of depressed and aggressive patients with Alzheimer's disease. Neurobiol Aging 35: 2691-700 (2014).
173. Vermeiren Y, Van Dam D, Aerts T, Engelborghs S, De Deyn PP. Brain region-specific monoaminergic correlates of neuropsychiatric symptoms in Alzheimer's disease. J Alzheimers Dis 41: 819-33 (2014).
174. O’Halloran CJ, Kinsella GJ, Storey E. The cerebellum and neuropsychological functioning: A critical review. J Clin Exp Neuropsychol 34: 35-56 (2012).
175. Goeb JL, Even C, Nicolas G, Gohier B, Dubas F, Garre JB. Psychiatric side effects of interferon-beta in multiple sclerosis. Eur Psychiatry 21: 186-93 (2006).
176. O’Connor JC, Andre C, Wang Y, Lawson MA, Szegedi SS, Lestage J, et al. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci 13: 4200-9 (2009).
177. Dobos N, Korf J, Luiten PG, Eisel UL. Neuroinflammation in Alzheimer's disease and major depression. Biol Psychiatry 67: 503-4 (2010).
178. Naude PJ, Nyakas C, Eiden LE, Ait-Ali D, van der Heide R, Engelborghs S, et al. Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease. FASEB J 26: 2811-23 (2012).
179. Naude PJ, Eisel UL, Comijs HC, Groenewold NA, De Deyn PP, Bosker FJ, et al. Neutrophil gelatinase-associated lipocalin: a novel inflammatory marker associated with late-life depression. J Psychosom Res 75: 444-50 (2013).
180. Naude PJ, den Boer JA, Comijs HC, Bosker FJ, Zuidersma M, Groenewold NA, et al. Sex-specific associations between Neutrophil Gelatinase-Associated Lipocalin (NGAL) and cognitive domains in late-life depression. Psychoneuroendocrinology 48: 169-77 (2014).
181. Naude PJ, Dekker AD, Coppus AM, Vermeiren Y, Eisel UL, van Duijn CM, et al. Serum NGAL is Associated with Distinct Plasma Amyloid-β Peptides According to the Clinical Diagnosis of Dementia in Down Syndrome. J Alzheimers Dis 45: 733-43 (2015).
182. Donnemiller E, Heilmann J, Wenning GK, Berger W, Decristoforo C, Moncayo R, et al. Brain perfusion scintigraphy with 99mTc-HMPAO or 99mTc-ECD and 123I-beta-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body disease. Eur J Nucl Med 24: 320-5 (1997).
183. Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, et al. Frontal lobe hypometabolism and depression in Alzheimer's disease. Neurology 50: 380-3 (1998).
184. Levy-Cooperman N, Burhan AM, Rafi-Tari S, Kusano M, Ramirez J, Caldwell C, et al. Frontal lobe hypoperfusion and depressive symptoms in Alzheimer disease. J Psychiatr Neurosci 33: 218-26 (2008).
185. Caroli A, Geroldi C, Nobili F, Barnden LR, Guerra UP, Bonetti M, et al. Functional compensation in incipient Alzheimer's disease. Neurobiol Aging 31: 387-97 (2010).
186. Kataoka K, Hashimoto H, Kawabe J, Higashiyama S, Akiyama H, Shimada A, et al. Frontal hypoperfusion in depressed patients with dementia of Alzheimer type demonstrated on 3DSRT. Psychiatr Clin Neurosci 64: 293-8 (2010).
187. Pedrosa R, Teixeira-Sousa V, Fonseca S, Bastos-Leite AJ. Earlyonset Alzheimer disease: the contribution of neuroimaging for the diagnosis. Psychiatr Res 182: 287-8 (2010).
188. Starkstein SE, Mizrahi R, Capizzano AA, Acion L, Brockman S, Power BD. Neuroimaging correlates of apathy and depression in Alzheimer's disease. J Neuropsychiatr Clin Neurosci 21: 259-65 (2009).
189. Hendricksen M, Thomas AJ, Ferrier IN, Ince P, O'Brien JT. Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer's disease with and without depression. Am J Psychiatry 161: 1096-102 (2004).
190. Chen CP, Alder JT, Bowen DM, Esiri MM, McDonald B, Hope T, et al. Presynaptic serotonergic markers in community-acquired cases of Alzheimer’s disease: correlations with depression and neuroleptic medication. J Neurochem 66: 1592-8 (1996).
191. Ballard C, Johnson M, Piggott M, Perry R, O’Brien J, Rowan E, et al. A positive association between 5HT re-uptake binding sites and depression in dementia with Lewy bodies. J Affect Disord 69: 219-23 (2002).
192. Lai MK, Tsang SW, Esiri MM, Francis PT, Wong PT, Chen CP. Differential involvement of hippocampal serotonin1A receptors and re-uptake sites in non-cognitive behaviors of Alzheimer's disease. Psychopharmacology (Berl) 213: 431-9 (2011).
193. Romano A, Pace L, Tempesta B, Lavecchia AM, Macheda T, Bedse G, et al. Depressive-like behavior is paired to monoaminergic alteration in a murine model of Alzheimer's disease. Int J Neuropsychopharmacol 18: pii: pyu020 (2014).
194. Tagariello P, Girardi P, Amore M. Depression and apathy in dementia: same syndrome or different constructs? A critical review. Arch Gerontol Geriatry 49: 246-249 (2009).
195. McPherson S, Fairbanks L, Tiken S, Cummings JL, Back-Madruga C. Apathy and executive function in Alzheimer’s disease. J Int Neuropsychol Soc 8: 373-81 (2002).
196. Nakaaki S, Murata Y, Sato J, Shinagawa Y, Hongo J, Tatsumi H. Association between apathy/depression and executive function in patients with Alzheimer’s disease. Int Psychogeriatry 20: 964-75 (2008).
197. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3: 243-54 (1991).
198. Levy ML, Cummings JL, Fairbanks LA, Masterman D, Miller BL, Craig AH, et al. Apathy is not depression. J Neuropsychiatr Clin Neurosci 10: 314-9 (1998).
199. Andersson S, Krogstad JM, Finset A. Apathy and depressed mood in acquired brain damage: relationship to lesion localization and psychophysiological reactivity. Psychol Med 29: 447-56 (1999).
200. Barnhart WJ, Makela EH, Latocha MJ. SSRI-induced apathy syndrome: a clinical review. J Psychiatr Pract 10: 196-9 (2004).
201. Guimaraes HC, Levy R, Teixeira AL, Beato RG, Caramelli P. Neurobiology of apathy in Alzheimer's disease. Arq Neuropsiquiatry 66: 436-43 (2008).
202. Chu CC, Tranel D, Damasio AR, Van Hoesen GW. The autonomic-related cortex: pathology in Alzheimer’s disease. Cereb Cortex 7: 86-95 (1997).
203. Marshall GA, Fairbanks LA, Tekin S, Vinters HV, Cummings JL. Neuropathological correlates of apathy in Alzheimer’s disease. Dement Geriatr Cogn Disord 21: 144-7 (2006).
204. Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67: 446-52 (2006).
205. Tekin S, Mega MS, Masterman DM, Chow T, Garakian J, Vinters HV, et al. Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol 49: 355-61 (2001).
206. Bruen PD, McGeown WJ, Shanks MF, Venneri A. Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer's disease. Brain 131: 2455-63 (2008).
207. Tunnard C, Whitehead D, Hurt C, Wahlund LO, Mecocci P, Tsolaki M, et al. Apathy and cortical atrophy in Alzheimer's disease. Int J Geriatr Psychiatry 26: 741-8 (2011).
208. Craig AH, Cummings JL, Fairbanks L, Itti L, Miller B, Li J, et al. Cerebral blood flow correlates of apathy in Alzheimer disease. Arch Neurol 53: 1116-20 (1996).
209. Migneco O, Benoit M, Koulibaly PM, Dygai I, Bertogliati C, Desvignes P, et al. Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer’s disease and nondemented patients. NeuroImage 13: 896-902 (2001).
210. Benoit M, Koulibaly PM, Migneco O, Darcourt J, Pringuey DJ, Robert PH. Brain perfusion in Alzheimer’s disease with and without apathy: a SPECT study with statistical parametric mapping analysis. Psychiatr Res 114: 103-11 (2002).
211. Mitchell RA, Herrmann N, Lanctot KL. The role of dopamine in symptoms and treatment of apathy in Alzheimer's disease. CNS Neurosci Therap 17: 411-27 (2011).
212. Martorana A, Koch G. "Is dopamine involved in Alzheimer's disease?" Front Aging Neurosci 25: 252 (2014).
213. Storga D, Vrecko K, Birkmayer JGD, Reibnegger G. Monoaminergic neurotransmitters, their precursors and metabolites in brains of Alzheimer patients. Neurosci Lett 203: 29-32 (1996).
214. Arai H, Kosaka K, Iiziku R. Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimertype dementia. J Neurochem 43: 388-93 (1984).
215. Nazarali AJ, Reynolds GP. Monoamine neurotransmitters and their metabolites in brain regions in Alzheimer’s disease: A postmortem study. Cell Mol Neurobiol 12: 581-7 (1992).
216. Cross AJ, Crow TJ, Ferrier IN, Johnson JA, Markakis D. Striatal dopamine receptors in Alzheimer-type dementia. Neurosci Lett 52: 1-6 (1984).
217. De Keyser J, Ebinger G, Vauquelin G. D1-dopamine receptor abnormality in frontal cortex points to a functional alteration of cortical cell membranes in Alzheimer’s disease. Arch Neurol 47: 761-3 (1990).
218. Sweet RA, Hamilton RL, Healy MT, Wisniewski SR, Henteleff R, Pollock BG, et al. Alterations of striatal dopamine receptor binding in Alzheimer disease are associated with Lewy body pathology and antemortem psychosis. Arch Neurol 58: 466-72 (2001).
219. Pinto T, Lanctot KL, Herrmann N. Revisiting the cholinergic hypothesis of behavioral and psychological symptoms in dementia of the Alzheimer's type. Ageing Res Rev 10: 404-12 (2011).
220. Drijgers RL, Aalten, P, Winogrodzka, A, Verhey, FRJ, Leentjens, AFG. Pharmacological treatment of apathy in neurodegenerative diseases: a systematic review. Dement Geriatr Cogn Disord 28: 13-22 (2009).
221. Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry 23: 170-7 (2008).
222. Ballard C, Corbett A. Agitation and aggression in people with Alzheimer's disease. Curr Opin Psychiatry 26: 252-9 (2013).
223. Lavretsky H. Neuropsychiatric symptoms in Alzheimer disease and related disorders: why do treatments work in clinical practice but not in the randomized trials? Am J Geriatr Psychiatry 16: 523-7 (2008).
224. Matthews KL, Chen CP, Esiri MM, Keene J, Minger SL, Francis PT. Noradrenergic changes, aggressive behavior, and cognition in patients with dementia. Biol Psychiatry 51: 407-16 (2002).
225. Lai MK, Chen CP, Hope T, Esiri MM. Hippocampal neurofibrillary tangle changes and aggressive behaviour in dementia. Neuroreport 21: 1111-5 (2010).
226. Hirono N, Mega MS, Dinov ID, Mishkin F, Cummings JL. Left frontotemporal hypoperfusion is associated with aggression in patients with dementia. Arch Neurol 57: 861-6 (2000).
227. Lancot KL, Herrmann N, Nadkarni NK, Leibovitch FS, Caldwell CB, Black SE. Medial temporal hypoperfusion and aggression in Alzheimer’s disease. Arch Neurol 61: 1731-7 (2004).
228. Poulin SP, Dautoff R, Morris JC, Barrett LF, Dickerson BC, for the Alzheimer's Disease Neuroimaging Initiative. Amygdala atrophy is prominent in early Alzheimer's disease and relates to symptom severity. Psychiatr Res 194: 7-13 (2011).
229. Trzepacz PT, Yu P, Bhamidipati PK, Willis B, Forrester T, Tabas L, et al. Frontolimbic atrophy is associated with agitation and aggression in mild cognitive impairment and Alzheimer's disease. Alzheimers Dement 9: S95-S104 (2013).
230. Minger SL, Esiri MM, McDonald B, Keene J, Carter J, Hope T, et al. Cholinergic deficits contribute to behavioral disturbance in patients with dementia. Neurology 55: 1460-7 (2000).
231. Garcia-Alloza M, Gil-Bea FJ, Diez-Ariza M, Chen CP, Francis PT, Lasheras B, et al. Cholinergic-serotonergic imbalance contributes to cognitive and behavioral symptoms in Alzheimer's disease. Neuropsychologia 43: 442-9 (2005).
232. Herrmann N, Rabheru K, Wang J, Binder C. Galantamine treatment of problematic behavior in Alzheimer disease: post-hoc analysis of pooled data from three large trials. Am J Geriatr Psychiatry 13(6): 527-34 (2005).
233. Cummings JL, McRae T, Zhang R; for the Donepezil-Sertraline Study Group. Effects of donepezil on neuropsychiatric symptoms in patients with dementia and severe behavioral disorders. Am J Geriatr Psychiatry 14: 605-12 (2006).
234. Palmer AM, Stratmann GC, Procter AW, Bowen DM. Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol 23: 616-20 (1988).
235. Lanctot KL, Herrmann N, Eryavec G, van Reekum R, Reed K, Naranjo CA. Central serotonergic activity is related to the aggressive behaviors of Alzheimer's disease. Neuropsychopharmacology 27: 646-54 (2002).
236. Ueki A, Ueno H, Sato N, Shinjo H, Morita Y. Serotonin transporter gene polymorphism and BPSD in mild Alzheimer's disease. J Alzheimers Dis 12: 245-53 (2007).
237. Sweet RA, Pollock BG, Sukonick DL, Mulsant BH, Rosen J, Klunk WE, et al. The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer disease. Int Psychogeriatr 13: 401-409 (2001).
238. Russo-Neustadt A, Zomorodian TJ, Cotman CW. Preserved cerebellar tyrosine hydroxylase-immunoreactive neuronal fibers in a behaviorally aggressive subgroup of Alzheimer’s disease patients. Neuroscience 87: 55-61 (1998).
239. Snaith RP, Zigmond AS. The hospital anxiety and depression scale. Br Med J (Clin Res Ed) 292: 344 (1986).
240. Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging. Am J Psychiatry 157: 708-14 (2000).
241. Engelborghs S, Maertens K, Nagels G, Vloeberghs E, Marien P, Symons A, et al. Neuropsychiatric symptoms of dementia: crosssectional analysis from a prospective, longitudinal Belgian study. Int J Geriatr Psychiatry 20: 1028-37 (2005).
242. Hashimoto H, Monserratt L, Nguyen P, Feil D, Harwood D, Mandelkern MA, et al. Anxiety and regional cortical glucose metabolism in patients with Alzheimer's disease. J Neuropsychiatr Clin Neurosci 18: 521-8 (2006).
243. Beauquis J, Vinuesa A, Pomilio C, Pavia P, Galvan V, Saravia F. Neuronal and glial alterations, increased anxiety, and cognitive impairment before hippocampal amyloid deposition in PDAPP mice, model of Alzheimer's disease. Hippocampus 24: 257-69 (2014).
244. Jeste DV, Finkel SI. Psychosis of alzheimer's disease and related dementias. diagnostic criteria for a distinct syndrome. Am J Geriatr Psychiatry 8: 29-34 (2000).
245. Forstl H, Besthorn C, Burns A, Geiger-Kabisch C, Levy R, Sattel A. Delusional misidentification in Alzheimer's disease: a summary of clinical and biological aspects. Psychopathology 27: 194-9 (1994).
246. Farber NB, Rubin EH, Newcomer JW, Kinscherf DA, Miller JP, Morris JC, et al. Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis. Arch Gen Psychiatry 57: 1165-73 (2000).
247. Ballard CG, Jacoby R, Del Ser T, Khan MN, Munoz DG, Holmes C, et al. Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies. Am J Psychiatry 161: 843-9 (2004).
248. McShane R, Gedling K, Reading M, McDonald B, Esiri MM, Hope T. Prospective study of relations between cortical Lewy bodies, poor eyesight, and hallucinations in Alzheimer's disease. J Neurol Neurosurg Psychiatry 59: 185-8 (1995).
249. Holroyd S, Shepherd ML, Downs JH III. Occipital atrophy is associated with visual hallucinations in Alzheimer's disease. J Neuropsychiatr Clin Neurosci 12: 25-8 (2000).
250. Lin SH, Yu CY, Pai MC. The occipital white matter lesions in Alzheimer's disease patients with visual hallucinations. Clin Imaging 30: 388-93 (2006).
251. Serra L, Perri R, Cercignani M, Spano B, Fadda L, Marra C, et al. Are the behavioral symptoms of Alzheimer’s disease directly associated with neurodegeneration? J Alzheimers Dis 21: 627-39 (2010).
252. Forstl H, Burns A, Levy R, Cairns N. Neuropathological correlates of psychotic phenomena in confirmed Alzheimer's disease. Br J Psychiatry 165: 53-9 (1994).
253. Lee DY, Choo IH, Kim KW, Jhoo JH, Youn JC, Lee UY, et al. vWhite matter changes associated with psychotic symptoms in Alzheimer’s disease patients. J Neuropsychiatr Clin Neurosci 18: 191-8 (2006).
254. Zubenko GS, Moossy J, Martinez AJ, Rao G, Claassen D, Rosen J, Kopp U. Neuropathologic and neurochemical correlates of psychosis in primary dementia. Arch Neurol 48: 619-24 (1991).
255. Lai MK, Lai OF, Keene J, Esiri MM, Francis PT, Hope T, et al. Psychosis of Alzheimer’s disease is associated with elevated muscarinic M2 binding in the cortex. Neurology 57: 805-11 (2001).
256. Edwards K, Koumaras, B, Chen M, Gunay, I, Mirski, D. Longterm effects of rivastigmine treatment on the need for psychotropic medications in nursing home patients with Alzheimer’s disease: results of a 52-week open-label study. Clin Drug Invest 2: 507-15 (2005).
257. Vermeiren Y, Van Dam D, Aerts T, Engelborghs S, Martin JJ, De Deyn PP. The monoaminergic footprint of depression and psychosis in dementia with Lewy bodies compared to Alzheimer's disease. Alzheimers Res Ther 7: 7 (2015).
258. Mega MS, Lee L, Dinov ID, Mishkin F, Toga AW, Cummings JL. Cerebral correlates of psychotic symptoms in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 69: 167-71 (2000).
259. Staff RT, Shanks MF, Macintosh L, Pestell SJ, Gemmell HG, Venneri A. Delusions in Alzheimer’s disease: SPET evidence of right hemispheric dysfunction. Cortex 35: 549-60 (1999).
260. Geroldi C, Bresciani L, Zanetti O, Frisoni GB. Regional brain atrophy in patients with mild Alzheimer's disease and delusions. Int Psychogeriatr 14: 365-78 (2002).
261. Mentis MJ, Weinstein EA, Horwitz B, McIntosh AR, Pietrini P, Alexander GE, et al. Abnormal brain glucose metabolism in the delusional misidentification syndromes: a positron emission tomography study in Alzheimer disease. Biol Psychiatry 38: 438-49 (1995).
262. Lopez OL, Becker JT, Brenner RP, Rosen J, Bajulaiye OI, Reynolds CF 3rd. Alzheimer's disease with delusions and hallucinations: neuropsychological and electroencephalographic correlates. Neurology 41: 906-12 (1991).
263. Edwards-Lee T, Cook I, Fairbanks L, Leuchter A, Cummings JL. Quantitative electroencephalographic correlates of psychosis in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol 13: 163-70 (2000).
264. Hofman MA, Swaab DF. Living by the clock: The circadian pacemaker in older people. Ageing Res Rev 5: 33-51 (2006).
265. Coogan AN, Schutova B, Husung S, Furczyk K, Baune BT, Kropp P, et al. The circadian system in Alzheimer's disease: disturbances, mechanisms, and opportunities. Biol Psychiatry 74: 333-9 (2013).
266. Bachman D, Rabins P. "Sundowning" and other temporally associated agitation states in dementia patients. Annu Rev Med 57: 499-511 (2006).
267. Benca R, Duncan MJ, Frank E, McClung C, Nelson RJ, Vicentic A. Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges. Brain Res Rev 62: 57-70 (2009).
268. Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res 342: 37-44 (1985).
269. Stopa EG, L Volicer, V Kuo-Leblanc, D Harper, D Lathi, B Tate, et al. Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia J Neuropathol Exp Neurol 58: 29-39 (1999).
270. Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol 70: 587-93 (2013).
271. Mander BA, Marks SM, Vogel JW, Rao V, Lu B, Saletin JM, et al. β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation. Nat Neurosci 18: 1051-1057 (2015).
272. Vanecek J, Watanabe K. Mechanisms of melatonin action in the pituitary and SCN. Adv Exp Med Biol 460: 191-8 (1999).
273. Pappolla MA, Chyan YJ, Poeggeler B, Frangione B, Wilson G, Ghiso J, et al. An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer’s disease. J Neural Transm 107: 203-31 (2000).
274. Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF. Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 35: 125-30 (2003).
275. Wu YH, Feenstra MG, Zhou JN, Liu RY, Torano JS, Van Kan HJ, et al. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 88: 5898-906 (2003).
276. Wisor JP, DM Edgar, J Yesavage, HS Ryan, CM McCormick, N Lapustea, et al. Sleep and circadian abnormalities in a transgenic mouse model of Alzheimer’s disease: A role for cholinergic transmission. Neuroscience 131: 375-85 (2005).
277. Fuh JL, Wang SJ, Cummings JL. Neuropsychiatric profiles in patients with Alzheimer's disease and vascular dementia. J Neurol Neurosurg Psychiatry 76: 1337-41 (2005).
278. Del Ser T, Hachinski V, Merskey H, Munoz DG. Alzheimer's disease with and without cerebral infarcts. J Neurol Sci 231: 3-11 (2005).
279. Berlow YA, Wells WM, Ellison JM, Sung YH, Renshaw PF, Harper DG. Neuropsychiatric correlates of white matter hyperintensities in Alzheimer's disease. Int J Geriatr Psychiatry 25: 780-8 (2010).
280. Boeve BF, Silber MH, Parisi JE, Dickson DW, Ferman TJ, Benarroch EE, et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 61: 40-5 (2003).