title: Does Alzheimer's disease begin in the brainstem?
abstract: Although substantial evidence indicates that the progression of pathological changes of the neuronal cytoskeleton is crucial in determining the severity of dementia in Alzheimer's disease (AD), the exact causes and evolution of these changes, the initial site at which they begin, and the neuronal susceptibility levels for their development are poorly understood. The current clinical criteria for diagnosis of AD are focused mostly on cognitive deficits produced by dysfunction of hippocampal and high-order neocortical areas, whereas noncognitive, behavioural and psychological symptoms of dementia such as disturbances in mood, emotion, appetite, and wake-sleep cycle, confusion, agitation and depression have been less considered. The early occurrence of these symptoms suggests brainstem involvement, and more specifically of the serotonergic nuclei. In spite of the fact that the Braak and Braak staging system and National Institutes of Aging - Reagan Institute (NIA-RI) criteria do not include their evaluation, several recent reports drew attention to the possibility of selective and early involvement of raphe nuclei, particularly the dorsal raphe nucleus (DRN), in the pathogenesis of AD. Based on these findings of differential susceptibility and anatomical connectivity, a novel pathogenetic scheme of AD progression was proposed. Although the precise mechanisms of neurofibrillary degeneration still await elucidation, we speculated that cumulative oxidative damage may be the main cause of DRN alterations, as the age is the main risk factor for sporadic AD. Within such a framework, beta-amyloid production is considered only as one of the factors (although a significant one in familial cases) that promotes molecular series of events underlying AD-related neuropathological changes.
authors.affiliation: Department of Neuroscience, Croatian Institute for Brain Research, Medical School Zagreb, Croatia. gsimic@hiim.hr
authors.forename: G
authors.initials: G
authors.lastname: Simic
authors.forename: G
authors.initials: G
authors.lastname: Stanic
authors.forename: M
authors.initials: M
authors.lastname: Mladinov
authors.forename: N
authors.initials: N
authors.lastname: Jovanov-Milosevic
authors.forename: I
authors.initials: I
authors.lastname: Kostovic
authors.forename: P R
authors.initials: PR
authors.lastname: Hof
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001933:Brain Stem / Q000473:pathology / Q000503:physiopathology*; D003599:Cytoskeleton / Q000473:pathology / Q000502:physiology; D018450:Disease Progression; D006801:Humans; D008959:Models, Neurological; D016874:Neurofibrillary Tangles / Q000473:pathology / Q000502:physiology; D015213:Neuroimmunomodulation / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D009483:Neuropsychological Tests; D018384:Oxidative Stress / Q000502:physiology; D011903:Raphe Nuclei / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D016875:tau Proteins
references.citation: J Neurosci. 1996 Jul 15;16(14):4491-500
references.pmid: 8699259
references.citation: Neurobiol Aging. 1986 Nov-Dec;7(6):489-502
references.pmid: 2882432
references.citation: Neuropathology. 2006 Dec;26(6):508-18
references.pmid: 17203586
references.citation: J Comp Neurol. 1997 Mar 24;379(4):482-94
references.pmid: 9067838
references.citation: Neurobiol Aging. 1997 Jul-Aug;18(4 Suppl):S99-105
references.pmid: 9330997
references.citation: Acta Neuropathol. 2001 Mar;101(3):256-70
references.pmid: 11307626
references.citation: Brain Res Rev. 2006 Aug;51(2):176-211
references.pmid: 16413610
references.citation: Arch Neurol. 1985 Nov;42(11):1097-105
references.pmid: 2864910
references.citation: Brain Pathol. 1998 Apr;8(2):367-76
references.pmid: 9546293
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: J Biol Chem. 1984 Apr 25;259(8):5301-5
references.pmid: 6425287
references.citation: Acta Neuropathol. 2009 Jul;118(1):5-36
references.pmid: 19381658
references.citation: Ann Neurol. 2005 Nov;58(5):748-57
references.pmid: 16247771
references.citation: Arch Neurol. 2003 May;60(5):729-36
references.pmid: 12756137
references.citation: J Psychiatr Res. 1975 Nov;12(3):189-98
references.pmid: 1202204
references.citation: Ann Neurol. 1997 Jan;41(1):17-24
references.pmid: 9005861
references.citation: Nat Rev Drug Discov. 2007 May;6(5):341-2
references.pmid: 17539055
references.citation: J Neurol Neurosurg Psychiatry. 1988 Jun;51(6):842-9
references.pmid: 3404192
references.citation: Neurobiol Aging. 2000 May-Jun;21(3):383-421
references.pmid: 10858586
references.citation: Proc Natl Acad Sci U S A. 1985 Jul;82(13):4531-4
references.pmid: 3859874
references.citation: Brain Pathol. 2006 Apr;16(2):124-30
references.pmid: 16768752
references.citation: Neurology. 1991 Apr;41(4):479-86
references.pmid: 2011243
references.citation: J Comp Neurol. 2003 Aug 25;463(3):281-302
references.pmid: 12820162
references.citation: Lancet Neurol. 2004 Apr;3(4):246-8
references.pmid: 15039037
references.citation: Acta Neuropathol. 1991;82(4):239-59
references.pmid: 1759558
references.citation: Immunol Lett. 2007 Nov 30;114(1):46-51
references.pmid: 17949824
references.citation: Am J Geriatr Psychiatry. 2009 Jun;17(6):493-502
references.pmid: 19472439
references.citation: Lancet Neurol. 2002 Sep;1(5):276
references.pmid: 12849422
references.citation: J Intern Med. 2004 Sep;256(3):183-94
references.pmid: 15324362
references.citation: Ann Neurol. 2001 Feb;49(2):202-13
references.pmid: 11220740
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):702-7
references.pmid: 16407119
references.citation: Brain. 2007 Oct;130(Pt 10):2607-15
references.pmid: 17698496
references.citation: Neurology. 2009 Mar 17;72(11):999-1007
references.pmid: 19289740
references.citation: Science. 1997 Oct 17;278(5337):412-9
references.pmid: 9334292
references.citation: J Neurol Neurosurg Psychiatry. 1994 Apr;57(4):419-25
references.pmid: 8163989
references.citation: Hum Genet. 2006 Apr;119(3):312-21
references.pmid: 16463022
references.citation: Arch Neurol. 1995 Jan;52(1):81-8
references.pmid: 7826280
references.citation: Neurobiol Aging. 1997 Jul-Aug;18(4 Suppl):S1-2
references.pmid: 9330978
references.citation: AJNR Am J Neuroradiol. 2009 May;30(5):893-9
references.pmid: 19279272
references.citation: J Cell Biol. 2006 Nov 20;175(4):541-6
references.pmid: 17101697
references.citation: Neurobiol Aging. 2008 Sep;29(9):1334-47
references.pmid: 17403556
references.citation: Lancet Neurol. 2003 Jan;2(1):15-21
references.pmid: 12849297
references.citation: J Neurosci. 2005 Aug 24;25(34):7709-17
references.pmid: 16120771
references.citation: Neuroscience. 1987 Nov;23(2):389-98
references.pmid: 2449630
references.citation: Biochemistry. 2003 Mar 18;42(10):2768-73
references.pmid: 12627941
references.citation: Am J Geriatr Psychiatry. 2002 Jan-Feb;10(1):24-35
references.pmid: 11790632
references.citation: Behav Brain Funct. 2009 Feb 28;5:13
references.pmid: 19250550
references.citation: J Neurol. 2006 Jun;253(6):794-800
references.pmid: 16511646
references.citation: Biochemistry. 1995 Sep 5;34(35):11117-27
references.pmid: 7669769
references.citation: Trends Neurosci. 1998 Oct;21(10):428-33
references.pmid: 9786340
references.citation: Arch Gen Psychiatry. 1997 Mar;54(3):257-63
references.pmid: 9075466
references.citation: Biochem J. 2006 Dec 15;400(3):511-20
references.pmid: 16939415
references.citation: Ann Neurol. 2000 Sep;48(3):344-53
references.pmid: 10976641
references.citation: Neurology. 2007 Mar 13;68(11):828-36
references.pmid: 17353470
references.citation: J Biol Chem. 2004 Aug 13;279(33):34873-81
references.pmid: 15190058
references.citation: Neurobiol Aging. 2009 Aug;30(8):1288-95
references.pmid: 18077060
references.citation: Acta Neuropathol. 2002 Apr;103(4):370-6
references.pmid: 11904757
references.citation: J Neuropathol Exp Neurol. 1996 Oct;55(10):1023-5
references.pmid: 8857998
references.citation: Prog Brain Res. 2008;172:233-64
references.pmid: 18772036
references.citation: Int J Mol Sci. 2009 Mar;10(3):1386-406
references.pmid: 19399255
references.citation: Acta Neurochir Suppl. 2006;96:267-71
references.pmid: 16671468
references.citation: Hum Mol Genet. 2007 Jan 1;16(1):15-23
references.pmid: 17135279
references.citation: J Neuropathol Exp Neurol. 2009 Jan;68(1):1-14
references.pmid: 19104448
references.citation: Neurology. 2007 Sep 4;69(10):1012-7
references.pmid: 17785670
references.citation: Neuropathol Appl Neurobiol. 2009 Aug;35(4):406-16
references.pmid: 19508444
references.citation: J Cell Biol. 1994 Mar;124(5):769-82
references.pmid: 8120098
references.citation: Acta Neuropathol. 2009 Jul;118(1):87-102
references.pmid: 19234858
references.citation: Nat Med. 2008 Aug;14(8):837-42
references.pmid: 18568035
references.citation: Brain Res Brain Res Rev. 1989 Oct-Dec;14(4):335-53
references.pmid: 2696574
references.citation: Nature. 2002 Apr 4;416(6880):535-9
references.pmid: 11932745
references.citation: J Neural Transm Suppl. 2000;(60):345-50
references.pmid: 11205152
references.citation: J Alzheimers Dis. 2008 Oct;15(2):199-210
references.pmid: 18953109
references.citation: J Comp Neurol. 2009 Apr 1;513(4):417-29
references.pmid: 19180552
references.citation: Neurology. 2003 Apr 22;60(8):1374-7
references.pmid: 12707450
references.citation: Acta Neuropathol. 1992;84(6):638-50
references.pmid: 1281956
references.citation: Neurology. 2000 Mar 28;54(6):1316-23
references.pmid: 10746604
references.citation: Mol Neurobiol. 1996 Jun;12(3):211-24
references.pmid: 8884749
references.citation: Science. 2001 Aug 24;293(5534):1491-5
references.pmid: 11520988
references.citation: Ann Neurol. 1985 Jun;17(6):573-7
references.pmid: 4026228
references.citation: Acta Neuropathol. 2009 Jul;118(1):151-66
references.pmid: 19271225
references.citation: Acta Neuropathol. 2009 Jul;118(1):53-69
references.pmid: 19184068
references.citation: J Neurocytol. 2001 Feb;30(2):145-58
references.pmid: 11577253
references.citation: Neuron. 1999 Nov;24(3):521-9
references.pmid: 10595506
references.citation: Neuroscience. 1994 Nov;63(2):499-516
references.pmid: 7891861
references.citation: J Cell Biol. 1991 Nov;115(3):717-30
references.pmid: 1918161
references.citation: Neuroscience. 2005;130(4):911-25
references.pmid: 15652989
references.citation: Cell. 2005 Feb 25;120(4):545-55
references.pmid: 15734686
references.citation: Neurology. 1996 Feb;46(2):406-12
references.pmid: 8614503
references.citation: J Neuropathol Exp Neurol. 2008 Jun;67(6):523-31
references.pmid: 18520771
references.citation: Acta Neuropathol. 1994;87(6):554-67
references.pmid: 7522386
references.citation: Brain Res Mol Brain Res. 1999 May 7;68(1-2):119-28
references.pmid: 10320789
references.citation: J Neurosci Res. 2002 Nov 1;70(3):402-37
references.pmid: 12391603
references.citation: Neuroreport. 2003 Jan 20;14(1):73-6
references.pmid: 12544834
references.citation: J Biol Chem. 1995 Jan 13;270(2):823-9
references.pmid: 7822317
references.citation: Neuropathology. 2004 Sep;24(3):254-60
references.pmid: 15484705
references.citation: Ann Neurol. 1981 Aug;10(2):122-6
references.pmid: 7283399
references.citation: Mol Med. 2003 Mar-Apr;9(3-4):112-22
references.pmid: 12865947
references.citation: Neurology. 2007 Feb 13;68(7):501-8
references.pmid: 17065593
references.citation: Science. 1987 Feb 20;235(4791):885-90
references.pmid: 2880399
references.citation: Br J Radiol. 2007 Dec;80 Spec No 2:S71-7
references.pmid: 18445747
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 6;103(23):8864-9
references.pmid: 16735465
references.citation: EMBO J. 1990 Dec;9(13):4225-30
references.pmid: 2124967
references.citation: Neurodegener Dis. 2006;3(6):313-9
references.pmid: 16954650
references.citation: Brain Res Mol Brain Res. 1998 Nov 12;62(1):101-5
references.pmid: 9795165
references.citation: J Nucl Med. 2009 Jun;50(6):878-86
references.pmid: 19443597
references.citation: Expert Rev Neurother. 2009 May;9(5):661-79
references.pmid: 19402777
references.citation: Acta Neuropathol. 2009 Jul;118(1):71-86
references.pmid: 19238406
references.citation: J Neural Transm Suppl. 1996;47:1-29
references.pmid: 8841954
references.citation: J Am Geriatr Soc. 1996 Sep;44(9):1078-81
references.pmid: 8790235
references.citation: J Nucl Med. 2009 Feb;50(2):191-7
references.pmid: 19164243
references.citation: Brain Res Brain Res Rev. 2000 Aug;33(1):95-130
references.pmid: 10967355
references.citation: Neurobiol Aging. 1992 Jul-Aug;13(4):461-8
references.pmid: 1508296
references.citation: J Neurochem. 1993 Sep;61(3):921-7
references.pmid: 8395566
references.citation: Exp Neurol. 2000 Sep;165(1):12-26
references.pmid: 10964481
references.citation: Ann Neurol. 1988 Aug;24(2):233-42
references.pmid: 3178178
references.citation: Neuroradiology. 2008 Apr;50(4):293-9
references.pmid: 18246334
references.citation: FEBS Lett. 2002 Feb 13;512(1-3):101-6
references.pmid: 11852060
references.citation: Neurobiol Aging. 2004 Oct;25(9):1197-203
references.pmid: 15312965
references.citation: Neurobiol Aging. 1992 Jan-Feb;13(1):179-89
references.pmid: 1311804
references.citation: Radiology. 2009 Apr;251(1):195-205
references.pmid: 19201945
references.citation: Z Zellforsch Mikrosk Anat. 1970;107(1):123-41
references.pmid: 4194341
references.citation: Coll Antropol. 2008 Jan;32 Suppl 1:51-8
references.pmid: 18405058
references.citation: Neurobiol Aging. 2008 Aug;29(8):1127-32
references.pmid: 18534718
references.citation: BMC Neurol. 2007 Jun 21;7:15
references.pmid: 17584929
references.citation: Neurology. 1984 Jul;34(7):939-44
references.pmid: 6610841
references.citation: Arch Neurol. 1994 Sep;51(9):888-95
references.pmid: 8080388
references.citation: J Neuropathol Exp Neurol. 1984 Jul;43(4):359-68
references.pmid: 6737007
references.citation: Arch Gen Psychiatry. 1996 Feb;53(2):175-82
references.pmid: 8629893
references.citation: Trends Neurosci. 2009 Mar;32(3):150-9
references.pmid: 19162340
references.citation: Lancet. 2004 Jan 31;363(9406):392-4
references.pmid: 15074306
references.citation: J Neurocytol. 2002 Sep-Nov;31(8-9):581-93
references.pmid: 14501200
references.citation: Ann Neurol. 2001 Jan;49(1):53-66
references.pmid: 11198297
references.citation: Curr Alzheimer Res. 2006 Sep;3(4):377-91
references.pmid: 17017868
references.citation: Neurosci Lett. 1992 Dec 14;148(1-2):23-6
references.pmid: 1300498
references.citation: Neurology. 1992 Mar;42(3 Pt 1):631-9
references.pmid: 1549228
references.citation: Trends Neurosci. 2004 Oct;27(10):607-13
references.pmid: 15374672
references.citation: J Neurochem. 2006 Feb;96(4):1005-15
references.pmid: 16412093
references.citation: Neuroscience. 1987 May;21(2):305-12
references.pmid: 3302759
references.citation: Can J Neurol Sci. 1982 Aug;9(3):303-6
references.pmid: 7116237
references.citation: J Biol Chem. 2006 Jan 20;281(3):1599-604
references.pmid: 16282321
references.citation: Acta Neuropathol. 2001 Apr;101(4):305-10
references.pmid: 11355301
references.citation: Biochim Biophys Acta. 2005 Jan 3;1739(2-3):268-79
references.pmid: 15615645
references.citation: J Neuropathol Exp Neurol. 2003 Jan;62(1):55-67
references.pmid: 12528818
references.citation: Neurobiol Aging. 2010 Oct;31(10):1669-78
references.pmid: 19004525
references.citation: PLoS One. 2008;3(11):e3637
references.pmid: 18982063
references.citation: Arch Neurol. 2006 Jan;63(1):38-46
references.pmid: 16401735
references.citation: J Neurol. 1999 Jan;246(1):6-15
references.pmid: 9987708
references.citation: Brain Res. 1997 Sep 5;767(2):305-13
references.pmid: 9367262
references.citation: Prog Neurobiol. 2000 Feb;60(2):139-65
references.pmid: 10639052
references.citation: Neuropathol Appl Neurobiol. 2000 Dec;26(6):553-67
references.pmid: 11123722
references.citation: J Neural Transm Suppl. 1987;24:109-29
references.pmid: 3316494
references.citation: Acta Neuropathol. 2009 Jul;118(1):37-52
references.pmid: 19306098
references.citation: Biochemistry. 1992 Nov 3;31(43):10626-33
references.pmid: 1420178
references.citation: Am J Psychiatry. 2004 Jun;161(6):1096-102
references.pmid: 15169699
references.citation: J Neurol Neurosurg Psychiatry. 2001 Sep;71(3):315-21
references.pmid: 11511703
references.citation: Int J Dev Neurosci. 1995 Oct;13(6):607-17
references.pmid: 8553895
references.citation: Coll Antropol. 2008 Jan;32 Suppl 1:43-50
references.pmid: 18405057
references.citation: Ann Neurol. 2004 Mar;55(3):306-19
references.pmid: 14991808
references.citation: J Neurol Neurosurg Psychiatry. 1983 Jan;46(1):96
references.pmid: 6842210