Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury

Journal of Neuropathology and Experimental Neurology

Volumn 68, Issue 7, 2009, Pages 709-735

  McKee, Ann C ^a,b,c,g   Cantu, Robert C ^b,d,e   Nowinski, Christopher J ^b,d   Hedley Whyte, E Tessa ^f   Gavett, Brandon E ^a   Budson, Andrew E ^a,c   Santini, Veronica E ^a   Lee, Hyo Soon ^a   Kubilus, Caroline A ^a   Stern, Robert A ^a,b  

^a Department of Neurology ^*  (United States)

^b BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Bedford Veterans Administration Medical Center   (United Kingdom)

^d Sports Legacy Institute   (United States)

^e Emerson Hospital   (Australia)

^f MASSACHUSETTS GENERAL HOSPITAL   (United States)

^g VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Athletes; Concussion; Dementia; Encephalopathy; Neurodegeneration; Tau protein; Traumatic brain injury

Indexed keywords

ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; ANABOLIC AGENT; APOLIPOPROTEIN E4; NEUROLEPTIC AGENT; TAU PROTEIN;

AGGRESSION; ALCOHOL ABUSE; ALCOHOL CONSUMPTION; AMNESIA; ANGER; APATHY; ASTROCYTE; ATHLETE; ATTENTION; AXONAL INJURY; BEHAVIOR CHANGE; BEHAVIOR DISORDER; BOXING; BRAIN ATROPHY; BRAIN CORTEX; BRAIN STEM; BRAIN VENTRICLE DILATATION; CELL LOSS; CHRONIC DISEASE; COGNITIVE DEFECT; COMPUTER ASSISTED TOMOGRAPHY; CONCUSSION; CONFUSION; DECISION MAKING; DEMENTIA; DEMOGRAPHY; DISORIENTATION; FALLING; FAMILY HISTORY; FOOTBALL; FRONTAL CORTEX; GAIT DISORDER; GENETIC RISK; HEAD INJURY; HEMISPHERE; HUMAN; MAMMILLARY BODY; MEMORY DISORDER; MENTAL CONCENTRATION; MICROSCOPY; NARCOTIC DEPENDENCE; NERVE CELL; NERVE CELL NECROSIS; NERVE DEGENERATION; NEURITE; NEUROFIBRILLARY TANGLE; NEUROFILAMENT; NEUROPATHOLOGY; NEUROPSYCHOLOGICAL TEST; NUCLEAR MAGNETIC RESONANCE IMAGING; PARANOIA; PARKINSONISM; PATHOLOGY; PERSONALITY DISORDER; PLANNING; PNEUMONIA; POSTCONCUSSION SYNDROME; PRACTICE GUIDELINE; PRIORITY JOURNAL; PROBLEM SOLVING; REVIEW; SEPTIC SHOCK; SEPTUM PELLUCIDUM; SHORT TERM MEMORY; SMOKING; SPEECH DISORDER; SPORT INJURY; STAINING; SUBICULUM; TAUOPATHY; TEMPORAL CORTEX; TEMPORAL LOBE; THALAMUS; TRAUMATIC BRAIN INJURY; VIOLENCE; WHITE MATTER; ADULT; AGED; BRAIN; BRAIN INJURY; BRAIN LEVEL; CASE REPORT; CELL DEATH; DISEASE COURSE; FEMALE; GENETIC PREDISPOSITION; GENETICS; MALE; MIDDLE AGED; PATHOPHYSIOLOGY; PHYSIOLOGY; SPORT;

ADULT; AGED; AGED, 80 AND OVER; AMYLOID BETA-PROTEIN; APOLIPOPROTEIN E4; ATHLETIC INJURIES; BRAIN; BRAIN CHEMISTRY; BRAIN INJURY, CHRONIC; CELL DEATH; DISEASE PROGRESSION; FEMALE; GENETIC PREDISPOSITION TO DISEASE; HEAD INJURIES, CLOSED; HUMANS; MALE; MIDDLE AGED; NEURONS; SPORTS; TAUOPATHIES;

EID: 68249157080     PISSN: 00223069     EISSN: None     Source Type: Journal    
DOI: 10.1097/NEN.0b013e3181a9d503     Document Type: Review

References (118)

1. Thurman DJ, Branche CM, Sniezek JE. The epidemiology of sportsrelated traumatic brain injuries in the United States: Recent developments. J Head Trauma Rehabil 1998;13:1-8
2. Langlois JA, Rutland -Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: A brief overview. J Head Trauma Rehabil 2006;21:375-78
3. Nowinski C. Head Games: Football's Concussion Crisis From the NFL to Youth Leagues. East Bridgewater, MA: Drummond Publishing Group; 2006
4. Roberts GW, Allsop D, Bruton C. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 1990;53:373-78
5. Webbe FM, Barth JT. Short-term and long-term outcome of athletic closed head injuries. Clin Sports Med 2003;22:577-92
6. Macciocchi SN, Barth JT, Alves W, et al. Neuropsychological functioning and recovery after mild head injury in collegiate athletes. Neurosurgery 1996;39:510-14
7. Collins MW, Lovell MR, Iverson GL, et al. Cumulative effects of concussion in high school athletes. Neurosurgery 2002;51:1175-79; [discussion 80-81]
8. Gaetz M, Goodman D, Weinberg H. Electrophysiological evidence for the cumulative effects of concussion. Brain Inj 2000;14:1077-88
9. Gaetz M, Weinberg H. Electrophysiological indices of persistent post-concussion symptoms. Brain Inj 2000;14:815-32
10. Bailes JE, Cantu RC. Head injury in athletes. Neurosurgery 2001;48: 26-45
11. Beckwith JG, Chu JJ, Greenwald RM. Validation of a noninvasive system for measuring head acceleration for use during boxing competition. J Appl Biomech 2007;23:238-44
12. Greenwald RM, Gwin JT, Chu JJ, et al. Head impact severity measures for evaluating mild traumatic brain injury risk exposure. Neurosurgery 2008;62:789-98
13. Geddes JF, Vowles GH, Nicoll JA, et al. Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol 1999;98:171-78
14. Hof PR, Knabe R, Bovier P, et al. Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathol 1991;82:321-26
15. Jordan BD, Kanik AB, Horwich MS, et al. Apolipoprotein E epsilon 4 and fatal cerebral amyloid angiopathy associated with dementia pugilistica. Ann Neurol 1995;38:698-99
16. Omalu BI, DeKosky ST, Hamilton RL, et al. Chronic traumatic encephalopathy in a national football league player: Part II. Neurosurgery 2006;59:1086-92
17. Omalu BI, DeKosky ST, Minster RL, et al. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 2005;57: 128-34
18. Roberts GW, Whitwell HL, Acland PR, et al. Dementia in a punch-drunk wife. Lancet 1990;335:918-19
19. Williams DJ, Tannenberg AE. Dementia pugilistica in an alcoholic achondroplastic dwarf. Pathology 1996;28:102-4
20. Cajigal S. Brain damage may have contributed to former wrestler's violent demise. Neurology Today 2007;7:1-16
21. Schwarz A. Expert ties ex-player's suicide to brain damage [New York Times Web site]. January 18, 2007. Available at: http://www.nytimes.com/2007/01/ 18/sports/football/18waters.html. Accessed January 26, 2008.
22. Aotsuka A, Kojima S, Furumoto H, et al. [Punch drunk syndrome due to repeated karate kicks and punches]. Rinsho Shinkeigaku 1990;30: 1243-46
23. Matser JT, Kessels AG, Jordan BD, et al. Chronic traumatic brain injury in professional soccer players. Neurology 1998;51:791-6
24. McCrory P, Turner M, Murray J. A punch drunk jockey? Br J Sports Med 2004;38:e3
25. Tysvaer AT, Storli OV, Bachen NI. Soccer injuries to the brain. A neurologic and electroencephalographic study of former players. Acta Neurol Scand 1989;80:151-56
26. Martland HS. Punch drunk. JAMA 1928;91:1103-7
27. Millspaugh JA. Dementia pugilistica. US Naval Med Bull 1937;35: 297-303
28. Courville CB. Punch drunk. Its pathogenesis and pathology on the basis of a verified case. Bull Los Angel Neuro Soc 1962;27:160-68
29. Corsellis JA, Bruton CJ, Freeman-Browne D. The aftermath of boxing. Psychol Med 1973;3:270-303
30. Brandenburg W, Hallervorden J. [Dementia pugilistica with anatomical findings.]. Virchows Arch 1954;325:680-709
31. Grahmann H, Ule G. [Diagnosis of chronic cerebral symptoms in boxers (dementia pugilistica & traumatic encephalopathy of boxers)]. Psychiatr Neurol (Basel) 1957;134:261-83
32. Neubuerger KT, Sinton DW, Denst J. Cerebral atrophy associated with boxing. AMA Arch Neurol Psychiatry 1959;81:403-8
33. Mawdsley C, Ferguson FR. Neurological disease in boxers. Lancet 1963;2:799-801
34. Constantinidis J, Tissot R. [Generalized alzheimer's neurofibrillary lesions without senile plaques (Presentation of one anatomo-clinical case)]. Schweiz Arch Neurol Neurochir Psychiatr 1967;100:117-30
35. Payne EE. Brains of boxers. Neurochirurgia (Stuttg) 1968;11:173-88
36. Hof PR, Delacourte A, Bouras C. Distribution of cortical neurofibrillary tangles in progressive supranuclear palsy: A quantitative analysis of six cases. Acta Neuropathol 1992;84:45-51
37. Geddes JF, Vowles GH, Robinson SF, et al. Neurofibrillary tangles, but not Alzheimer-type pathology, in a young boxer. Neuropathol Appl Neurobiol 1996;22:12-16
38. Newell KL, Drachman DA. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 12-1999. A 67-year-old man with three years of dementia. N Engl J Med 1999; 340:1269-77
39. Schmidt ML, Zhukareva V, Newell KL, et al. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate alzheimer's disease. Acta Neuropathol 2001;101:518-24
40. Schwarz A. Lineman, dead at 36, exposes brain injuries [New York Times Web site]. June 15, 2007. Available at: http://www.nytimes.com/2007/06/15/ sports/football/15brain.html. Accessed March 11, 2009
41. Areza-Fegyveres R, Rosemberg S, Castro RM, et al. Dementia pugilistica with clinical features of alzheimer's disease. Arq Neuropsiquiatr 2007;65(3B):830-33
42. Critchley M. Medical aspects of boxing, particularly from a neurological standpoint. Br Med J 1957;1:357-62
43. McNair DM, Kahn RJ. Self-assessment of cognitive deficits. In: Crook T, Ferris S, Bartus R, eds. Assessment in Geriatric Psychopharmacology. New Canaan, CT: Mark Powley, 1984
44. Spitznagel MB, Tremont G. Cognitive reserve and anosognosia in questionable and mild dementia. Arch Clin Neuropsychol 2005;20:505-15
45. Galvin JE, Roe CM, Powlishta KK, et al. The AD8: A brief informant interview to detect dementia. Neurology 2005;65:559-64
46. Pfeffer RI, Kurosaki TT, Harrah CH Jr, et al. Measurement of functional activities in older adults in the community. J Gerontol 1982;37: 323-29
47. Hof PR, Bouras C, Buee L, et al. Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and alzheimer's disease cases. Acta Neuropathol 1992;85:23-30
48. Feany MB, Mattiace LA, Dickson DW. Neuropathologic overlap of progressive supranuclear palsy, Pick's disease and corticobasal degeneration. J Neuropathol Exp Neurol 1996;55:53-67
49. Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 1996;55:97-105
50. Perl DP, Hof PR, Purohit DP, et al. Hippocampal and entorhinal cortex neurofibrillary tangle formation in Guamanian Chamorros free of overt neurologic dysfunction. J Neuropathol Exp Neurol 2003;62:381-88
51. Hirano A. Amyotrophic lateral sclerosis and parkinsonism-dementia complex on Guam: Immunohistochemical studies. Keio J Med 1992; 41:6-9
52. Tokuda T, Ikeda S, Yanagisawa N, et al. Re-examination of ex-boxers' brains using immunohistochemistry with antibodies to amyloid betaprotein and tau protein. Acta Neuropathol 1991;82:280-85
53. Uryu K, Chen XH, Martinez D, et al. Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol 2007;208:185-92
54. Eggers AE. Redrawing Papez' circuit: A theory about how acute stress becomes chronic and causes disease. Med Hypotheses 2007;69:852-57
55. Papez JW. A proposed mechanism of emotion. 1937. J Neuropsychiatry Clin Neurosci 1995;7:103-12
56. Bird CM, Burgess N. The hippocampus and memory: Insights from spatial processing. Nat Rev Neurosci 2008;9:182-94
57. Gaetz M. The neurophysiology of brain injury. Clin Neurophysiol 2004;115:4-18
58. Holbourn AHS. Mechanics of head injury. Lancet 1943;2:438-41
59. Ommaya AK, Gennarelli TA. Cerebral concussion and traumatic unconsciousness. Correlation of experimental and clinical observations of blunt head injuries. Brain 1974;97:633-54
60. Buee L, Hof PR, Bouras C, et al. Pathological alterations of the cerebral microvasculature in alzheimer's disease and related dementing disorders. Acta Neuropathol 1994;87:469-80
61. Bouras C, Giannakopoulos P, Good PF, et al. A laser microprobe mass analysis of brain aluminum and iron in dementia pugilistica: Comparison with alzheimer's disease. Eur Neurol 1997;38:53-58
62. Graham DI, McIntosh TK, Maxwell WL, et al. Recent advances in neurotrauma. J Neuropathol Exp Neurol 2000;59:641-51
63. Strich SJ. Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neurosurg Psychiatry 1956; 19:163-85
64. Maxwell WL, McCreath BJ, Graham DI, et al. Cytochemical evidence for redistribution of membrane pump calcium-ATPase and ecto-Ca-ATPase activity, and calcium influx in myelinated nerve fibres of the optic nerve after stretch injury. J Neurocytol 1995;24:925-42
65. Giza CC, Hovda DA. The neurometabolic cascade of concussion. J Athl Train 2001;36:228-35
66. Hovda DA, Lee SM, Smith ML, et al. The neurochemical and metabolic cascade following brain injury: Moving from animal models to man. J Neurotrauma 1995;12:903-6
67. McKenzie KJ, McLellan DR, Gentleman SM, et al. Is beta-APP a marker of axonal damage in short-surviving head injury? Acta Neuropathol 1996;92:608-13
68. Blumbergs PC, Scott G, Manavis J, et al. Staining of amyloid precursor protein to study axonal damage in mild head injury. Lancet 1994;344: 1055-56
69. Gentleman SM, Nash MJ, Sweeting CJ, et al. Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury. Neurosci Lett 1993;160:139-44
70. Graham DI, Gentleman SM, Lynch A, et al. Distribution of beta-amyloid protein in the brain following severe head injury. Neuropathol Appl Neurobiol 1995;21:27-34
71. Masumura M, Hata R, Uramoto H, et al. Altered expression of amyloid precursors proteins after traumatic brain injury in rats: In situ hybridization and immunohistochemical study. J Neurotrauma 2000;17:123-34
72. McKenzie JE, Gentleman SM, Roberts GW, et al. Increased numbers of beta APP-immunoreactive neurones in the entorhinal cortex after head injury. Neuroreport 1994;6:161-64
73. Murakami N, Yamaki T, Iwamoto Y, et al. Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus. J Neurotrauma 1998;15:993-1003
74. Pierce JE, Trojanowski JQ, Graham DI, et al. Immunohistochemical characterization of alterations in the distribution of amyloid precursor proteins and beta-amyloid peptide after experimental brain injury in the rat. J Neurosci 1996;16:1083-90
75. Roberts GW, Gentleman SM, Lynch A, et al. βA4 amyloid protein deposition in brain after head trauma. Lancet 1991;338:1422-23
76. Roberts GW, Gentleman SM, Lynch A, et al. Beta amyloid protein deposition in the brain after severe head injury: Implications for the pathogenesis of alzheimer's disease. J Neurol Neurosurg Psychiatry 1994;57:419-25
77. Smith DH, Chen XH, Nonaka M, et al. Accumulation of amyloid beta and tau and the formation of neurofilament inclusions following diffuse brain injury in the pig. J Neuropathol Exp Neurol 1999;58:982-92 (Pubitemid 29441926)
78. Uryu K, Laurer H, McIntosh T, et al. Repetitive mild brain trauma accelerates Abeta deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis. J Neurosci 2002;22:446-54
79. Smith DH, Nakamura M, McIntosh TK, et al. Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein. Am J Pathol 1998;153:1005-10
80. Ikonomovic MD, Uryu K, Abrahamson EE, et al. Alzheimer's pathology in human temporal cortex surgically excised after severe brain injury. Exp Neurol 2004;190:192-203
81. DeKosky ST, Abrahamson EE, Ciallella JR, et al. Association of increased cortical soluble abeta42 levels with diffuse plaques after severe brain injury in humans. Arch Neurol 2007;64:541-44
82. Graham DI, Gentleman SM, Nicoll JA, et al. Altered beta-APP metabolism after head injury and its relationship to the aetiology of alzheimer's disease. Acta Neurochir Suppl 1996;66:96-102
83. Gentleman SM, Greenberg BD, Savage MJ, et al. A beta 42 is the predominant form of amyloid beta-protein in the brains of short-term survivors of head injury. Neuroreport 1997;8:1519-22
84. Brody DL, Magnoni S, Schwetye KE, et al. Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 2008;321:1221-24
85. Geddes DM, LaPlaca MC, Cargill RS 2nd. Susceptibility of hippocampal neurons to mechanically induced injury. Exp Neurol 2003;184: 420-27
86. Colicos MA, Dixon CE, Dash PK. Delayed, selective neuronal death following experimental cortical impact injury in rats: Possible role in memory deficits. Brain Res 1996;739:111-19
87. Bramlett HM, Kraydieh S, Green EJ, et al. Temporal and regional patterns of axonal damage following traumatic brain injury: A beta-amyloid precursor protein immunocytochemical study in rats. J Neuropathol Exp Neurol 1997;56:1132-41
88. Dixon CE, Kochanek PM, Yan HQ, et al. One-year study of spatial memory performance, brain morphology, and cholinergic markers after moderate controlled cortical impact in rats. J Neurotrauma 1999;16: 109-22
89. Smith DH, Chen XH, Pierce JE, et al. Progressive atrophy and neuron death for one year following brain trauma in the rat. J Neurotrauma 1997;14:715-27
90. Maxwell WL, Domleo A, McColl G, et al. Post-acute alterations in the axonal cytoskeleton after traumatic axonal injury. J Neurotrauma 2003; 20:151-68
91. Maxwell WL, MacKinnon MA, Smith DH, et al. Thalamic nuclei after human blunt head injury. J Neuropathol Exp Neurol 2006;65: 478-88
92. Kay AD, Day SP, Kerr M, et al. Remodeling of cerebrospinal fluid lipoprotein particles after human traumatic brain injury. J Neurotrauma 2003;20:717-23 (Pubitemid 36993447)
93. Hughes DG, Jackson A, Mason DL, et al. Abnormalities on magnetic resonance imaging seen acutely following mild traumatic brain injury: Correlation with neuropsychological tests and delayed recovery. Neuroradiology 2004;46:550-58
94. Kraus MF, Susmaras T, Caughlin BP, et al. White matter integrity and cognition in chronic traumatic brain injury: A diffusion tensor imaging study. Brain 2007;130:2508-19
95. Salmond CH, Menon DK, Chatfield DA, et al. Diffusion tensor imaging in chronic head injury survivors: Correlations with learning and memory indices. Neuroimage 2006;29:117-24
96. Chappell MH, Ulug AM, Zhang L, et al. Distribution of microstructural damage in the brains of professional boxers: A diffusion MRI study. J Magn Reson Imaging 2006;24:537-42
97. Zhang L, Ravdin LD, Relkin N, et al. Increased diffusion in the brain of professional boxers: A preclinical sign of traumatic brain injury? AJNR Am J Neuroradiol 2003;24:52-57
98. Ariza M, Pueyo R, Matarý́n Mdel M, et al. Influence of APOE polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury. J Neurol Neurosurg Psychiatry 2006;77: 1191-93
99. Chiang MF, Chang JG, Hu CJ. Association between apolipoprotein E genotype and outcome of traumatic brain injury. Acta Neurochir (Wien) 2003;145:649-53
100. Friedman G, Froom P, Sazbon L, et al. Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology 1999;52:244-48
101. Nicoll JA, Roberts GW, Graham DI. Apolipoprotein E epsilon 4 allele is associated with deposition of amyloid beta-protein following head injury. Nat Med 1995;1:135-37
102. Nicoll JA, Roberts GW, Graham DI. Amyloid beta-protein, APOE genotype and head injury. Ann N Y Acad Sci 1996;777:271-5
103. Hartman RE, Laurer H, Longhi L, et al. Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of alzheimer's disease. J Neurosci 2002;22:10083-87
104. Cantu RC. Recurrent athletic head injury: Risks and when to retire. Clin Sports Med 2003;22:593-603
105. Gosselin N, Theriault M, Leclerc S, et al. Neurophysiological anomalies in symptomatic and asymptomatic concussed athletes. Neurosurgery 2006;58:1151-61; [discussion 1151-61]
106. Mayers L. Return-to-play criteria after athletic concussion: A need for revision. Arch Neurol 2008;65:1158-61
107. Arfanakis K, Haughton VM, Carew JD, et al. Diffusion tensor MR imaging in diffuse axonal injury. AJNR Am J Neuroradiol 2002;23: 794-802
108. Bergsneider M, Hovda DA, Lee SM, et al. Dissociation of cerebral glucose metabolism and level of consciousness during the period of metabolic depression following human traumatic brain injury. J Neurotrauma 2000;17:389-401
109. De Beaumont L, Brisson B, Lassonde M, et al. Long-term electrophysiological changes in athletes with a history of multiple concussions. Brain Inj 2007;21:631-44
110. Guskiewicz KM, McCrea M, Marshall SW, et al. Cumulative effects associated with recurrent concussion in collegiate football players: The NCAA Concussion Study. JAMA 2003;290:2549-55 (Pubitemid 37443284)
111. Kozlowski DA, James DC, Schallert T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 1996;16:4776-86
112. Corsellis JA, Brierley JB. Observations on the pathology of insidious dementia following head injury. J Ment Sci 1959;105:714-20
113. Rudelli R, Strom JO, Welch PT, et al. Posttraumatic premature alzheimer's disease. Neuropathologic findings and pathogenetic considerations. Arch Neurol 1982;39:570-75
114. Klein RL, Lin WL, Dickson DW, et al. Rapid neurofibrillary tangle formation after localized gene transfer of mutated tau. Am J Pathol 2004;164:347-53
115. Weaver CL, Espinoza M, Kress Y, et al. Conformational change as one of the earliest alterations of tau in alzheimer's disease. Neurobiol Aging 2000;21:719-27
116. Su JH, Cummings BJ, Cotman CW. Early phosphorylation of tau in alzheimer's disease occurs at Ser-202 and is preferentially located within neurites. Neuroreport 1994;5:2358-62
117. Lewis J, McGowan E, Rockwood J, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 2000;25:402-5
118. Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293:1487-91