Uncorrected Author Proof: What Is The Relationship of Traumatic Brain Injury To Dementia?

Journal of Alzheimer’s Disease xx (20xx) x–xx 1
DOI 10.3233/JAD-161002
IOS Press
1 Review
2 What is the Relationship of Traumatic

Brain Injury to Dementia?
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3
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4 Mario F. Mendeza,b,∗
5
a Department of Neurology, David Geffen School of Medicine, University of California Los Angeles (UCLA),
Los Angeles, CA, USA
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6
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b Department of Neurology, Neurobehavior Unit, V.A. Greater Los Angeles Healthcare System, Los Angeles,
8 CA, USA
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Accepted 31 January 2017
9 Abstract. There is a long history linking traumatic brain injury (TBI) with the development of dementia. Despite significant
10 reservations, such as recall bias or concluding causality for TBI, a summary of recent research points to several conclusions
11
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on the TBI-dementia relationship. 1) Increasing severity of a single moderate-to-severe TBI increases the risk of subsequent
12 Alzheimer’s disease (AD), the most common type of dementia. 2) Repetitive, often subconcussive, mild TBIs increases
13 the risk for chronic traumatic encephalopathy (CTE), a degenerative neuropathology. 3) TBI may be a risk factor for other
14 neurodegenerative disorders that can be associated with dementia. 4) TBI appears to lower the age of onset of TBI-related
15 neurocognitive syndromes, potentially adding “TBI cognitive-behavioral features”. The literature further indicates several
16 specific risk factors for TBI-associated dementia: 5) any blast or blunt physical force to the head as long as there is violent head
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17 displacement; 6) decreased cognitive and/or neuronal reserve and the related variable of older age at TBI; and 7) the presence
18 of apolipoprotein E ␧4 alleles, a genetic risk factor for AD. Finally, there are neuropathological features relating TBI with
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19 neurocognitive syndromes: 8) acute TBI results in amyloid pathology and other neurodegenerative proteinopathies; 9) CTE
20 shares features with neurodegenerative dementias; and 10) TBI results in white matter tract and neural network disruptions.
21 Although further research is needed, these ten findings suggest that dose-dependent effects of violent head displacement in
22 vulnerable brains predispose to dementia; among several potential mechanisms is the propagation of abnormal proteins along
23 damaged white matter networks.
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24 Keywords: Alzheimer’s disease chronic traumatic encephalopathy, dementia, traumatic brain injury
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25 INTRODUCTION longevity. Likewise, TBI is a major public health 31
problem, occurring in as many as four million people 32
26 Dementia and traumatic brain injury (TBI) are every year in the U.S. [2]. There is a long liter- 33
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27 among the most prevalent neurological disorders ature associating TBI and dementia [3, 4], from 34
28 [1]. Alzheimer’s disease (AD), the most common early descriptions of the “punch-drunk” syndrome 35
29 form of dementia, is a virtual epidemic, increas- and “dementia pugilistica” among boxers to the cur- 36
30 ing in prevalence as populations achieve greater rent burgeoning information on chronic traumatic 37
encephalopathy (CTE) among athletes and others 38

∗ Correspondence to: Mario F. Mendez, MD, PhD, Neurobe- exposed to multiple, repetitive mild TBIs [5]. These 39
havior Unit (691/116AF), V.A. Greater Los Angeles Healthcare
Center, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA. Tel.:
developments, along with a series of epidemiologi- 40
+1 310 478 3711, /Ext. 42696; Fax: +1 310 268 4181; E-mail: cal studies, have solidified TBI as a risk factor for 41
mmendez@UCLA.edu. neurocognitive syndromes; however, in the process 42
ISSN 1387-2877/17/$35.00 © 2017 – IOS Press and the authors. All rights reserved
2 M.F. Mendez / TBI in Dementia
43 they have led to many questions about how TBI and GENERAL TBI-DEMENTIA CLINICAL 66
44 dementia interrelate [6]. RELATIONSHIPS 67
45 Although this is a complex relationship, the current

46 literature has begun to answer these questions and Increasing severity of a single 68
47 unravel the relationship between TBI and dementia. moderate-to-severe TBI increases the risk of 69
48 A review of the literature suggests a number of tenta- subsequent AD, the most common type of 70
49 tive conclusions, subject to many reservations such as dementia 71
50 the potential for recall bias in reporting head injuries
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51 and referral bias in research participation [7]. The Studies report a relationship between a prior 72
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52 nature of TBI itself is broad and can range from single moderate-to-severe TBI and the eventual develop- 73
53 severe injuries to multiple small subconcussive TBIs ment of AD [8–13]. Although a number of studies 74
54 and to concussion, a term often used synonymously have failed to document the association [13–16], 75
55 with mild TBI. Likewise, the term dementia refers to most reports, and three meta-analyses of 11–19 well- 76
56 a decline in two or more areas of cognition that can characterized studies [3, 8, 17], indicate that, in the 77
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57 be associated with a range of pathologies beyond that aggregate, there is evidence to conclude that a single 78
58 of AD. Both TBI and dementia each vary in a num- moderate-to-severe TBI is a risk factor for AD (See 79
59 ber of other ways, including symptoms, course, other Fig. 1) [3, 8, 17–19]. The largest and most recent 80
60 associated factors, biomarkers, animal modeling, and meta-analysis of the TBI risk for AD versus controls 81
found an overall odds ratio (OR) of 1.4 (95% Con-
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61 others. While unable to determine all variables that 82
62 affect the TBI-dementia relationship, a current review fidence Interval [CI]: 1.02–1.90), and an increased 83
63 of this evolving literature does point to ten potential risk of TBI for mild cognitive impairment, which is 84
64 emerging trends and preliminary conclusions regard- often a precursor to dementia [17]. In the two ear- 85
65 ing the complex relationship. lier meta-analysis, males, but not females, were at 86
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Fig. 1. Odds ratios and confidence intervals for Alzheimer’s disease. Reprinted from the Journal of Neurosurgery, Perry et al., 2016 [17],
with permission.
M.F. Mendez / TBI in Dementia 3
87 increased risk of AD from TBI [3, 8], but this gender there is widespread attention of the risk of CTE to 137
88 difference does not persist in other studies [17, 20]. professional football players and other athletes with 138
89 In addition, the limited number of prospective stud- increasing years of exposure to possible mild and 139
90 ies show a relationship between moderate-to-severe repetitive TBIs [39, 40]. The clinical and neuropatho- 140
91 TBI and AD or other dementia [9–11]. In one of the logical aspects of CTE have occurred not just in 141
92 most important ones, investigators evaluated the risk athletes but, despite a scarcity of neuropathological 142
93 for dementia among 548 U.S. World War II veterans cases, among veterans, who are often prone to repeti- 143
94 50 years after confirmed TBIs, compared to 1,228 tive mild TBIs [5, 39–41]. This is further implied from 144
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95 with other types of injuries [10]. They found that a epidemiological data from the VA National Database 145
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96 record of moderate or worse TBI was significantly [24]. Of 188,764 veterans older than 54 years of age 146
97 associated with AD or other dementia [10]. and followed for about 9 years, the presence of any 147
98 In sum, a single moderate or severe TBI, espe- TBI, including blast-force TBI, increased their risk 148
99 cially if recent rather than remote, is essentially the of developing dementia by 60% (OR: 1.57; 95% CI: 149
100 major known environmental risk factor for AD [3, 8, 1.35–1.83) [24]. 150
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101 21], and this risk increases with increasing severity of
102 the head trauma. These studies indicate that a when TBI may even increase the risk for other 151
103 TBI is of moderate severity, there may be a two-fold neurodegenerative disorders that can be 152
104 increased risk of AD or other dementia, and when associated with dementia 153
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105 TBI is severe, there may be a four-fold increased
106 risk [10]. Epidemiological studies report that TBI may 154
increase the risk of developing non-AD neurodegen- 155
107 Repetitive, often subconcussive, mild TBIs erative disorders potentially associated with cognitive 156
108 increases the risk for chronic traumatic impairment or dementia. Examining a California 157
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109 encephalopathy (CTE), a type of dementia statewide administrative health database, investiga- 158
tors assessed the risk of dementia among 51,799 159
110 The vast majority of TBIs are mild (loss of con- patients 55 years of age or older who had had a TBI 160
111 sciousness <30 minutes; post-traumatic amnesia < 24 during the preceding 5–7 years [34]. They found that 161
112 hours) [2]. Recent studies now show that mild TBI, moderate-to-severe TBI can increase the risk of dif- 162
particularly if repetitive, can also increase the risk ferent types of dementia with a minimum hazard ratio
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113 163
114 of dementia [22–28]. The long-term risk of demen- adjusted for age of 1.26 (95% CI: 1.21–1.32) [34]. 164
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115 tia from repetitive mild TBIs is a crucial question In the prospective study of U.S. World War II vet- 165
116 for athletes and among veterans [29, 30], as mild erans, there was an increased risk of both AD and 166
117 TBIs are common from participation in contact sports non-AD dementias after a single moderate or severe 167
118 and from military deployment [31–33]. A Taiwanese TBI [10]. In addition to AD, specific neurodegenera- 168
119 study of one million people with three years follow- tive conditions linked to TBI include frontotemporal 169
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120 up found a three-fold increased risk for dementia dementia (FTD) and to Parkinson’s disease (PD) and 170
121 in those with a history of mild TBIs [23], and amyotrophic lateral sclerosis (ALS), two conditions 171
122 the California statewide health database found an with the potential for associated cognitive decline. 172
123 increased risk of dementia from mild TBIs in elderly TBI appears to be a risk factor for FTD. A study 173
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124 individuals [34]. from the National Alzheimer’s Coordinating Center 174
125 The repetitive occurrence of mild TBIs appears to (NACC) database of autopsy-confirmed cases of FTD 175
126 be much more of a risk for later dementia from CTE, a found that a history of a remote TBI with five or more 176
127 neuropathological disorder associated with TBI, than minutes of loss of consciousness was more common 177
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128 just one prior episode. We have long known of the among 1,016 cases with FTD pathology compared to 178
129 association of TBI with the “punch drunk syndrome” 2,015 normal controls (OR: 1.67; 95% CI: 1.00–2.78) 179
130 or dementia pugilistica on neuropathology in boxers, [42]. In a prior retrospective case-control study of 80 180
131 now known at CTE [35]. Clinically, CTE often resem- patients with FTD compared to controls, investiga- 181
132 bles AD in the delayed deterioration of cognition [36, tors found 19 (23.8%) who had had a history of TBI 182
133 37], although one form of CTE manifests primar- [43], and in another retrospective case–control study 183
134 ily with behavioral changes such as depression and involving 845 veterans, a history of prior TBI was 184
135 suicidality, apathy and aloofness, poor impulse con- association with a 4.4 times greater risk of develop- 185
136 trol, and behavioral disinhibition [5, 38]. Recently, ing FTD compared to controls [44]. Furthermore, in 186
187 a large retrospective cohort study involving 147,510 the Swedish Patient Register [55, 56]. Furthermore, 239
188 patients in Taiwan, those with evidence of a prior one meta-analysis of 12 studies did not find that a 240
189 TBI had a 4.13 times greater risk of developing FTD single prior TBI was a risk factor for ALS [57]. 241
190 compared to non-TBI controls [45]. More epidemiological studies with neuropatholog- 242
191 Studies have also reported TBI as a risk factor ical correlation would help resolve some of these 243
192 for PD. In a case-control study of 196 persons with discrepancies. 244
193 PD in the Rochester, Olmsted County Epidemiology

194 Project [46], there was a greater history of prior TBI TBI appears to lower the age of onset of 245
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195 among the PD cases than among matched controls dementia, potentially adding “TBI 246
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196 (OR: 4.3; 95% CI: 1.2–15.2), and this was most sig- cognitive-behavioral features” 247
197 nificant among those who had more severe TBI or

198 were previously hospitalized with a TBI. In a large There is evidence that TBI may lower the age of 248
199 retrospective cohort study of inpatient or emergency onset of any dementia or permit crossing of the thresh- 249
200 room data of patients presenting with TBI, there was old into dementia at an earlier age [20, 25, 58–60]. 250
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201 an increased risk of PD in the subsequent 5–7 years There is a particularly high prevalence of early-onset 251
202 of 44% (adjusted hazard’s ratio of 1.44; 95% CI: dementias among populations that have a high inci- 252
203 1.31–1.58), and the risk was greater with increased dence of TBIs, such as U.S. and other veterans [58, 253
204 severity and frequency of the TBI [47]. An interest- 59, 61]. Among Swedish young men who had median 254
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205 ing case-control study of 93 twins reported that prior follow-up of 33 years, those with a history of prior 255
206 TBI increased the risk for PD (OR: 3.8; 95% CI: TBI had an increased risk for early-onset dementia 256
207 1.3–11) [48]. The risk of PD after a history of TBI of 50% (OR: 1.5; 95% CI: 1.1–2.0), which increased 257
208 was also increased in the prospective study of U.S. with the severity and frequency of TBIs [22]. More- 258
209 veterans from World War II [10]. Additionally, one over, in a meta-analysis, the relative risk for AD was 259
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210 meta-analysis of 22 case studies found an increased 1.63 with a TBI 10 or more years prior to onset, but 260
211 risk of PD from TBI of 57% [49], and a second meta- increased to 5.33 with a TBI within 10 years, suggest- 261
212 analysis of 15 studies found an increased association ing that more recent TBIs accelerate the emergence 262
213 of TBI with PD (OR: 1.45; 95% CI: 1.18–1.78) [17]. of AD [3]. 263
214 After reports of an unusually increased risk of ALS In a large study, investigators used the NACC Uni- 264
after TBI among football (soccer) players in Italy [50, form Dataset (UDS) to compare the prevalence of a
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215 265
216 51], investigators examined this association in other history of TBI between AD patients with an early 266
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217 populations. In one case-control study of 109 patients age of onset (<65 years; n = 1,429) versus those with 267
218 with ALS compared to matched controls, investiga- a later age of onset (>65 years; n = 4,292) [20]. This 268
219 tors found an increased risk for ALS among those study also examined the prevalence of TBI in a cohort 269
220 with a history of two or more TBIs (OR: 3.1, 95% CI: of 115 early-onset AD patients attending a university 270
221 1.2–8.1) or if a single TBI had occurred in the prior subspecialty clinic. Despite potential recall bias, the 271
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222 10 years (OR: 3.2; 95% CI: 1.0–10.2) [52]. In another prevalence of a history of TBI among the early-onset 272
223 case-control study of 77 patients with ALS compared AD patients from both cohorts, was 13.5–13.9%, 273
224 to 185 controls, those with a TBI between age 30–40 compared to 7.8% for the NACC late-onset cohort 274
225 had an OR for ALS of 14.2 (CI 1.04–194.42) [53]. (p < 0.001). The NACC early-onset AD patients with 275
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226 Among veterans, including 241 with ALS and 597 a history of TBI, compared to those without, were 276
227 controls, those with TBIs in the prior 15 years had more likely to have disinhibition and irritability, clin- 277
228 an adjusted OR of 2.33 (95% CI: 1.18–4.61) [54], ical signs of frontal lobe dysfunction often associated 278
229 and this association was strongest among those with with “TBI cognitive-behavioral features” (see Fig. 2) 279
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230 had an APOE ␧4 allele. One meta-analysis reported [20]. 280
231 a moderately increased risk of ALS with prior TBIs TBI not only lowers that age of onset of demen- 281
232 (OR: 1.7; 95% CI: 1.3, 2.2) [52], but a subsequent tia, but also alters the clinical manifestations. Frontal 282
233 meta-analysis of four studies did not quite find an injury from TBI may cause patients to have execu- 283
234 elevated risk (OR = 2.07; 95% CI = 0.94–4.56) [17]. tive deficits, and orbitofrontal and anterior temporal 284
235 In contrast, some case-control studies did not find injury may manifest as disturbances in social aware- 285
236 an association between TBI resulting in hospitaliza- ness and impulse/emotional control. In addition, 286
237 tion and subsequent ALS, including in the Oxford dementia patients with a history of TBI have 287
238 Linkage study and among 4,004 ALS patients from had better memory and verbal fluency but more 288
blast-force TBI may increase the risk for the even- 317
tual development of dementia [24]. This cognitive 318
sequalae from blast-force TBI may resemble that 319
from blunt-force TBI [73]. 320
The clinical, as well as neuropathological, aspects 321
of CTE have occurred in those exposed to blast- 322
forces [39, 40, 72, 74]. A case series found CTE 323
in postmortem brains from U.S. veterans exposed 324
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to blast-force as well as blunt-force TBI [72, 74]. 325
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Investigators have replicated this evidence of blast- 326
force CTE among mice exposed to blast winds of 330 327
miles/hour [72], and studies on blast impact on mice 328
show that, although it is a different brain force than 329
from brain impact, the brain pathology resembles that 330
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Fig. 2. Prevalence of neuropsychiatric inventory symptoms among of CTE and of blunt-force trauma [72]. Furthermore, 331
early-onset Alzheimer’s disease patients with (n = 178) and with- L.E. Goldstein and colleagues indicate that there may 332
out (n = 1,234) a history of traumatic brain injury. *Significance to
be an absence of the neuropathology of CTE when the 333
p = 0.01 level for disinhibition (29.0% versus 21.6%; χ2 = 6.19)
and for irritability (48.1% versus 39.3%; χ2 = 6.40). Reprinted animal’s head is kept stationary during experimen- 334
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from the Journal of Alzheimer’s Disease, Mendez et al., 2015 [20], tal head trauma, hence equating the risks from both 335
with permission from IOS Press. blast and blunt TBI with violent head displacement 336
[72, 75]. Other studies indicate that most TBI has in 337
289 depression and neurological symptoms in gait and common a sliding of the brain relative to the skull 338
290 motor speed [62]. This “TBI cognitive-behavioral with rotation and deformation stress at anchoring 339
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291 profile” includes disproportionately impaired cogni- points [76]. 340
292 tive tests of attention, processing speed, and executive

293 functions, compared to memory and language func- Decreased cognitive and/or neuronal reserve and 341
294 tions, as well as a greater psychiatric history the related variable of older age at TBI. 342
295 (depression, apathy, irritability, poor impulse control

and social-emotional disturbances, post-traumatic Prior mild TBIs may permit the development of AD
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296 343
297 stress disorder, and substance abuse) [63–65]. not by the direct promotion of AD neuropathology 344
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but by lowering neuronal or cognitive reserve. The 345
298 SPECIFIC RISK FACTORS FOR concept of “reserve” refers to resiliency in the face of 346
299 TBI-ASSOCIATED NEUROCOGNITIVE brain damage, with “brain reserve” suggesting neu- 347
300 DECLINE AND DEMENTIA ronal number and vulnerability to pathology and its 348
clinical expression and “cognitive reserve” suggest- 349

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301 Any blast or blunt physical force to the head as ing neuroplasticity, connectivity, and the capability 350
302 long as there is violent head displacement for alternate, cognitive strategies. Common indica- 351
tors of cognitive reserve include level of education, 352
303 Most data are on blunt-force or impact TBI, but occupational attainment, and baseline intelligence. 353
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304 recent studies on blast-force TBI have implications Epidemiological studies show that the lower the edu- 354
305 for the relationship of TBI to neurocognitive decline cation and occupational ranking, the greater the risk 355
306 and dementia. The majority of mild TBIs from recent for AD and other dementias [77, 78]. The attainment 356
307 combat deployments have been due to exposure to of high occupational achievement appears to delay 357
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308 explosive devices such as mortar blasts or impro- the onset of cognitive and behavioral decline and 358
309 vised explosive devices [66], and this blast-force mild the clinical aspects of CTE [79]. Conversely, a lower 359
310 TBI has become the “signature” injury of recent U.S. intelligence quotient before penetrating TBI among 360
311 military engagements [67]. In addition to persistent Vietnam veterans may be associated with greater cog- 361
312 post-concussive symptoms [32, 33, 68–70], blast- nitive decline on 30-year follow-up [80]. 362
313 force mild TBI may be associated with post-traumatic Neuronal and cognitive reserve decline with age, 363
314 cognitive impairment [71, 72], and there may be late suggesting that age at the time of the TBI is a risk 364
315 cognitive, behavioral, and neuroimaging changes [63, factor. The older the age at the time of TBI, the 365
316 65]. As indicated in the VA National Database study, more likely the person is to develop dementia, as 366
367 well as to develop amyloid-␤ plaques, a hallmark After a TBI, the major effect of APOE ␧4 has been 399
368 pathology of AD [81]. In another study, mild TBIs poor post-traumatic outcomes [93]. In a series of stud- 400
369 increased the risk of developing dementia by 20% if ies of brain injury, including a meta-analysis of 14 401
370 they occurred at age 65 or older, but not at a younger prospective TBI studies, there were poorer neurolog- 402
371 age [34]. ical outcomes if the patient had an APOE ␧4 allele 403
than if they did not have an APOE ␧4 allele [93–97]. 404
Among boxers with 12 or more professional bouts,

The presence of apolipoprotein E ␧4 alleles, a
405
372
those with an APOE ␧4 allele had worse cognitive- 406
genetic risk factor for AD
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373
behavioral outcomes than those without an APOE ␧4 407
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374 Investigators have proposed that APOE ␧4 alleles allele [90], and among 53 professional football play- 408
375 may be synergistic or additive with TBI in increasing ers, those with an APOE ␧4 allele had worse cognitive 409
376 the risk for developing AD [82, 83]. The pres- test scores than those without an APOE ␧4 allele [91]. 410
377 ence of one or two APOE ␧4 alleles is the major Moreover, in one study, the presence of an APOE ␧4 411
known susceptibility gene for the development of allele increased the risk of unfavorable outcomes at 412
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378
379 AD, increasing the risk by 3 or 12 fold, respectively six months or more after a TBI [93, 98], and other 413
380 [84], and shifting the age of onset of dementia to a studies showed that this poorer outcome was particu- 414
381 younger age [85]. APOE ␧4 impairs the efficiency of larly evident among younger patients or children [99, 415
382 proteolytic breakdown and clearance of A␤ [84, 86, 100]. The reason of an association of APOE ␧4 with 416
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383 87], and this may link TBI to the development of AD poor post-traumatic outcomes is unknown but may 417
384 [85, 88, 89]. Several studies indicate that TBI par- relate to impaired mechanisms of repair. 418
385 ticularly increases risk for AD if the patient has an

386 APOE ␧4 allele [82, 83]. After an acute TBI, those NEUROPATHOLOGICAL FEATURES 419
387 with an APOE ␧4 allele have a greater frequency of RELATING TBI TO DEMENTIA 420
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388 deposition of A␤ at autopsy than those without an
389 APOE ␧4 allele, especially if they are homozygous Acute TBI results in amyloid pathology and 421
390 for the gene [87]. In addition to AD, among boxers neurodegenerative proteinopathies 422
391 and football players, the presence of an APOE ␧4

392 allele may also increase the likelihood of dementia Acute TBI results in multiple neuropathological 423
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393 pugilistica or CTE on neuropathology [90, 91]. But processes that may predispose to dementia, including 424
394 not all studies show a TBI-APOE association. In one inflammation, microglial activation, and oxidative 425
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395 case-control study of 230 AD cases and 390 controls stress [101, 102], but, as evidenced in CTE, one of 426
396 with at least one APOE ␧4 allele, there was no sig- the most notable mechanisms is a predisposition to 427
397 nificant variation in the TBI-AD risk by APOE ␧4 abnormal proteins associated with neurodegeneration 428
398 genotype [92]. [103]. A single moderate-to-severe TBI may increase 429
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TBI AD
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Aβ
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Fig. 3. Amyloid (A␤) deposition in traumatic brain injury (TBI) and Alzheimer’s disease (AD). Left: Tissue resected from temporal cortex
of acute severe TBI patients showing A␤ staining. Right: Tissue form patient with AD showing similar A␤ staining. Reprinted from
Experimental Neurology, Ikonomovic et al., 2004 [114], with permission from Elsevier.
430 both A␤ and hyperphosphorylated tau deposition, the 60 years of age have had tau pathology compared to 482
431 abnormal protein components that are the substrates only 9% of 47 control brains, and the tau among the 483
432 of the neuritic plaques and neurofibrillary tangles of TBI patients appears more widespread in the sulcal 484
433 AD [104, 105]. depths and superficial layers of the cortex, whereas it 485
434 After an acute TBI, there has been strong evidence is limited to the entorhinal cortex and hippocampus 486
435 for increased A␤ production and accumulation, both in the control brains [120]. 487
436 in humans and mice (see Fig. 3) [103, 106–112].

437 Although not established, this post-traumatic A␤ may CTE shares features with neurodegenerative 488
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438 be in a prefibrillar, non-aggregated, oligomeric form dementias 489
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439 and may also be detected in the cerebrospinal fluid
440 (CSF) up to 72 hours after acute TBI [113]. Among As previously noted, repetitive mTBI, including 490
441 152 TBI brains from people ranging from 8 weeks blast-force mTBIs, can result in CTE, which is char- 491
442 to 85 years old and from 4 hours to 2.5 years after acterized by phospho-tau containing neurofibrillary 492
443 TBI, 20% of those <50 years of age and 60% of tangles irregularly located in perivascular neurons 493
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444 those 51–60 had A␤ deposition, compared to none and glia in the depth of sulci [5, 58, 72, 125, 126]. 494
445 of the controls [81]. Investigators have discovered In CTE, there is progressive deposition of phospho- 495
446 non-plaque A␤ intracellularly in 80% of temporal tau and other neurodegenerative proteins in the brain, 496
447 cortex samples surgically excised from 18 patients similar to neurodegenerative dementias [5, 58, 61, 497
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448 2–16 hours after a TBI [114]. Additional CSF find- 120, 123, 125, 127, 128]. The neuronal hyperphos- 498
449 ings after an acute TBI not only include alterations phorylated tau deposits in CTE have a3 R/4 R tau 499
450 A␤, but also in tau, S100b, glial fibrillary acidic isoform ratio similar to AD [129]. Furthermore, 500
451 protein, neuron-specific enolase, neurofilament light among neuropathologically-diagnosed cases of CTE 501
452 protein, ubiquitin C-terminal hydrolase, and others [126], over half also have A␤ deposition, which is 502
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453 [115], but the post-TBI levels of all these proteins usu- present in AD, but which may not have a primary 503
454 ally return to normal and have not proven to predict pathophysiological role in CTE [5, 130]. Patients 504
455 later neurocognitive decline. Genetic polymorphisms with CTE may have TAR DNA-binding protein 505
456 are associated with A␤ degradation and clearance 43 and some have ␣-synuclein, which are other 506
457 and may predispose a subset of post-TBI patients to abnormal proteins seen in neurodegeneration [5, 39, 507
greater A␤ accumulation and aggregation [110, 116, 130]. Additional pathology in CTE can include neu-
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458 508
459 117]. In mouse models, the increased production of roinflammation with monocytes and activation of 509
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460 A␤ after an acute TBI can be decreased by preventing brain microglia, and traumatic blood-brain barrier 510
461 amyloid precursor protein secretase enzymes and the disruption. 511
462 prevention of A␤ accumulation [118, 119]. CTE is a TBI-related neurodegeneration that is 512
463 In contrast to AD, most of the post-traumatic distinct despite sharing features with other neu- 513
464 axonal A␤ may not be in fibrillar, thioflavin-S pos- rodegenerative disorders. There is a predominant 514
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465 itive neuritic plaques characteristic of AD [120]. involvement and deposition of abnormal tau in cor- 515
466 On autopsy, amyloid plaques do not occur in most tical layers II and III rather than layers V and VI as 516
467 patients with TBIs (70%) [81, 114]; only 30% of in AD [131]. There is axonopathy from small blood 517
468 patients, who die of TBI, have actual A␤ plaques vessel injury and extensive tau-immunoreactivity 518
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469 similar to those of AD [121]. perivascularly in superficial cortical layers, especially 519
470 In addition to the accumulation of A␤, there is pro- in the depth of sulci in the frontal lobes [5, 39]. 520
471 duction of abnormal tau protein after a TBI [107, Many patients with a history of TBI have orbitofrontal 521
472 122]. Although most tau transgenic mice exposed to and anterior temporal injury, and CTE starts as a 522
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473 multiple TBIs per day have not shown an accumu- focal neuropathology in frontal neocortex rather than 523
474 lation of phospho-tau [123], which is seen in AD, mesolimbic or parietal changes as in typical AD 524
475 investigators frequently find tau pathology among [5, 132]. Positron emission tomography (PET) with 525
476 players of contact sports even in the absence of frank radioligands that bind to fibrillary insoluble protein 526
477 CTE [5, 39, 72, 124]. After an acute TBI, there is tau aggregates, although not established in terms of tau 527
478 hyperphosphorylation as well as increased tau lev- specificity or CTE neuropathology, are beginning to 528
479 els in the CSF, but not the tau-derived neurofibrillary document increased PET binding in TBI patients 529
480 tangles of AD [114]. Among 39 patients surviving with clinically probable CTE [133–135]. Investi- 530
481 severe TBI for up to 47 years, 34% of those less than gators have also associated the neuropathological 531
532 findings of CTE with the clinical and neuropatho-

533 logical changes of FTD, PD, and ALS [5].
534 TBI results in white matter tract and neural

535 network disruptions
536 Acute brain damage is associated with diffuse

537 axonal injury (DAI) and white matter pathway dis-
f
538 ruption [29, 30, 63, 136, 137], evidenced by diffusely
roo
539 distributed and discontinuous areas of white matter
540 abnormalities [138, 139]. During a TBI, the cortex
541 moves at different speed relative to subcortical white
542 matter, with consequent shear forces and deformation
543 stress, axonal and vessel stretching, and microbleeds
rP
544 with resultant DAI. Post-TBI, DTI shows stretches of
545 axons with damaged axonal membrane permeability
Fig. 4. Diffusion tensor imaging showing axon injury and white
546 and ionic shifts, with calcium damage to mitochon-
matter tract disruption in frontal corpus callosum region due to
547 dria, and resultant energy failure and breakdown of traumatic brain injury. Blue indicates greater disruption. From
tho
548 microtubules. Hence, where there is DAI, there is Emily Dennis, Laboratory of Neuro Imaging Keck School of
549 failure of axonal transport, increased axonal A␤ and Medicine, and Paul M. Thompson, Ph.D., University of Southern
California.
550 other abnormal protein accumulation, and released
551 A␤ and hyperphosphorylated tau [37, 103, 110, 120,
552 121, 140]. Recent work suggests, but does not estab- bombardment compared to those with limited expo- 582
Au
553 lish, that these abnormal proteins could then spread sure, demonstrating a potential cumulative effect of 583
554 in a prion-like fashion along white matter connec- injury [151]. In AD and mild cognitive impairment, 584
555 tions and functional neural networks [141]. Clearly, DTI has also shown early disruption of whole- 585
556 much more research is needed in order to establish brain white matter connectivity and long-range tracts 586
557 this putative mechanism. such as the cingulum, uncinate fasciculus, superior 587
Similar TBI and AD effects on white matter tracts longitudinal fasciculus, inferior fronto-occipital fas-
d
558 588
559 on diffusion tensor imaging (DTI) suggest a reduc- ciculus, and corpus callosum [152–157]. 589
cte
560 tion of functional long-distance connectivity between There is growing evidence that both TBI and AD 590
561 frontal and caudal brain regions and a possible mech- target functional neural networks with disconnection 591
562 anism for the synergy of TBI with AD and other occurring before other neuropathology [158–164]. 592
563 dementias (see Fig. 4). DTI measures the integrity In AD, resting state functional MRI classically 593
564 of white matter, and, although functional anisotropy shows early dysfunction of the default mode net- 594
rre
565 measures of DTI may decrease, increase, or remain work (DMN) in the precuneus/posterior cingulate and 595
566 unchanged after TBI [142–144], there are frequent the mesial temporal lobe, even before any clinical 596
567 reductions of functional anisotropy in the corpus symptoms [165–173], with an eventual loss of cross- 597
568 callosum, cingulum, and other major fiber bundles network relations as the severity of AD increases 598
co
569 [145]. On DTI, some investigators report diffusely [174]. After mild TBI, resting state functional MRI 599
570 distributed and discontinuous areas of white matter also shows abnormalities in neural networks [125, 600
571 abnormalities in patients with mild TBIs [125], as 175]; there is decreased connectivity of the DMN 601
572 well as in veterans who have had blast-force TBIs immediately after TBI which then increases during 602
Un
573 [139, 146, 147]. Among boxers, investigators report later stages, possibly as a form of compensation 603
574 abnormalities in alternate DTI measures of white for injury to other neural networks. Investigators 604
575 matter integrity (mean diffusivity, axial diffusivity, report the development of hyperconnectivity of the 605
576 radial diffusivity) compared to controls [148, 149], DMN associated with repetitive subconcussive mTBI 606
577 and among soccer players and other athletes, there [176]. In contrast, there may be hyperconnectivity 607
578 may be increased (abnormal) axial diffusivity in the in frontally-based executive and salience networks in 608
579 corpus callosum and other major tracts [145, 150, AD [177–179]. A possible explanation for these find- 609
580 151]. Investigators have found significantly more DTI ings is that TBIs promote AD through enhancing the 610
581 abnormalities among veterans heavily exposed to early impairment of the DMN, but later diverge with 611
612 subsequent opposite effects as other neural networks sum, this review can stimulate future studies on the 661
613 become involved. important relationship between TBI and AD, CTE, 662
and other forms of neurodegeneration with potential 663
dementia. 664
614 CONCLUSIONS
615 This literature clarifies several aspects of the TBI- ACKNOWLEDGMENTS 665
616 dementia relationship. First, the risk of dementia
f
617 increases with increased severity, frequency, and This work was supported by the Nation Institutes 666
roo
618 repetitiveness of TBIs, but does not dependent on the of Health [NIA R01AG050967]. 667
619 type of physical force to the head. This finding sug- Authors’ disclosures available online (http://j-alz. 668
620 gests a cumulative effect of violent head displacement com/manuscript-disclosures/16-1002r2). 669
621 with consequent brain deformation, shear forces on

622 axons, and DAI. Second, the impact of these forces
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Journal of Alzheimer’s Disease xx (20xx) x–xx 1

2 What is the Relationship of Traumatic

25 INTRODUCTION longevity. Likewise, TBI is a major public health 31

problem, occurring in as many as four million people 32

encephalopathy (CTE) among athletes and others 38

mmendez@UCLA.edu. neurocognitive syndromes; however, in the process 42

44 dementia interrelate [6]. RELATIONSHIPS 67

45 Although this is a complex relationship, the current

49 tive conclusions, subject to many reservations such as dementia 71

50 the potential for recall bias in reporting head injuries

found an overall odds ratio (OR) of 1.4 (95% Con-

increase the risk of developing non-AD neurodegen- 155

tors assessed the risk of dementia among 51,799 159

193 PD in the Rochester, Olmsted County Epidemiology

197 nificant among those who had more severe TBI or

230 had an APOE ␧4 allele. One meta-analysis reported [20]. 280

tual development of dementia [24]. This cognitive 318

sequalae from blast-force TBI may resemble that 319

from blunt-force TBI [73]. 320

The clinical, as well as neuropathological, aspects 321

of CTE have occurred in those exposed to blast- 322

in postmortem brains from U.S. veterans exposed 324

force CTE among mice exposed to blast winds of 330 327

miles/hour [72], and studies on blast impact on mice 328

show that, although it is a different brain force than 329

from brain impact, the brain pathology resembles that 330

292 tive tests of attention, processing speed, and executive

295 (depression, apathy, irritability, poor impulse control

but by lowering neuronal or cognitive reserve. The 345

clinical expression and “cognitive reserve” suggest- 349

tors of cognitive reserve include level of education, 352

than if they did not have an APOE ␧4 allele [93–97]. 404

Among boxers with 12 or more professional bouts,

385 ticularly increases risk for AD if the patient has an

391 and football players, the presence of an APOE ␧4

436 in humans and mice (see Fig. 3) [103, 106–112].

532 findings of CTE with the clinical and neuropatho-

534 TBI results in white matter tract and neural

536 Acute brain damage is associated with diffuse

and other forms of neurodegeneration with potential 663

616 dementia relationship. First, the risk of dementia

620 gests a cumulative effect of violent head displacement com/manuscript-disclosures/16-1002r2). 669

621 with consequent brain deformation, shear forces on

637 relatives. Ann Neurol 33, 494-501. 687

639 of A␤, hyperphosphorylated tau, and other abnor-

1013 pathogenesis of Alzheimer’s disease. J Neurol Neurosurg 1536-1539. 1078

1026 79-100. 440. 1091

1145 992. NINDS/NIBIB consensus meeting to define neuropatho- 1210

1405 Filippi M (2012) Resting state fMRI in Alzheimer’s dis-

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