1
Journal of Alzheimer’s Disease xx (20xx) x–xx
DOI 10.3233/JAD-190913
IOS Press
5
6
7
8
9
10
11
12
f
oo
4
Pr
3
Alby Eliasa,b , Tia Cumminsa,c , Fiona Lamba , Regan Tyrrella , Vincent Dored , Rob Williamsc ,
Jeffrey V. Rosenfelde,f , Malcolm Hopwoodb , Victor L. Villemagnea and Christopher C. Rowea,∗
a Department
of Molecular Imaging and Therapy, Austin Health, The University of Melbourne, VIC, Australia
of Psychiatry, The University of Melbourne, VIC, Australia
c Florey Institute of Neuroscience and Mental Health, VIC, Australia
d Commonwealth Scientific and Industrial Research Organization (CSIRO), Australia
e Department of Surgery, Monash University, VIC, Australia
f Department of Neurosurgery, Alfred Hospital, Melbourne, VIC, Australia
b Department
or
2
Amyloid-, Tau, and
18
F-Fluorodeoxyglucose Positron
Emission Tomography in Posttraumatic
Stress Disorder
uth
1
14
15
16
17
18
19
20
21
22
23
24
Abstract.
Background: Epidemiological studies suggest a relationship between posttraumatic stress disorder (PTSD) and dementia.
Objective: This study assessed whether Alzheimer’s disease (AD) imaging biomarkers were elevated in Vietnam veterans
with PTSD.
Methods: The study compared cognition, amyloid-, tau, regional brain metabolism and volumes, and the effect of APOE
in 83 veterans with and without PTSD defined by the Clinician’s Administered PTSD Scale.
Results: The PTSD group had significantly lower education, predicted premorbid IQ, total intracranial volume, and Montreal
Cognitive Assessment score compared with the controls. There was no difference between the two groups in the imaging or
genetic biomarkers for AD.
Conclusion: Our findings do not support an association between AD pathology and PTSD of up to 50 years duration.
Measures to assess cognitive reserve, a factor that may delay the onset of dementia, were lower in the PTSD group compared
with the controls and this may account for the previously observed higher incidence of dementia with PTSD.
rre
cte
13
dA
Accepted 15 October 2019
Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, positron emission tomography, posttraumatic stress disorder,
tau
27
INTRODUCTION
29
30
Un
28
co
26
25
Posttraumatic stress disorder (PTSD) is a chronic
and disabling condition with a lifetime prevalence
of 1–9% in the general population and an increased
∗ Correspondence
to: Alby Elias, 145 Studley St, Heidelberg,
VIC, Australia. Tel.: +61 417325223; E-mail: alby.elias@
unimelb.edu.au.
prevalence in military veterans [1, 2]. Previous
studies that provided compelling evidence for cognitive impairment in combat-related PTSD sparked
a series of investigations that examined the association between PTSD and dementia in Vietnam
veterans [3, 4]. Several epidemiological studies have
recently demonstrated an increased incidence of
dementia including Alzheimer’s disease (AD) on
clinical criteria in older veterans with PTSD com-
ISSN 1387-2877/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved
31
32
33
34
35
36
37
38
39
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
f
47
oo
46
Pr
45
METHODS
Participant recruitment
or
44
The institutional review board of Austin Health,
one of the major metropolitan hospitals in Melbourne,
provided ethics approval and written informed consent was obtained from all participants.
Participants were Australian male Vietnam veterans recruited from the community via advertisement.
Interested veterans went through preliminary screening. We applied the following exclusion criteria:
substance abuse in the past six months, traumatic
brain injury, psychosis, bipolar affective disorder, dementia, existing diagnosis of mild cognitive
impairment (MCI), and any unstable medical condition that could have made participation difficult or
have a significant impact on cognitive assessment.
MCI and dementia were excluded to reduce recruitment bias and avoid confounding of the diagnosis of
PTSD. Veterans who passed the initial screening had
a face-to-face evaluation with a psychiatrist.
uth
43
[23]. Whether tau accumulation or other types of
neurodegeneration explain the elevated incidence of
dementia in PTSD remains unknown. The aim of this
study was to use 18 F-florbetaben and 18 F-AV-1451 to
quantify A and tau burden, respectively, 18 F-FDG
to estimate regional brain metabolism, and MRI to
measure regional brain volume in Vietnam veterans
with and without PTSD. Our hypothesis is that veterans with PTSD have increased AD pathology as
detected by neuroimaging biomarkers for AD, and
neurodegeneration prior to a diagnosis of mild cognitive impairment or dementia.
rre
cte
42
pared with those without PTSD [5–9]. Furthermore,
structural and functional magnetic resonance imaging (MRI) studies have shown reduced volumes of
structures involved in cognition such as hippocampi,
amygdala, and anterior cingulate cortex along with
reduced activity in the anterior cingulate cortex in
PTSD [10, 11]. Metabolic imaging studies with 18 Ffluorodeoxyglucose positron emission tomography
(FDG PET) have produced inconsistent findings in
PTSD with a tendency to hypometabolism in anterior cingulate, limbic, and temporal regions [12].
These studies had small, middle aged cohorts. In contrast, more specific patterns of brain hypometabolism
occur in most dementia syndromes [13]. Brain
hypometabolism reflects synaptic dysfunction and
loss and is regarded as a measure of neurodegeneration that may precede the onset of symptoms by
several years [14, 15]. The hypometabolic findings
characteristic of AD relate to posterior brain regions,
in particular the posterior cingulate gyrus and parietotemporal cortex.
The previous studies did not examine the specific
pathological biomarkers of AD, amyloid- (A) and
tau, in PTSD. Deposition of extracellular neuritic
plaques and intracellular neurofibrillary tangles is
the pathological hallmark of AD [16]. Enabling in
vivo and early detection of A and tau using specific
radioactive ligands, amyloid and tau PET represents
a breakthrough in AD research. The uptake of these
radioactive tracers is a proxy measure of A and
tau although not the same as the autopsy, which is
the gold standard for AD diagnosis. A plaques can
be detected on PET up to 20 years before the onset
of dementia due to AD [17, 18]. Compared with
A plaques, the progression of neurofibrillary tangles is believed to occur closer to the development
of symptoms and consequently has shown a better
correlation with neuronal damage and cognitive deterioration in patients with AD [19]. Current knowledge
of the role of A and tau in the pathogenesis of
AD, although not fully understood, is expanding and
the relationship may be best described as synergistic
[20]. Animal studies have observed elevated A in
PTSD [21]. Exposure to psychological trauma and
corticotrophin-releasing factor have been reported to
enhance both A plaque formation and tau phosphorylation [22].
A recent study by the Alzheimer’s Disease
Neuroimaging Initiative (ADNI) group in Vietnam veterans (ADNI-DOD study) did not find an
increased risk of AD with PTSD according to the
global A burden estimated from 18 F-florbetapir PET
co
41
Un
40
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
dA
2
Brain imaging
All participants underwent 20-min PET scans
acquired 90 min after a slow IV bolus administration
of 250 MBq (±10%) of 18 F-florbetaben and 70 min
after the injection of 370 MBq of 18 F-AV-1451.
Scans were acquired on a Siemens PET/CT mCT128
and CT attenuation correction was applied. Image
reconstruction used the Ordered Subset Expected
Maximization algorithm. There was no correction
for partial volume effect. We analyzed the PET
scans with the Computational Analysis of PET from
AIBL and calculated standardized uptake value ratio
(SUVR) of 18 F-florbetaben using cerebellar grey matter uptake as the reference to quantify global A
burden [24]. Amyloid burden was also calculated in
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
Clinical and cognitive assessment
f
147
oo
146
We used Clinician’s Administered PTSD Scale
(CAPS) - DSM-IV version to assess PTSD [26]. A
score of 40 or more and a history of combat exposure constituted the inclusion criteria for the PTSD
group. This score was based on the existing diagnostic utility data for a range of selected cut-off scores
which indicated that a CAPS score of 40 had 93%
sensitivity and 80% specificity for dichotomous classification of PTSD [27]. A CAPS score of 30 or less
and military experience formed the inclusion criteria
for the control group. We have chosen these scores
to ensure a clear separation between the diagnostic
groups and controls. Subjects who scored between
30 and 40 were excluded from the analysis based
on the presumption that they had fluctuating and
sub-threshold symptoms. The Geriatric Depression
Scale (GDS) measured depressive symptoms [28].
Participants underwent APOE 4 genotyping. A vascular risk factor score was calculated by giving one
point to each of the following: hypertension, ischemic
heart disease, previous history of stroke, atrial fibrillation, current smoking, diabetes mellitus, body mass
index over 30, and hypercholesterolemia. Sum of all
points gave cumulative vascular risk score. Veterans
with mild, moderate, or severe traumatic brain injury
according to the criteria set by the U.S Department
of Defense (DoD) were excluded.
A standardized neuropsychological test battery
assessed cognitive functions [29–35]. The following
tests measured memory component: the delayed paragraph recall from the Logical Memory Test II, Rey
Auditory Verbal Learning Test 30-min delay, and the
Rey-Osterrieth complex figure test (ROCFT) 30-min
delay. We calculated a composite memory score from
these three tests using standard deviation and mean
scores from the control population. We used Trail
Making Test part A to assess the visual orientation and
processing speed, part B to measure executive function, Wechsler Adult Intelligence Scale to measure
attention, categorical fluency test to assess semantic
fluency, and ROCFT to assess visuospatial orientation and constructional skills. The Mini-Mental State
Examination and the Montreal Cognitive Assessment
Pr
145
or
144
uth
143
dA
142
and cortical thickness were then estimated using
a software Computational Quantification program
[24]. The Harmonized Hippocampus protocol was
used to define the hippocampus region of interest.
Volumetry was adjusted for the TICV by dividing the
regional volume by TICV.
rre
cte
141
Centiloid units using the standard Centiloid method
cortical region of interest normalized to whole cerebellum as previously described [25]. 18 Florbetaben
scan was read visually by three readers and the classification into negative or positive scan was based on
majority results. The visual inspection was based on
brain amyloid plaque load, which was derived from
the regional cortical tracer uptake in the four regions:
lateral temporal cortex, frontal cortex, posterior cingulate cortex/precuneus, and parietal cortex. Typical
transverse PET slices were judged as negative if the
tracer uptake in the grey matter was lower than that of
the white matter and positive if the uptake in the grey
matter was equal to or more than that in the white
matter. The SUVR of 18 F-AV-1451, using cerebellar
grey matter uptake as the reference region, estimated
global and regional tau deposition. We measured
tau in the following regions: mesial temporal; temporoparietal; and rest of the neocortex.
A part of the data analyzed in the preparation of
this article were obtained from the ADNI database
(http://adni.Ioni.usc.edu). The primary goal of ADNI
has been to test whether serial MRI, PET, other
biological markers and clinical and neuropsychological assessment can be combined to measure the
progression of MCI and early AD. For up-to-date
information, see http://www.adni.info.org.
For the acquisition of 18 F-FDG PET scan, participants fasted for four hours and then had an
injection of 200 MBq of 18 F-FDG. As per standard practice, they remained in a quiet, darkened
room for 30 min with eyes open in order to keep
the occipital metabolism consistent. Acquisition was
commenced 30 min after the injection on a Philips
Allegro PET camera. A post-injection transmission scan for attenuation correction was performed.
Acquisition time was 20 min. Reconstruction was
performed with a RAMLA filter. SUVR was calculated for frontal, mesial temporal, and rest of the
neocortex. Participants underwent 3-Tesla Siemens
Trio brain MRI for the measurement of hippocampal volume and total intracranial volume (TICV). A
three-dimensional (3D) T1 magnetization-prepared
rapid gradient echo (MPRAGE) was acquired
with the following parameters: FoV = 260 × 256,
Matrix = 240 × 256, 160 slices, 1.0 × 1.0 × 1.2 mm
voxels, TR = 2300 ms, TE = 2.98 ms, flip angle = 9◦ .
The T1 weighted images were rigidly registered to the
Montreal Neurological Institute (MNI) average brain
and segmented into grey and white matter and cerebrospinal fluid space with Expectation Maximisation
Segmentation algorithm. Partial tissue classification
co
140
Un
139
3
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
246
247
248
249
277
RESULTS
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
278
279
280
281
282
283
284
285
286
287
288
co
254
From 2014 March to May 2017, 169 male Vietnam
veterans expressed interest in the study. 20 veterans
later withdrew from the study for reasons of inconvenience and perceived distress. After excluding 66
veterans (including three veterans who had CAPS
score between 30 and 40) for the reasons shown in
Fig. 1, we collected the neuropsychological and PET
data from the remaining 83 veterans. A diagnosis of
lifetime PTSD was present in 53 veterans, and 30 veterans were controls. Among veterans with lifetime
PTSD, a diagnosis of current PTSD was present in
Un
253
PET imaging
There was no significant difference between the
PTSD group and the controls in the mean SUVR
of the A tracer, 18 F-florbetaben (p = 0.927, Cohen’s
d = 0.02). According to the visual inspection of 18 Fflorbetaben scans, 7 (21.8%) veterans with current
PTSD and 4 (10.5%) veterans without PTSD had
a positive scan. This difference was not significant
(χ2 = 0.57, p = 0.48). In the multivariable regression
analysis with 18 F-florbetaben SUVR as the dependent
variable and current PTSD, age, APOE 4, and vascular risk factors as the independent variables, current
PTSD did not predict 18 F-florbetaben SUVR (standardized coefficient  = –0.093, p = 0.513), whereas
APOE 4 did (R2 = 0.126, standardized coefficient
 = 0.185, p = 0.043). The regional and global uptake
of the tau tracer, 18 F-AV-1451 did not differ between
the PTSD and control groups (Table 3). 18 F-AV1451
SUVR did not correlate with any cognitive score.
There was no significant correlation between the
severity of PTSD as measured by CAPS score and
global or regional 18 F-AV-1451 SUVRs. There were
no differences in the 18 F-FDG SUVRs between the
groups (Table 2). There was no correlation between
rre
cte
276
The PTSD and the control groups were compared
for the following outcome variables: 18 F-florbetaben
SUVR and Centiloid units, 18 F-AV-1451 and 18 FFDG SUVRs, MRI regional volumes, and cognitive
test scores. Age, APOE 4, and vascular risk factors were analyzed as covariates in a multivariable
regression analysis because of their known association with amyloid retention. For this study, current
PTSD was the explanatory variable for the primary
analysis given a priori that it is the persistence of
symptoms that is related to the risk of AD in late life.
Life-time history of PTSD was also examined. The
two-tailed results were corrected for multiple comparisons using the Benjamini-Hochberg procedure.
Chi-square (χ2 ) was used to analyze categorical variables, such as positive or negative 18 F-florbetaben
scan, and APOE E 4 status. Pearson correlation test
was performed for the whole sample to test correlation between the tracer SUVRs and CAPS scores.
The analyses were performed on SPSS version 21.
Using florbetapir A PET results from normal controls in the ADNI study, we calculated that to detect
a group difference with an effect size of 0.75, with
80% power at ␣ = 0.05, required 29 subjects in each
group.
252
f
245
oo
244
Pr
Statistical analysis
243
30. All veterans experienced PTSD symptoms either
during or soon after military service.
The participants’ characteristics are shown in
Table 1. The median current CAPS score for the
PTSD group was 52.50 compared with 4 for the
control group (Mann-Whitney U = 0.000, p < 0.001).
Veterans with current PTSD were slightly younger
than those without PTSD (PTSD group mean age:
67.80 ± 2.48 versus the control group mean age:
70.23 ± 5.46; p = 0.043; CI = 0.220–4.64; Cohen’s
d = 0.57). Median predicted premorbid IQ (104 versus 114; U = 201.00; p < .001) and years of education
(11 versus 12; U = 305.00; p = 0.043) were significantly lower whereas the median GDS score (5.50
versus 1, U = 130.00, p < .001) was significantly
higher in the PTSD group than in the controls.
The TICV was significantly lower in the PTSD
group than in the control group (1565.173 ± 1114.31
cm3 versus 1674.12 ± 1474.64 cm3 ; p = 0.010;
CI = 33.59–184.307; Cohen’s d = 0.40). The median
vascular risk factor score did not differ significantly between the groups (1 versus 2, U = 384.50,
p = 0.318). APOE 4 carrier status was available for
55 (92%) participants, and at least one allele was
present in 7 (24%) veterans with PTSD and 2 (9%)
controls (χ2 = 2.70, p = 0.10).
or
251
242
uth
250
(MoCA) measured global cognitive function [36, 37].
Along with the measurement of attention, delayed
recall, and visuospatial abilities, MOCA assesses
executive function using an alternation task adapted
from the Trail Making Test Part B, phonemic fluency
task and two-item verbal abstraction task. Wechsler’s
Test of Adult Reading (WTAR) estimated premorbid
Intelligent Quotient (IQ) [35]. WTAR was adjusted
for age and then predicted IQ was calculated using
published criteria.
241
dA
4
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
uth
or
Pr
oo
f
5
dA
Fig. 1. Participants recruitment.
Table 1
Participant characteristics
Age
Predicted IQ
Years of education
Total Intracranial Volume (cm3 )
GDS Score
341
342
343
344
345
346
347
348
349
350
351
352
353
354
p
(corrected)
70.23 ± 5.46
114 (5)
12.0 (5)
1674.12 ± 1474.64
1 (2)
67.80 ± 2.48
104 (12)
11 (4)
1565.17 ± 1114.31
5.50 (5)
0.043
<0.001
0.043
0.01
<0.001
co
340
Current PTSD
(n = 30)
Mean ± SD)/Median
(Interquartile Range)
the severity of PTSD as measured by CAPS and 18 FFDG SUVR in any region. We repeated the analysis
for subjects with lifetime PTSD with and without current PTSD (n = 53) against the same control group
(n = 30). There was no significant difference in the
uptake of any tracer globally or regionally between
the two groups.
Adding the U.S. ADNI-DOD study amyloid PET
data expanded the sample size to a total of 97 Vietnam veterans with PTSD and 85 controls. Centiloid
units were calculated to allow the merging of scans
obtained with the different A PET tracers, florbetapir and florbetaben. The combined data did not
reveal a significant difference between the two groups
in the Centiloid values (PTSD Mean: 9.01 ± 20.73;
versus Control Mean 14.37 ± 26.12 Cohen’s d = 0.22;
Un
339
Controls
(n = 30)
Mean ± SD/Median
(Interquartile Range)
rre
cte
Variables
Median rank: 89.85 versus 93.39, p = 0.651; MannWhitney U = 3962.00). More veterans in the control
group than in the PTSD group had a positive amyloid scan based on Centiloid score of 25 or more (13
versus 7, χ2 = 7.47, p = 0.024, uncorrected). With the
additional ADNI data APOE 4 was present in 23
veterans with PTSD and 17 veterans without PTSD
(χ2 = 0.567, p = 0.451, uncorrected).
MRI results
Forty of the lifetime PTSD group including 30 with
ongoing or current PTSD, and 25 controls underwent MRI. Others did not have MRI for reasons
of inconvenience and metal safety. The TICV was
slightly but significantly lower in the current PTSD
355
356
357
358
359
360
361
362
363
364
365
366
367
368
6
A. Elias et al. / Amyloid-β, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
Current PTSD
(n = 30)
Median/mean
(interquartile range)
p
1.21 (0.13)
1.16 (0.12)
1.17 (0.11)
1.17 (0.11)
1.13 (0.14)
0.75 ± 0.05
1.05 ± 0.08
1.06 ± 0.07
1.22 (0.16)
1.21 (0.20)
1.16 (0.18)
1.14 (0.16)
1.10 (0.13)
0.74 ± 0.04
1.03 ± 0.05
1.04 ± 0.06
0.610
0.804
0.610
0.610
0.620
0.344
0.384
0.303
18 F-florbetaben
18 F-AV-1451
(mesial temporal)
18 F-AV-1451 (temporoparietal)
18 F-AV-1451 (rest of neocortex)
Global 18 F-AV-1451
18 F-fludeoxyglucose (mesial temporal)
18 F-fludeoxyglucose (frontal)
18 F-fludeoxyglucose (rest of neocortex)
oo
Controls
(n = 30)
Median/mean
(interquartile range)
Pr
Tracers
f
Table 2
PET Tracer binding expressed in SUVR
Table 3
MRI volumes in PTSD and controls, adjusted for total intracranial volume
0.18 ± 0.01
0.19 ± 0.01
0.08 ± 0.01
0.08 ± 0.01
0.75 ± 0.08
0.69 ± 0.06
0.17 ± 0.02
0.17 ± 0.02
0.33 ± 0.03
0.28 ± 0.04
0.19 ± 0.01
0.19 ± 0.01
0.08 ± 0.01
0.08 ± 0.008
0.72 ± 0.08
0.68 ± 0.07
0.17 ± 0.01
0.17 ± 0.02
0.32 ± 0.04
0.27 ± 0.04
p
or
Current PTSD
(n = 24)
uth
Left hippocampus
Right hippocampus
Left amygdala
Right amygdala
Left middle frontal cortex
Right middle frontal cortex
Left orbitofrontal cortex
Right orbitofrontal cortex
Left anterior cingulate cortex
Right anterior cingulate cortex
Controls
(n = 25)
Mean
dA
Variables
0.116
0.131
0.492
0.571
0.332
0.468
0.774
0.660
0.670
0.574
Table 4
Cognitive functions in PTSD and controls
Controls
(n = 30)
Mean ± SD/
Median
(interquartile range)
Current PTSD
(n = 30)
Mean ± SD/
Median
(interquartile range)
p
17.73 ± 3.99
38.97 ± 9.91
37 (15)
90 (42)
29.43 ± 2.97
47.17 ± 10.56
0.02 ± 0.74
29 (1)
28 (4)
15.40 ± 4.10
38.13 ± 11.44
34 (17)
97.50 (65)
30.40 ± 5.99
44.70 ± 9.22
–0.15 ± 0.69
28 (2)
26 (4)
0.135
0.860
0.882
0.182
0.555
0.535
0.535
0.182
0.027
rre
cte
Variables
co
Digit Span
Categorical fluency
Trail making test A (time to completion, s)
Trail making test B (time to completion, s)
Rey Osterrieth complex figure copy test
RAVLT Learning trials
Composite Memory score
MMSE
MoCA
369
370
371
372
373
374
375
376
Un
RAVLT, Rey Auditory Verbal Learning Test; MMSE, Mini-Mental State Examination; MoCA, Montreal
Cognitive Assessment.
group than in the control group (1565.173 ± 1114.31
cm3 versus 1674.12 ± 1474.64 cm3 ; p = 0.01;
CI = 33.59–184.307; Cohen’s d = 0.40). There was
no significant difference between veterans with and
without current PTSD in the adjusted volumes of
the hippocampus, amygdala, anterior cingulate cortex, middle frontal, or orbitofrontal cortex on either
side (Table 3). The analysis was repeated with sub-
jects who had a lifetime diagnosis of PTSD. The
TICV was significantly lower in the lifetime PTSD
group compared with the control group, but volumetric grey matter measures did not significantly
differ between the groups. There was no significant
correlation between volumetric measure and severity of current PTSD as quantified by the CAPS
score.
377
378
379
380
381
382
383
384
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
f
392
oo
391
There is abundant literature on cognitive function,
structural brain imaging, and incidence of dementia
in Vietnam veterans with PTSD, but little is known
about the AD pathological biomarkers in PTSD. This
study measured A and tau in vivo in Vietnam veterans with PTSD against veterans without PTSD.
This ensured a homogenous population with military experience in both groups and an age range in
which preclinical AD pathology is developing and
detectable in the general population. The present
study did not show a significant association between
PTSD and increased amyloid deposition in the brain
as measured by 18 F-florbetaben. Global amyloid burden or regional amyloid as reflected in the visual
inspection was not significantly different between the
PTSD and the control groups. Amyloid deposition
is the earliest detectable marker of AD and amyloid
PET scans become abnormal up to 20 years before
the clinical diagnosis of AD dementia [17, 18]. Our
co
390
Un
389
Pr
DISCUSSION
388
or
414
387
rre
cte
413
The performance of both groups was within the
normal range of age-adjusted published norms of
the neuropsychological tests except on the MoCA
where the mean score for the PTSD group (25.27)
was fractionally below the conventional cut-off score
of 26. In comparison with the controls, veterans with
current PTSD scored lower on global cognitive function as measured by the MoCA (Median: 26 versus
28; U = 250.00; p = 0.027). We performed a multivariable regression analysis after log-transformation
of the total MoCA score. The predicted premorbid IQ and the GDS score significantly correlated
with the total MoCA score and also differed between
the groups. Therefore, these variables were included
in the model along with current PTSD as explanatory (independent) variables with the MoCA as the
dependent variable. The regression analysis met all
assumptions. In the regression analysis (adjusted
R2 = 0.249), the difference in the performance on
the MoCA ( = –0.252, p = 0.081) did not retain significance when predicted premorbid IQ ( = –0.341,
p = 0.009) and depression score ( = 0.006; p = 0.611)
were adjusted. The cognitive scores are summarized in Table 3. There was no significant difference
between the PTSD groups and the controls in the
other cognitive measures. The correlation between
predicted premorbid IQ and TICV was significant
(r = 0.351, p = 0.013).
386
finding is consistent with the results from the USbased ADNI Veterans study that also did not find an
association between PTSD and increased A deposition [23]. Like our findings, the PTSD cohort in the
ADNI-DOD veterans study had worse global cognition than controls. The ADNI-DOD data revealed a
significantly lower level of education in the PTSD
group, and our study showed the same.
To the best of our knowledge, this is the first
study to report tau deposition in PTSD along with
A, regional brain metabolism and brain volumetry
along with neuropsychological data. This is perhaps
the most comprehensive assessment of biomarkers of
AD in PTSD. We found no increase in binding of the
tau tracer 18 F-AV-1451 in PTSD. Similarly, there was
no difference between the PTSD group and the controls in regional brain metabolism or regional brain
volumetry. If PTSD causes neurodegeneration associated with various dementia syndromes, then it would
be likely that after 40 or more years of symptoms
in the age group under study, some change would
be present. 18 F-FDG PET scan has been reported as
showing abnormality several years before the onset
of AD dementia [14, 15]. Similarly, alterations in
hippocampal and regional cortical volumes in PTSD
could be temporary, or the mild volume reductions
as previously described may be masked by the atrophy that occurs with normal aging. Our participants
were in their 60 s and 70 s, and the effect of aging
may have had more impact on volumetric changes
than PTSD itself, in cortical as well as hippocampal
regions. A longitudinal study is required to address
these possibilities.
Commensurate with the finding of no difference
between PTSD and the control status regarding A,
tau, and regional brain metabolism and volumes,
there was no evidence of an independent association
between PTSD and cognitive impairment. Although
previous studies, mostly done in younger veterans,
have shown impaired cognitive function in PTSD, our
findings suggest that cognitive functions are mostly
intact in older veterans with PTSD and the mild
impairment we found in the global cognitive performance was reflective of predicted premorbid IQ and
the affective state. Our finding is in line with previous
data that suggested lower premorbid IQ as a vulnerability factor for the development of PTSD upon
trauma exposure and associated cognitive impairment [38, 39]. A co-twin-control study of veterans
found that premorbid cognitive ability, as measured
by Armed Forces Qualification Test, predicted the
future risk of PTSD in a dose dependent manner indi-
uth
Cognitive functions
dA
385
7
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
f
493
oo
492
Pr
491
or
490
uth
489
the previous epidemiological studies may be reflective of this difference. The clinical implication is that
treatments that aim to restore physical and cognitive
activities in patients with PTSD may increase CR
and lead to dementia risk reduction. In this context,
reverse causation hypothesis is also valid: i.e., people
with higher reserve may more frequently choose to
engage in these types of activities.
This study has several limitations. We could not
access direct measurements of pre-military IQ; premorbid IQ in our study was an indirect measure based
on the WTAR. Nonetheless, WTAR was validated
and used in the cognitive assessment of traumatic
brain injury studies [47]. Secondly, given the negative
findings, type II error is an important consideration.
Although there were small numbers of veterans with
a positive amyloid scan and the samples were underpowered for Chi-square test, the analysis for the
global burden of amyloid by SUVR had 80% power
to detect a difference with effect size of 0.75 or more.
For the amyloid imaging, adding the ADNI data did
give improved power sufficient to detect an effect
size of 0.43. Another limitation of the study was that
large numbers of veterans met the exclusion criteria.
Among the excluded veterans some declined participation because of perceived stress. Whether they had
more severe PTSD or would have altered the results
is unknown. The ADNI-DOD study also reported a
large number of excluded veterans. Head injury, substance abuse, and medical illnesses are comorbid with
PTSD and such factors may lead to restricted inclusion of veterans. Limited inclusion could impact the
generalizability of findings. The literature of CR and
BR is complex and still evolving, and an explanation
of the relationship between PTSD and dementia, being far from being conclusive, needs more
research.
In conclusion, our findings indicate that PTSD
is not associated with an increased prevalence of
the biomarkers for the specific pathology of AD or
other forms of progressive neurodegeneration. Compared with the controls, veterans with PTSD had a
relatively low cognitive reserve. Given that high cognitive reserve may delay the onset of dementia, low
cognitive reserve in PTSD may explain its previous
association with dementia.
rre
cte
488
cating the role premorbid intellectual function in the
adaptive coping ability after trauma [39]. It should be
noted that patients with PTSD do not form a low IQ
group because the premorbid IQ in the PTSD group
was consistent with the expected general population
average, but the veteran controls were above average.
The findings of the present study and those of the
ADNI-DOD veterans study do not lend support to a
direct link between PTSD and AD pathology. Therefore, it is worth exploring the potential explanatory
factors behind the previously reported association
between PTSD and dementia including AD [5–9].
The present study suggests a low cognitive reserve
(CR) in PTSD. Cognitive reserve is a potential mechanism to buffer the impact of the pathological process
associated with AD [40]. With high CR more pathological load is required to produce the same degree
of cognitive impairment than with low CR possibly
because of recruitment of alternate functional circuits particularly in the dorsolateral prefrontal cortex
[41]. High CR affords protection against the onset
of dementia, not the neuropathological markers of
AD suggesting the role of CR as neurocompensation
rather than neuroprotection [42].
According to our findings, predicted premorbid
intelligence and education, the proxy measures of CR
and TICV which is a measure of brain reserve (BR)
were significantly lower in the PTSD group than in the
controls. A recent study demonstrated that increased
intracranial volume mitigated adverse effects of
dementia pathology on cognitive function, particularly attention and executive function [43]. Likewise,
premorbid cognitive performance predicted the onset
of dementia independent of the potent genetic risk
factor for AD, APOE 4 [44]. Furthermore, physical and cognitive engagement and leisure activities
contribute to CR, but evidence suggests that avoidant
behavior and hyperarousal symptoms of PTSD may
preclude such activities [45, 46]. We postulate that
the relatively low CR and other dementia risk factors
associated with PTSD may account for previously
observed higher incidence of dementia with PTSD.
It may be noted, however, that it is not the abnormally low CR or BR that may explain the association
of PTSD and dementia. It is a relative concept in comparison with the controls that is worth considering and
the previously reported increased risk of dementia
with PTSD was also in comparison with the controls.
This may suggest that while subjects with PTSD may
have the same risk as that of general population, those
without PTSD may have additional protection against
the onset of dementia from increased CR or BR and
co
487
Un
486
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
dA
8
ACKNOWLEDGMENTS
The authors thank the U.S. Department of Defense
and Piramal Pharmaceuticals for supporting this
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
f
595
[3]
[4]
[5]
[6]
[7]
oo
594
[2]
Pr
593
or
592
639
Eisen SA, Griffith KH, Xian H, Scherrer JF, Fischer ID,
Chantarujikapong S, Hunter J, True WR, Lyons MJ, Tsuang
MT (2004) Lifetime and 12-month prevalence of psychiatric
disorders in 8,169 male Vietnam War era veterans. Mil Med
169, 896-902.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas
KR, Walters EE (2005) Lifetime prevalence and age-ofonset distributions of DSM-IV disorders in the National
Comorbidity Survey Replication. Arch Gen Psychiatry 62,
593-602.
Vasterling JJ, Duke LM, Brailey K, Constance JI, Allain AN
Jr, Sutker PB (2002) Attention, learning, and memory performances and intellectual resources in Vietnam veterans:
PTSD and no disorder comparisons. Neuropsychology 16,
5-14.
Scott JC, Matt GE, Wrocklage KM, Crnich C, Jordan J,
Southwick SM, Krystal JH, Schweinsburg BC (2015) A
quantitative meta-analysis of neurocognitive functioning in
posttraumatic stress disorder. Psychol Bull 141, 105-140.
Yaffe K, Vittinghoff E, Lindquist K, Barnes D, Covinsky
KE, Neylan T, Kluse M, Marmar C (2010) Post-traumatic
stress disorder and risk of dementia among U.S. Veterans.
Arch Gen Psychiatry 67, 608-613.
Qureshi SU, Kimbrell T, Pyne JM, Magruder KM, Hudson TJ, Petersen NJ, Yu HJ, Schulz PE, Kunik ME (2010)
Greater prevalence and incidence of dementia in older veterans with posttraumatic stress disorder. J Am Geriatr Soc
58, 1627-1633.
Mawanda F, Wallace RB, McCoy K, Abrams TE (2017)
PTSD, psychotropic medication use and the risk of dementia among US veterans: A retrospective cohort study. J Am
Geriatr Soc 65, 1043-1050.
Flatt JD, Gilsanz P, Quesenberry CP, Albers KB, Whitmer RA (2018) Post-traumatic stress disorder and risk of
dementia among members of a health care delivery system.
Alzheimers Dement 14, 28-34.
Wang TY, Wei HT, Liou YJ, Su TP, Bai YM, Tsai SJ, Yang
AC, Chen TJ, Tsai CF, Chen MH (2016) Risk of developing
dementia among patients with posttraumatic stress disorder:
A nationwide longitudinal study. J Affect Disord 205, 306310.
Lanius RA, Williamson PC, Densmore M, Boksman K,
Gupta MA, Neufeld RW (2001) Neural correlates of
traumatic memories in posttraumatic stress disorder: A
functional MRI investigation. Am J Psychiatry 158, 19201922.
Bromis K, Calem M, Reinders AATS, Williams SCR,
Kempton MJ (2018) Meta-analysis of 89 structural MRI
studies in posttraumatic stress disorder and comparison with
major depressive disorder. Am J Psychiatry 175, 989-998.
Zandieh S, Bernt R, Knoll P, Wenzel T, Hittmair K, Haller
J, Hergan K, Mirzaei S (2016) Analysis of the metabolic
and structural brain changes in patients with torture-related
post-traumatic stress disorder (TR-PTSD) using 18 F-FDG
PET and MRI. Medicine (Baltimore) 95, e3387.
Teune LK, Bartels AL, de Jong BM, Willemsen AT, Eshuis
SA, de Vries JJ, van Oostrom JC, Leenders KL (2010) Typical cerebral metabolic patterns in neurodegenerative brain
diseases. Mov Disord 25, 2395-2404.
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate
A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM,
Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins
uth
591
[1]
dA
590
REFERENCES
[8]
rre
cte
589
study. The study utilized the infrastructure and
resources of Australian Imaging Biomarkers and
Lifestyle (AIBL) Study of ageing.
Part of the data analyzed in preparation of
this article were obtained from the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) database
(http://adni.loni.usc.edu). As such, the investigators
within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not
participate in analysis or writing of this report. A
complete listing of ADNI investigators can be found
at: http://adni.loni.usc.edu/wp-content/uploads/how
to apply/ADNI Acknowledgement List.pdf
ADNI is funded by the National Institute on Aging,
the National Institute of Biomedical Imaging and
Bioengineering, and through generous contributions
from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation;
Araclon Biotech; BioClinica, Inc.; Biogen; BristolMyers Squibb Company; CereSpir, Inc.; Cogstate;
Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and
Company; EuroImmun; F. Hoffmann-La Roche Ltd
and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer
Immunotherapy Research & Development, LLC.;
Johnson & Johnson Pharmaceutical Research &
Development LLC.; Lumosity; Lundbeck; Merck
& Co., Inc.;Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis
Pharmaceuticals Corporation; Pfizer Inc.; Piramal
Imaging; Servier; Takeda Pharmaceutical Company;
and Transition Therapeutics. The Canadian Institutes
of Health Research is providing funds to support
ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the
National Institutes of Health (http://www.fnih.org).
The grantee organization is the Northern California Institute for Research and Education, and the
study is coordinated by the Alzheimer’s Therapeutic
Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory
for Neuro Imaging at the University of Southern California.
This study was modelled on the U.S. Alzheimer’s
Disease Neuroimaging Initiative - Department of
Defense veterans study. Authors presented this work
in the Annual Meeting of American Psychiatric
Association, May 2016 in Atlanta and also in the
Alzheimer’s Association International Conference,
July 2017 in London.
Authors’ disclosures available online (https://
www.j-alz.com/manuscript-disclosures/19-0913r2).
co
588
Un
587
9
[9]
[10]
[11]
[12]
[13]
[14]
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
676
677
678
679
680
681
682
683
684
685
686
687
688
689
690
691
692
693
694
695
696
697
698
699
700
701
702
709
710
711
712
713
[16]
714
715
[17]
716
717
718
719
720
721
722
[18]
723
724
725
726
727
728
729
[19]
730
731
732
733
[20]
734
735
736
[21]
737
738
739
740
741
742
[22]
743
744
745
746
747
748
[23]
749
750
co
751
752
753
754
755
756
757
[24]
758
759
760
761
762
763
764
765
766
767
[25]
[28]
f
[15]
Un
708
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
oo
707
[27]
Weathers FW, Keane TM, Davidson JR (2001) ClinicianAdministered PTSD Scale: A review of the first ten years
of research. Depress Anxiety 13, 132-156.
Shalev AY, Freedman SA, Peri T, Brandes D, Sahar T (1997)
Predicting PTSD in trauma survivors: Prospective evaluation of self-report and clinician-administered instruments.
Br J Psychiatry 170, 558-564.
Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey
M, Leirer VO (1983) Development and validation of a geriatric depression screening scale: A preliminary report. J
Psychiatr Res 17, 37-49.
Wechsler D (1997) Wechsler Memory Scale-Revised. The
Psychological Corporation, San Antonio, TX.
Wechsler D (1987) Wechsler Adult Intelligence Scale - Third
Edition. The Psychological Corporation, San Antonio, TX.
Delis DC, Kaplan E, Kramer JH (2001) Delis-Kaplan Executive Function System. The Psychological Corporation, San
Antonio, TX.
Rey A, Osterrieth PA (1993) Translations of excerpts
from Rey’s ‘Psychological Examination of Traumatic
Encephalopathy’and Osterrieth’s ‘The Complex Figure
Test’. Clin Neuropsychol 7, 2-21.
Rey A (1964) L’examen Clinique en psychologie. Presses
Universitaires de France, Paris.
Reitan RM (1958) Validity of the Trail Making Test as an
indicator of organic brain damage. Percept Mot Skills 8,
271-276.
Wechsler D (2001) Wechsler Test of Adult Reading: WTAR.
The Psychological Corporation, San Antonio, TX.
Folstein MF, Folstein SE, McHugh PR (1975) Mini-Mental
State, A practical method for grading the cognitive state of
patients for the clinician. J Psychiatr Res 2, 189-198.
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau
S, Whitehead V, Collin I, Cummings JL, Chertkow H
(2005) The Montreal Cognitive Assessment, MoCA: A brief
screening tool for mild cognitive impairment. J Am Geriatr
Soc 53, 695-699.
Macklin ML, Metzger LJ, Litz BT, McNally RJ, Lasko NB,
Orr SP, Pitman RK (1998) Lower precombat intelligence is
a risk factor for posttraumatic stress disorder. J Consult Clin
Psychol 66, 323-326.
Kremen WS, Koenen KC, Boake C, Purcell S, Eisen SA,
Franz CE, Tsuang MT, Lyons MJ (2007) Pretrauma cognitive ability and risk for posttraumatic stress disorder: A twin
study. Arch Gen Psychiatry 64, 361-368.
Stern Y (2012) Cognitive reserve in ageing and Alzheimer’s
disease. Lancet Neurol 11, 1006-1012.
Morbelli S, Perneczky R, Drzezga A, Frisoni GB, Caroli
A, van Berckel BN, Ossenkoppele R, Guedj E, Didic M,
Brugnolo A, Naseri M, Sambuceti G, Pagani M, Nobili F
(2013), Metabolic networks underlying cognitive reserve
in prodromal Alzheimer disease: A European Alzheimer
disease consortium project. J Nucl Med 54, 894-902.
Brayne C, Ince PG, Keage HAD, McKeith IG, Matthews
FE, Polvikoski T. EClipSE Collaborative Members (2010)
Education, the brain and dementia: Neuroprotection or compensation? EClipSE Collaborative Members. Brain 133,
2210-2216.
Groot C, van Loenhoud AC, Barkhof F, van Berckel BNM,
Koene T, Teunissen CC, Scheltens P, van der Flier WM,
Ossenkoppele R (2018) Differential effects of cognitive
reserve and brain reserve on cognition in Alzheimer disease.
Neurology 90, e149-e156.
Cervilla J, Prince M, Joels S, Lovestone S, Mann A (2004),
Premorbid cognitive testing predicts the onset of dementia
Pr
706
[26]
or
705
RN, Masters CL, Mayeux R, Ringman JM, Rossor MN,
Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network (2012) Clinical and
biomarker changes in dominantly inherited Alzheimer’s disease. N Eng J Med 367, 795-804.
Chételat G, Desgranges B, Landeau B, Mézenge F, Poline
JB, de la Sayette V, Viader F, Eustache F, Baron JC
(2008) Direct voxel-based comparison between grey matter
hypometabolism and atrophy in Alzheimer’s disease. Brain
131, 60-71.
Wilcock GK, Esiri MM (1982), Plaques, tangles and dementia. J Neurol Sci 56, 343-356.
Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE,
Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O’Keefe
G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke
C, Salvado O, Head R, Martins R, Masters CL, Ames D,
Villemagne VL (2010) Amyloid imaging results from the
Australian Imaging, Biomarkers and Lifestyle (AIBL) study
of aging. Neurobiol Aging 31, 1275-1283.
Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis
KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff
P, Ames D, Rowe CC, Masters CL; Australian Imaging
Biomarkers and Lifestyle (AIBL) Research Group (2013)
Amyloid  deposition, neurodegeneration, and cognitive
decline in sporadic Alzheimer’s disease: A prospective
cohort study. Lancet Neurol 12, 357-367.
Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT
(1992) Neurofibrillary tangles but not senile plaques parallel
duration and severity of Alzheimer’s disease. Neurology 42,
631-639.
Nisbet RM, Polanco JC, Ittner LM, Gotz J (2015), Tau
aggregation and its interplay with amyloid-. Acta Neuropathol 129, 207-220.
Justice NJ, Huang L, Tian JB, Cole A, Pruski M, Hunt AJ
Jr, Flores R, Zhu MX, Arenkiel BR, Zheng H (2015) Posttraumatic stress disorder-like induction elevates -amyloid
levels, which directly activates corticotropin-releasing factor neurons to exacerbate stress responses. J Neurosci 35,
2612-2623.
Carroll JC, Iba M, Bangasser DA, Valentino RJ, James MJ,
Brunden KR, Lee VM, Trojanowski JQ (2011) Chronic
stress exacerbates tau pathology, neurodegeneration, and
cognitive performance through a corticotropin-releasing
factor receptor-dependent mechanism in a transgenic mouse
model of tauopathy. J Neurosci 31, 14436-14449.
Weiner MW, Harvey D, Hayes J, Landau SM, Aisen
PS, Petersen RC, Tosun D, Veitch DP, Jack CR Jr,
Decarli C, Saykin AJ, Grafman J, Neylan TC; Department
of Defense Alzheimer’s Disease Neuroimaging Initiative
(2017) Effects of traumatic brain injury and posttraumatic stress disorder on development of Alzheimer’s
disease in Vietnam Veterans using the Alzheimer’s Disease
Neuroimaging Initiative: Preliminary report. Alzheimers
Dement 3, 177-188.
Bourgeat P, Villemagne VL, Dore V, Brown B, Macaulay
SL, Martins R, Masters CL, Ames D, Ellis K, Rowe CC, Salvado O, Fripp J; AIBL Research Group (2015) Comparison
of MR-less PiB SUVR quantification methods. Neurobiol
Aging 36, S159-S166.
Klunk WE, Koeppe RA, Price JC, Benzinger TL, Devous
MD Sr, Jagust WJ, Johnson KA, Mathis CA, Minhas D,
Pontecorvo MJ, Rowe CC, Skovronsky DM, Mintun MA
(2015) The Centiloid Project: Standardizing quantitative
amyloid plaque estimation by PET. Alzheimers Dement 15,
1-15.
uth
704
dA
703
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
[37]
[38]
rre
cte
10
[39]
[40]
[41]
[42]
[43]
[44]
768
769
770
771
772
773
774
775
776
777
778
779
780
781
782
783
784
785
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
820
821
822
823
824
825
826
827
828
829
830
831
832
A. Elias et al. / Amyloid-, Tau, and 18 F-Fluorodeoxyglucose Positron Emission Tomography
f
oo
[46]
Pr
839
or
838
uth
837
[47]
between posttraumatic stress disorder and lack of exercise,
poor diet, obesity and co-occuring smoking: A systematic
review and meta-analysis. Health Psychol 37, 407-416.
Green RE, Melo B, Christensen B, Ngo LA, Monette G,
Bradbury C (2008) Measuring premorbid IQ in traumatic
brain injury: An examination of the validity of the Wechsler
Test of Adult Reading (WTAR). J Clin Exp Neuropsychol
30, 163-172.
dA
[45]
rre
cte
836
co
835
and Alzheimer’s disease better than and independently of
APOE genotype. J Neurol Neurosurg Psychiatry 75, 11001106.
Cheng S-T (2016) Cognitive reserve and the prevention of
dementia: The role of physical and cognitive activities. Curr
Psychiatry Rep 18, 85.
van den Berk-Clark C, Secrest S, Walls J, Hallberg E,
Lustman PJ, Schneider FD, Scherrer JF (2018) Association
Un
833
834
11
840
841
842
843
844
845
846
847