Bayram2018 Si

Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19
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1 56
2 Review Article 57
3 58
4 Current understanding of magnetic resonance imaging biomarkers and 59
5 60
6 memory in Alzheimer’s disease 61
7 62
8 63
9 Q9 Ece Bayram*, Jessica Z. K. Caldwell, Sarah J. Banks 64
10 Department of Neurology, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA 65
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Abstract Alzheimer’s disease (AD) is caused by a cascade of changes to brain integrity. Neuroimaging bio-
14 69
markers are important in diagnosis and monitoring the effects of interventions. As memory impair-
15 70
ments are among the first symptoms of AD, the relationship between imaging findings and memory
16 71
deficits is important in biomarker research. The most established magnetic resonance imaging (MRI)
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finding is hippocampal atrophy, which is related to memory decline and currently used as a diagnostic
18 73
criterion for AD. While the medial temporal lobes are impacted early by the spread of neurofibrillary
19 74
tangles, other networks and regional changes can be found quite early in the progression. Atrophy in
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several frontal and parietal regions, cortical thinning, and white matter alterations correlate with
21 76
memory deficits in early AD. Changes in activation and connectivity have been detected by functional
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MRI (fMRI). Task-based fMRI studies have revealed medial temporal lobe hypoactivation, parietal
23 78
hyperactivation, and frontal hyperactivation in AD during memory tasks, and activation patterns of
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these regions are also altered in preclinical and prodromal AD. Resting state fMRI has revealed al-
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terations in default mode network activity related to memory in early AD. These studies are limited in
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part due to the historic inclusion of patients who had suspected AD but likely did not have the dis-
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order. Modern biomarkers allow for more diagnostic certainty, allowing better understanding of neu-
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roimaging markers in true AD, even in the preclinical stage. Larger patient cohorts, comparison of
29 84
candidate imaging biomarkers to more established biomarkers, and inclusion of more detailed neu-
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ropsychological batteries to assess multiple aspects of memory are needed to better understand the
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memory deficit in AD and help develop new biomarkers. This article reviews MRI findings related
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to episodic memory impairments in AD and introduces a new study with multimodal imaging and
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comprehensive neuropsychiatric evaluation to overcome current limitations.
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Ó 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an
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open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
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4.0/).
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38 Keywords: Alzheimer’s disease; Dementia; Magnetic resonance imaging; Memory; Biomarker 93
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40 95
41 96
42 1. Introduction treatments, and symptomatic treatment is limited in efficacy. 97
43 Trials of novel therapeutics increasingly target the earliest 98
44 Alzheimer’s disease (AD) is a progressive neurodegenera- 99
brain changes, when a disease-modifying trajectory could
45 tive disorder resulting from pathological changes which typi- 100
potentially result in reduction or elimination of clinical
46 cally spread through brain networks in a predictable pattern.
impact. Memory measures remain an important way of as- 101
47 AD pathology leads to early decline in memory, and some pa- 102
sessing such clinical impact and are required in clinical trials
48 thology can be detected years before measurable cognitive or 103
in the United States [1]. 104
49 functional change. At present, there are no disease-modifying
50
Accurate diagnosis of AD was, until recently, confirmed 105
51 only at autopsy. Today, there are several imaging biomarkers 106
52 measuring neurodegeneration and amyloid b (Ab) deposi- 107
53 Q1 *Corresponding author. Tel.: 702-701-7892; Fax: ---. tion in the brain to support the diagnosis [2]. Atrophy on 108
E-mail address: bayrame@ccf.org 109
54
https://doi.org/10.1016/j.trci.2018.04.007
2352-8737/ Ó 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
REV 5.5.0 DTD TRCI159_proof 13 June 2018 8:01 pm ce

2 E. Bayram et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19
110 structural magnetic resonance imaging (MRI), hypometabo- 2. Structural MRI 168
111 lism on fluorodeoxyglucose positron emission tomography 169
112 (FDG-PET), and increased levels of craniospinal fluid Aging is associated with a slow decline in both white mat- 170
113 (CSF) total and phosphorylated tau are used to assess neuro- ter (WM) and gray matter (GM) volumes, and this atrophy 171
114 rate is increased in AD [7]. Although GM atrophy has 172
degeneration. CSF Ab42 and Ab PET, on the other hand, are
115 been more frequently assessed in AD, structural MRI ap- 173
used to assess Ab pathology. Preclinical studies focus on
116 proaches also allow for the assessment of cortical thickness, 174
117 groups at risk for AD, as defined by the apolipoprotein E 175
as well as shape and WM alterations. This section will focus
Q10 e4 (APOEe4) status or examine cognitively normal control 176
(CNC) performance in the context of other AD biomarkers, on studies investigating the relationship between episodic
177
memory performance and structural changes in GM and
118 such as CSF Ab. Large, shared, multisite, longitudinal multi- 178
modal data sets such as the AD Neuroimaging Initiative and WM using different imaging analysis approaches 179
119
(Table 1). Structural differences between CNC and partici- 180
120 similar studies initiated in Asia, Europe, and Australia allow
121 for widespread exploration of structural and functional mag- pants within AD spectrum without any episodic memory as- 181
122 netic resonance imaging (fMRI) and PET data in addition to sociations are beyond the scope of this review and will not be 182
123 clinical, cognitive, and fluid biomarker data across the spec- discussed. 183
124 184
trum of disease. While there are several limitations, these
125 2.1. GM changes 185
data sets are an important resource in understanding imaging
126 186
biomarkers in AD. Hippocampal atrophy is included in the 2011 NIA criteria Q4 187
127
Memory is a complex construct. AD has an early and spe- 188
128 for ADD and MCI due to AD [3,5]. Before the advent of Ab
129 cific impact on episodic memory (i.e., the ability to learn and PET imaging, hippocampal volumetric changes that can be 189
130 remember new information) [3], which can broadly be sub- determined noninvasively and relatively cheaply using 190
131 divided into encoding (or learning), recall, and recognition. MRI were one of the earliest detectable imaging changes 191
132 Different types of stimuli (e.g., words, faces, and shapes) and in AD. These changes can be quantified using 192
133 memory tests (e.g., single trial and multi-trial presentations, 193
NeuroQuant, an FDA-approved imaging processing tool Q5
134 free and prompted recall) can be used to detect deficits in 194
[42]. Decline in hippocampal volume and thickness has 195
135 these aspects of memory, and typically used measures often been consistently associated with memory deficits in AD 196
136 differ between clinical and research settings. Nonetheless,
137
continuum. In preclinical AD, hippocampal and entorhinal 197
many studies of AD MRI biomarkers and biomarker candi-
138 cortex volume, and hippocampal and parahippocampal 198
dates have included memory measures as correlates or vali- thickness have been associated with verbal memory 199
139
dating factors. [9,12,30]. There have also been reported associations 200
140
141 At present, despite exploration of imaging biomarkers between reduced medial temporal lobe (MTL) volume in 201
142 for AD, few have become widely accepted and approved CNC with AD risk factors and future memory decline [8]. 202
143 for clinical use, and most remain experimental. In this tar- Further along the course of the disease, in MCI and ADD, 203
144 geted review, we focused on MRI studies. Following the decline in hippocampal volume and MTL thickness was 204
145 conceptualization of AD as a biological and clinical con- 205
associated with worsening in verbal memory
146 tinuum by Aisen et al [4], we assessed the MRI findings 206
[13,16,19,21,23–27,29,33–35,39,40]. Although less 207
147 within preclinical (clinically normal individuals with evi- extensively studied, visual memory has been associated 208
148 dence of AD pathology), and clinical (mild cognitive
149
with hippocampal volume in amnestic MCI (aMCI) [39]. 209
impairment [MCI] or prodromal AD, and AD dementia
150 Studies of hippocampal subregions revealed that CA1 vol- 210
[ADD]) phases of AD. The transition between these phases ume declines within hippocampus were particularly related 211
151
is subtle, and individuals may report cognitive decline even 212
152 with recall performance in aMCI and ADD [26,29,37].
153
when neuropsychological testing does not suggest any With time, GM changes in AD spread outside the MTL. 213
154 impairment. As episodic memory is the first cognitive Extratemporal regions implicated in episodic memory 214
155 domain to be affected along the course of AD, we aimed decline include the posterior cingulate gyrus (PCG)/precu- 215
156 to investigate the association between MRI findings and neus [28,30,31] and middle frontal gyrus [27,28]. Both 216
157 episodic memory performance specifically. Current diag- 217
atrophy and thinning of these regions were associated with
158 nostic criteria of MCI (prodromal AD) and ADD are based 218
memory decline. In MCI patients, who converted to ADD 219
159 on clinical history, neuropsychological testing, and neuro- over time, decreased inferior frontal gyrus volume was 220
160 logic and psychiatric examinations [5,6]. Imaging
161
associated with the verbal memory decline [38], suggesting 221
methods, CSF, and blood tests are used only to support
162 extratemporal involvement may be predictive of disease pro- 222
the diagnosis and to exclude other dementia causes. gression. 223
163
Nevertheless, subtle findings on MRI have been reported 224
164
165 years before the onset of clinical symptoms. Thus, 225
2.2. WM changes
166 imaging findings correlating with the clinical profile may 226
167 help identify underlying mechanisms and therapeutic While AD is a disease primarily associated with GM loss, 227
targets for the debilitating memory deficit in AD. concomitant WM change has a role in cognitive expression. 228

E. Bayram et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19 3
229 Table 1 290

230 Structural MRI correlates of episodic memory 291
231 Episodic 292
232 Author, year Study groups memory test Imaging analysis method Imaging correlates of episodic memory 293
233 Q2
294
Preclinical AD
234 Jagust, 60 CNC (6 dementia Word list HC and entorhinal HC and entorhinal cortex volume predicted delayed
295
235 et al 2006 [8] or MCI converters) cortex volumetry/ recall decline over time. 296
236 (2-year follow-up) FDG-PET 297
237 Lind, 30 APOEe4 carrier, Word HC volumetry R HC volume negatively correlated with number of 298
238 et al 2006 [9] 30 noncarrier CNC categorization false alarms in APOEe4 carriers. 299
239 task 300
240 Westlye, 31 APOEe4 carrier, CVLT-II Entorhinal Entorhinal WM FA positively correlated with 301
241 et al 2012 [10] 61 noncarrier CNC cortex, memory in the APOEe4 carriers. 302
242 (3-4 year follow-up) parahippocampal 303
gyrus thickness
243 304
and WM
244 volumetry, DTI
305
245 Zhuang, 193 CNC (20 aMCI Logical Memory, VBM, DTI Lower baseline L parahippocampal cingulum, 306
246 et al 2012 [11] converters in 2 years) RAVLT inferior temporal lobe WM, parahippocampal 307
247 gyrus, thalamus FA associated with worse verbal 308
248 memory decline. L parahippocampal gyrus WM 309
249 was predictive of subsequent memory decline. 310
250 Dowell, 21 APOEe4 carrier, Word list HC and Parahippocampal thickness positively correlated 311
251 et al 2016 [12] 20 noncarrier young parahippocampus with memory in young APOEe4 carriers. 312
252 CNC, and 17 APOEe4 thickness, WM 313
carrier, 20 noncarrier volumetry
253 314
mid-age CNC
254 MCI
315
255 Chetelat, 21 aMCI Word list VBM/FDG-PET HC volume positively correlated with memory. 316
256 et al 2003 [13] 317
257 Stoub, 40 aMCI, 50 CNC East Boston HC and entorhinal Entorhinal cortex, HC and total parahippocampal 318
258 et al 2006 [14] Story, cortex volumetry, WM were significant predictors of memory. 319
259 WMS-R, WM VBM 320
260 CERAD-WL 321
261 Goldstein, 14 aMCI, 9 CNC CERAD-WL, DTI Temporal and whole brain apparent diffusion 322
262 et al 2009 [15] Story A of coefficient negatively, whole brain FA positively 323
Logical correlated with verbal memory in aMCI.
263 324
Memory,
264 BVMT-R
325
265 Wang, 10 MCI (4 ADD CERAD-WL, HC, parahippocampal MTL volume positively correlated with memory. 326
266 et al 2009 [16] converters in 3 Logical Memory gyrus, amygdala 327
267 years), 12 CNC volumetry, lobar 328
268 masking method 329
269 for frontal, lateral 330
270 temporal, parietal 331
271 occipital ROIs/SPECT 332
272 Zhuang, 76 aMCI, 51 naMCI, Logical Memory, HC DBM, fornix DTI L fornix radial diffusivity negatively correlated with 333
et al 2012 [17] 206 CNC RAVLT, Benton verbal memory.
273 334
Visual Retention
274 Test
335
275 Meyer, 25 aMCI CERAD, CANTAB, VBM Temporal WM volume positively correlated with 336
276 et al 2013 [18] WMS-R pattern recognition. Parahippocampal gyrus and L 337
277 precuneus WM volume positively correlated with 338
278 story recall. 339
279 Fujishima, 186 MCI, 136 CNC Logical Memory II Cortical thickness, L entorhinal cortex thickness positively; WMH 340
280 et al 2014 [19] WMH probability volume in the posterior periventricular regions and 341
281 map of the whole brain near the R anterior horn of the lateral ventricle 342
282 negatively correlated with memory. 343
Remy, 22 aMCI, 15 CNC RCFT, DMS48 test HC volumetry, DTI L uncinate fasciculus FA positively correlated with
283 344
et al 2015 [20] recognition.
284 Peter, 20 MCI, 20 CNC Verbal Learning HC and basal HC volume positively correlated with memory.
345
285 et al 2016 [21] and Memory Test forebrain 346
286 cholinergic 347
287 system 348
288 volumetry 349
289 (Continued ) 350

351 Table 1 412

352 Structural MRI correlates of episodic memory (Continued ) 413
353 Episodic 414
355 416
Gyebnar, 18 aMCI, 20 naMCI, CANTAB, Voxel- and ROI- Voxel-based: R inferior frontal gyrus pars
356 417
et al 2018 [22] 27 CNC RAVLT based DTI triangularis FA negatively correlated with visual
357 418
memory. L parahippocampal gyrus MD
358 negatively correlated with verbal memory. 419
359 ROI-based: Left cingulum MD negatively 420
360 correlated with verbal memory, and L stria 421
361 terminalis/crus of the fornix MD positively 422
362 correlated with visual memory. 423
363 ADD 424
364 Deweer, 18 ADD WMS, CVLT, Hippocampal Hippocampal formation volume positively correlated 425
365 et al 1995 [23] Grober and formation, with memory. 426
Buschke test amygdala,
366 427
caudate nucleus,
367 428
and ventricle
368 volumetry 429
369 Kramer, 13 ADD, 11 CVLT HC, frontal, anterior HC volume was the only predictor of delayed recall. 430
370 et al 2005 [24] frontotemporal temporal lobes, 431
371 dementia, 10 semantic and posterior 432
372 dementia, 8 CNC cortex volumetry 433
373 Sarazin, 35 ADD The Free and VBM, HC volumetry, VBM: L MTL, and thalamus volume positively 434
374 et al 2010 [25] Cued Selective and three-dimensional correlated with total recall. Automatic 435
375 Reminding Test hippocampal hippocampal volumetry: L HC volume positively 436
surface-based correlated with total recall. Three-dimensional
376 437
shape analysis hippocampal surface-based shape analysis: HC
377 438
CA1 field volume positively correlated with free Q3
378 and total recall. 439
379 Yakushev, 20 ADD, 18 CNC CERAD HC volumetry L body-tail volume positively correlated with recall 440
380 et al 2010 [26] and diffusivity in ADD. L head diffusivity negatively correlated 441
381 with delayed verbal recall. 442
382 Wolk, 146 ADD RAVLT, Logical Rostral MTL, rostral HC, MTL, caudal middle frontal gyrus, temporal 443
383 et al 2011 [27] Memory, inferior temporal pole thickness positively correlated with memory. 444
384 ADAS-Cog- gyrus, temporal 445
385 Word list pole, angular gyrus, 446
supramarginal gyrus,
386 447
superior parietal
387 448
lobule, precuneus,
388 superior frontal 449
389 gyrus, inferior 450
390 frontal sulcus/caudal 451
391 middle frontal 452
392 gyrus thickness 453
393 Irish, 11 ADD, 11 semantic Modified version VBM R frontal pole, R PCG and precuneus, L inferior 454
394 et al 2012 [28] dementia, 10 CNC of the past– temporal and L middle frontal gyri volume 455
395 future task positively correlated with past retrieval in ADD 456
and CNC.
396 457
Kerchner, 9 ADD HVLT-R, CA1-SP, CA1-SRLM, CA1- SRLM and entorhinal cortex width, HC
397 458
et al 2012 [29] BVMT-R, and entorhinal volume positively correlated with recall.
398 Logical cortex thickness; 459
399 Memory DG/CA3 and 460
400 hippocampal 461
401 cross-sectional 462
402 area (proxy for 463
403 total HC volume) 464
404 volumetry 465
405 Dore, 40 ADD, 93 CNC CVLT-II, Logical HC, temporal lobe, R temporal lobe and R precuneus/PCG thickness 466
et al 2013 [30] Memory II precuneus and positively correlated with memory in CNC with
406 467
PCG thickness high PiB retention. HC thickness positively
407 468
combined with a correlated with memory in both CNC groups.
408 voxel-based 469
409 approach/PiB PET 470
411 472

473 Table 1 534

474 Structural MRI correlates of episodic memory (Continued ) 535
475 Episodic 536
477 538
Irish, 10 ADD, 10 Modified version VBM L PCG volume positively correlated with past
478 539
et al 2013 [31] frontotemporal of the past– retrieval in ADD and CNC.
479 540
dementia, 10 CNC future task
480 MCI and ADD 541
481 Fellgiebel, 17 aMCI, 25 Delayed verbal DTI PCG bundle FA positively, MD negatively correlated 542
482 et al 2005 [32] ADD, 21 CNC recall test with memory. 543
483 Leube, 21 MCI, 12 Verbal learning VBM HC, L perirhinal cortex, L parahippocampal gyrus, L 544
484 et al 2008 [33] ADD, 29 CNC and memory test ventral anterior cingulate and R posterior 545
485 entorhinal cortex, R middle temporal gyrus 546
486 volume positively correlated with memory. 547
487 Sexton, 8 MCI, 7 ADD, 8 CNC HVLT-R, RCFT HC volumetry, HC volume, L crus of the fornix FA positively; 548
et al 2010 [34] cingulum and cingulate gyrus MD negatively correlated with
488 549
fornix DTI memory.
489 550
Molinuevo, 24 aMCI, 27 MCI CERAD-recall VBM L lateral, medial, inferior, and R medial, inferior gyri
490 et al 2011 [35] (ADD converters of constructional volume positively correlated with memory over 551
491 in 2 years), 31 ADD, praxis, delayed time. L medial temporal gyrus positively 552
492 27 CNC text memory, correlated with delayed text memory. 553
493 memory 554
494 alteration tests 555
495 Bosch, 16 aMCI, 15 ADD, CERAD-recall of DTI Whole brain FA positively correlated with memory. 556
496 et al 2012 [36] 15 CNC constructional 557
497 praxis, Grober 558
and Buschke test
498 559
Kerchner, 15 aMCI, 11 ADD, HVLT-R, BVLT-R, CA1-SP, CA1-SRLM, CA1-SRLM width positively correlated with recall in
499 560
et al 2013 [37] 9 young CNC, Logical Memory and entorhinal aMCI.
500 18 old CNC cortex thickness; 561
501 DG/CA3 and 562
502 hippocampal 563
503 cross-sectional 564
504 area volumetry 565
505 Defrancesco, 14 MCI, 13 MCI CERAD-WL, GM and WM VBM, L putamen and inferior frontal gyrus volume 566
506 et al 2014 [38] (ADD converters), CERAD-figural MD reflected by positively correlated with verbal memory in ADD 567
507 28 CNC memory apparent diffusion converters. 568
coefficient maps
508 569
Bonner-Jackson, 82 aMCI, 13 naMCI, 72 HVLT-R, BVMT-R HC volumetry Bilateral HC volume positively correlated with
509 570
et al 2015 [39] other neurological memory. HC volume positively correlated with
510 disorders, 34 non-verbal memory in aMCI. 571
511 ADD, 25 CNC 572
512 Gomar, 9 aMCI, 9 ADD, 44 CNC Relational and Entorhinal, perirhinal, HC volume, perirhinal and parahippocampal 573
513 et al 2017 [40] item-specific parahippocampal thickness predicted encoding performance. 574
514 encoding task cortices thickness, 575
515 HC volumetry 576
516 Reas, 12 MCI, 13 ADD, 31 CNC WMS-R, CVLT, Restriction spectrum Fornix, uncinated, inferior fronto-occipital, inferior 577
517 et al 2017 [41] CERAD imaging in fiber longitudinal and arcuate fasciculi neurite density 578
tracts, HC and positively correlated with recall. HC and
518 579
entorhinal cortex entorhinal cortex isotropic free water diffusion
519 580
GM; DTI negatively correlated with memory.
520 581
521 Abbreviations: MCI, mild cognitive impairment; APOEe4, apolipoprotein E e4; CNC, cognitively normal control; aMCI, amnestic mild cognitive impair- 582
522 ment; ADD, Alzheimer’s disease dementia; naMCI, nonamnestic mild cognitive impairment; CVLT, California Verbal Learning Test; RAVLT, Rey Auditory 583
523 Verbal Learning Test; WMS-R, Wechsler Memory Scale-Revised; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; CERAD-WL, CE- 584
RAD-Word list; BVMT-R, Brief Visuospatial Memory Test-Revised; CANTAB, Cambridge Neuropsychological Test Automated Battery; RCFT, Rey Complex
524 585
Figure Test; DMS48, delayed matching to sample-48 items; ADAS-Cog, Alzheimer’s Disease Assessment Scale-cognitive subscale; HVLT-R, Hopkins Verbal
525 Learning Test-Revised; HC, hippocampus; FDG-PET, fluorodeoxyglucose positron emission tomography; WM, white matter; DTI, diffusion tensor imaging;
586
526 VBM, voxel-based morphometry; ROI, region of interest; SPECT, single-photon emission computed tomography; DBM, deformation based morphometry; 587
527 WMH, white matter hyperintensity; MTL, medial temporal lobe; CA1-SP, CA1-stratum pyramidale; CA1-SRLM, CA1-stratum radiatum/stratum 588
528 lacunosum-moleculare; DG/CA3, dentate gyrus/CA3; PCG, posterior cingulate gyrus; PiB PET, Pittsburgh compound B PET; GM, gray matter; MD, mean 589
529 diffusivity; R, right; L, left; FA, fractional anisotropy. 590
530 591
531 592
532 593
533 594

595 Table 2 656

596 Task-based fMRI correlates of episodic memory 657
597 Imaging analysis 658
598 Author, year Study groups Episodic memory test method Imaging correlates of episodic memory 659
599 660
Preclinical AD
600 Han, 12 APOEe4 carrier, 13 Word pair association Whole brain, ROI Increased R anterior cingulate, lingual, middle temporal,
661
601 et al 2007 [45] noncarrier CNC (HC)/HC middle frontal gyri, PCG, precuneus and cerebellar 662
602 volumetry tonsil activation in APOEe4 carriers. 663
603 Quiroz, 20 Presenilin 1 Face-name Whole brain, ROI Increased right anterior HC activation during encoding in 664
604 et al 2010 [46] mutation carriers, association (HC) presenilin 1 mutation carriers. 665
605 19 noncarrier CNC 666
606 Adamson, 10 APOEe4 carrier, 11 Spatial encoding ROI (HC) Reduced HC activation in APOEe4 carriers. 667
607 et al 2011 [47] noncarrier CNC 668
608 Erk, 19 subjective memory Face-profession ROI (HC, DLPFC) Reduced right HC activation, increased right DLPFC 669
et al 2011 [48] impairment, 20 association activation in subjective memory impairment group.
609 670
CNC
610 Chen, 35 APOEe4 carrier, 40 Picture encoding Seed ROI based on Reduced precuneus deactivation, reduced postcentral,
671
611 et al 2017 [49] noncarrier CNC group cortical precentral, inferior occipital gyri, inferior parietal 672
612 morphology lobule activation in APOEe4 carriers. 673
613 differences and 674
614 DMN/cortical 675
615 thickness 676
616 MCI 677
617 Johnson, 14 MCI, 14 CNC Picture encoding Reference group Reduced R HC head and body, L lateral frontal, R 678
618 et al 2006 [50] activation inferior temporal lobe activation in MCI during novel 679
pictures. Reduced R PCG/precuneus activation during
619 680
previously learned items in MCI.
620 Petrella, 2006 20 aMCI, 20 CNC Face-name Whole brain Reduced frontal cortex, L cerebellum activation during
681
621 et al [51] association encoding. Reduced frontal lobe, L HC; increased 682
622 posterior frontal lobe activation during retrieval. 683
623 Heun, 21 MCI, 29 CNC Verbal encoding Whole brain Increased R superior, inferior and L middle frontal gyri 684
624 et al 2007 [52] activation in MCI. 685
625 Kircher, 21 MCI, 29 CNC Verbal encoding Whole brain Increased L HC, medial frontal, postcentral and 686
626 et al 2007 [53] cingulate gyri activation in MCI 687
627 Dannhauser, 10 aMCI, 10 CNC Verbal encoding Whole brain Reduced L ventrolateral PFC activation stretching into 688
628 et al 2008 [54] premotor cortex in aMCI. 689
Trivedi, 16 aMCI, 23 CNC Picture encoding Whole brain, ROI Reduced inferior frontal, R inferior parietal and
629 690
et al 2008 [55] (frontal cortex, parahippocampal cortex activation in aMCI during
630 MTL, PCG, encoding. Reduced L inferior frontal cortex; increased
691
631 inferior parietal R HC activation in aMCI during recognition. 692
632 cortex) 693
633 Machulda, 19 aMCI, 12 naMCI, Scene encoding Whole brain Reduced temporoparietal and frontal activation in MCI 694
634 et al 2009 [56] 29 CNC during encoding. Reduced temporoparietal activation 695
635 in aMCI during recognition. 696
636 Mandzia, 14 MCI, 14 CNC Object and animal ROI (HC and Reduced L superior and middle temporal, R middle 697
637 et al 2009 [57] encoding parahippocampal temporal gyri, precuneus, L cuneus, anterior 698
638 gyrus) cingulate, R lentiform nucleus, caudate and putamen 699
activation during deep encoding. Reduced L
639 700
parahippocampal, fusiform, R middle temporal gyri,
640 R inferior frontal, inferior parietal regions, caudate, L
701
641 cerebellum, middle occipital gyrus and cuneus 702
642 activation during shallow encoding. Reduced L HC, 703
643 superior and middle frontal, R lateral inferior and 704
644 medial frontal gyri, cingulate, L thalamus and middle 705
645 occipital gyrus activation in during deeply encoded 706
646 item recognition. Reduced L lentiform nucleus and 707
647 putamen; increased L fusiform and superior frontal, R 708
648 cingulate gyri activation during shallowly encoded 709
item recognition.
649 710
Clement and 28 MCI, 12 CNC Word pair association Whole brain, ROI Increased R dorsolateral, ventrolateral PFC, premotor
650 Belleville, (HC) and motor area activation MCI with higher cognition
711
651 2010 [58] scores. Reduced R occipital lobe and L inferior 712
652 parietal lobule; increased dorsal L inferior parietal 713
653 lobule activation in MCI with lower cognition scores. 714
654 Increased L temporal regions, R precentral gyrus, 715

717 Table 2 778

718 Task-based fMRI correlates of episodic memory (Continued ) 779
721 782
dorsolateral PFC, L inferior and bilateral superior
722 783
parietal lobules activation in the MCI with higher
723 784
cognition scores compared with MCI with lower
724 scores. 785
725 Clement, 12 MCI, 10 CNC Verbal encoding Whole brain, ROI Reduced occipital lobe, R middle and superior temporal 786
726 et al 2010 [59] (HC) gyri, R thalamus, R anterior cingulate, R medial 787
727 frontal lobe; increased L ventrolateral PFC activation 788
728 during encoding. Reduced medial frontal lobe; 789
729 increased premotor area activation during retrieval. 790
730 Yassa, 10 aMCI, 10 CNC Picture encoding ROI (L CA3/DG, Increased CA3/DG and reduced entorhinal cortex 791
731 et al 2010 [60] CA1, subiculum, activation. 792
entorhinal cortex)
732 793
Hampstead, 18 aMCI, 16 CNC Object-location Whole brain, ROI Reduced ventral and dorsal visual streams, frontal areas,
733 794
et al 2011 [61] association (HC) dorsal precuneus, HC, perirhinal cortex, PCG,
734 retrosplenial cortex, thalamus; increased mid- 795
735 precuneus and L temporoparietal junction activation. 796
736 Hanseeuw, 16 aMCI, 16 CNC Verbal encoding Whole brain/HC HC volume positively correlated with associative 797
737 et al 2011 [62] volumetry memory in aMCI. Reduced L anterior HC activation. 798
738Q6 Lenzi, 15 aMCI, 14 CNC Verbal encoding, Whole brain, ROI Increased R superior temporal gyrus activation. This 799
739 et al 2011 [83] Story Recall (HC, L inferior activation negatively correlated with Story Recall. 800
740 temporal, R 801
741 superior temporal 802
gyri)/VBM
742 803
Giovanello, 12 aMCI, 12 CNC Word pair association Whole brain Reduced R inferior and superior frontal gyri, increased
743 804
et al 2012 [63] anterior cingulate and inferior frontal gyrus activation.
744 Jin, 8 aMCI, 8 CNC Scene encoding, face- Whole brain, ROI Reduced MTL; increased medial PFC, L precentral and 805
745 et al 2012 [64] occupation and (MTL) superior motor area activation during scene encoding. 806
746 object-location Increased L angular gyrus, R cuneus/precuneus 807
747 association activation during face-occupation task. Reduced R 808
748 Rolandic operculum, insula; increased precentral and 809
749 postcentral gyri activation during the object-location 810
750 task. 811
751 ADD 812
Rombouts, 12 ADD, 10 CNC Picture encoding Whole brain Reduced activation in L HC and bilateral
752 813
et al 2000 [65] parahippocampal gyrus.
753 814
Kato, 7 ADD, 8 young CNC, Picture encoding Whole brain/ Reduced R entorhinal cortex, supramarginal gyrus,
754 et al 2001 [66] 8 old CNC hippocampal prefrontal regions, L anterior inferior temporal lobe 815
755 formation and activation during encoding. Activations in these 816
756 entorhinal cortex regions positively correlated with memory in the 817
757 volumetry overall sample. 818
758 Gron, 12 ADD, 12 major Geometric pattern Whole brain Reduced parahippocampal gyrus, HC, temporal cortex, 819
759 et al 2002 [67] depressive disorder encoding R anterior caudate; increased L middle frontal, R 820
760 patients, 12 CNC inferior frontal gyri and inferior parietal cortex 821
761 activation. 822
Lustig, 23 ADD, 32 young Verbal encoding ROI (lateral Reduced medial parietal/PCG deactivation.
762 823
et al 2003 [68] CNC, 27 old CNC parietotemporal,
763 824
medial frontal,
764 medial parietal/ 825
765 PCG, L frontal 826
766 region) 827
767 Sperling, 7 ADD, 10 young Face-name Whole brain/HC Reduced hippocampal formation; increased medial 828
768 et al 2003 [69] CNC, 10 old CNC association volumetry parietal cortex, R PCG, superior frontal cortex 829
769 activation during encoding. Increased superior frontal 830
770 cortex activation during recall. 831
771 Golby, 7 ADD, 7 CNC Scene encoding Whole brain, ROI Reduced MTL, fusiform, lateral occipital activation. 832
et al 2005 [70] (hippocampal
772 833
gyrus,
773 834
parahippocampal
774 gyrus, entorhinal 835
775 cortex, subiculum, 836
777 838

839 Table 2 900

843 904
fusiform gyrus,
844 905
calcarine cortex)
845 906
Gould, 12 ADD, 12 CNC Visuospatial paired Whole brain No differences.
846 et al 2005 [71] association 907
847 Pariente, 12 ADD, 17 CNC Face-name Whole brain Increased parietofrontal network activation during 908
848 et al 2005 [72] association encoding. Reduced R HC, increased L parietal lobule 909
849 and the L inferior frontal gyrus activation during 910
850 recall. 911
851 Remy, 8 ADD, 11 CNC Verbal encoding Whole brain/VBM, Reduced inferior parietal cortex, inferior frontal gyrus, L 912
852 et al 2005 [73] HC volumetry precentral gyrus, R temporal associative area, L PCG, 913
853 L perirhinal cortex, and cerebellum; increased medial 914
cerebellum and L middle frontal gyrus activation
854 915
during encoding. Reduced L inferior frontal and
855 916
precentral gyri, R lenticular nucleus, R HC and
856 retrosplenial cortex, R inferior parietal cortex, 917
857 superior temporal gyrus and cerebellum; increased 918
858 inferior temporal gyrus, L lateral middle and superior 919
859 frontal gyri activation during recognition. 920
860 Gould, 12 ADD, 12 CNC Visuospatial paired Whole brain, ROI Increased L medial and R lateral prefrontal cortex 921
861 et al 2006 [74] association (bilateral inferior, activation during encoding. 922
862 middle, superior 923
863 frontal gyri, medial 924
prefrontal cortex)
864 925
Pihlajamaki, 15 ADD, 29 CNC Face-name Whole brain, ROI (HC Whole brain: Increased middle and inferior prefrontal
865 926
et al 2008 [75] association and medial parietal gyri, L superior parietal lobule, intraparietal sulcus
866 regions) and supramarginal gyrus activation. ROI: Increased L 927
867 MTL activation. Reduced precuneus, R PCG, L lateral 928
868 parietal cortex deactivation. 929
869 Peters, 16 ADD, 16 CNC Verbal encoding Whole brain, ROI Reduced middle frontal, L inferior frontal and transverse 930
870 et al 2009 [76] (inferior frontal, temporal gyri, R precuneus activation during 931
871 precentral, middle encoding. Reduced supplementary motor area, 932
872 frontal gyri, insula, superior frontal, precentral, supramarginal, L 933
873 posterior parietal, postcentral and R middle frontal gyri; increased 934
caudate, fusiform gyrus activation during recognition.
874 935
cerebellum,
875 936
inferior parietal
876 sulcus, HC, 937
877 parahippocampus) 938
878 MCI and ADD 939
879 Machulda, 9 MCI, 9 ADD, 11 Picture encoding ROI (HC, Reduced MTL activation in MCI and ADD. 940
880 et al 2003 [77] CNC parahippocampal 941
881 and fusiform gyri) 942
882 Dickerson, 9 MCI, 10 ADD, 10 Face-name ROI (hippocampal Increased HC activation in MCI. Reduced HC and 943
883 et al 2005 [78] CNC association formation, entorhinal activation in ADD. 944
entorhinal cortex)/
884 945
MTL volumetry
885 946
Celone, 15 low-CDR MCI, 12 Face-name Whole brain, ROI Increased HC and functionally connected neocortical
886 et al 2006 [79] high-CDR MCI, 10 association (determined by regions activation, increased DMN deactivation in 947
887 ADD, 15 CNC regions MCI group with low CDR. Reduced HC activation 948
888 contributing and DMN deactivation in MCI group with high CDR 949
889 significantly to the and ADD. 950
890 independent 951
891 components) 952
892 Hamalainen, 14 MCI, 15 ADD, 21 Picture-name Whole brain Increased thalamus and L ventral visual stream 953
893 et al 2007 [80] CNC association extending to the posterior parahippocampal gyrus and 954
HC activation in MCI.
894 955
Petrella, 34 aMCI, 13 ADD, 28 Face-name Whole brain Reduced MTL; increased the posteromedial cortex
895 956
et al 2007 [81] CNC association, CVLT activation along the spectrum from CNC to ADD.
896 Posteromedial cortex activation magnitude associated 957
897 with CVLT. 958
899 960

961 Table 2 1022

965 1026
Pihlajamaki and 30 MCI (10 APOEe4 Face-name ROI (PCG, Reduced L precuneus in MCI; bilateral PCG/precuneus
966 1027
Sperling, 2009 [82] carriers), 15 ADD association retrosplenial and deactivation in ADD. Reduced R PCG and bilateral
967 1028
(9 APOEe4 precuneal regions) precuneus deactivation in APOEe4 carrier CNC
968 carriers), 29 CNC compared to noncarrier CNC; reduced cuneus 1029
969 (8 APOEe4 deactivation in APOEe4 carrier ADD compared to 1030
970 carriers) noncarrier ADD. 1031
971 1032
Abbreviations: APOEe4, apolipoprotein E e4; CNC, cognitively normal control; MCI, mild cognitive impairment; aMCI, amnestic mild cognitive impair-
972 1033
ment; naMCI, nonamnestic mild cognitive impairment; ADD, Alzheimer’s disease dementia; CDR, Clinical Dementia Rating; CVLT, California Verbal
973 Learning Test; ROI, region of interest; HC, hippocampus; DLPFC, dorsolateral prefrontal cortex; DMN, default mode network; MTL, medial temporal
1034
974 lobe; PCG, posterior cingulate gyrus; DG, dentate gyrus; L, left; R, right; VBM, voxel-based morphometry; PFC, prefrontal cortex. 1035
975 1036
976 1037
977 1038
Diffusion tensor imaging metrics characterizing brain WM changes, including loss of WM integrity in MTL and
978 1039
integrity are commonly affected in the AD continuum. fasciculi connected to MTL assessed by formal diffusion
979 1040
980 Increased WM integrity for the whole brain was associated tensor imaging metrics and hyperintensities in posterior re- 1041
981 with better memory performance in CNC, MCI, and ADD, gions of the brain, were also related to memory decline 1042
982 suggesting whole brain fractional anisotropy might be an and should be assessed further in confirmed AD samples. 1043
983 overall marker of severity, rather than a specific measure 1044
984 [15,36]. 1045
3. Functional MRI
985 Genetic status may mediate the relationship between 1046
986 MRI findings and cognition. In APOEe4 carriers, loss of en- fMRI is an indirect measure of brain activity relying on 1047
987 torhinal WM integrity was related to worse memory perfor- blood-oxygen-level dependent response, which is a proxy 1048
988 mance [10]. However, other factors such as lower baseline 1049
for neural activation. fMRI can be separated into task-
989 1050
MTL WM integrity have also been identified as predictors based, when a participant is asked to engage in a task during
990 1051
of memory decline in CNC converting to aMCI in 2 years scanning, or resting state, when the participant is asked to lie
991 1052
992 [11], which can have the potential to be used as a biomarker still without engaging in a task. In this section, we will sum- 1053
993 for early diagnosis. MTL WM volume and integrity marize studies finding differences between those with pre- 1054
994 continued to have positive correlations with memory in clinical or clinical AD and CNC, either on memory tasks 1055
995 aMCI and ADD [14,17,18,26,32,34]. Similar to GM during fMRI, or with resting state fMRI interpreted in rela- 1056
996 changes, which include both MTL and extratemporal tion to memory scores. 1057
997 regions, precuneus WM volume reduction was also 1058
998 associated with worsened memory in aMCI [18]. Several 1059
999 3.1. Task-based fMRI 1060
fasciculi including uncinate, fornix, and cingulum, which
1000 are connected to medial temporal regions, were implicated Many studies have implemented task-based fMRI to 1061
1001 1062
in studies associating fiber density and memory [20,22,41]. investigate memory-related activation patterns in AD
1002 1063
In addition to these WM volume and integrity changes, (Table 2). A variety of tasks have been used, most notably as-
1003 1064
1004 Fujishima et al [19] reported that increased number of sociation tasks that pair two different stimuli (e.g., a face and 1065
1005 WMHs, pointing to increased vascular impairment, in the a name). Whereas most studies include verbal stimuli, 1066
1006 bilateral periventricular regions was related to worse recall several studies use nonverbal stimuli (e.g., scene and picture 1067
1007 performance in MCI. encoding). Results of these studies support and extend the 1068
1008 Besides these more common MRI techniques, other ap- previously mentioned structural MRI findings. 1069
1009 proaches including diffusion kurtosis imaging, relaxometry, 1070
1010 and magnetic transfer imaging may prove to be helpful in 3.1.1. Preclinical AD 1071
1011 investigating WM integrity with high accuracy for whole Individuals with AD risk exhibit changes in blood- 1072
1012 brain mapping [43,44]. However, the number of studies oxygen-level dependent responses even before the onset of 1073
1013 using these approaches within the AD continuum is memory deficits. These changes are nonlinear, with different 1074
1014 1075
currently relatively small. activation patterns in MTL and heightened activation in
1015 1076
1016 In summary, structural imaging studies show that hippo- frontal lobes sometimes reported. For example, reduced 1077
1017 campal atrophy, which is closely related to episodic memory deactivation of PCG/precuneus [45,49,82], increased 1078
1018 performance, is an established neurodegeneration biomarker frontal activation [45], and altered MTL activation have all 1079
1019 in AD. Volume and cortical thickness of several additional been reported, with one study reporting hyperactivation 1080
1020 regions, including PCG and precuneus, require further atten- [45] and another reporting hypoactivation in preclinical 1081
1021 tion in terms of relationship to memory performance. WM APOEe4 carriers [47]. Both presenilin 1 mutation carriers 1082

1083 and individuals with subjective memory impairment had during verbal or visual encoding and recognition 1144
1084 hippocampal hypoactivation [46,48]. Frontal [66,73,76]. Although results are not consistent, there 1145
1085 hyperactivation was also observed in individuals with seems to be a tendency for frontal hyperactivation 1146
1086 subjective memory impairment [48]. These activation pat- [67,69,72,74,75]. 1147
1087 1148
terns in preclinical AD are suggestive of compensatory Overall, task-based fMRI findings suggest that episodic
1088 1149
mechanisms within these regions which are capable of main- memory tasks lead to MTL hypoactivation, frontal hyperac-
1089 1150
1090 taining normal levels of cognition. tivation, and reduced PCG/precuneus deactivation in ADD. 1151
1091 Although preclinical AD and MCI samples have activation 1152
1092 3.1.2. Mild cognitive impairment differences within these regions, the results are not consis- 1153
1093 Both hypoactivation [50,51,57,59,61,62,64,77] and tent yet to provide early diagnosis or disease-tracking 1154
1094 hyperactivation [53,78,80,83] of the MTL during memory biomarker candidates. The discrepancy of the results appear 1155
1095 tasks have been reported in MCI. This difference may be a to be caused by inclusion of mixed patient samples, distinct 1156
1096 result of the particular memory process being assessed, as verbal and visual memory tasks, and implementing different 1157
1097 suggested by a study by Trivedi et al [55] reporting hypoac- analysis methods for imaging. In conclusion, task-based 1158
1098 tivation of parahippocampal cortices during encoding and fMRI seems like a promising tool which can detect early 1159
1099 1160
hyperactivation of hippocampus during recognition in changes along the AD continuum requiring further investi-
1100 1161
aMCI. A study showing CA3/dentate hyperactivation and gations for biomarker research in AD.
1101 1162
1102 entorhinal hypoactivation also suggested that discrepant 1163
1103 findings in MTL may be caused by different activation pat- 1164
3.2. Resting state fMRI
1104 terns in MTL structures and hippocampal subregions [60]. 1165
1105 The discrepancy may also be due to the mixed sample of By its nature, resting state fMRI (rsfMRI) does not 1166
1106 MCI patients included in the studies. For example, MCI pa- involve a task, but the connectivity metrics calculated from 1167
1107 tients with lower dementia score as determined by Clinical these data can be used to assess relationships with memory 1168
1108 Dementia Rating had hippocampal hyperactivation and tasks completed outside of the scanner (Table 3). This tech- 1169
1109 decreased default mode network (DMN) deactivation, nique allows the investigation of functional connectivity be- 1170
1110 whereas the activation pattern was completely opposite in tween two regions and/or within specific networks impaired 1171
1111 1172
MCI patients with higher dementia scores [79]. in AD.
1112 1173
Similar to MTL, while some studies show reduced PCG/
1113 1174
1114 precuneus activation [50,61,64], some report 3.2.1. Preclinical AD 1175
1115 hyperactivation or reduced deactivation within these In APOEe4 carriers, verbal memory decline was related 1176
1116 regions [53,81,82,84]. PCG/precuneus is part of the DMN, to reduced anterior and posterior connectivity as shown by 1177
1117 and hyperactivation of these areas is possibly due to whole brain dynamic functional connectivity [87]. Studies 1178
1118 reduced deactivation of the DMN while performing a task. using seed-based analysis reported that verbal memory 1179
1119 Frontal cortex activation is usually reduced [50,51,54– decline was associated with reduced left medial temporal gy- 1180
1120 57,59,61,63] while several studies show hyperactivation in rus; and DMN and executive control network connectivity 1181
1121 several frontal regions including precentral gyrus [85,86]. When episodic memory performance related to 1182
1122 [51,52,59,64]. Dividing the MCI sample into two groups structural changes within DMN regions, reduced 1183
1123 1184
depending on cognitive performance, Clement and deactivation shown by task-based fMRI and connectivity
1124 1185
Belleville [58] revealed that frontal activation during a ver- decline of this network shown by rsfMRI are considered
1125 1186
1126 bal memory task was decreased in MCI patients with more altogether, this network appears to play a significant role 1187
1127 cognitive decline. Temporoparietal regions are also reported in AD and could be used for early diagnosis. 1188
1128 to be affected with some studies showing hypoactivation of 1189
1129 these regions during picture or scene encoding tasks [55– 3.2.2. Clinical AD 1190
1130 57,64] and some reporting hyperactivation [61]. These find- The relationship between DMN connectivity reduction 1191
1131 ings suggest that future studies may benefit from better and episodic memory decline persisted in MCI 1192
1132 defined samples instead of including different types of [88,93,101,104] and ADD [100,101,104]. Longitudinal 1193
1133 MCI (aMCI and naMCI) patients with various levels of de- studies showed that the progression of memory decline in 1194
1134 mentia. aMCI was related to the decline of functional connectivity 1195
1135 between PCC and other DMN regions [88], precentral gyrus Q7 1196
1136 1197
3.1.3. Alzheimer’s disease dementia [99], hippocampal formation [94], and hippocampus subre-
1137 1198
1138 In ADD, MTL hypoactivation [65–67,69,70,72,77– gions [89]. Xie et al investigated the connectivity between 1199
1139 79,81] and PCG/precuneus hyperactivation [69,81] or regions with atrophy in aMCI and revealed that both atrophy 1200
1140 reduced deactivation [68,75,82] are the most consistent of hippocampus, precuneus, insula, postcentral gyrus, and 1201
1141 findings. Affected regions are not limited to these more frontal regions and connectivity reduction between these re- 1202
1142 commonly reported areas in the brain. Activation in frontal gions were associated with worse memory performance. 1203
1143 regions including prefrontal and motor areas were altered Decreased MTL connectivity with locus coeruleus [95], 1204

1205 1266
Table 3
1206 1267
rsfMRI correlates of episodic memory
1207 1268
1208 Episodic 1269
1210 Preclinical AD 1271
1211 Goveas, 20 APOEe4 RAVLT Seed-based voxel-wise connectivity DMN connectivity positively correlated with 1272
1212 et al 2013 [85] carrier, 26 analysis (DMN-PCG, ECN-R memory. ECN: Operculum clusters and R 1273
1213 noncarrier CNC dorsolateral PFC, Salience inferior/superior parietal cortex clusters 1274
1214 network-R orbital anterior insula)/ negatively, R inferior temporal gyrus 1275
VBM positively correlated with memory.
1215 1276
Matura, 20 APOEe4 Word list Seed-based functional connectivity L medial temporal gyrus connectivity
1216 1277
et al 2014 [86] carrier, 43 (L PCG) positively correlated with recognition.
1217 noncarrier CNC 1278
1218 Quevenco, 13 APOEe4 carrier, Verbal Whole brain dynamic functional Anterior-posterior connectivity positively 1279
1219 et al 2017 [87] 24 noncarrier Learning connectivity/PiB PET correlated with memory. 1280
1220 CNC (2-year and Memory 1281
1221 follow-up) Test 1282
1222 MCI 1283
1223 Bai, 26 aMCI, 18 CNC AVLT, RCFT ICA Reduced connectivity between PCG/ 1284
1224 et al 2011 [88] (20-month follow-up) precuneus and mean DMN independent 1285
components over time was correlated with
1225 1286
episodic memory decline in the aMCI.
1226 1287
Bai, 26 aMCI, 18 CNC AVLT, RCFT Seed-based functional connectivity Reductions in baseline hyperfunctional
1227 et al 2011 [89] (20-month follow-up) (HC subregions; CA, DG and connectivity between the PCG/precuneus 1288
1228 subiculum) and mean DMN independent components 1289
1229 in aMCI were positively correlated with 1290
1230 memory decline over time. 1291
1231 Agosta, 12 aMCI, 13 CNC Babcock Story ICA No associations. 1292
1232 et al 2012 [90] Recall, 1293
1233 RAVLT, RCFT 1294
1234 Liang, 16 MCI, 16 CNC CVLT Seed-based functional connectivity Angular gyrus and R precuneus connectivity 1295
et al 2012 [91] (inferior parietal cortex, angular negatively correlated with CVLT in MCI.
1235 1296
gyrus, supramarginal gyrus)/VBM
1236 1297
Xie, 30 aMCI, 26 CNC RAVLT, RCFT Seed-based functional connectivity Intrinsic connectivity of insula positively
1237 et al 2012 [92] (insula subregions) correlated with memory in aMCI. 1298
1238 Wang, 18 aMCI, 23 euthymic CVLT-II ICA/VBM DMN connectivity positively correlated with 1299
1239 et al 2013 [93] CNC, 16 CNC CVLT-II. Positive correlations were most 1300
1240 evident in the R HC, R hippocampal gyrus 1301
1241 and R thalamus. 1302
1242 Dunn, 24 aMCI, 33 naMCI RAVLT Seed-based functional connectivity PCG-hippocampal formation connectivity 1303
1243 et al 2014 [94] (DMN-PCG, anteromedial strength positively correlated with 1304
1244 prefrontal cortex; MTL- retrieval in aMCI. 1305
hippocampal formation,
1245 1306
parahippocampal gyrus,
1246 1307
retrosplenial cortex, posterior
1247 intraparietal lobule, ventromedial 1308
1248 PFC; dorsal medial PFC 1309
1249 subsystem-dorsomedial PFC, 1310
1250 lateral temporal cortex, 1311
1251 temporoparietal junction, temporal 1312
1252 pole)/HC volumetry 1313
1253 Jacobs, 18 aMCI, 18 CNC Verbal word Seed-based functional connectivity R locus coeruleus-L parahippocampal gyrus 1314
1254 et al 2015 [95] learning task (locus coeruleus)/GM volumetry connectivity positively correlated with 1315
memory in aMCI.
1255 1316
Xie, 30 aMCI, 26 CNC Auditory Verbal Seed-based functional connectivity GM volume and intrinsic connectivity
1256 1317
et al 2015 [96] Memory Test, (regions with atrophy in aMCI positively correlated with memory.
1257 RCFT determined by VBM; bilateral 1318
1258 precuneus and insula, L postcentral 1319
1259 gyrus, medial frontal gyrus, middle 1320
1260 frontal gyrus and HC) 1321
1261 Dillen, 24 aMCI, 27 subjective WMS-IV Logical Seed-based functional connectivity Retrosplenial and frontal medial, L lateral 1322
1262 et al 2016 [97] cognitive impairment, memory and (retrosplenial cortex, PCG)/GM occipital cortex connectivities positively 1323
1263 25 CNC Design memory, volumetry correlated with verbal learning in MCI. 1324
1264 Verbal learning 1325
memory test
1265 1326
(Continued )

1327 Table 3 1388

1328 rsfMRI correlates of episodic memory (Continued ) 1389
1329 Episodic 1390
1331 1392
Franzmeier, 44 Ab 1 aMCI, RAVLT, ADAS, Seed-based functional connectivity At low levels of L frontal cortex connectivity,
1332 1393
et al 2017 [98] 24 Ab- CNC WMS Logical (L frontal cortex)/FDG-PET lower precuneus hypometabolism was
1333 1394
Memory I and associated with worse memory; at high
1334 II, MMSE levels of L frontal cortex connectivity, the 1395
1335 effect was reduced. 1396
1336 Zhang, 32 aMCI, 40 CNC AVLT Seed-based functional connectivity R PCG connectivity with the L and R central 1397
1337 et al 2017 [99] (R PCG) sulci, L precentral gyrus positively 1398
1338 correlated with recall in aMCI. 1399
1339 ADD 1400
1340 Balthazar, 22 ADD, 26 CNC RAVLT Seed-based functional connectivity DMN connectivity positively correlated with 1401
1341 et al 2014 [100] (PCG) memory scores in the overall sample. 1402
MCI and ADD
1342 1403
Binnewijzend, 23 MCI, 39 ADD, RAVLT ICA Regional connectivity within the DMN
1343 1404
et al 2012 [101] 43 CNC (2.8 year positively correlated with memory.
1344 follow-up; 7/23 1405
1345 MCI converted 1406
1346 to ADD) 1407
1347 Pasquini, 22 MCI, 21 ADD, CERAD-WL ICA Local intrinsic functional connectivity of the 1408
1348 et al 2015 [102] 22 CNC HC negatively correlated with recall in 1409
1349 ADD. 1410
1350 Zhang, 76 aMCI, 19 ADD, RAVLT, MMSE, Functional connectivity between Medial frontal gyrus and parahippocampus 1411
1351 et al 2016 [103] 23 CNC ADAS, Logical 18ROIs/Ab PET, APOEe4 status functional connectivity negatively 1412
Memory I and II correlated with memory in aMCI and
1352 1413
ADD.
1353 1414
Contreras, 21 aMCI, 8 ADD, 16 CVLT-II ICA (resting-state network, visual DMN and frontoparietal network
1354 et al 2017 [104] subjective cognitive network, DMN and frontoparietal connectivity positively correlated with 1415
1355 decline, 13 CNC network) recall. 1416
1356 1417
1357 Abbreviations: APOEe4, apolipoprotein E e4; CNC, cognitively normal control; aMCI, amnestic mild cognitive impairment; MCI, mild cognitive impair- 1418
ment; naMCI, nonamnestic mild cognitive impairment; Ab, amyloidb; ADD, Alzheimer’s disease dementia; RAVLT, Rey Auditory Verbal Learning Test;
1358 1419
AVLT, Auditory Verbal Learning Test; RCFT, Rey Complex Figure Test; CVLT, California Verbal Learning Test; WMS, Wechsler Memory Scale; ADAS,
1359 Alzheimer’s Disease Assessment Scales; MMSE, Mini–Mental State Examination; CERAD-WL, Consortium to Establish a Registry for Alzheimer’s
1420
1360 Disease-Word list; DMN, default mode network; ECN, executive control network; PCG, posterior cingulate gyrus; R, right; PFC, prefrontal cortex; VBM, 1421
1361 voxel-based morphometry; L, left; PiB PET, Pittsburgh compound B positron emission tomography; ICA, independent component analysis; HC, hippocampus; 1422
1362 DG, dentate gyrus; MTL, medial temporal lobe; HC, hippocampus; GM, gray matter; FDG-PET, fluorodeoxyglucose positron emission tomography; ROI, re- 1423
1363 gion of interest. 1424
1364 1425
1365 1426
1366 frontal medial cortex, and lateral occipital cortex [97] was related to memory decline, whereas MTL connectivity re- 1427
1367 1428
associated with worse verbal memory scores. Focusing on sults are not that consistent throughout the AD continuum.
1368 1429
insula subregions revealed that increased intrinsic connec- Whereas preclinical and prodromal AD samples have
1369 1430
1370 tivity of insula was also associated with better memory per- reduced connectivity in association with worse memory per- 1431
1371 formance [92]. Combining both rsfMRI and FDG-PET formance, this pattern in reversed in ADD. Although DMN 1432
1372 approaches, Franzmeier et al [98] revealed an interaction be- findings are rather consistent, there is still a need for more 1433
1373 tween functional connectivity of frontal cortex and precu- studies with sufficient power before rsfMRI can provide a 1434
1374 neus hypometabolism. With decreased frontal connectivity, reliable AD biomarker or tracking tool. Future studies may 1435
1375 precuneus hypometabolism was associated with reduced benefit from combining rsfMRI with other imaging tech- 1436
1376 memory performance, whereas this association was lower niques, including FDG-PET, and defining patient samples 1437
1377 at higher levels of frontal connectivity in aMCI. This study better by supporting the clinical criteria with established 1438
1378 suggests that memory performance does not only rely on structural MRI, PET, and CSF findings. 1439
1379 functional connectivity but also metabolism of DMN re- 1440
1380 1441
gions. Finally, in contrast to findings in aMCI, worse mem-
1381 4. Molecular MRI 1442
1382 ory performance was associated with increased middle 1443
1383 frontal gyrus and parahippocampus connectivity [103], and Proton magnetic resonance spectroscopy can be used to 1444
1384 intrinsic hippocampal connectivity [102] in ADD. assess changes in cell-specific metabolites, including choline, 1445
1385 To summarize, rsfMRI findings have revealed that MTL creatine, glutamine, glutamate, glutathione, N-acetyl aspar- 1446
1386 and DMN connectivity changes in AD are related to episodic tate (NAA), and myo-inositol. Levels of NAA, reflecting 1447
1387 memory. Reductions in DMN connectivity are closely neuronal loss or dysfunction, decrease in AD; whereas 1448

1449 Table 4 1510

1450 Molecular MRI correlates of episodic memory 1511
1451 Episodic 1512
1453 1514
MCI
1454 Didic, 28 aMCI, 28 CNC DMS48 NAA/MI in hippocampal formation and Anterior subhippocampal cortex and L
1515
1455 et al 2010 [108] perirhinal/entorhinal cortices anterior HC NAA/MI positively correlated 1516
1456 with memory in the overall sample. 1517
1457 Duffy, 54 MCI, 41 CNC RAVLT GSH in anterior and posterior cingulate PCG GSH negatively correlated with 1518
1458 et al 2014 [107] memory. 1519
1459 ADD 1520
1460 Chantal, 14 ADD, 14 CNC CVLT NAA, Cho, Cr, MI in MTL L HC NAA positively correlated with 1521
1461 et al 2002 [109] memory. 1522
1462 MCI and ADD 1523
Rami, 27 aMCI, 35 Text Memory Test, MI/Cr ratio, NAA in PCG, L temporal pole L temporal pole MI/Cr ratio negatively
1463 1524
et al 2007 [110] ADD, 27 CNC Wordlist and L posterior temporoparietal region correlated with encoding. PCG NAA
1464 Learning Test, positively, MI/Cr ratio in all of the regions
1525
1465 Memory negatively correlated with memory 1526
1466 Alteration Test alteration. 1527
1467 Foy, 21 MCI, 39 CERAD NAA, MI, Cho, Cr 1 phosphocreatine in HC NAA positively correlated with memory in 1528
1468 et al 2011 [111] ADD, 38 CNC MCI and ADD. 1529
1469 Lim, 16 aMCI, 23 Seoul Verbal NAA/Cr ratio in PCG NAA/Cr positively correlated with memory 1530
1470 et al 2012 [112] ADD, 22 CNC Learning Test, in the overall sample. 1531
1471 HVLT-R 1532
1472 Watanabe, 42 aMCI, 67 WMS-R NAA (N-acetylaspartate and N- HC NAA positively, MI negatively correlated 1533
et al 2012 [113] ADD, 54 CNC acetylaspartylglutamate), MI in HC and with memory in the overall sample.
1473 1534
PCG
1474 Jahng, 24 aMCI, 24 Face-name Functional MRS; glutamine and glutamate NAA and Cr highest in young CNC, and
1535
1475 et al 2016 [114] ADD, 23 association complex, NAA, Cr, MI in PCG/precuneus lowest in AD (AD , aMCI , old 1536
1476 young CNC, CNC , young CNC) during the task. 1537
1477 24 old CNC 1538
1478 1539
Abbreviations: aMCI, amnestic mild cognitive impairment; CNC, cognitively normal control; MCI, mild cognitive impairment; ADD, Alzheimer’s disease
1479 1540
dementia; DMS48, delayed matching to sample-48 items; RAVLT, Rey Auditory Verbal Learning Test; CVLT, California Verbal Learning Test; CERAD,
1480 Consortium to Establish a Registry for Alzheimer’s Disease; HVLT-R, Hopkins Verbal Learning Test-Revised; WMS-R, Wechsler Memory Scale-Revised; 1541
1481 NAA, N-acetylaspartate; MI, myo-inositol; GSH, glutathione; Cho, choline; Cr, creatine; PCG, posterior cingulate gyrus; L, left; HC, hippocampus; MRS; mag- 1542
1482 netic resonance spectroscopy. 1543
1483 1544
1484 1545
1485 increased myo-inositol levels, reflecting glial cell activation, glutathione levels with decreased memory performance are 1546
1486 have been reported in MCI and AD [105,106]. Glutathione suggestive of early compensation in MCI [107]. These mol- 1547
1487 is an intracellular antioxidant in the brain and has yet to be ecules may prove to be markers to track disease progression 1548
1488 extensively studied in AD [107]. In addition, there are only with future longitudinal studies investigating the course of 1549
1489 1550
a few studies evaluating the association between these metab- the levels of these molecules within specific regions in asso-
1490 1551
olite alterations and memory performance in particular ciation with cognitive decline.
1491 1552
1492 (Table 4). 1553
1493 Levels of NAA in MTL have been consistently reported 1554
5. Arterial spin labeling MRI
1494 to have positive associations with verbal memory perfor- 1555
1495 mance both in MCI and ADD [108,109,111–113]. In Arterial spin labeling magnetic resonance imaging 1556
1496 addition to the positive correlation between PCG NAA and measures cerebral blood flow (CBF), which is a more direct 1557
1497 verbal memory scores [110], NAA within this regions evaluation of brain physiology compared with the blood- 1558
1498 decrease along the AD continuum [114]. Levels of NAA oxygen-level dependent response measured by fMRI. A 1559
1499 were shown to decrease with age (as shown by the difference small number of studies on this MRI technique reported 1560
1500 between young and old CNCs) and AD progression. Patients that the CBF alterations are associated with episodic mem- 1561
1501 with ADD had the lowest NAA and creatine concentration, ory within the AD continuum (Table 5). 1562
1502 1563
followed by aMCI patients, whereas young CNCs had the Decreases in MTL CBF are detected even in the preclin-
1503 1564
1504 highest concentration in PCG/precuneus. As myo-inositol ical phase in individuals with AD risk [115]. Structures of 1565
1505 increases in AD, it also seems to be negatively correlated MTL and PCG/precuneus CBF are closely associated with 1566
1506 with verbal memory in MCI and AD [110,113]. These verbal memory performance in this sample of individuals. 1567
1507 results suggest that increased neuronal dysfunction Individuals with positive Ab, subjective cognitive decline, 1568
1508 coupled with glial cell activation play a role in the verbal and APOEe4 carriers have a decline in verbal memory per- 1569
1509 memory deterioration in MCI and AD. Elevated formance coupled with increased CBF [117–119]. 1570

1571 Table 5 1632

1572 Arterial spin labeling magnetic resonance imaging correlates of episodic memory 1633
1573 Episodic 1634
1575 1636
Preclinical AD
1576 Fleisher, 13 CNC (positive family Face-name CBF and BOLD Decreased CBF and BOLD response during
1637
1577 et al 2009 [115] history of AD and at association signal response in MTL encoding in the high risk group. 1638
1578 least one copy of the 1639
1579 APOEe4; high risk), 1640
1580 10 CNC without 1641
1581 these risk factors 1642
1582 Bangen, 16 CNC with high, CVLT-II CBF in caudate, Trend for positive correlation between MTL 1643
1583 et al 2014 [116] 55 with low thalamus, MTL, CBF and memory in high vascular risk 1644
1584 vascular risk posteromedial and group. 1645
frontal cortices
1585 1646
Zlatar, 21 APOEe4 carrier, WMS-R, CVLT-II Voxel-wise analysis R anterior cingulate, L HC, parahippocampal
1586 et al 2016 [117] 38 noncarrier CNC gyrus, insula, putamen, middle temporal,
1647
1587 supramarginal, R middle and superior 1648
1588 temporal gyri CBF negatively correlated 1649
1589 with verbal memory in APOEe4 carriers. 1650
1590 Bangen, 15 Ab1, 47 Ab- CNC AVLT CBF in HC, PCG, HC, PCG and precuneus CBF negatively 1651
1591 et al 2017 [118] (florbetapir PET) precuneus and correlated with recall in Ab1 CNC. 1652
1592 postcentral gyrus 1653
1593 Hays, 35 subjective cognitive CVLT-II, WMS-R Voxel-wise analysis PCG, corpus callosum, HC, L medial and 1654
1594 et al 2017 [119] decline, 35 CNC inferior temporal, fusiform gyri, R inferior 1655
frontal gyrus CBF negatively correlated
1595 1656
with verbal memory in subjective
1596 cognitive decline CNC.
1657
1597 Preclinical AD and MCI 1658
1598 Bangen, 16 MCI (8 APOEe4 Picture encoding CBF and BOLD No CBF or BOLD difference between CNC 1659
1599 et al 2012 [120] carriers), 29 CNC signal response and MCI; and APOEe4 carriers and 1660
1600 (14 APOEe4 carriers) in MTL noncarriers. 1661
1601 Wierenga, 20 MCI (9 APOEe4 WMS-R, CVLT-II Whole brain CBF L parahippocampal and fusiform gyri CBF 1662
1602 et al 2012 [121] carriers), 40 positively correlated with verbal memory 1663
1603 CNC (13 APOEe4 in APOEe4 carriers. 1664
1604 carriers) 1665
MCI
1605 1666
Xu, 2007 12 aMCI, 14 CNC RAVLT, scene Voxel-wise analysis Reduced R precuneus, cuneus and PCG CBF
1606 et al [122] encoding during the task. CBF positively correlated
1667
1607 with RAVLT in the overall sample. 1668
1608 Xie, 2016 65 aMCI, 62 CNC Scene encoding Voxel-wise analysis Reduced MTL, temporal pole, precuneus, 1669
1609 et al [123] and CBF in PCG, PCG, L lingual and fusiform gyri, cuneus, 1670
1610 precuneus, HC, superior occipital lobe CBF during the 1671
1611 parahippocampal gyrus task. 1672
1612 Abbreviations: CNC, cognitively normal control; AD, Alzheimer’s disease; APOEe4, apolipoprotein E e4; Ab, amyloidb; MCI, mild cognitive impairment; 1673
1613 aMCI, amnestic mild cognitive impairment; CVLT-II, California Verbal Learning Test-II; WMS-R, Wechsler Memory Scale-Revised; AVLT, Auditory Verbal 1674
1614 Learning Test; RAVLT, Rey Auditory Verbal Learning Test; CBF, cerebral blood flow; BOLD, blood-oxygen-level dependent; MTL, medial temporal lobe; HC, 1675
1615 hippocampus; PCG, posterior cingulate gyrus; R, right; L, left. 1676
1616 1677
1617 1678
1618 Although there are no directional data regarding this ture. However, results to date suggest that arterial spin label- 1679
1619 association, this may be suggestive of a compensatory ing magnetic resonance imaging holds a potential to provide 1680
1620 response within these regions aimed toward improving the biomarkers which can be used in early diagnosis and pro- 1681
1621 performance. gression of AD. 1682
1622 In line with other MRI approaches, MCI patients show 1683
1623 decreased CBF responses in MTL and PCG/precuneus, 1684
1624 6. Limitations and future directions 1685
which correlate with the verbal memory performance
1625 1686
1626 [122,123]. Superior occipital lobe CBF is reduced when Existing literature suggests that MRI, widely available in 1687
1627 tasks demanding visual encoding are used [123]. clinical and research settings, may offer several potential 1688
1628 Owing to diversity of the episodic memory tests used in biomarkers related to episodic memory impairment in AD. 1689
1629 the current studies, and the small number of studies to Structural and functional alterations in different regions 1690
1630 date, conclusions about how arterial spin labeling relates may increase the predictive value of hippocampal atrophy 1691
1631 to episodic memory across the AD process would be prema- assessed by MRI for AD diagnosis. As MRI findings 1692

1693 correlate with episodic memory deficits, they have the poten- of AD. Future work building from the current protocol will 1754
1694 tial to offer more insight into the etiology of the disease and incorporate task-based fMRI to further understand task- 1755
1695 more utility for tracking progression over time. based network connectivity in relation to the Ab status and 1756
1696 Nevertheless, there are several limitations to using MRI neuropsychological performance. Using multimodal imag- 1757
1697 1758
in AD. Imaging is expensive, requires skilled staff for acqui- ing and including nonverbal memory tests in addition to ver-
1698 1759
sition and analysis, and is time consuming. In most of the bal tests will expand on previous imaging studies.
1699 1760
1700 studies, cohort sizes tend to be small, limiting confidence Navigational tasks used in animal studies are rarely imple- 1761
1701 in results [28,31,65,67,69–74,77–81,124,125]. The mented in human research, limiting the translational value 1762
1702 existence of large shared data sets such as AD of these studies. Thus, by using navigational tasks, we aim 1763
1703 Neuroimaging Initiative mitigates this to some extent and to overcome this existing limitation. 1764
1704 has been extremely useful in better understanding 1765
1705 structural aspects of the disease. However, AD 1766
7. Conclusions
1706 Neuroimaging Initiative is also limited in functional 1767
1707 imaging data as it includes only rsfMRI and no task-based Several MRI and fMRI metrics, including hippocampal 1768
1708 sequences. In addition, the neuropsychological battery in- atrophy, hold the potential to become AD biomarkers and 1769
1709 1770
cludes only verbal memory testing. This is also true of may be more relevant to the preclinical stages. However,
1710 1771
many clinical research studies that limit our understanding most imaging studies include only one modality with either
1711 1772
1712 of the relationship between rsfMRI and nonverbal measures. verbal or nonverbal memory tasks, which prevent general- 1773
1713 This differs from the task-based literature, where many tasks ized conclusions to be drawn from their findings. Investi- 1774
1714 found to differentiate between AD and other cohorts involve gating the underlying pathology of AD through the 1775
1715 nonverbal stimuli such as faces and scenes. combination of multimodal imaging and extensive neuro- 1776
1716 Another limitation is the use of clinical criteria for prob- psychological evaluation may help in early diagnosis and 1777
1717 able AD in most of the mentioned studies. For example, only in testing the effectiveness of novel therapeutics. Longitudi- 1778
1718 a few used hippocampal atrophy, CSF Ab, or PET to support nal studies with larger participant samples, where clinical 1779
1719 the AD diagnosis [20,26,41,73,78,80,90,95,97,98]. Remy AD diagnosis has been supported by multiple biomarkers, 1780
1720 et al [20] included hypometabolism assessed by FDG-PET, could provide a better understanding of the disease. 1781
1721 1782
medial temporal atrophy shown by MRI, and the level of
1722 1783
phospho-tau and Ab-tau index to confirm the AD diagnosis Acknowledgments
1723 1784
1724 within their patient sample. The rest of the studies included 1785
in our review relied only on clinical criteria. Without the This work was supported by the National Institute of General
1725 1786
1726 integration of supporting biomarkers, the positive predictive Medical Sciences (Grant: P20GM109025). 1787
1727 value of clinical diagnostic criteria is rather limited with 1788
1728 poor negative predictive value [126]. If biomarkers revealing 1789
1729 Ab deposition and neurodegeneration are present at the same RESEARCH IN CONTEXT 1790
1730 time as clinical criteria, likelihood of AD dementia is signif- 1791
1731 icantly increased [127]. Thus, whenever possible, these bio- 1792
1732 markers should be implemented to reliably define study 1793
1733 1. Systematic review: Memory impairments are among 1794
samples.
1734 the most common and early symptoms of Alz- 1795
Although investigating differences on a whole brain level
1735 heimer’s disease (AD). Structural and functional 1796
1736 may help discover other regions implicated in episodic 1797
changes assessed by magnetic resonance imaging
1737 memory performance, these analyses may not be efficient 1798
are related to memory performance.
1738 in detecting subtle changes. Compared with region-of- 1799
1739 interest analyses, whole brain analyses require spatial blur- 2. Interpretation: Magnetic resonance imaging findings 1800
1740 ring and corrections for multiple comparisons leading to in AD associated with memory performance can be 1801
1741 decline in power to detect small changes [45]. More power- used as potential biomarkers in the future. However, 1802
1742 ful analysis methods should be favored in biomarker current conflicting results are probably due to the fact 1803
1743 research to obtain more reliable results. that most studies use limited memory tests in small 1804
1744 Moving forward, it seems that multimodal biomarker patient samples with probable AD diagnosis. 1805
1745 studies that use both Ab and/or tau PET ligands and both 1806
1746 3. Future directions: More extensive neuropsychologi- 1807
structural and functional MRI might become more common
1747 cal batteries should be implemented in larger patient 1808
1748 in AD. Our own research supported by a Center for Biomed- 1809
groups with multimodal imaging. The diagnosis for
1749 ical Research Excellence award from the National Institute 1810
AD should be supported by currently available bio-
1750 of General Medical Sciences will use Ab PET, resting state 1811
markers to achieve more reliable results.
1751 fMRI, and neuropsychological testing including verbal, 1812
1752 nonverbal, and navigational memory techniques in an 1813
1753 attempt to fill some of the gaps in the current understanding 1814

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Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2018) 1-19

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