Journal of Alzheimer’s Disease xx (20xx) x–xx 1

DOI 10.3233/JAD-190958
IOS Press

1 Positive Association Between Cognitive

2 Function and Cerebrospinal Fluid Orexin
A Levels in Alzheimer’s Disease

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3

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4 Soichiro Shimizua,∗ , Naoto Takenoshitaa , Yuta Inagawaa , Akito Tsugawaa , Daisuke Hirosea ,
5 Yoshitsugu Kanekoa , Yusuke Ogawaa , Shuntaro Serisawaa , Shu Sakuraia , Kentaro Hiraoa ,
Hidekazu Kanetakaa , Takashi Kanbayashib , Aya Imanishic , Hirofumi Sakuraia and Haruo Hanyua

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6

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a Department of Geriatric Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
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b InternationalInstitute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba,
9 Ibaraki, Japan
10
c Department of Neuropsychiatry, Akita University School of Medicine, Akita, Japan

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Accepted 9 October 2019 Au
11 Abstract.
12 Background: Recently, many studies have investigated the association between orexin A and Alzheimer’s disease (AD).
13 However, it remains to be determined whether the observed changes in orexin A levels are associated with pathological
14 changes underlying AD, or cognitive function. In particular, a direct association between cerebrospinal fluid (CSF) orexin A
15 levels and cognitive function has not been reported to date.
16 Objective: The aim of this study was to identify whether there is a direct association between the orexinergic system and
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17 cognitive function in AD.

18 Methods: For this study, we included 22 patients with AD and 25 control subjects who underwent general physical, neu-
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19 rological, and psychiatric examinations, neuroimaging, and CSF collection by lumbar puncture were enrolled. Correlations
20 between CSF orexin A levels and CSF AD biomarker levels (i.e., levels of phosphorylated tau [p-tau], A␤42 , and A␤42 /A␤40 )
21 were assessed to confirm the results of previous studies. Moreover, the correlation between CSF orexin A levels and Mini-
22 Mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores were
23 analyzed.
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24 Results: There was a significant positive correlation between CSF orexin-A levels and cognitive function (MMSE scores:
25 r = 0.591, p = 0.04, MoCA score: r = 0.571, p = 0.006) in AD patients.
26 Conclusion: This is the first study to our knowledge demonstrating an association between cognitive function and CSF orexin
27 A levels in AD. Our results suggest the possibility that orexinergic system overexpression is not always a negative factor for
28 cognitive function In AD.
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29 Keywords: Alzheimer’s disease, cerebrospinal fluid Alzheimer’s disease biomarker, cognitive function, hypocretin 1, orexin A
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30 INTRODUCTION disease characterized by progressive cognitive and 33

behavioral impairment [1]. Although the main 34

31 Alzheimer’s disease (AD), which is the most characteristic of AD is cognitive decline, sleep distur- 35

32 common cause of dementia, is a neurodegenerative bance is common in AD. Sleep disturbance is a highly 36

∗ Correspondence
disruptive behavioral symptom, and there is associ- 37
to: Soichiro Shimizu, MD, Department of
ation between sleep disturbance and AD pathology. 38
Geriatric Medicine, Tokyo Medical University, 6-7-1 Nishishin-
juku, Shinjuku-ku, Tokyo 160-0023, Japan. Tel.: +81 3 3342 6111; Indeed, epidemiological studies have reported that 39

E-mail: soichiroshimizu@gmail.com. up to 45% of AD patients have sleep disturbances 40

ISSN 1387-2877/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved
 2 S. Shimizu et al. / Association between cognitive function and orexin A in AD

41 [2]. In addition, previous studies showed the high MATERIALS AND METHODS 93

42 risk of development of dementia, particularly AD,

43 in patients with primary insomnia [3, 4]. Tononi Patients 94

44 et al. suggests that sleep-wake behavior plays an

45 important role in a crucial brain function that is For this study, we included 47 subjects free of psy- 95

46 associated with cognition and synaptic plasticity chotropic drugs and who underwent CSF collection 96

47 [5]. Insufficient sleep facilitates the accumulation by lumbar puncture for diagnosis at the Mem- 97

48 of amyloid-␤ (A␤) in the brain, which may poten- ory Disorder Clinic in the Department of Geriatric 98

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49 tially trigger earlier neuropathological changes in AD Medicine, Tokyo Medical University: 22 AD and 25 99

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50 [6]. In fact, previous studies of cerebrospinal fluid controls. 100

51 (CSF) analysis and Pittsburgh compound B positron All subjects underwent general physical, neu- 101

52 emission tomography (PET) showed an associa- rological, and psychiatric examinations, extensive 102

53 tion between changes in sleep quantity and quality laboratory tests, and single photon emission tomog- 103

54 and A␤ brain burden in cognitively normal older raphy (SPECT) and magnetic resonance imaging 104

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55 adults [7–9]. Moreover, an association between sleep (MRI) to establish a clinical diagnosis and to exclude 105

56 disturbance and AD pathology has been reported other potential causes of dementia (i.e., stroke, 106

57 in patients with mild cognitive impairment (MCI) dementia with Lewy bodies, Parkinson’s disease, 107

58 and AD [10–12]. Therefore, an association between depression, vitamin B12 deficiency, hypothyroidism, 108

hyperammonemia, intake of drugs acting on the cen-

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59 sleep disturbance and AD pathology appears to 109

60 exist. tral nervous system or of any type of hypnotic, etc.). 110

61 The hypothalamic neurotransmitter orexin A After above extensive examination, AD patients were 111

62 (hypocretin 1) is considered to be a crucial molecule determined by three geriatric neurologists (H.H., 112

63 of the orexinergic system. It is widely known K.H., and S.S.). Patients with AD had to meet the 113
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64 that patients with narcolepsy have a deficiency National Institute on Aging and Alzheimer’s Associ- 114

65 in orexin A [13, 14] and orexin A contributes ation (NIA-AA) criteria for a diagnosis of probable 115

66 to regulation of the sleep-wake cycle by increas- AD [1]. Moreover, to increase the probability that 116

67 ing arousal levels and maintaining wakefulness the subjects included in the study actually had AD 117

68 [15]. Through both direct as well as trans-synaptic pathological change, we used the NIA-AA research 118

modulation of various pathways, hippocampal framework [29]. Biomarkers of A␤ plaques (labeled

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69 119

70 neurotransmission is controlled by orexin A. There- “A”) are defined as low A␤42 (<500 pg/mL) or 120

elevation of A␤42 /A␤40 ratio (0.05>). Biomarkers

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71 fore, orexin A may play an important role in 121

72 hippocampal-dependent cognitive tasks. In particu- of tau (labeled “T”) are elevated CSF phosphory- 122

73 lar, orexin-mediated modulation of ␥-aminobutyric lated tau (p-tau) (50 > pg/mL). The cut-off values 123

74 acid (GABA) and glutamate levels in the hip- are determined based on the best value for dis- 124

75 pocampus may potentially contribute to disruption criminating AD from other dementias and cognitive 125
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76 of the sleep-wake cycle as well as cognitive unimpaired subjects who expected CSF collection by 126

77 function [16]. Recently, the association between some complaints in our department (i.e., headache, 127

78 orexin A and AD pathology has been investigated parkinsonism, and cognitive decline, etc.). Based 128

79 [17–26]. on above criteria, we defined participants with A+ 129

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80 However, no studies to our knowledge have found T+ as “AD” group (n = 22). On the other hand, the 130

81 a direct association between cognitive function and control group included subjects with normal neu- 131

82 orexin A levels in the CSF of patients with AD. There- ropsychological measurements (MMSE score  25) 132

83 fore, the aim of this study was to clarify whether who underwent clinical neurological investigation, 133
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84 there is a correlation between cognitive function (i.e., neuroimaging, and lumbar puncture for diagnos- 134

85 Mini-Mental State Examination [MMSE] [27] and tic purposes. We defined participants with (A– T–) 135

86 Japanese version of the Montreal Cognitive Assess- [29] who had MMSE score  25 as control group 136

87 ment [MoCA-J] [28] scores) and CSF orexin A (n = 25). 137

88 levels in AD. In addition, we aimed to confirm the This study was approved by the ethics commit- 138

89 results of previous studies investigating the asso- tee of Tokyo Medical University. Written informed 139

90 ciation between the levels of orexin A and AD consent was obtained from all subjects (either from 140

91 biomarkers (i.e., levels of phosphorylated tau [p-tau], the patients themselves or their closest relative) 141

92 A␤42 , and A␤40 /A␤42 ). before entry, following a detailed explanation of the 142
 S. Shimizu et al. / Association between cognitive function and orexin A in AD 3

143 lumbar puncture and biochemical analysis of the CSF. Statistical analysis 167

144 All procedures were in accordance with the ethical

145 standards on human investigation and with the prin- Values were expressed as means ± SD and ana- 168

146 ciples of the declaration of Helsinki. lyzed using Spearman’s rank correlation coefficient 169

and linear regression. A p-value of less than 0.05 170

was considered to indicate a statistically significant 171

147 CSF samples and assays difference between two groups. All analyses were 172

performed using IBM SPSS statistics version 24 soft- 173

CSF was collected in polypropylene tubes follow-

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148
ware (Chicago, IL). 174
ing standardized conditions and using an atraumatic

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149

150 needle, preferably between 11 AM and 2 PM under

151 fasting conditions to minimize the effects of diurnal RESULTS 175

152 variations of CSF biomarkers. Samples were cen-

153 trifuged (3,000 rpm, 10 min) and preserved at –80◦ C Table 1 shows the characteristics of the partic- 176

until analysis. ipants. There were significant differences between 177

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154

155 Levels of p-tau, A␤40 , and A␤42 were ana- two groups in MMSE scores, MoCA-J scores and p- 178

156 lyzed using a commercially available enzyme-linked tau. Table 2 shows the correlation between cognitive 179

157 immunosorbent assay, as previously described [30]. function and AD biomarker, and CSF orexin A. In 180

158 CSF orexin A (hypocretin 1) was measured at whole subjects, there were no significant association 181

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159 Akita University using an 125 I radioimmunoassay kit between CSF orexin A levels and CSF biomarker, and 182

160 (Phoenix Pharmaceuticals, Belmont, CA) as previ- cognitive function (Table 2). In control group, there 183

161 ously described [15, 31]. The detection limit was was significant correlation between CSF orexin A 184

162 40 pg/mL. As CSF orexin A levels can be reliably level and p- tau (r = 0.495, p = 0.026) (Table 2, Fig. 1). 185

163 measured in frozen CSF stored for several years [31], On the other hand, there was significant correlation 186
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164 CSF samples collected for diagnostic purposes of AD between CSF orexin A level and cognitive function 187

165 (storage period: 4 days to 4 years in a –80◦ C freezer) (MMSE and MoCA-J scores) (Table 2, Fig. 2) in AD. 188

166 were used. MMSE (r = 0.591, p = 0.04; Fig. 2a) and MoCA-J 189

(r = 0.571, p = 0.006; Fig. 2b) in AD. 190

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Table 1
Characteristics of the participants
DISCUSSION 191
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Control (25) AD (22) p

We found a significant positive correlation between 192
Male /Female 15/10 11/11 0.4914
Age 71.4 ± 11.2 73.9 ± 8.0 0.43711
CSF orexin A levels and cognitive function. This is 193

MMSE scores 27.1 ± 1.8 21.7 ± 4.2 >0.001 the first study demonstrating an association between 194

MoCA-J scores 21.3 ± 4.2 17.8 ± 4.8 0.01 cognitive function and CSF orexin A levels in AD. 195
P-tau 42.6 ± 10.8 89.9 ± 28.5 >0.001 Recently, associations between orexin A and AD
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196
A␤42 185.6 ± 83.4 162.4 ± 97.4 0.393
A␤42 /A␤40 ratio 0.43 ± 1.54 0.03 ± 0.02 0.261
pathology have been investigated, and previous stud- 197

Orexin 301.0 ± 64.0 322.2 ± 84.4 0.359 ies suggest that overexpression of the orexinergic 198

MMSE, Mini Mental State Examination; MoCA-J, Japanese ver- system might be associated with AD pathology 199

sion of the Montreal Cognitive Assessment; P-tau, phosphorylated [10–12, 17–26]. However, it remained to be deter- 200
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tau; A␤40 , amyloid-␤ 40; A␤42 , amyloid-␤ 42. mined whether the changes observed in orexin 201

Table 2
Correlation between CSF orexin A level and CSF biomarker, and that between CSF orexin level and cognitive function
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All subjects (47) Control (25) AD (22)

Correlation coefficient p Correlation coefficient p Correlation coefficient p
P-tau 0.2 0.204 0.495 0.026 –0.004 0.984
A␤40 0.23 0.143 0.308 0.186 0.098 0.663
A␤42 0.097 0.541 0.291 0.214 0.026 0.91
A␤42 /A␤40 ratio –0.122 0.441 –0.163 0.493 –0.025 0.913
MMSE 0.194 0.212 –0.273 0.232 0.591 0.04
MoCA-J 0.151 0.34 –0.399 0.081 0.571 0.006
MMSE, Mini Mental State Examination; MoCA-J, Japanese version of the Montreal Cognitive Assessment; P-tau,
phosphorylated tau; A␤40 , amyloid-␤ 40; A␤42 , amyloid-␤ 42.
 4 S. Shimizu et al. / Association between cognitive function and orexin A in AD

correlation between CSF orexin levels and CSF A␤42 211

levels as an AD biomarker. Concentrations of A␤42 212

in the CSF were found to decrease as a function of 213

estimated years from expected symptom onset, reach- 214

ing significantly low levels 10 years before expected 215

symptom onset [34, 35]. Therefore, the lack of a cor- 216

relation between A␤42 levels and orexin A levels in 217

our present study as well as previous studies might be 218

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owing to the possible effects of low CSF A␤42 levels 219

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reaching a plateau in both MCI and AD patients. 220

In fact, one recent study results could not support 221

the hypothesis that sleep disturbance predict subse- 222

quent cognitive decline [36], and the significance of 223

CSF orexin A levels in patients with AD remain to be 224

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clarified [11, 12, 21, 33]. Moreover, in patients with 225

MCI and AD, CSF orexin A levels were only found 226

Fig. 1. Scatterplots of CSF orexin A and p-tau levels in control

to directly correlate with CSF tau levels [11, 23]. Pre- 227

group. Significant positive correlations were found between CSF vious studies showing the association between levels 228

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orexin A and p-tau levels in control group. of CSF orexin A and tau in patients with AD [11, 229

23] suggest that dysregulation of the orexinergic sys- 230

202 A levels are associated with pathological changes tem, found as increased CSF orexin A levels in AD 231

203 underlying AD, or occur secondary to changes in patients, is associated with tau-mediated neurode- 232

204 the sleep-wake cycle or cognitive function. Previous generation. In contrast with these previous studies, 233
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205 studies showed, in non-demented people, there is an Gabelle et al. could not find association between CSF 234

206 association between CSF A␤ levels and poor sleep orexin A and tau [12] similar to our study. Unfortu- 235

207 quality [9, 32, 33]. On the other hand, there is no nately, we could find an association between CSF 236

208 study that showed the association between CSF A␤ orexin A and p-tau levels in only control subjects but 237

209 levels and sleep quality in AD. Moreover, previous not in AD patients. Heterogeneities in sample size, 238

populations, CSF sample collection time, methods for

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210 studies [11, 12] and our study were unable to find 239
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Fig. 2. Scatterplots of CSF orexin A levels and MMSE scores (a) and MoCA-J scores (b) in AD group. Significant positive correlations
were found between CSF orexin A levels and both cognitive function scale scores.
 S. Shimizu et al. / Association between cognitive function and orexin A in AD 5

240 CSF orexin-A measurement, and associated comor- mechanism for cholinergic dysfunction, may have 292

241 bidities, such as sleep disturbances, may explain these positive effects on cognitive function. Based on this 293

242 discordant results. hypothesis, there are two possibilities to explain the 294

243 Even if there is an association between the orexin- association between CSF orexin A levels and cog- 295

244 ergic system and AD pathology, the direct association nitive function. First, there is the possibility that 296

245 between the orexinergic system and cognitive func- patients with AD, whose orexinergic system is over- 297

246 tion in AD remains unclear. Previous studies were expressed to compensate for cholinergic dysfunction, 298

247 unable to find an association between CSF orexin A are able to maintain cognitive function to a certain 299

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248 levels and cognitive function. Moreover, in our study, extent. The second possibility is that wakefulness, 300

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249 there was an association between CSF orexin A and which is controlled by orexin overexpression, may 301

250 p-tau levels in only control subjects but not in AD affect cognitive function. 302

251 patients. On the other hand, we could find an associ- On the other hand, a possible explanation for the 303

252 ation between CSF orexin A and cognitive function in lack of an association between CSF orexin A lev- 304

253 only AD patients but not in control subjects. Hence, els and cognitive function in previous studies may be 305

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254 these results are lines of evidence that there is a yet that the effects of the orexinergic system on cognitive 306

255 unclear mutual association among orexinergic system function are not that strong. To explain these hypothe- 307

256 dysfunction, AD pathology, and cognitive function. ses, we will need to consider differences between 308

257 As previous studies [11, 23] showed that CSF orexin studies regarding the participants’ AD stage, sample 309

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258 A levels increased in association with the progres- size, CSF collection time, associated comorbidities, 310

259 sion of AD severity, we expected CSF orexin A such as sleep disturbances, as well as the method 311

260 levels and cognitive function to be negatively cor- used for orexin A quantification (radioimmunoas- 312

261 related in AD patients. However, surprisingly, we say versus fluorescence immunoassays or enzyme 313

262 found that CSF orexin A levels and cognitive function immunoassays). Therefore, to better understand the 314
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263 were positively correlated. Therefore, we hypothe- role of the orexinergic system in AD, further longitu- 315

264 sized the possibility that orexinergic overexpression, dinal studies investigating wake-promoting and AD 316

265 which corresponds to a progression of AD pathology, biomarkers in the CSF, sleep-wake profiles, and A␤ 317

266 is not always a negative factor for cognitive func- burden quantified by amyloid PET are required. 318

267 tion. Liguori et al. [11] documented that cognitive This study has several crucial limitations. Firstly, 319

impairment is associated with sleep structure dete- this study was carried out in a single memory disorder
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268 320

269 rioration. The association between sleep alteration clinic; therefore, the number of patients enrolled was 321
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270 and dementia is very likely to result from pathologi- relatively small. Secondly, sleep-wake profiles were 322

271 cal changes in AD, particularly upon dysregulation not assessed by clinical interviews or objective mea- 323

272 of the cholinergic system, which is typical of the surements, such as actigraphy or polysomnography. 324

273 disease. Therefore, based on previous studies [37, However, the main aim of this study was to iden- 325

274 38], the authors concluded that sleep impairment tify the role of the orexinergic system in cognitive 326
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275 may be caused by an imbalance between choliner- function. Thirdly, cognitive function was evaluated 327

276 gic and orexinergic systems, with an overexpression only by MMSE and MoCA-J. Finally, in our study, 328

277 of the latter because of the absence of the cholin- the absence of healthy controls is not a trivial limita- 329

278 ergic feedback owing to its damage. Gabelle et tion. However, there is a fundamental ethical problem 330
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279 al. hypothesized that high CSF orexin A levels in in collecting CSF from normal subjects by lumbar 331

280 AD patients may be a result of increased orexin puncture, for purposes other than diagnosis. There- 332

281 release, as a compensatory mechanism involving fore, further studies including larger subject numbers, 333

282 the lateral hypothalamus in the neurodegenerative assessment of sleep-wake profiles, more detailed 334
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283 process of AD [12]. We agree with this proposal neuropsychological assessments, normal control sub- 335

284 of a compensatory mechanism by Gabelle et al. jects, and pathological analyses are needed to confirm 336

285 Indeed, basal forebrain cholinergic neurons, which our results. 337

286 are wakefulness-promoting neurons [39], die dur- In conclusion, this study is the first study to our 338

287 ing the neurodegeneration in AD. This may lead to knowledge that found a direct positive association 339

288 the upregulation of other arousal systems, including between CSF orexin A levels and cognitive function. 340

289 orexin-producing neurons. Our results suggest the possibility that orexinergic 341

290 Therefore, we hypothesized that orexinergic system overexpression is not always a negative factor 342

291 overexpression, which occurs as a compensatory for cognitive function. 343

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344 ACKNOWLEDGMENTS F (2014) Orexinergic system dysregulation, sleep impair- 403

ment, and cognitive decline in Alzheimer disease. JAMA 404
Neurol 71, 1498-1505. 405
345 This research was supported by AMED under [12] Gabelle A, Jaussent I, Hirtz C, Vialaret J, Navucet S, 406
346 Grant Number JP17dm0107139h0002. Grasselli C, Robert P, Lehmann S, Dauvilliers Y (2017) 407

347 We are grateful to the medical editors of the Cerebrospinal fluid levels of orexin-A and histamine, and 408

348 Department of International Medical Communica- sleep profile within the Alzheimer process. Neurobiol Aging 409
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