Sei sulla pagina 1di 18

Original Article Obstructive sleep apnea exaggerates cognitive dysfunction in stroke 

patients 
Yan Zhang a, b, *, 1, Wanhua Wang a b, 1, Sijie Cai c, Qi Sheng c, Shenggui Pan d, Fang Shen a, b, Qing 
Tang a, b, Yang Liu e 

Department of Neurology, The Kunshan Affiliated Hospital of Jiangsu University, 215300 Kunshan, China b Department of 
Neurology, The First People's Hospital of Kunshan, 215300 Kunshan, China c 
Department of Respiratory Medicine, The Kunshan Affiliated Hospital of Jiangsu University, 215300 Kunshan, China d 
Department of Rehabilitation Medicine, The Kunshan Affiliated Hospital of Jiangsu University, 215300 Kunshan, China e 
Department of Neurology, Saarland University, 66421 Homburg, Germany 
a r t i c l e i n f o 
Article history: Received 19 October 2016 Received in revised form 20 November 2016 Accepted 28 November 2016 Available 
online 4 February 2017 
Keywords: Cognition Obstructive sleep apnea Prospective memory Sleep and stroke 
a b s t r a c t 
Background: Obstructive sleep apnea (OSA) is very common in stroke survivors. It potentially worsens the cognitive dysfunction 
and inhibits their functional recovery. However, whether OSA independently damages the cognitive function in stroke patients is 
unclear. A simple method for evaluating OSA- induced cognitive impairment is also missing. Methods: Forty-four stroke patients 
six weeks after onset and 24 non-stroke patients with snoring were recruited for the polysomnographic study of OSA and sleep 
architecture. Their cognitive status was evaluated with a validated Chinese version of Cambridge Prospective Memory Test. The 
relationship between memory deficits and respiratory, sleeping, and dementia-related clinical variables were analyzed with 
correlation and multiple linear regression tests. Results: OSA significantly and independently damaged time- and event-based 
prospective memory in stroke patients, although it had less power than the stroke itself. The impairment of prospective memory 
was correlated with increased apneaehypopnea index, decreased minimal and mean levels of peripheral oxygen saturation, and 
disrupted sleeping continuity (reduced sleep efficiency and increased micro- arousal index). The further regression analysis 
identified minimal levels of peripheral oxygen saturation and sleep efficiency to be the two most important predictors for the 
decreased time-based prospective memory in stroke patients. Conclusions: OSA independently contributes to the cognitive 
dysfunction in stroke patients, potentially through OSA-caused hypoxemia and sleeping discontinuity. The prospective memory 
test is a simple but sensitive method to detect OSA-induced cognitive impairment in stroke patients. Proper therapies of OSA 
might improve the cognitive function and increase the life quality of stroke patients. 
© 2017 Elsevier B.V. All rights reserved. 
1. Introduction 
Obstructive  sleep  apnea  (OSA)  is  characterized  by repeated collapses of the upper airway during sleep, and is common in the 
general population. Its mean prevalence is 22% and 17% in men and 
women,  respectively  [1].  In  stroke  patients, the prevalence can rise to 72% [2]. OSA is an independent risk factor of stroke [3,4]. 
It  also  contributes  to  the  occurrence  of  stroke  through exaggerating hy- pertension, diabetes mellitus, and cardiovascular disease 
[5e7].  Moreover,  OSA  has  been  shown  to  inhibit  the  recovery  of  stroke  patients.  Stroke  patients  with  OSA  showed  lower 
functional ca- pacity and spent longer time in the rehabilitation than non-OSA 
DOI of original article: http://dx.doi.org/10.1016/j.sleep.2016.12.014. * Corresponding author. Department of Neurology, The 
Kunshan Hospital Affiliated to Jiangsu University, Qianjinxi Road, No. 91, 215300 Kunshan, Jiangsu 
stroke  patients  [8,9].  Fortunately,  OSA  is  treatable  with  contin-  uous  positive  airway  pressure  (CPAP)  and  maxillomandibular 
advancement [10e12]. Thus, proper OSA therapy not only prevents 
Province, China. Fax: þ86 512 57501112. 
stroke, but also optimizes the stroke rehabilitation. Since 
there are E-mail address: 2573560757@qq.com (Y. Zhang). 1 These two authors contributed equally to this study. 
still more than 10 million major strokes every year in the world 
http://dx.doi.org/10.1016/j.sleep.2016.11.028 1389-9457/© 2017 Elsevier B.V. All rights reserved. 
Contents lists available at ScienceDirect 

Sleep Medicine 
journal homepage: www.elsevier.com/locate/sleep 
Sleep Medicine 33 (2017) 183e190 
 
[13], a timely diagnosis of OSA in stroke patients and the following recovery training has become extremely important. 
Cognitive dysfunction, shown as a variety of deficits in attention, executive function, memory, language and visuoperceptual 
ability, is a common consequence of stroke [14,15]. Prospective studies have shown that impaired visuospatial construction and 
memory, or inattention and perceptual disorders within one month after stroke, predicts a poor functional outcome after six 
months [16,17]. Recently, OSA has been shown to worsen the attention, executive functioning, visuoperception, psychomotor 
ability, and intelligence of stroke patients, which causes difficulty in the rehabilitation of stroke patients [18]. In the follow-up 
study, CPAP therapy was able to significantly improve the cognitive function of stroke patients, although the effect of CPAP on 
functional recovery is still under investigation [19]. Thus, OSA potentially damages the cognitive function, which subsequently 
mediates the negative effects of OSA on stroke recovery. The improvement of cognitive function can be used to evaluate the 
efficacy of anti-OSA therapy in stroke patients. However, studies investigating the relationship between OSA and cognitive 
impairment in stroke patients are rare. In few pub- lished studies, there was not a control group of non-stroke patients with OSA, 
which can be used to investigate the independent effects of OSA and stroke on cognitive dysfunction [18,19]. The underlying 
pathophysiological mechanisms through which OSA impairs the cognitive function of stroke patients are unclear either. To 
address these questions, our study recruited both stroke and non-stroke patients and carefully examined both respiratory 
parameters and the structure of sleep. In order to find a method with which the clinicians (especially in local hospitals and 
without extensive training for psychological analysis), can also successfully examine the cognitive status of stroke patients, we 
used the prospective memory test to evaluate cognitive function; the patient was simply requested to perform a planned action at 
a certain future time or after a certain event occurred [20]. 
2. Materials and methods 
2.1. Patients 
In  this  study,  all  65  stroke  patients  (ischemic,  hemorrhagic  and  subarachnoid  hemorrhage)  admitted  to  the  Department  of 
Neurology,  Kunshan  affiliated  Hospital  of  Jiangsu  University, China, from June 2013 to June 2015 were invited, and 44 patients 
were  enrolled  into this study according to the following criteria: (1) stroke confirmed by a neurologist, (2) age between 30 and 65 
years  old,  (3)  admission  at  six  weeks  after  stroke,  (4)  able  to  participate  in  the  sleep  study  and neuropsychological assessment, 
and  (5)  sufficiently  fluent  in  lingual  communication.  The  exclusion  criteria  was  as  follows:  (1)  severe,  unstable  medical 
conditions,  respiratory  failure,  or  history  of  severe  congestive  heart  failure,  (2)  traumatic  brain  injury,  (3)  severe  aphasia, 
confusion,  or  severe  psychiatric  comorbidity,  (4)  central  sleep  apnea,  or  (5)  any previ- ously diagnosed sleep diseases including 
narcolepsy,  periodic  limb  movement disorder and Parkinson's disease-related sleep disor- ders. In order to investigate the relative 
contribution  of  OSA  to  cognitive  dysfunction  of  stroke  patients,  we  also  recruited  24  non-  stroke  patients,  who  were  over  18 
years  old  and  came  to  our  outpatient  service  due  to  snoring  (they  had  no  previous  diagnosis  of neurological, psychiatric and/or 
respiratory  disease).  All  sub-  jects  received overnight polysomnography. Before poly- somnography, the subjects were evaluated 
for  sleeping  and  cognitive  function  by  using  Epworth  sleepiness  scale  (ESS),  Mini-  mental  state  examination  (MMSE),  and 
prospective memory test. The study was approved by the Ethics Committee of Jiangsu 
Y. Zhang et al. / Sleep Medicine 33 (2017) 183e190 184 
University and written informed consent was obtained from each participant. 
2.2. Polysomnographic study 
All  stroke  patients  underwent  one  night  (!8  h)  of  polysomno-  graphic  study  at  the  sleep  laboratory  of  our  department  six 
weeks  after  stroke  onset.  Non-stroke  patients  participated  in  the  poly-  somnographic  (PSG)  test  without  drinking  alcoholic  or 
caffeinated  drinks  in  the  last  two  days.  The  overnight  sleep  polysomnograph  (Alice  5  Diagnostic  Sleep  System;  Philips 
Healthcare,  Andover,  USA)  included  electroencephalography  (C3/A2,  C4/A1,  O1/A2,  and  O2/  A1),  electrooculography, 
submental  electromyography,  bilateral  anterior  tibialis  electromyography,  electrocardiography,  nasal  airflow  measurement 
(sensed  by both thermistor and pressure transducer), monitoring of thoracoabdominal movements, oxygen saturation, snoring and 
body position. 
Sleep  stages  and  respiratory  events  were  analyzed  against  the  Sleep  Medicine  Criteria  (American  Academy,  2007)  [21]. 
Apnea was defined as a reduction of airflow of !90% for at least 10 s and hypopnea was defined as a reduction of airflow of !50% 
for  at  least  10  s  followed  by  an  oxygen  desaturation  of  !3%.  Apneas  with  thoracic  motion,  without  thoracic  motion,  and  with 
initial  lack  of  motion  followed  by  respiratory  effort,  were  classified  as  obstruc-  tive,  central,  and  mixed  apneas,  respectively. 
OSA  was  diagnosed  when  at  least  50%  of  the  respiratory  events were of the obstructive type. The apneaehypopnea index (AHI) 
was  defined  as  the  mean  number  of  apneas  and  hypopneas  per  hour  in  bed.  Patients  with  AHI  <5 were referred to as non-OSA 
patients  and  enrolled  in  the  control  group  of  this  study.  Other  OSA-associated  respiratory  pa-  rameters,  including  minimum  of 
peripheral  oxygen  saturation  (SpO2),  mean  of  SpO2  and  percentage  of  time  with  SpO2  at  <90%  were  recorded.  Sleep 
architecture  variables  were  also  examined,  such  as  sleep  efficiency,  sleep  stages,  and  microarousal  index.  Sleep  efficiency  is 
percentage  of  sleeping  duration  divided  by  the  total  time  spent  in  the  bed.  Microarousal  index  was  the  number  per  hour  of 
microarousals which last 3e15 s. 
2.3. Epworth sleepiness scale (ESS) 
The  ESS  is  a  self-administered  questionnaire  that  is  widely  used  for  subjective  assessment of daytime sleepiness. It contains 
eight  items  involving  eight  daily-life  scenarios,  with  each  item  being  assessed  on  a zero-to-three point scale. The total scores of 
ESS range from 0 to 24. The cutoff point for excessive daytime sleepi- ness is set at >10 [22]. 
2.4. Mini-mental state examination 
The  Chinese  version of the MMSE questionnaire consists of several subscales: orientation, immediate and short-term memory 
recall,  attention/calculation,  language,  and  visuospatial  skills.  Cognitive  deficit  on  the  MMSE  is  defined  as  a score less than 27 
[23]. 
2.5. Prospective memory test 
The  prospective  memory  test  was  assessed  with  a  validated Chinese version of Cambridge Prospective Memory Test (CAM- 
PROMPT)  [24].  The  CAMPROMPT  comprises  six  prospective  mem-  ory  tasks  which  are  either  cued  by  events  (event-based 
prospective  memory  tasks;  n  1⁄4  3)  or  by  time  (time-based  prospective  memory  tasks;  n  1⁄4  3).  In  this  test,  participants  were 
asked  to  remember  carrying  out  three  time-  and  three  event-based  prospective  mem-  ory  tasks  while  working  on  a  number  of 
other activities (pencil and 
 
with paper tasks, such as a general knowledge quiz or word-finding 
zero and one, respectively), and the 
dementia-related factors puzzle) for a 20-minute period. The CAMPROMPT generates 
[age, gender, hypertension, diabetes, smoking, 
drinking, education, scores on all six tasks, each with a maximum score of six; higher 
body mass index (BMI), cholesterol and 
homocysteine]. To deter- scores indicate better prospective memory performance. 
mine the relative contributing power of respiratory and 
sleeping All participants were asked to repeat the instructions before 
disorders in the cognitive dysfunction of stroke 
patients, all respi- beginning the CAMPROMPT to ensure that they understood what 
ratory and sleeping parameters (together with the 
above described they had to do during the test. The explanation of assay instructions 
dementia-related factors) were analyzed as 
independent variables was repeated to participants who appeared uncertain about the 
to predict the dependent variable: time- or event-based 
prospec- test. Upon completion of the CAMPROMPT, participants were again 
tive memory, with a multiple linear regression analysis 
with the asked to repeat the requirements of the test to make sure they 
method of “stepwise.” In this analysis, non-stroke 
patients were not remembered and understood the instructions. Two well-trained 
included. psychiatrists had assessed the prospective 
memory and other cognitive functions. 
3. Results 
2.6. Statistical analysis 
3.1. Characteristics of the participants 
Data analyses were performed using SPSS (version 19.0, IBM, 
To investigate the effects of OSA on cognitive 
function of stroke New York, USA). We used descriptive statistics to characterize the 
patients, we screened 65 stroke patients and found 44 
patients sample in terms of demographic, clinical, sleep, and stroke vari- 
eligible. Twenty-one patients were discharged due to 
their severe ables. To compare values between two independent groups, we 
or exaggerated symptoms, which made the 
polysomnographic and used parametric (Student t test) and nonparametric tests (c2 
test) 
cognitive studies impossible. The polysomnographic 
and cognitive where appropriate. To test the differences among three groups, 
examinations for all recruited patients were performed 
six weeks one-way analysis of variance (ANOVA) and c2 
test were used. The 
after stroke onset. Out of 44 stroke patients, nine 
(20.45%) received Pearson correlation analysis was performed to assess the rela- 
a diagnosis of mild OSA (15 > AHI ! 5) and 18 
patients (40.91%) tionship between time- or event-based prospective memory and 
were diagnosed with moderate-to-severe OSA (AHI ! 
15). Seven- respiratory parameters (eg, AHI, minimum of SpO2, mean of SpO2 
teen patients (38.64%) without OSA (AHI < 5) were 
considered as and the percentage of time with SpO2 at <90%) and sleep param- 
non-OSA control stroke patients. All patients except 
one patient eters (eg, sleep efficiency, sleep time at stages 1, 2, 3 and rapid eye 
with moderate to severe OSA were diagnosed with 
stroke for the movement, and microarousal index). To investigate whether OSA 
first time (Table 1). The functional status of patients 
after stroke was an independent risk factor of cognitive dysfunction in stroke 
was evaluated with NIHSS, which showed that the 
functional re- patients, stroke and non-stroke patients were pooled into one 
covery was not different between patients with 
different severity of single study group. A multiple linear regression analysis with the 
OSA (Table 1; one-way ANOVA, p > 0.05). Other 
clinical data of method of “enter” was used to predict time- or event-based pro- 
participating stroke patients was shown in Table 1. 
The age (range: spective memory with potential predictors: OSA (without OSA, 
35e73 years; 57.3 ± 9.6 years), sex distribution (male: 
70.5%), time with mild and moderate-to-severe OSA were coded with zero, one 
of education (range: 6e15 years; 8.3 ± 2.8 years), 
obesity shown and two, respectively), stroke (with and without stroke were coded 
with BMI (25.3 ± 3.3), rates of diabetes (18.2%), smoking (34.1%) and 
Table 1 Characteristics of stroke patients. 
Characteristics Moderate to severe OSA (n 1⁄4 18) Mild OSA (n 1⁄4 9) Non-OSA (n 1⁄4 17) p Value 
Age (year) 59.4 ± 10.2 58.2 ± 9.1 54.6 ± 9.1 0.336a Sex (males) 13 (72.2%) 7 (77.8%) 11 (64.7%) 0.768 

Educations (year) 8.5 ± 3.3 8.0 ± 3.4 8.1 ± 2.1 0.888 

BMI 26.3 ± 3.0 24.8 ± 2.4 24.6 ± 3.9 0.295a Hypertension 17 (94.4%) 6 (66.7%) 10 (58.8%) 0.042 

Diabetes 6 (33.3%) 0 2 (11.8%) 0.072 

Smoking 3 (16.7%) 5 (55.6%) 7 (41.2%) 0.097 

Drinking 3 (16.7%) 2 (22.2%) 1 (5.9%) 0.456b Cholesterol 4.6 ± 0.8 4.6 ± 1.2 4.7 ± 1.1 0.966 

Homocysteine 17.0 ± 11.7 18.3 ± 13.4 14.8 ± 3.9 0.672 

Stroke type 0.527b 
Ischemia 11 (61.1%) 7 (77.8%) 13 (76.5%) Hemorrhage 7 (38.9%) 2 (22.2%) 4 (23.5%) Subarachnoid hemorrhage 0 0 0 Stroke 
location 0.779 

Cortex 2 (11.1%) 2 (22.2%) 2 (11.8%) Cerebellum 2 (11.1%) 0 1 (5.9%) Brain stem 14 (77.8%) 7 (77.8%) 14 (82.4%) Recurrent 
stroke 1 (5.6%) 0 (0%) 0 (0%) 0.478 

Minimum of SpO2 79.1 ± 5.0 89.4 ± 3.64 92.0 ± 2.2 <0.001 

Mean of SpO2 93.8 ± 3.2 97.1 ± 1.17 96.4 ± 1.3 0.001 

Percentage of time with SpO2 at <90% 6.7 ± 13.2 0.2 ± 0.3 0.0 ± 0.0 0.049 

Apneaehypopnea index 38.2 ± 17.4 8.1 ± 2.3 2.7 ± 1.3 <0.001 

NIHSS 3.5 ± 3.5 2.7 ± 2.6 3.4 ± 2.7 0.780 

Values are presented as mean (standard deviation) or n (%). BMI, body mass index; OSA, obstructive sleep apnea; SpO2, 
peripheral oxygen saturation; NIHSS, National Institutes of Health Stroke Scale. 

One-way ANOVA. b c2 test. 
Y. Zhang et al. / Sleep Medicine 33 (2017) 183e190 185 
 
with drinking (13.6%), serum concentrations of cholesterol 
various severity of OSA did not differ in the 
scores (Fig. 1A; (4.6 ± 1.0 mmol/L) and homocysteine (16.4 ± 9.8 mmol/L), as well as 
one-way ANOVA, p > 0.05). stroke types (ischemia, 
hemorrhage, or subarachnoid hemorrhage) 
In non-stroke patients, we have observed that both 
time- and and locations (cortex, cerebellum, or brain stem) were not signifi- 
event-based prospective memory significantly 
declined in OSA cantly different between different OSA groups (one-way ANOVA or 
patients compared with non-OSA controls (Fig. 1B; t 
test, p < 0.001). c2 
test, p > 0.05). However, the rate of hypertension in the group of 
The MMSE did not show difference between these 
two groups of patients (94.4%) suffering from moderate-to-severe OSA was 
non-stroke patients (Fig. 1B). significantly higher than 
that in the groups of patients with mild 
We continued to ask whether OSA independently 
contributed to (66.7%) or no OSA (58.8%) (c2 
test, p < 0.05). AHI and other respi- 
the cognitive dysfunction of stroke patients and how 
strong the ratory parameters, such as minimum of SpO2, mean of SpO2 and 
contribution was. We pooled stroke and non-stroke 
patients, and percentage of time with SpO2 at <90% were significantly changed 
performed a multiple linear regression (with the 
method of in patients with moderate-severe OSA compared to other patients 
“enter”) to examine whether OSA and stroke 
independently pre- with mild or no OSA (one-way ANOVA, p < 0.05). 
dicted time- or event-based prospective memory. Age, 
gender, In 24 non-stroke snoring patients, 17 (70.83%) received a diag- 
hypertension, diabetes, smoking, drinking, education, 
BMI, nosis of OSA (AHI ! 5), among which 16 patients (66.67%) were 
cholesterol, and homocysteine were also included as 
independent diagnosed of moderate-to-severe OSA (AHI ! 15). We have 
variables in the regression analysis as they potentially 
affect the observed that BMI and cholesterol, which were associated with 
cognitive function. These 12 independent variables 
were able to obesity, were significantly higher in OSA group than in the non-OSA 
reliably predict the time and event-based prospective 
memory (F- controls (p < 0.05; see Table 2). Interestingly, the serum concen- 
tests for time-based prospective memory: F (12, 55) 
1⁄4 22.139, tration of homocysteine was also strongly increased by OSA (from 
p < 0.0001, R 

1⁄4 0.828; and for event-based 
prospective memory: F 10.5 ± 2.8 to 16.0 ± 4.9, t test, p 1⁄4 0.011). It was similar to stroke 
(12, 55) 1⁄4 7.045, p < 0.0001, R patients that snoring 
patients with OSA showed significantly higher AHI and reduced saturation of oxygen in the peripheral circulation (p < 0.05; see 
Table 2). 
3.2. OSA is independently involved in the cognitive dysfunction of stroke patients 
To  evaluate  the  effects  of  OSA  on  cognitive  functions  of  stroke  patients,  we  performed  MMSE  and  time-  or  event-based 
prospec-  tive  memory  assays.  Three  groups  of  stroke patients with different severity of OSA had shown significant difference in 
the  prospective  memory  (Fig.  1;  one-way  ANOVA,  p  <  0.05).  In  the  further  post-hoc  Bonferroni  tests,  we  observed  that 
time-based  prospective  memory  was  already  impaired  in  patients  with  mild  OSA  as  compared  to  non-OSA  patients  (Fig.  1A; 
one-way  ANOVA,  p  <  0.001);  whereas,  the  event-based  prospective  memory  in  patients  with  mild OSA was not different from 
that  in  non-OSA  stroke  patients.  When  the  two  groups  with  mild  OSA  and  non-OSA  stroke  patients  were  combined  and 
compared  with  the  group  of  stroke  patients  with  moderate-to-severe  OSA,  we  clearly  observed  that  event-based  prospective 
memory was also impaired in moderate-to-severe OSA patients (Fig. 1A; t test, p 1⁄4 0.003). In MMSE, all patients 

1⁄4  0.606).  Indeed,  OSA  and  stroke  were  two independent predictors for the loss of both time- 
and  event-based  prospective  memory,  although  stroke  had  relatively  more  power  than  OSA  to  impair  the  prospective  memory 
(Table  3;  The  coefficients  of  stroke  and  OSA  were  À8.16  and  À2.68  for  the  prediction  of time-based prospective memory, and 
À5.51  and  À1.38  for  event-based  prospective  memory,  respectively;  p  <  0.01).  For  the  event-based  prospective  memory,  the 
serum  concentration  of  cholesterol  was  another  significant  predictor  (p  <  0.05),  although  it  had  very  weak  power  (with  the 
coefficient of À0.68) compared to stroke and OSA. 
3.3. OSA-associated hypoxemia is correlated with the impaired cognitive functions in stroke patients 
In  order  to  understand  how  OSA  impaired  the  prospective  memory,  we  made  correlation  tests  between  the  time-  or  event- 
based  prospective  memory  and  AHI  and  other  OSA-associated  respiratory  parameters.  Indeed,  time-based  prospective  memory 
was  significantly  correlated  with AHI, minimal or mean level of SpO2, and percentage of time, during which SpO2 was less than 
90%  (Table  4;  Pearson  correlation  tests,  p  <  0.05).  The  event-based  prospective  memory  was  significantly correlated with AHI 
and minimal level of SpO2, but not with mean level of SpO2, and 
Table 2 Characteristics of patients with snoring. 
Characteristics OSA (n 1⁄4 17) Non-OSA (n 1⁄4 7) p Value 
Age (year) 43.9 ± 10.8 39.7 ± 12.9 0.423a Sex (males) 15 (88.2%) 5 (71.4%) 0.315 

Educations (year) 12.2 ± 3.9 12.0 ± 4.1 0.896 

BMI 28.5 ± 4.0 24.4 ± 2.3 0.019 

Hypertension 11 (64.7%) 3 (42.9%) 0.324 

Diabetes 5 (29.4) 3 (42.9%) 0.525 

Smoking 8 (47.1%) 1 (14.3%) 0.132 

Drinking 2 (11.8) 0 0.343 

Cholesterol 5.0 ± 1.1 4.3 ± 0.3 0.019 

Homocysteine 16.0 ± 4.9 10.5 ± 2.8 0.011 

Minimum of SpO2 71.4 ± 15.6 92.7 ± 1.8 0.000 

Mean of SpO2 93.0 ± 6.6 96.4 ± 1.3 0.008 

Percentage of time with SpO2 at <90% 17.4 ± 22.8 0 0.006 

Apneaehypopnea index 50.0 ± 23.8 1.5 ± 1.1 <0.001 

Values are presented as mean (standard deviation) or n (%). BMI, body mass index; OSA, obstructive sleep apnea; SpO2, 
peripheral oxygen saturation. 

Student t test. b c2 test. 
Y. Zhang et al. / Sleep Medicine 33 (2017) 183e190 186 
 
Y. Zhang et al. / Sleep Medicine 33 (2017) 183e190 187 
Fig.  1.  Obstructive  sleep  apnea  impairs  prospective  memory.  Forty-four  stroke  and  24  non-stroke  patients  with  snoring  were 
recruited  and  examined  with  poly-  somnography  for  the  diagnosis  of  OSA  and  with  Cambridge  Prospective  Memory  Test  and 
MMSE  for  their  cognitive  status.  A,  Cognitive  scores  of  MMSE  and  time-based  prospective  memory  (PM)  between  stroke 
patients  with  different  severity  of  OSA  were  compared with one-way ANOVA followed by post-hoc Bonferroni tests; The score 
of  event-based  PM  in  moderate-to-severe  OSA  group  was  compared  to  the  score  of  combined  groups  of  stroke  patients  with 
non-OSA  and  mild  OSA  with  t  test  (n  1⁄4  17,  9  and  18  for  non-OSA,  mild  and  moderate-to-severe  OSA,  respectively).  B, 
Cognitive  scores  between  snoring  patients  with  and  without  OSA  were  compared  with  t  tests  (n  1⁄4  7  and 17 for non-OSA and 
OSA, respectively). **: p < 0.01 and ***: p < 0.001. 
Table 3 Linear regression analysis to predict time or event-based prospective memory. 
Independent variables TPM EPM 
Coefficients p Value Coefficients p Value 
(Constant) 17.87 <0.001 15.77 0.001 Stroke À8.16 <0.001 À5.51 <0.001 OSA À2.68 <0.001 À1.38 0.002 age À0.03 0.515 0.02 
0.641 Gender À0.06 0.946 0.15 0.874 Hypertension 1.18 0.082 0.89 0.244 Diabetes À1.12 0.117 À0.23 0.773 Cholesterol À0.03 
0.925 À0.68 0.047 Homocysteine 0.02 0.510 0.06 0.170 Body mass index 0.08 0.389 0.06 0.588 Smoking À0.28 0.714 À0.14 
0.871 Drinking À1.04 0.302 À0.32 0.782 Education 0.06 0.656 0.18 0.237 
TPM, time-based prospective memory; EPM, event-based prospective memory; OSA, obstructive sleep apnea. 
percentage  of  time  with  SpO2  at  <90%  (Table  4;  Pearson  correlation  tests,  p  <  0.05). When coefficients in different correlation 
tests  were  compared,  we  observed  that  the  minimal  level  of  SpO2  (which  referred  to  the  hypoxemia  in  patients),  was  the most 
prominently  correlated  with  the  impaired  prospective  memory  (Table  4).  Of  note,  in  non-stroke  patients,  both  time-  and 
even-based prospec- tive memory was not correlated with AHI and reduction of pe- ripheral oxygen saturation (data not shown). 
3.4. OSA-associated impairment of sleep efficiency is correlated with damaged cognitive functions in stroke patients 
OSA  causes  sleep  fragmentation,  which  potentially  damages  cognitive  function  [25].  We  continued  to  examine  effects  of 
OSA  on  the  architecture  of  sleep.  The  sleep  efficiency  of  stroke  patients  without  OSA  was  84.6  ±  4.8%,  which  significantly 
decreased  in  stroke  patients  with mild (75.4 ± 12.8%) and moderate-to-severe OSA (78.9 ± 8.8%) (Table 5; one-way ANOVA, p 
<  0.05).  The  microarousal  index  differed  between  these  three  groups  of  stroke  patients  with different severity of OSA (Table 5; 
non-OSA:  10.1  ±  4.3;  mild  OSA:  11.9  ±  6.8;  and  moderate-to-severe  OSA:  34.7  ±  17.8;  one-way  ANOVA,  p  <  0.05).  The 
percentages  of  time  during  stage  1,  2,  or  3,  or  during  the  rapid  eye movement (REM) stage among total sleeping time, were not 
different  between  these  three  groups  of  stroke  patients  (Table  5; one-way ANOVA, p > 0.05); however, when all stroke patients 
with  mild  to  severe  OSA  were  combined  and  compared to patients without OSA, we have observed that the time at stage 3 [also 
named  slow  wave  sleep  (SWS)]  was  significantly  shortened  by  OSA  (14.6  ±  3.5%  in  non-OSA  patients  and  11.0  ±  5.7%  in 
patients  with  OSA;  t  test,  p  1⁄4  0.025).  Similarly,  OSA  significantly  shortened  the  sleeping  time  at  stage  3  and  increased  the 
microarousal  index  in  patients  suffering  from  snoring  (Table  6;  t  test,  p  <  0.05).  The  examination  with  a  self-  administered 
questionnaire,  ESS, had not shown the effects of OSA on the daytime sleepiness in both stroke and snoring patients (Tables 5 and 
6; p > 0.05). 
When  we  made  correlation  tests  between  the  prospective  memory  and  variable  sleep  parameters,  we  observed  time- but not 
event-based  prospective memory was significantly correlated with sleep efficiency and microarousal index in stroke patients with 
similar  coefficient  values  (Table  7;  p  <  0.05).  In  non-stroke  patients,  neither  time-  nor  even-based  prospective  memory  was 
correlated with all parameters related to the sleep structure (data not shown). 
3.5. Hypoxemia and sleep disruption independently contribute to the cognitive dysfunction of stroke patients 
After  we  observed  that  both  hypoxemia  and  sleep  efficiency  were  correlated  with  the  prospective  memory,  we  further 
determined  their  relative  contribution  to  the  OSA-induced  cognitive  dysfunction  in  stroke  patients  with  a  multiple  linear 
regression  with  stepwise  method.  Among  the  21  different  respiratory  parameters  (eg, AHI, minimal or mean level of SpO2, and 
percentage  of  time  with  SpO2  at  <90%),  sleep  parameters  (eg,  sleep  efficiency,  sleeping  time  at  stage  1,  2,  3  and  REM,  and 
microarousal  index),  and  dementia-related  clinical  factors  (age,  gender,  hypertension,  diabetes,  smoking,  drinking,  education, 
BMI,  cholesterol,  homocysteine,  and  NIHSS),  three  independent  variables:  minimal  level  of  SpO2  (Coefficients:  0.286,  p  < 
0.001),  sleep  efficiency  (Coefficients:  0.127,  p  1⁄4  0.004)  and  age  (Coefficients:  À0.134, p 1⁄4 0.002) were significantly entered 
the statistical model to predict the time-based memory [F (3, 40) 1⁄4 20.049, p < 0.001, R 

1⁄4  0.601].  Similarly,  in  the  prediction  of  event-based  prospective  memory,  AHI  (Coefficients: 
À0.079, p < 0.004), cholesterol (Coefficients: À1.259, p 1⁄4 0.002) and 
 
Table 4 Correlation tests between prospective memory and variable OSA parameters in stroke patients. 
AHI Minimum of SpO2 Mean of SpO2 Percentage of time with SpO2 at <90% 
TPM Pearson correlation À0.507 0.608 0.364 À0.302 
p Value <0.001 <0.001 0.015 0.046 EPM Pearson correlation À0.343 0.356 0.162 À0.206 
p Value 0.022 0.018 0.294 0.179 
AHI, apneaehypopnea index; SpO2, peripheral oxygen saturation; TPM, time-based prospective memory; EPM, event-based 
prospective memory. 
Table 5 Sleep architecture of stroke patients. 
Moderate-to-severe OSA (n 1⁄4 18) mild OSA (n 1⁄4 9) non-OSA (n 1⁄4 17) p Value 

Sleep efficiency 78.9 ± 8.8 75.4 ± 12.8 84.6 ± 4.8 0.028 Stage 1 (%) 12.6 ± 7.4 11.0 ± 4.2 10.1 ± 4.4 0.433 Stage 2 (%) 58.7 ± 
5.6 59.4 ± 6.9 55.6 ± 4.8 0.168 Stage 3 (%) 11.2 ± 6.4 10.4 ± 4.4 14.6 ± 3.5 0.076 REM (%) 17.5 ± 7.2 19.3 ± 5.8 19.8 ± 4.7 
0.509 Microarousal index 34.7 ± 17.8 11.9 ± 6.8 10.1 ± 4.3 <0.001 ESS 11.6 ± 2.3 11.3 ± 2.5 11.5 ± 1.7 0.947 
Values are presented as mean (standard deviation). OSA, obstructive sleep apnea; REM, rapid eye movement; ESS, Epworth 
sleepiness scale. 

One-way ANOVA. 
Table 6 Sleep architecture of snoring patients. 
Sleep parameter OSA (n 1⁄4 17) Non-OSA (n 1⁄4 7) p Value 
declarative and retrospective memory, and followed supervisory executive functions [26]. Impairment of prospective memory oc- 

curs frequently after stroke with a similar rate of retrospective 
Sleep efficiency Stage 1 (%) Stage 2 (%) 90.8 ± 5.2 88.3 ± 12.5 11.1 ± 5.5 6.6 ± 3.0 62.3 ± 6.6 57.2 ± 8.3 0.493 0.055 0.121 
memory, but more often than impairments in attention and exec- utive functioning [27]. Prospective memory tests have been used 
to identify memory deficits in Hong Kong Chinese stroke patients 
Stage 3 (%) 4.3 ± 4.7 13.2 ± 5.2 <0.001 
with 95.5% of sensitivity and 55.9% of specificity [28]. 
We examined REM (%) 22.2 ± 4.5 23.0 ± 4.2 0.714 
prospective memory to evaluate the effect of OSA on 
cognitive Microarousal index 43.8 ± 22.0 7.4 ± 3.7 ESS 12.9 ± 3.1 12.7 ± 1.4 <0.001 
0.893 
function. We did observe that prospective memory, especially time- based prospective memory, is impaired in stroke patients in 
an OSA Values are presented as mean (standard deviation). OSA, obstructive sleep apnea; REM, rapid eye movement; ESS, 
Epworth sleepiness scale. a 
Student t test. 
severity-dependent manner; event-based prospective memory appears to be less affected by OSA. After MMSE failed to detect 
cognitive dysfunction in stroke patients with OSA in our and other's studies [29], the prospective memory test proved to be a 
preferable testing method, as it is simpler than the domain-specific neuro- education (Coefficients: 0.483, p 1⁄4 0.001) were 
significantly entered 
psychological tests and will be more acceptable to 
clinicians. the statistical model [F (3, 40) 1⁄4 9.953, p < 0.001, and R 

1⁄4 0.427]. 
Stroke as a major brain disorder often damages cognitive func- tion [14,15]. In published studies, OSA has been associated 
with 
4. Discussion 
severer cognitive dysfunction in stroke patients and the pattern of OSA-related cognitive impairment different from the typical 
OSA  is  very  common  in  stroke  survivors.  In  our  study,  61.36%  stroke  patients  suffered  from  OSA.  OSA  was  reported  to 
exaggerate  cognitive  dysfunction  of  stroke  patients,  which  potentially  impaired  their  rehabilitation  [18,19].  Our  study  has 
clarified  that  OSA  is  an independent risk factor in additional to stroke impairing the cognitive function (eg, prospective memory) 
of  stroke  patients.  As  a  potential  underlying  pathogenic  mechanism,  OSA  decreases  the  oxygen supply to the brain and reduces 
sleep efficiency. 
Prospective memory is a form of memory that involves remembering to perform a planned action at a certain future time point 
or after a certain event occurs [20]. It requires episodic, 
stroke-caused  cognitive  deficits  [18,19];  however,  it  remains  diffi-  cult  to  conclude  whether  OSA  independently  contributes  to 
cognitive  impairment  in  stroke  patients.  In  our  study,  we  recruited  non-stroke  patients  in  additional  to  stroke  patients.  After 
stroke  was  used  as  a  potential  predictor  of prospective memory deficits in a multiple linear regression analysis, we observed that 
both  OSA  and  stroke  are  two  independent  risk  factors  with stroke having more power than OSA. In non-stroke patients, we also 
observed  that  OSA  impairs  prospective  memory,  which  is  in  accordance  with  the  previous  observations  that  OSA  negatively 
affects cognitive functioning in the general population [30]. It should be also noted 
Table 7 Correlation tests between prospective memory and variable sleep parameters in stroke patients. 
Sleep efficiency Stage 1 Stage 2 Stage 3 REM Microarousal index 
TPM Pearson correlation 0.382 À0.178 À0.194 0.292 0.101 À0.394 
p Value 0.011 0.246 0.208 0.055 0.513 0.008 EPM Pearson correlation 0.140 À0.041 0.089 À0.070 0.015 À0.260 
p Value 0.364 0.790 0.564 0.653 0.925 0.088 
REM, rapid eye movement; TPM, time-based prospective memory; EPM, event-based prospective memory. 
Y. Zhang et al. / Sleep Medicine 33 (2017) 183e190 188 
 
that  the  toxic  effect  of  OSA  on  prospective  memory  in  stroke  patients  is  more  pronounced  than  in  non-stroke  patients,  which 
might be due to the less capacity of the brain of stroke patients than that of snoring patients to compensate OSA-induced neuronal 
degeneration. 
We  also  investigated  the  potential  pathophysiological  mechanisms  mediating  OSA-induced  cognitive  deficits  in  stroke 
patients.  Both  blood  oxygen  levels  (eg,  minimal  and  mean  level  of  SpO2)  and  air  flow  through  the  respiratory tracts (eg, AHI) 
were  correlated  to  the  impaired  prospective  memory  in  our  experiments.  However,  the values of coefficients in correlation tests 
and  the  regression  analysis  both  demonstrated  that  the  minimal  level  of  SpO2  was  the  most  important  risk  factor  in  the loss of 
time-based  prospective  memory.  AHI  was  detected  as  an  independent  predic-  tor  of  the  decline  of  event-based  prospective 
memory.  However,  the  coefficient  of  AHI  was  tiny  compared  to  the coefficients for education and the cholesterol concentration 
in  blood.  A  number of previous studies have associated OSA-related cognitive dysfunction with hypoxia [30e32]. Our study may 
further  suggest  that  the  extremely  low  level  of  oxygen  in  the  blood  (even  lasting for short time) is more important to induce the 
neurodegeneration  in  the  brain  than the hypoxemia, which might last for longer time but with a relative higher level of oxygen in 
the blood. 
OSA  causes fragmentation of sleep due to repeated arousals [25]. In a study of patients with insomnia, sleep discontinuity was 
shown  to  damage  the  attention  and  episodic  memory  [33].  In  OSA  patients,  the  number  of  microarousals  predicts  deficits  of 
episodic  memory,  especially  the  recollection  of  spatial  and  temporal  contexts  [34].  In  our  study,  we  have  observed  that  the 
decrease  of  prospective  memory  is  correlated  with  sleep  efficiency  and  microarousal  index,  although  only  sleep  efficiency 
entered the regression analysis to predict deficit of time-based prospective memory. 
It  should  be  noted  that  in  both  stroke and snoring patients, OSA tended to shorten sleeping time at the slow wave stage. SWS 
is essential in the consolidation of declarative memory in young and healthy people [35e39]. As a potential mechanism, the active 
behavior  first generates a labile information store in the hippo- campus; during SWS, this temporally encoded hippocampal infor- 
mation  is  reactivated  and  transmitted  to  the  cerebral  cortex  and  integrated  into  a  more  permanent  memory  [40].  However,  the 
episodic  memory-promoting  effect  of  SWS  is  lost  during  aging  [39,41].  In  epileptic  patients  with  accelerated  long-term 
forgetting,  SWS  adversely  affects  the  declarative  memory  [42].  In  stroke  pa-  tients, SWS activity increases over the infarct area 
and  decreases  at  the  peri-infarct  area  [43].  Moreover,  arteriolosclerosis  and  subcor-  tical  infarcts  in  older  adults  are  associated 
with  sleep  fragmentation  [44].  Thus,  the  effects  of  SWS  on  the  formation  of declarative memory in stroke patients remain to be 
determined. 
Most  importantly,  OSA  is  a  treatable  disorder.  CPAP  therapy  has  been  shown  to  improve  episodic  memory,  attention,  and 
executive-  functioning  in  non-stroke  OSA  patients  [45e47].  Recently,  the  similar  therapeutic  effect  was  also  observed in stroke 
patients suffering of OSA [19]. CPAP and other anti-OSA therapies also improve sleep efficiency and reduce sleep fragmentation 
[46,48]. 
There  are  several  limitations  of  our  study.  First,  the sample size of our study is small. Second, there might be a selection bias 
in  the  sample  of  non-stroke  snoring  patients.  It  is  expected  that  only  these  patients  with  severe  OSA-related  symptoms,  like 
daytime sleepi- ness and significant sleep disturbance, visited our hospital. It might explain why 70.83% snoring patients suffered 
from  OSA  and  most  of  them  were  diagnosed  with  severe  OSA;  the  percentage  of  OSA  patients  is  higher  than  that  of  stroke 
patients.  Third,  stroke  patients were significantly older than non-stroke control patients in our study. During aging, the amount of 
SWS decreases and the frag- mentation of SWS increases, which results in decreased slow-wave 
Y. Zhang et al. / Sleep Medicine 33 (2017) 183e190 189 
activity  [49].  Indeed,  the  sleep-dependent  consolidation  of  declar-  ative  memory  has  been  observed  to  decline  with  aging, 
especially  in  untreated  OSA  patients  [39,41,50].  Thus,  the  contributing  power  of  stroke  was  potentially  overestimated  in  the 
regression  analysis  to  predict  prospective  memory  loss.  Fourth,  we  did  not use a comprehensive neuropsychological assessment 
battery  to  evaluate  cognitive  function  of  stroke  patients.  We  are  not  able to compare the prospective memory deficits with other 
OSA-induced  domain-  specific  cognitive  dysfunction.  Thus,  we  are  unclear  whether  the  prospective  memory  assay  is  the  best 
method to detect cognitive impairment in stroke patients with OSA. 
5. Conclusion 
Our  study  demonstrates  that  OSA significantly and indepen- dently contributes to cognitive dysfunction in Chinese stroke pa- 
tients,  which  is  associated  with  hypoxemia  and  disrupted  continuity  of  sleep.  In  stroke  patients  with  OSA,  proper  anti-OSA 
therapies  might  improve  the  cognitive  function,  facilitate  the  functional  recovery  and  increase  the  quality  of  life  of  stroke 
patients. 
Funding sources 
This  work  was  supported  by  the  program  “Clinical  and  basic  research  of  brain”  (KYC004)  from  the  Kunshan  affiliated 
hospital of Jiangsu University, and the Suzhou development plan for science and technology in 2013 (SYSD2013022, to YZ). 
Conflict of interest 
The authors declare that they have no conflict of interest in regard to this work. 
The  ICMJE  Uniform  Disclosure  Form for Potential Conflicts of Interest associated with this article can be viewed by clicking 
on the following link: http://dx.doi.org/10.1016/j.sleep.2016.11.028. 
References 
[1] Franklin KA, Lindberg E. Obstructive sleep apnea is a common disorder in the population-a review on the epidemiology of 
sleep apnea. J Thorac Dis 2015;7: 1311e22. [2] Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA patients: 
a meta-analysis. J Clin Sleep Med 2010;6:131e7. [3] Valham F, Mooe T, Rabben T, et al. Increased risk of stroke in patients 
with coronary artery disease and sleep apnea: a 10-year follow-up. Circulation 2008;118:955e60. [4] Yaggi HK, Concato J, 
Kernan WN, et al. Obstructive sleep apnea as a risk factor 
for stroke and death. N Engl J Med 2005;353:2034e41. [5] Lee CH, Sethi R, Li R, et al. Obstructive sleep apnea and 
cardiovascular events after percutaneous coronary intervention. Circulation 2016;133:2008e17. [6] Lindberg E, Theorell-Haglow 
J, Svensson M, et al. Sleep apnea and glucose metabolism: a long-term follow-up in a community-based sample. Chest 
2012;142:935e42. [7] Peppard PE, Young T, Palta M, et al. Prospective study of the association be- tween sleep-disordered 
breathing and hypertension. N Engl J Med 2000;342: 1378e84. [8] Kaneko Y, Hajek VE, Zivanovic V, et al. Relationship of 
sleep apnea to func- tional capacity and length of hospitalization following stroke. Sleep 2003;26: 293e7. [9] Yan-fang S, 
Yu-ping W. Sleep-disordered breathing: impact on functional 
outcome of ischemic stroke patients. Sleep Med 2009;10:717e9. [10] Bratton DJ, Gaisl T, Wons AM, et al. CPAP vs 
mandibular advancement devices and blood pressure in patients with obstructive sleep apnea: a systematic review and 
meta-analysis. JAMA 2015;314:2280e93. [11] Salord N, Fortuna AM, Monasterio C, et al. A randomized controlled trial of 
continuous positive airway pressure on glucose tolerance in obese patients with obstructive sleep apnea. Sleep 2016;39:35e41. 
[12] Zaghi S, Holty JC, Certal V, et al. Maxillomandibular advancement for treat- ment of obstructive sleep apnea: a 
meta-analysis. JAMA Otolaryngol Head Neck Surg 2015:1e9. [13] Rothwell PM. AVERT: a major milestone in stroke research. 
Lancet 2015;386: 
7e9. 
 
[14] Leys D, Henon H, Mackowiak-Cordoliani MA, et al. Poststroke dementia. 
Lancet Neurol 2005;4:752e9. [15] Levine DA, Galecki AT, Langa KM, et al. Trajectory of cognitive decline after 
incident stroke. JAMA 2015;314:41e51. [16] Park J, Lee G, Lee SU, et al. The impact of acute phase domain-specific 
cognitive function on post-stroke functional recovery. Ann Rehabil Med 2016;40:214e22. [17] Nys GM, van Zandvoort MJ, de 
Kort PL, et al. The prognostic value of domain- specific cognitive abilities in acute first-ever stroke. Neurology 2005;64: 821e7. 
[18] Aaronson JA, van Bennekom CA, Hofman WF, et al. Obstructive sleep apnea is related to impaired cognitive and functional 
status after stroke. Sleep 2015;38:1431e7. [19] Aaronson JA, Hofman WF, van Bennekom CA, et al. Effects of continuous 
positive airway pressure on cognitive and functional outcome of stroke pa- tients with obstructive sleep apnea: a randomized 
controlled trial. J Clin Sleep Med 2016;12:533e41. [20] McDaniel MA, Einstein GO. The neuropsychology of prospective 
memory in normal aging: a componential approach. Neuropsychologia 2011;49: 2147e55. [21] Berry RB, Budhiraja R, Gottlieb 
DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated 
Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 
2012;8: 597e619. [22] Johns MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of 
wakefulness test and the Epworth sleepiness scale: failure of the MSLT as a gold standard. J Sleep Res 2000;9:5e11. [23] Yu ES, 
Liu WT, Levy P, et al. Cognitive impairment among elderly adults in 
Shanghai, China. J Gerontol 1989;44:S97e106. [24] Wilson BA, Emslie H, Foley J, et al. The Cambridge prospective 
memory test. 
London: Harcourt Assessment; 2005. [25] Kimoff RJ. Sleep fragmentation in obstructive sleep apnea. Sleep 1996;19: 
S61e6. [26] Martin T, McDaniel MA, Guynn MJ, et al. Brain regions and their dynamics in prospective memory retrieval: a 
MEG study. Int J Psychophysiol 2007;64: 247e58. [27] Kant N, van den Berg E, van Zandvoort MJ, et al. Functional correlates 
of 
prospective memory in stroke. Neuropsychologia 2014;60:77e83. [28] Man DW, Chan MK, Yip CC. Validation of the 
Cambridge prospective memory test (Hong Kong Chinese version) for people with stroke. Neuropsychol Rehabil 
2015;25:895e912. [29] Sandberg O, Franklin KA, Bucht G, et al. Sleep apnea, delirium, depressed mood, cognition, and ADL 
ability after stroke. J Am Geriatr Soc 2001;49: 391e7. [30] Yaffe K, Laffan AM, Harrison SL, et al. Sleep-disordered breathing, 
hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011;306:613e9. [31] Gelber RP, Redline 
S, Ross GW, et al. Associations of brain lesions at autopsy 
with polysomnography features before death. Neurology 2015;84:296e303. 
Y. Zhang et al. / Sleep Medicine 33 (2017) 183e190 190 
[32] Launer LJ, Hughes TM, White LR. Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia aging study 
autopsy study. Ann Neurol 2011;70: 774e80. [33] Fortier-Brochu E, Morin CM. Cognitive impairment in individuals with 
insomnia: clinical significance and correlates. Sleep 2014;37:1787e98. [34] Daurat A, Foret J, Bret-Dibat JL, et al. Spatial 
and temporal memories are affected by sleep fragmentation in obstructive sleep apnea syndrome. J Clin Exp Neuropsychol 
2008;30:91e101. [35] Deliens G, Leproult R, Neu D, et al. Rapid eye movement and non-rapid eye movement sleep contributions 
in memory consolidation and resistance to retroactive interference for verbal material. Sleep 2013;36:1875e83. [36] Axmacher N, 
Haupt S, Fernandez G, et al. The role of sleep in declarative memory consolidationedirect evidence by intracranial EEG. Cereb 
Cortex 2008;18:500e7. [37] Cedernaes J, Rangtell FH, Axelsson EK, et al. Short sleep makes declarative 
memories vulnerable to stress in humans. Sleep 2015;38:1861e8. [38] Griessenberger H, Hoedlmoser K, Heib DP, et al. 
Consolidation of temporal 
order in episodic memories. Biol Psychol 2012;91:150e5. [39] Scullin MK. Sleep, memory, and aging: the link between 
slow-wave sleep and episodic memory changes from younger to older adults. Psychol Aging 2013;28:105e14. [40] Mitra A, 
Snyder AZ, Hacker CD, et al. Human cortical-hippocampal dialogue in 
wake and slow-wave sleep. Proc Natl Acad Sci U S A 2016;113:E6868e76. [41] Baran B, Mantua J, Spencer RM. Age-related 
changes in the sleep-dependent 
reorganization of declarative memories. J Cogn Neurosci 2016;28:792e802. [42] Atherton KE, Nobre AC, Lazar AS, et al. 
Slow wave sleep and accelerated 
forgetting. Cortex 2016;84:80e9. [43] Poryazova R, Huber R, Khatami R, et al. Topographic sleep EEG changes in the 
acute and chronic stage of hemispheric stroke. J Sleep Res 2015;24:54e65. [44] Lim AS, Yu L, Schneider JA, et al. Sleep 
fragmentation, cerebral arterio- losclerosis, and brain infarct pathology in community-dwelling older people. Stroke 
2016;47:516e8. [45] Dalmases M, Sole-Padulles C, Torres M, et al. Effect of CPAP on cognition, brain function, and structure 
among elderly patients with OSA: a randomized Pilot study. Chest 2015;148:1214e23. [46] Kushida CA, Nichols DA, Holmes 
TH, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea pa- tients: the 
Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35:1593e602. [47] Castronovo V, Scifo P, Castellano 
A, et al. White matter integrity in obstructive 
sleep apnea before and after treatment. Sleep 2014;37:1465e75. [48] Hetzenecker A, Escourrou P, Kuna ST, et al. Treatment 
of sleep apnea in chronic heart failure patients with auto-servo ventilation improves sleep fragmentation: a randomized controlled 
trial. Sleep Med 2016;17:25e31. [49] Varga AW, Ducca EL, Kishi A, et al. Effects of aging on slow-wave sleep dy- namics and 
human spatial navigational memory consolidation. Neurobiol Aging 2016;42:142e9. [50] Djonlagic I, Guo M, Matteis P, et al. 
Untreated sleep-disordered breathing: links to aging-related decline in sleep-dependent memory consolidation. PLoS One 
2014;9:e85918. 

Potrebbero piacerti anche