Sleep Apnea,Cognitive Profile,and Vascular Changes: An Intriguing Relationship

Abstract

Background:

Sleep breathing disorders can affect cognitive performances through complex brain anatomical and functional changes.

Objective:

Our aim was to evaluate the correlations between cognitive performances and obstructive sleep apnea syndrome (OSAS), as well as the possible influence of vascular factors.

Methods:

Thirty-four non-demented OSAS patients and 34 controls were submitted to a neuropsychological evaluation and to a vascular screening including the study of cerebrovascular reactivity by means of the breath-holding index (BHI) calculation. After 6 months, polisomnographic, neuropsychologic, and hemodynamics assessment was repeated in patients.

Results:

At baseline, some cognitive performances involved in executive and memory functions were significantly lower in patients with respect to controls. Significantly lower values in mean BHI were also detected in patients with respect to controls (p < 0.0001). At the 6-month evaluation, 18 patients had a reduction in OSAS severity (group 1) and 16 remained stable (group 2). Group 1 patients had a significant improvement in left and mean BHI (p < 0.001) and in short-term (p = 0.02) and long-term Rey Auditory Verbal Learning Test (p < 0.001). No change in cerebrovascular reactivity and cognitive profile was detected in group 2 patients.

Conclusions:

Patients with OSAS may experience a reduced cognitive efficiency. Improvement of OSAS was associated to favorable hemodynamic changes and increased level of performances in verbal memory tasks so suggesting an involvement of vascular underlying mechanisms in sustaining cognitive dysfunctions in OSAS. Our preliminary data suggest the need for further studies to deepen the knowledge about the relationships between OSAS, cerebral hemodynamic compromise, and cognitive impairment risk.

Keywords

Cerebral hemodynamics cognitive performances obstructive sleep apnea

INTRODUCTION

Sleep exerts a significant role in the regulation of cerebral activity and preservation of brain anatomic integrity through different and complex mechanisms. During night-time, a remodeling of synapses occurs and, in particular, only necessary synapses are preserved [1]. Moreover, a scavenger role has been suggested by recent experimental studies indicating that cortical interstitial spaces increase by more than 60% during sleep, resulting in an improved efficiency in amyloid-β (Aβ) clearance [2]. Sleep problems could contribute to the pathology of cognitive impairment [3] and the preservation of a restorative sleep is fundamental for memory consolidation through the transfer of information from hippocampus to the anterior brain regions [4]. Sleep is a dynamic process involving a network that may be altered by degenerative processes. Different investigations demonstrated a high prevalence of sleep disturbances in patients with Alzheimer’s disease (AD) [5, 6]. In summary, the interaction between sleep alterations and neurodegeneration is complex and bidirectional.

Obstructive sleep apnea syndrome (OSAS) patients exhibit vascular alterations and brain damages topography similar to those observed in AD patients [3]. Based on these considerations, it can be hypothesized that an early treatment of OSAS should slow or, at least partially, reverse the pathogenic mechanisms involved in the development of cognitive and vascular damage.

The main purpose of this study was to assess the neuropsychological patterns of patients with OSAS. The possibility to influence cognitive performances through an early diagnosis and treatment was also evaluated. In an attempt to expand knowledge about the complex interactions among degenerative changes, sleep profile and vascular alterations in influencing the cognitive status in OSAS patients, an evaluation of cerebral hemodynamics and polysomnographic data was performed.

MATERIALS AND METHODS

Patients were selected from consecutive subjects referred to our sleep outpatient service by general practitioners from 2014 to 2015 for suspected OSAS. The following exclusion criteria were considered: referred or documented or treated dementia from any cause or any severe psychiatric disease; years of education <three years; family history of cognitive impairment; exposure or history of substance abuse in the last 12 months; ongoing therapy with drugs that may impair cognitive functions; neurological diseases or conditions potentially interfering with cognitive activity (i.e., post-traumatic and vascular encephalophaties, neurodegenerative diseases); evidence of carotid, vertebrobasilar, and intracranial stenosis (>50%) or occlusion according to validated criteria [7, 8]; referred or documented cardiac failure (defined as a left ventricular ejection fraction below 50%); referred or documented or treated dementia from any cause or any severe psychiatric disease significant neck vessels stenosis; referred or documented cardiac failure (defined as a left ventricular ejection fraction below 50%); mental retardation; cancer and/or autoimmune diseases; diseases that can lead to cognitive impairment (such as thyroid disorders, syphilis, deficiency diseases, severe liver and kidney diseases, HIV infection); any other sleep disorders in addition to OSAS.

A structural interview was performed in order to deliver information about the possible presence of OSAS. Patients’ partners were involved, especially in the case of unawareness of snoring and breath interruption episodes. All patients underwent a careful physical examination and information collection to rule out other diseases potentially predisposing to OSAS. The following data were also collected: body mass index (BMI), neck circumference, Mallampati score for the assessment of oropharyngeal appearance [9], heart rate and oxyhemoglobin saturation (SpO2) and presence of craniofacial dysmorphism, defined as the presence of retrognathia, micrognathia increase in soft palate thickness, length and area, in tongue’s length and area and in intermaxillay space length [10]. The Berlin questionnaire (BQ) [11] was administered to all patients in order to quantify the risk of OSAS as low and high risk. In high risk patients, a polysomnography (PSG) was performed. Nocturnal PSG recordings were performed using EBNeuro instrument (BE Micro–Holter EEG). The following parameters were recorded: electroencephalogram (EEG) with surface electrodes positioned in F3, F4, C3, C4, O1, O2, electrooculogram (EOG) with 2 electrodes placed 1 cm at the side and 1 cm above or below the external canthus of each eye, mastoid reference (A1 or A2), electromyogram (EMG) with 2 surface electrodes placed in submental region, in correspondence of the mylohyoid muscle. Together with PSG recordings, other parameters were recorded: airflow (using nasal pressure recording), snoring sound (by means of a vibration sensor), electrocardiogram, oxygen saturation (SpO2) of hemoglobin and heart rate obtained from pulse oximetry, thoracic and abdominal movements recorded by using inductive plethysmography, body position (by means of a specific sensor), and thoracic and abdominal respiratory efforts. Sleep events were scored manually according to the American Academy of Sleep Medicine criteria [12]. Evaluation of intracranial circle was performed by means of transcranial Doppler (Multidop X/TCD; Elektronische Systeme, GmbH, Germany) according to validated criteria [8]. Cerebrovascular reactivity to hypercapnia was measured with the Breath-Holding Index (BHI) [13]. This index is obtained by dividing the percentage increase in mean flow velocity (MFV), occurring during breath-holding, by the length of time (seconds) the subjects hold their breath after a normal inspiration. BHI = ([breath-holding MFV – basal MFV/basal MFV]×100/seconds of breath-holding). Two transducers placed on the temporal bone window with a stable angle of insonation secured by a head frame were used to obtain a bilateral continuous measurement of flow velocity of middle cerebral arteries. Subjects were requested to hold their breath for a period of 30 s. Breath-holding length and efficiency was monitored by a capnometer. For each patient, three recordings were obtained, and the BHI values included in the analysis were the mean of the three tests. For the analysis, left, right and mean (right-left) values were considered.

All study subjects underwent a global cognitive status screening assessment (MMSE) [14] followed by a single cognitive domain neuropsychological evaluation. In particular, all subjects were tested with specific and standardized neuropsychological tasks exploring cognitive aspects that have been frequently described as involved in OSAS patients [15]: logical-deductive abilities: Progressive Raven Matrices [16]; selective and sustained attention: Stroop Colour Word Test [17]; verbal and spatial working memory: Digit Span and Corsi Cubes respectively [18]; verbal fluency: Category Fluency Test [19] and Letter Fluency Test [20]; constructive praxis: Rey Figure B copy [21]; spatial memory: Rey Figure B immediate (ST) and delayed (LT) recall [21]; verbal memory: Rey Auditory Verbal Learning Test (Rey AVLT short- term/long- term) [22, 23].

Controls subjects were recruited from consecutive subjects undergoing neck vessels ultrasonographic examination for the presence of vascular risk factors in the outpatient department in which a diagnosis of OSAS was excluded based on the results of a structured interview including the administration of the BQ [11]. They were selected by matching them for age and sex with the analyzed cohort first. Then, we chose a frequency-matching approach to check for potential confounders and standardize the cohort’s characteristics (years of education, BMI and proportion of diabetes, hypertension, smoking, and dyslipidemia). All included control subjects were submitted to the same protocol of cognitive and vascular assessment planned for OSAS patients.

After inclusion, pharmacological treatment of vascular risk factors was planned according to international guidelines [24]. For OSAS patients, the most appropriate treatments and corrective approaches including continuous positive airway pressure (CPAP), weight loss, abstinence from alcohol or tobacco consumption, respect of sleep hygiene, correct body position in bed and use of oral appliances were recommended.

Six months (T₁) after inclusion (T₀), patients were submitted to the following evaluations:

nocturnal polysomnigraphy to assess the evolution of the sleep parameters (the exam was performed after a 7-day interruption of CPAP);

neuropsychological assessment to evaluate the onset of cognitive impairment or a possible modification of the neuropsychological profile;

ultrasonographic evaluation of intracranial vessels to assess cerebral hemodynamics.

Clinical conditions and adherence to prescribed therapy were assessed. All participants gave their informed written consent according to the Declaration of Helsinki.

Statistical analysis

Sex and OSAS severity were synthesized as binary variables. OSAS improvement at 6 months was collected as a dichotomous factor, and was used as the main grouping variable. Subjects who had a polysomnographic improvement after treatment were labeled as group 1. Patients who remained stable despite treatment were labeled as group 2.

Age, left BHI at baseline (T₀) and at 6 months (T₁), right BHI at T₀ and at T₁, mean BHI at T₀ and T₁, neuropsychologic variables at T₀ and T₁ were collected and treated as continuous variables. All the polysomnographic parameters recorded, such as apnea-hypopnea index (AHI), oxygen desaturation index (ODI), % time spent with SaO2 <90% (T 90), % average desaturation (AD Sa = 2), % sleep efficiency (SE), total sleep time (min), % N1 sleep of total sleep time, % N2 sleep of total sleep time, % N3 sleep of total sleep time, % REM sleep of total sleep time, and sleep onset (min), were synthesized as continuous factors.

When comparing continuous variables between group 1 and group 2, we adopted t-test for paired samples. When we confronted continuous factors between the case and the control group we used thet-test for independent samples. Dichotomous variables were cross-tabulated and compared with chi-squared test.

A GLM/multivariate model for repeated measures considering group 1 and group 2 was set up to analyze the relationship between OSAS improvement after therapy and mean of BHI at T₀ and T₁ controlling for age and sex as covariates. The same model was then adopted to evaluate how OSAS and BHI improvement could impact on neuropsychological outcomes and sleep parameters, selecting only the tests that were significantly different at T₀ and T₁.

RESULTS

Thirty-four OSAS patients and 34 controls were included. Mean age, sex distribution, BMI, years of education, prevalence of hypertension, diabetes, smoking habit, dyslipidemia were similar in the two groups (Table 1). All included subjects were right-handed.

Table 1

Demographic characteristics of OSAS patients (whole population and divided in two groups according to the evolution of OSAS after treatment) and healthy controls

	Patients	Controls	p	Group 1	Group 2	p
	n = 34	n = 34		(improved)	(stable)
				n = 18	n = 16
Age (±SD)	65.05 (±8.99)	66.08 (±7.88)	0.617	63.40 (±10.19)	66.81 (±9.31)	0.338
Male sex (n, %)	28 (82.9%)	29 (85.2%)	0.741	16 (88.9%)	12 (75.0%)	0.290
Education, y (±SD)	7.26 (±2.36)	6.98 (±3.04)	0.673	8.19 (±3.26)	7.09 (±1.96)	0.249
BMI (±SD)	25.35 (±4.22)	26.17 (±2.14)	0.316	25.69 (±4.32)	24.96 (±3.97)	0.511
Hypertension n (%)	20 (58.8%)	18 (52.9%)	0.625	11 (61.1%)	9 (56.2%)	0.774
Dyslipidemia n (%)	12 (35.3%)	13 (38.2%)	0.801	7 (38.9%)	5 (31.2%)	0.642
Diabetes n (%)	8 (23.5%)	9 (26.4%)	0.779	5 (27.8%)	3 (18.7%)	0.536
Smoking n (%)	6 (17.6%)	5 (14.7%)	0.742	3 (16.7%)	3 (18.7%)	0.874

Patients with an AHI between 15 and 30 were considered to have moderate OSAS (n = 19), and patients with an AHI greater than 30 had severe OSAS (n = 15) [25]. Treatment with CPAP was prescribed to all patients in addition to all the other conservative and non-conservative adjunctive treatments.

Regarding cognitive profile, t-test showed some significant differences between patients and controls. In particular, the cognitive performances were lower in patients with respect to controls in the following tasks: Stroop Test T1 and T2 (the time required for completion of the first and second part of the test) and E1 and E2 (the number of mistakes made in the first and second part of the test) (p < 0.001), Rey Figure short-term (p = 0.035), Rey AVLT short-term/long-term (p < 0.0001 and <0.001, respectively) and semantic and phonetic fluency test (p < 0.001). Considering cerebrovascular reactivity, we observed a significant difference between patients and controls in mean BHI (p < 0.0001). These findings are described in details in Table 2.

Table 2

Results of the cognitive evaluation and cerebrovascular reactivity test (BHI) in patients at baseline (T₀) and in controls. Values are mean±SD

Neuropsychological evaluation	Patients (T₀)	Controls	p
Mini-Mental State Examination	28.58 (±1.86)	28.63 (±1.07)	0.892
Progressive Raven Matrices	28.26 (±6.01)	29.84 (±3.97)	0.205
Stroop Test T1^*	36.53 (±7.46)	30.28 (±8.45)	<0.001
Stroop Test T2^*	79.56 (±13.87)	66.43 (±16.36)	<0.001
Stroop Test E1^*	2.35 (±1.20)	0.05 (±0.25)	<0.001
Stroop Test E2^*	2.41 (±3.05)	1.05 (±2.07)	0.035
Digit Span	4.94 (±1.39)	5.20 (±0.87)	0.359
Corsi Cubes	5.05 (±1.13)	4.86 (±0.78)	0.423
Rey Figure short-term^*	20.38 (±9.07)	23.98 (±3.34)	0.035
Rey Figure long-term	19.85 (±9.19)	22.90 (±3.80)	0.080
Rey AVLT short-term^*	25.12 (±13.75)	40.45 (±7.98)	<0.0001
Rey AVLT long-term^*	5.49 (±3.68)	8.02 (±2.33)	<0.001
Verbal Fluency^*	36.61 (±10.97)	44.37 (±8.13)	<0.001
Phonetic Fluency^*	23.29 (±10.01)	34.87 (±9.87)	<0.001
BHI mean value^*	0.753 (±0.30)	1.160 (±0.24)	<0.0001

^*significant differences.

Then, we classified OSAS patients in group 1 (n = 18): subjects who had an improvement in OSAS severity after treatment and group 2 (n = 16): subjects whose OSAS severity remained stable. Classification of OSAS as improved or stable was based on the AHI values at T₁ that allowed to verify whether each single patient could be switch to a lower OSAS severity category (from severe to moderate or mild and from moderate to mild or absent).

Group 1 and group 2 did not significantly differ regarding baseline OSAS severity, BMI, age, sex, and prevalence of hypertension, diabetes, smoking, and dyslipidemia (Table 1).

In group 1 patients a significant difference in AHI (p < 0.001), ODI (p < 0.001), and T 90 (p = 0.022) between T₀ and T₁ was detected (while the other parameters remained stable. Group 2 subjects did not show any significant difference between T₀ and T₁ (Table 3).

Table 3

Polysomnographic data at baseline (T₀) and at the 6-month follow-up evaluation (T₁) in patients with improved or stable OSAS severity. Values are mean±SD

PSG	Group 1 (improved) n = 18			Group 2 (stable) n = 16
	T₀	T₁	p	T₀	T₁	p
AHI^*	31.17 (±15.02)	25.94 (±4.51)	<0.001	32.12 (±15.61)	33.09 (±14.72)	0.858
ODI^*	32.98 (±16.17)	23.31 (±7.81)	<0.001	24.03 (±12.52)	27.11 (±9.43)	0.438
T 90 (%)^*	18.21 (±21.44)	12.62 (±16.26)	0.022	15.14 (±8.77)	17.36 (±10.28)	0.516
AD SaO2%	87.70 (±3.04)	83.88 (±18.67)	0.235	85.24 (±3.85)	84.27 (±5.73)	0.578
SE (%)	77.20 (±20.82)	83.10 (±15.06)	0.527	78.22 (±7.61)	80.46 (±4.38)	0.316
TST(min)	326.48 (±137.77)	306.44 (±125.28)	0.669	373.55 (±125.25)	382.33 (±105.26)	0.831
N1 (%)	18.18 (±11.97)	16.22 (±12.78)	0.638	20.3 (±3.78)	18.71 (±4.86)	0.309
N2 (%)	54.44 (±15.61)	53.89 (±17.39)	0.921	51.85 (±4.27)	54.34 (±6.52)	0.211
N3 (%)	9.75 (±6.58)	11.06 (±8.51)	0.609	12.70 (±0.56)	11.23 (±3.44)	0.102
REM (%)	16.90 (±5.8)	18.71 (±4,97)	0.322	15.24 (±5.95)	15.87 (±2.92)	0.706
SOL (min)	14.34 (±8.77)	15.91 (±10.23)	0.624	14.34 (±8.77)	15.91 (±10.23)	0.644

^*significant differences. AHI, apnea–hypopnea index; ODI, oxygen desaturation index; T 90, Time spent with SaO2 < 90_%; AD Sa02, average O2 desaturation; SE, sleep efficiency; TST, total sleep time; N1, N1 sleep of total sleep time; N2, N2 sleep of total sleep time; N3, N3 sleep of total sleep time REM sleep of total sleep time Sleep onset latency; REM, REM sleep of total sleep time%; SOL, sleep onset latency.

Group 1 patients had a significant difference between the two evaluations in left BHI and mean BHI (p < 0.001). No significant difference in cerebrovascular reactivity was found in group 2. Analyzing the cognitive profile, a significant difference in short-term (p = 0.02) and long-term Rey AVLT test (p < 0.001) between T₀ and T₁ was found in group 1. No difference was detected in group 2 subjects (Table 4).

Table 4

Hemodynamic and cognitive results obtained at entry (T₀) and at the 6-month follow-up evaluation (T₁) in patients with stable or improved OSAS severity. Values are mean±SD

Variable	Improved (n = 18)			Stable (n = 16)
	T₀	T₁	p	T₀	T₁	p
Right BHI	0.769 (±0.39)	0.917 (±0.27)	0.12	0.817 (±0.352)	0.843 (±0.453)	0.74
Left BHI^*	0.669 (±0.36)	0.917 (±0.43)	<0.001	0.818 (±0.288)	0.880 (±0.213)	0.50
Mean BHI^*	0.676 (±0.32)	0.888 (±0.32)	<0.001	0.830 (±0.271)	0.872 (±0.254)	0.31
BMI	25.69 (±4.32)	26.32 (±3.68)	0.64	24.96 (±3.97)	26.01 (±4.21)	0.47
MMSE	28.7 (±1.48)	29.0 (±1.72)	0.22	28.43 (±2.25)	28.63 (±2.18)	0.61
Progressive Raven Matrices	27.50 (±7.33)	29.7 (±5.29)	0.23	29.13 (±4.13)	26.75 (±6.40)	0.09
Stroop Test T1	37.39 (±15.7)	34.0 (±11.61)	0.22	35.56 (±19.7)	31.69 (±7.23)	0.42
Stroop Test T2	80.94 (±50.8)	79.6 (±55.95)	0.72	78.00 (±36.2)	72.2 (±30.5)	0.22
Stroop Test E1	4.28 (±17.6)	11.0 (±46.42)	0.33	0.19 (±0.544)	0.06 (±0.250)	0.16
Stroop Test E2	1.83 (±3.68)	2.28 (±5.57)	0.69	3.06 (±4.06)	7.44 (±13.6)	0.14
Digit Span	4.83 (±1.69)	4.89 (±0.90)	0.89	5.06 (±0.998)	5.13 (±0.806)	0.72
Corsi cubes	5.15 (±1.29)	5.10 (±1.01)	0.77	4.94 (±0.929)	4.88 (±1.408)	0.87
Rey Figure short-term	22.1 (±8.13)	23.1 (±8.05)	0.18	18.44 (±9.93)	21.13 (±10.3)	0.20
Rey Figure long-term	21.4 (±8.50)	21.8 (±9.24)	0.74	18.09 (±9.89)	19.88 (±10.4)	0.33
Rey Words short-term^*	23.9 (±13.8)	34.1 (±13.9)	0.02	26.23 (±14.2)	23.46 (±11.6)	0.20
Rey Words long-term^*	5.19 (±10.6)	8.44 (±9.77)	<0.001	3.92 (±2.98)	2.23 (±2.52)	0.19
Verbal Fluency	34.9 (±13.9)	38.3 (±12.90)	0.27	38.44 (±6.22)	37.94 (±8.58)	0.70
Phonetic Fluency	24.2 (±11.3)	28.0 (±10.09)	0.13	22.31 (±8.63)	25.94 (11.41)	0.14

^*significant differences.

GLM/Multivariate model for repeated measures was run to evaluate changes in cerebrovascular reactivity and neuropsychological variables and to assess the differences between subjects of group 1 and group 2 correcting for covariates. In the first model, mean BHI values resulted significantly improved for group 1 subjects (T₀: 0.833; 95% CI:0.667–0.999; T₁: 0.875; 95% CI:0.714–1.037; p = 0.009) whilethey remained stable in group 2 patients (T₀: 0.833;95% CI:0.667–0.999; T₁: 0.875; 95% CI:0.714–1.037; p = 0.009).

We then applied the same multivariate model to left and right BHI, underlining that right BHI was not statistically different in the two time points in both groups, while left BHI was significantly higher at T₁ with respect to T₀ only in group 1 subjects.

DISCUSSION

The results of this study show the presence of a significant association between OSAS and reduced efficiency in cognitive performances in subjects without a history of dementia. The simultaneous presence of a significant difference in some neuropsychological performances and cerebrovascular reactivity status between patients and controls suggests a possible pathogenic role of unfavorable circulatory changes in sustaining the cognitive dysfunctions in OSAS. Episodes of apnea-hypopnea are accompanied by brief microarousals resulting in sleep fragmentation and diminished amounts of slow wave and REM sleep [26]. Consequently, an improvement of the nocturnal respiratory status obtained by a reduction in OSAS severity, is expected to induce favorable changes in sleep architecture. In the group of patients who had an improvement of OSAS severity, we did not observe significant changes in sleep parameters but only a slight tendency to improve. This unexpected result may have various explanations including the possibility that the different duration of the disease may have influenced the potential for reversibility of the unfavorable changes in sleep architecture. In this respect, we were unable to precisely define when each included patient had begun to suffer from OSAS. Moreover, different OSAS phenotypes might explain the variability in the response to treatment. In our study, we only analyzed sleep macrostructure. It is possible that the study of sleep microstructure would have been able to provide greater potential in monitoring the effects of CPAP treatment [27]. In the present study, we did not investigate the possible presence of other subtle sleep disorders including periodic limb movements that can be present regardless of patient’s awareness and therefore they are not normally detected on history collection but require an instrumental evaluation [28]. Alzheimer’s disease, which is the most common form of dementia, affects millions of people and its prevalence is continuously and dramatically increasing [29]. The lack of effective therapies and the demonstration that the clinical manifestations of AD appear many years after the gradual occurrence of pathological changes in the brain, has underlined the necessity to shift attention on the identification of modifiable risk factors [30]. Different investigations have underlined a significant correlation between OSAS and cognitive alterations [3]. The increasing amount of evidence regarding the possible involvement of vascular factors in promoting cognitive deterioration [31] has suggested that brain hypoperfusion plays a pivotal role in sustaining the pathogenic link between OSAS and cognitive deterioration [32, 33]. In this respect, the fragmentation of sleep and hypoxia occurring in OSAS patients, may induce an altered deposition of Aβ and a cholinergic dysfunction that are well-known conditions able to produce microvascular dysfunction that, in turn, is a risk factor for the promotion of degenerative changes [34, 35]. This particular aspect seems to configure a vicious circle in which neurodegenerative, vascular and respiratory pathologic changes feed each other so contributing to the development of dementia.

In the present study, we focused our attention on subjects without clinically relevant cognitive dysfunctions in order to verify whether the presence of OSAS was associated with subclinical reduced cognitive performances. Our data, besides confirming the presence in OSAS patients of a performance reduction in tasks exploring sustained attention, verbal memory, and semantic and phonetic fluency, suggest that an effective treatment may improve mental abilities, in particular the memory functions. It is interesting to underline that an increased score in verbal memory tasks, observed in the group of patients who had a severity reduction in OSAS after a 6-month period of treatment, was associated to a recovery in vasomotor reactivity. The correspondence between mental performances and the hemodynamic status in cerebral areas involved in the specifically investigated cognitive activity, has been previously investigated and demonstrated [36, 37]. The possibility that the simultaneous improvement in cognitive and hemodynamic aspects has a specific pathophysiologic link, is suggested by the fact that the improvement in the scores of Rey AVLT short and long-term, that explore left mesial temporal lobe functions, was associated to an increase in the ipsilateral BHI. There is no apparent reason for explaining the lack of a significant difference in right BHI between baseline and follow-up evaluation in the group of patients with improved OSAS. It could be hypothesized that the relatively low number of patients have influenced this result by preventing the achievement of a significant difference between baseline BHI values and those obtained after treatment. In our study population, about half of the patients did not show an improvement in their nocturnal respiratory parameters. A relevant cause might be a reduced compliance to CPAP treatment. Regarding this aspect, we were unable to obtain precise information since most of patients did not perform the necessary instrumental controls to assess the adequacy of the CPAP treatment and data were delivered by means of an interview at the end of the follow-up. Finally, in some cases, the compliance with additional indicated measures, such as weight loss, abstinence from alcohol or tobacco consumption, respect of sleep hygiene, correct body position in bed, and use of oral appliances might have been insufficient.

CPAP can reduce or delete respiratory unfavorable events leading to a recovery from hypoxia and sleep fragmentation. Improvement of nocturnal circulatory conditions may reduce vascular morbidity and mortality [38 –40]. Although it has been demonstrated that CPAP treatment can increased gray matter volume in the hippocampal and frontal regions, data about the efficacy in improving cognitive activities are controversial [3 , 42]. The timeliness and precocity of OSAS diagnosis and treatment is probably the main reason for the contradictory data about this issue. Accordingly, in our study, the reduction of OSAS severity was not associated to an improvement in all the cognitive performances. It is possible that in some patients, anatomic and functional alterations were already stabilized and not subject to change at the start of treatment. The same problem may also justify the finding of a partial recovery of cerebrovascular. Our study has several limitations. Among them, the small sample size, the lack of neuroimaging data and of precise details about the adherence to CPAP and other conservative treatments should be underlined. Further, even if patients were consecutively selected, the percentage of men included in our study was above 80%. This aspect can have different explanation, including a higher prevalence of sleep-related breathing disorders in men that also have more evident clinical manifestations, thus increasing the probability of a more rapid request for a medical consult with respect to women [43]. However, the imbalance between men and women suggest caution for the generalization of our results.

Due to the above-mentioned limitations, the results of our study should be considered as preliminary but able to raise working hypotheses for the planning of systematic investigations aimed at managing people with sleep-related breathing disorders.

According to our preliminary results, sleep and vascular disorders should be carefully investigated early in subjects at risk for cognitive deterioration. A full consideration and evaluation of the possible presence of sleep disorders require a comprehensive strategy aimed at reducing the burden of cognitive deterioration. In particular, detecting and treating OSAS before the occurrence of irreversible cerebral changes should be considered of keen interest for the clinical implications related to increase the prevention strategies for reducing the risk of dementia.

Footnotes

ACKNOWLEDGMENTS

The study was partially supported by the Italian Association for the Research in Alzheimer’s Disease (AIRAlzh Onlus) and by a research grant from the National Consumers’ Cooperatives – Coop (ANCC-COOP), Italy.

Authors’ disclosures available online ().

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