Assessment of Sleep Pattern in Egyptian Elderly with Vascular Dementia

Study Objectives: Growing evidence suggests that sleep disturbances is common in vascular dementia (VaD). The goal of the current study is to assess the disturbance in sleep pattern in patients with VaD, and compare it to healthy normally cognitive elderly individuals. We next studied whether there are meaningful differences in the Subjective sleep assessment: Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and sleep measurements by polysomnography (PSG) in VaD patients. Study design: Case control study. Subject and methods: Overnight PSG recordings and self-reported sleep measures were obtained from 20 healthy elderly subjects and 20 VaD patients at the sleep laboratory. Results: This study showed abnormal subjective sleep quality in all patients and revealed that the most common sleep complaints among VaD patients were: excessive daytime sleepiness (EDS), sleep disordered breathing (SDB), insomnia, restless leg syndrome (RLS), periodic limb movements (PLMS) and REM behavioral disordered (RBD) respectively. Moreover, patients spent more time in stage I sleep, but less time in slow wave sleep (SWS) and REM sleep compared to control populations, with delayed REML and less 1 st REML. Also, increased sleep fragmentation; wakefulness after sleep onset (WASO) & sleep fragmentation index (SFI), increased arousal index (AI) & PLMS index were detected in VaD patients. prevention of progression of VaD.


Introduction
Vascular dementia (VaD), the second most common cause of dementia after Alzheimer dementia (AD), represents not less than 20% of cases and is expected to increase in coming years [1]. The pervasiveness of both VaD and AD rises dynamically with age, with the risk of VaD doubling every 5.3 years [2]. Vascular-type pathology and mixed pathology are respectively two and three times more likely in demented patients [3]. In Egypt, the dementia prevalence ranged from 2.01% to 5.07% and dementia increased with age, with the rapid increase among those aging >80 [4].
Because of their dependency and negative financial impact upon their families and healthcare providers, VaD is a major public health issue and its prevention playing the crucial role [5].
Sleep is important to normal cognitive functioning, particularly for the formation and consolidation of new memories. Circadian rhythm and sleep complaints are common in the aging population, particularly in those with dementia [6]. In vascular dementia, neuropsychiatric manifestations are very common (90%), and the most common presenting symptoms are sleep disturbances (61%), depression (46%), and apathy (44%). Sleep disturbance is one of the most important domains of behavioral and psychological symptoms in patients with dementia. Past research has demonstrated that sleep disturbance is related to reduce executive function and an increased mortality rate in older adults [7].
Accurately diagnosing sleep disorders in dementia patients can be quite tricky, due to an abundance of underlying causes, mitigating factors and common causal symptoms. Given the rising prevalence of vascular dementia with aging, the development of more sensitive diagnostic and prognostic tools will be critical for elucidating and modifying VaD pathophysiology to alleviate the personal and socioeconomic impact of cognitive decline in the elderly [8]. Also any delay of early detection or corrective treatment of vascular cognitive impairment (VCI) causes the condition to progress to dementia [9]. Also, patients with mixed pathologies have nearly twice the incremental risk of dementia compared with patients with only Alzheimer-type lesions. Consequently, many cases of dementia could be prevented or delayed by targeting the vascular component [10].
In the current study, we assessed the disturbance in sleep pattern by both the sub-   [13]. Mood assessment by

Study Subject
Cornell Scale for Depression in Dementia [14] and Taylor Anxiety Scale were used to exclude patients with depression or anxiety [15]. Subjective sleep assessment was assessed using psychometric sleep assessment questionnaire (applied to the caregivers); an Arabic version for sleep evaluation [16]. This instrument includes validated Arabic translations of other sleep assessment scales; 1) The PSQI [17] and 2) Subjective daytime sleepiness assessment using the ESS [18]. Objective sleep assessment was done using PSG. PSG record includes the following parameters; the electroencephalogram (EEG, leads C3-A2 and 01-A2),

Statistical Analysis
Data were processed by standard analytical procedures [20]

Demographic Data
VaD patients and control group showed similar demographic profiles (Table 1).
There were with no statistical significant difference as regards age or sex between both groups. But there was statistical significant difference between both groups regarding body mass index (BMI) with high BMI in the VaD group. As regards activities of Daily Living (ADL) there was statistical significant difference between VaD group and control group, most of VaD patients had low ADL. There was statistical significant difference between VaD group and control group regarding CDR ( Table 2).
There was a statistical significant difference between VaD group and control group regarding MMSE (Table 3).

Subjective Sleep Assessment
There was a statistical significant difference between VaD group and control group regarding ESS and PSQI between both groups with higher results among patient group (Table 4).
There was a statistical significant correlation between CDR & MMSE and PSQI (the more severe the cognitive impairment, the poorer sleep quality). But, there was no statistical significant correlation between CDR & MMSE and ESS (no relation between degree of cognitive impairment and excessive daytime sleepiness) ( Table 5).

Polysomnography Results
As regards sleep efficiency and continuity, the results showed poorer sleep efficiency,

Discussion
Sleep is considered to be important for cognitive function, cognitive deficits and sleep disorders are influenced by one another [21]. Given the rising prevalence of cerebrovascular diseases and dementia with aging, the development of more sensitive neuropsychological and neuroimaging diagnostic and prognostic tools, will be crucial for elucidating and modifying VCI pathophysiology to develop new modes of intervention for disease prevention and treatment.
The present study revealed significant correlation for Apnea, RDI & SPO2 with BMI; more Apnea and RDI with high BMI and more average SpO2 desaturation with high BMI.
Hypertension was present in 80% of VaD patients in this study. These findings denote the importance of hypertension as risk factors for vascular dementia.
This fact was supported by the report of Hebert et al. (2000) [22]. Also, hyperlipidemia was present in 80% and cardiac diseases in 60% of VaD patients. Diabetes mellitus (DM) was present in 50% of VaD patients in this study. The association between dementia and DM can be explained through the effect of DM on cerebral blood flow especially with regards to reactivity and autoregulation or serving as a risk factor for clinically overt and silent brain insults.
However, the severity of SPO2 desaturation, was associated with high ESS; excessive daytime sleepiness and also those with an abnormal ESS had higher BMI and higher AHI. Taken together, the data suggests that SE and continuity was poorer in patients with VaD in this study, as the sleep-wake cycle is regulated by a complex interplay of mechanisms located mainly in the brainstem, hypothalamus, and thalamus [29]. And any lesion such as an acute stroke, which directly affects the thalamocortical network function has the potential to disrupt the sleep-wake cycle and lead to sleep disturbances [30]. As lesions of the cortex might compromise this process with abnormal deactivation of frontal and thalamic areas from presleep wakefulness to non-REM sleep and hence primarily affect sleep continuity [31].
In the present study there was a significant negative correlation between AI & RDI and ADL and significant correlation for SE, AI & RDI with the ESS score severity. Similar results were reported by Jiang et al. (2013) as they found that patients with vascular cognitive impairment-no dementia had higher PSQI scores compared with controls [9]. Compared with controls, patients had reduced TST, decreased SWS and REM sleep, longer SL, lower SE, and increased AI and PLMS index.
The present study was guided by the idea that REM sleep parameters may reflect different pathophysiological mechanisms between AD and VaD.
As, cholinergic neurons are important determinants of REM sleep, with cholinergic activity low during SWS and high during REM sleep [32]. Stroke causes a central imbalance of neurotransmitters, such as acetylcholine, serotonin, and melatonin, causing sleep structure abnormalities [33]. A similar REM parameter dysfunction was present in AD; reduced REM duration, and increased first REML episode [34]. But, this can be explained because of the dependence of REM sleep on the integrity of cholinergic neurotransmission and the widespread deterioration of cholinergic systems throughout the basal forebrain in AD [35].
The present study revealed a positive significant correlation between ESS, Apnea, RDI & SPO2 and BMI score. Similar findings were reported by Bassetti et al. (2006), as they found a significant correlation between apnea-hypopnea index and BMI [36]. Also, Erkinjuntti et al. (1987) reported that patients with multi-infarct dementia tended to have more apneas/hypopneas than those with AD, and apneas/hypopneas tended to increase in direct proportion to the severity of dementia [37]. However, Karaca (2016) found no correlation between BMI and sleep quality (PSQI) [38]. This discrepancy may result from differences in evaluation methods; subjective and/or PSG, and differences in the patients' age range.
Circadian rhythm disturbances are common in patients with dementia and affect more than 80 % of those over age 65, resulting in insomnia, excessive daytime sleepiness, and day/night reversal [39]. Similar to the present study, Guarnieri et al. (2012) found that VD patients had disrupted sleep-wake cycles asso-  [24]. Both the degradation of sleep quality and the disintegration of the sleep-wake cycle in VaD may reflect the disruptive effects of the vascular lesions on the neural network dedicated to sleep regulation. Since most of the lacunes in VaD are located predominately in the internal capsule, basal ganglia, and the periventricular white matter. These lesions could disconnect the pathways leading to and from the suprachiasmatic nucleus, which might be involved in the regulation of the circadian sleep-wake cycle. Furthermore, stroke lesions may alter other circadian functions such as sleep-related secretion of growth hormone and melatonin [40]. Post stroke hypersomnia or EDS is due to reduced arousal because of lesions involving the ascending arousal pathways. This occurs in patients with bilateral lesions of the thalamus, subthalamic and hypothalamic area, tegmental midbrain, and pons, where fibers of the ascending arousal pathways can be severely injured even by single small lesions [41]. White matter hyperintensities (WMHs) severity was significantly associated with sleep disturbance, with most symptoms related to daytime hypersomnolence and restless sleep. This finding might be explained by disruption of the frontal-subcortical neuronal circuits and basal ganglia [42]. Baillet et al. (2017) found that a higher sleep fragmentation was associated with a reduction in white matter integrity due to WMHs [43]. Also, greater sleep fragmentation was associated with more severe arteriolosclerosis and subcortical infarcts in brain autopsies in community-dwelling older people [44].
Strokes related insomnia are associated with caudate or subcortical, thalamic and brainstem (thalamo-mesencephalic, pontomesencephalic, and pontine tegmentum) lesions. Patients may presented by inversion of the sleep-wake cycle with insomnia, night-time agitation, and daytime hypersomnia [45].
Researchers have been unable to link SDB frequency, type, or severity to the location of the stroke, however autonomic networks responsible for respiratory control may be disrupted with lesions in forebrain structures that control respiration as part of integrated behaviors such as speech or exercise [46]. Hemispheric strokes in the frontal cortex, basal ganglia, or internal capsule may cause respiratory apraxia, with impaired voluntary modulation of breathing amplitude and frequency, leaving patients unable to take a deep breath or hold the breath [47]. Also, the medulla may be less responsive to rising Pco 2 levels during sleep [48]. SDB includes; OSA, central and mixed apnea; is linked with white matter disease on magnetic resonance imaging and silent strokes [49]. SDB patients are at a higher risk of developing cognitive impairment or incident AD [50] [51].
OSA is a common feature of vascular dementia, and leads to fragmented sleep, increased nocturnal confusion, and excessive daytime sleepiness [52]. In the acute post-stroke period, there is a high prevalence of central apneas, which typically resolve [53]. Central sleep apnea and Cheyne-Stokes respiration is caused by motor dysfunction that lead to destabilization of the upper airways due to involvement of pyramidal-related musculature without affecting swallowing and cause a higher instability of the upper respiratory tract during the night [54]. Post stroke PLMS may be of primary type; is not always associated with sleep disturbance, and may be due to unilateral hemispheric, pontine base or tegmentum and spinal strokes [55]. But, patients with bilateral RLS had lesions in both the corona radiata and basal ganglia, whereas patients with lesions only in the corona radiata had either contralateral or bilateral RLS [56]. Most commonly, RLS was accompanied by PLMS in sleep [47]. A common mechanism behind both PLM and RLS might be due to dysfunction of the dopaminergic system, possibly on the level of either pre-and/or post-synaptic striatal and/or spinal dopamine receptors [57]. Evidence supporting an association between wandering in dementia and RLS and/or PLMS; as neuroimaging studies have suggested reduced dopamine reuptake in the caudate and putamen among AD patients who wander relative to those who did not [58]. Cases of stroke have been described in association with RBD include lesions in the pontine tegmentum, midbrain, or paramedical thalamus which may trigger visual hallucinations, especially at sleep onset [59]. Thalamus, temporal, parietal, and occipital lobes strokes may lead to increased dreaming and nightmares and/or a syndrome of dream-reality confusion [60]. Patients with strokes in the pons, midbrain, or paramedian thalamus may experience peduncular hallucinosis which characterized by complex, colorful, dreamlike visual hallucinations, especially in the evening and at sleep onset. Peduncular hallucinosis may represent a release of REM sleep mentation and may be associated with insomnia [45].
In this study there were no significant correlation between MRI findings (the presence of cortical or subcortical infarction, frontal, thalamic or lacunar infarction, different types of diffuse white matter hyperintensities, degree of brain atrophy and side of infarction; left, right or bilateral) and sleep parameters (subjective sleep assessment; ESS & PSQI or PSG parameters; SE, SL, AI, RDI & SPO2, WASO and SFI) and this might be due to associated widespread injury and dysfunction throughout the brain in cases of stroke [61]. Similar findings were reported by Karaca (2016) who reported that there was no significant correlation between right-left cerebral involvement and sleep quality [38]. Lutsey et al. (2016) found that neither OSA nor abnormal sleep duration were statistically significantly associated with cerebral infarcts, white matter brain volumes or regional brain volumes by MRI imaging in VaD and AD patients [62].
However, some studies suggest that right-sided strokes decrease REM and REM density, while left-sided strokes decrease NREM stages. Körner et al. [63] found Simple questions of the patient or bed-partner for the symptoms and signs of the OSA, such as loud snoring, observed apneas, and daytime sleepiness, would help identify those in need of further diagnostic evaluation as OSA which is a treatable disorder [68]. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline. Instrumental assessment; PSG should be used in selected patients.

Limitations and Strengths
This study has some limitations which have to be taken into consideration. First, the sample size was relatively small, resulting in low statistical power for detecting significant differences between groups. Second, the difficulty of doing second PSG to confirm results and any day to day variation of sleep disturbances. Third, the sample lack different stages of VaD, as severe cases were excluded from the study.
Despite these limitations this work is unique in that: 1) used an extensive clinical evaluation including a combination of neurological examinations and a detailed neuropsychological tests in order to define the cognitive status of each participant; 2) assessment of sleep disorders by means of subjective and objective instruments as, PSG is essential for a correct diagnosis of some sleep disturbances like SDB and measures sleep architecture; 3) state-of-the-art brain MRI assessment was used and; 4) provide insights into sleep disturbances in VaD patients and highlights the importance of this frequently missed aspect in the care of dementia patients and their caregivers.

Conclusions
The information provided in this study helps provide insights into the impor-