Hypersomnolence : Older people may be at risk of developing new medical conditions

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Older people who experience daytime sleepiness may be at risk of developing new medical conditions, including diabetes, cancer and high blood pressure, according to a preliminary study released today that will be presented at the American Academy of Neurology’s 72nd Annual Meeting in Toronto, Canada, April 25 to May 1, 2020.

The condition called hypersomnolence is defined as excessive daytime sleepiness even after having seven or more hours of sleep.

It can be debilitating for some people, affecting the way that they perform at work and in other daily activities.

“Paying attention to sleepiness in older adults could help doctors predict and prevent future medical conditions,” said study author Maurice M. Ohayon, M.D., Ph.D., DSc, of Stanford University in Stanford, Calif., and a member of the American Academy of Neurology.

“Older adults and their family members may want to take a closer look at sleeping habits to understand the potential risk for developing a more serious medical condition.

The study involved 10,930 people; 34% of participants were 65 years or older.

Researchers interviewed participants over the phone two times, three years apart. In the first interview, 23% of people over 65 met the criteria for excessive sleepiness. In the second interview, 24% reported excessive sleepiness. Of those, 41% said the sleepiness was a chronic problem.

The study found that people who reported sleepiness in the first phone interview had a 2.3 times greater risk of developing diabetes or high blood pressure three years later than those who did not experience sleepiness.

They were also twice as likely to develop cancer. Of the 840 people who reported sleepiness at the first interview, 52 people, or 6.2%, developed diabetes compared to 74 people, or 2.9% of those who were never sleepy during the day. Also, of the 840 people who reported sleepiness, 20 people, or 2.4%, developed cancer compared to 21 people, or 0.8% of those who were never sleepy during the day.

The results remained the same after researchers adjusted for other factors that could affect daytime sleepiness, such as gender and sleep apnea.

People who reported daytime sleepiness during both interviews had a 2.5 times greater risk of developing heart disease.

People who reported sleepiness only in the second interview were 50% more likely to also have diseases of the musculoskeletal system and connective tissue, such as arthritis, tendinitis and lupus, than those who did not have daytime sleepiness.

A limitation of the study was that it relied on participants’ memories, rather than monitoring their sleep length and quality and daytime sleepiness in a sleep clinic.


Sleep is an essential physiological phenomenon characterized by changes in various physiological functions, including brain activity, respiration, and heart rate. Sleep plays a vital role in the functioning of the brain by forming new pathways and processing information. Many studies have shown that enough sleep helps to improve memory and learning, increase attention and creativity, and assist decision making (Krueger et al., 2016).

The amount of sleep a person needs varies, but adults need an average of seven hours and thirty minutes of sleep per day. Older people require more sleep. Sleep consists of two states that are known as rapid eye movement (REM) sleep and nonrapid eye movement (NREM) sleep. REM is good for memory retention.

When in REM, the brain takes information from the short-term memory and transfers it to long-term memory. NREM includes all sleep stages other than REM and is also called atmospheric sleep.

Unlike REM sleep, there is usually little or no eye movement. NREM sleep can be broken down into four stages: stage 1, stage 2, stage 3, and stage 4, and growth hormone production and cell recovery begin (Susic, 2007).

When sleep is insufficient, or sleep quality is poor, this can have various adverse effects on the musculoskeletal system, heart, lungs, and even emotions. This can harm a person’s health. Sleep disorders have a high prevalence, affecting 25 to 30% of the population.

They are known to cause poor quality of life due not only to secondary physical illnesses but also from psychological stress caused by the sleep disorder (Kiley et al., 2019). Indeed, inadequate sleep has been widely acknowledged to be a risk factor for obesity, diabetes, heart disease, and dementia (Xie et al., 2017).

Dementia is a condition associated with a significant decrease in cognitive abilities, including memory deficits, sudden mood changes, problems with normal communication and reasoning. There is increasing research on the close relationship between sleep disorders and cognitive decline, but further investigation is needed (Guarnieri, 2019).

Scientific studies have long focused on one gender, with the assumption that studies of one gender would lead to similar results. However, lots of conditions display sex/gender differences in terms of their prevalence and pathogenesis. The gender of patients has shown to affect the risk of getting particular conditions as well as the patient’s prognosis (Golden and Voskuhl, 2017).

Additionally, sex/gender differences in the pharmacokinetics of medicines can also affect the efficacy and side effects of certain drugs (Tannenbaum et al., 2016). Moreover, for the concept of personalized medicine, the investigation of sex/gender differences is likely to be critical in developing therapeutic strategies for various conditions (Kim et al., 2018).

Increasing evidence indicates that gender factors can affect the pathogenesis of conditions, including sleep disorders and dementia. According to recent studies, insomnia, the most common type of sleep disorder, has a higher prevalence in females than in males (Morphy et al., 2007Aurora et al., 2010).

However, sex/gender differences in other sleep disorders are not thoroughly understood. This review includes a description of the sex/gender differences that exist in the prevalence of sleep disorder subtypes and hypnotic therapeutics. This article further reviews sex/gender differences in seven categories of sleep disorders as a potential risk factor for incident dementia. This includes all-cause dementia and subtypes, such as Alzheimer’s dementia (AD) and vascular dementia (VD).

SEX/GENDER DIFFERENCES IN THE PREVALENCE OF SLEEP DISORDER SUBTYPES

The International Classification of Sleep Disorders identifies seven major categories of sleep disorders. These include insomnia, sleep-related breathing disorders, central disorders of hypersomnolence, circadian rhythm sleep-wake disorders, sleep-related movement disorders, and parasomnias. The sex/gender differences in the prevalence of sleep disorders have been summarize in Table 1.

Insomnia

Insomnia is defined as difficulty in starting sleep, maintaining sleep, and waking up early in the morning. Before diagnosing insomnia, sleep disorders that significantly disrupt daily functioning are important factors to consider. Primary insomnia is a symptom of sleep deprivation, not due to medical, mental or environmental causes.

The main symptom is having trouble sleeping or not recovering from starting or maintaining sleep for more than a month (Hung et al., 2018). Insomnia accounts for between 30 to 35% of all sleep-related conditions. The frequency of severe or chronic insomnia is between 10 to 15% (Buysse, 2013).

Regarding the sex/gender differences in the prevalence of insomnia, many studies have reported that insomnia occurs more frequently in women (Morphy et al., 2007). Insomnia diagnoses are twice in women than in men in the United States of America. Postmenopausal conditions are associated with increased sleep problems, but not with sleep or fatigue (Phillips and Mannino, 2005).

Insomnia symptoms on more than two nights a week were reported in 27.6% of the sample (30.5% in women, 24.5% in men, p<0.001). In the case of chronic insomnia, the incidence was 9.3%. This was higher in women (12.9%) than in men (6.2%) (Singareddy et al., 2012).

In contrast, Breslau et al. (1996) reported that the sex/gender differences between insomnia and hypersomnia alone were not significant, but that the lifetime prevalence of insomnia and hypersomnia was 1.9 times higher in women than in men. It was also reported that women over 65 had the highest risk of insomnia (risk rate, 1.73; 95% confidence interval (CI)=1.65–1.83), and women were increasingly at high risk for insomnia as they aged compared to men (Aurora et al., 2010).

Another multivariate logistic regression analysis shows that depression is the single most powerful factor for women’s gender when it comes to insomnia or sleep disorders. Emphasize that this insomnia is a symptom associated with mental and physical health problems that require proper mental and medical treatment (Bixler et al., 2002). Also, the incidence of depression increased by approximately 1.8 times among those with insomnia symptoms. This could be associated with physical disabilities, sex/gender differences, and former passive occupations (Kim et al., 2009).

Sleep-related breathing disorders (SBD)

SBD is characterized by abnormal breathing during sleep. These disorders are classified as obstructive sleep apnea, central sleep apnea, sleep-related hypoventilation disorders, and sleep-related hypoxia disorders (Sateia, 2014). The prevalence of SBD has not been well studied in women, since age, body mass index, and menopause have a considerable impact on the outcomes.

Obstructive sleep apnea is defined as at least five apnea low respiration indices per hour and is prevalent in 24% of American adult men and 9% of women (Young et al., 1993). The Apnea-Hypopnea Index (AHI) is an index used to indicate the severity of sleep apnea. Shown as the number of apnea and hypopnea events per hour of sleep (Bonakis et al., 2009) sleep apnea (a pause while breathing) should last for at least 10 seconds.

Apnea is associated with reduced blood oxygenation. To determine the apnea severity score, the AHI is calculated by dividing the number of apnea events by the total sleep time. Adult AHI values are classified as normal when they are 5 or less, mild sleep apnea between 5 and 15, moderate sleep apnea between 15 and 30, and severe sleep apnea when 30 and above.

One study found that for clinically defined sleep apnea, the prevalence in men and women was 3.9% and 1.2%, respectively, showing 3-fold higher prevalence in men. The prevalence of sleep apnea was significantly lower in premenopausal women (0.6%) and postmenopausal women with hormone replacement therapy (0.5%).

These data indicate that menopause is a significant risk factor for sleep apnea in women, and that hormone replacement is associated with reduced risk (Bixler et al., 2001). Snoring occurred in 46% of men and 25% of women and tended to increase with age (Duran et al., 2001).

Of adults between 30 and 70 years old, about 13% of men and 6% of women have moderate to severe SBD, which an AHI score of 15 or higher. It was also estimated that 14% of men and 5% of women also had AHI 5 or higher with daytime sleepiness (Peppard et al., 2013).

The prevalence of SBD in childhood may also vary by gender, and boys have a higher prevalence at 50–100% than girls (Lumeng and Chervin, 2008). Several studies suggest the length of men’s airways as one of the causes of the higher prevalence of sleep apnea in males. Men’s airways are more extended than women’s, regardless of their body height, which suggests that men’s airways may have a greater tendency to collapse (Jordan et al., 2014).

Central disorders of hypersomnolence (CDH)

The main symptom of hypersomnolence is characterized by excessive daytime sleepiness (EDS) despite regular day and nighttime sleep timings (Khan and Trotti, 2015). This affects between 4% to 6% of the population (Dauvilliers and Buguet, 2005). Such sleepiness can be caused by medical conditions, sleep disorders, illegal and prescribed substances, work, and family needs (including shift work), and insufficient time asleep (Khan and Trotti, 2015). This review focuses on the main symptoms of hypersomnolence.

More than a tenth of the Australian adult population has EDS, 10.4% for men, and 13.6% for women. The prevalence of EDS increases with age, affecting about one-third of people over 80 years old (Hayley et al., 2014).

The prevalence of EDS in Koreans was 12.2%, 10.7% for men, and 13.7% for women. EDS is associated with a variety of factors in Korean adults, and habitual snoring or sleep problems increases the risk of EDS (Joo et al., 2009). EDS was reported by 16.8% of participants in a Brazilian town. The prevalence of EDS was higher in women than men in the 18–29 and 45–60 age groups (Hara et al., 2004).

The prevalence of EDS was 14.9% for boys and 18.2% for girls in South Korean high school students. The difference in the amount of time asleep reported between boys and girls (6.3 h versus 6.5 h per day) is statistically significant (p<0.001). However, sleep latency in girls, as with the frequency of nightmares (p<0.001), was longer (p<0.01) (Joo et al., 2005).

Sex/gender differences in the prevalence of EDS in Norway were significant only in the oldest group (over 60 years), with greater prevalence among men (Pallesen et al., 2007). In results from France using the Epworth Sleepiness Scale (ESS), EDS was reported in 12% of men and 6% of women (Tsuno et al., 2007).

In Saudi Arabia, the prevalence of EDS was 20.5% (female 22.2%, male 19.5%, p=0.136) with no significant difference between men and women. However, a stratified statistical analysis showed that women had a higher prevalence of shorter nighttime sleep than men (25.3% for women, 19.0% for men, p=0.036) (Fatani et al., 2015).

Circadian rhythm sleep-wake disorders (CRSD)

The circadian rhythm is often called the human internal clock and is about 24 h. The migration phase interacts with homeostatic sleep that drives to create waking hours during the day and lasting sleep at night. When this cycle is broken, sleep for 24 h is fragmented and scattered, which leads to sleep problems (Romeijn et al., 2012).

CRSDs include delayed sleep phase disorder (DSPD), advanced sleep phase disorder (ASPD), familial advanced sleep phase syndrome, irregular sleep-wake rhythm disorder), shift work sleep disorder and jet lag disorder (Thorpy, 2012).

The prevalence of DSPD is about 1.1–4.5% in adolescents and 0.48–1.5% in adults. Sex/gender differences in the prevalence of DSPD have not been reported in adults, but it is more common in adolescent boys (4.5%) than girls of a similar age (2.7%) (Singer et al., 2016).

The prevalence of ASPD in New Zealand ranged from 0.25% to 7.13%, and the prevalence of DSPD ranged from 1.51 to 8.90%. The prevalence of ASPD was higher among men, increased with age, and decreased with age among those living in more deprived areas. The prevalence of DSPD was higher among people living in more deprived areas and decreased with age (Paine et al., 2014). Studies looking at the prevalence of sex/gender differences relating to work sleep disorder are rare. Oginska et al. (1993) used questionnaires and self-reporting to find that female crane drivers got less sleep and were more prone to sleepiness at work than men. Subjects on weekly shifts were younger and had a higher proportion of women than the other two groups. Day shift workers reported more difficulty getting to sleep than fixed weekly workers (Ohayon et al., 2002).

Female workers may tend to sleep less than men and become sleepy at work, but the evidence of this is weak. As a potential risk factor for the development of jet lag disorder, gender has not been thoroughly studied, and no definitive conclusions have been drawn.

Many studies have included only male subjects, and only one case analyzes gender as a risk factor. Using multiple regression analysis, males were found to be less fatigued after a long flight of more than 10 h. As such, there is not enough data to conclude gender as a risk factor for jet lag disorder (Sack et al., 2007). CRSD patients were younger than patients with other types of insomnia. However, no difference could be found in its prevalence due to gender (Dagan, 2002).

Parasomnia

Parasomnia is a sleep disorder associated with abnormal movements, behaviors, emotions, perceptions, and dreams that occur between sleep stages or when waking up. Parasomnia is a combination of dissociated sleep states that are partially awakened during the transition between awakening, NREM sleep, and REM sleep (Fleetham and Fleming, 2014).

These include sleepwalking, drooling, night terrors, nightmares, diggers, and REM sleep behavior disorders. Each disease varies in its frequency and can occur every night or only a few times a year (Kazaglis and Bornemann, 2016). REM sleep behavior disorder (RBD) is the clinically most relevant REM parasomnia (Howell, 2012).

A review of 115 patients with polysomnogram-identified RBD at the Academic Sleep Center found a 2:1 ratio of males (65%) to females (35%) (Ju et al., 2011). In younger groups under 50, males were more prevalent than females (M:F=1.4:1) but smaller in numbers than older groups over 50 years old (M:F=3:1) (Bonakis et al., 2009).

Behavioral symptoms during sleep were similar in male and female patients. However, female patients were diagnosed with symptoms when they were older than men (72.1 vs. 66.4 years, p<0.05) (Wing et al., 2008).

Sleep-related movement disorders (SRMD)

Sleep-related movement disorders are abnormal movements that occur during sleep or when falling asleep. Sleep-related movement disorders include Restless Leg Syndrome (RLS; Willis-Ekbom Disease), periodic limb movement disorders, rhythmic movement disorders, sleep-related bruxism, and sleep-related leg cramps (Silber, 2013).

In the case of RLS, repeated limb movements occur during sleep, but waking paresthesia is the most common symptom (Sateia, 2014). RLS is a common cause of sleep initiation and maintenance failures, affecting about 8–10% of the population (Howell, 2012).

Many studies have reported a higher prevalence of RLS in women than in men (Lopes Da Silva and Storm Van Leeuwen, 1977Kushida et al., 2006Anderson and Shneerson, 2009Patil et al., 2019). The prevalence of RLS was 3.9% to 14.3% for groups that met the minimum diagnostic criteria of the International RLS Study Group.

Sex/gender differences in the prevalence of RLS are about twice as high in women as men. Also, the age of onset increases in Europe and North America, but not in Asian countries. Symptoms of anxiety and depression are consistently associated with RLS (Ohayon et al., 2012).

Among the Appalachian care population, people with RLS are older than those without RLS, have lower-incomes, are more likely to be unemployed, disabled, non-Hispanic Caucasians, women and are less likely to be college-educated (Innes et al., 2013). Sleep-related motor disorders are reported to have a higher prevalence in women, but some studies have reported no difference in the prevalence between genders (Tannenbaum et al., 2016Golden and Voskuhl, 2017).

IMPACT OF SLEEP DISORDER AS A RISK FACTOR FOR DEMENTIA IN MEN AND WOMEN

Sleep disturbance has been widely reported to be causatively related to various conditions, including cardiovascular disease, diabetes, and neurological disorders. Although the relationship between sleep disorders and the prevalence of neurogenic diseases has been widely reported, most studies have focused on sleep apnea, and relatively few studies have investigated the relationship between insomnia and neurological disorders (Gu et al., 2010Crowley, 2011).

Besides sleep disturbance, dementia is also one of the most common and significant health problems in older adults. Increasing investigations suggest that sleep disorders can affect the pathogenesis of all-cause dementia or their subtypes, such as AD and VD. As shown in Table 3, we summarize the causative role of seven categories of sleep disorders in the incidence of dementia, including AD and VD, in men and women.

Insomnia

A recent study from Taiwan’s National Health Institute has reported that patients with primary insomnia showed a 2.14- fold (95% confidence interval, 2.01–2.29) increase in dementia risk than those without insomnia. In their study, younger patients under the age of 40 with primary insomnia had a higher incidence of dementia than older patients. Consistently, other recent studies also demonstrated that sleep disturbances could enhance the risk of developing dementia, and insomnia may increase the risk of AD (Shi et al., 2018).

Also, another recent study conducted in older adults reported that insomnia was associated with a significantly increased risk of all-cause dementia (de Almondes et al., 2016). Given gender-related differences in the impact of insomnia on the incidence of dementia, a study has reported that male patients with chronic insomnia were associated with an increased risk of cognitive decline independent of depression.

After adjustment for possible confounders, nondepressed men with chronic insomnia were 49% more likely to experience cognitive decline than without insomnia. For women, on the other hand, chronic insomnia also tended to be associated with an increased risk of cognitive decline, but only in those who also had high levels of depressive symptoms.

In general, for both men and women, those with depressive symptoms showed a higher risk of poor cognitive performance. Subjective reports of insomnia by older persons are correlated with objective sleep disturbances, as documented by polysomnography.

However, polysomnographic data indicates that older women may have less objectively disturbed sleep than older men, even though they tend to report more sleep complaints (Bliwise, 1993).

One potential explanation for this discrepancy is that men have a higher threshold for reporting sleep complaints, and therefore, those men who report having insomnia could have significantly more disturbed sleep than the women who report insomnia (Cricco et al., 2001). This may explain why the association between chronic insomnia and cognitive decline as observed in men was not in women.

Taken together, these findings elucidate the influence of sleep disturbances on the incidence of dementia both in younger adults and older adults. However, the mechanism underlying the association between primary insomnia and dementia is unclear, and the information about the subtype or level of insomnia necessary to induce dementia is not clear. Therefore, further research in this area is needed to validate these findings.

Sleep-related breathing disorders (SBD)

SBD, a disorder characterized by recurrent arousals from sleep and intermittent hypoxemia, is common among older adults and affects up to 60% of older adults (Yaffe et al., 2011). A number of adverse health outcomes, including hypertension, cardiovascular disease, and diabetes have been associated with SBD (Young and Peppard, 2000Ip et al., 2002Punjabi et al., 2004).

Cognitive impairment has also been linked to SBD, but the majority of studies have been cross-sectional or have relied on non-objective measures of SBD, therefore limiting the ability to conclude the directionality of association.

The data from the National Health Insurance Research Database, which is managed by the Taiwanese National Health Research Institutes have shown that the hazard ratio (HR) of dementia is 1.44 times greater for patients with SA. It has also been reported that female (HR: 2.38, 95% CI=1.51–3.74; p< 0.001), but not male, SA patients were more likely to develop dementia within a 5-year follow-up period (Chang et al., 2013). When SA patients were divided into 4 groups according to age (40–49, 50–59, 60–69, ≥70), those in the 50–59 group, 60–69 group, and ≥70 groups displayed a greater risk of developing dementia.

This statistical significance persisted in the 50–59 group and ≥70 groups after adjusting for potential confounders (50–59 group, adjusted HR 3.63, 95% CI=1.67–7.88; ≥70 groups, adjusted HR 1.53, 95% CI=1.01–2.33). For females with SA, the risk of dementia increased after age 50 (Chang et al., 2013).

One prospective cohort study that used overnight polysomnography confirmed that women aged 65 years or older with SBD had a higher risk of developing cognitive impairment and dementia as compared with women without SBD (Yaffe et al., 2011).

Measures of sleep fragmentation (arousal index and wake after sleep onset) or sleep duration (total sleep time) were not associated with a risk of cognitive impairment. The increased risk for cognitive impairment related to SBD opens a new avenue for additional research on the risk of developing dementia and the exploration of preventive strategies that target sleep quality, including SBD.

A study (Chang et al., 2013) focusing on the impact of SA on the risk of developing the two most common forms of dementia, AD and VD, reported that SA could increase the risk of VD (adjust HR: 1.93, 95% CI=1.00–3.77; p<0.005). A recent study (Culebras and Anwar, 2018) further demonstrated that older women (mean age 82.3 years) with moderate to severe obstructive sleep apnea were more likely to develop mild cognitive impairment or VD (adjusted odds ratio [AOR], 1.85; 95% CI=1.11–3.08).

Hypoxia is the main feature of SA affecting cognition, and microinfarcts are the major lesions of VD. Recent observations indicate that the frontal cortex in patients with SA suffering hypoxia may be abnormally thin (Macey et al., 2018).

Although the authors suggest direct hypoxic damage of the cortical cells, a thin cortex might be the consequence of transneuronal degeneration as a result of a disconnection at the periventricular white matter level.

Therefore, SA may be a risk factor for subcortical ischemic VD, also known as Binswanger disease, a form of VD in the elderly (Roman, 1987). Uncontrolled SA of moderate to severe intensity may accelerate neurological deterioration during acute stroke stages and worsen the prognosis for recovery during rehabilitation. There is also compelling and mounting evidence that SA with chronic intermittent hypoxia underlies VD resulting from subcortical ischemic disease. Proper management of SA may decrease the clinical impact of stroke risk factors, improve the neurological outcomes after stroke, and lessen the progression of subcortical ischemic vascular disease.

Central disorders of hypersomnolence (CDH)

In addition to insomnia, EDS is one of the most frequently reported sleep disruptions in older adults (Foley et al., 1995). Among several longitudinal studies performed in community-dwelling elderly, EDS has been reported to be associated with an increased risk (30%) in cognitive impairment using the MMSE score, independently of clinical characteristics and the APOE genotype. Consistently, some prospective epidemiologic research have reported a link between EDS and cognitive impairment in the elderly.

One longitudinal study performed for older Japanese-American men has also reported an association between EDS and dementia incidence over a 3 year follow-up period (Foley et al., 2001). In addition, EDS has been suggested to be strongly predictive for VD in men, but not as a predictor for non-VD (Elwood et al., 2011). Other studies confirm this finding in both genders, within a larger sample number of older adults and more extended follow-up period (Jaussent et al., 2012).

EDS is one of the well-known nonmotor symptoms of Parkinson’s disease (PD), affecting up to 50% of patients with PD (Hobson et al., 2002). In 8 years of follow-up longitudinal study, a significant increase has been shown in the prevalence of EDS from 4.1% to 40.8% in the patients with PD, suggesting that EDS increases progressively with PD (Gjerstad et al., 2006Tholfsen et al., 2015).

In addition, an epidemiologic research has indicated that EDS may be associated with a 3-fold increase in the incident PD, suggesting EDS as a preclinical marker for PD. Since RBD has been considered as a marker of α-synucleinopathies (Wing et al., 2015Iranzo et al., 2016), there has been attention focused on developing new markers for the progress of RBD toward PD, such as loss of olfactory function (Fantini et al., 2006Mahlknecht et al., 2015), defected color vision (Postuma et al., 2015a), depression (Wing et al., 2012), and cognitive decline (Molano et al., 2010)

. Furthermore, a recent study indicated that EDS patient with RBD would have potential for a rapid conversion to PD (Arnulf et al., 2015). From these results, EDS is suggested to be a possible biomarker for neurodegeneration in RBD. Further studies are need to clarify the neurochemical and neural circuitry underlying EDS in RBD.

Circadian rhythm sleep-wake disorders (CRSD)

During waking, there has been known to be rhythms in synaptic plasticity (Chaudhury et al., 2005) and behavioral flexibility (Aston-Jones and Cohen, 2005) Aging has been known to be linked with alteration of circadian rhythms, such as decreased amplitude (peak activity), fragmentation of rhythms, altered entrainment (Hofman and Swaab, 2006).

The timing of circadian activity is also reported to advance with age, leading to an earlier onset time of sleepiness in the evening, and an earlier waking in the morning (Czeisler et al., 1992). Abnormalities of sleep–wake rhythm in the elderly patient with dementia have been suggested to show a shorter life span (Gehrman et al., 2004) and increased risk for AD (Satlin et al., 1995). So far, little information is available regarding the causes of age-dependent changes in circadian activity in older adults without dementia and the following results on health.

It has been reported that older (≥65) women and men of community-dwelling with disturbed circadian activity show an increased risk for mortality (Paudel et al., 2010Tranah et al., 2011). In a prospective study examining the relationship of sleep-associated characteristics during late adulthood and subsequent incidence of dementia up to 17 years later, increased incident dementia was shown in the group of short (≤6 h) and extended (>9 h) TIB as well as in the group of later rise time (Bokenberger et al., 2017).

However, there has been no clear evidence supporting a link between increased risk of dementia with bedtime, sleep quality, or heavy snoring. The mechanism underlying the increased dementia risk implicated from short TIB might be a decreased interstitial clearance of metabolic waste linked to decreased time of sleep, subsequently leading to elevated level of extraneuronal β-amyloid (Kang et al., 2009Spira et al., 2013). Later riser, which may indicate delayed circadian activity rhythm has been reported to show an atypical feature in the cognitively impaired elderly (Bokenberger et al., 2017).

From these reports, it is suggested that circadian activity rhythms may be biomarkers for advanced aging and dementia even though further study is need to understand the mechanism for this link.

Parasomnias

RBD has been reported to be a preclinical symptom of asynucleinopathies, such as dementia with Lewy bodies (DLB) and PD (Schenck et al., 1996). RBD has been also implicated as a possible risk factor for aggravation of autonomic function and cognition in PD patients (Postuma et al., 2011). In addition, the occurrence of RBD in PD patients can be higher in patient dementia than those without dementia (Marion et al., 2008). Thus, the existence of clinical RBD could be associated with deteriorated motor and autonomic function, and incidence of dementia in PD patients.

Based on a prospective study of a population-based sample, shorter REM sleep percentage and longer latency to REM sleep were shown to be independently associated with a higher risk of incident dementia (Pase et al., 2017). Greater wake after sleep onset, a measure of difficulty maintaining sleep, was also associated with an increased risk of dementia, but only in a fully adjusted statistical model. Stages of non-REM sleep were not associated with dementia incidence in our sample.

The mechanisms linking REM sleep to incident dementia are yet to be determined. It has been reported that the association between REM sleep percentage and dementia is independent of numerous confounders such as pharmacologic intervention for mood disorders, which adversely interfere with REM sleep (Pase et al., 2017). REM sleep is thought to promote synaptic consolidation and to upregulate the activity of immediate early genes implicated in synaptic plasticity (Diekelmann and Born, 2010).

Thus, REM sleep can buffer from synaptic loss and cognitive impairment by supporting the formation of new networks. Though there are biologically plausible mechanisms to explain these results, more studies are needed to explore the mechanisms linking REM sleep to AD pathology and incident dementia.

Individuals suffering from RBD tend to be male with symptoms starting in later middle age. Idiopathic RBD is a robust prodromal marker of synuclein–dependent neurodegenerative disorder, such as DLB and PD. Pathologic studies have demonstrated that patients with RBD have a more diffuse and severe deposition of synuclein (Postuma et al., 2015b). PD patients with RBD is more likely to occur in males than females. From these results, it is implicated that PD patients with clinical RBD symptoms may develop dementia in a shorter period of time than those with normal REM sleep, suggesting the clinical RBD symptoms as a preclinical marker for dementia incidence.

Sleep-related movement disorders (SRMD)

SRMD is considered to be a class of sleep disorders, which is characterized by simple, stereotyped repetitive movements during sleep. Patients with SRMD are reported to experience fragmented sleep, disturbance of sleep initiation, and excessive daytime sleepiness, resulting in decreased quality of life (Pigeon and Yurcheshen, 2009). Among SRMD, periodic limb movement disorder and restless legs syndrome are the most common sleep complaints, which involve nocturnal involuntary limb movements.

The prevalence of periodic limb movement disorder and RLS has been reported to affect 3 to 10% of the general population, increasing with age (Ohayon and Roth, 2002). Both conditions have been reported to be associated with several physical disorders and mental abnormalities. They have been linked to poorer quality of life through fatigue, compromised work performance, and impaired social and family life (Earley and Silber, 2010). It has been suggested that SRMD is a common complication and comorbidity of neurodegenerative disorders such as PD.

However, the relationship of SRMD, such as periodic limb movement disorder and RLS with cognitive impairments like dementia, remains unclear. Researches investigating the relationship between sleep disorders and cognitive illness have predominantly focused on sleep behavior disorders and degenerative dementia.

A recent longitudinal study using data from the National Health Insurance Research Database showed that individuals with SRMD had 3.952 times (95% CI=1.124–4.767) higher risk of developing all-cause dementia as compared with individuals without SRMD (Lin et al., 2015). These results showed that SRMD patients aged between 45 and 64 years old exhibited the highest risk of developing all-cause dementia (HR: 5.320, 95% CI=1.770–5.991), followed by patients age >65 (HR: 4.123, 95% CI=2.066–6.972) and <45 (HR: 3.170, 95% CI=1.050–4.128), respectively (Lin et al., 2015).

Females with SRMD had a higher risk of developing all-cause dementia (HR: 4.372, 95% CI=1.175–5.624), compared to men (HR: 2.567, 95% CI=1.006–2.977). The impact of SRMD on dementia risk progressively increased by various follow-up time intervals (<1 year, 1–2 years, and >2 years). Furthermore, RLS patients had a higher risk of VD (OR: 2.39, 95% CI=1.10–5.20, p=0.029). However, this was not statistically significant.


Provided by American Academy of Neurology

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