Sleep is a dynamic process that affects both psychological and physiological functioning. Due to the overlap between psychiatric problems and neurodegenerative symptoms, psychiatrists are uniquely positioned to encounter aging patients with neurodegeneration and concurrent sleep disturbances.
Sleep Disturbances in Synucleinopathies
The pathological hallmark of these disorders is accumulation of Lewy bodies, consisting of intraneuronal alpha-synuclein aggregates.3 Sleep disturbances noted in these conditions are listed in Table 2. We focus on the main conditions associated with sleep impairment within this category.
Disturbances Noted in Synuclein Neurodegenerative Disorders
Parkinson's disease (PD) is characterized by the tetrad of tremor, rigidity, bradykinesia/akinesia, and postural instability. Sleep disturbances are common, afflicting approximately 60% to 98% of the patients.3
REM sleep behavior disorder. REM sleep behavior disorder (RBD) is characterized by excessive electromyographic tone in REM sleep, facilitating dream enactment behavior.4 Its manifestation ranges from vivid dream-enacting behaviors such as vocalization, screaming, yelling, and shouting to motoric actions including flailing of the arms, throwing punches, kicking of legs, thrashing about, and jumping out of bed.4
The frequency of RBD in PD ranges from 30% to 54%.5 Its diagnosis requires a clinical history of dream enactment as well as the polysomnographic marker of increased tonic activity (sustained muscle activity) in chin muscles and phasic activity (transient bursts of muscle activity) in limb leads.4,5
The association between RBD and alpha-synuclein disorder is well established. It is considered to be a prodromal feature of these neurodegenerative disorders (PD, dementia with Lewy bodies [DLB], mulitple system atrophy) and can predate the clinical manifestation by years to decades. The role of RBD as a harbinger of the evolution of neurodegeneration highlights its importance as an area of intense research. It is clinically relevant as studies are being conducted on the prediction of phenoconversion and potential neuroprotective agents. RBD not only has prognostic implications, but it can also lead to injuries to the patient and bed partner.6
Ensuring physical safety is the mainstay of treatment in RBD. Clonazepam in bedtime doses of 0.5 to 1 mg and melatonin at doses of 3 to 15 mg have conferred clinical benefit in controlling nocturnal behaviors, abnormal dreaming, and preventing injuries.6 Regular surveillance of these patients should be conducted to detect signs of evolution of PD/DLB.
Parasomnia overlap disorder. Parasomnia overlap disorder (POD) is a variant of RBD in the International Classification of Sleep Disorders, third edition, and consists of RBD and a non-REM (NREM) sleep parasomnia affecting the same patient.4 POD was formally identified in 1997 in a series of 33 patients with video polysomnography (PSG)-documented RBD and a disorder of arousal from NREM sleep consisting of sleepwalking (SW) and sleep terrors.7 Subsequently, the classification of POD was expanded to include various other types of NREM parasomnias, such as sleep related eating disorder and sexsomnia.8
POD in PD was first identified in 2007.9 A retrospective study conducted in a movement disorders clinic found that of 165 consecutive patients with PD seen over 2 years, 6 had de novo adult-onset SW, comprising 3.6% of the patients with PD. Four of these 6 patients also had RBD confirmed by video-PSG, meaning they also had POD. The authors commented that neurodegenerative changes associated with PD at the brainstem level can affect the ascending control of state transition (leading to dissociated arousals from NREM and/or REM sleep) and the descending control of locomotion and muscle tone, together giving rise to various sleep-related behavioral disturbances, including SW, RBD and POD.
The same group then conducted a prospective questionnaire-based survey of SW and RBD in PD.10 They found that 9% (36/417) of patients with PD reported SW and 72% of these 36 patients also had presumed RBD (based on their responses to a validated RBD screening questionnaire), and therefore had POD.
In another related study by the same group,11 video-PSG and detailed clinical examinations were conducted in 30 patients with PD from the above-mentioned survey.10 There were 10 patients with a history of SW, 10 patients with a history of RBD, and 10 patients with no history of either SW or RBD. Video-PSG showed that 8 of 10 patients with PD and SW also had RBD, and thus POD was documented in 80% of these patients. Patients with PD and SW were more disabled from PD, with significantly higher depression and anxiety scores, higher Hoehn and Yahr scores, and lower activities of daily living scores (greater functional disability). Patients with PD and POD also had significantly more dyskinesia and hallucinations. The authors concluded that the presence of POD in most patients with PD in this study suggests a common underlying disturbance of motor control during sleep in PD, with variable manifestations across NREM and REM sleep stages.11
Insomnia is the most prevalent sleep disturbance, noted in 60% to 80% of patients with PD.12 A study comprised of 689 patients with PD reported that 81% had fragmented sleep, 40% had early morning awakenings, 38% had nonrestorative sleep, 31% had nocturnal awakenings, and 18% had difficulty initiating sleep.13 Its prevalence increases with disease severity and duration. The causation is multifactorial with both nocturnal motor symptoms, such as tremors, rigidity, stiffness, dystonia, akathisia and restless legs syndrome (RLS), and nonmotor symptoms such as nocturia, anxiety, depression, and hallucinations leading to sleep fragmentation.
Polysomnographic monitoring has demonstrated low SE, increased WASO, and less SWS and REM sleep in PD patients.14 Neurodegeneration of dopaminergic and brain stem nuclei has been implicated in intrinsic pathophysiological processes.15 Alteration in light exposure and dysfunction of suprachiasmatic nuclei can cause circadian rhythm disruption, which can contribute to sleep disturbance.
Management of insomnia should be aimed at addressing underlying factors that warrant careful identification and individualized management. Dopamine agonists and controlled-release levodopa formulation should be instituted in case of disruptive nocturnal motor symptoms such as stiffness, rigidity, and RLS.14 Other systemic and emotional symptoms such as nocturia, anxiety, depression, and hallucinations should be addressed appropriately. Pharmacological options should be considered with great caution due to the risks of falls and confusion. There is a paucity of evidence in the literature regarding the selection of the optimal agent. Doxepin, 10 mg, and melatonin, 3 to 5 mg at bedtime, have shown some subjective improvement.15,16 Another study showed positive response to a combination of cognitive behavior therapy (CBT-I) for 90 minutes weekly together with light exposure for 30 minutes daily.15
Hypersomnolence is not only reported subjectively in approximately 50% of PD patients, but objective testing has also been corroborative.17 According to one study, a multiple sleep latency test demonstrated a mean sleep latency of fewer than 5 minutes in select patients with PD.17 Pathological examination of PD cases has revealed loss of hypothalamic hypocretinergic neurons as compared to controls.18 The prevalence of excessive daytime sleepiness (EDS) increases with disease progression.
Various factors contribute to the development of EDS, including intrinsic pathology, pharmacological treatment such as levo-dopa and dopamine agonists, obstructive sleep apnea (OSA), depression, and circadian rhythm disruption.19
Hypersomnia can physically manifest as either persistent sleepiness or sleep attacks. Sleep attacks are sudden irresistible sleep episodes without any preceding warning. They are associated with dopaminergic therapy, with frequency ranging from 38% to 43%.19,20
Treatment should be aimed at examining carefully all the factors involved, such as lowering of medication doses if possible, or treatment of any comorbid OSA. Modafinil in doses of 200 to 400 mg has also shown some modest subjective benefit.19
Restless Legs Syndrome/Periodic Limb Movements of Sleep
RLS is characterized by the urge to move the legs accompanied by unpleasant sensations, which is worsened by immobility at night and partially alleviated by movement.4 Its frequency is reported to be 7.9% to 20.8% in patients with PD.21 It can contribute to insomnia by delaying sleep onset and is considered an early feature, and not a risk factor, of PD. Periodic limb movements in sleep (PLMS) are periodic and repetitive leg movements of sleep frequently seen in association with RLS, but typically are not associated with arousals. The pathophysiological mechanism involves basal ganglia and dopaminergic dysfunction, which is corroborated by clinical response to dopaminergic medications.13
Dementia with Lewy bodies. The prevalence of RBD in patients with DLB is 50% to 80%.5 The salient features of RBD and other sleep disturbances noted are discussed in detail in the preceding section. Insomnia, circadian rhythm disorder with early morning awakenings, RBD, visual hallucination, and nocturnal confusional wandering are common.20 Without PSG recording it can be difficult to distinguish confusional arousals arising out of NREM sleep from visual hallucinations and RBD. Cases with progression of disease may demonstrate ambiguous sleep, which is manifested by disintegration of various sleep stages caused by degeneration of brainstem structures involved.20 OSA, RLS, and PLMS are just as common as in the general population.
Multiple system atrophy. The frequency of RBD in multiple system atrophy (MSA) is highest in comparison to the other synucleinopathies, ranging from 80% to 95%.8 Many factors, such as urinary symptoms, anxiety, depression, inability to change positions due to rigidity and medications, can cause sleep fragmentation. Disrupted sleep and insomnia are noted in approximately 50% of patients, whereas EDS is reported in 28% of patients.21,22 Details of these were discussed previously in the section on PD; therefore, we will focus primarily on sleep-related breathing dysfunction noted in MSA.
Sleep-related breathing disorders, both obstructive and central type, are common in MSA. OSA frequency ranges from 15% to 37%.21 Degeneration of brain centers responsible for chemoreceptor sensitivity and control of rhythmogenesis has been noted, which can lead to reduced ventilatory drive, irregular breathing, and fatal respiratory insufficiency.23,24 Central sleep apnea in the form of Cheyne-Stokes respiration is frequently seen. Especially noteworthy is nocturnal stridor, which is present in 20% of cases.22 Stridor is a distinct high-pitched inspiratory sound noted in sleep but can also be present in the awake state and is a poor prognostic indicator.20,21 Paradoxical dystonic vocal cord adduction during inspiration is proposed as a pathophysiological mechanism. Positive airway pressure and tracheostomy can alleviate stridor and OSA to some degree.21
Sleep Disturbances in Tauopathies
The term “tauopathy” encompasses neurodegenerative disorders characterized by abnormal aggregation of microtubule-associated cytosolic protein called “tau.”21,25 We focus on the main disorders and associated sleep disturbances (Table 3).
Sleep Disturbances Noted in Tauopathies
Sleep Disturbances in Alzheimer's Disease
Alzheimer's disease (AD) is the most common age-related progressive neurodegenerative disorder, resulting in impairment in cognition, orientation, and functional capacity.26 It is characterized by neuronal loss and deposition of extracellular beta amyloid and intracellular neurofibrillary tangles (made of tau) in the hippocampus and cortex. It is believed that sleep-wake disturbances may occur in up to 25% to 40% of patients with AD.20,25
Pathogenesis of sleep disturbance in AD. The interaction of sleep disturbances and AD is bidirectional. Animal studies and human pilot studies have shown that short sleep duration, poor sleep quality, and longer sleep latency have been related to accumulation of beta amyloid protein in the brain. It has been observed that concentrations of beta amyloid levels in the brain rise during wakefulness and fall during sleep, postulating that sleep facilitates beta amyloid clearance.27 Also, cerebrospinal fluid levels of beta amyloid are significantly increased in sleep deprivation and reduced during periods of increased sleep when treated with orexin receptor antagonist.28 A prospective study in cognitively normal elderly patients with the APOE4 gene, showed that sleep consolidation significantly reduced the incidence of AD and neurofibrillary tangle density.29 Thus, these studies suggest that presymptomatic amyloid deposition affects sleep, and that lterations in sleep or activity parameters might be an early biomarker of impending AD.
Insomnia and sleep architecture changes. Commonly noticed behavioral symptoms of AD are nighttime agitation and daytime somnolence, which could in part be related to sleep architecture alteration seen in patients with AD.26 As AD progresses, TST is significantly reduced due to increased sleep onset latency, nocturnal awakenings, and WASO, eventually leading to increased percentage of time spent in stage N1 sleep. The percentage of time spent in true delta wave of SWS is diminished in patients with AD when compared to cognitively intact elderly people.30 There is a notable reduction in the quantitative Stage R sleep compared to age-matched controls; however, the number of REM sleep episodes, latency to REM sleep, and REM sleep atonia is preserved.31 It is hypothesized that cholinergic neurons in the nucleus basalis of Meynert are vulnerable to neurodegenerative stress, and cholinergic neurotransmission dysfunction by beta amyloid accumulation, which might lead to REM deficits seen in AD.32
Circadian sleep rhythm disturbances. Circadian sleep rhythm disturbances (CSRD) are common in people with AD and directly correlate with severity of the disease. Normal attenuation of circadian rhythms with aging is further exaggerated in patients with AD. In addition to the age-related factors that alter the circadian sleep rhythm, there are other factors affecting sleep rhythm in AD by hampering Zeitgebers entrainment, from reduction in perceived environmental light due to degeneration of the melanopsin-containing retinal ganglion cells and optic nerve to decreased physical activity and limited social contacts.25
It is assumed that dysfunction of the suprachiasmatic nucleus resulting in alterations in melatonin secretion rhythm is the primary cause of circadian dysfunction in AD; however, melatonin supplementation has failed to show improvement in the sleep-wake cycle, raising concerns for melatonin receptor degeneration as well.33 CSRD in AD is more pronounced as the disease progresses, eventually leading to phase delay of the nocturnal sleep period and circadian core-body temperature rhythm.34 Additionally, circadian rest-activity patterns based on actigraphy are also disorganized with significant lower daytime activity and higher nighttime activity, recorded in institutionalized patients with AD.34 Most prevalent behavioral symptoms related to CSRD include irregular sleep-wake patterns such as insomnia from restlessness, frequent night awakenings and poor SE, increased unintended daytime naps, disabling late-afternoon or evening agitation (“sundowning”), and nocturnal wandering.
Obstructive sleep apnea. Recent data suggest that patients with AD are 5 times more likely to present with OSA compared to a patient without cognitive deficits.35 It is known that the APOE4 genotype of AD is associated with OSA, although the underlying mechanisms seem unclear. A recent study has suggested that even in the absence of APOE4, OSA can increase the risk of dementia.35 It is hypothesized that hypoxia and sleep fragmentation in OSA promote beta amyloid accumulation, which is the underlying AD pathology. It has also been suggested that patients in early stages of AD with OSA, upon optimal treatment with continuous positive airway pressure, may improve cognitive functioning (verbal learning, memory, cognitive flexibility, and mental processing speed), and may also delay the progression of dementia.35 RBD is rarely seen in AD, but when present there is concurrent Lewy body pathology.25
Sleep disturbances in frontotemporal dementia. Frontotemporal dementia (FTD) is characterized by focal atrophy of frontal and temporal regions of the brain resulting in loss of executive or language abilities, personality changes, loss of disinhibition, poor social awareness, loss of empathy, perseverative behaviors, and appetite disturbances.36 Sleep disorders in patients with FTD are akin to those in AD. Actigraphy and PSG data indicate that patients with FTD undergo a decrease in TST and SE and have an increase in WASO. Patients with FTD appear to have an increased nocturnal activity and decreased morning activity as compared to patients with AD at a comparable level of cognitive impairment. They have also demonstrated alteration in rest/activity pattern suggestive of possible phase delay. Insomnia is prevalent in FTD and is thought to be primarily behavioral in nature. OSA seems as prevalent as in patients with AD. RLS is reportedly seen in approximately 8% of patients with FTD, and RBD is rare. There is limited literature regarding potential impact of management of sleep disturbances in patients with FTD.36
Sleep disturbances in progressive supranuclear palsy. Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by supranuclear ophthalmoplegia (decrease in vertical eye movements), postural instability (axial rigidity), falls, parkinsonism, and pseudobulbar palsy. There is a decrease in TST and SE with increase in nocturnal activity and WASO.37 As seen in AD, NREM sleep is altered with an increase in alpha activity and a decrease in the number of sleep spindles and time spent in SWS. There is also a decrease in REM sleep, which is thought to be related to preferential degeneration of pedunculopontine tegmental nuclei that are involved in REM sleep generation.
Insomnia in PSP is thought to be worse than noted in AD or PD. It affects sleep maintenance and tends to worsen as the disease progresses.37 CSRD are not well characterized in PSP. There is a decrease in amplitude of the core body temperature (when compared to PD) and loss of nocturnal drop in blood pressure (similar to MSA). Sleep-disordered breathing is not significantly associated with PSP. RBD is noted infrequently in patients with PSP.5
Sleep Disturbances in Corticobasal Degeneration
Corticobasal degeneration (CBD) is represented by progressive asymmetrical rigidity, apraxia, and symptoms of cortical and basal ganglionic dysfunction. There is a paucity of literature on sleep disorders in patients with CBD. Most accounts remain anecdotal. A descriptive study of five patients with CBD showed all of them had insomnia, four had PLMS and RLS, and two had sleep-disordered breathing.38 None of them had RBD.