Curr Sleep Medicine Rep DOI 10.1007/s40675-017-0078-z

SLEEP AND NEURODEGENERATIVE DISORDERS (Y-E JU, SECTION EDITOR)

REM Sleep Behavior Disorder and Other Sleep Disturbances in Non-Alzheimer Dementias Stuart J. McCarter 1 & Michael J. Howell 2

# Springer International Publishing AG 2017

Abstract Purpose of Review The study aimed to review recent updates of our understanding of REM sleep behavior disorder (RBD) and other sleep disorders in non-Alzheimer’s disease (AD) dementias. Recent Findings Numerous recent discoveries have provided insight into the role of RBD and sleep in patients with non-AD dementias. Imaging modalities such as DaTscan and cerebral blood flow may be useful for monitoring phenoconversion in idiopathic RBD patients to Parkinson’s disease (PD) or dementia with Lewy bodies (DLB). Patients with isolated REM sleep without atonia have non-motor signs of neurodegenerative disease. Colon mucosal biopsies in iRBD patients have shown presence of α-synuclein aggregates. Recent genetic models of RBD and neuroimaging have furthered evidence for the locus subcoeruleus/sublateral dorsal nucleus as the center for the generation and maintenance of REM muscle atonia. Circadian rhythm disturbances likely play a large role in nighttime insomnia, daytime sleepiness, autonomic symptoms, motor variations, and hallucinations in PD and DLB. Early onset stridor in patients with multiple system atrophy

This article is part of the Topical Collection on Sleep and Neurodegenerative Disorders * Michael J. Howell [email protected]

(MSA) portends a worse prognosis than late onset stridor, and treatment of stridor is associated with survival. Summary Our ability to predict phenoconversion in idiopathic RBD is improving and will be highly important as Bhigh risk^ phenoconverters are identified for enrollment in neuroprotective clinical trials. Treatments of RBD improve but do not fully eliminate DEB; therefore, the risk for sleep-related injury remains a concern even among seemingly well-treated patients. Excessive daytime sleepiness (EDS) secondary to neuropathology, sedating medications, sleep disordered breathing (SDB), restless legs syndrome (RLS), and circadian rhythm alterations are common in the non-AD dementias, leading to significant caregiver burden and worsening of cognition. Addressing primary sleep disorders is the mainstay of treatment for EDS. RLS is a frequent co-morbidity in non-AD dementias. Initial management of RLS includes ensuring serum a ferritin level of >75 μg/L and therapy with gabapentin encarbil (which is less likely to cause augmentation than dopamine agonists). All MSA patients should be evaluated for the presence of nocturnal stridor, which should be treated if present. Therapies targeting the circadian system are often an underutilized therapeutic avenue in the management of sleep, motor, autonomic, and psychiatric symptoms in PD and DLB patients. Keywords REM sleep behavior disorder . Sleep . Dementia . Dementia with Lewy bodies . Frontotemporal dementia . Excessive daytime sleepiness

Stuart J. McCarter [email protected]

Introduction 1

University of Minnesota Medical School, 420 Delaware St SE, Minneapolis, MN 55455, USA

2

Department of Neurology, University of Minnesota Medical Center, 420 Delaware St SE, Minneapolis, MN 55455, USA

Non-Alzheimer (non-AD) neurodegenerative dementias comprise several clinical diagnoses secondary to different underlying pathologies including dementia with Lewy bodies

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(DLB), Parkinson’s disease dementia (PDD), and frontotemporal lobar degeneration (FTD). DLB and PDD both result from the abnormal accumulation of the protein α-synuclein and may be collectively referred to as Lewy body disease (LBD) [1]. DLB and PDD are clinically distinguished from each other based on the relationship between motor and cognitive dysfunction, that is, if patient’s present with cognitive impairment before or within 1 year of motor dysfunction, they are diagnosed with DLB, and if motor symptoms have been present for a year or longer prior to cognitive difficulties, they meet criteria for a diagnosis of PDD [2]. Multiple system atrophy (MSA), another α-synucleinopathy characterized by parkinsonism, ataxia, and profound autonomic dysfunction, also frequently presents with significant cognitive impairment [3]. FTD is a heterogeneous group of dementias including behavioral variant FTD (bvFTD) and primary progressive aphasia (PPA), which may be caused by the accumulation of various proteins including tau, progranulin, and fused sarcoma protein [4, 5]. Sleep disturbances are common in the non-AD dementias, frequently worsening cognitive function and contributing to significant caregiver burden. Sleep disorders are common in all dementia types; however, they appear to be most prevalent among patients with LBD [6–8]. While rapid eye movement (REM) sleep behavior disorder (RBD) is the best-recognized sleep disorder in LBD, daytime hypersomnolence, restless legs syndrome (RLS), and circadian rhythm disorders are also common. Disordered sleep, particularly circadian rhythm and nocturnal behavioral disturbances, is common in FTD patients; however, few studies have systematically studied sleep disturbances in FTD [9•]. This review will discuss the association between RBD and LBD, recent developments in the understanding of RBD as a prodromal neurodegenerative disease, and other sleep disorders commonly seen in non-AD dementias. REM Sleep Behavior Disorder 1. Background and Epidemiology RBD, first described in humans in 1986, is characterized by the Bacting out of dreams^ due to the loss of normal skeletal muscle paralysis during REM sleep, potentially leading to severe injury [10]. RBD most commonly presents after the age of 50, with 70–90% of reported RBD cases being male [11–13, 14••]. However, RBD is underrecognized in women due to the frequently less violent nature of dream enactment behaviors and the sex difference in life expectancy, as elderly women are less likely to have bed partners than elderly men, and thus may have unwitnessed dream enactment behaviors [15]. The prevalence of RBD is estimated to be between 0.38 and 2% in large population-based studies [16–18]. However, it is more prevalent among the elderly, with 6% of community dwelling individuals aged 70–89 years endorsing a history of dream enactment behaviors [19]. RBD appears to be at least

partially heritable, with primary relatives having a four times greater likelihood of RBD compared with relatives of those without RBD [20]. Additionally, mutations in GBA, which encodes the enzyme Glucocerebrosidase, have been associated with a sixfold increased risk of RBD [21]. Other factors associated with increased risk of RBD include head injury, smoking, pesticide exposure, lower level of education, and farming [22]. RBD is divided into two types: idiopathic RBD, with no apparent cause, and secondary RBD, which is related to another neurological disorder. Most commonly, secondary RBD is associated with α-synuclein mediated neurodegenerative disorders, including PD, DLB, and MSA [14••, 16, 23–25]. Among the synucleinopathies, the prevalence of RBD varies: 40–60% in PD, 80% in DLB, and 80–95% in MSA [26–31]. However, since 82–91% of idiopathic RBD patients ultimately develop LBD over longitudinal follow-up, idiopathic RBD is best considered to be an early manifestation of a progressive neurodegenerative disorder [11, 23, 28, 32–37]. 2. Diagnosis and Phenomenology of RBD The minimal diagnostic criteria of RBD according to the International Classification of Sleep Disorders (ICSD) 3 include (A) repeated episodes of sleep-related vocalizations and/or complex motor behaviors; (B) these behaviors are documented by polysomnography to occur during REM sleep or, based on the clinical history of dream enactment, are presumed to occur during REM sleep; (C) polysomnographic recording demonstrates REM sleep without atonia; or (D) the sleep disturbance is not better explained by another sleep disorder, mental disorder, medication, or substance use [38]. The core clinical feature of RBD is a history of witnessed dream enactment by the patient’s bed partner, with or without recall of dream mentation by the patient [7, 10, 11, 17, 28]. Patients frequently endorse vivid recall of their dreams for weeks or longer, with dream mentation of being chased, or needing to defend themselves against an attack by animals or people [17, 39–41]. Collateral history obtained from the patient’s bed partner is crucial in diagnosing RBD patients, as many individuals are unaware of their behaviors. Coherent vocalizations such as shouting, screaming, laughing, and swearing are commonplace in RBD [16, 17, 24, 28]. Repetitive, often subtle, movements during REM, particularly in the hands, known as Bhand babbling,^ are the most frequent RBD clinical phenomena captured on video during polysomnography (PSG). More serious behaviors such as punching, kicking, or leaving the bed increase the risk for sleep-related injury [17, 42]. Approximately half (55%) of RBD patients have suffered an injury ranging from a minor bruise to subdural hematomas and fractures [12, 14••, 42]. PSG with evidence of REM sleep without atonia (RSWA) continues to be the gold standard for RBD diagnosis given its ability to differentiate RBD from NREM parasomnias, such as

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sleep walking, sleep terrors, nocturnal seizures, and confusional arousals, as well as diagnose and treat sleep disordered breathing; however, PSG may not be routinely available/ feasible given its expense. Several screening questionnaires centered around the core question of BHave you ever been told that you act out your dreams?^ have been developed with high sensitivity (93–100%) and specificity (87.2–95%) for RBD diagnosis [43–45]. Patients screening positive for this question may be considered to have Bprobable^ RBD [38]. Occasionally, patients may be found to have incidentally elevated REM sleep muscle tone in the absence of a history of dream enactment. These patients are often taking antidepressant medications (particularly selective serotonin reuptake inhibitors and tricyclic antidepressants), which have been shown to increase RSWA [46]. Recent evidence suggests that some individuals with isolated RSWA go on to develop RBD on follow-up and that a large percentage (70%) have subtle nonmotor features of a neurodegenerative disease [47•]. These findings suggest that in some cases antidepressant medications do not induce RBD but instead unmask RBD in a person at risk for developing a neurodegenerative disorder. 3. RBD as a Prodromal Feature of Neurodegenerative Disease RBD evolves in association with several synucleinopathy phenotypes including PD/PDD, nonamnestic mild cognitive impairment, DLB, and MSA [14••]. Up to 94% of patients with probable RBD, and 98% of RBD patients confirmed by PSG, have synucleinopathy neurodegeneration at autopsy [36]. Longitudinal studies indicate that idiopathic RBD patients have 12–45% risk of developing parkinsonism or dementia within 5 years of RBD and 60–91% risk after 15 or more years from RBD diagnosis [28, 29, 31, 37, 48]. Idiopathic RBD patients often manifest subtle symptoms of neurologic dysfunction consistent with the early stages of a developing synucleinopathy, including decreased color vision, decreased olfaction, and autonomic nervous system disturbances such as constipation, erectile dysfunction, and orthostatic hypotension. Many of these symptoms may be present for more than 20 years prior to the evolution of clinical signs of parkinsonism [28, 49, 50, 51••, 52–55]. Olfactory dysfunction in particular appears to be highly sensitive for the prediction of conversion from RBD along to clinical PD or DLB within 5 years [34, 52, 53]. Further, impaired color vision is also associated with poor disease-free survival. Approximately 70–80% of RBD patients with poor color vision develop clinical PD or RBD within 5 years [34, 51••]. Older age at RBD diagnosis and RBD that occurs in the absence of antidepressant use are also significant risk factors for development of a clinically defined neurodegenerative disease [52]. RBD patients also have abnormalities in attention, executive function, decision-making abilities, verbal memory, and verbal learning compared to age-matched controls; when such

cognitive abnormalities are present in idiopathic RBD, there is increased risk for developing dementia [56–59]. Further, RBD itself appears to be a risk factor for dementia in patients with PD, with PD + RBD patients having a greater likelihood of dementia than PD patients without RBD [56]. Several biomarkers have been studied in hopes of predicting phenoconversion to a clinically overt neurologic syndrome. 123I-FP-CIT SPECT (DaTscan) which measures presynaptic dopamine binding has shown decreased uptake in the putamen in RBD patients, which decreases over time with progression of disease toward clinically overt PD, suggesting that DaTscan may be a useful imaging technique to follow progression of RBD [60]. 18F-Fluorodeoxyglucose (18F-FDG)-PET scan in idiopathic RBD patients shows brainstem and cortical changes that are similar to 18F-FDGPET changes seen in PD. In addition, the altered metabolism is correlated with RBD symptom duration [61••]. Reduced cerebral blood flow (CBF) has been found in occipito-parietotemporal of RBD patients with mild cognitive impairment and is similar to that seen in DLB and PDD patients. Further, increased hippocampal CBF has been found to be predictive of future PD/DLB in a 3-year follow-up study of RBD patients. More recently, tissue staining for alphasynuclein immunoreactivity has been introduced in RBD patients. Thus far, alpha-synuclein aggregates have been found in the submandibular gland as well as submucosal nerve fibers or ganglia of the colon in idiopathic RBD patients [62, 63]. The findings of colonic alpha-synuclein in the enteric nervous system in iRBD patients as well as three reported cases of synuclein staining tissue from the colon in asymptomatic patients undergoing routine colonoscopy years prior to the onset of clinical PD symptoms have sparked interest in the enteric nervous system as an inciting location of synucleinopathy neurodegeneration [64]. 4. RBD and Lewy Body Disease Dream enactment is common in DLB, and PSG-confirmed RBD is present in as many as 83% of DLB patients [65]. In fact, DLB and RBD are so closely associated that including RBD as a core feature of DLB increases the likelihood of DLB diagnosis sixfold [66]. Importantly, DLB patients with RBD have a shorter duration of dementia, earlier onset of parkinsonism and visual hallucinations, and lower neuritic plaque scores than DLB patients without RBD, indicating that DLB + RBD is a specific subtype of DLB which may have more widespread neurodegeneration than DLB without RBD [67]. This association is important for clinicians to recognize, as DLB + RBD patients may have more motor and behavioral dysfunction requiring more intensive caregiver support than DLB patients without RBD. These findings are analogous to those in patients with PD + RBD who also have worse motor functioning and a significantly greater risk of developing PDD than PD without RBD. Taken together, the presence of RBD in patients with

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parkinsonism portends worse cognitive and motor performance, and appropriate patient and caregiver education and support should be given at an early stage. Among the synucleinopathies, RBD is most common in patients with MSA, occurring in >88% of patients, with approximately 50% reporting RBD symptoms before the onset of neurologic symptoms [68]. The exact mechanism for this is unknown, but it likely has to do with widespread brainstem degeneration seen in patients with MSA [69]. Given the widespread prevalence of RBD in MSA, few studies exist comparing the differences between MSA patients with and without RBD, although a small study suggested no significant cognitive impairments associated with the presence of RBD, unlike in PD [70]. However, the presence of RBD in patients with autonomic failure is suggestive of a central etiology, such as MSA [71]. 5. RBD in Non-Synucleinopathies While RBD can be considered a core feature of DLB, it rarely occurs in patients with FTD, with only one case report existing in the current literature [72]. Given its rarity in FTD, the presence of RBD in a patient with presumed FTD should prompt skepticism of the diagnosis and pursue further examination for other neurodegenerative syndromes. RBD does occur in patients with AD, with two studies showing a 15% prevalence of dream enactment behaviors in AD, with only few of these patients having RSWA on PSG [73, 74]. However, due to the frequent pathologic overlap between AD and DLB, the presence of RBD in a patient clinically diagnosed with AD suggests comorbid underlying synuclein pathology, with the largest clinicopathologic series of RBD patients showing 34% having comorbid AD and Lewy body disease while only 3.4% of pure AD pathology brains had a history of dream enactment behaviors [36]. Pathophysiology of RBD Rodent and feline studies as well as human brain lesion case reports of RBD have informed much of our understanding of REM sleep atonia control. RBD-type behaviors were first demonstrated by selective lesioning of the cat locus coeruleus in 1965 [75]. More recent data suggest REM atonia generation and maintenance is controlled by a region adjacent to the locus coeruleus, the locus subcoeruleus (SubC)/sublateraldorsal nucleus (SLD), in the dorsal pons [76]. Additionally, a variety of other nuclei influence the generation and maintenance of REM sleep including the cholinergic pedunculopontine nucleus (PPN) and laterodorsal tegmental nucleus (LDTN) with more recent data suggesting the lateral hypothalamus plays a prominent role in the control of REM sleep [77]. In humans, ischemic stroke, inflammatory lesions, and tumors of the pons/medulla have all been associated with the development of RBD, further supporting brainstem

localization for REM sleep muscle atonia control [78]. Neuromelanin imaging with 3 T MRI in PD-RBD and iRBD patients shows decreases signal intensity in the locus coeruleus/subcoeruleus area that correlates with degree of RSWA providing further in vivo evidence for the importance of this area in RBD pathophysiology [79, 80].. Additionally, patients with limbic encephalitis have been reported to develop RBD, suggesting limbic influence in the generation and maintenance of REM sleep [78, 81]. The SubC/SLD contains primarily excitatory glutamatergic neurons with both caudal and rostral projections [82]. Rostral projections excite thalamocortical neurons, the basal forebrain, and lateral hypothalamus to generate REM sleep (EEG) [82]. However, more recent data has called into question the influence of the SubC/SLD on the generation of the cortical features of REM sleep [83]. More importantly, caudal projections to the ventromedial medulla (VMM), the nucleus raphe magnus, as well as the ventral and lateral gigantocellular nuclei are responsible for hyperpolarizing spinal motoneurons leading to the REM sleep muscle atonia [82, 84]. Because of the strong association of RBD with PD, the Braak staging hypothesis of PD may provide a possible explanation for the occurrence of RSWA and RBD symptoms in PD and perhaps also in DLB, especially in those who have RBD prior to the onset of motor and cognitive dysfunction. Braak has postulated six stages of progressive and selective ascending Lewy body deposition and Lewy neurite accumulation based on the clinical phenotype of PD, corroborated by pathologic examination [85]. In stage 1, Lewy bodies and neurites begin to accumulate in the dorsal motor nucleus of the vagus in the medulla, while in stage 2, Lewy bodies and neurite progress rostrally through the magnocellularis reticular nucleus, subceruleus-ceruleus complex (including the SLD), olfactory bulb, and anterior olfactory nucleus. RBD symptoms are considered to be part of stage 2. Stages 3 and 4 are considered the parkinsonian stage, with progression of Lewy deposits to the substantia nigra, the pedunculopontine nucleus, and the amygdala occurring in stage 3, while stage 4 results from progression of Lewy deposits into the temporal mesocortex. Widespread neurodegeneration occurs in stages 5 and 6, with Lewy deposits affecting the neocortex, causing cognitive impairment [85]. While the Braak staging may explain the presence of idiopathic RBD as a Bprodromal^ synucleinopathy, it does not fully explain why some patients with PD never develop RBD and why RBD develops after the onset of cognitive and motor symptoms in some patients with PD and DLB. 6. Treatment of RBD Fortunately, RBD is a readily treatable condition in the majority of cases. Initial treatment strategies include ensuring bedroom safety by removing objects that may cause injury such as any beside item that could be picked up and wielded as a weapon, in particular, firearms, followed by

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pharmacologic therapy. Preventing sleep-related injury is the main goal of RBD treatment. Idiopathic RBD patients (compared with secondary RBD) and those who clearly recall dreams have been found to be associated with risk of injury; however, higher frequency of dream enactment behaviors has not been shown to have a greater risk of injury, highlighting the importance of RBD treatment, even in patients with infrequent episodes of dream enactment [42]. Bed rails, placing the mattress on the floor, or barriers between the patient and bed partner may help minimize injury and bed alarms may help abort severe dream enactment episodes [86]. Confusional arousals resulting from obstructive sleep apnea may mimic RBD episodes and frequently worsen dream enactment behaviors [87]. Thus, treatment of sleep disordered breathing may often decrease the frequency of dream enactment behaviors [88]. Melatonin and clonazepam are the mainstays of pharmacologic treatment for RBD and appear to have equal efficacy in reducing DEB frequency and injury; however, DEB is rarely entirely eliminated [13, 32, 89–92]. Clonazepam, a GABAA receptor modulator, was the first treatment to be reported as effective for RBD [13]. Studies suggest significant improvement in RBD symptoms with a dose of 0.5–1 mg given approximately 30 min before bedtime [12, 13, 15, 31, 91–95]. In addition to reducing DEBs, clonazepam reduces the frequency of nightmares and violent dreams but does not restore REM sleep muscle atonia. This suggests that clonazepam improves RBD symptoms by decreasing the intensity of dreaming rather than directly modulating REM sleep muscle control in the brainstem [82, 92, 96, 97]. Of note, clonazepam can worsen the severity of obstructive sleep apnea and cognitive impairment as well as cause sleepiness, dizziness, unsteadiness, and sexual dysfunction. It also may be less effective in patients with a clinically diagnosed neurodegenerative disease when compared with melatonin [32, 91, 97]. Therefore, patients with cognitive impairment, dementia, and sleep apnea must be monitored carefully when treated with clonazepam. Melatonin, at a median effective dose of 6 mg (range 3– 18 mg) 30 min before bedtime, has been shown to significantly reduce DEBs and DEB-related injury with fewer side effects than clonazepam. Adverse effects are dose related and primarily include daytime sleepiness; however, headaches, nausea, and hallucinations have been reported [32, 91, 98]. Melatonin appears to be a more efficacious treatment for patients with secondary RBD due to its more tolerable side effect profile [91]. Melatonin directly reduces REM motor tone and thus decreases DEBs [89, 90, 99]. There is evidence that iRBD and PD-RBD patients show altered circadian rhythm, and it has been suggested that melatonin may reduce DEB by helping to re-entrain the circadian oscillation of normal REM atonia [100]. As melatonin is not FDA regulated, there is a large variation in composition between brands and likely impacts the efficacy of melatonin for RBD treatment [101]. Ramelteon, FDA-regulated melatonin receptor agonist, has

not been shown to be effective in significantly reducing RSWA or RBD severity in one small open-labelled clinical trial of idiopathic RBD patients, albeit with some subjective improvement in symptoms in a few patients [102]. At this time, ramelteon for the treatment of RBD requires further study and current evidence does not support its use as a primary treatment for RBD. Other treatments of RBD have been limited to case reports or small series with limited efficacy. Pramipexole has shown mixed results in RBD, varying from little or no effect, to moderate reduction of RBD episodes [103–106]. Pramipexole would potentially have dual efficacy in DLB patients by treating both motor symptoms of DLB and reducing DEB. Donepezil, which is commonly prescribed for the putative cognitive benefits in patients with dementia, has also been reported to reduce motor events related to RBD; however, data are limited [107, 108]. Excessive Daytime Sleepiness Excessive daytime sleepiness (EDS) is a common feature of non-AD dementias, especially LBD. EDS is frequently multifactorial, with underlying neuropathology, sedating medications, sleep disordered breathing (SDB), RLS, frequent periodic limb movement of sleep (PLMS), and circadian rhythm alterations likely contributing to different degrees in different patients [6]. LBD patients have degeneration of the locus coeruleus, basal forebrain, and dorsal raphe, which are all associated with the ascending reticular activating system [109]. These findings lead to some cases where Bnarcolepsylike^ sleepiness is seen in PD/PDD and DLB. The hypersomnia is frequently debilitating, leading to significant burden on caregivers [8]. In one study, >50% of DLB patients had evidence for pathologic sleepiness (<5 min sleep latency on the Multiple Sleep Latency Test). These findings contrasted with the more normal range of sleepiness in patients with Alzheimer’s disease [109]. PD patients have been found to have hypocretin neuronal loss of the lateral hypothalamus, the cardinal pathological feature of narcolepsy [110]. Patients with PD have also been shown to have blunted circadian rhythm amplitude of melatonin secretion when compared with healthy controls, findings that adversely influence sleep quality and quantity in PD (see below) [111]. EDS is also prevalent in FTD, with one study reporting >60% of patients complaining of daytime hypersomnolence [6]. However, when compared with LBD patients, daytime sleepiness in FTD is likely secondary to nocturnal behavioral disturbances rather than degeneration of nuclei involved in the maintenance of wakefulness [9•]. Initial treatment strategies include optimizing the duration and circadian timing of sleep as well as addressing underlying primary sleep disorders including SDB, RLS, and PLMS. However, pathologic sleepiness frequently persists. In these

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RLS is a clinical diagnosis based on the presence of four cardinal features: (1) an urge to move the legs, typically with uncomfortable leg sensations; (2) symptoms worsen with rest; (3) there is transient relief with movement; and (4) symptoms demonstrate a diurnal pattern more severe in the evening [114]. RLS is a common cause of sleep disruption in all dementias; however, it appears to be most prevalent in LBD, occurring in up to 75% of patients [6, 8]. RLS is caused by a deficiency or dysfunction of CNS dopamine. As iron is a co-factor in the rate-limiting step, tyrosine hydroxylase, in dopamine metabolism, its deficiency can worsen RLS symptoms. Thus, the initial treatment of RLS involves ensuring that serum ferritin levels are >75 μg/L. Iron can be replaced orally with ferrous gluconate combined with vitamin C (which increases elemental iron’s enteric absorption). The most common side effect of oral iron is constipation and gastrointestinal discomfort. IV ferrous sulfate plus vitamin C has been shown to be most efficacious at rapidly increasing ferritin stores [115]. Pharmacologically, pramipexole (0.125–1.0 mg), rotigotine (1–4 mg), and gabapentin encarbil (600–1200 mg) have the strongest evidence for efficacy, with pregabalin (100–300 mg) and ropinirole (1–4 mg) also showing efficacy. The dopaminergic agonists pramipexole, rotigatine, and ropinirole have the added benefit of potentially improving the parkinsonism symptoms associated with LBD; however, the dopaminergic agonists are associated with augmentation (the worsening of RLS symptoms over time with chronic therapy) when compared with gabapentin [115]. Further, dopamine agonists should be used with caution as they may worsen impulse control disorders, particularly in FTD patients who may be less inhibited secondary to their dementia [116].

patients [6, 8]. Under normal conditions, the 24-h circadian rhythm, generated by the suprachiasmatic nucleus (SCN) located in the anterior hypothalamus, utilizes external zeitgebers (primarily morning light but also exercise and feeding) to synchronize the physiologic clock to the environment. Circadian rhythms are responsible for the generation and maintenance of several physiologic functions including behavioral, cardiovascular, and body temperature regulation [117]. Disruptions of the SCN through neurodegeneration or erratic exposure to zeitgebers (German for time-giver) have the potential to drastically alter the natural sleep-wake cycle, leading to mismatch between desired sleep-wake behaviors, potentially resulting in inappropriate nocturnal activity and daytime sleepiness and inactivity, a major cause of caregiver burden and burnout. Most studies of circadian rhythm dysfunction of LBD patients have been in PD. In PD, circadian dysfunction may manifest in several unique ways. There is often a reversal of day-night/wake-sleep rhythmicity as well as autonomic instability and motor fluctuations [117]. Importantly for DLB, altered circadian rhythms are associated with more frequent nocturnal hallucinations [118]. These findings suggest that therapies directed at restoring normal circadian rhythms (see below) could potentially reduce hallucinations in DLB, which are common and often distressing to the patient and/or their caregivers. Circadian rhythm disruptions are common in FTD [119, 120]. However, in contrast to PD, patients with FTD are reported to have normal body temperature variation, suggesting an intact SCN, and that sleep initiation difficulties are frequently behavioral (i.e., prolonged napping during the daytime), rather than due to a degeneration of neural pathways [120]. While no randomized control trials for insomnia/circadian rhythm alterations have been performed in LBD or FTD, the dual foundation of circadian therapy is evening low dose (0.5 mg) melatonin 2–4 h prior to bedtime along with morning sunlight (or 10,000 lx light box) for 30–120 min immediately after awakening in the morning. Additionally, ensuring consistent zeitgebers through exposure to regular daytime exercise and scheduled meals may help normalize circadian rhythm [112]. Behavioral modification such as discouraging prolonged daytime napping and encouraging regular routine in FTD is often an efficacious insomnia symptom in FTD. Benzodiazepines and other hypnotics are not recommended for primary treatment of circadian rhythm disorders [112].

Circadian Rhythm Disturbances

Nocturnal Stridor

Circadian rhythm disturbances, which can manifest as difficulty falling asleep at night along with excessive daytime sleepiness, are common in neurodegenerative disorders. Among the non-AD dementias, circadian rhythm disorders occur in 47–67% of LBD patients and up to 48% of FTD

Nocturnal stridor due to laryngeal dysfunction has been reported to occur in 31–42% of MSA patients and is associated with increased risk of sudden death in MSA [121, 122]. Further, early onset stridor portends a worse prognosis than late onset stridor [122]. Several treatment options for

cases, modafinil at 100–200 mg may decrease EDS and improve daytime functioning; however, they are not FDA approved for use in dementia. Alternative stimulants include armodafinil and amphetamine-based agents such as methylphenidate and atomoxetine [112, 113]. However, given the predisposition of DLB patients to psychosis, DLB patients taking stimulant medications should be monitored for worsening psychiatric symptoms. Other concerning side effects include insomnia, anxiety, and potentially fatal cardiac arrhythmias. Restless Legs Syndrome

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nocturnal stridor exist including continuous positive airway pressure (CPAP), bi-level positive airway pressure (BiPAP), and tracheostomy for patients with both nocturnal and daytime stridor [123, 124]. Treatment of stridor was associated with increased survival in MSA patients in one large study [122]. Thus, all patients with a suspected diagnosis of MSA should undergo video polysomnography to evaluate and treat stridor.

Conclusion Sleep disorders are common in non-Alzheimer’s disease dementias, frequently worsening cognitive impairment, and increasing caregiver burden. REM sleep behavior disorder is strongly associated with LBD and is often a prodromal syndrome of alpha-synuclein pathology. Conversely, RBD rarely occurs in FTD, and thus the presence of RBD in a patient with FTD should prompt clinicians to consider alternative etiologies such as AD, as comorbid LBD is common with AD, and is likely responsible for RBD in these patients. As the presence of RBD in an otherwise neurologically normal individual heralds the presence of underlying neurodegeneration, RBD provides a promising window of opportunity to develop neuroprotective therapies. More recent evidence suggests patients with isolated RSWA (without a history of dream enactment) also have non-motor signs of neurodegenerative disease, possibly providing an even earlier window to slow the progression of neurodegeneration. Treatment of RBD with clonazepam and melatonin reduces injury; however, treatment rarely eliminates all dream enactment behaviors, and patients should be counseled as such. EDS, RLS, and circadian rhythm dysfunction are common in both LBD and FTD patients, with LBD patients being more frequently affected. RLS and circadian rhythm changes may contribute to EDS; however, degeneration of networks associated with alertness also contributes to pathologic sleepiness in these disorders. Alterations in the circadian rhythms are also associated with worse motor, autonomic, and psychiatric symptoms and provide an underutilized therapeutic avenue for therapy. All MSA patients should undergo video polysomnography to evaluate for the presence of nocturnal stridor, which is associated with decreased survival and responds favorably to treatment with continuous positive airway pressure or tracheostomy, possibly prolonging survival in MSA. Given the high frequency of sleep disorders in non-AD dementias, patients should be screened for these conditions and treated to maximize daytime function.

Michael J. Howell is a co-owner of the Sleep Performance Institute. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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12. Compliance with Ethical Standards 13. Conflict of Interest Stuart J. McCarter declares no potential conflicts of interest.

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