Curr Neurol Neurosci Rep (2013) 13:373 DOI 10.1007/s11910-013-0373-0

SLEEP (M THORPY AND M BILLIARD, SECTION EDITORS)

Parkinson Disease and Sleep: Sleep–Wake Changes in the Premotor Stage of Parkinson Disease; Impaired Olfaction and Other Prodromal Features Alex Iranzo

# Springer Science+Business Media New York 2013

Abstract Parkinson disease (PD) has a premotor stage where neurodegeneration occurs before parkinsonism becomes apparent. Identification of individuals at this stage provides an opportunity to study early disease progression and test disease-modifying interventions. Hyposmia, constipation, depression and hypersomnia are part of this premotor phase and predictive of future development of PD. However, these features are common in the general population, and they are most often the result of causes other than incipient PD. In contrast, most individuals with idiopathic REM sleep behavior disorder (IRBD) eventually develop PD and other synucleinopathies. IRBD individuals with hyposmia, substantia nigra hyperechogenicity, and abnormal striatal dopamine transporter imaging findings have increased short-term risk of developing a synucleinopathy. IRBD is an optimal target to test disease-modifying agents in the PD prodromal phase. Serial dopamine transporter imaging, but not olfactory tests, may serve to monitor the disease process in future diseasemodifying trials in IRBD. Keywords Parkinson disease . Premotor stage . Disease-modifying interventions . Olfactory dysfunction . Constipation . Depression . Excessive daytime sleepiness REM sleep behavior disorder . Sleep . Sleep–wake changes

Introduction Parkinson disease (PD) is a progressive neurodegenerative disease. The pathologic hallmarks of PD are neuronal loss This article is part of the Topical Collection on Sleep A. Iranzo (*) Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, CIBERNED, C/Villarroel 170, 08036 Barcelona, Spain e-mail: [email protected]

and Lewy bodies that stain for α-synuclein in the substantia nigra and other vulnerable structures [1]. PD has long been considered a movement disorder because physicians and researchers focused on the characterization, pathophysiology, and treatment of motor features such as bradykinesia, tremor, rigidity, postural instability, gait problems, and dyskinesia. In fact, the current clinical diagnosis criteria for PD only require the identification of motor symptoms [2]. Parkinsonism in PD is caused by dysfunction of the nigrostriatal dopaminergic system. It is estimated that motor symptoms are first clinically noticeable when there is 40-60 % neuronal loss in the substantia nigra. However, PD patients present with other symptoms, such as sleep disorders, depression, dementia, hyposmia, pain, hallucinations, and dysautonomic features including constipation and postural hypotension (Table 1). Most of these nonmotor symptoms are not related to dopamine deficiency and appear clinically either before or after the clinical appearance of parkinsonism. In fact, sleep disorders, depression, constipation, and loss of smell may precede the onset of the cardinal motor symptoms of PD, in what has been called the premotor stage of this disease [3]. This is in line with a proposed staging model of disease in PD, where the neurodegenerative process occurs first in the peripheral autonomic nervous system, lower brainstem, and olfactory bulb before reaching the substantia nigra in the midbrain and causing parkinsonism [4]. This prodromal phase provides an invaluable opportunity to study early disease events and disease progression, and to test novel interventions that could slow or even stop the neurodegenerative process. Identification of individuals at the premotor stage of PD is a major challenge [5]. In this article, I will review the characteristics and relevance of these nonmotor symptoms that may occur during the prodromal stage of PD, namely, loss of smell, constipation, depression, excessive daytime sleepiness, and REM sleep behavior disorder (RBD).

373, Page 2 of 9

Curr Neurol Neurosci Rep (2013) 13:373

Table 1 Nonmotor symptoms in Parkinson disease Symptoms that may precede the onset of motor symptoms

Other nonmotor symptoms

REM sleep behavior disorder Impaired olfaction Constipation Depression

Urinary frequency and urgency Nocturia Impaired male erection Reduced sex drive

Excessive daytime sleepiness

Insomnia Anxiety Apathy Fatigue Hallucinations Delusions Psychosis Dysphagia Dopaminergic dysregulation syndrome Impulse control disorder Hyperhidrosis Blurred vision Facial seborrhea Weight loss Orthostatic hypotension Pain Ageusia Diplopia Drooling Dribbling Mild cognitive impairment Dementia

Impaired Olfaction Olfactory dysfunction is common in PD and includes impairments in odor identification (the ability to name an odor), discrimination (the nonverbal distinction of different smells), and detection (the threshold or the perception of odors at low concentrations) [6]. Among these three domains, odor identification is the most frequent in subjects with PD [7]. Olfaction is impaired in 70–90 % of patients with sporadic PD and occurs early in the disease [6]. Loss of smell in PD causes little disability, and some PD patients are not aware that they have lost their sense of smell until they undergo olfactory tests [6, 8, 9]. Most studies found that olfactory dysfunction is unrelated to gender, parkinsonism duration and severity, dopaminergic therapy [6], and cognition [10]. Most longitudinal studies have reported that odor deficits are stable over time despite progression of the disease [11]. This in agreement with the

observation that olfactory disturbance is similar between subjects with short and long parkinsonism duration [12]. From these findings taken together, olfactory function is frequent and severe when PD is first diagnosed, does not deteriorate over time, and is not useful for monitoring disease progression. A floor effect in olfactory loss is reached at the very early stage of disease, possibly before the onset of motor symptoms. Several lines of evidence indicate that impaired olfaction is a premotor marker of PD: 1. Olfactory deficits in odor detection, identification, and discrimination are commonly found in untreated subjects with a recent diagnosis of PD [7]. 2. Some PD patients report that olfactory deficits preceded the onset of motor signs by several years [13]. 3. Individuals with idiopathic hyposmia report nonmotor PD features including depression, constipation, and a history suggestive of RBD [14]. 4. Subjects with idiopathic hyposmia may show subclinical substantia nigra damage as demonstrated by dopamine transporter imaging and transcranial sonography [15]. 5. Longitudinal follow-up of aging men with idiopathic hyposmia shows an increased risk of developing PD with time [16]. 6. First-degree asymptomatic relatives of patients with PD frequently have loss of smell and abnormal dopamine transporter imaging findings [17]. These relatives with impaired olfaction have an increased risk of developing PD with time [18•]. 7. Impaired olfaction is present in other populations with high risk of developing PD such as those with idiopathic RBD (IRBD) [19, 20]. 8. Olfactory identification can be impaired in incidental Lewy body disease (individuals without parkinsonism and dementia in whom autopsy revealed Lewy bodies in the substantia nigra) [21]. The pathophysiology of olfactory loss in PD is unclear. Neuropathologic changes in (1) the olfactory bulb and the anterior olfactory nucleus in the early disease and (2) the olfactory cortex and limbic structures in advances stages may both be involved [22]. Lewy bodies have been shown in all these structures in subjects with antemortem diagnosis of PD. Hyposmia has been related to nigrostriatal denervation in the early stages of PD [23], whereas cholinergic deficits in the limbic cortex may occur in later stages [24]. In PD patients, a 100 % increase in the number of dopaminergic cells in the olfactory bulb has been found [25], a finding that may explain the loss of smell in PD since dopamine inhibits olfactory transmission between receptor neurons and mitral cells in the olfactory bulb. This would also explain why dopaminergic

Curr Neurol Neurosci Rep (2013) 13:373

agents do not improve olfactory function in PD. There is no effective treatment for loss of smell in PD.

Constipation In PD, constipation may precede the onset of parkinsonism. It is three times more frequent in PD patients than in the general population [26]. In one study, the strongest risk factors associated with later PD diagnosis were history of constipation, family history of PD or tremor, and lack of smoking history [27]. A demonstration that constipation can be part of the prodromal phase of PD came from a large population-based prospective epidemiologic study conducted in 6,790 healthy men. In this study, after a 24-year period of follow-up, the risk of PD in men with less than one bowel movement per day increased to a 4.1-fold excess when compared with men with two bowel movements per day, and to a 4.5-fold excess versus men with fewer than two bowel movements per day. The authors of the study concluded that infrequent bowel movements are associated with an elevated risk of PD [28]. Constipation is reported by 25-55 % of PD patients [29, 30]. It is common in patients with a recent diagnosis of PD, and 25-90 % report that bowel dysfunction preceded parkinsonism [29, 31]. In one study with 129 PD patients and 120 controls, constipation was more frequent in patients than in controls (53.6 % vs 8.3 %), and 87 % patients reported that this symptom occurred before parkinsonism [29]. Autonomic dysfunction is the main cause of constipation in PD, leading to slow bowel movements and reduced colon transit. Postmortem neuropathologic data in PD have showed that Lewy pathology and α-synuclein aggregates are found in the central and peripheral autonomic nervous system structures that regulate gastrointestinal tract function, namely, the dorsal motor nucleus of the vagus, the paravertebral sympathetic ganglia, sacral segments of the spinal cord, and the enteric nervous system in the Meissner and Auerbach plexuses (particularly in the lower esophagus and in the submucosal plexus in the stomach and colon, but also in the stomach, duodenum, and minor salivary glands) [4]. Biopsy studies in individuals with early untreated PD have also shown αsynuclein inclusions in the colonic submucosa [32•]. This αsynuclein disease can be detected in patients who underwent colonic biopsy 2–5 years before the diagnosis of PD and the onset of parkinsonism [33]. This is in line with postmortem data showing that these structures are affected by α-synuclein disease earlier than in the substantia nigra, and this would explain why constipation may antedate parkinsonism in some individuals with PD [4, 34, 35]. Treatment of constipation in PD includes increased fiber and fluid intake, stool softeners, osmotic laxatives prokinetic agents, colchicine, and pyridostigmine.

Page 3 of 9, 373

Depression Depression in PD impairs quality of life and increases disability and caregivers’ distress. PD patients with depression experience low motivation, lack of energy, anxiety, and poor concentration. In contrast, typical depressive symptoms such as sadness, guilt, and worries may be not prominent. Approximately 40-50 % of PD patients are affected by depressive symptoms during the course of the illness [36]. A metaanalysis showed a prevalence of 17 % for major depression, 22 % for minor depression, and 13 % for dysthymia [37]. Early age of PD onset and cognitive impairment are associated with increased risk of depression. Depression may be predictive of future development of PD. Approximately 20 % of patients complain of depressive symptoms before the onset of parkinsonism [38]. Depression is not linked to disease severity in subjects already diagnosed with PD. Depression can predate the diagnosis of PD by up to 20 years, but its incidence shows a particular rise during the 3–6-year period before diagnosis [38–40]. Case–register studies have shown that depressed patients have a 2.2-fold to 3.2-fold risk of developing PD [40–42]. Depression in PD is not a reactive process but has a genuine biological basis. Abnormalities in both noradrenaline and serotonin transmission from the locus coeruleus and dorsal raphe nucleus to limbic and cortical structures have been implicated in the pathogenesis of depression in the setting of PD. Impairment in dopaminergic transmission may also be involved. Treatment of depression in PD patients includes selective serotonin reuptake inhibitors, venlafaxine, mirtazapine, reboxetine, and pramipexole.

Excessive Daytime Sleepiness Excessive daytime sleepiness (EDS) is characterized by the inability to stay awake during the day, resulting in undesirable lapses into sleep. In PD, EDS is a common complex phenomenon that may lead to social problems and automobile accidents and may have a negative impact on quality of life. EDS in PD is manifested as a state of continuous and persistent hypersomnolence or as episodes of sudden onset of sleep (“sleep attacks”). Predisposing factors for developing EDS in PD include dopaminergic therapy, dementia, parkinsonism severity and duration, hallucinations, circadian sleep–wake cycle disruption, nocturnal sleep quantity and quality, obstructive sleep apnea, depression, and genetic susceptibility. The nature of EDS in PD involves multiple factors, with the intrinsic effect of the dopaminergic medication and the disease itself being the most relevant. It is thought that development of EDS in PD is related to progressive cell loss in the dopaminergic and nondopaminergic brain structures and networks

373, Page 4 of 9

that modulate the sleep–waking mechanisms. This is in line with the finding of the association between EDS and the advanced stage of parkinsonism and longer duration of the disease suggesting that severer and widespread brain damage leads to the development or worsening of EDS [43]. Longitudinal studies showed that the prevalence of EDS in PD increases over time in parallel with cognitive decline and disease progression [44]. The association of EDS as a predictor of PD comes from a single study [45]. In this study, EDS was assessed in 3,078 men aged 71–93 years in the Honolulu-Asia Aging Study from 1991 to 1993. All individuals were men free of prevalent PD and dementia. Follow-up for incident PD was based on three repeat neurological assessments from 1994 to 2001. EDS was defined as “being sleepy most of the day” and no scales or other assessments were used to define the existence of EDS. EDS was observed in 7.9 % of the men (244 of 3,078) included in the study. During the course of the 7-year followup, 43 men developed PD. Thirty-four (79 %) of these 43 subjects had no EDS at the baseline, and the remaining nine (21 %) had EDS at the baseline. In those with EDS at the baseline, PD was diagnosed in 34 subjects. After age adjustment, there was more than a threefold excess in the risk of PD in men with EDS versus men without EDS. The authors of this study concluded that EDS may be associated with an increased risk of developing PD and speculated that damage of the lower brainstem structures that modulate the sleep– wake cycle may have contributed to the development of EDS before the appearance of parkinsonism. The strengths of this study were that it was an epidemiologic, longitudinal study, evaluating a large cohort, with a long clinical follow-up of 7 years. The limitations of this study were that it included only men, it included only aging individuals of more than 70 years, the definition of EDS was not validated, and the cause of EDS was not investigated. In the general population the commonest causes of EDS are sleep-related breathing disorders, insufficient sleep syndrome, and depression, but the occurrence of these conditions was not evaluated. This study needs to be replicated because EDS has not been convincingly investigated as a hallmark of neurodegeneration preceding parkinsonism.

REM Sleep Behavior Disorder RBD is a parasomnia confined to REM sleep. It is characterized by abnormal motor and vocal behaviors (e.g., jerking, kicking, shouting, crying, laughing) and nightmares (e.g., being attacked or chased by people) linked to REM sleep without atonia. RBD is the result of the dysfunction of the brainstem structures that regulate muscle atonia during REM sleep, namely, the magnocellularis nucleus in the medulla and

Curr Neurol Neurosci Rep (2013) 13:373

the locus subcoeruleus in the pons. Polysomnography with audiovisual recording is needed to confirm the diagnosis of RBD and to exclude other sleep disorders that can mimic its symptoms, including obstructive sleep apnea, nocturnal hallucinations, periodic limb movements during sleep, and confusional awakenings. RBD may be idiopathic or related to (1) focal brainstem or limbic lesions, (2) the use of medications such as antidepressants and lipophilic beta blockers, (3) narcolepsy, and (4) neurodegenerative diseases, particularly the synucleinopathies PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [46, 47•, 48•]. There is the following strong evidence that RBD may be the prodromal stage of these three synucleinopathies. Longitudinal studies from three different groups have shown that subjects with IRBD eventually develop a synucleinopathy. In the seminal work, parkinsonism developed in 11 of 29 IRBD subjects (38 %) nearly 4 years after the diagnosis of IRBD and at a mean interval of nearly 13 years after the onset of RBD symptoms [49]. After 16 additional years of follow-up, 21 IRBD patients from the original cohort developed PD, DLB, and MSA [50]. In a second series, 26 of 93 IRBD patients (28 %) developed PD, DLB, or MSA after a mean follow-up of 5 years [51]. In a study conducted in our institution, 20 of 44 IRBD patients (45 %) developed a defined neurodegenerative syndrome after a mean follow-up of 5 years [52]. Emerging disorders were PD, DLB, and less frequently MSA and mild cognitive impairment. We found that patients who developed a motor or cognitive disorder were those with a longer clinical follow-up. This suggested that the rate of conversion to these disorders would be increased with extended follow-up. To test this hypothesis, in a second study we aimed to determine the frequency and nature of the defined neurodegenerative syndromes that emerged in our original cohort after 7 years of additional follow-up. Of the 44 subjects from the original cohort, 36 (82 %) developed a defined neurodegenerative syndrome after a median follow-up of 10.5 years [53••]. Sixteen patients were diagnosed with PD, 14 patients were diagnosed with DLB, one patient was diagnosed with MSA, and five patients were diagnosed with mild cognitive impairment. With use of the Kaplan–Meier method, the rates of neurological disease-free survival from IRBD diagnosis at our center were 65.2 % at 5 years, 26.6 % at 10 years, and 7.5 % at 14 years. Of the four remaining disease-free individuals who underwent neuroimaging and olfactory tests, all had decreased striatal dopamine transporter uptake, one had substantia nigra hyperechogenicity on transcranial sonography, and two had impaired olfaction on smell tests. In three patients, the antemortem diagnoses of PD and DLB were confirmed by neuropathologic examination showing widespread Lewy bodies in the brain, and α-synuclein aggregates in the peripheral autonomic nervous system in one of them.

Curr Neurol Neurosci Rep (2013) 13:373

In these three cases, neuronal loss and Lewy body disease were found in the brainstem nuclei that regulate REM sleep atonia. Thus, most of the IRBD individuals from our cohort developed a synucleinopathy disorder with time. Subjects that remained disease-free at follow-up showed markers of increased short-term risk of developing PD and DLB in IRBD, such as decreased striatal dopamine transporter binding and hyposmia. Our findings indicated that IRBD is the prodromal phase of the synucleinopathies. Patients with IRBD may present with abnormalities that are characteristic features of PD, including olfactory deficits [19, 20, 54••, 55], color vision impairment [54••], cognitive abnormalities on neuropsychological testing [56], subtle cortical electroencephalographic slowing [57], dysautonomic abnormalities [58], reduced cardiac 123I-m-iodobenzylguanidine uptake [59], decreased levels of dopamine transporter in the striatum [60], and increased substantia nigra echogenicity [61] (Table 2). To the best of my knowledge, there are no studies that have addressed formally the frequency and characteristics of EDS, depression, and constipation in IRBD. Longitudinal studies have evaluated whether these abnormalities change over time in IRBD and can predict the development of PD and other synucleinopathies. In one study,

Table 2 Clinical and subclinical abnormalities in idiopathic REM sleep behavior disorder Reduced arm swinging Face akinesia Depression Impaired olfaction Color vision impairment Asymptomatic cognitive abnormalities on cognitive tests, especially in the executive, memory, and visuospatial domains Cortical electroencephalographic slowing Orthostatic hypotension Systolic blood pressure drop Decreased beat-to-beat variability in the cardiac rhythm Constipation Reduced postprandial ghrelin response Urinary symptoms Erectile symptoms Episodes of acute psychosis after minor or major surgery Reduced cardiac 123I-m-iodobenzylguanidine uptake Decreased levels of dopamine transporter in the striatum, particularly in the left putamen Substantia nigra hyperechogenicity Brainstem changes in diffusion tensor imaging Decreased cortical and increased pontine perfusion

Page 5 of 9, 373

olfactory identification was tested at the baseline and annually for 5 years in 62 IRBD patients [54••]. During follow-up, 21 subjects developed PD and DLB, and in these subjects the mean baseline olfactory score was lower (poorer) than in subjects who remained disease-free. Those with impaired olfaction at the baseline had a 65 % risk of developing PD or DLB, whereas those with normal olfaction had a 14 % risk. There was a nonsignificant slight decline of 1.7 % olfactory score expected value per year. It was concluded that in IRBD, impairment of olfactory identification is a marker of an evolving synucleinopathy but shows only slight decline over time. In another study, 19 IRBD patients and 19 controls underwent serial clinical evaluations and olfactory identification and detection tests during a 4-year follow-up period [55]. In subjects with IRBD, olfactory identification and detection deficits were observed in most of the patients but did not worsen over time, even in the four who later developed PD and MSA. It was concluded that serial olfactory tests will not serve as an outcome measure in future disease-modifying trials in IRBD. Our group has conducted two other prospective studies in IRBD assessing dopamine transporter imaging and transcranial sonography, two neuroimaging tools that evaluate the state of the substantia nigra. Dopamine transporter imaging evaluates the presynaptic dopaminergic innervation of the striatum, whereas transcranial sonography is thought to reflect the iron content within the substantia nigra. Decreased 2βcarbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT) uptake in the basal ganglia and hyperechogenicity of the substantia nigra occurs in 90-100 % of individuals diagnosed with PD. In a first work, 43 IRBD subjects underwent both dopamine transporter imaging with 123I-FP-CIT and transcranial sonography at te baseline and were clinically assessed after 2.5 years of follow-up [62•]. Seventeen patients (40 %) had reduced FP-CIT striatal binding and 27 (36 %) had substantia nigra hyperechogenicity. Twenty-seven patients(63 %) had reduced FP-CIT uptake and/or substantia nigra hyperechogenicity. Fifteen subjects had both normal FP-CIT uptake and substantia nigra echogenicity. After 2.5 years of clinical follow-up, eight subjects (19 %), all with reduced FP-CIT uptake and/or substantia nigra hyperechogenicity at the baseline, developed clinically defined PD (n=5), DLB (n=2), and MSA (n=1). All 15 patients with normal neuroimaging findings at the baseline remained disease-free after the same follow-up period. In summary, decreased striatal FP-CIT binding and substantia nigra hyperechogenicity were useful markers to identify IRBD individuals at increased short-term risk of developing PD, DLB, and MSA. This suggested that IRBD subjects with these markers would be the ideal target population for entry into clinical trials to test disease-modifying agents. In a second study, we evaluated 20 IRBD patients and 20 controls who underwent serial dopamine transporter imaging

373, Page 6 of 9

at the baseline and again after 1.5 and 3 years [63••]. Compared with controls, the patients had reduced mean FP-CIT binding in all four striatal regions at the baseline and after 3 years. Striatal FP-CIT uptake was reduced compared with that in controls in ten patients (50 %) at the baseline and in 13 patients(65 %) after 3 years. In patients, the mean reduction in FP-CIT uptake from the baseline to 3 years was 19 % in the left putamen, 16 % in the right putamen, 11 % in the left caudate, and 7 % in the right caudate. After adjustment for the baseline striatal uptake ratios, the decline in FP-CIT binding at the baseline to 3 years was greater in the patients than in controls in the left putamen, right putamen, and left caudate, but not in the right caudate. At the 3-year assessment, three patients were diagnosed with PD. These patients had the lowest FP-CIT uptake at the baseline and a mean reduction in FP-CIT uptake at 3 years of 33 % in the left putamen, 30 % in the right putamen, 26 % in the left caudate, and 24 % in the right caudate. Thus, this study showed that in IRBD, serial dopamine transporter imaging shows a decline in striatal tracer uptake that reflects progressive nigrostriatal dopaminergic dysfunction with time. Longitudinal 123I-FP-CIT single photon emission computed tomography can be used to monitor the progression of nigrostriatal deficits in patients with IRBD, and could be useful in studies of potential diseasemodifying compounds in these patients. The only two IRBD subjects examined neuropathologically to date without clinical evidence of parkinsonism or dementia had predominant lower brainstem Lewy bodies with minimal damage in the substantia nigra [64, 65]. In sporadic PD, RBD occurs in approximately 40-50 % of patients [66, 67]. The frequency of RBD increases with time in subjects already diagnosed with PD [68]. The types of RBD-related unpleasant dreams, dream-enacting behaviors, and polysomnographic abnormalities are similar among sporadic PD and IRBD patients [69]. About 65 % of PD patients are unaware of their nighttime behaviors, and 20 % do not recall fearful dreams [69]. RBD in PD may precede, coincide with, or follow the onset of parkinsonism. In about 20 % of cases, RBD occurs before the onset of parkinsonism [69]. In patients with IRBD who developed parkinsonism, voice and face akinesia intersected earliest (estimated prodromal interval of nearly 10 years), followed by rigidity (4.4 years), gait abnormalities (4.4 years), and limb bradykinesia (4.2 years) [70]. In one prospective study following clinically 44 IRBD patients, 16 (13 men and three women) were diagnosed with PD [53••]. The mean age at PD diagnosis was 75 years, the RBD duration at the time of the diagnosis of PD was 13 years, and the interval between diagnosis of RBD and diagnosis of PD was 5.5 years. Five PD patients developed dementia. In these patients, the interval between diagnosis of PD and diagnosis of dementia was 6 years.

Curr Neurol Neurosci Rep (2013) 13:373

RBD in PD is associated with age [67, 71], male gender [71], longer parkinsonism duration [72, 73], akinetic-rigid subtype [74, 75], freezing [71], falls [67], longer disease duration [67], parkinsonism severity [67], cardiac autonomic denervation [76], orthostatic hypotension [77], asymptomatic abnormalities in neuropsychological testing [78], electroencephalographic slowing [79], mild cognitive impairment [80], and dementia [81]. For unknown reasons, RBD responds to clonazepam and melatonin at bedtime [46, 69]. However, clonazepam does not diminish the risk of developing a synucleinopathy in IRBD. Pramipexole [82] and subthalamic deep brain stimulation do not improve RBD symptoms [83, 84]. When available, IRBD is an optimal candidate to test disease-modifying medications to stop or slow the neurodegenerative process before the onset of parkinsonism and dementia.

Conclusion Hyposmia, constipation, depression, and hypersomnia are part of the prodromal stage of PD and are predictive of future development of this disease. However, the specificity and positive predictive value of IRBD seems to be much higher to identify underlying PD. IRBD is a candidate to test diseasemodifying agents in future trails to slow or halt the degenerative process occurring in the prodromal phase of PD and other synucleinopathies. Compliance with Ethics Guidelines Conflict of Interest Alex Iranzo declares that he has no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.

References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. Dickson DW, Braak H, Duda JE, et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol. 2009;8:1150–7. 2. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinic-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181–4. 3. Tolosa E, Gaig C, Santamaria J, Compta Y. Diagnosis and the premotor phase of Parkinson disease. Neurology. 2009;72 Suppl 2:S12–20.

Curr Neurol Neurosci Rep (2013) 13:373 4. Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24:197–211. 5. Berg D, Marek K, Ross GW, Poewe W. Defining at-risk populations for Parkinson’s disease: lessons from ongoing studies. Mov Disord. 2012;27:656–65. 6. Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology. 1988;38:1237–44. 7. Tissingh G, Berendese HW, Bergmans P, et al. Loss of olfaction in de novo and treated Parkinson’s disease: possible implications for early diagnosis. Mov Disord. 2011;16:41–6. 8. Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav. 1984;32:489–502. 9. Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. “Sniffing sticks”: olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Sens. 1997;22:39–52. 10. Doty RL, Riklan M, Deems DA, Reynolds C, Stellar S. The olfactory and cognitive deficits of Parkinson’s disease: evidence for independence. Ann Neurol. 1989;25:166–71. 11. Herting B, Schulze S, Reichmann H, Haehner A, Hummel T. A longitudinal study of olfactory function in patients with idiopathic Parkinson’s disease. J Neurol. 2008;255:367–70. 12. Iijima M, Kobayakawa T, Saito S, et al. Differences in odor identification among subtypes of Parkinson disease. Eur J Neurol. 2011;18:425–9. 13. Müller B, Larsen JP, Wentzel-Larsen T, Skeie GO, Tysens OB. for the Parkwest Study Group. Autonomic and sensory symptoms and signs in incident, untreated Parkinson’s disease: frequent but mild. Mov Disord. 2011;26:65–72. 14. Sideworf A, Jennings A, Eberly, et al. Impaired olfaction and other prodromal features in the Parkinson at-risk syndrome study. Mov Disord. 2012;27:406–12. 15. Sommer U, Hummel T. Cormann, et al. Detection of presymptomatic Parkinson’s disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord. 2004;19:1196–202. 16. Ross GB, Petrovitch H, Abbot RD, et al. Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann Neurol. 2008;63:167–73. 17. Ponsen MM, Stoffers D, Booji J, van Eck-Smit BLF, Wolters E, Berendse HW. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol. 2004;56:173–81. 18. • Ponsen MM, Stoffers D, Booji J, Wolters E, Booji J, Berendse HW. Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2010;81:396–9. This is a study showing that individuals who have idiopathic hyposmia plus abnormal dopamine transporter imaging findings have an increased risk of being diagnosed with PD. 19. Stiasny-Kolster K, Doerr Y. Möller, et al. Combination of “idiopathic” REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain. 2005;128:126–37. 20. Fantini ML, Postuma RB, Montplaisir J, Ferini-Strambi L. Olfactory deficit in idiopathic rapid eye movement sleep behavior disorder. Brain Res Bull. 2006;70:386–90. 21. Ross GW, Abbott RD, Petrovich H, et al. Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord. 2006;21:2062–7. 22. Benarroch EE. Olfactory system. Functional organization and involvement in neurodegenerative disease. Neurology. 2010;75: 1104–8. 23. Siderworf A, Newberg A, Chou KL, et al. [99mTC] TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease. Neurology. 2005;64:1716–20.

Page 7 of 9, 373 24. Bohnen NI, Müller MLTM, Kotagal V, et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain. 2010;133:1747–54. 25. Huisman E, Uylings HBM, Hoogland PV. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson’s disease. Mov Disord. 2004;19:687–92. 26. Kaye J, Gage H, Kimber A, et al. Excess burden of constipation in Parkinson’s disease: a pilot study. Mov Disord. 2006;21:1270–1. 27. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol. 2012;72:893–901. 28. Abbot RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology. 2001;57:456–62. 29. Cersosimo MG, Raina GB, Pecci C, et al. Gastrointestinal manifestations in Parkinson’s disease: prevalence and occurrence before motor symptoms. J Neurol. 2013;260:1332–8. 30. Chauduhuri KR, Martinez-Marin P, Schapira AV, et al. An international multicentre pilot study of the first comprehensive selfcompleted non motor symptoms questionnaire for Parkinson’s disease: The NMSQuest study. Mov Disord. 2006;21:916–23. 31. Ueki A, Otsuka M. Life style risks in Parkinson’s disease: association between decreased water intake and constipation. J Neurol. 2004;251 Suppl 7:18–23. 32. • Shannon KM, Keshavarizian, Mutlu E, et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov Disord. 2012;27:709–15. Patients with a recent diagnosis of PD show positive α-synuclein aggregates in the colon. This evidences that abnormalities in the peripheral autonomic nervous system occur in the early stages of PD. 33. Shannon KM, Keshavarizian, Dodiya H, et al. Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s disease? Evidence from 3 cases. Mov Disord. 2012;27:716–9. 34. Braak H, deVos RAI, Bohl J, Del Tredici K. Gastric alphasynuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett. 2006;396:67–72. 35. Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, et al. Do alpha-synuclein aggregates in autonomic plexus predate Lewy body disorders?: a cohort study. Neurology. 2007;68:2012–8. 36. Tandberg E, Larsen JP, Aarsland D, Cummings JL. The occurrence of depression in Parkinson’s disease: a community based study. Arch Neurol. 1996;53:175–9. 37. Reijnders JS, Ehrt U, Weber WE, et al. A systematic review of prevalence studies of depression in Parkinson’s disease. Mov Disord. 2008;23:183–9. 38. Santamaría J, Tolosa E, Valles A. Parkinson’s disease with depression: a possible subgroup of idiopathic parkinsonism. Neurology. 1986;36:1130–3. 39. Shiba M, Bower JH, Maraganore DM, et al. Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. Mov Disord. 2000;15:669–77. 40. Leentjens AFG, Van den Akker M, Metsemakers JFM, Lousberg R, Verhey FRJ. Higher incidence of depression preceding the onset of Parkinson’s disease: a register study. Mov Disord. 2003;18:414–8. 41. Nilsson FM, Kessing LV, Bolwig TC. Increased risk of developing Parkinson’s disease for patients with major affective disorder: a register study. Acta Psychiatr Scand. 2001;104:380–6. 42. Nilsson FM, Kessing LV, Sorensen TM, Andersen PK, Bolwig TG. Major depressive disorder in Parkinson’s disease: a register-based study. Acta Psychiatr Scand. 2002;106:202–11. 43. Iranzo A. Parkinson’s disease and sleepiness. Sleep Med Clin. 2006;1:127–37. 44. Ondo WG, Dat Vuong K, Khan H, Atassi F, Kwak C, Jankovic J. Daytime sleepiness and other sleep disorders in Parkinson’s disease. Neurology. 2001;57:1392–6.

373, Page 8 of 9 45. Abbott RD, Ross GW, White LR, et al. Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology. 2005;65:1442–6. 46. Iranzo A, Santamaria J, Tolosa E. The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases. Sleep Med Rev. 2009;13:385–401. 47. • Boeve B. REM sleep behavior disorder. Ann N Y Acad Sci. 2010;1184:15–54. This is an extensive and excellent review of the clinical implications of RBD. 48. • Arnulf I. REM sleep behavior disorder: motor manifestations and pathophysiology. Mov Disord. 2012;27:677–89. This is an extensive and excellent review of the manifestations and physiopathology of RBD. 49. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology. 1996;46:388–93. 50. Schenck CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older males initially diagnosed with idiopathic REM sleep behavior disorder (IBD): 16 year update on a previously reported series. Sleep Med. 2013. doi:10.1016/j.sleep.2012.10.009. 51. Postuma RB, Gagnon JF, Vendette M, Fantini ML, MassicotteMarquez J, Montplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology. 2009;72:1296–300. 52. Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disease: a descriptive study. Lancet Neurol. 2006;5:572–7. 53. •• Iranzo A, Tolosa E, Gelpi E, et al. Neurodegenerative status and post-mortem pathology in idiopathic rapid-eye-movement disorder: an observational cohort study. Lancet Neurol. 2013;12:443–53. This is a prospective study showing that most IRBD individuals develop PD and other synucleinopathies with time. 54. •• Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY. Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder. Ann Neurol. 2011;69:811–8. This is a prospective study showing that IRBD patients with hyposmia have an increased short-term risk of developing a synucleinopathy. This study also shows that olfactory deficits do not worsen with time in IRBD. 55. Iranzo A, Serradell M, Vilaseca I, et al. Longitudinal assessment of olfactory function in idiopathic REM sleep behavior disorder. Parkinsonism Relat Disord. 2013;19:600–4. 56. Ferini-Strambi L, Di Gioia MR, Castronovo V, Oldani A, et al. Neuropsychological assessment in idiopathic REM sleep behavior disorder. Neurology. 2004;62:41–5. 57. Massicotte-Marquez J, Carrier J, Décary A, et al. Slow-wave sleep and delta power in rapid eye movement sleep behavior disorder. Ann Neurol. 2005;57:277–82. 58. Ferini-Strambi L, Oldani A, Zucconi M, Smirne S. Cardiac autonomic activity during wakefulness and sleep in REM sleep behavior disorder. Sleep. 1996;19:367–9. 59. Miyamoto T, Miyamoto M, Inoue Y, et al. Reduced cardiac 123IMBIG scintigraphy in idiopathic REM sleep behavior disorder. Neurology. 2006;67:2236–8. 60. Eisensehr I, Linke R, Noachtar S, et al. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Brain. 2000;123:1155–60. 61. Stockner H, Iranzo A, Seppi K, et al. Midbrain hyperechogenicity in idiopathic REM sleep behavior disorder. Mov Disord. 2009;24:1906–9. 62. • Iranzo A, Lomeña F, Stockner H, for the Sleep Innsbruck Barcelona (SINBAR) group, et al. Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol. 2010;9:1070–7. This is a prospective study showing that IRBD

Curr Neurol Neurosci Rep (2013) 13:373

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

patients with decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity have an increased short-term risk of developing a synucleinopathy. •• Iranzo A, Valldeoriola F, Lomeña F, et al. Serial dopamine transporter imaging of nigrostriatal function in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study. Lancet Neurol. 2011;10:797–805. This is a prospective study showing that dopamine transporter imaging findings of nigrostriatal function deteriorate with time in IRBD. Uchiyama M, Isse K, Tanaka K, et al. Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology. 1995;45:709–12. Boeve BF, Dickson DW, Olson EJ, et al. Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med. 2007;8:60–4. Gagnon JF, Bédard MA, Fantini ML, et al. REM sleep behavior disorder and REM sleep without atonia in Parkinson's disease. Neurology. 2002;59:585–9. Sixel-Döring F, Trautmann E, Mollenhauer B, Trenkwalder C. Associated factors for REM sleep behavior disorder in Parkinson disease. Neurology. 2011;77:1048–54. Gjestard MD, Boeve B, Wentzel-Larsen T, Aarsland D, Larsen JP. Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson’s disease over time. J Neurol Neurosurg Psychiatry. 2008;79:387–91. Iranzo A, Santamaría J, Rye DB, et al. Characteristics of idiopathic REM sleep behavior disorder and that associated with MSA and PD. Neurology. 2005;65:247–52. Postuma RN, Lang AE, Gagnon JF, Pelletier A, Montplaisir JY. How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. Brain. 2012;27:617–26. Romenets SR, Gagnon JF, Latreille V, et al. Rapid eye movement sleep behaviour disorder and subtypes of Parkinson disease. Mov Disord. 2012;27:996–1003. Wetter TC, Trenkwalder C, Gershanik O, Högl B. Polysomnographic measures in Parkinson’s disease: a comparison between patients with and without REM sleep disturbances. Wien Klin Wochenschr. 2001;113:249–53. De Cock VC, Vidailhet M, Leu S, et al. Restoration of normal muscle control in Parkinson’s disease during REM sleep. Brain. 2007;130:450–6. Kumru H, Santamaria J, Tolosa E, Iranzo A. Relation between subtype of Parkinson’s disease and REM sleep behavior disorder. Sleep Med. 2007;8:779–83. Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J. REM sleep behavior disorder in Parkinson’s disease is associated with specific motor features. J Neurol Neurosurg Psychiatry. 2008;79:1117–21. Postuma RB, Montplaisir J, Lanfranchi P, et al. Cardiac autonomic denervation in Parkinson’s disease is linked to REM sleep behavior disorder. Mov Disord. 2012;26:1529–33. Postuma RB, Gagnon JF, Vendette M, Charland K, Montplaisir J. Manifestations of Parkinson disease differ in association with REM sleep behavior disorder. Mov Disord. 2008;23:1665–72. Vendette M, Gagnon JF, Décary A, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology. 2007;69:1843–9. Gagnon JF, Fantini ML, Bedard MA, et al. Association between waking EEG slowing and REM sleep behavior disorder in PD without dementia. Neurology. 2004;62:401–6. Gagnon JF, Vendette M, Postuma RB, et al. Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease. Ann Neurol. 2009;66:39–47. Postuma RB, Bertrand JA, Montplaisir J, Desjardins C, Vendette M, Rios Romentes S, et al. Rapid eye movement sleep behaviour disorder and risk of dementia in Parkinson disease. Mov Disord. 2012;27:720–6.

Curr Neurol Neurosci Rep (2013) 13:373 82. Kumru H, Iranzo A, Carrasco E, et al. Lack of effect of pramipexole on REM sleep behavior disorder in subjects with Parkinson’s disease. Sleep. 2008;31:1418–21. 83. Iranzo A, Valldeoriola F, Santamaria J, et al. Sleep symptoms and polysomnographic architecture in advanced Parkinson’s disease

Page 9 of 9, 373 after chronic bilateral subthalamic stimulation. J Neurol Neurosurg Psychiatry. 2002;72:661–4. 84. Arnulf I, Bejjani BP, Garma L, et al. Improvement of sleep architecture in PD with subthalamic stimulation. Neurology. 2000;55: 1732–4.