Convergent patterns of structural brain changes in rapid eye movement sleep behavior disorder and Parkinson's disease on behalf of the German rapid eye movement sleep behavior disorder study group.

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is considered a prodromal state of Parkinson's disease (PD). We aimed to characterize patterns of structural brain changes in RBD and PD patients using multimodal MRI. METHODS: A total of 30 patients with isolated RBD, 29 patients with PD, and 56 age-matched healthy controls (HC) underwent MRI at 3T, including tensor-based morphometry, diffusion tensor imaging, and assessment of cortical thickness. RESULTS: RBD individuals showed increased volume of the right caudate nucleus compared with HC, and higher cerebellar volume compared with both PD subjects and HC. Similar to PD subjects, RBD patients displayed increased fractional anisotropy (FA) in the corticospinal tracts, several tracts mainly related to non-motor function, and reduced FA of the corpus callosum compared with HC. Further, RBD subjects showed higher FA in the cerebellar peduncles and brainstem compared with both, PD patients and HC. PD individuals exhibited lower than normal volume in the basal ganglia, midbrain, pedunculopontine nuclei, and cerebellum. In contrast, volume in PD subjects was increased in the thalamus compared with both HC and RBD subjects. CONCLUSIONS: We found convergent patterns of structural brain alterations in RBD and PD patients compared with HC. The changes observed suggest a co-occurrence of neurodegeneration and compensatory mechanisms that fail with emerging PD pathology. Our findings strengthen the hypothesis of RBD and PD constituting a continuous disease spectrum.

A53T-α-synuclein overexpression in murine locus coeruleus induces Parkinson's disease-like pathology in neurons and glia.

Degeneration of noradrenergic locus coeruleus neurons occurs during the prodromal phase of Parkinson's disease and contributes to a variety of non-motor symptoms, e.g. depression, anxiety and REM sleep behavior disorder. This study was designed to establish the first locus coeruleus α-synucleinopathy mouse model, which should provide sufficient information about the time-course of noradrenergic neurodegeneration, replicate cardinal histopathological features of the human Parkinson's disease neuropathology and finally lead to robust histological markers, which are sufficient to assess the pathological changes in a quantitative and qualitative way. We show that targeted viral vector-mediated overexpression of human mutant A53T-α-synuclein in vivo in locus coeruleus neurons of wild-type mice resulted in progressive noradrenergic neurodegeneration over a time frame of 9 weeks. Observed neuronal cell loss was accompanied by progressive α-synuclein phosphorylation, formation of proteinase K-resistant α-synuclein-aggregates, accumulation of Ubi-1- and p62-positive inclusions in microglia and induction of progressive micro- and astrogliosis. Apart from this local pathology, abundant α-synuclein-positive axons were found in locus coeruleus output regions, indicating rapid anterograde axonal transport of A53T-α-synuclein. Taken together, we present the first model of α-synucleinopathy in the murine locus coeruleus, replicating essential morphological features of human Parkinson's disease pathology. This new model may contribute to the research on prodromal Parkinson's disease, in respect to pathophysiology and the development of disease-modifying therapy.

Affective and cognitive Theory of Mind in patients with parkinson's disease.

Theory of Mind (ToM), which is the ability to infer other people's mental states such as beliefs or desires, is an important prerequisite for social interaction. Affective and cognitive subcomponents of ToM can be impaired selectively in neurological and psychiatric disorders. This study examines ToM in 21 Parkinson's disease (PD) patients and 21 healthy control (HC) subjects, using the computerized "Yoni task" that assesses affective and cognitive ToM abilities and an extensive battery of neuropsychological tests. Furthermore, questionnaires to assess health-related quality of life and depressive symptoms were applied and correlations to ToM were investigated. Compared to the control subjects, PD patients scored lower on both the affective (PD: 76% versus HC: 89%; p = 0.006) and cognitive (PD: 80% versus HC: 92%; p = 0.002) ToM subscales but not on control items (PD: 90% versus HC: 95%; p = 0.077). The ToM abilities were not associated with other cognitive functions, depressive symptoms or clinical data. However, affective ToM was correlated with health-related quality of life (p = 0.01). Parkinson patients are impaired in affective as well as cognitive ToM. These deficits are largely independent from other cognitive impairments, depressive symptoms and motor impairment. The relationship of affective ToM to the health-related quality of life of PD patients points to a clinical relevance of this issue and suggests that ToM dysfunctions must be regarded as an important non-motor feature of Parkinson's disease.

Restless Legs Syndrome (RLS) and Parkinson's disease (PD)-related disorders or different entities?

The relationship between Restless Legs Syndrome (RLS) and Parkinson's disease (PD) is still controversial. Most genetic, pathological, and imaging data argue against a close association of these two disorders. Still, many studies reported an increased prevalence of RLS in PD patients. These studies are difficult to interpret because the current diagnostic criteria for RLS have not been validated in PD patients. Although many PD patients suffer from motor restlessness due to parkinsonism and may thus mimic RLS, the risk for (secondary) RLS in PD patients is probably slightly increased. This review provides an overview of the current pertinent literature and discusses the possible association between RLS and PD.

Haplotype analysis of the engrailed-2 gene in young-onset Parkinson's disease.

BACKGROUND/AIMS: Engrailed-2 is a homeobox transcription factor that is expressed in mesencephalic dopaminergic neurons from development to adulthood and probably plays an important role in the survival of these neurons. METHODS: Here, we investigated six single-nucleotide polymorphisms (SNPs) in the promoter region (rs1345514) or transcribed part (rs3735653, rs6460013, rs1861972, rs2361689, and rs3808330) of the engrailed-2 gene, respectively, in 103 discordant pairs with young-onset Parkinson's disease (YOPD). RESULTS: The nominally significant p values in the single-marker and haplotype-based association analysis were suggestive of an association of SNP rs1345514 with YOPD. CONCLUSION: Altogether, our data suggest the possibility that variations of the engrailed-2 gene are implicated in the development of YOPD, although our results with respect to SNP rs1345514 should be verified in an independent sample.

Continuous sleep EEG monitoring in PD patients with and without sleep attacks.

The pathogenesis of sleep attacks in Parkinson's disease (PD) is still unresolved. We investigated seven matched pairs of PD patients with and without a history of sleep attacks using continuous sleep EEG recording. According to the event marker altogether 12 sleep attacks were identified in three patients with a history of sleep attacks. All sleep attacks were characterized by NREM stage 1 and 2 sleep, whereas no sleep onset REM episodes were recorded. Five sleep attacks fulfilled our criteria for microsleep episodes lasting less than 120 s. The cumulative duration of microsleep episodes during the day was 27.7+/-20 min in patients with a history of sleep attacks vs. 6.4+/-4.1 min in patients without a history of sleep attacks (p=0.03), i.e., the majority of microsleep episodes were not perceived by the patients. In summary, our study suggests that sleep attacks are intrusions of NREM stage 1 and 2 sleep into wakefulness and can be identical to microsleep episodes. Future studies should systematically address the awareness of short sleep episodes in patients with PD and other disorders with increased daytime sleepiness.

Daytime sleepiness and the COMT val158met polymorphism in patients with Parkinson disease.

STUDY OBJECTIVE: A preliminary study by our group suggested an association between daytime sleepiness and the catechol-O-methyltransferase (COMT) val158met polymorphism (rs4680) in patients with Parkinson disease (PD). We sought to confirm this association in a large group of patients with PD. DESIGN: Genetic association study in patients with PD. SETTING: Movement disorder sections at 2 university hospitals. PARTICIPANTS: PD patients with and without episodes of suddenly falling asleep matched for antiparkinsonian medication, disease duration, sex, and age, who participated in a previous genetic study on dopamine-receptor polymorphisms. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: In this study, 240 patients with PD (154 men; age 65.1 +/- 6.1 years; disease duration 9.4 +/- 6.0 years) were included. Seventy had the met-met (LL), 116 the met-val (LH), and 54 the val-val (HH) genotype. In the combined LL+LH group (featuring reduced COMT activity), the mean Epworth Sleepiness Scale (ESS) score was 9.0 +/- 5.9 versus 11.0 +/- 6.1 in the HH (high COMT activity) group (P = .047). Forty-seven percent of the LL and LH patients had sudden sleep onset compared with 61% of the HH patients (P = .07). Logistic regression, however, showed that both pathologic ESS scores (i.e., > 10) and sudden sleep onset were predicted by subjective disease severity (P < .001 each) but not by the COMT genotype. CONCLUSIONS: Our previous finding that the L-allele may be associated with daytime sleepiness could not be confirmed in the present study. Altogether, our data do not support a clinically relevant effect of the COMT genotype on daytime sleepiness in PD.

Driving in Parkinson's disease: mobility, accidents, and sudden onset of sleep at the wheel.

Only few studies have addressed driving ability in Parkinson's disease (PD) to date. However, studies investigating accident proneness of PD patients are urgently needed in the light of motor disability in PD and--particularly--the report of "sleep attacks" at the wheel. We sent a questionnaire about sudden onset of sleep (SOS) and driving behavior to 12,000 PD patients. Subsequently, of 6,620 complete data sets, 361 patients were interviewed by phone. A total of 82% of those 6,620 patients held a driving license, and 60% of them still participated in traffic. Of the patients holding a driving license, 15% had been involved in and 11% had caused at least one accident during the past 5 years. The risk of causing accidents was significantly increased for patients who felt moderately impaired by PD, had an increased Epworth Sleepiness Scale (ESS) score, and had experienced SOS while driving. Sleep attacks at the wheel usually occurred in easy driving situations and resulted in typical fatigue-related accidents. Those having retired from driving had a more advanced (subjective) disease severity, higher age, more frequently female gender, an increased ESS score, and a longer disease duration. The study revealed SOS and daytime sleepiness as critical factors for traffic safety in addition to motor disabilities of PD patients. The results suggest that real sleep attacks without any prior sleepiness are rare. However, our data underline the importance of mobility for patients and the need for further studies addressing the ability to drive in PD.

Predictors of sudden onset of sleep in Parkinson's disease.

With respect to the ongoing discussion of "sleep attacks" in Parkinson's disease (PD), we sought to estimate the prevalence of sudden onset of sleep (SOS) with and without preceding sleepiness in PD, to identify associated factors, and to define the role of antiparkinsonian medication in SOS. We sent a questionnaire about SOS, sleep behaviour, and medication to 12,000 PD patients. The response rate was 63%, from which 6,620 complete data sets could be analysed. A total of 42.9% of our population reported SOS, 10% of whom never experienced sleepiness before the appearance of SOS (4.3% of all), and we identified the administration of all dopaminergic drugs as a risk factor for SOS. However, SOS occurred earlier after introduction of nonergoline dopamine agonists (DA) and was more strongly associated with nonergoline DA in younger patients (below 70 years) with a shorter disease duration (up to 7 years) but, actually, medication was less efficient in predicting SOS than most other factors considered such as higher age, male sex, longer disease duration, and the report of sleep disturbances. This survey strongly suggests that SOS is a multifactorial phenomenon. Some subgroups are at particular risk of experiencing SOS under nonergoline DA, especially at the beginning of this therapy. Our results support the current notion that SOS, in part, can be attributed to PD-specific pathology because disease duration and subjective disease severity have been shown to be predictors of SOS. We recommend the development of a standardised question to recognise SOS and to facilitate the comparison of prevalence estimates.

Clinical symptomatology and treatment of restless legs syndrome and periodic limb movement disorder.

Patients with restless legs syndrome (RLS) suffer from sensory and motor symptoms evoked in the limbs at rest. Symptoms increase in the evening and during the night. The circadian rhythm and the presence of involuntary periodic limb movement in sleep (PLMS) which are frequently associated with arousals probably cause the leading symptom of sleep disturbances in RLS. Patients who do not have typical RLS symptoms but whose polysomnography shows PLMS that either impact on sleep continuity or daytime functioning are diagnosed as having the periodic limb movement disorder (PLMD). Dopaminergic agents such as levodopa/dopa decarboxylase inhibitor (DDI) and dopamine agonists are considered the treatment of choice for RLS and PLMS. This article gives an overview of the epidemiology, pathophysiology, clinical symptomatology and diagnosis of RLS and PLMD and focuses on treatment strategies in both disorders.