Sleep and non-motor symptoms in Parkinson’s disease

Beyond the cardinal motor symptoms, bradykinesia, rigidity, tremor and postural instability, defining the diagnosis of Parkinson’s disease, there is a big spectrum of non-motor features that patients may suffer from and that may reduce their quality of life. Non-motor symptoms are not only frequent but also often under-reported by patients and caregivers. As they are frequently under-recognized by clinicians, they remain consequently under-treated. This review wants to give a short overview of the importance of non-motor symptoms on patients’ quality of life and helpful assessment tools that might facilitate recognition of non-motor features during clinical setting. Given the wide range of non-motor symptoms in Parkinson’s disease, we concentrate on common issues such as depression and sleep disorders like sleep-onset insomnia or sleep maintenance insomnia and restless legs syndrome. Thereby, we present some recent studies that have investigated the efficacy of dopaminergic drugs, especially dopamine agonists, revealing possible treatment strategies and thus improving disease management.     

Clinical features associated with REM sleep behavior disorder symptoms in the early stages of Parkinson’s disease

We aimed to characterize the clinical features associated with REM sleep behaviour disorder (RBD) in early stage Parkinson’s disease (PD). Presence of clinical RBD was determined according to ICSD minimal clinical criteria and a validated RBD questionnaire. We registered time of appearance of RBD symptoms in relation to PD onset and the occurrence of RBD symptoms in the past in non-RBD patients. RBD and non-RBD groups were compared in terms of motor and cognitive dysfunction. The same comparisons were made between patients who reported RBD symptoms at some point in time (including those non-RBD patients that reported occurrence of RBD symptoms in the past) and those who did not (RBDS and non-RBDS, respectively). We assessed 75 patients. Forty-one (55%) patients presented with RBD, 19 beginning before PD onset. Five non-RBD patients reported having had RBD symptoms in the past. There were no significant differences between RBD and non-RBD patients. RBDS group presented a significantly higher proportion of non-tremor motor sub-type compared to non-RBDS patients. Our results suggest that RBD is very frequent in the early stages of PD. In some patients, RBD symptoms could have disappeared before or in the first years after motor disturbance onset. Non-tremor motor sub-type was related to RBD symptoms history, rather than to the presence of RBD clinical criteria at time of evaluation, suggesting that the physiopathological changes that cause the association with motor status could remain, in spite of symptom fluctuation.     

REM sleep behavior disorder in early Parkinson’s disease predicts the rapid dopaminergic denervation

ObjectiveTo test the hypothesis that REM sleep behavior disorder (RBD) in early Parkinson's disease (PD) predicts rapid progression of dopaminergic denervation.Methods123I-FP-CIT single photon emission computed tomography (SPECT) scans were performed sequentially at baseline, 1 year, 2 years, and 4 years in 416 de novo patients with PD. RBD screening questionnaire scores >5 at baseline placed the participant in the likely-RBD group. Temporal changes in the specific binding ratio (SBR; caudate, putamen. sum of both, striatum) were compared between the likely-RBD and the non-likely-RBD groups for more or less affected striatum with a repeated measure ANOVA.ResultsLikely-RBD was reported in 37.7% of the drug-naïve PD patients at baseline. The likely-RBD and non-likely-RBD groups did not have significant differences in the baseline clinical features including gender, age, disease duration, UPDRS motor score, and striatal SBR. Striatal SBR decreased significantly over four years in both groups (P < .001). In the analysis of a more affected striatum, striatal SBR decreased significantly faster in the likely-RBD group than in the non-likely-RBD group (P < .05 for all), whereas it was not statistically significant for the less affected striatum. The mean striatal SBR value (mean value of both striata), especially the caudate SBR, indicated greater acceleration of denervation in the likely-RBD group than in the non-likely-RBD group over time (P < .05).ConclusionLikely-RBD in PD predicts accelerating dopaminergic denervation, thereby implicating it as a marker for a poor prognosis or distinctive subtype in PD.     

Does REM sleep behavior disorder change in the progression of Parkinson’s disease?

Objectives/backgroundRapid eye movement (REM) Sleep Behavior Disorder (RBD) in Parkinson's disease (PD) may be associated with a malignant phenotype. Despite its prognostic value, little is known about the time course of RBD in PD. In this study, we aimed to ascertain whether or not RBD is a stable feature in PD. In this study, we prospectively evaluated clinical and neurophysiological features of RBD, including REM Sleep Without Atonia (RSWA), in PD patients with RBD at baseline and after three years then assessed whether the changes in measures of RSWA parallel the progression of PD.Patients/methodsIn sum, 22 (17M, mean age 64.0 ± 6.9 years) moderate-to-advanced PD patients (mean PD duration at baseline:7.6±4.8 years) with RBD, underwent a video-polysomnography (vPSG) recording and clinical and neuropsychological assessment at baseline and after three years.ResultsAt follow-up, the self-assessed frequency of RBD symptoms increased in six patients, decreased in six and remained stable in 10, while RSWA measures significantly increased in all subjects. At follow-up, patients showed worse H&Y stage (p = 0.02), higher dopaminergic doses (p = 0.05) and they performed significantly worse in phonetic and semantic fluency tests (p = 0.02; p = 0.04). Changes in RSWA correlated significantly with the severity in levodopa-induced dyskinesia (r = 0.61,p = 0.05) and motor fluctuation (r = 0.54,p = 0.03) scores, and with the worsening of executive functions (r = 0.78,p = 0.001) and visuo-spatial perception (r = −0.57,p = 0.04).ConclusionDespite the subjective improvement of RBD symptoms in one-fourth of PD patients, all RSWA measures increased significantly at follow-up, and their changes correlated with the clinical evolution of motor and non-motor symptoms. RBD is a long-lasting feature in PD and RSWA is a marker of the disease's progression.     

REM sleep behavior disorder in Japanese patients with Parkinson’s disease: a multicenter study using the REM sleep behavior disorder screening questionnaire

REM sleep behavior disorder (RBD) is known to be observed more frequently in patients with an α-synucleinopathy such as Parkinson's disease (PD) than in the general population. The precise prevalence of RBD in Japanese PD patients is not known. Therefore, we investigated the prevalence and the clinical characteristics of patients with RBD in a large population of Japanese patients with PD. We investigated various clinical features and employed the Japanese version of the RBD screening questionnaire on 469 non-demented Japanese PD patients in this multicenter study. Probable or possible RBD was detected in 146 patients (31.1%) and was significantly associated with longer PD duration, higher Hoehn and Yahr stage, higher Unified Parkinson's Disease Rating Scale part III subscale (7 items), more motor fluctuations, and a higher levodopa-equivalent daily dose (p < 0.01). As to the major autonomic dysfunctions, severe constipation was significantly more frequent in PD patients with RBD than in those without it (p < 0.01). The RBD symptoms of 53 patients (39.0%) preceded the onset of PD motor symptoms. The median interval from the onset of RBD symptoms to PD motor symptoms was 17.5 years, and 3 patients had intervals of over 50 years. This large-scale multicenter study revealed that RBD is a frequent non-motor symptom in Japanese patients with PD, which may precede the onset of motor symptoms. Moreover, RBD that increases with the duration and severity of PD may be associated with autonomic dysfunction.     

Decreased sleep spindle density in patients with idiopathic REM sleep behavior disorder and patients with Parkinson’s disease

ObjectiveTo determine whether sleep spindles (SS) are potentially a biomarker for Parkinson’s disease (PD).MethodsFifteen PD patients with REM sleep behavior disorder (PD + RBD), 15 PD patients without RBD (PD − RBD), 15 idiopathic RBD (iRBD) patients and 15 age-matched controls underwent polysomnography (PSG). SS were scored in an extract of data from control subjects. An automatic SS detector using a Matching Pursuit (MP) algorithm and a Support Vector Machine (SVM) was developed and applied to the PSG recordings. The SS densities in N1, N2, N3, all NREM combined and REM sleep were obtained and evaluated across the groups.ResultsThe SS detector achieved a sensitivity of 84.7% and a specificity of 84.5%. At a significance level of α = 1%, the iRBD and PD + RBD patients had a significantly lower SS density than the control group in N2, N3 and all NREM stages combined. At a significance level of α = 5%, PD − RBD had a significantly lower SS density in N2 and all NREM stages combined.ConclusionsThe lower SS density suggests involvement in pre-thalamic fibers involved in SS generation. SS density is a potential early PD biomarker.SignificanceIt is likely that an automatic SS detector could be a supportive diagnostic tool in the evaluation of iRBD and PD patients.     

SNCA 3′UTR genetic variants in patients with Parkinson’s disease and REM sleep behavior disorder

REM sleep behavior disorder (RBD) is an early marker of Parkinson’s disease (PD); however, it is still unclear which patients with RBD will eventually develop PD. Single nucleotide polymorphisms (SNPs) in the 3′untranslated region (3′UTR) of alpha-synuclein (SNCA) have been associated with PD, but at present, no data is available about RBD. The 3′UTR hosts regulatory regions involved in gene expression control, such as microRNA binding sites. The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3′UTR in patients with “idiopathic” RBD (iRBD) and in patients with PD. We recruited 113 consecutive patients with a diagnosis of iRBD (56 patients) or PD (with or without RBD, 57 patients). Sequencing of SNCA-3′UTR was performed on genomic DNA extracted from peripheral blood samples. Bioinformatic analyses were carried out to predict the potential effect of the identified genetic variants on microRNA binding. We found three SNCA-3′UTR SNPs (rs356165, rs3857053, rs1045722) to be more frequent in PD patients than in iRBD patients (p = 0.014, 0.008, and 0.008, respectively). Four new or previously reported but not annotated specific genetic variants (KP876057, KP876056, NM_000345.3:c*860T>A, NM_000345.3:c*2320A>T) have been observed in the RBD population. The in silico approach highlighted that these variants could affect microRNA-mediated gene expression control. Our data show specific SNPs in the SNCA-3′UTR that may bear a risk for RBD to be associated with PD. Moreover, new genetic variants were identified in patients with iRBD.     

REM sleep behaviour disorder in Parkinson’s disease: a questionnaire-based study

Abstract The aim of the study was to determine the clinical frequency and features of REM sleep behaviour disorder (RBD) in a large population of Parkinsons disease (PD) patients using defined diagnostic criteria both for RBD and PD. Six trained neurologists used a semistructured questionnaire based on ICSD-R diagnostic criteria for RBD to evaluate 200 PD patients and their caregivers. Interobserver reliability for the diagnosis of RBD was substantial (Kappa 0.65). Five patients were excluded from the study because of an MMSE lower than 25. The demographic and PD clinical features were compared in the clinically defined RBD group and in those without RBD (NRBD). Then the RBD features during the last year were analysed in the affected group. Out of 195 patients, 66 fulfilled the ICSD-R criteria for RBD; 62 patients reported RBD during the last year (frequency 31.8%). RBD features: two or more episodes per week in 35.5%; upper limb movements in 87%; lower limb movements in 79%; vocalisations during events in 85%. RBD onset was before PD in 27% of patients; 69% of the RBD group had injured themselves or their caregivers during sleep. According to multivariate analysis, RBD was associated with male gender, age and PD duration. Brief training and the use of a semistructured questionnaire may help the neurologist in dealing with sleep disturbances in PD patients. The search for RBD symptoms in PD is highly recommended, especially in patients with a long disease duration, the risk of sleep-related injuries being high.Bologna, Genova, Parma and Pisa Universities group for the study of REM Sleep Behavior Disorder (RBD) in Parkinsons Disease     

Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson’s disease

Non-motor symptoms (NMS) of Parkinson’s disease (PD) have only recently been increasingly recognized for their impact on a patient’s quality of life. In this study, we applied the validated, comprehensive self-completed NMS questionnaire for PD (NMS Quest) to 101 patients with young-onset PD (onset between 21 and 45 years, YOPD) and 107 patients with late-onset PD (onset of PD ≥ 55 years, LOPD). The mean total NMS (NMSQ-T) was 11.9 ± 6.0 (range: 0 to of a maximum of 26) in LOPD and 7.7 ± 5.8 (range: 0 to of a maximum of 26) in YOPD (p < 0.05). Compared to YOPD, dribbling of saliva, loss of taste/smell, nocturia, forgetfulness, loss of interest, hallucinations, lack of concentration, anxiety, change in libido and difficulty in sexual activities, were significantly more prevalent in LOPD. The only NMS more prevalent in YOPD were restless legs and sweating, although such findings might be associated with drug effects. Among the nine NMS Quest domains, in both LOPD and YOPD patients the three most prevalent domains were depression/anxiety, urinary and sexual. Also, in both groups, hallucinations/delusions had the lowest frequency. In the multivariate linear regression model, the Hoehn and Yahr (HY) stage of the disease and activities of daily living scores in YOPD patients, while only the HY stage in LOPD patients appeared to be statistically significant predictors of increasing number of NMS. In contrast to a previous suggestion that YOPD patients might have an increased risk for NMS, we found a higher prevalence of NMS in LOPD patients than in those with YOPD.     

Association between fatigue and other motor and non-motor symptoms in Parkinson’s disease patients

Although fatigue is a common non-motor symptom in patients affected by Parkinson’s disease (PD), its association with motor and other non-motor symptoms is still largely unclear. We assessed fatigue in PD patients studying the possible association with motor and non-motor symptoms. Eighty-one PD patients were included in the study. The PD Fatigue Scale (PFS) and the Fatigue Severity Scale (FSS) scale were used to measure fatigue. Non-motor symptoms were assessed with the Non-Motor Symptoms Scale (NMSS). Motor impairment was assessed using the modified Hoehn and Yahr (HY) staging and the Unified PD Rating Scale (UPDRS) part-III and IV. Bivariate tests comparing all independent variables between patients with our without fatigue were used. Significant predictors of presence and severity of fatigue were determined with different models of logistic regression analyses. Fatigue severity was significantly higher in female patients. Bivariate test showed significant higher NMSS score in fatigued patients according to PFS (p < 0.00001) and FFS (p < 0.001), while HY was higher only in fatigued patients according to FSS (p < 0.022). Significant correlations between severity of fatigue and HY stage (p < 0.002) and UPDRS-III score (p < 0.001) were found, while, among specific non-motor symptoms, anhedonia presented with the most significant correlation (p < 0.003). Binary logistic regression confirmed NMSS as the main variable predicting presence of fatigue, while HY was significant as predicting variable only in the FSS model. Strongest non-motor symptoms predictors of severity were those included in Domain 3 (mood/anxiety) and Domain 2 (sleep disorders) of the NMSS. A significant increase in severity of fatigue related to the burden of non-motor symptoms (mainly affective and sleep disorders) was observed. Our findings indicate a moderate discrepancy in the ratings of the two fatigue scales, with PFS principally directed towards the burden of non-motor symptoms. Finally, the accurate individuation of the factors underlying fatigue, assessed with the systematic administration of holistic evaluation scales such as the NMSS, might improve current strategies used in the treatment of this disabling condition.     

Gender-related differences in the burden of non-motor symptoms in Parkinson’s disease

Differences in the expression of non-motor symptoms (NMS) by Parkinson's disease (PD) patients may have important implications for their management and prognosis. Gender is a basic epidemiological variable that could influence such expression. The present study evaluated the prevalence and severity of NMS by gender in an international sample of 951 PD patients, 62.63% males, using the non-motor symptoms scale (NMSS). Assessments for motor impairment and complications, global severity, and health state were also applied. All disease stages were included. No significant gender differences were found for demographic and clinical characteristics. For the entire sample, the most prevalent symptoms were Nocturia (64.88%) and Fatigue (62.78%) and the most prevalent affected domains were Sleep/Fatigue (84.02%) and Miscellaneous (82.44%). Fatigue, feelings of nervousness, feelings of sadness, constipation, restless legs, and pain were more common and severe in women. On the contrary, daytime sleepiness, dribbling saliva, interest in sex, and problems having sex were more prevalent and severe in men. Regarding the NMSS domains, Mood/Apathy and Miscellaneous problems (pain, loss of taste or smell, weight change, and excessive sweating) were predominantly affected in women and Sexual dysfunction in men. No other significant differences by gender were observed. To conclude, in this study significant differences between men and women in prevalence and severity of fatigue, mood, sexual and digestive problems, pain, restless legs, and daytime sleepiness were found. Gender-related patterns of NMS involvement may be relevant for clinical trials in PD.     

Comparison study of olfactory function and substantia nigra hyperechogenicity in idiopathic REM sleep behavior disorder, Parkinson’s disease and normal control

Rapid eye movement (REM) sleep behavior disorder (RBD) is a preclinical feature of synucleinopathies, such as Parkinson’s disease (PD).This study aimed to investigate the presence of potential early manifestations of parkinsonism, such as olfactory dysfunction and substantia nigra (SN) hyperechogenicity, in idiopathic RBD (iRBD) patients, PD patients and normal controls. We performed an olfactory function test using the cross-cultural smell identification test (CC-SIT) and midbrain transcranial sonography (TCS) in 15 patients with iRBD as confirmed by polysomnography, 30 patients with PD, and 30 normal controls. The CC-SIT scores of the iRBD patients and PD patients were significantly lower than those of the normal controls and similar between iRBD and PD (mean ± SD, 7.1 ± 2.2 and 7.6 ± 2.4 vs. 10.4 ± 1.2, respectively, p < 0.01). The sum of bilateral SN echosignals in the iRBD patients was greater than that of the normal controls but lower than that of the PD patients (0.29 ± 0.47, 0.11 ± 0.17 and 0.72 ± 0.41 cm², respectively, p < 0.01). In conclusion, we found that the concomitant abnormality of olfaction and increased SN echogenicity was more frequent in iRBD compared with normal control. Olfactory dysfunction and SN hyperechogenicity could be preclinical manifestations of parkinsonism in iRBD patients.     

Functional evaluation of central cholinergic circuits in patients with Parkinson’s disease and REM sleep behavior disorder: a TMS study

Central cholinergic dysfunction has been reported in patients with Parkinson?s disease (PD) and hallucinations by evaluating short latency afferent inhibition (SAI), a transcranial magnetic stimulation protocol which gives the possibility to test an inhibitory cholinergic circuit in the human brain. REM sleep behavior disorder (RBD) was also found to be associated with cognitive impairment in PD patients. The objective of the study was to assess the cholinergic function, as measured by SAI, in PD patients with RBD (PD-RBD) and PD patients without RBD (PD-nRBD). We applied the SAI technique in 10 PD-RBD patients, in 13 PD-nRBD patients and in 15 age-matched normal controls. All PD patients and control subjects also underwent a comprehensive battery of neuropsychological tests. Mean SAI was significantly reduced in PD-RBD patients when compared with PD-nRBD patients and controls. Neuropsychological examination showed mild cognitive impairment in 9 out of the 10 PD-RBD patients, and in 5 out of the 13 PD-nRBD. SAI values correlated positively with neuropsychological tests measuring episodic verbal memory, executive functions, visuoconstructional and visuoperceptual abilities. Similar to that previously reported in the idiopathic form of RBD, SAI abnormalities suggest a cholinergic dysfunction in PD patients who develop cognitive impairment, and present findings indicate that RBD is an important determinant of MCI in PD.     

Parkinson’s disease-like motor and non-motor symptoms in rotenone-treated zebrafish

The pesticide rotenone is widely used to produce Parkinson’s disease (PD)-like symptoms in rodents, but few studies have examined whether rotenone-treated zebrafish can serve as an animal model of PD. Here, we report that 4 weeks of rotenone treatment induced motor and non-motor PD-like symptoms in adult zebrafish. Compared with control fish, rotenone-treated fish spent less time swimming at a fast speed, indicating a deficit in motor function. In the light-dark box test, rotenone-treated fish exhibited longer latencies to enter the dark compartment and spent more time in the light compartment, reflecting anxiety- and depression-like behavior. Furthermore, rotenone-treated fish showed less of an olfactory preference for amino acid, indicating olfactory dysfunction. These behavioral symptoms were associated with decreased levels of dopamine in the brains of rotenone-treated fish. Taken together, these results suggest that rotenone-treated zebrafish are a suitable model of PD.