Taro Kadowaki

Nocturnal disturbances and restlessness in Parkinson's disease: Using the Japanese version of the Parkinson's disease sleep scale-2

OBJECTIVE The aim of this study was to assess the validity and the reliability of the Japanese version of the Parkinsons disease sleep scale (PDSS)-2 and to use this scale to identify nocturnal symptoms and their impact on patients quality of life. METHODS A cross-sectional, case-controlled study was conducted consisting of 93 patients with Parkinsons disease (PD) and 93 age- and gender-matched control subjects. The Japanese version of the PDSS-2 was used for the evaluation of nocturnal disturbances. The patients quality of life was evaluated with the Parkinsons Disease Quality of Life questionnaire (PDQ-39) and their depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II), respectively. In addition, the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Parkinson Fatigue Scale (PFS) were administered. RESULTS As assessed using the PDSS-2, PD patients had significantly impaired scores compared with control subjects (15.0±9.7 vs. 9.1±6.6, p<0.001). The ESS, BDI-II and PFS scores were significantly impaired in PD patients compared with controls. A satisfactory internal consistency and test-retest reliability score were obtained for the PDSS-2 total score (Cronbachs alpha=0.86). The PDSS-2 was correlated with the PSQI, ESS, BDI-II, PFS, PDQ-39 summary index, all of the PDQ-39 domains and Unified Parkinsons Disease Rating Scale part III. The frequency of restless legs syndrome (RLS) was not significantly different between PD patients and controls (5.5% vs. 2.2%), but nocturnal restlessness was significantly more frequent in PD patients than controls. Stepwise linear regression analyses revealed the PDQ-39 summary index and the PSQI global score as significant predictors for the PDSS-2 total score. CONCLUSIONS Our study confirmed the usefulness of the Japanese version of the PDSS-2 that enables the comprehensive assessment of nocturnal disturbances in PD. The association between RLS and nocturnal restlessness in PD requires further study.

Expression of Iba1 protein in microglial cells of zitter mutant rat.

Microglial activation has been associated with the pathogenesis of neurodegenerative disease. To characterize microglial responses in the zitter mutant rat, which shows progressive spongy degeneration, the development of microglial cells was investigated using ionized calcium-binding adaptor molecule (Iba1) antibody as a specific marker of microglial cells. Neurochemical analysis showed transiently increased Iba1 protein levels in the brains of developing Sprague-Dawley (SD) rats. However, high Iba1 protein readings continued in aged zitter rats. Immunohistochemical analysis revealed time-course differences in the transformation of microglia between SD and zitter rats and prolonged activation of microglial cells in the zitter rat. In the zitter rat, activated microglial cells characterized by swollen cell bodies and shorter, thicker processes were distributed throughout the brain from 2-weeks- to 2-months-old. After 2-months-old, numbers of activated microglial cells gradually decreased. However, these cells were not observed in SD rats. Iba1-immunoreactive cell-clusters organized by at least five activated microglial cells were also prominent in the zitter brain. These differences reflect the neuropathology of this mutant rat triggered by deletion of the attractin gene. The present data may thus suggest that microglial cells directly or indirectly contribute to progressive spongy degeneration in zitter mutant rats.

Probable rapid eye movement sleep behavior disorder, nocturnal disturbances and quality of life in patients with Parkinson's disease: a case-controlled study using the rapid eye movement sleep behavior disorder screening questionnaire

BackgroundIncreasing evidence provides a clear association between rapid eye movement sleep behavior disorders (RBD) and Parkinson’s disease (PD), but the clinical features that determine the co-morbidity of RBD and PD are not yet fully understood.MethodsWe evaluated the characteristics of nocturnal disturbances and other motor and non-motor features related to RBD in patients with PD and the impact of RBD on their quality of life. Probable RBD (pRBD) was evaluated using the Japanese version of the RBD screening questionnaire (RBDSQ-J).ResultsA significantly higher frequency of pRBD was observed in PD patients than in the controls (RBDSQ-J ≥ 5 or ≥ 6: 29.0% vs. 8.6%; 17.2% vs. 2.2%, respectively). After excluding restless legs syndrome and snorers in the PD patients, the pRBD group (RBDSQ-J≥5) showed higher scores compared with the non-pRBD group on the Parkinson’s disease sleep scale-2 (PDSS-2) total and three-domain scores. Early morning dystonia was more frequent in the pRBD group. The Parkinson’s Disease Questionnaire (PDQ-39) domain scores for cognition and emotional well-being were higher in the patients with pRBD than in the patients without pRBD. There were no differences between these two groups with respect to the clinical subtype, disease severity or motor function. When using a cut-off of RBDSQ-J = 6, a similar trend was observed for the PDSS-2 and PDQ-39 scores. Patients with PD and pRBD had frequent sleep onset insomnia, distressing dreams and hallucinations. The stepwise linear regression analysis showed that the PDSS-2 domain “motor symptoms at night”, particularly the PDSS sub-item 6 “distressing dreams”, was the only predictor of RBDSQ-J in PD.ConclusionOur results indicate a significant impact of RBD co-morbidity on night-time disturbances and quality of life in PD, particularly on cognition and emotional well-being. RBDSQ may be a useful tool for not only screening RBD in PD patients but also predicting diffuse and complex clinical PD phenotypes associated with RBD, cognitive impairment and hallucinations.

Evaluation of cutoff scores for the Parkinson's disease sleep scale-2

The Parkinsons Disease Sleep Scale (PDSS)‐2 is a recently developed tool for evaluating disease‐related nocturnal disturbances in patients with Parkinsons disease (PD). However, its cutoff score has not been clinically assessed. We determined the optimal cutoff score of the Japanese version of the PDSS‐2.

Chronic treatment with melatonin attenuates serotonergic degeneration in the striatum and olfactory tubercle of zitter mutant rats.

The effects of chronic treatment with the antioxidant hormone melatonin on degeneration of serotonergic fibers were studied in the striatum and olfactory tubercle of the zitter rat, which shows a loss-of-function mutation of the glycosylated transmembrane protein attractin. In these animals, serotonergic fibers in the striatum and olfactory tubercle undergo spontaneous and progressive degeneration as a result of abnormal metabolism of reactive oxygen species. Homozygous zitter (zi/zi) rats were provided ad libitum access to drinking water containing melatonin for 9 months (M) after weaning. High-performance liquid chromatography analysis revealed that melatonin treatment significantly increased serotonin in the caudate-putamen, (CPU), nucleus accumbens (NA) and olfactory tubercle (OT). Immunohistochemical staining for serotonin was consistent with the neurochemical data and further demonstrated substantially increased numbers of serotonergic nerve terminals in these areas. Aberrant serotonergic fibers characterized by swollen varicosities (>1 microm in diameter) were observed in the CPU and NA of 10 M zi/zi rats. The number of these fibers decreased after melatonin treatment ended. Furthermore, hyperinnervation of serotonergic fibers was observed in the OT of melatonin-treated zi/zi rats. These results suggest that melatonin protects serotonergic fibers and terminals in zitter rats and/or promotes their neuroplasticity.

Improved learning in microencephalic rats

Environmental enrichment (EE) facilitates recovery from behavioral abnormalities and spatial memory disabilities in several neurological disease models. Exposure to EE improves spatial memory acquisition and enhances the survival of newly generated cells in the dentate gyri of adult rodents. However, the effects of EE on spatial learning and neurogenesis in the methylazoxymethanol acetate‐induced microencephalic rat have not been investigated. Depletion of serotonin in the rat hippocampus is known to influence spatial memory and adult neurogenesis, suggesting a role for serotonin in these processes. To confirm this hypothesis, male methylazoxymethanol acetate‐induced microencephalic rats were exposed to EE or conventional housing after weaning; half of these rats further received intracisternal 5,7‐dihydroxytryptamine on postnatal day 3, to induce long‐lasting depletion of serotonin. As adults, these microencephalic rats were observed using the Morris water maze test and examined for hippocampal neurogenesis. EE alleviated the impairment of spatial memory acquisition and enhanced neurogenesis in the dentate gyri of adult microencephalic rats. Injection of 5,7‐dihydroxytryptamine during the neonatal period caused pronounced reductions in hippocampal serotonin levels in these rats. Long‐lasting depletion of serotonin eliminated the EE‐induced alleviation of spatial memory acquisition and neurogenesis impairment in microencephalic rats. The present results suggest that EE alleviates spatial memory performance deficits in microencephalic rats and further indicate that serotonin might be involved in the underlying mechanisms through increased hippocampal neurogenesis. These data provide new insights into therapeutic interventions for individuals with human migration disorders associated with learning disabilities.

Characterizing restless legs syndrome and leg motor restlessness in patients with Parkinson's disease: A multicenter case-controlled study

BACKGROUND We investigated the prevalence and impact of restless legs syndrome (RLS) and leg motor restlessness (LMR) in patients with Parkinsons disease (PD) in a multicenter study. METHODS A total of 436 PD patients and 401 age- and sex-matched controls were included in this study. RLS was diagnosed based on four essential features. LMR was diagnosed when a participant exhibited the urge to move his or her legs but did not meet the four essential features of RLS. RESULTS The RLS prevalence did not differ between PD patients and controls (3.4% vs. 2.7%), while LMR prevalence was significantly higher in PD patients than in controls (12.8% vs. 4.5%). PD patients with RLS or LMR had a higher prevalence of excessive daytime sleepiness (EDS) (50.7%, vs. 6.9%), probable REM sleep behavior disorder (38.0% vs. 3.4%) and PD-related sleep problems (49.3% vs. 20.7%) than controls with RLS or LMR. RLS/LMR preceding PD onset was related to an older age of PD onset. CONCLUSION Our study revealed an increased prevalence of LMR but not RLS in PD patients. LMR could be an early manifestation of PD; however, whether LMR is within the range of RLS or whether LMR and RLS constitute different entities in PD requires further studies.

Anhedonia and its correlation with clinical aspects in Parkinson's disease

Anhedonia is one of the non-motor symptoms observed in the Parkinsons disease (PD). However, there is no clear relationship between anhedonia and its correlation with other symptoms of PD. The aim of this study is to evaluate the characteristics of anhedonia and its correlation with clinical aspects of PD in a relatively large cohort. We enrolled 318 patients with PD and 62 control subjects for this study. Patients and subjects were tested using the Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition for the assessment of anhedonia and depression. We also investigated the correlation among clinical aspects of PD, anhedonia, and depression in patients with PD. The Snaith-Hamilton Pleasure Scale Japanese version and the Beck Depression Inventory 2nd edition scores were significantly higher in patients with PD than in control subjects (p=0.03 and p=0.0006, respectively). All PD patients with anhedonia had a significantly higher score on the unified Parkinsons disease rating scale (UPDRS) parts I and II compared to PD patients without anhedonia. Additionally, all PD patients with depression scored significantly higher on UPDRS part I-IV than PD patients without depression. The patients with anhedonia and without depression had mild motor severity and their treatment was relatively low dosage. These results suggest that anhedonia and depression are slightly linked, but not the same. PD patients with only anhedonia may be closely linked apathy found in untreated early stages of PD.

Oseltamivir-induced dyskinesia in Parkinson’s disease

Oseltamivir is widely used for the treatment of influenza, and Japan is known to be the country with the highest usage of this drug worldwide [1]. However, there are concerns regarding the abnormal behavior that is sometimes associated with oseltamivir treatment during influenza virus infection, especially in children and adolescents [2,3]. We report the first case in which a marked improvement in parkinsonism with an increase in dyskinesia was observed in a Parkinson’s disease (PD) patient following the administration of oseltamivir for influenza infection. Our department followed a 63-year-old woman with a 25-year history of PD symptoms. Five years after the initial onset of symptoms, motor fluctuation occurred. Seventeen years after the disease onset, her dyskinesia improvedwith the reduction of dopaminergic treatment, but she became akinetic. Therefore, she was treated with bilateral subthalamic nucleus deep brain stimulation (STN DBS). After surgery, her akinesia improved, but she was still impaired by bradykinesia: she was usually in a wheel chair and was only able to walk with a cane or pushcart. Her medications included levodopa/carbidopa (300 mg), pramipexole (4.5 mg), selegiline hydrochloride (5 mg) and zonisamide (25 mg). In February 2009, she presented to her local clinic with a high fever (39 C) (see Fig. 1). The Influenza B virus was detected, and 75 mg of oseltamivir was subsequently administered twice daily (for five days). In the evening on the first day of treatment she displayed abnormal behaviors. Risking serious injury, she rapidly ran up anddown the stairs for no apparent reason. Subsequently, unpredictable dyskinesia developed. Two days later, she became afebrile. On day 3, she was able to walk independently to the supermarket. On day 6, severe dyskinesia was noted in the limb and trunk in the outpatient clinic (see video, segment 1). She had been taking her dopaminergic medication regularly, and it was confirmed that her DBS system was switched on. Her motor function significantly improved with a reduction in the “off state.” This improvement in motor function lasted for 14 days until the STNDBS systemwas accidentally switched off when she passed through a security device at

Rhinorrhea in Parkinson's disease: A consecutive multicenter study in Japan

Recent reports suggest that rhinorrhea, defined as the presence of a runny nose unrelated to respiratory infections, allergies, or sinus problems, occurs more frequently among patients with Parkinsons disease (PD) than among healthy controls. We conducted a questionnaire survey in a multicenter study throughout Japan and compared the frequency of rhinorrhea between 231 PD and 187 normal control (NC) subjects. After excluding patients with rhinitis or paranasal sinusitis, a total of 159 PD and 59 NC subjects were included in our analysis. Rhinorrhea occurred more frequently in PD patients than NC subjects (33.3% vs. 11.9%; P=0.01). Among PD patients, rhinorrhea was more common in men than women (P=0.005). Rhinorrhea was not correlated with disease duration, modified Hoehn and Yahr score, disease type (akinesia rigidity vs. tremor dominant), or cardiac sympathetic function (evaluated by (123)I-metaiodobenzylguanidine uptake). To our knowledge, this is the first multicenter study on the frequency of PD-related rhinorrhea in Asian countries.