Takayasu Mishima

A Novel DCTN1 mutation with late‐onset parkinsonism and frontotemporal atrophy

Depression, parkinsonism, and hypoventilation (Perry syndrome) or familial motor neuron disease have been linked to mutations in dynactin P150Glued (DCTN1).

Beneficial Effects of Ramelteon on Rapid Eye Movement Sleep Behavior Disorder Associated with Parkinson's Disease - Results of a Multicenter Open Trial

Objective Melatonin is effective for treating patients with rapid eye movement sleep behavior disorder (RBD). Ramelteon, a novel hypnotic, acts as a melatonin receptor agonist. In the current study, we investigated the effects of ramelteon on sleep disorders, including RBD, in patients with Parkinsons disease (PD). Methods We evaluated 35 patients from multiple centers with idiopathic PD accompanied by sleep disturbances (age: 69.1±11.1 years; 17 men, 18 women; PD morbidity: 6.9±5.7 years; Hoehn & Yahr stage: 2.5±0.8; levodopa dose equivalent: 561±401 mg/day). The patients received 8 mg of ramelteon before sleep once daily for 12 weeks. Motor and sleep symptoms were evaluated both before and after ramelteon administration. Results Of the 35 patients enrolled in this study, 24 (68.6%) were diagnosed with probable RBD (pRBD) using the Japanese version of the RBD screening questionnaire. Ramelteon administration reduced the severity of sleep disturbances in patients with PD. It also lowered scores on the Japanese version of the RBD questionnaire in patients with PD and pRBD. Conclusion Ramelteon may have beneficial effects on sleep disturbances, especially on RBD in patients with PD.

Perry Syndrome: A Distinctive Type of TDP-43 Proteinopathy

Perry syndrome is a rare atypical parkinsonism with depression, apathy, weight loss, and central hypoventilation caused by mutations in dynactin p150glued (DCTN1). A rare distal hereditary motor neuropathy, HMN7B, also has mutations in DCTN1. Perry syndrome has TAR DNA-binding protein of 43 kDa (TDP-43) inclusions as a defining feature. Other TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with and without motor neuron disease (FTLD-MND). TDP-43 forms aggregates in neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear inclusions, dystrophic neurites (DNs), as well as axonal spheroids, oligodendroglial cytoplasmic inclusions, and perivascular astrocytic inclusions (PVIs). We performed semiquantitative assessment of these lesions and presence of dynactin subunit p50 lesions in 3 cases of Perry syndrome and one of HMN7B. We compared them with 3 cases of FTLD-MND, 3 of ALS, and 3 of hippocampal sclerosis (HpScl). Perry syndrome had NCIs, DNs, and frequent PVIs and spheroids. Perry syndrome cases were similar, but different from ALS, FTLD-MND, and HpScl. TDP-43 pathology was not detected in HMN7B. Dynactin p50 inclusions were observed in both Perry syndrome and HMN7B, but not in the other conditions. These results suggest that Perry syndrome may be distinctive type of TDP-43 proteinopathy.

Cytoplasmic aggregates of dynactin in iPSC-derived tyrosine hydroxylase-positive neurons from a patient with Perry syndrome

BACKGROUND Perry syndrome is a rare autosomal dominant disorder clinically characterized by parkinsonism with depression/apathy, weight loss, and central hypoventilation. Eight mutations in DCTN1 gene have been reported. A novel disease model is required because the detailed pathogenesis remains unclear. METHODS To develop a novel model, we generated induced pluripotent stem cells (iPSCs) from a Perry syndrome patient with F52L mutation in DCTN1, and describe clinical and neuroimaging investigations. We differentiated iPSCs into tyrosine hydroxylase (TH)-positive neurons. Immunocytochemistry analyses of control and mutant were performed. RESULTS The patient displayed levodopa responsive parkinsonism. Dopamine transporter single photon emission tomography showed markedly decreased uptake in the striatum, and metaiodobenzylguanidine cardiac scintigraphy also showed decreased uptake. Perry syndrome TH-positive neurons showed dynactin aggregates in cytoplasm. CONCLUSIONS TH-positive neurons from Perry syndrome iPSCs recapitulated an aspect of the disease phenotype of Perry syndrome.

The Prevalence of Constipation and Irritable Bowel Syndrome in Parkinson’s Disease Patients According to Rome III Diagnostic Criteria

Background: Gastrointestinal symptoms are one of the most common non-motor features of Parkinson’s disease (PD). Recently, a report from Taiwan revealed that irritable bowel syndrome (IBS) may be associated with an increased risk of developing PD; however, the prevalence of IBS in PD patients has not been fully evaluated. Rome III criteria are widely assessed with a questionnaire to determine functional gastrointestinal disorders. Objective: We assessed the prevalence of constipation and IBS in PD patients in our cohort using Rome III criteria. Methods: Between October 2014 and April 2015, 118 patients with PD were treated at Fukuoka University Hospital and were enrolled in this study. Rome III criteria were used to diagnose constipation and IBS. Results: Constipation and IBS were detected in 32 (27.1%) and 20 patients (17.0%), respectively. The most common symptom related to constipation was straining during defecation (77.1%). Among constipation symptoms, patients’ self-awareness of constipation was mostly related to straining during defecation (odds ratio 5.27, 95% confidence interval 1.475–18.811). The number of constipation symptoms was correlated with the severity of the Hoehn-Yahr Stage (p < 0.05) and total levodopa equivalent dose (p < 0.05). Conclusions: This is the first report to investigate the prevalence of IBS in PD patients with Rome III criteria. We found a higher prevalence of IBS compared with the general population. The prevalence of constipation based on Rome III criteria was much lower than that reported in previous studies. Further studies are warranted to evaluate gastrointestinal symptoms in PD patients using comparable questionnaires.

Impulse control disorders and punding in Perry syndrome

Impulse control disorders (ICDs) are psychiatric conditions characterized by poor impulse control such as pathological gambling, hypersexuality, compulsive shopping, compulsive eating, explosive aggressive behavior, reckless driving, and reckless generosity [1,2]. Punding is defined as a complex prolonged, purposeless, and repetitive behavior. It has been increasingly recognized that ICDs and punding are more prevalent in patients with Parkinsons disease (PD) compared with a normal population [1], most likely due to dopaminergic therapy such as levodopa plus pramipexole and ropinirole [3]. Perry syndrome is a rare autosomal dominant neurodegenerative disorder caused by DCTN1 mutations. Parkinsonism is one of the most characteristic features of patients with Perry syndrome, along with apathy/depression, unexpected weight loss, and central hypoventilation [4]. Parkinsonism that occurs in patients with Perry syndrome generally responds well to high dose of dopaminergic therapy; however, to date, neither ICDs nor punding have been reported in patients with Perry syndrome. Herein, we describe two Japanese patients with Perry syndrome who developed ICDs and punding after initiation of dopaminergic therapy. Both patients were from the same family pedigree whomwe previously reported (Fig. 1A).

Daytime sleepiness in dementia with Lewy bodies is associated with neuronal depletion of the nucleus basalis of Meynert

INTRODUCTION Excessive daytime sleepiness is a commonly reported clinical feature of dementia with Lewy bodies (DLB) that can occur early in the disease. Cholinergic depletion is known to be severe in DLB, even when dementia severity is mild. The nucleus basalis of Meynert serves as a primary source of cortical acetylcholine, and has a role in facilitating cortical activation and arousal. We sought to determine whether daytime sleepiness at the initial evaluation of patients with DLB was associated with neuronal loss in the nucleus basalis of Meynert. METHODS Autopsy-confirmed patients who met clinical criteria for probable DLB at their initial evaluation and who were administered the informant-completed Epworth Sleepiness Scale were included in the study (n = 40). Each patient had a dementia at baseline (80% with mild severity) and two or more features of parkinsonism, visual hallucinations, fluctuations, or probable REM sleep behavior disorder. Quantitative digital pathology of the nucleus basalis of Meynert was performed in the DLB group and in 20 non-DLB autopsy controls. RESULTS DLB had greater neuronal depletion in the nucleus basalis of Meynert (p < 0.0001) than pathologic controls. Sleepiness was present in 58% of the DLB group and those with daytime sleepiness had significantly lower neuron counts in the nucleus basalis of Meynert than their non-sleepy counterparts (p = 0.001). Regression modeling revealed that sleepiness was a stronger predictor of neuronal loss in the nucleus basalis of Meynert than visual hallucinations, fluctuations or dementia severity (p = 0.003). CONCLUSIONS Excessive daytime sleepiness in early DLB is indicative of a more profound loss of basal forebrain cholinergic integrity.

Effect of hachimijiogan on memory impairment induced by beta-amyloid combined with cerebral ischemia in rats

Alzheimers disease (AD) is a chronic neurodegenerative condition most often found in older people. Cerebrovascular disease is commonly found in patients with AD. Hachimijiogan (HJG) is a herbal medicine commonly used to treat age‐related disease. The aim of this study was therefore to investigate whether HJG could improve memory impairment in rats treated with amyloid‐β protein (Aβ) and cerebral ischemia (Aβ + CI).

Dysphagia in Perry Syndrome: Pharyngeal Pressure in Two Cases

Background: To investigate the impact of dysphagia in Perry syndrome (PS), an autosomal dominant parkinsonism caused by mutation of DCTN1, which is associated with hypoventilation, depression, and weight loss. Case Presentation: We used tongue pressure measurements and manofluorography to investigate swallowing function in 2 patients with PS. Case 1, a 60-year-old male showing parkinsonism, and case 2, a 49-year-old male admitted with pneumonia, were diagnosed as having PS based on the DCTN1 gene analysis. Case 1 showed a pharyngeal retention of the bolus on videofluorography (VF) and a few swallows were required for its passage into the esophagus. However, tongue pressure and manometry were within the normal range. This patient could eat a normal diet under supervision. Case 2 required artificial ventilation and tube feeding on admission. The VF image showed a slow transfer of the bolus, delayed swallow reflex, and pharyngeal retention of the bolus that required several swallows for its passage into the esophagus. The tongue pressure was within the normal range, but manometry showed a significant decrease in pressure at the hypopharynx and upper esophageal sphincter. The oral intake of the patients was limited to 2 cups of jelly per day. Conclusions: The investigation of swallowing dysfunction of 2 cases of PS showed that maintaining pharyngeal pressure within the normal range was very important for oral feeding success and prognosis.

Behavioral defects in a DCTN1G71A transgenic mouse model of Perry syndrome

Perry syndrome is a rare neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and central hypoventilation. Our previously-conducted genome-wide association scan and subsequent studies identified nine mutations in DCTN1, the largest protein subunit of the dynactin complex, in patients with Perry syndrome. These included G71A in the microtubule-binding cytoskeleton-associated protein Gly-rich domain of p150Glued. The dynactin complex is essential for function of the microtubule-based cytoplasmic retrograde motor dynein. To test the hypothesis that the G71A mutation in the DCTN1 gene is sufficient to cause Perry syndrome, we generated DCTN1G71A transgenic mice. These mice initially developed normally, but young animals showed decreased exploratory activity and aged animals showed impaired motor coordination. These behavioral defects parallel apathy-like symptoms and parkinsonism encountered in Perry syndrome. TDP-43 aggregates were not detected in the substantia nigra and cerebral cortex of the transgenic mice, although pathological aggregates of TDP-43 have been considered a major neuropathological feature of Perry syndrome. Our study reveals that a single mutation in the DCTN1 gene recapitulates symptoms of Perry syndrome patients, and provides evidence that DCTN1G71A transgenic mice represent a novel rodent model of Perry syndrome.