Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

Japanese multicenter database of healthy controls for [123I]FP-CIT SPECT.

PURPOSE: The aim of this multicenter trial was to generate a [123I]FP-CIT SPECT database of healthy controls from the common SPECT systems available in Japan. METHODS: This study included 510 sets of SPECT data from 256 healthy controls (116 men and 140 women; age range, 30-83 years) acquired from eight different centers. Images were reconstructed without attenuation or scatter correction (NOACNOSC), with only attenuation correction using the Chang method (ChangACNOSC) or X-ray CT (CTACNOSC), and with both scatter and attenuation correction using the Chang method (ChangACSC) or X-ray CT (CTACSC). These SPECT images were analyzed using the Southampton method. The outcome measure was the specific binding ratio (SBR) in the striatum. These striatal SBRs were calibrated from prior experiments using a striatal phantom. RESULTS: The original SBRs gradually decreased in the order of ChangACSC, CTACSC, ChangACNOSC, CTACNOSC, and NOACNOSC. The SBRs for NOACNOSC were 46% lower than those for ChangACSC. In contrast, the calibrated SBRs were almost equal under no scatter correction (NOSC) conditions. A significant effect of age was found, with an SBR decline rate of 6.3% per decade. In the 30-39 age group, SBRs were 12.2% higher in women than in men, but this increase declined with age and was absent in the 70-79 age group. CONCLUSIONS: This study provided a large-scale quantitative database of [123I]FP-CIT SPECT scans from different scanners in healthy controls across a wide age range and with balanced sex representation. The phantom calibration effectively harmonizes SPECT data from different SPECT systems under NOSC conditions. The data collected in this study may serve as a reference database.

Daily step count and all-cause mortality in a sample of Japanese elderly people: a cohort study.

BACKGROUND: This study aimed to examine the relationship between pedometer-assessed daily step count and all-cause mortality in a sample of elderly Japanese people. METHODS: Participants included 419 (228 males and 191 females) physically independent, community-dwelling 71-year-old Japanese people. The number of steps per day was measured by a waist-mounted pedometer for seven consecutive days at baseline. Participants were divided into quartiles based on their average number of steps/day (first quartile, < 4503 steps/day; second quartile, 4503-6110 steps/day; third quartile, 6111-7971 steps/day; fourth quartile, > 7972 steps/day) and were followed up over a mean period of 9.8 years (1999-2010) for mortality. RESULTS: Seventy-six participants (18.1%) died during the follow-up period. The hazard ratios (adjusted for sex, body mass index, cigarette smoking, alcohol intake, and medication use) for mortality across the quartiles of daily step count (lowest to highest) were 1.00 (reference), 0.81 (95%CI, 0.43-1.54), 1.26 (95%CI, 0.70-2.26), and 0.46 (95%CI, 0.22-0.96) (P for trend = 0.149). Participants in the highest quartile had a significantly lower risk of death compared with participants in the lowest quartile. CONCLUSION: This study suggested that a high daily step count is associated with a lower risk of all-cause mortality in physically independent Japanese elderly people.

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

[Depression in Parkinson's disease].

Depression affects Parkinson's disease (PD) patient's QOL. Although it changes with the diagnostic criteria used, the frequency of depression in PD is approximately 10-30%. Anhedonia is characteristic in PD. According to research on anhedonia in PD using the Snaith-Hamilton Pleasure Scale (SHAPS), the positive ratio of anhedonia is high in PD. The SHAPS score significantly correlates with the severity of PD and duration of the disease. An examination of the literature on depression before the development of motor symptoms of PD revealed that the risk of PD is high in patients with a history of depression. Pathologically, the substantia nigra is affected in the later stages and raphe nuclei are affected in the early stages. This suggests that depression is a prodromal symptom of PD.

A Case of Unilateral Recurrent Nerve Palsy with Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease in which peripheral sensory and motor nerves of the four limbs are impaired due to autoimmune mechanism-induced demyelinating changes through a 2-month or longer chronic course. The incidence of complication by cranial neuropathy has been reported to be 15%, but there have been very few reports on disorder of the vagus nerve and its branch, the recurrent nerve. We report a patient who developed left recurrent nerve palsy with CIDP. The patient was a 48-year-old male. The disease developed as progressive muscle weakness and numbness of the four limbs 3 years before and was diagnosed as CIDP. The symptoms had been improved by high-dose intravenous gamma-globulin therapy. However, from 2 months before he became aware of breathy hoarseness, and bilateral decreased grip strength and sensory disturbance of the upper and lower limbs recurred and progressed. On laryngoscopy disorder of left vocal fold movement and glottal closure incompetence during phonation were observed, and neurogenic changes were detected in the left thyroarytenoid muscle by needle electromyography for the intrinsic laryngeal muscles. High-dose intravenous gamma-globulin therapy was performed and left vocal fold movement recovered with recovery of bilateral grip strength and sensory disturbance of the upper and lower limbs, and phonation was also normalized.

FLAMES with Elevated Myelin Basic Protein Followed by Myelitis.

The pathophysiology of unilateral cortical fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis with seizures (FLAMES) is unclear. A 26-year-old man was referred because of a seizure. FLAIR showed an increased signal intensity and swelling of the right frontal cortex. His symptoms and imaging abnormalities were improved after intravenous methylprednisolone therapy. MOG antibody was detected both in serum and cerebrospinal fluid (CSF). Therefore, the patient was diagnosed with FLAMES. Myelin basic protein (MBP) was elevated in CSF. The high MBP value in the CSF in the present case suggested that demyelination as well as inflammation can occur in some FLAMES patients.

Voxel-based analysis of age and gender effects on striatal [123I] FP-CIT binding in healthy Japanese adults.

OBJECTIVE: Although previous studies have investigated age and gender effects on striatal subregional dopamine transporter (DaT) binding, these studies were mostly based on a conventional regions of interest-based analysis. Here, we investigated age and gender effects on striatal DaT binding at the voxel level, using a multicenter database of [(123)I] N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ([(123)I] FP-CIT)-single photon emission computed tomography (SPECT) scans in 256 healthy Japanese adults. METHODS: We used the Southampton method to calculate the specific binding ratios (SBRs) of each subject's striatum and then converted the [123I] FP-CIT SPECT images to quantitative SBRs images. To investigate the effects of age and gender effects on striatal DaT binding, we performed a voxel-based analysis using statistical parametric mapping. Gender differences were also compared between young to middle-aged subjects and elderly subjects (age threshold: 60 years). RESULTS: When all subjects were explored as a group, DaT binding throughout the striatum decreased with advancing age. Among all subjects, the females showed higher DaT binding in the bilateral caudate compared to the males. In the young to middle-aged subjects, the females showed higher DaT binding throughout the striatum (with a slight caudate predominance) versus the males. In the elderly, there were no gender differences in striatal DaT binding. CONCLUSION: Our findings of striatal subregional age- and gender-related differences may provide useful information to construct a more detailed DaT database in healthy Japanese subjects.

Abnormal cardiac [(123)I]-meta-iodobenzylguanidine uptake in multiple system atrophy.

[(123)I]-Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is useful for distinguishing multiple system atrophy (MSA) from Parkinson disease. In this study, longitudinal observation using MIBG myocardial scintigraphy was carried out in patients with MSA to evaluate the association of myocardial MIBG uptake with clinical features. A total of 96 MIBG examinations were performed in 52 patients with MSA. The heart/mediastinum (H/M) ratio of MIBG uptake at 240 minutes after injection was below the lower limit in 16 patients with MSA (31.3%). Overall, the H/M ratio correlated with neither disease duration nor severity. In the follow-up observations, the H/M ratio did not show any specific trends, in contrast with the continuous decrease observed in patients with Parkinson's disease. This data clearly showed that cardiac MIBG uptake cannot necessarily be preserved in patients with MSA and that approximately 30% of patients with MSA showed decreased MIBG uptake without any correlation to disease duration or severity.

Early depressive symptoms after ischemic stroke are associated with a left lenticulocapsular area lesion.

BACKGROUND: Poststroke depression is one of the most frequent and important complications of stroke. Although many studies of depression after stroke have been reported, clinical association between the risk of depression after stroke and the lesion location remains unclear. The presence of depression after stroke reportedly confers a poor prognosis; however, early recognition of depressive symptoms may improve outcomes. We examined the relation between lesion location and presence of depressive symptoms 1 month after ischemic stroke, with a view toward early management of depressive symptoms. METHODS: In all, 134 consecutive patients with ischemic stroke were followed up to determine whether depression was present 1 month after stroke onset. Depressive symptoms were assessed by means of the Zung Self-rating Depression Scale. The lesion location was determined on magnetic resonance or computed tomography images. RESULTS: The incidence of depressive symptoms 1 month after stroke onset was 34.3%. Backward stepwise logistic regression analysis showed hypertension, education, and the presence of a left lenticulocapsular infarct, in particular, to be independent predictors of depressive symptoms. CONCLUSIONS: Patients with ischemic stroke, particularly in the left lenticulocapsular area, should be carefully evaluated for early detection and treatment of depressive symptoms, which may greatly influence outcome.

Elevated cardio-ankle vascular index may be related to future stroke risk in Japanese subjects.

BACKGROUND: The cardio-ankle vascular index (CAVI) has been proposed as a useful parameter for arteriosclerotic diseases. However, whether it is associated with stroke risk in Japanese subjects remains unclear. METHODS: In total, 280 Japanese subjects (92 females, 52.6 ± 5 years old) underwent a medical check-up. CAVI value and risk factors for arterial dysfunction were evaluated; the predicted 10-year stroke risk was measured by the Japan Public Health Center study. RESULTS: Age, sex, body mass index, and systolic blood pressure were significant independent predictors of CAVI. CAVI values were significantly elevated in the high, compared with the medium-low and low predicted risk groups. A significant odds ratio (OR) for the high-risk group was noted in the highest quartile of CAVI values (OR, 14.67; 95% confidence interval [CI], 3.17-68.0), compared with the lowest quartile, after adjusting for potential confounders. A significant OR for very high predicted stroke risk was also found for each quartile increase (OR, 3.04; 95% CI, 1.87-4.94) and 1-standard deviation increase (OR, 2.24; 95% CI, 1.52-3.30) in CAVI value. CONCLUSION: Elevated CAVI values were related to an elevated predicted stroke risk, suggesting that CAVI could be a suitable surrogate marker for finding subjects at an increased risk of first-ever stroke.

Effect of istradefylline on mood disorders in Parkinson's disease.

Depression is the most common psychiatric complication in patients with Parkinson's disease (PD). Istradefylline, a new anti-parkinsonian agent with completely different mechanism, improves depression-like symptoms in an experimental disease model; however, there is no report of its effects in PD patients. In this study, the effectiveness of istradefylline for treatment of mood disorders in patients with PD was examined in an open-label trial. Thirty PD patients were enrolled. All patients had scores of higher than cut-off level in at least one of the following batteries: Snaith-Hamilton Pleasure Scale Japanese version (SHAPS-J), Apathy scale, or Beck Depression Inventory-2nd edition (BDI). Following study enrollment, all patients received 20 mg of istradefylline, and the dose was increased to 40 mg after 4 weeks. Results from these 3 batteries and the Unified Parkinson's Disease Rating Scale (UPDRS) score were assessed every 2-4 weeks until 12 weeks and the changes in these scores were analyzed. Following administration of istradefylline, the scores of SHAPS-J, Apathy scale, and BDI were significantly improved over time. Significant improvement was also found in the UPDRS score; however, no significant correlation was observed between the score change in these 3 batteries and UPDRS motor function. This is the first study to show the effectiveness of istradefylline for treatment of mood disorders in PD independent of improvement of parkinsonian motor symptoms. In the future, this should be confirmed in a double-blind placebo-controlled trial.

Parkinsonism Relating to Intoxication with Glyphosate.

We herein report the case of a 38-year-old man who developed parkinsonism 4 years after ingesting glyphosate. The patient presented with right-sided bradykinesia and cogwheel rigidity without autonomic symptoms. Magnetic resonance imaging of the brain and [123I]-metaiodobenzylguanidine myocardial scintigraphy were normal. A drastic response to levodopa and the presence of levodopa-induced dyskinesia without strong non-motor symptoms were seen in this patient. We considered that young-onset atypical parkinsonism was associated with a history of sublethal glyphosate ingestion. Epidemiologic investigations have shown that exposure to pesticides is a risk factor for Parkinson's disease (PD). Our findings support the notion that glyphosate exposure might be related to the onset of PD.

[A case of Creutzfeldt-Jakob disease with codon 129 polymorphism and codon 180 point mutation].

We report a 79-year-old Japanese man with histlogically-diagnosed Creutzfeldt-Jakob disease (CJD) with codon 129 polymorphism and codon 180 point mutation. At the time of the first examination, we diagnosed and treated as Alzheimer's disease with cerebrovascular disease because of laterality of cortex accumulation and an accumulation decrease of perforating branch areas at the SPECT ((123)I-IMP). His status rapidly progressed to an apallic state and died of lung abscess 12 months later. None of the members of his family had neuromuscular disorders. EEG (electroencephalogram) did not reveal periodic synchronous discharges (PSD). Prion protein gene analysis showed Codon 129 polymorphism (Met/Val) and codon 180 point mutation (Val/Ile). The autopsy findings revealed spongiform changes and numerous senile plaque formation in the cerebral cortex. The hippocampus and the cerebellar cortex were well preserved and did not show lacunar infarctions. CJD patients with combination of the codon 180 point mutation and codon 129 polymorphism of the PrP gene have rarely been reported.

[Apheresis therapy in Guillain-Barré syndrome].

Based on previous randomized controlled-trials (RCTs), plasma exchange (PE) has been established as an effective treatment for Guillain-Barré syndrome (GBS). Double filtration plasmapheresis (DFPP) and immunoadsorption plasmapheresis (IAPP) may be effective for GBS, however their effectiveness have not been established because any RCTs have not been available so far. Intravenous immunoglobulin (IVIG) has also been established to be effective for GBS according to several RCTs, however complications have been more frequent in PE than IVIG. Therefore IVIg treatment should be considered as the first choice for GBS, and PE treatment remains as the second-line if IVIg treatment is contraindicated.

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

Anhedonia is one of the non-motor symptoms observed in the Parkinson's 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 Parkinson's 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.

[A case of infarction in brainstem and cerebellum as a initial symptom with bilateral hearing loss].

A 56-year old male presented with a sudden onset of bilateral hearing difficulty. He complained of dizziness and gait disturbance at the onset and subsequently developed bilateral hearing loss and tinnitus. Brain MRI revealed multiple infarcts in bilateral middle cerebellar peduncles, bilateral cerebellar hemispheres and the right cerebral peduncle. Three dimentional computed tomography angiography (3D-CTA) showed severe stenosis of bilateral vertebral arteries. Infarcts were located in the border zone between anterior inferior cerebellar artery (AICA) and superior cerebellar artery (SCA), suggesting hemodynamic infarctions. Auditory brain stem responses (ABR) were recorded three times. The initial ABR demonstrated all waves except for wave I on day 14. Wave I on the left was normal, while wave I peak latency on the right was prolonged. On day 61, all waves were recorded, although peak latencies of waves III to V and interpeak intervals of the wave I to III on the right side were prolonged. Involvements of the cochlear nerve and pontine auditory pathway were suggested from the ABR abnormalities in this case.

A Japanese multicenter survey characterizing pain in Parkinson's disease.

BACKGROUND: Pain is a frequent, troublesome symptom of PD but is under-recognized and poorly understood. AIM: We characterized pain prevalence, severity, and location in PD, to better understand its pathophysiology and improve diagnosis and treatment. SUBJECTS AND METHODS: A cross-sectional controlled study was conducted at 19 centers across Japan. A total of 632 subjects with Mini-Mental State Examination scores ≥24 were enrolled, including 324 PD patients and 308 controls. Sex and mean age did not differ between the two groups. Demographic and clinical data were collected. Pain was assessed using questionnaires, the SF-36v2 bodily pain scale, and a body illustration for patients to indicate the location of pain in 45 anatomical areas. RESULTS: Pain prevalence in the PD group was 78.6%, significantly higher than in controls (49.0%), as was its severity. There was no correlation between SF-36v2 score and motor scores, such as Unified Parkinson's Disease Rating Scale III or Hoehn & Yahr scores. Pain distribution was similar between groups, predominantly in the lower back, followed by the gluteal region, lower legs, thighs, posterior neck, and shoulders. CONCLUSION: Pain is a significant problem in the Japanese PD population and we discuss its pathophysiology.