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Objectives To evaluate the long-term efficacy and safety of zonisamide, an antiepileptic agent, in dementia with Lewy bodies (DLB). Design Phase three clinical trial with 12 week, randomized, placebo-controlled, double-blind, and subsequent 40 week, open-label, extension periods. Setting A total of 109 centers in Japan between April 2015 and November 2017. Participants Outpatients diagnosed with probable DLB. Intervention Outpatients were randomly assigned to receive placebo (P) or zonisamide 25 or 50 mg/day for 12 weeks. In the subsequent open-label 40 week period, all patients initially received zonisamide 25 mg/day for at least 2 weeks followed by optional flexible dosing with zonisamide 25 or 50 mg/day for the remaining period. Measurements The primary outcome was efficacy on motor symptoms, assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score, over the total 52 week trial period. Effects on behavioral and psychological symptoms of dementia and cognitive function, and safety were also evaluated. Results In total, 335 patients were included in the long-term analysis: 106, 117, and 112 in the P-, 25mg-, and 50mg-Flex groups, respectively. UPDRS-III score continued to improve for an additional 12 to 16 weeks in the open-label period (mean [standard deviation] change from baseline at Week 28: −5.1 [7.3] and −6.3 [8.2] in the 25mg- and 50mg-Flex groups) and remained almost constant thereafter. No unexpected neurological or psychiatric adverse events occurred, and no adverse events increased in incidence in the open-label period. Conclusions Long-term treatment with zonisamide was well tolerated and yielded sustained improvement in motor symptoms. Trial registration JapicCTI-152839 (Registered on 9 March 2015) https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152839

Introduction There is considerable intra- and inter-individual variability in the pharmacokinetics (PK) of levodopa after oral administration. Inter-individual variability in levodopa PK has also been demonstrated in fasting single-dose studies. We examined the factors that affect levodopa PK in patients with Parkinson's disease (PD) and quantified the intensity of their respective effects. Methods We studied 220 patients who underwent PK assessment after administration of 1 tablet of levodopa/DOPA decarboxylase inhibitor (DCI) combination, which contained 10 mg carbidopa/100 mg levodopa or 25 mg benserazide/100 mg levodopa. PK was evaluated using non-compartmental analysis. Results In total, 220 PD patients (including 112 men) were studied. The mean age (±standard deviation) and mean disease duration was 68.1 ± 8.9 and 7.7 ± 5.8 years, respectively. The Cmax of levodopa was 9.0 ± 4.0 ng/mL, Tmax was 41.4 ± 40.2 min, and area under the blood concentration–time curve up to 4 h (AUC4hr) was 12.3 ± 3.7 ng/mL*4hr. Factors affecting AUC4hr were analyzed using multiple linear regression models. Age (1.1 ± 0.23 per +10 years, p = 3.1E-8), sex (2.2 ± 0.5 for female, p = 1.9E-5), DCI (1.4 ± 0.4 for benserazide, p = 0.0028), and body weight (−0.77 ± 0.22 per +10 kg, p = 5.4E-4) were significantly related to AUC4hr, while disease duration, dyskinesia status, and eGFR were not related to AUC4hr and Cmax. Conclusion Female, aging, difference formulations of DCI, or lower body weight independently contributes to increased AUC4hr of levodopa in Japanese patients with PD in this study.

Long-term treatment of Parkinson’s disease (PD) by levodopa leads to motor complication “wearing-off”. Zonisamide is a nondopaminergic antiparkinsonian drug that can improve “wearing-off” although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose “off” time decreased ≥1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and “off” time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced “off” time (PAdjusted = 4.85 × 10−9). Carriers of responsive genotype showed >7-fold decrease in mean “off” time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10−7). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing “off” time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of “wearing-off” in PD by genotype-guided zonisamide treatment.

We consider nonlinear scalar field equations involving the Sobolev-critical exponent at high frequencies $\omega$. Since the limiting profile of the ground state as $\omega \to \infty$ is the Aubin-Talenti function and degenerate in a certain sense, from the point of view of perturbation methods, the nondegeneracy problem for the ground states at high frequencies is subtle. In addition, since the limiting profile (Aubin-Talenti function) fails to lie in $L^{2}(\mathbb{R}^{d})$ for $d=3,4$, the nondegeneracy problem for $d=3,4$ is more difficult than that for $d\ge 5$ and an applicable methodology is not known. In this paper, we solve the nondegeneracy problem for $d=3,4$ by modifying the arguments in [2, 3]. We also show that the linearized operator around the ground state has exactly one negative eigenvalue., Comment: 35 pages

Introduction:Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy., Methods:This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG., Results:Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score., Conclusion:Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores.

In this paper, we prove the global well posedness and the decay estimates for a $\mathbb Q$-tensor model of nematic liquid crystals in $\mathbb R^N$, $N \geq 3$. This system is coupled system by the Navier-Stokes equations with a parabolic-type equation describing the evolution of the director fields $\mathbb Q$. The proof is based on the maximal $L_p$ -$L_q$ regularity and the $L_p$ -$L_q$ decay estimates to the linearized problem., Comment: 29 pages

Dementia greatly contributes to poor prognosis in patients with Parkinson's disease (PD). We previously reported that severe olfactory dysfunction may be a good predictor of Parkinson's disease dementia (PDD). In this trial, we investigated whether early administration of donepezil to patients with severe hyposmia can reduce the development of PDD.This was a multi-centre, randomized, double-blind, parallel group, placebo-controlled trial in patients with non-demented PD with severe hyposmia (The Donepezil Application for Severe Hyposmic Parkinson's Disease [DASH-PD] study). A total of 201 patients were randomly allocated to receive donepezil or placebo in addition to standard therapy for PD. Patients were followed up every 6 months until the onset of PDD or for a maximum of 4 years. The primary endpoint was the onset of dementia. The secondary endpoint was cognitive impairment measured by Addenbrooke's Cognitive Examination-Revised (ACE-R) and the Clinical Dementia Rating (CDR).(UMIN000009958: February 2013 to May 2019).A total of 201 hyposmic patients with PD were randomly assigned to a treatment: 103 to donepezil and 98 to placebo. Overall, 141 (70%) patients completed the 4-year intervention. During follow-up, 7 of 103 (6.8%) patients in the donepezil group and 12 of 98 (12.2%) patients in the placebo group developed PDD; however, the hazard ratio of PDD incidence was not statistically significant (hazard ratio (HR), 0.609; 95% confidence interval, 0.240 to 1.547;Administration of donepezil to PD patients with severe olfactory dysfunction for 4 years did not change the incidence of dementia but had a beneficial effect on neuropsychological function, with good tolerability.The Ministry of Health Labour and Welfare and the Japan Agency for Medical Research and Development provided funding for this study.

ObjectiveInterindividual variations in responsiveness to zonisamide in patients with Parkinson’s disease (PD) have been observed in clinical settings. To decipher the molecular mechanisms determining the efficacy of zonisamide, we conducted whole transcriptome sequencing analysis of patients with PD.MethodsWe selected 23 super-responders (SRs) and 25 non-responders (NRs) to zonisamide from patients with PD who had participated in a previous clinical trial for the approval of zonisamide for the treatment of ‘wearing-off’. Whole transcriptome analysis of peripheral blood was conducted on samples taken before and 12 weeks after zonisamide treatment. We performed differential gene expression analysis to compare between the SRs and NRs at each time point.ResultsDifferentially expressed genes in the pre-treatment samples were significantly enriched for glutamatergic synapses and insulin-like growth factor binding (Padj=7.8 × 10−3and 0.029, respectively). The gene sets associated with these functions changed more dynamically by treatment in SRs than NRs (p=7.2 × 10−3and 8.2 × 10−3, respectively).ConclusionsOur results suggest that the efficacy of zonisamide in PD patients is associated with glutamate-related synaptic modulation and p53-mediated dopaminergic neural loss. Their transcriptomic differences could be captured before treatment, which would lead to the realisation of future personalised treatment.

Introduction Resting-state functional connectivity magnetic resonance imaging (rsfcMRI) of rapid eye movement (REM) sleep behavior disorder (RBD) may provide an early biomarker of α-synucleinopathy. However, few rsfcMRI studies have examined cognitive networks. To elucidate brain network changes in RBD, we performed rsfcMRI in patients with polysomnography-confirmed RBD and healthy controls (HCs), with a sufficiently large sample size in each group. Methods We analyzed rsfcMRI data from 50 RBD patients and 70 age-matched HCs. Although RBD patients showed no motor signs, some exhibited autonomic and cognitive problems. Several resting-state functional networks were extracted by group independent component analysis from HCs, including the executive-control (ECN), default-mode (DMN), basal ganglia (BGN), and sensory-motor (SMN) networks. Functional connectivity (FC) was compared between groups using dual regression analysis. In the RBD group, correlation analysis was performed between FC and clinical/cognitive scales. Results Patients with RBD showed reduced striatal-prefrontal FC in ECN, consistent with executive dysfunctions. No abnormalities were found in DMN. In the motor networks, we identified reduced midbrain-pallidum FC in BGN and reduced motor and somatosensory cortex FC in SMN. Conclusion We found abnormal ECN and normal DMN as a possible hallmark of cognitive dysfunctions in early α-synucleinopathies. We replicated abnormalities in BGN and SMN corresponding to subclinical movement disorder of RBD. RsfcMRI may provide an early biomarker of both cognitive and motor network dysfunctions of α-synucleinopathies.

Background Patients with Parkinson's disease and related disorders (PDRD) may exhibit dropped head syndrome (DHS), which does not yet have an effective treatment. Objectives To evaluate the effect of combining lidocaine injection into the bilateral scalene muscles and neck corset wearing on dropped head syndrome. Methods We performed needle electromyography assessments of the scalene, sternocleidomastoid (SCM), levator scapulae, splenius capitis, and trapezius muscles. Patients received 2.5–5 ml injections of 1% lidocaine into both sides of the scalene muscles for 4/5 consecutive days and were instructed to wear a neck corset. We measured the neck flexion angle, which formed between the horizontal line and the straight line passing through the ear canal and orbital fossa, before (baseline) and after (Day 8 and Day 90) the intervention. Results Seven males and eight females (mean age, 68.9 years; range 56 to 85 years) who had PDRD with dropped head syndrome were enrolled in this study. Needle electromyography examination revealed abnormal discharge of the scalene muscles in all patients when the neck position was corrected; however, some patients did not show abnormal discharge of the SCM muscle. At Day 8, we observed an improvement of the neck flexion angle in 13 of the 15 patients, from an average of 27.7° ± 13.9° to 11.7 ± 14.6°. At Day 90, the average neck flexion angle was 15.3° ± 17.2°. Conclusions Combining lidocaine injection into the scalene muscles and neck corset wearing is an effective treatment regimen for DHS in patients with PDRD.

Long-term treatment of Parkinson’s disease (PD) by levodopa leads to motor complication “wearing-off”. Zonisamide is a nondopaminergic antiparkinsonian drug that can improve “wearing-off” although response to the treatment varies between individuals. To clarify the genetic basis of zonisamide responsiveness, we conducted a genome-wide association study (GWAS) on 200 PD patients from a placebo-controlled clinical trial, including 67 responders whose “off” time decreased ≥1.5 h after 12 weeks of zonisamide treatment and 133 poor responders. We genotyped and evaluated the association between 611,492 single nucleotide polymorphisms (SNPs) and “off” time reduction. We also performed whole-genome imputation, gene- and pathway-based analyses of GWAS data. For promising SNPs, we examined single-tissue expression quantitative trait loci (eQTL) data in the GTEx database. SNP rs16854023 (Mouse double minute 4, MDM4) showed genome-wide significant association with reduced “off” time (PAdjusted = 4.85 × 10−9). Carriers of responsive genotype showed >7-fold decrease in mean “off” time compared to noncarriers (1.42 h vs 0.19 h; P = 2.71 × 10−7). In silico eQTL data indicated that zonisamide sensitivity is associated with higher MDM4 expression. Among the 37 pathways significantly influencing “off” time, calcium and glutamate signaling have also been associated with anti-epileptic effect of zonisamide. MDM4 encodes a negative regulator of p53. The association between improved motor fluctuation and MDM4 upregulation implies that p53 inhibition may prevent dopaminergic neuron loss and consequent motor symptoms. This is the first genome-wide pharmacogenetics study on antiparkinsonian drug. The findings provide a basis for improved management of “wearing-off” in PD by genotype-guided zonisamide treatment.

INTRODUCTION Needle electromyography (EMG) has been an important diagnostic tool, although discomfort may limit its use in some children. We investigated the diagnostic utility of the clustering index (CI) method, a quantitative analysis for surface EMG (SEMG), in children. METHODS SEMG was recorded from the tibialis anterior muscle. Discriminant analysis between patients with neurogenic disorders and patients with myopathy was performed for whole epochs by using the CI and area values. RESULTS Forty-five children (29 with myopathy, 16 with neurogenic disorders; age 9 ± 3.9 years) were enrolled. The mean discriminant function value of the neurogenic group was 0.58 ± 0.88 (-0.48-2.30), whereas that of the myopathic group was -0.55 ± 0.70 (-2.38-0.68). When the cutoff value was set at the limit of the other group, 17 of 29 children with myopathy and 7 of 16 children with neurogenic disorders were correctly classified. DISCUSSION The CI method can be a useful noninvasive diagnostic tool in children with neuromuscular disorders. Muscle Nerve 58:824-827, 2018.

Background The facial expression of medical staff has been known to greatly affect the psychological state of patients, making them feel uneasy or conversely, cheering them up. By clarifying the characteristics of facial expression recognition ability in patients with Lewy body disease, the aim of this study is to examine points to facilitate smooth communication between caregivers and patients with the disease whose cognitive function has deteriorated. Methods During the period from March 2016 to July 2017, we examined the characteristics of recognition of the six facial expressions of “happiness,” “sadness,” “fear,” “anger,” “surprise,” and “disgust” for 107 people aged 60 years or more, both outpatient and inpatient, who hospital specialists had diagnosed with Lewy body diseases of Parkinson’s disease, Parkinson’s disease with dementia, and dementia with Lewy bodies. Based on facial expression recognition test results, we classified them by cluster analysis and clarified features of each type. Results In patients with Lewy body disease, happiness was kept unaffected by aging, age of onset, duration of the disease, cognitive function, and apathy; however, recognizing the facial expression of fear was difficult. In addition, due to aging, cognitive decline, and apathy, the facial expression recognition ability for sadness and anger decreased. In particular, cognitive decline reduced recognition of all of the facial expressions except for happiness. The test accuracy rates were classified into three types using the cluster analysis: “stable type,” “mixed type,” and “reduced type”. In the “reduced type”, the overall facial recognition ability declined except happiness, and in the mixed type, recognition ability of anger particularly declined. Conclusion There were several facial expressions that the Lewy body disease patients were unable to accurately identify. Caregivers are recommended to make an effort to compensate for such situations with language or body contact, etc., as a way to convey correct feeling to the patients of each type.

Introduction Camptocormia is characterized by a pathological forward flexion of the trunk, which is reversible when lying and worsened by standing and walking. So far there is no consensus on how to measure the angle of flexion, and studies therefore give differing results. Harmonization is needed for both research and clinical practice. Orthopedic measures are not useful for this purpose. Methods Two expert raters independently analyzed the photographs of 39 Parkinson patients with camptocormia while standing. They used four different methods to determine the camptocormia angle. The results were compared statistically. An international Consensus Group reviewed the results and drafted recommendations. Results The four methods yielded camptocormia angles that differed by up to 50% in the same patient. Inter-rater reliability and test-retest reliability also differed, but were satisfactory to excellent. Conclusion This Consensus Group concluded that two of the methods qualified as reliable measures of the trunk angles in standing patients based on their clinimetric properties. They propose that the ‘total camptocomia angle’ be the angle between the line from the lateral malleolus to the L5 spinous process and the line between the L5 spinous process and the spinous process of C7. They also propose that the ‘upper camptocormia angle’ be the angle of the lines between the vertebral fulcrum to the spinous processes of L5 and C7, respectively. An app is provided on the web for these measurements ( http://www.neurologie.uni-kiel.de/de/axial-posturale-stoerungen/camptoapp ).

Background Obtaining an adequate number of patients to conduct a natural history study for rare diseases such as Becker muscular dystrophy (BMD) is difficult. Objectives The present study used data from Remudy, a national registry for neuromuscular diseases in Japan, to conduct a phenotypic analysis of BMD. Methods We analyzed Remudy data of participants with dystrophinopathy. All participants who were aged 17 and older and were ambulant at age 13 were included in this study. Participants were divided into two groups: those with BMD who were ambulant at age 17, and those with intermediate muscular dystrophy (IMD) who lost ambulation by age 17. Frequent mutations were analyzed by age at ambulation, cardiopulmonary function, and genotype. For clinical comparisons, participants who were administered steroids were excluded. Results From July 2009 through September 2015, 192 participants had registered with Remudy. Mean participant age was 34.80±13.3 (range, 17-78) years, and 52.1% of participants were ambulant. Of the entire study population, 50.5% had cardiomyopathy and 35.9% had respiratory failure. Three participants required invasive ventilation and 30 required non-invasive ventilation. Nineteen of the 30 non-invasive ventilator users were part-time users. In total, 138 (71.9%) had BMD and 54 (28.1%) had IMD. The most frequent mutation was ex45_ex47del (36 participants). Among participants with frequent in-frame mutations, those with the ex45-49del mutation lost their ambulation earlier than those with the ex45_ex47del mutation. A total of 67 different exon deletions and duplications were identified in the study population. Conclusion We clarified the clinical phenotypes of Japanese patients with BMD/IMD using data from Remudy. Our results suggest that not only IMD but also BMD are associated with risk of respiratory dysfunction.

Background Little is known about the relationship between Becker Muscular Dystrophy (BMD) and developmental problems, school life, employment, and mental problems. We aimed to clarify whether BMD is a risk factor for developmental disorders, problematic behavior, psychiatric diseases, and other social difficulties in school life and employment. Methods Adults with genetically or immunohistochemically confirmed BMD from the Registry of Muscular Dystrophy in Japan (REMUDY) were asked to complete a questionnaire regarding patient history, school life, employment, and mental problems. Results In total, 125 (68.3%) of 183 participants with BMD (median age, 37.2 years) completed the questionnaire. Of these, ten had developmental disorders (mental retardation, autism, and speech disturbance). Fifty-eight (44%) experienced bullying in school, and 39 felt the reason for bullying was physical handicap. Sixteen participants experienced problematic behavior such as cutting class, domestic violence, violent incidents, suicide attempts, or self-mutilation. Employment histories were noted by 92 (73%), of whom 15 could not continue to work due to physical handicaps. Fifteen participants had psychiatric disorders, with 5, 3 and 1 having neurosis, depression, and bipolar disorder, respectively. The other 6 participants with psychiatric disorders did not specify their diagnoses. Patients carrying a Dp140 expression change had significantly more incidences of developmental disorders, but not bullying, problematic behavior, workplace difficulties, or psychiatric disorders. Conclusions Patients with BMD risk bullying and workplace difficulties, as well as developing psychiatric disorders. Parents, teachers, and supporters should be mindful of the daily environment of BMD patients and provide support to help them cope with stress.

Brain-computer interfaces (BCIs) show potential as neuroprosthetic and neurorehabilitative interventions for patients with motor impairments. However, recent evidence suggests that BCIs depend on c...

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. 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. 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. 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.

We conducted a questionnaire survey to collect epidemiological information on patients with Scans Without Evidence of Dopaminergic Deficit (SWEDD). We sent questionnaires to 4,970 neurology specialists in Japan in July 2015 and received responses from 933 of them. The total number of patients reported to have Parkinson's disease was 39,532, which included 237 cases of SWEDD in patients (111 males, 125 females, and 1 case without a gender description). The disease duration in patients with SWEDD was short; 127 cases (53.6%) had a duration less than 3 years, and 78 cases (32.9%) had a duration of 3 years or more but less than 7 years. By age, 59 cases (24.9%) occurred in individuals in their 60s, and 106 cases (44.7%) occurred in individuals in their 70s. Sixty-three neurologists stated that they performed dopamine transporter single photon emission computed tomography (DaT SPECT) on almost all patients with Parkinson's disease. They treated a total of 3,600 patients with Parkinson's disease which included 107 cases of SWEDD; therefore, approximately 3.0% of Parkinson's patients were estimated have SWEDD. The causes of SWEDD were unknown (101 cases), essential tremor (22 cases), vascular Parkinsonism (14 cases), and drug-induced Parkinsonism (14 cases). The majority of neurologists had doubts about the diagnosis of Parkinson's disease prior to confirming the diagnosis using DaT SPECT for reasons such as: normal findings on meta-iodobenzylguanidine (MIBG) myocardial scintigraphy, poor responses to anti-Parkinson drugs, lack of true akinesia, unchanged symptoms, and atypical symptoms. Two hundred and nineteen cases included reports on treatment paradigms following the SWEDD diagnosis. Of those cases, patients in 159 cases were maintained on the same treatment following diagnosis.

Parkinson’s disease (PD) is caused by a selective degeneration of dopamine neurons. The relationship between dopamine transporter (DAT) density and gray matter volume has been unclear. Here we investigated the voxelwise correlation between gray matter volume and DAT binding measured by 123I-N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) single-photon emission computed tomography (SPECT; DaTscan™ imaging) in PD. Thirty-one male patients with PD were examined with MRI and DaTscan. To measure nigrostriatal dopaminergic degeneration in PD, the specific binding ratio (SBR) of the striatum was obtained by DaTscan. Voxel-based morphometry (VBM) of 3D T1-weighted images was used to evaluate the relationships between the regional gray matter volume and the SBR in the striatum. There were significant positive correlations between the SBR and the gray matter volume in the right pulvinar and posterior middle temporal gyrus and a trend level in the left pulvinar, all of which are associated with the second visual pathway. The nigrostriatal dopaminergic degeneration might affect the secondary visual pathway, leading to visual dysfunctions in PD.

Background Because soluble (or secreted) amyloid precursor protein-β (sAPPβ) and -α (sAPPα) possibly reflect pathological features of Alzheimer’s disease (AD), they are potential biomarker candidates for dementia disorders, including AD and mild cognitive impairment (MCI) due to AD (MCI-AD). However, controversial results have been reported regarding their alterations in the cerebrospinal fluid (CSF) of AD and MCI-AD patients. In this study, we re-assessed the utility of sAPPα and sAPPβ in CSF as diagnostic biomarkers of dementia disorders. Methods We used a modified and sensitive detection method to analyze sAPPs levels in CSF in four groups of patients: AD (N = 33), MCI-AD (N = 17), non-AD dementia (N = 27), and disease controls (N = 19). Phosphorylated tau (p-tau), total tau, and Aβ42 were also analyzed using standard methods. Results A strong correlation was observed between sAPPα and sAPPβ, consistent with previous reports. Both sAPPα and sAPPβ were highly correlated with p-tau and total tau, suggesting that sAPPs possibly reflect neuropathological changes in the brain. Levels of sAPPα were significantly higher in MCI-AD cases compared with non-AD and disease control cases, and those of sAPPβ were also significantly higher in MCI-AD and AD cases relative to other cases. A logistic regression analysis indicated that sAPPα and sAPPβ have good discriminative power for the diagnosis of MCI-AD. Conclusions Our findings collectively suggest that both sAPPs are pathologically relevant and potentially useful biomarkers for early and accurate diagnosis of dementia disorders. We also suggest that careful measurement is important in assessing the diagnostic utility of CSF sAPPs. Electronic supplementary material The online version of this article (10.1186/s40364-017-0108-5) contains supplementary material, which is available to authorized users.

Objective Dementia with Lewy bodies (DLB) is often cited as the second most common dementia after Alzheimer’s disease (AD). It is clinically important to distinguish DLB from AD because specific side effects of antipsychotic drugs are limited to DLB. The relative preservation of cingulate glucose metabolism in the posterior cingulate gyri versus that in the precuni, known as the cingulate island sign (CIS), in patients with DLB compared with AD is supposed to be highly specific for diagnosing DLB. In a previous study, using brain perfusion SPECT, the largest value (0.873) for the area under the receiver operating characteristic (ROC) curve (AUC) for differentiating DLB from AD was obtained with the ratio of the posterior cingulate gyri from an early Alzheimer’s disease-specific hypoperfusion volume of interest (VOI) versus the medial occipital lobe. Two purposes of this study are as follows: one is optimization of VOI setting for calculating CIS values and the other is to evaluate their accuracy and simultaneously to retest the method described in our previous paper. Methods We conducted a retest of this SPECT method with another cohort of 13 patients with DLB and 13 patients with AD. Furthermore, we optimized VOIs using contrast images obtained from group comparisons of DLB and normal controls; the same 18 patients with DLB and 18 normal controls examined in our previous study. We obtained DLB-specific VOIs from areas where brain perfusion was significantly decreased in DLB. As the numerators of these ratios, early Alzheimer’s disease-specific VOIs were used after subtracting DLB-specific VOIs. The DLB-specific VOIs were used as the denominator. Results In retest, the obtained AUC was 0.858 and the accuracy, sensitivity, and specificity were 84.6, 84.6, and 84.6%, respectively. The ROC curve analysis with these optimized VOIs yielded a higher AUC of 0.882; and the accuracy, sensitivity, and specificity of these new CIS ratios were 84.6, 92.3, and 76.9%, respectively, with a threshold value of 0.281. Conclusion Optimized CISs using brain perfusion SPECT are clinically useful for differentiating DLB from AD.

Gerstmann-Straussler-Scheinker syndrome caused by the P102L mutation in the prion protein gene (GSS102) is usually characterized by the onset of slowly progressive cerebellar ataxia, with dementia occurring much later. Because of the relatively long disease course and the prominence of progressive cerebellar ataxia in the early stage, GSS102 is often misdiagnosed as other neurodegenerative disorders. We present two cases of genetically proven GSS102L, both of which present with atrophy and decreased blood flow of the thalamus as determined by voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) advance software and easy Z-score analysis for 99mTc-ethyl cysteinate dimer-SPECT, respectively. These thalamic abnormalities have not been fully evaluated to date, and detecting them might be useful for differentiating GSS102 from other neurodegenerative disorders.

There is considerable intra- and inter-individual variability in the pharmacokinetics (PK) of levodopa after oral administration. Inter-individual variability in levodopa PK has also been demonstrated in fasting single-dose studies. We examined the factors that affect levodopa PK in patients with Parkinson's disease (PD) and quantified the intensity of their respective effects.We studied 220 patients who underwent PK assessment after administration of 1 tablet of levodopa/DOPA decarboxylase inhibitor (DCI) combination, which contained 10 mg carbidopa/100 mg levodopa or 25 mg benserazide/100 mg levodopa. PK was evaluated using non-compartmental analysis.In total, 220 PD patients (including 112 men) were studied. The mean age (±standard deviation) and mean disease duration was 68.1 ± 8.9 and 7.7 ± 5.8 years, respectively. The Cmax of levodopa was 9.0 ± 4.0 ng/mL, Tmax was 41.4 ± 40.2 min, and area under the blood concentration-time curve up to 4 h (AUCFemale, aging, difference formulations of DCI, or lower body weight independently contributes to increased AUC

In this paper, we consider the compressible fluid model of Korteweg type which can be used as a phase transition model. It is shown that the system admits a unique, global strong solution for small initial data in $\mathbb R^N$, $N \geq 3$. In this study, the main tools are the maximal $L_p$-$L_q$ regularity and $L_p$-$L_q$ decay properties of solutions to the linearized equations.