Noise Pareidolia Test in Parkinson's Disease and Atypical Parkinsonian Syndromes: A Retrospective Study.

INTRODUCTION: Pareidolias, or visual misperceptions, are a non-motor symptom of Parkinson's disease (PD) with unclear pathophysiology. The noise pareidolia test (NPT) is a tool for screening pareidolias. The usefulness of the NPT in differentiating PD from atypical parkinsonian syndromes (APS) is also unknown. METHODS: We retrospectively investigated 74 patients with PD and 18 patients with APS who took the NPT. Correlations between the number of pareidolic responses, gray matter volume, and cerebral blood flow were also examined in the patients with PD. RESULTS: The median number of pareidolic responses in patients with PD and patients with APS was 0 (interquartile range (IQR): 0-3) and 0 (IQR: 0-1), respectively, and tended to be higher in patients with PD than in those with APS (p = 0.077). It was significantly higher in patients with PD who had hallucinations (2; IQR: 0-9) (p = 0.016). The area under the receiver operating characteristic curve for the number of pareidolic responses in the NPT was 0.62 when used to differentiate PD and APS, and the optimal cutoff number of pareidolic responses was 2/3. Sensitivity and specificity were 25.7% and 100%, respectively. In the PD group, the number of pareidolic responses was correlated with age (r = 0.27; p = 0.021) and the Frontal Assessment Battery (FAB) score (r = -0.34; p = 0.0099). Magnetic resonance imaging showed no significant correlation between the number of pareidolic responses and the volume of focal gray matter. On cerebral hypoperfusion mapping, the left parietal lobe had a significant correlation with the number of pareidolic responses (r = 0.35; p = 0.027). CONCLUSION: The number of pareidolic responses in NPT was suggested to be useful as a red flag to rule out APS in differentiating PD from APS. In PD without dementia, the number of pareidolic responses was associated with reduced blood flow in the left parietal lobe.

Japanese Mucuna pruriens (Hasshou beans) Showed Fast-acting and Long-lasting Effects in Parkinson's Disease.

Objective Mucuna pruriens (MP) is a legume whose seeds contain levodopa (LD), which has potential therapeutic effects against Parkinson's disease (PD). However, further research is needed to thoroughly evaluate its efficacy and safety for treating this condition. In this study, we analyzed the pharmacokinetics of MP grown in Japan and investigated its mechanism of action in PD. Methods MP seeds ground after roasting (containing 4.02% LD per MP powder) were used as the reagent and compared with an equivalent LD/carbidopa (CD) preparation. This clinical trial was conducted using a crossover design among PD patients attending our institution. Each patient received a single dose of 100/10 mg LD/CD tablets and 11 g of MP reagent. Results Among the seven patients with PD, MP prolonged the ON time 2-fold compared to LD/CD. The LD concentrations after MP intake were higher than those after LD/CD intake, whereas dyskinesia did not increase. An analysis of the LD metabolites showed that the 3-O-methyl-dopa/LD metabolic ratio was significantly lower after MP ingestion than after LD/CD ingestion, indicating that MP has a catechol-O-methyl transferase inhibitory effect. Conclusions This is the first report of a pharmacokinetic analysis conducted on actual patients with PD showing that MP significantly prolongs the ON time. The advantages of MP as a treatment for PD have been confirmed: it is inexpensive, as effective as LD, works faster and longer than LD, and does not increase dyskinesia.

Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation.

Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.

Predictive value of the neutrophil-to-lymphocyte ratio for treatment response in patients diagnosed with definite or probable autoimmune encephalitis/encephalopathy.

Introduction: Autoimmune encephalitis/encephalopathy (AE) is a complex and heterogeneous disease, making it difficult to predict the prognosis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential prognostic tool, but its usefulness remains a matter of debate. This study aimed to explore prognostic factors in cases of clinically definite or probable AE, including those with autoantibody-negative, or unknown status. Methods: Data on patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status, were retrospectively collected from the admission records of our department between January 2013 and December 2022. These patients were then categorized into either a good- or poor-response group, based on their short-term treatment response. Clinical characteristics, auxiliary examinations, and treatments were compared between the two groups. A multivariable logistic regression model was constructed to identify independent predictors of poor short-term treatment response by Akaike information criterion backward stepwise method. Results: A total of 31 patients were included in the final analysis, with 18 of them included in the poor-response group. In the univariable analysis, the poor-response group had a higher proportion of patients with a modified Rankin Scale (mRS) high score upon admission, female, epileptic seizures, or NLRs of 3.93 or higher than the good-response group (all p < 0.10). Furthermore, the multivariable logistic regression analysis revealed that the mRS score upon admission [OR: 5.51, 95% confidence intervals (CI): 1.29-23.50, p = 0.02], epileptic seizures (OR: 10.01, 95% CI: 1.16-86.66, p = 0.04), and NLRs of 3.93 or higher (OR: 11.37, 95% CI: 1.12-114.68, p = 0.04) were significantly associated with poor short-term treatment response. Conclusion: The NLR may play a supplementary role in predicting the short-term treatment response in patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status.

Diagnostic utility of susceptibility-weighted imaging in amyotrophic lateral sclerosis.

Susceptibility-weighted imaging (SWI) was developed as a diagnostic tool for amyotrophic lateral sclerosis (ALS). However, its sensitivity and specificity are insufficient for accurate diagnosis. Herein, we investigated a new, simple evaluation method for SWI as a diagnostic marker for ALS. We retrospectively investigated 36 patients with ALS and 19 healthy controls. The low signal intensity was semi-quantitatively evaluated on SWI using the motor cortex low intensity (MCLI) score: the sum score of the visual evaluation for the signal intensity of the bilateral primary motor cortices (orofacial, upper-limb, and lower-limb regions) from 0 (isointense) to 2 (markedly hypointense) with a total of 12 points. The mean MCLI score of two independent raters was significantly higher in ALS (median [interquartile range]; 5 [4-6]) than in controls (0 [0-1]), p < 0.0001. When the cutoff value of the MCLI score was set to 3, the area under the receiver operating characteristic curve was 0.973, and the sensitivity and specificity were 0.92 and 1.00, respectively. The MCLI score was not significantly correlated with age, disease duration, and ALS functional rating scale-revised (FRS-R), but was significantly correlated with the progression rate (∆FRS) (ρ = 0.39, p = 0.021) and upper motor neuron score (ρ = 0.51, p = 0.0014). Therefore, MCLI scoring is a useful diagnostic marker for ALS as the MCLI score was correlated with the UMN and ∆FRS scores.

[Late-Onset Dyskinesia Occurring During Antipsychotic Treatment for Schizophrenia: Management of Tardive Dyskinesia Based on the Latest Knowledge].

Tardive dyskinesia is a drug-induced involuntary movement related to long-term use of dopamine receptor-blocking agents. If there is no improvement upon discontinuation or change in the causative drug, treatment needs to be initiated. The most effective drug is the vesicular monoamine transporter 2 selective inhibitor. Other drugs, such as clonazepam, amantadine, yokukansan, and Ginkgo biloba extract, may be effective in some patients. Botulinum toxin treatment and deep brain stimulation are potential treatment options for patients with tardive dyskinesia that is refractory to the aforementioned agents. Optimal treatment should be selected while monitoring for mental illnesses.

Validation of the Japanese Version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS).

Introduction: The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (PD)-Rating Scale (QUIP-RS) was developed to assess the severity of impulsive and compulsive behaviors (ICBs) in PD. We aimed to validate the Japanese version of QUIP-RS and determine the characteristics of ICBs in Japan. Methods: We translated the QUIP-RS into Japanese, back-translated it to English, and obtained confirmation from the original author that the questionnaire remained appropriate. The participants for the validation study were 161 PD patients, identified by continuous sampling at two institutions, who were diagnosed with ICBs through a semistructured interview and completed the QUIP-RS-J. Sensitivity, specificity, and cutoff values were calculated using receiver operating characteristic (ROC) curves. Interinstitutional reliability and test-retest reliability were also assessed for a subset of participants. Results: Twenty-six (16.1%) participants were diagnosed with ICB. The optimal cutoff value of the QUIP-RS-J total score was 6, with area under the curve (AUC) = 0.889 and sensitivity/specificity of 0.92/0.71. Each subscale also showed high AUC (0.89-1.00), sensitivity (0.92-1.00), and specificity (0.71-1.00). Compared with the English version, the optimal cutoff point for binge eating was higher and hypersexuality lower. The total score tended to be higher when described by an informant. Conclusion: The present study validated the Japanese version of QUIP-RS. Use of QUIP-RS-J enables standardized assessment of ICBs and can be used in clinical research, including international multicenter studies.

A single-arm open-label pilot study of brief mindfulness meditation to control impulsivity in Parkinson's disease.

BACKGROUND: Impulse control disorders are detrimental neuropsychiatric symptoms of Parkinson's disease. Increased impulsivity is a predisposing factor for impulse control disorders and should therefore be controlled. Recently, mindfulness meditation as a non-drug therapy has been reported to be useful in improving neuropsychiatric symptoms, such as impulsivity. METHODS: We performed a prospective single-arm, open-label pilot trial to investigate the effectiveness of mindfulness meditation to control impulsivity in patients with Parkinson's disease (UMIN clinical trials registry: UMIN000037779). RESULTS: Twenty patients with Parkinson's disease were enrolled in an 8-week mindfulness meditation program. As a primary outcome, we investigated whether the score of the Barratt Impulsiveness Scale (BIS-11) was significantly reduced after the intervention. As an exploratory examination, functional connectivity changes were also assessed by resting-state functional magnetic resonance imaging. After the intervention, the BIS-11 score was decreased from 59.5 [55.6, 63.3] (mean [95% confidence interval]) to 55.2 [50.3, 60.1] (ΔBIS-11: -4.2, [-7.5, -0.9]). Functional connectivity was increased in the default mode network (DMN) at a cluster including the precuneus, posterior cingulate gyrus, and left posterior lobe (false discovery rate-adjusted p [FDR-p] = 0.046) and in the right frontoparietal network (FPN) at the medial frontal lobe (FDR-p = 0.039). CONCLUSIONS: This open-label, single-arm pilot study provided preliminary data for mindfulness meditation to control the impulsivity of patients with PD. A brief mindfulness meditation program may be effective in controlling impulsivity in PD and may change the functional connectivity of the DMN and right FPN.

Preventive effect of a heparinoid-containing product on the application site reaction of the rotigotine transdermal patch in Parkinson's disease: A pilot randomized clinical trial (the SkinHeRo study).

INTRODUCTION: The rotigotine transdermal patch (RTP) is a dopamine agonist used to treat Parkinson's disease (PD) but is sometimes discontinued because of application site reactions (ASRs). We aimed to investigate the effect of a heparinoid-containing product (HCP) for preventing ASRs due to the RTP by conducting a randomized controlled pilot trial. METHODS: Twenty patients with idiopathic non-demented PD were randomized to the skin care group using a HCP (group H) and the non-skin care group (group N). The primary outcome was the change in the baseline Skindex-16 score (ΔSkindex-16) at week 4. In addition, skin symptoms were also evaluated using the Dermatology Life Quality Index (DLQI) and International Contact Dermatitis Research Group (ICDRG) system for clinical scoring allergic patch test reactions up to week 8. RESULTS: The ΔSkindex-16 score at week 4 tended to be lower in group H than in group N, although the difference was not statistically significant (-1.5 ± 2.0 vs 1.3 ± 10.9, p = 0.53). When the patients with baseline Skindex-16 scores ≥ 7 were excluded, the ΔSkindex-16 at week 4 was significantly lower in group H (-1.5 ± 2.0 vs 6.1 ± 8.6, p = 0.042). The DLQI also tended to be lower in group H at weeks 4 and 8, but not significantly (p = 0.066 and p = 0.077, respectively). The ICDRG score at week 4 was significantly lower in group H (p = 0.044). CONCLUSION: We suggest that the HCP has a preventive effect against ASRs cause by the RTP.

Increased large-scale inter-network connectivity in relation to impulsivity in Parkinson's disease.

Impulsivity is a neuropsychiatric feature of Parkinson's disease (PD). We investigated the pathophysiology of impulsivity in PD using resting-state functional magnetic resonance imaging (rs-fMRI). We investigated 45 patients with idiopathic PD and 21 healthy controls. Based on Barratt Impulsiveness Scale (BIS-11) score, PD patients were classified as higher (PD-HI) or lower impulsivity (PD-LI). Functional connectivity (FC) between various large-scale brain networks were analysed using the CONN toolbox. FC between the right frontoparietal network (FPN) and medial visual network (MVN) was significantly higher in PD-HI patients than PD-LI patients (false discovery rate [FDR]-adjusted p = 0.0315). FC between the right FPN and MVN had a significant positive correlation with total BIS-11 score (FDR-adjusted p = 0.010) and the attentional impulsivity (FDR-adjusted p = 0.046) and non-planning impulsivity subscale scores (FDR-adjusted p = 0.018). On the other hand, motor impulsivity subscale score had a significant negative correlation with the FC between the default-mode and salience networks (right supramarginal gyrus, FDR-adjusted p = 0.018; anterior cingulate cortex, FDR-adjusted p = 0.027); this trend was observed in healthy controls. The attentional and non-planning impulsivity, regarded as 'cognitive' impulsivity, may be associated with dysfunction in integration of perceptual information and flexible cognitive control in PD.

Migration of a Percutaneous Endoscopic Gastrojejunostomy Tube into the Colon with Small Intestinal Telescoping.

Continuous duodenal levodopa/carbidopa intestinal gel delivery by a gastrostomy infusion system improves control of Parkinson's disease. The overall complication rates of percutaneous endoscopic gastrojejunostomy were reported to be 41% and 59% for immediate and delayed adverse events, respectively. A 72-year-old woman underwent percutaneous endoscopic gastrojejunostomy using the delivery system noted above. Abdominal pain and vomiting occurred 3 months later. Esophagogastroduodenoscopy showed a longitudinal ulcer extending from the lower gastric body to the ileum end, with small intestinal telescoping. Colonoscopy showed a large bezoar of food residue that was attached around the tip of the tube, reaching the ascending colon, which may have acted as an anchor. Thus, the gastric antrum and small intestine were shortened with telescoping. This complication was resolved by crushing the bezoar with forceps during colonoscopy and can be prevented by consuming a fiber-free diet and periodic exchanges of the tube using esophagogastroduodenoscopy.

Effects of soybean ingestion on pharmacokinetics of levodopa and motor symptoms of Parkinson's disease--In relation to the effects of Mucuna pruriens.

Mucuna pruriens is a levodopa-containing legume and its favorable effects on motor complications in Parkinson disease patients have been reported. The aim of this study was to investigate the effects of another legume, soybeans, on the pharmacokinetics and metabolism of levodopa. Seven parkinsonian patients with the wearing-off phenomenon and dyskinesia and five healthy volunteers participated in this study. We conducted a crossover study of the clinical effects on the participants before and after taking either levodopa (100mg)/carbidopa (10mg) only (LD/CD) or levodopa/carbidopa with 11 g of ground soybeans (LD/CD/soy). Parkinsonism and dyskinesia before and after ingestion of these substances were evaluated using UPDRS part III, the modified Abnormal Involuntary Movement Scale (mAIMS) and a self-rating scale. The concentrations of plasma levodopa and its major metabolites were measured by high-performance liquid chromatography. Clinical assessment and blood sampling were conducted before and three hours after the ingestion of ground soybeans. When the patients took LD/CD/soy, they had a significantly longer on-period (p=0.028) and a lower mAIMS score (p<0.001). From the comparison of the results of pharmacokinetic study before and after taking LD/CD or LD/CD/soy, the estimated marginal mean (EMM) of HVA after LD/CD/soy increased in the PD group. EMMs of 3-OMD after LD/CD/soy significantly decreased both in PD patients and healthy controls. These results indicate that soy partly increased the bioavailability of levodopa and suppressed levodopa degradation through COMT. Soybeans may have favorable effects on the motor complications occurring under current levodopa therapy. Further investigation to clarify the mechanism underlying such effects is required.

Ultrasonography of the diaphragm in amyotrophic lateral sclerosis: clinical significance in assessment of respiratory functions.

Our objective was to evaluate diaphragm thicknesses during respiration by ultrasonography, and compare with conventional measurements of respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Thirty-six consecutive ALS patients and 19 age-matched healthy volunteers participated. Ultrasonography of the diaphragm in the zone of apposition was performed. Maximal diaphragm thickness during the maximal inspiratory effort (DTmax) and minimum diaphragm thickness at the end expiratory position (DTmin) were measured using ultrasonography. The thickening ratio (TR), defined as the ratio of DTmin to DTmax, was calculated. All patients underwent conventional pulmonary function testing. Arterial blood gas analysis was also performed. The diaphragm was clearly identifiable by ultrasonography. DTmax, DTmin and the TR were all significantly decreased in ALS patients with %VC (vital capacity) < 80, compared with those in either ALS patients with %VC ≥ 80 or healthy controls. DTmax, DTmin and the TR were all significantly correlated with %VC. In addition, significant inverse correlations were found between all three parameters and pCO(2). The inter-observer reliability of measurements of diaphragm thickness was high. In conclusion, sonography of the diaphragm can provide additional or complementary information for assessing respiratory functions in patients with ALS.