Clinico-imaging features of subjects at risk of Lewy body disease in NaT-PROBE baseline analysis.

Individuals with prodromal symptoms of Lewy body disease (LBD), such as rapid eye movement sleep behavior disorder (RBD), often showed imaging defects similar to patients with Parkinson's disease and dementia with Lewy bodies. We examined dopamine transporter (DaT) single-photon-emission computed tomography (SPECT) and metaiodobenzylguanidine (MIBG) scintigraphy in 69 high-risk subjects with ≥2 prodromal symptoms (dysautonomia, hyposmia, and probable RBD) and 32 low-risk subjects without prodromal symptoms, whom were identified through a questionnaire survey of health checkup examinees. The high-risk subjects had significantly worse scores on Stroop test, line orientation test, and the Odor Stick Identification Test for Japanese than the low-risk subjects. The prevalence of abnormalities on DaT-SPECT was higher in the high-risk group than in the low-risk group (24.6% vs. 6.3%, p = 0.030). A decreased uptake on DaT-SPECT was associated with motor impairment, and MIBG scintigraphy defects were associated with hyposmia. The simultaneous evaluation of DaT-SPECT and MIBG scintigraphy may capture a wide range of individuals with prodromal LBD.

Longitudinal analysis of premotor anthropometric and serological markers of Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder in which nonmotor symptoms, such as constipation and hyposmia, precede the onset of motor symptoms by 20 years. The aim of this study was to identify biomarkers at the premotor stage of PD. We assessed the differences in longitudinal changes in anthropometric and serological indices obtained from health check-up data before and after the onset of motor symptoms between male and female PD patients and healthy subjects. We enrolled 22 male and 23 female PD patients and 60 male and 60 female healthy controls. A mixed-effects model was used to estimate the trajectory of each clinical marker over the years before and after motor symptoms onset in the PD subjects, which were then compared with the trajectories of the healthy controls. The results showed a premotor blood pressure increase in female PD patients and premotor decreases in haematocrit, total cholesterol and low-density lipoprotein cholesterol in the male patients. Our results indicated that blood pressure, haematocrit and serum cholesterol levels are potential premotor markers of PD. Additionally, the changes in anthropometric and serological indices before PD motor symptoms onset were sex specific.

Subjects at risk of Parkinson's disease in health checkup examinees: cross-sectional analysis of baseline data of the NaT-PROBE study.

INTRODUCTION: The present study aimed to survey the prevalence of prodromal symptoms of Parkinson's disease (PD) in Japanese health checkup examinees, for identifying at-risk subjects. METHODS: We conducted a questionnaire survey of annual health checkup examinees without neurological symptoms using the following self-reported questionnaires: Japanese version of the Scale for Outcomes in Parkinson's disease for Autonomic Symptoms (SCOPA-AUT); Self-administered Odor Question (SAOQ); REM Sleep Behavior Disorder Screening Scale (RBDSQ); Beck Depression Inventory-Second Edition (BDI-II); Epworth Sleepiness Scale (ESS); and Physical Activity Scale for the Elderly (PASE). The presence of prodromal symptoms was determined using the 90th percentile threshold of each questionnaire. Subjects ≥ 50 years of age with ≥ 2 core prodromal symptoms (dysautonomia, hyposmia, and RBD), were classified as at risk. RESULTS: Between March 2017 and March 2018, 4,953 participants sufficiently answered the questionnaires. Among 2,726 subjects ≥ 50 years of age, 155 were classified as at risk. These subjects had worse values of BDI-II (12.0 ± 8.3 vs. 4.4 ± 3.8, p < 0.001) and ESS (9.6 ± 5.0 vs. 6.3 ± 3.2, p < 0.001), in addition to SCOPA-AUT, SAOQ, and RBDSQ. Male at-risk subjects showed lower values of hemoglobin (14.8 ± 1.3 vs. 15.0 ± 1.1, p = 0.032) and low density lipoprotein cholesterol (114.5 ± 30.3 vs. 123.0 ± 28.9, p = 0.004) than the examinees reporting no prodromal symptoms. CONCLUSION: Approximately 6% of the population aged 50 years or older was at risk for PD. Male at-risk subjects had mild hematological and metabolic changes relevant to PD.

Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials.

BACKGROUND: Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, hereditary neuromuscular disease characterized by muscle atrophy, weakness, contraction fasciculation, and bulbar involvement. Although the causative gene, androgen receptor, has been identified, the development of novel therapeutics for SBMA is incomplete. In this study, the efficacy and safety of leuprorelin acetate administration for patients with SBMA, using the pooled data of two randomized-controlled trials, was studied. METHODS: Two randomized double-blinded studies (JASMITT-06DB and JASMITT-11DB) were done as multicentric, investigator-initiated clinical trials in Japan. In both studies, eligible patients were randomly assigned 1:1 to receive leuprorelin acetate administration once per 12 weeks for 48 weeks. The primary endpoint was the longitudinal change of pharyngeal barium residues from the baseline data measured with videofluorographic swallowing analyses. The pooled analysis plan was decided upon after the 06B study was finished and before the 11DB study began. RESULTS: The primary endpoint difference between the leuprorelin group and the placebo group was pharyngeal barium residue after initial swallowing, - 4.12% (95% CI, - 8.40-0.15; p = 0.058). The primary endpoint of this study does not reach significant results, although inter-group differences of pharyngeal barium residues after the initial swallowing indicated that leuprorelin acetate may be effective at each assessment point in both study groups. CONCLUSIONS: The efficacy of leuprorelin acetate for patients with SBMA was statistically similar in two randomized-controlled trials, and suggested that leuprorelin acetate may be effective and safe. Further investigations are needed to clarify the promising efficacy of the drug.

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. METHODS: The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. FINDINGS: 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727). INTERPRETATION: 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. FUNDING: Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.

The profile of motor unit number estimation (MUNE) in spinal and bulbar muscular atrophy.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat in the androgen receptor (AR) gene. The fundamental histopathological finding of this disease is an extensive loss of lower motor neurons in the spinal cord and brainstem. It is, however, difficult to evaluate clinically the degree of motor neuron degeneration, which stresses the need for biomarkers to detect the remaining neuronal function. METHODS: The authors performed motor unit number estimation (MUNE) in 52 patients with SBMA, to investigate whether this method could be a potential biomarker of SBMA, and re-evaluated MUNE 1 year later in a subgroup of the patients. RESULTS: The number of functioning motor units was remarkably reduced in patients with SBMA compared with controls, and was correlated with both ipsilateral grip power and disease duration. A longitudinal analysis demonstrated a further reduction in motor units within 1 year. CONCLUSIONS: The results suggest that MUNE is an electrophysiological parameter that reflects the severity and progression of motor neuron degeneration in patients with SBMA.

Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). Animal studies have shown that the pathogenesis of SBMA is dependent on serum testosterone level. This study is aimed at evaluating the efficacy and safety of androgen deprivation by leuprorelin acetate in patients with SBMA. METHODS: Fifty SBMA patients underwent subcutaneous injections of leuprorelin acetate or placebo in a randomized, placebo-controlled trial for 48 weeks, followed by an open-label trial for an additional 96 weeks, in which 19 patients of the leuprorelin group and 15 of the placebo group received leuprorelin acetate. The patients who did not participate in the open-label trial were also followed up for the 96-week period (UMIN000000474). RESULTS: Leuprorelin acetate significantly extended the duration of cricopharyngeal opening in videofluorography and decreased mutant AR accumulation in scrotal skin biopsy. The patients treated with leuprorelin acetate for 144 weeks exhibited significantly greater functional scores and better swallowing parameters than those who received placebo. Autopsy of one patient who received leuprorelin acetate for 118 weeks suggested that androgen deprivation inhibits the nuclear accumulation or stabilization, or both, of mutant AR in the motor neurons of the spinal cord and brainstem. INTERPRETATION: These observations suggest that administration of leuprorelin acetate suppresses the deterioration of neuromuscular impairment in SBMA by inhibiting the toxic accumulation of mutant AR. The results of this phase 2 trial support the start of large-scale clinical trials of androgen deprivation for SBMA.

Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. Because the progression of SBMA is slow, it is plausible to identify biomarkers that monitor disease course for therapeutic development. To verify whether the 6-min walk test (6MWT) is a biomarker of SBMA, we performed the 6MWT in 35 genetically confirmed patients and in 29 age-matched healthy controls. The walk distance covered within 6 min (6MWD) was significantly less in SBMA than it was in controls (323.3 +/- 143.9 m and 637.6 +/- 94.2 m, respectively; P < 0.001). In test-retest analysis, the intraclass correlation coefficient for the 6MWD was high in SBMA patients (r = 0.982). In a 1-year follow-up the 6MWD significantly decreased at a rate of 11.3% per year. Our observations suggest that the 6MWT is a biomarker that can be used to monitor progression of motor impairment in SBMA.

Molecular genetics and biomarkers of polyglutamine diseases.

Polyglutamine diseases are hereditary neurodegenerative disorders caused by an abnormal expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract. To date, nine polyglutamine diseases are known: Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA) and six forms of spinocerebellar ataxia (SCA). The diseases are inherited in an autosomal dominant fashion except for SBMA, which shows an X-linked pattern of inheritance. Although the causative gene varies with each disorder, polyglutamine diseases share salient genetic features as well as molecular pathogenesis. CAG repeat size correlates well with the age of onset in each disease, shows both somatic and germline instability, and has a strong tendency to further expand in successive generations. Aggregation of the mutant protein followed by the disruption of cellular functions, such as transcription and axonal transport, has been implicated in the etiology of neurodegeneration in polyglutamine diseases. Although animal studies have provided promising therapeutic strategies for polyglutamine diseases, it remains difficult to translate these disease-modifying therapies to the clinic. To optimize "proof of concept", the process for testing candidate therapies in humans, it is of importance to identify biomarkers which can be used as surrogate endpoints in clinical trials for polyglutamine diseases.