METHODS: Two hundred subjects (104 patients, 96 controls) underwent extensive clinical phenotyping. Stool samples were analyzed using 16S rRNA gene sequencing. Fecal metabolomics were performed using two platforms, nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry.
RESULTS: Fecal microbiome and metabolome composition in PD was significantly different from controls, with the largest effect size seen in NMR-based metabolome. Microbiome and NMR-based metabolome compositional differences remained significant after comprehensive confounder analyses. Differentially abundant fecal metabolite features and predicted functional changes in PD versus controls included bioactive molecules with putative neuroprotective effects (eg, short chain fatty acids [SCFAs], ubiquinones, and salicylate) and other compounds increasingly implicated in neurodegeneration (eg, ceramides, sphingosine, and trimethylamine N-oxide). In the PD group, cognitive impairment, low body mass index (BMI), frailty, constipation, and low physical activity were associated with fecal metabolome compositional differences. Notably, low SCFAs in PD were significantly associated with poorer cognition and low BMI. Lower butyrate levels correlated with worse postural instability-gait disorder scores.
INTERPRETATION: Gut microbial function is altered in PD, characterized by differentially abundant metabolic features that provide important biological insights into gut-brain pathophysiology. Their clinical relevance further supports a role for microbial metabolites as potential targets for the development of new biomarkers and therapies in PD. ANN NEUROL 2021;89:546-559.
PATIENTS AND METHODS: We analysed 1748 admissions for fever in 315 Singapore children with non-HR acute lymphoblastic leukaemia (ALL) (MS2003, n = 183; MS2010, n = 132), comprising 76% of the total cohort (n = 413), to study the impact of these changes.
RESULTS: The new 2010-PVa which has no doxorubicin, was associated with significantly fewer hospitalisations due to fever (0.08 versus 0.30 admissions per block [A/blk], p
OBJECTIVE: To assess knowledge and perceptions regarding PD in a large multiethnic urban Asian cohort of patients and caregivers.
METHODS: We conducted a survey at a university hospital neurology clinic, using a novel Knowledge and Perception of Parkinson's Disease Questionnaire (KPPDQ).
RESULTS: The KPPDQ had satisfactory psychometric properties among patients and caregivers. Five hundred subjects were recruited with a 97% response rate (211 patients, 273 caregivers). Non-motor symptoms such as urinary problems, visual hallucinations and pain were relatively poorly recognized. Many (≈ 50-80%) respondents incorrectly believed that all PD patients experience tremor, that PD is usually familial, and that there is a cure for PD. About one-half perceived PD to be caused by something the patient had done in the past, and that PD medications were likely to cause internal organ damage. Issues of stigma/shame were relevant to one-third of patients, and 70% of patients perceived themselves to be a burden to others. Two-thirds of participants felt that PD imposed a heavy financial toll. Participants were about equally divided as to whether they would consider treatment with deep brain stimulation, tube feeding or invasive ventilation. Over three-quarters of patients expressed a preference to die at home.
CONCLUSIONS: Important knowledge gaps, misperceptions and perspectives on PD were identified, highlighting the need for further efforts to raise awareness and provide accurate information regarding PD, and to address patient's and caregivers' needs and preferences.
METHODS: We randomised 429 children with newly diagnosed ALL to 15-minute vs 3-hour infusion for the first dose of VCR to study if prolonging the first dose of VCR infusion improved response. In a subgroup of 115 B-ALL and 20 T-ALL patients, we performed VCR plasma (n = 135 patients) and intracellular (n = 66 patients) pharmacokinetic studies. The correlations between pharmacokinetic parameters and intracellular VCR levels with early treatment response, final outcome and ABCB1 genotypes were analysed.
RESULTS: There was no significant difference between 15-minute and 3-hour infusion schedules in median Day 8 peripheral or bone marrow blast response. Plasma VCR pharmacokinetic parameters did not predict outcome. However, in B-ALL, Day 33 minimal residual disease (MRD) negative patients and patients in continuous complete remission had significantly higher median intracellular VCR24h levels (P = .03 and P = .04, respectively). The median VCR24h intracellular levels were similar among the common genetic subtypes of ALL (P = .4). Patients homozygous for wild-type ABCB1 2677GG had significantly higher median intracellular VCR24h (P = .04) than 2677TT.
CONCLUSION: We showed that in childhood B-ALL, the intracellular VCR24h levels in lymphoblasts affected treatment outcomes. The intracellular VCR24h level was independent of leukaemia subtype but dependent on host ABCB1 G2677T genotype.
METHODS: In this three-year longitudinal study, 125 subjects (77 PD patients and 48 spousal/sibling controls) underwent clinical, biochemical and body composition assessments using dual-energy X-ray absorptiometry.
RESULTS: Patients were older than controls (65.6 ± 8.9 vs. 62.6 ± 7.1, P = 0.049), with no significant differences in gender, comorbidities, dietary intake and physical activity. Clinically significant weight loss (≥5% from baseline weight) was recorded in 41.6% of patients, with a doubling of cases (6.5 to 13.0%) classified as underweight at study end. Over three years, patients demonstrated greater reductions in BMI (mean -1.2 kg/m2, 95%CI-2.0 to -0.4), whole-body fat percentage (-2.5% points, 95%CI-3.9 to -1.0), fat mass index (FMI) (-0.9 kg/m2, 95%CI-1.4 to -0.4), visceral fat mass (-0.1 kg, 95%CI-0.2 to 0.0), and subcutaneous fat mass (-1.9 kg, 95%CI-3.4 to -0.5) than in controls, with significant group-by-time interactions after adjusting for age and gender. Notably, 31.2% and 53.3% of patients had FMI<3rd (severe fat deficit) and <10th centiles, respectively. Muscle mass indices decreased over time in both groups, without significant group-by-time interactions. Multiple linear regression models showed that loss of body weight and fat mass in patients were associated with age, dyskinesia, psychosis and constipation.
CONCLUSIONS: We found progressive loss of weight in PD patients, with greater loss of both visceral and subcutaneous fat, but not muscle, compared to controls. Several associated factors (motor and non-motor disease features) were identified for these changes, providing insights on possible mechanisms and therapeutic targets.
METHODS: 93 patients and 78 spousal/sibling controls underwent comprehensive assessment of diet, clinical status, muscle strength/performance, frailty, body composition (using dual-energy X-ray absorptiometry), and serum levels of neurogastrointestinal hormones and inflammatory markers.
RESULTS: PD patients were older than controls (66.0 ± 8.5 vs. 62.4 ± 8.4years, P = 0.003). Mean body mass index (24.0 ± 0.4 vs. 25.6 ± 0.5kg/m2, Padjusted = 0.016), fat mass index (7.4 ± 0.3 vs. 9.0 ± 0.3kg/m2, Padjusted<0.001), and whole-body fat percentage (30.7 ± 0.8 vs. 35.7 ± 0.9%, Padjusted<0.001) were lower in patients, even after controlling for age and gender. There were no between-group differences in skeletal muscle mass index and whole-body bone mineral density. Body composition parameters did not correlate with disease duration or motor severity. Reduced whole-body fat percentage was associated with higher risk of motor response complications as well as higher levels of insulin-growth factor-1 and inflammatory markers. PD patients had a higher prevalence of sarcopenia (17.2% vs. 10.3%, Padjusted = 0.340) and frailty (69.4% vs. 24.2%, Padjusted = 0.010). Older age and worse PD motor severity were predictors of frailty in PD.
CONCLUSIONS: We found reduced body fat with relatively preserved skeletal muscle mass, and a high prevalence of frailty, in PD. Further studies are needed to understand the patho-mechanisms underlying these alterations.
METHODS: A multi-ethnic cohort of PD patients from Malaysia (n = 499, including 185 Malays) were tested using a next-generation sequencing-based PD gene panel. The prevalence and clinico-radiological features of patients with the PINK1 p. Leu347Pro mutation are described. This mutation has previously only been reported in people of Filipino or Chamorro (native Guamanian) ancestry.
RESULTS: Homozygous p. Leu347Pro mutations were found in five unrelated Malay patients, yielding a prevalence of 6.9% among Malays with PD onset ≤50 years (2.7% of the Malay group overall). This variant was not detected in the homozygous state in 300 Malay controls, but two were heterozygous carriers (0.67%) indicating a relatively high population frequency in keeping with the high frequency of PARK-PINK1 among Malay patients. Interesting clinical features were observed, e.g., differences in the age at PD onset and clinical progression, despite having the same point mutations. Previously unreported brain MRI abnormalities involving the corticospinal tract and hypothalamus, and "loss of the swallow tail" sign, were documented.
CONCLUSIONS: This report contributes to the very limited literature on PD genetics in the Malay population, and more broadly to the epidemiological, phenotypic and neuroimaging characterization of PARK-PINK1. It also further supports the pathogenicity of the p. Leu347Pro variant.
METHODS: A retrospective analysis of 2068 fever episodes during ALL therapy was used for model building and subsequent internal validation.
RESULTS: Three hundred and seventy-seven patients were treated for ALL in two institutions with comparable critical and supportive care resources. A total of 55 patients accounted for 71 admissions to the critical care unit for sepsis that led to eight septic deaths during a 16-year study period. A retrospective analysis of risk factors for sepsis enabled us to build a model focused on 13 variables that discriminated admissions requiring critical care well: area under the receiver operating characteristic curve of .82; 95% CI .76-.87, p
METHODS: Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age- and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay.
RESULTS: A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta-analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H.
CONCLUSION: This study reports that the N551K-R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.
METHODS: We prospectively characterized the clinical features and disease burden in a consecutively-recruited multi-ethnic Asian PSP cohort. Patients were extensively phenotyped using the Movement Disorder Society (MDS-PSP) clinical diagnostic criteria and the PSP-Clinical Deficits Scale (PSP-CDS). Caregiver burden was measured using the modified Zarit Burden Interview (ZBI). Investigations (neuroimaging and genetic tests) were reviewed.
RESULTS: There were 104 patients (64.4% male; 67.3% Chinese, 21.2% Indians, 9.6% Malays), consisting of 48.1% Richardson syndrome (PSP-RS), 37.5% parkinsonian phenotype (PSP-P), and 10.6% progressive gait freezing phenotype (PSP-PGF). Mean age at motor onset was 66.3 ± 7.7 years, with no significant differences between the PSP phenotypes. Interestingly, REM-sleep behaviour disorder (RBD) symptoms and visual hallucinations (considered rare in PSP) were reported in 23.5% and 22.8% of patients, respectively, and a family history of possible neurodegenerative or movement disorder in 20.4%. PSP-CDS scores were highest (worst) in PSP-RS; and correlated moderately with disease duration (rs = 0.45, P
PATIENTS AND METHODS: Three hundred sixty-nine children with favorable-risk BCP-ALL (age 1-9 years, no extramedullary disease, and no high-risk genetics) who cleared minimal residual disease (≤0.01%) at the end of remission induction were enrolled into Ma-Spore (MS) ALL trials. One hundred sixty-seven standard-risk (SR) patients (34% of Malaysia-Singapore ALL 2003 study [MS2003]) were treated with the MS2003-SR protocol and received 120 mg/m2 of anthracyclines during delayed intensification while 202 patients (42% of MS2010) received an anthracycline-free successor protocol. The primary outcome was a noninferiority margin of 1.15 in 6-year event-free survival (EFS) between the MS2003-SR and MS2010-SR cohorts.
RESULTS: The 6-year EFS of MS2003-SR and MS2010-SR (anthracycline-free) cohorts was 95.2% ± 1.7% and 96.5% ± 1.5%, respectively (P = .46). The corresponding 6-year overall survival was 97.6% and 99.0% ± 0.7% (P = .81), respectively. The cumulative incidence of relapse was 3.6% and 2.6%, respectively (P = .42). After adjustment for race, sex, age, presenting WBC, day 8 prednisolone response, and favorable genetic subgroups, the hazard ratio for MS2010-SR EFS was 0.98 (95% CI, 0.84 to 1.14; P = .79), confirming noninferiority. Compared with MS2003-SR, MS2010-SR had significantly lower episodes of bacteremia (30% v 45.6%; P = .04) and intensive care unit admissions (1.5% v 9.5%; P = .004).
CONCLUSION: In comparison with MS2003-SR, the anthracycline-free MS2010-SR protocol is not inferior and was less toxic as treatment for favorable-risk childhood BCP-ALL.
OBJECTIVES: Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients.
METHODS: Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients.
RESULTS: We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN.
CONCLUSIONS: The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.
MATERIALS AND METHODS: Eight hundred and twenty-eight subjects (404 PD patients, and 424 age and gender-matched control subjects without neurological disorders) were recruited. Genotyping was done by Taqman® allelic discrimination assay on an Applied Biosystems 7500 Fast Real-Time PCR machine.
RESULTS: The heterozygous A419V genotype was found in only 1 patient with PD, compared to 3 in the control group (0.4% vs 1.3%), giving an odds ratio of 0.35 (95% confidence interval (CI), 0.01 to 3.79; P = 0.624).
CONCLUSION: A419V is not an important LRRK2 risk variant in our Asian cohort of patients with PD. Our data are further supported by a literature review which showed that 4 out of 6 published studies reported a negative association of this variant in PD.