Clinical Applicability of Automated Hematology Analyzer Research Parameters for Disease Diagnosis: a Reference Interval Study.

BACKGROUND: We established reference intervals for research parameters of complete blood cell count and examined their usefulness for diagnosing certain diseases. METHODS: Reference intervals for 26 basic and 38 research parameters were established for 3,457 and 1,325 men and 2,742 and 830 women aged 20 - 59 and ≥ 60 years, respectively. Research parameter values for patients with iron deficiency anemia (IDA), appendicitis, sepsis, and myelodysplastic syndromes (MDS) were compared against gender- and age-matched reference values. RESULTS: Seven basic and 10 research parameters among men and one research parameter among women required partitioning by age. No partitioning by gender was required. Further, 67% patients with IDA showed micro red blood cell ratio values above the upper reference limits of their corresponding age and gender subgroups; 3% and 5% patients with appendicitis showed immature granulocyte percentages and counts above the upper reference limits, respectively; 12% - 42% of patients with sepsis showed numerous values exceeded their reference limits, and 67% and 100% patients with MDS showed neutrophil cell complexity and structural dispersion values outside their reference ranges, respectively. CONCLUSIONS: Overall, < 60% of research parameter values were outside their reference ranges among most patients, indicating their limited diagnostic usefulness.

Dysregulation of the causative genes for hereditary parkinsonism in the midbrain in Parkinson's disease.

BACKGROUND AND OBJECTIVES: Many hereditary movement disorders with complex phenotypes without a locus symbol prefix for familial PD present as parkinsonism; however, the dysregulation of genes associated with these phenotypes in the SNpc of PD patients has not been systematically studied. METHODS: Gene set enrichment analyses were performed using 10 previously published genome-wide expression datasets obtained by laser-captured microdissection of pigmented neurons in the SNpc. A custom-curated gene set for hereditary parkinsonism consisting of causative genes (n = 78) related to disorders with a parkinsonism phenotype, but not necessarily idiopathic or monogenic PD, was constructed from the Online Mendelian Inheritance in Man database. RESULTS: In 9 of the 10 gene expression data sets, gene set enrichment analysis showed that the disease-causing genes for hereditary parkinsonism were downregulated in the SNpc in PD patients compared to controls (nominal P values <0.05 in five studies). Among the 63 leading edge subset genes representing downregulated genes in PD, 79.4% were genes without a locus symbol prefix for familial PD. A meta-gene set enrichment analysis performed with a random-effect model showed an association between the gene set for hereditary parkinsonism and PD with a negative normalized enrichment score value (-1.40; 95% CI: -1.52∼-1.28; P < 6.2E-05). CONCLUSION: Disease-causing genes with a parkinsonism phenotype are downregulated in the SNpc in PD. Our study highlights the importance of genes associated with hereditary movement disorders with parkinsonism in understanding the pathogenesis of PD. © 2017 International Parkinson and Movement Disorder Society.

Exploring the Link between Chronic Kidney Disease and Alzheimer's Disease: A Longitudinal Follow-Up Study Using the Korean National Health Screening Cohort.

Chronic kidney disease (CKD) and Alzheimer's disease (AD) are common chronic diseases in the elderly population. Although a relationship between CKD and the occurrence of AD has been proposed, previous research results have been disputed, and further investigation is necessary to confirm this relationship. In this longitudinal follow-up study, we examined data from the Korean National Health Insurance Service-Health Screening Cohort, consisting of 15,756 individuals with CKD and 63,024 matched controls aged ≥40 years who received health check-ups between 2002 and 2019. Overlap-weighted Cox proportional hazard regression models were exploited to calculate hazard ratios (HRs) for the association between CKD and AD. During the monitoring period, individuals with CKD had a greater incidence of AD than those without CKD (15.80 versus 12.40 per 1000 person years). After accounting for various factors, CKD was significantly associated with a 1.14-fold increased likelihood of developing AD, with a 95% confidence interval ranging from 1.08 to 1.20. In subgroup analysis, this relationship persisted irrespective of age (≥70 or <70), sex, income, smoking status, alcohol consumption, place of residence, or fasting blood glucose level. Additionally, the association between CKD and AD was still evident among patients who were overweight or obese, those with normal blood pressure or cholesterol levels, and those without any other health conditions or with a CCI score of ≥2. These results suggest that CKD could increase the probability of developing AD in the Korean adult population irrespective of demographic or lifestyle conditions. This may make it challenging to predict AD in patients with CKD, emphasizing the importance of frequent AD screening and management.

Risk for Esophageal Cancer Based on Lifestyle Factors-Smoking, Alcohol Consumption, and Body Mass Index: Insight from a South Korean Population Study in a Low-Incidence Area.

Esophageal cancer constitutes a global public health challenge. However, South Korean population-specific information on the association of lifestyle (smoking, alcohol consumption, and obesity status) with esophageal cancer risk is sparse. This nested case-control study analyzed the Korean national health screening cohort data (2002-2019) of 1114 patients with esophageal cancer and 4456 controls (1:4 propensity-score matched for sex, age, income, and residential region). Conditional and unconditional logistic regression analyses, after adjustment for multiple covariates, determined the effects of lifestyle factors on esophageal cancer risk. Smoking and alcohol consumption increased the esophageal cancer risk (adjusted odds ratio [95% confidence interval]: 1.37 [1.15-1.63] and 1.89 [1.60-2.23], respectively). Overweight (body mass index [BMI] ≥ 23 to <25 kg/m2), obese I (BMI ≥ 25 to <30 kg/m2), or obese II (BMI ≥ 30 kg/m2) categories had reduced odds of esophageal cancer (0.76 [0.62-0.92], 0.59 [0.48-0.72], and 0.47 [0.26-0.85], respectively). In the subgroup analyses, the association of incident esophageal cancer with smoking and alcohol consumption persisted, particularly in men or those aged ≥55 years, whereas higher BMI scores remained consistently associated with a reduced esophageal cancer likelihood across all age groups, in both sexes, and alcohol users or current smokers. Underweight current smokers exhibited a higher propensity for esophageal cancer. In conclusion, smoking and alcohol drinking may potentially increase the risk, whereas weight maintenance, with BMI ≥ 23 kg/m2, may potentially decrease the risk, for esophageal cancer in the South Korean population. Lifestyle modification in the specific subgroups may be a potential strategy for preventing esophageal cancer.

Incident Rheumatoid Arthritis Following Statin Use: From the View of a National Cohort Study in Korea.

Safety issues regarding the potential risk of statins and incident rheumatoid arthritis (RA) have been raised, but the existing data are largely based on Caucasian populations, and continue to have biases and require further validation in Asian populations. Here, we aimed to verify the risk of RA depending on the duration of previous statin use and statin types using a large-scale, nationwide database. This study enrolled 3149 patients with RA and 12,596 matched non-RA participants from the national health insurance database (2002−2015), and investigated their statin prescription histories for two years before the index date. Propensity score overlap-weighted logistic regression was applied after adjusting for multiple covariates. The prior use of any statins and, specifically, the long-term use of lipophilic statins (>365 days) were related to a lower likelihood of developing RA ((odds ratio (OR) = 0.73; 95% confidence intervals (CI) = 0.63−0.85, p < 0.001) and (OR = 0.71; 95% CI = 0.61−0.84, p < 0.001), respectively). Subgroup analyses supported these preventive effects on RA in those with dyslipidemia, independent of sex, age, smoking, alcohol use, hypertension, and hyperglycemia. Hydrophilic statin use or short-term use showed no such associations. Our study suggests that prior statin use, especially long-term lipophilic statin use, appears to confer preventive benefits against RA.

Association between Migraines and Prior Proton Pump Inhibitor Use: A Nested Case-Control Study Using a National Health Screening Cohort.

The effect of proton pump inhibitor (PPI) use on migraine risk remains controversial. We explored the odds of migraines in relation to prior PPI use and treatment duration. Data from the Korean National Health Insurance Service-Health Screening Cohort (2002−2015) were analyzed in this nested case-control study involving 28,159 participants with incident migraines and 112,636 controls (1:4 matched by sex, age, income, and residential region). The baseline covariates were balanced by performing propensity score overlap weighting-based adjustments, and the effect of prior PPI use (past vs. current) and treatment duration (<30 and 30−365 days vs. ≥365 days) on incident migraines was evaluated using logistic regression. In past and current PPI users, prior PPI use raised the likelihood of migraines (adjusted odds ratio [95% confidence interval]: 2.56 [2.36−2.79] and 4.66 [4.29−5.06], respectively). Participants who used PPI for <30, 30−365, or ≥365 days exhibited high odds of migraines (2.49 [2.29−2.72], 4.41 [4.05−4.79], and 4.14 [3.77−4.54], respectively). Incident migraines with or without aura also increased independently of PPI use history or duration. In summary, prior PPI use, irrespective of the elapsed time since use and the duration of use, is possibly associated with incident migraines with or without aura.

Comparison of Concordance of Peptic Ulcer Disease, Non-Adenomatous Intestinal Polyp, and Gallstone Disease in Korean Monozygotic and Dizygotic Twins: A Cross-Sectional Study.

Epidemiological studies have suggested the role of multiple genetic and environmental factors in the development of non-neoplastic gastrointestinal (GI) diseases; however, little information is available on these factors in the Korean population. Therefore, this cross-sectional study explored the effect of these factors by analyzing the concordance of several benign GI disorders in 525 monozygotic twins compared to that in 122 dizygotic twins aged >20 years from the Healthy Twin Study data of the Korean Genome and Epidemiology Study (2005-2014). Chi-square test, Wilcoxon rank-sum, and binomial and multinomial logistic regression models were used for statistical analysis. There was lack of concordance of gastric/duodenal ulcers and cholelithiasis/cholangitis between monozygotic twins compared to that in dizygotic twins, suggesting that environmental factors may mediate those concordant disease expressions in monozygotic twins. The concordance of intestinal polyps in monozygotic twins was 32% lower than that in dizygotic twins (p = 0.028), indicating that the effect of genetic factors on the risk for intestinal polyp development may be low. In conclusion, the lack or low concordance of several benign GI diseases between monozygotic and dizygotic twin groups suggests the relative importance of environmental factors, indicating that these are preventable diseases.

The burden of rare damaging variants in hereditary atypical parkinsonism genes is increased in patients with Parkinson's disease.

Increased burdens of rare coding variants in genes related to lysosomal storage disease or mitochondrial pathways were reported to be associated with idiopathic Parkinson's disease. Under a hypothesis that the burden of damaging rare coding variants is increased in causative genes for hereditary parkinsonism, we analyzed the burdens of rare coding variants with a case-control design. Two cohorts of whole-exome sequencing data and a cohort of genome-wide genotyping data of clinically validated idiopathic Parkinson's disease cases and controls, which were open to the public, were used. The sequence kernel association test-optimal was used to analyze the burden of rare variants in the hereditary parkinsonism gene set, which was constructed from the Online Mendelian Inheritance in Man database through manual curation. The hereditary parkinsonism gene set consisted of 17 genes with a locus symbol prefix for familial Parkinson's disease and 75 hereditary atypical parkinsonism genes. We detected a significant association of enriched burdens of predicted damaging rare coding variants in hereditary parkinsonism genes in all three datasets. Meta-analyses of the rare variant burden test in a subgroup of gene sets revealed an association between burdens of rare damaging variants with PD in a hereditary atypical parkinsonism gene set, but not in a subgroup gene set with a locus symbol prefix for familial Parkinson's disease. Our results highlight the roles of rare damaging variants in causative genes for hereditary atypical parkinsonian disorders. We propose that Mendelian genes associated with hereditary disorders accompanying parkinsonism are involved in Parkinson's disease-related genetic networks.

Meta-Analysis of Differentially Expressed Genes in the Substantia Nigra in Parkinson's Disease Supports Phenotype-Specific Transcriptome Changes.

BACKGROUND: Studies regarding differentially expressed genes (DEGs) in Parkinson's disease (PD) have focused on common upstream regulators or dysregulated pathways or ontologies; however, the relationships between DEGs and disease-related or cell type-enriched genes have not been systematically studied. Meta-analysis of DEGs (meta-DEGs) are expected to overcome the limitations, such as replication failure and small sample size of previous studies. PURPOSE: Meta-DEGs were performed to investigate dysregulated genes enriched with neurodegenerative disorder causative or risk genes in a phenotype-specific manner. METHODS: Six microarray datasets from PD patients and controls, for which substantia nigra sample transcriptome data were available, were downloaded from the NINDS data repository. Meta-DEGs were performed using two methods, combining p-values and combing effect size, and common DEGs were used for secondary analyses. Gene sets of cell type-enriched or disease-related genes for PD, Alzheimer's disease (AD), and hereditary progressive ataxia were constructed by curation of public databases and/or published literatures. RESULTS: Our meta-analyses revealed 449 downregulated and 137 upregulated genes. Overrepresentation analyses with cell type-enriched genes were significant in neuron-enriched genes but not in astrocyte- or microglia-enriched genes. Meta-DEGs were significantly enriched in causative genes for hereditary disorders accompanying parkinsonism but not in genes associated with AD or hereditary progressive ataxia. Enrichment of PD-related genes was highly significant in downregulated DEGs but insignificant in upregulated genes. CONCLUSION: Downregulated meta-DEGs were associated with PD-related genes, but not with other neurodegenerative disorder genes. These results highlight disease phenotype-specific changes in dysregulated genes in PD.

Familial Hyperekplexia, a Potential Cause of Cautious Gait: A New Korean Case and a Systematic Review of Phenotypes

Familial hyperekplexia, also called startle disease, is a rare neurological disorder characterized by excessive startle responses to noise or touch. It can be associated with serious injury from frequent falls, apnea spells, and aspiration pneumonia. Familial hyperekplexia has a heterogeneous genetic background with several identified causative genes; it demonstrates both dominant and recessive inheritance in the α1 subunit of the glycine receptor (GLRA1), the ß subunit of the glycine receptor and the presynaptic sodium and chloride-dependent glycine transporter 2 genes. Clonazepam is an effective medical treatment for hyperekplexia. Here, we report genetically confirmed familial hyperekplexia patients presenting early adult cautious gait. Additionally, we review clinical features, mode of inheritance, ethnicity and the types and locations of mutations of previously reported hyperekplexia cases with a GLRA1 gene mutation.

A Validation Study of a Smartphone-Based Finger Tapping Application for Quantitative Assessment of Bradykinesia in Parkinson's Disease.

BACKGROUND: Most studies of smartphone-based assessments of motor symptoms in Parkinson's disease (PD) focused on gait, tremor or speech. Studies evaluating bradykinesia using wearable sensors are limited by a small cohort size and study design. We developed an application named smartphone tapper (SmT) to determine its applicability for clinical purposes and compared SmT parameters to current standard methods in a larger cohort. METHODS: A total of 57 PD patients and 87 controls examined with motor UPDRS underwent timed tapping tests (TT) using SmT and mechanical tappers (MeT) according to CAPSIT-PD. Subjects were asked to alternately tap each side of two rectangles with an index finger at maximum speed for ten seconds. Kinematic measurements were compared between the two groups. RESULTS: The mean number of correct tapping (MCoT), mean total distance of finger movement (T-Dist), mean inter-tap distance, and mean inter-tap dwelling time (IT-DwT) were significantly different between PD patients and controls. MCoT, as assessed using SmT, significantly correlated with motor UPDRS scores, bradykinesia subscores and MCoT using MeT. Multivariate analysis using the SmT parameters, such as T-Dist or IT-DwT, as predictive variables and age and gender as covariates demonstrated that PD patients were discriminated from controls. ROC curve analysis of a regression model demonstrated that the AUC for T-Dist was 0.92 (95% CI 0.88-0.96). CONCLUSION: Our results suggest that a smartphone tapping application is comparable to conventional methods for the assessment of motor dysfunction in PD and may be useful in clinical practice.

Neuroimaging studies and whole exome sequencing of PLA2G6-associated neurodegeneration in a family with intrafamilial phenotypic heterogeneity.

BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) encompasses infantile- or atypical neuroaxonal dystrophy, and adult-onset dystonia-parkinsonism. Examination of the intrafamilial phenotypic variability of PLAN by neuroimaging data and background genetic differences has not been reported. METHODS: We report clinical, genetic (whole exome sequencing data), and neuroimaging findings from a Korean PLAN family showing intrafamilial phenotypic variability. Non-synonymous single nucleotide variants (SNVs) in Mendelian disorder genes related to parkinsonism, dystonia, ataxia, dementia or neurodegeneration with brain iron accumulation were compared between affected siblings. RESULTS: The proband presented with adult-onset dystonia-parkinsonism, whereas the affected brother presented with childhood-onset atypical neuroaxonal dystrophy. In the proband, an [18F]FP-CIT PET study showed markedly reduced uptake in the whole putamen, but fluid attenuated inversion recovery and gradient echo MRI studies revealed mild hypointensities in the substantia nigra and the putamen and severe hypointensities in the pallidum. On the other hand, in the affected brother, MRI scans showed severe hypointensities in the substantia nigra and the pallidum, and a [18F]-FP-CIT PET scan was normal. Analysis of the non-synonymous SNVs that were not shared between the two family members revealed non-synonymous SNVs related to parkinsonism including a novel heterozygous mutation (p.T44N) in FBX07 (PARK15) only in the proband, and non-synonymous SNVs related to neurodegeneration with brain iron accumulation in the affected brother. CONCLUSION: Our data suggests that dopaminergic neuronal degeneration may not secondary to iron accumulation in PLAN. The burden of pathogenic SNVs may influence the intrafamilial phenotypic variability of PLAN.