Cognitive Dysfunction in Drug-induced Parkinsonism Caused by Prokinetics and Antiemetics.

The use of prokinetics/antiemetics is one of the leading causes of drug-induced parkinsonism (DIP) observed in neurology clinics. Cognitive dysfunction in DIP has recently been recognized, but pathologies related with cognitive dysfunction is unknown. Among our retrospective cohort of 385 consecutive parkinsonian patients enrolled in our parkinsonism registry, 14 patients were identified who satisfied our inclusion criteria: parkinsonism caused by prokinetics/antiemetics, existing T1-weighted 3D volumetric MR images, and normal [(18)F]-N-3-fluoropropyl-2-ß-carboxymethoxy-3-ß-(4-iodophenyl) nortropane PET scan images. For the comparison of volumetric MR data, 30 age- and sex-matched healthy individuals were included in this study. Among 14 patients with DIP, 4 patients were diagnosed with dementia, and all other patients had mild cognitive impairment (MCI). Comparisons of MR volumetric data between DIP patients with MCI and controls show that cortical gray matter volumes are reduced bilaterally in DIP (P=0.041) without changes in either total white matter volume or total intracranial volume. Among subcortical structures, the volume of the right hippocampus is reduced in DIP patients compared with controls (P=0.011, uncorrected). In DIP, cortical thickness is reduced in the bilateral lingual (P=0.002), right fusiform (P=0.032) and part of the left lateral occipital gyri (P=0.007). Our results suggests that cognitive dysfunction in DIP caused by prokinetics/antiemetics is common. Structural changes in the brain by 3D MRI may be associated with cognitive decline in DIP.

Association between eupatilin and reduction in small bowel bleeding in aspirin users and aspirin plus acid suppressant users.

BACKGROUND/AIMS: Capsule endoscopy (CE) has shown that low-dose aspirin occasionally causes small bowel (SB) bleeding. We herein evaluated the protective effects of mucoprotective agents (MPAs) on SB bleeding in aspirin users using the nationwide database of claims data from the National Health Insurance Service (NHIS). METHODS: As CE is an insured procedure, we constructed an aspirin-SB cohort using NHIS claims data, with a maximum follow- up period of 24 months. Patients with anemia, melena, or hematochezia that occurred within 4 weeks before and after performing CE were suspected to have SB bleeding. A Cox proportional hazards regression model was used to determine the risk factors for SB bleeding. Subgroup analyses were conducted among patients who used acid suppressants, such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists. RESULTS: A total of 15,542 aspirin users were included. Anticoagulant use (hazard ratio [HR], 3.22), high Charlson comorbidity index score (≥ 2) (HR, 3.54), and PPI use (HR, 2.85) were significantly associated with SB bleeding, whereas eupatilin use (HR, 0.35) was a preventive factor. SB bleeding occurred more frequently in concurrent users of acid suppressants than in nonusers (1.3% vs. 0.5%). Subgroup analysis revealed that eupatilin significantly reduced the risk of SB bleeding in aspirin users with concurrent use of acid suppressants (HR, 0.23 vs. 2.55). CONCLUSION: Eupatilin was associated with a reduced risk of SB bleeding in both aspirin users and those with concomitant use of acid suppressants. Eupatilin use should be considered for aspirin users, especially for those concomitantly taking acid suppressants.

Comorbidities and the use of comedications among patients with chronic hepatitis C in Korea: A nationwide cross-sectional study.

BACKGROUND/AIMS: Chronic hepatitis C (CHC) is the second leading cause of liver-related mortality and is more prevalent in the elderly population in Korea. Decisions to initiate treatment and selection of proper antiviral agents may be challenging among elderly patients due to relevant comorbidities, comedications, and drug-drug interaction (DDI). It may be helpful to understand the current demographic status and comorbidities of CHC patients in the country. METHODS: Patients aged ≥ 18 years and diagnosed with CHC (KCD-7 code B18.2) were extracted from the Korean Health Insurance Review & Assessment Service database in 2018. Data on comorbidities and comedications were assessed and potential DDIs were analyzed. RESULTS: A total of 50,476 patients with CHC, with a mean age of 60.3 years and 46.7% male patients were identified. The proportion of patients with cirrhosis, hepatocellular carcinoma, and liver transplantation was 6.0%, 4.1%, and 0.3%, respectively and 37.2% of patients were more than 65 years of age. The three most common comorbidities were diseases of the digestive system (83.7%), respiratory system (58.2%), and musculoskeletal system and connective tissue (57.6%). The three most common comedications were analgesics (91.6%), gastrointestinal agents (85%), and antibacterials (80.3%). Lipid-lowering agents and anticonvulsants were prescribed in 28.5% and 14.8% of patients. Rate of potential DDI for contraindication was 2.2%, 13.1%, and 15.6% with sofosbuvir/velpatasvir, ledipasvir/sofosbuvir, and glecaprevir/pibrentasvir. CONCLUSION: With the increasing age of patients with CHC, comorbidity, comedication, and potential DDI should be considered when choosing antivirals in Korea. Sofosbuvir-based regimens showed favorable DDI profiles among Korean patients.

Correlations between COMT polymorphism and brain structure and cognition in elderly subjects: An observational study.

ABSTRACT: The catechol-O-methyltransferase (COMT) gene has been noted to play an important role in individual variations in the aging process. We investigated whether COMT polymorphism could influence cognition related to white matter networks. More specifically, we examined whether methionine (Met) allele loading is associated with better individual cognitive performance. Thirty-four healthy elderly participants were recruited; each participant's COMT genotype was determined, and Korean version of Montreal Cognitive Assessment scores and a diffusion tensor image were obtained for all participants. The Met carrier group showed significantly lower mean diffusivity, axial diffusivity, and radial diffusivity values for the right hippocampus, thalamus, uncinate fasciculus, and left caudate nucleus than the valine homozygote group. The Met carrier group also scored higher for executive function and attention on the Korean version of Montreal Cognitive Assessment. Based on these results, we can assume that the COMT Met allele has a protective effect on cognitive decline contributing to individual differences in cognitive function in late life period.

Agraphia in Korean patients with early onset Alzheimer's disease.

BACKGROUND: Agraphia in Korean patients may be different from agraphia in other patients who use alphabetical writing systems due to the "visuoconstructional script" characteristics of the Korean writing system, Hangul. Patients with early onset Alzheimer's disease (EOAD) have a severe degree of hypometabolism in the parietal area, which is known to be involved in processing visuospatial function. Thus, we explored the diverse error patterns manifested in writing single syllables in Korean patients with EOAD. METHODS: A study sample of 35 patients with EOAD and 18 healthy controls (HC) performed a Hangul writing task. We analyzed the erroneous responses of the subjects according to visuoconstructional and linguistic characteristics. In addition, we evaluated the relationship between Hangul writing and the neuropsychological variables as well as the severity of dementia. RESULTS: When comparing the total number of erroneous responses between EOAD and HC groups, the performances of EOAD patients were significantly worse than those of HC. EOAD patients demonstrated visuoconstructional errors even in the early stages of the disease. Severity of dementia and multiple cognitive domains such as attention, language, immediate memory, and frontal executive functions significantly correlated with the performance of Hangul writing. CONCLUSION: Our findings suggest that patients with EOAD exhibit not only linguistic errors but also visuoconstructional manifestations of agraphia, which are associated with cognitive impairments in the multiple domains.

Is phonological-lexical representation preserved in moderate stage Alzheimer disease? Evidence from the efficacy of Korean syllabic cues.

Patients with Alzheimer disease (AD) usually experience naming difficulty due to storage and access problems in phonological-lexical representation. Investigating naming response patterns followed by cueing may help us to understand the underlying mechanism of naming deficits in AD. A total of 221 patients with mild cognitive impairment and AD [Clinical Dementia Rating (CDR) 0.5, 1, 2] were included as subjects. Sixty items of the Korean version of the Boston Naming Test were given, and upon failure, semantic/syllabic cues were verbally presented. From the results, even in the CDR 2 group, which is considered to be a moderate stage of AD, syllabic cues significantly facilitated correct responses. Our findings are in contrast with previous studies conducted with English-speaking patients, which reported that phonological-lexical representation may have been disrupted in the moderate stage of AD, and that none of the cues facilitated correct word retrieval. The difference may be ascribed to the fact that direct access to the phonological-lexical representation via syllabic cues was possible in the confrontation naming task performed by the Korean patients. It can be concluded that phonological-lexical representation in moderate stage Korean AD might be partially preserved because syllabic cues in AD patients were effective in facilitating target words.

Seoul Neuropsychological Screening Battery-dementia version (SNSB-D): a useful tool for assessing and monitoring cognitive impairments in dementia patients.

The Seoul Neuropsychological Screening Battery (SNSB) is one of the standardized neuropsychological test batteries widely used in Korea. However, it may be a bit too lengthy for patients with decreased attention span; and it does not provide the score of global cognitive function (GCF), which is useful for monitoring patients longitudinally. We sought to validate a dementia version of SNSB (SNSB-D) that was shorter than the original SNSB and contained only scorable tests with a GCF score of 300. We administered SNSB-D to patients with mild cognitive impairment (MCI) (n=43) and Alzheimer's disease (AD) (n=93), and normal controls (NC) (n=77). MCI and AD groups had GCF scores significantly different from NC group, and GCF scores were able to distinguish patients with Clinical Dementia Rating of 0.5 and 1. Test-retest reliability was high, with a correlation coefficient of 0.918 for AD, 0.999 for MCI, and 0.960 for NC. The GCF score significantly correlated with the Mini-Mental State Examination (MMSE). Through ROC-curve analysis, GCF scores were found to yield more accurate diagnoses than the MMSE. The SNSB-D is a valid, reliable tool for assessing the overall cognitive function, and can be used to monitor cognitive changes in patients with dementia.

KDM3A regulates Slug expression to promote the invasion of MCF7 breast cancer cells in hypoxia.

Oxygen deprivation (hypoxia), which frequently occurs in the tumour microenvironment, is a strong driver of the phenotypic transition of cancer cells. An increase in metastatic potential such as cell invasion is a well-known phenotypical change induced in hypoxia. The present study demonstrated that lysine demethylase 3A (KDM3A), a Jumonji C domain-containing KDM, is involved in the hypoxia-induced invasion of MCF7 breast cancer cells. KDM3A depletion inhibits the induction of cell invasion without affecting MCF7 cell survival rate or proliferation under hypoxic conditions, whereas KDM3A overexpression enhances MCF7 cell invasion even under normoxic conditions. KDM3A suppresses E-cadherin expression, which is associated with epithelial-to-mesenchymal transition (EMT)-mediated cell invasion in hypoxia. In addition, KDM3A promotes the expression of Slug, an EMT transcription factor that negatively regulates E-cadherin expression. Consistent with this finding, the removal of the repressive transcription marker, dimethylated histone H3 at lysine 9 from the Slug promoter is dependent on hypoxia-induced recruitment of KDM3A. Collectively, the results of the present study suggest that KDM3A is a crucial transcriptional coactivator of Slug expression to induce MCF7 breast cancer cell invasion in hypoxia, and that inhibition of KDM3A may efficaciously prevent metastatic cancer development.

Increasing comorbidities in a South Korea insured population-based cohort of patients with chronic hepatitis B.

BACKGROUND: It is controversial whether chronic hepatitis B (CHB) patients have more non-liver comorbidities than non-CHB subjects. AIM: To characterise the demographics, comorbidity and health utilisation of CHB patients in South Korea and compare them to matched controls. METHODS: Using the Health Insurance Review & Assessment Service (HIRA) 2007-2016 database, adult patients with claims for CHB analysed. CHB cases and non-CHB controls matched in a 1:4 ratio using propensity score matching method. RESULTS: The age of CHB patients significantly increased from a mean 46.9 years in 2007 to 52.3 years in 2016. The proportions of persons having both liver-related and non-liver related comorbidities were higher in CHB patients compared to matched controls (dyslipidaemia [37.23% vs 23.77%, P < 0.0001], hypertension [29.39% vs 25.27%, P < 0.0001] chronic kidney disease (CKD) [3.02% vs 1.14%, P < 0.0001] and osteoporosis/fracture [OF] [4.09% vs 3.23%, P < 0.0001]). Approximately 50% of CHB patients had more than one comorbidity among CKD, diabetes, DLP, and OF. The odds of CKD in CHB patients were 1.42 times higher, and the odds of OF in CHB patients were 1.09 times higher than matched controls after adjustment for confounders (P < 0.0001). CONCLUSION: Prevalence of liver as well as non-liver comorbidities in patients with CHB was higher than matched controls and increased over time.

Measurement of Acceptable Noise Level with Background Music.

BACKGROUND AND OBJECTIVES: Acceptable noise level (ANL) is a measure of the maximum background noise level (BNL) that a person is willing to tolerate while following a target story. Although researchers have used various sources of target sound in ANL measures, a limited type of background noise has been used. Extending the previous study of Gordon-Hickey & Moore (2007), the current study determined the effect of music genre and tempo on ANLs as possible factors affecting ANLs. We also investigated the relationships between individual ANLs and the familiarity of music samples and between music ANLs and subjective preference. SUBJECTS AND METHODS: Forty-one participants were seperated into two groups according to their ANLs, 29 low-ANL listeners and 12 high-ANL listeners. Using Korean ANL material, the individual ANLs were measured based on the listeners' most comfortable listening level and BNL. The ANLs were measured in six conditions, with different music tempo (fast, slow) and genre (K-pop, pop, classical) in a counterbalanced order. RESULTS: Overall, ANLs did not differ by the tempo of background music, but music genre significantly affected individual ANLs. We observed relatively higher ANLs with K-pop music and relatively lower ANLs with classical music. This tendency was similar in both low-ANL and high-ANL groups. However, the subjective ratings of music familiarity and preference affected ANLs differently for low-ANL and high-ANL groups. In contrast to the low-ANL listeners, the ANLs of the high-ANL listeners were significantly affected by music familiarity and preference. CONCLUSIONS: The genre of background music affected ANLs obtained using background music. The degree of music familiarity and preference appears to be associated with individual susceptibility to background music only for listeners who are greatly annoyed by background noise (high-ANL listeners).

Reduction of Continuous Theta Burst Stimulation-Induced Motor Plasticity in Healthy Elderly With COMT Val158Met Polymorphism.

OBJECTIVE: To delineate whether cortical plasticity induced by continuous theta burst stimulation (cTBS) differed according to catechol-O-methyltransferase (COMT) gene polymorphism in healthy older adults. METHODS: Eighteen healthy older volunteers (mean age 73.78±5.04; 12 females and 6 males) were recruited. Volunteers randomly assigned in either a sham-first or real cTBS first group participated in two separate TMS visits with at least a 2-day wash-out period. Genotyping was carried out at baseline by a separate researcher who was blinded. cTBS was delivered in a hot spot over M1 at an active motor threshold of 80%. Motor evoked potentials (MEPs) were obtained at 120% of the resting motor threshold before and after sham/cTBS. RESULTS: The relative MEP to baseline was significantly decreased 0 and 10 minutes post-stimulation and increased 40 minutes post-stimulation, as compared with the sham condition. Immediately after cTBS, the Val/Val group had a significantly reduced relative MEP value, as compared with the MET carrier group. CONCLUSION: In healthy older persons, cTBS-induced motor plasticity was reduced in the COMT Val/Val group as compared with the (158)Met carrier group.

Neurobehavioral dysfunction in patients with subcortical vascular mild cognitive impairment and subcortical vascular dementia.

Amnestic mild cognitive impairment (MCI) is considered to be a prodromal stage of Alzheimer's disease. Likewise, subcortical vascular MCI (svMCI) is considered as a prodromal stage of subcortical vascular dementia (SVaD). The objective of this study was to investigate neuropsychiatric features in patients with svMCI compared to healthy controls and patients with SVaD. We evaluated 31 patients with svMCI, 42 with SVaD, and 28 healthy controls who underwent neuropsychiatric assessments using the Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI). On both the NPI and FBI, SVaD patients had the most severe neuropsychiatric symptoms, followed by svMCI patients and then healthy controls, suggesting that svMCI might be a prodromal stage of SVaD in terms of neuropsychiatric abnormalities. When we compared the differences of mean scores between negative and positive symptoms in FBI, negative symptoms tended to be more predominant than positive symptoms in both svMCI and SVaD patients, but the tendency was stronger in SVaD patients than in svMCI patients. These results suggest that vascular cognitive impairment with small vessel disease would start with both negative and positive neuropsychiatric symptoms and progress to present more severe negative symptoms. These behavioral ratings may be useful for early detection of vascular cognitive impairment associated with small vessel disease.

Cortical thinning related to periventricular and deep white matter hyperintensities.

Previous studies showed that white matter hyperintensities (WMH) are related to cognitive decline in patients with mild cognitive impairment (MCI) or dementia. Moreover, periventricular WMH (periventricular white matter hyperintensities (PWMH)) and deep WMH (deep white matter hyperintensities (DWMH)) may have different effects on cognition. The purpose of this study is to investigate the contributions of PWMH and DWMH to the topography of cortical thinning and to investigate the relationship among WMH, cortical thinning, and cognitive impairments. Participants included 226 patients with Alzheimer's disease or subcortical vascular dementia, and 135 patients with amnestic MCI or subcortical vascular MCI. Cortical thickness was measured using the surface based method. The topography of cortical thinning related to WMH was distributed in the frontal and perisylvian regions, which was similar to that of PWMH. In contrast, there were only small areas of cortical thinning inversely associated with DWMH, which were distributed in medial frontal and lingual gyrus. PWMH, but not DWMH, were associated with the frontal thinning and executive dysfunction; where both PWMH and frontal thinning were independently associated with executive dysfunction. Our results suggest that PWMH are associated with frontal thinning, which is further associated with frontal executive dysfunction.

Voxel-based analysis of diffusion tensor imaging in patients with subcortical vascular cognitive impairment: correlates with cognitive and motor deficits.

BACKGROUND AND PURPOSE: Patients with small vessel disease show high-signal intensity on T2-weighted magnetic resonance (MR) images that represent ischemic cell damage. However, despite a similar degree of ischemic change, the amount and the severity of clinical presentations may vary. We investigated the clinical correlations of ischemic changes using voxel-based morphometric analyses of diffusion tensor imaging (DTI). METHODS: Twenty-seven MCI and 34 dementia patients were included who all had significant small vessel disease on magnetic resonance imaging (MRI). In all patients, neuropsychological tests, a rating on the Pyramidal and Extrapyramidal scale (PEPS) for motor deficits, and 3-Tesla MRI including DTI scans were performed. Voxel-based analysis of the fractional anisotropy and mean diffusivity maps were computed. RESULTS: Cognitive scores correlated with the DTI abnormalities in supratentorial areas with regional specificity according to each cognitive test. Unexpectedly, cognitive deficits in most neuropsychological tests, even in some frontal tasks, were associated with disruption of posterior white matter integrities. Motor deficits correlated with both supra- and infratentorial lesions. CONCLUSION: Our findings suggest that in patients with small vessel disease who show cognitive and motor impairments, a specific distribution of fiber tract damage is more related with clinical deficits than is the severity of the total ischemia.

Effects of demographic factors on cortical thickness in Alzheimer's disease.

The aim of this study was to investigate the effect of demographic factors (age of onset, sex and years of education) on the distribution of cortical thickness in a large sample of patients with Alzheimer's disease (AD). The study participants consisted of 193 AD patients and 142 controls with no cognitive impairment (NCI) that were measured with cortical thickness across the entire brain. The effects of demographic factors on cortical thickness were analyzed by applying linear regression after controlling confounding factors. Older individuals in NCI group showed more cortical thinning in frontal, temporal association cortices and insula than younger participants. Early onset AD was associated with cortical thinning in the parietal lobe, whereas late onset AD was associated with cortical thinning in the medial temporal region. The NCI group demonstrated sex-related differences in cortical thickness, although those differences were not present in the AD group. While the education effect was absent in NCI individuals, high levels of education in the AD group correlated with cortical thinning in the frontal and temporoparietal association cortices. Our results show that AD with earlier onset and higher education had suffered more pronounced cortical atrophy in specific parts of the brain than their counterparts, which may be related to cognitive reserve theory.

The cortical neuroanatomy of neuropsychological deficits in mild cognitive impairment and Alzheimer's disease: a surface-based morphometric analysis.

Patients with probable Alzheimer's disease (AD) and the amnesic form of mild cognitive impairment (aMCI) often demonstrate several types of neuropsychological deficits. These deficits are often related to cortical atrophy, induced by neuronal degradation. The purpose of this study is to investigate whether different anatomic patterns of cortical atrophy are associated with specific neuropsychological deficits. The participants were 170 patients with AD and 99 patients with aMCI. All participants underwent the Seoul Neuropsychological Screening Battery (SNSB), which includes tests that assess attention, language, visuospatial functions, verbal and visual memory, and frontal/executive functions. Cortical atrophy (thinning) was quantified by measuring the thickness of the cortical mantle across the entire brain using automated, three-dimensional magnetic resonance imaging. The relationship between cortical thickness and neuropsychological performance was analysed using stepwise multiple linear regression analyses. These analyses (corrected P<.001) showed that several specific brain regions with cortical thinning were associated with cognitive dysfunction including: digit span backward, verbal and picture recall, naming and fluency, drawing-copying, response inhibition and selective attention. Some of the other functions, however, were not associated with specific foci of cortical atrophy (digit span forward, the word reading portion of the Stroop test, word and picture recognition). Our study, involving a large sample of participants with aMCI and AD, provides support for the postulate that cortical thinning-atrophy in specific anatomic loci are pathological markers for specific forms of cognitive dysfunction.

Cortical thinning in vascular mild cognitive impairment and vascular dementia of subcortical type.

BACKGROUND AND PURPOSE: Amnestic mild cognitive impairment (MCI) is known to be a preclinical stage of Alzheimer's disease (AD). Similarly, MCI associated with small-vessel disease (svMCI), might be a forme froste of subcortical vascular dementia (SVaD). Patterns of cortical thinning in addition to the ischemia rating on MRI may further elucidate the clinical characteristics and pathogenesis of SVaD and svMCI. We tried to determine if svMCI differs from SVaD in the distribution of cortical atrophy, which may help understand the hierarchy between svMCI and SVaD and possibly also how svMCI evolves into SVaD. METHODS: Twenty patients with SVaD, 34 patients with svMCI, 115 patients with AD, and 96 individuals with normal-cognition (NC) were imaged with magnetic resonance imaging (MRI) including 3-dimensional volumetric images for cortical thickness analysis across the entire brain. RESULTS: Compared to NC, svMCI patients showed cortical thinning in inferior frontal and orbitofrontal gyri, anterior cingulate, insula, superior temporal gyrus, and lingual gyrus, while cortical thinning in SVaD patients involved all these areas plus dorsolateral prefrontal and temporal cortices. CONCLUSION: Our findings suggest the presence of hierarchy between svMCI and SVaD, and that the cognitive decline from svMCI to SVaD is associated with lesions in dorsolateral prefrontal and temporal cortices.

The influence of illusory motion on line bisection performance in normal subjects.

The present study examines whether illusory movement (IM) of a horizontal line, induced by a moving background (MB), influences line-bisection performance in normal subjects. The first experiment attempted to identify the speeds of MB that induce IM. We found that when speed is increased from 1.53 degrees to 13.3 degrees/sec, IM increases, but that with further speed increases, IM decreases. Leftward MB induces rightward IM, and vice versa. In the second experiment, we had subjects bisect lines at MB speeds that had been shown to induce IM in the first experiment. We found that leftward MB induced a rightward bias, and vice versa. We also found that there was a relationship between the magnitude of IM and the degree of bias. In the third experiment, by making the target line larger than the MB, we made the conditions where IM was presumably absent. Unlike the results of bisection performed with IM, subjects showed a bias in the direction of the MB. Overall, these experiments demonstrated that the perception of motion induces subjects to attend in the direction of movement.