Digital clock drawing test reflects visuospatial ability of older drivers.

Objectives: To keep older drivers safe, it is necessary to assess their fitness to drive. We developed a touch screen-based digital Clock Drawing Test (dCDT) and examined the relationship between the dCDT scores and on-road driving performance of older drivers in a community-setting. Methods: One hundred and forty-one community-dwelling older drivers (range; 64-88 years old) who participated in this study were included in the analysis. Participants completed the dCDT, the Mini-Mental State Examination-Japanese (MMSE-J), and an on-road driving assessment. We examined the relationship between dCDT scores using the method by Rouleau et al. (maximum 10 points) and the on-road driving performance based on a driving assessment system originally developed by Nagoya University. Results: Multiple regression analyses showed that errors in the driving test were associated with dCDT score for the items "confirmation," "turning left" and "maintains driving lane position". Discussion: This study confirmed the relationship between the dCDT score and driving errors, such as confirmation, turning left and maintaining driving lane position. The increase in these errors indicates a decline in visuospatial ability while driving. The dCDT score may reflect older drivers' visuospatial abilities while driving.

Relationship Between Fasting Blood Glucose Levels in Middle Age and Cognitive Function in Later Life: The Aichi Workers' Cohort Study.

BACKGROUND: There is limited evidence regarding the relationship between Diabetes mellitus (DM) in middle age and mild cognitive impairment after a follow-up. Therefore, we investigated the relationship between fasting blood glucose (FBG) levels in middle age and cognitive function assessed using the Japanese version of the Montreal Cognitive Assessment (MoCA-J) in later life, following over 15 years of follow-up in the Aichi Workers' Cohort Study in Japan. METHODS: Participants were 253 former local government employees aged 60-79 years in 2018 who participated in a baseline survey conducted in 2002. Using baseline FBG levels and self-reported history, participants were classified into the normal, impaired fasting glucose (IFG) and, and DM groups. Total MoCA-J score ranges from 0 to 30, and cognitive impairment was defined as MoCA-J score ≤25 in this study. A general linear model was used to estimate the mean MoCA-J scores in the FBG groups, adjusted for age, sex, educational year, smoking status, alcohol consumption, physical activity, body mass index, systolic blood pressure, total cholesterol, and estimated glomerular filtration rate. RESULTS: The mean MoCA-J score in the total population was 25.0, and the prevalence of MoCA-J score ≤25 was 49.0%. Multivariable-adjusted total MoCA-J scores were 25.2, 24.8, and 23.4 in the normal, IFG, and DM groups, respectively. The odds ratio of MoCA-J score ≤25 in the DM group was 3.29. CONCLUSION: FBG level in middle age was negatively associated with total MoCA-J scores assessed later in life, independent of confounding variables.

Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial.

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism.

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder's core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, -0.57; 95% CI, -1.27 to 0.13; P = 0.023) and confirmatory trials (-0.41; -0.62 to -0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen's d = -0.78; 95% CI, -1.21 to -0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen's d = -0.46; 95% CI, -0.90 to -0.01) and 6 weeks (P = 0.10, Cohen's d = -0.35; 95% CI, -0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen's d = -1.24; 95% CI, -1.71 to -0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals' facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

Evaluation of the components of mediastinal cystic lesions using imaging techniques.

OBJECTIVE: To identify and differentiate patients with mediastinal cysts from those with cystic tumors requiring surgery. METHODS: A total of 36 patients with mediastinal cystic lesions were enrolled. The patients were separated into two groups based on pathological findings : those with mediastinal cysts (n=23) and those with mediastinal tumors (n=13). The cystic components were measured using imaging parameters including mean computed tomography (CT) value, apparent diffusion coefficient (ADC), T1 signal intensity ratio (T1SIratio), and T2 signal intensity ratio (T2SI-ratio), acquired from magnetic resonance imaging (MRI) ; and standardized maximum uptake value (SUVmax) from18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Both groups were statistically compared. RESULTS: Comparative parameters between the cysts and tumors revealed the following ratios : CT value, 40.9?21.2 versus (vs) 24.8?12.9 (p = 0.019) ;SUVmax, 1.18?0.50 vs 4.32?3.52 (p = 0.003) ; ADC, 3.46?0.96 vs 2.68?0.74 (p = 0.022) ; T1SI-ratio, 1.06?0.60 vs 1.35? 0.92 (p = 0.648) ; T2SI-ratio, 5.40?1.80 vs 4.33?1.58 (p = 0.194). However, there was no correlation between FDG uptake and ADC value. CONCLUSIONS: SUVmax from18F-FDG PET/CT and ADC derived from MRI were effective in facilitating preoperative diagnosis to differentiate mediastinal cysts from tumors. However, these examinations may be complementary to one another, not dominant. J. Med. Invest. 66 : 106-111, February, 2019.

Differential effects of physical activity and sleep duration on cognitive function in young adults.

PURPOSE: Although exercise and sleep duration habits are associated with cognitive function, their beneficial effects on cognitive function remain unclear. We aimed to examine the effect of sleep duration and daily physical activity on cognitive function, elucidating the neural mechanisms using near-infrared spectroscopy (NIRS). METHODS: A total of 23 healthy young adults (age 22.0 ± 2.2 years) participated in this study. Exercise amount was assessed using a uniaxial accelerometer. We evaluated total sleep time (TST) and sleep efficiency by actigraphy. Cognitive function was tested using the N-back task, the Wisconsin Card Sorting Test (WCST), and the Continuous Performance Test-Identical Pairs (CPT-IP), and the cortical oxygenated hemoglobin levels during a word fluency task were measured with NIRS. RESULTS: Exercise amount was significantly correlated with reaction time on 0- and 1-back tasks (r = -0.602, p = 0.002; r = -0.446, p = 0.033, respectively), whereas TST was significantly correlated with % corrects on the 2-back task (r = 0.486, p = 0.019). Multiple regression analysis, including exercise amount, TST, and sleep efficiency, revealed that exercise amount was the most significant factor for reaction time on 0- and 1-back tasks (ß = -0.634, p = 0.002; ß = -0.454, p = 0.031, respectively), and TST was the most significant factor for % corrects on the 2-back task (ß = 0.542, p = 0.014). The parameter measured by WCST and CPT-IP was not significantly correlated with TST or exercise amount. Exercise amount, but not TST, was significantly correlated with the mean area under the NIRS curve in the prefrontal area (r = 0.492, p = 0.017). CONCLUSION: Exercise amount and TST had differential effects on working memory and cortical activation in the prefrontal area. Daily physical activity and appropriate sleep duration may play an important role in working memory.

Effects of hypnotics on prefrontal cortex activity during a verbal fluency task in healthy male subjects: A near-infrared spectroscopy study.

OBJECTIVE: To assess the effects of hypnotics on prefrontal cortex activity in healthy subjects using near-infrared spectroscopy (NIRS) in a double-blind, placebo-controlled crossover trial. METHODS: Eighteen healthy males received acute doses of ramelteon (8 mg), triazolam (0.125 mg), or placebo in a predetermined randomization schedule, with a washout period of more than 1 week. All subjects performed a verbal fluency task during NIRS assessments at baseline and at 1 and 4 hr post-dose. The number of words correctly generated during the task (behavioral performance) and scores on the Stanford Sleepiness Scale (SSS) were also recorded at each test time. RESULTS: Compared with the placebo, triazolam (0.125 mg) significantly decreased oxyhemoglobin (oxy-Hb) concentration change in NIRS during the posttask period and significantly increased behavioral performance, whereas triazolam (0.125 mg) and ramelteon (8 mg) significantly increased SSS scores. CONCLUSIONS: The differential effects of two types of hypnotics on oxy-Hb change measured by NIRS were observed in acute dosing, suggesting that when assessing brain activity of patients with psychiatric disorders, researchers should consider how certain types of hypnotics can influence brain function. This would also provide useful information to clinicians when prescribing hypnotics suitable for their patients' conditions.

Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights.

Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders.

Genetic and animal model analyses reveal the pathogenic role of a novel deletion of RELN in schizophrenia.

Reelin protein (RELN), an extracellular matrix protein, plays multiple roles that range from embryonic neuronal migration to spine formation in the adult brain. Results from genetic studies have suggested that RELN is associated with the risk of psychiatric disorders, including schizophrenia (SCZ). We previously identified a novel exonic deletion of RELN in a patient with SCZ. High-resolution copy number variation analysis revealed that this deletion included exons 52 to 58, which truncated the RELN in a similar manner to the Reln Orleans mutation (Relnrl-Orl). We examined the clinical features of this patient and confirmed a decreased serum level of RELN. To elucidate the pathophysiological role of the exonic deletion of RELN in SCZ, we conducted behavioral and neurochemical analyses using heterozygous Relnrl-Orl/+ mice. These mice exhibited abnormalities in anxiety, social behavior, and motor learning; the deficits in motor learning were ameliorated by antipsychotics. Methamphetamine-induced hyperactivity and dopamine release were significantly reduced in the Relnrl-Orl/+ mice. In addition, the levels of GABAergic markers were decreased in the brain of these mice. Taken together, our results suggest that the exonic deletion of RELN plays a pathological role, implicating functional changes in the dopaminergic and GABAergic systems, in the pathophysiology of SCZ.

Evaluation method regarding the effect of psychotropic drugs on driving performance: A literature review.

Although automobile driving is necessary for many people, including patients with mental disorders, the influence of psychotropic drugs on driving performance remains unclear and requires scientific verification. Therefore, the objective of this study was to conduct a review of the literature in order to aid the development of a valid evaluation method regarding the influence of medication on driving performance. We conducted a literature search using two sets of terms on PubMed. One set was related to psychotropic drugs, and the other to driving tests. We excluded reviews and case studies and added literature found on other sites. A total of 121 relevant reports were found. The experiments were roughly divided into on-the-road tests (ORT) and driving simulators (DS). Although highway driving tests in ORT are most often used to evaluate driving performance, DS are becoming increasingly common because of their safety and low cost. The validity of evaluation methods for alcohol should be verified; however, we found that there were few validated tests, especially for DS. The scenarios and measurement indices of each DS were different, which makes it difficult to compare the results of DS studies directly. No evaluation indices, except for SD of lateral position, were sufficiently validated. Although highway ORT are the gold standard, DS were shown to have an increasing role in evaluating driving performance. The reliability of DS needs to be established, as does their validation with alcohol in order to accumulate more high-quality evidence.

Aberrant functional connectivity between the thalamus and visual cortex is related to attentional impairment in schizophrenia.

Resting-state (rs) functional magnetic resonance imaging (fMRI) studies have revealed dysfunctional thalamocortical functional connectivity (FC) in schizophrenia. However, the relationship between thalamocortical FC and cognitive impairment has not been thoroughly investigated. We hypothesized that aberrant thalamocortical FC is related to attention deficits in schizophrenia. Thirty-eight patients with schizophrenia and 38 matched healthy controls underwent rs-fMRI and task fMRI while performing a Flanker task. We observed decreased left thalamic activation in patients with schizophrenia using task fMRI to determine the thalamic seed. A seed-based analysis using this seed was performed in the whole brain to assess differences in thalamocortical FC between the groups. Significantly worse performance was observed in the patient group. The rs-fMRI analysis revealed significantly increased FC between the left thalamus seed and the occipital cortices/postcentral gyri in patients when compared to controls. In the patient group, significant positive correlations were observed between the degree of FC from the left thalamus to the bilateral occipital gyri, which correspond to the visual cortex, and the Flanker effect. No significant correlation was detected in the control group. These results indicate that aberrant FC between the left thalamus and the visual cortex is related to attention deficits in schizophrenia.

Driving performance of stable outpatients with depression undergoing real-world treatment.

AIM: Although the effects of psychotropics on driving ability have received much attention, little research is available on driving performance of stable outpatients with depression undergoing real-world treatment. This observational study investigated driving performance, cognitive functions, and depressive symptomatology of partly remitted outpatients with depression under daily-practice psychopharmacologic treatment. METHODS: Seventy stable outpatients with depression and 67 healthy volunteers were enrolled. Patients' prescriptions were not controlled in order to capture the real-world treatment environment. Participants underwent three driving tasks - road-tracking, car-following, and harsh-braking - using a driving simulator, and three cognitive tasks - Continuous Performance Test, Wisconsin Card Sorting Test, and Trail-Making Test. The Symptom Assessment Scale - Structured Interview Guide for the Hamilton Depression Rating Scale, Beck Depression Inventory-II, Social Adaptation Self-Evaluation Scale, and Stanford Sleepiness Scale were also completed. RESULTS: Although many patients received various pharmacologic treatments, there were no significant differences in the three driving tasks between outpatients with depression and healthy controls. Difficulty of maintaining set in the Wisconsin Card Sorting Test was significantly increased in patients with depression. Results on the Social Adaptation Self-Evaluation Scale were significantly associated with road-tracking and car-following performance, in contrast to results on the Hamilton Depression Rating Scale and the Beck Depression Inventory-II. CONCLUSION: We conclude that partly remitted depressive patients under steady-state pharmacologic treatment do not differ from healthy controls with respect to driving performance, which seems to be more affected by psychosocial functioning than by pharmacologic agents. This, however, should be investigated systematically in an off/on study.

Verbal Memory Impairment in Patients with Subsyndromal Bipolar Disorder.

BACKGROUNDS: Several domains of cognitive function, including learning memory and executive function, are impaired in mood disorders. Also, the relationship between disturbances of these two cognitive domains has been suggested. In line with the recent initiative to establish a standard measure of cognitive decline in bipolar disorder, the present study was conducted to (1) test the criterion-related validity and test-retest reliability of the California Verbal Learning Test (CVLT)-II Japanese version, and (2) determine if type of word learning tasks (i.e., with or without a category structure) affects severity of verbal memory deficits in patients with subsyndromal bipolar disorder. METHODS: Thirty-six patients with bipolar disorder with mild symptoms and 42 healthy volunteers participated in the study. We first compared effect sizes for memory deficits in patients among the CVLT-II, Brief Assessment of Cognition in Schizophrenia (BACS), and Hopkins Verbal Memory Tests-Revised (HVLT-R). We next evaluated the correlations between scores of the CVLT-II vs. those of the BACS and HVLT-R. Bipolar patients were re-assessed with the same (standard) or alternate forms of the CVLT-II and HVLT-R 1 month later. RESULTS: Scores on the CVLT-II 1-5 Free Recall and Long-delay Free Recall, as well as the HVLT-R Immediate Recall, but not the BACS List Learning were significantly lower for patients compared to control subjects. The effect sizes for cognitive decline due to the illness were comparable when measured by the CVLT-II and HVLT-R, ranging from 0.5 to 0.6. CVLT-II scores were significantly correlated with those of the HVLT-R and BACS. Test-retest reliability of the CVLT-II was acceptable, and no significant practice effect was observed when the alternate form was used. There was no consistent relationship between mood symptoms and performance on the CVLT-II. CONCLUSION: These results suggest the CVLT-II Japanese version is able to discriminate between bipolar disorder patients and healthy controls with good sensitivity and validity. Data in this study also indicate that the degree of verbal memory deficits in bipolar disorder may be influenced by memory organizational strategy.

Regional decrease in gray matter volume is related to body dissatisfaction in anorexia nervosa.

Anorexia nervosa (AN) is a psychiatric disorder, in which the prognosis for some patients is poor. The etiology and effective treatments for AN have not been established. We examined morphometric changes in the brain of AN and clarified how the changes were associated with symptoms and pathophysiology. We enrolled 52 participants: 7 with the restrictive type of AN, 13 with the binge-eating/purging type, 3 with eating disorder not otherwise specified, and 29 healthy controls. Participants underwent T1-weighted MRI. Group differences between patients and controls in gray matter volume (GMV) were analyzed using voxel-based morphometry. Age and body mass index (BMI) were considered covariates. Correlations between regional GMVs and drive for thinness and body dissatisfaction were examined. Patients had decreased GMV in the superior/middle temporal gyrus (STG/MTG), pulvinar, and superior frontal gyrus after correction for age and BMI, and in the STG/MTG, middle frontal gyrus, and cingulate after correction for age. A correlational group difference was detected for body dissatisfaction and GMV in the STG. Our findings suggest that decreased GMV in the STG is related to body dissatisfaction that could come from impaired visuospatial perception, together with GMV decreases in several regions, which may be involved in development of AN.

Estimated cognitive decline in patients with schizophrenia: A multicenter study.

AIM: Studies have reported that cognitive decline occurs after the onset of schizophrenia despite heterogeneity in cognitive function among patients. The aim of this study was to investigate the degree of estimated cognitive decline in patients with schizophrenia by comparing estimated premorbid intellectual functioning and current intellectual functioning. METHODS: A total of 446 patients with schizophrenia (228 male, 218 female), consisting of three sample sets obtained from 11 psychiatric facilities, and 686 healthy controls participated in this study. The Wechsler Adult Intelligence Scale-III (WAIS-III) was used to measure the participants' current full-scale IQ (FSIQ). The premorbid IQ was estimated using the Japanese Adult Reading Test-25. Estimated cognitive decline (difference score) was defined as the difference between the estimated premorbid IQ and the current FSIQ. RESULTS: Patients with schizophrenia showed greater estimated cognitive decline, a lower FSIQ, and a lower premorbid IQ compared with the healthy controls. The mean difference score, FSIQ, and estimated premorbid IQ were -16.3, 84.2, and 100.5, respectively, in patients with schizophrenia. Furthermore, 39.7% of the patients had a difference score of 20 points or greater decline. A discriminant analysis showed that the difference score accurately predicted 81.6% of the patients and healthy controls. CONCLUSION: These results show the distribution of difference score in patients with schizophrenia. These findings may contribute to assessing the severity of estimated cognitive decline and identifying patients with schizophrenia who suffer from cognitive decline.

Influence of sleep duration on cortical oxygenation in elderly individuals.

AIM: Short sleep duration is a risk factor for cardiovascular diseases. Cerebral blood flow and its regulation are affected by pathological conditions commonly observed in the elderly population, such as dementia, atherosclerosis, diabetes mellitus (DM), stroke, and hypertension. The purpose of this study was to examine the influence of sleep duration on cortical oxygenated hemoglobin (OxyHb) using near-infrared spectroscopy (NIRS). METHODS: Seventy-three individuals (age, 70.1 ± 3.9 years, 51 men and 22 women) participated in this study. Cortical OxyHb levels were measured with NIRS. We evaluated age, body mass index (BMI), smoking status, alcohol intake, sleep duration, hypertension, DM, and hyperlipidemia using a questionnaire. Blood pressure was measured using plethysmography. RESULTS: Peak OxyHb and area under the NIRS curve significantly decreased in participants with sleep duration <7 h compared with those with sleep duration ≥7 h (0.136 ± 0.212 mM·mm vs 0.378 ± 0.342 mM·mm, P = 0.001; 112.0 ± 243.6 vs 331.7 ± 428.7, P = 0.012, respectively). Sleep duration was significantly correlated with peak OxyHb level and area under the NIRS curve (r = 0.378, P = 0.001; r = 0.285, P = 0.015, respectively). Multiple regression analysis, including age, BMI, sex, smoking status, alcohol intake, sleep duration, hypertension, DM, and hyperlipidemia revealed that sleep duration was the only significant independent factor associated with peak OxyHb and area under the NIRS curve (ß = 0.343, P = 0.004; ß = 0.244, P = 0.049, respectively), and smoking status was independently correlated with time to the peak OxyHb (ß = -0.319, P = 0.009). CONCLUSION: Sleep duration may be an important factor that influences cortical oxygenation in the elderly population.

Risk factors for elevated liver enzymes during refeeding of severely malnourished patients with eating disorders: a retrospective cohort study.

BACKGROUND: There are few previous reports regarding the cause and evolution of liver injury in patients with anorexia nervosa (AN) during the refeeding process, and its management remains controversial. This study aimed to determine the risk factors for elevated liver enzymes during refeeding and their effect on the therapeutic process in severely malnourished patients with eating disorders. METHODS: In a retrospective cohort study of 167 female inpatients in a single hospital from January 2004 to March 2015, 67 who had normal alanine aminotransferase (ALT) levels on admission were divided into two groups according to the presence or absence of elevated ALT levels during refeeding, and then compared. RESULTS: The median age and body mass index (BMI) of the patients on admission were 22 [interquartile range (IQR), 16-33] years and 12.2 (IQR, 11.1-13.0) kg/m2, respectively. Compared with their cohorts, significantly more patients in the early onset age group (<15 years old) had elevated ALT levels during refeeding (67% vs. 33%, p = 0.033), as did patients with longer median time to nadir BMI (3.0 vs. 0 days, p = 0.03). In addition, onset age [odds ratio (OR): 0.274; 95% confidence interval (CI): 0.077-0.981; p = 0.047] and time to nadir BMI (OR: 1.271; 95% CI: 1.035-1.56; p = 0.022) were significantly associated with the odds of elevated ALT levels during refeeding. CONCLUSIONS: The results of this study suggest that early age at onset may be a potential risk factor for elevated ALT levels during refeeding in severely malnourished patients with eating disorders. Furthermore, elevated ALT levels during refeeding were significantly associated with delay in the start of weight gain. No significant relationship was found between the amount of initial prescribed calories and elevated ALT levels during refeeding. The median time to maximum ALT was 27 (IQR, 21-38) days after the refeeding process started.