Sequencing Analysis of Plasma Epstein-Barr Virus DNA Reveals Nasopharyngeal Carcinoma-Associated Single Nucleotide Variant Profiles.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. Plasma EBV DNA is a validated screening tool for NPC. In screening, there are some individuals who do not have NPC but carry EBV DNA in plasma. Currently it is not known from screening if there may be any genotypic differences in EBV isolates from NPC and non-NPC subjects. Also, low concentrations of EBV DNA in plasma could pose challenge to such EBV genotypic analysis through plasma DNA sequencing. METHODS: In a training dataset comprised of plasma DNA sequencing data of NPC and non-NPC subjects, we studied the difference in the EBV single nucleotide variant (SNV) profiles between the two groups. The most differentiating SNVs across the EBV genome were identified. We proposed an NPC risk score to be derived from the genotypic patterns over these SNV sites. We subsequently analyzed the NPC risk scores in a testing set. RESULTS: A total of 661 significant SNVs across the EBV genome were identified from the training set. In the testing set, NPC plasma samples were shown to have high NPC risk scores, which suggested the presence of NPC-associated EBV SNV profiles. Among the non-NPC samples, there was a wide range of NPC risk scores. These results support the presence of diverse SNV profiles of EBV isolates from non-NPC subjects. CONCLUSION: EBV genotypic analysis is feasible through plasma DNA sequencing. The NPC risk score may be used to inform the cancer risk based on the EBV genome-wide SNV profile.

Cognitive anosognosia is associated with frontal dysfunction and lower depression in Parkinson's disease.

BACKGROUND AND PURPOSE: Anosognosia refers to a deficit of self-awareness or impaired insight for cognitive and behavioral problems. Cognitive anosognosia was explored in de novo patients with Parkinson's disease (PD) and its relationship to cognitive function and neuropsychiatric symptoms was investigated. METHODS: The cross-sectional study enrolled 340 drug-naïve patients with PD. According to the presence of mild cognitive impairment (MCI) and subjective cognitive complaint, patients were classified as patients with cognitive anosognosia (PD-CA, n = 74), with normal cognitive recognition (PD-NR, n = 184) or with cognitive underestimation (PD-CU, n = 82). After controlling for covariates, cognitive performance and neuropsychiatric symptoms were compared between the PD groups. RESULTS: Cognitive anosognosia was found in 21.8% of patients with de novo PD. The PD-CA group showed poorer performance in all cognitive domains except for attention. Amongst PD patients with MCI, those with cognitive anosognosia showed lower composite z-scores in the Stroop color reading test than those without. The Beck Depression Inventory score in the PD-NR group was lower than that in the PD-CU group and higher than that in the PD-CA group. The Cognitive Complaints Interview score mediated the association between cognitive anosognosia and Beck Depression Inventory score. CONCLUSIONS: Cognitive anosognosia in PD was associated with greater frontal dysfunction and lower depression. Since cognitive anosognosia has a harmful impact on PD patients and their caregivers due to overestimation of their abilities in everyday life, early identification of cognitive anosognosia in PD is important in management and prognosis.

Sex-dependent association of urate on the patterns of striatal dopamine depletion in Parkinson's disease.

BACKGROUND AND PURPOSE: The aim was to investigate the relationship between the serum urate (UA) levels and patterns of striatal dopamine depletion in patients with de novo Parkinson's disease (PD). METHODS: In all, 167 de novo PD patients who underwent 18 F-fluorinated N-3-fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane positron emission tomography scans were enrolled. After quantifying dopamine transporter (DAT) availability in each striatal subregion, sex-dependent patterns of striatal dopamine depletion were analysed by measuring (i) dopamine depletion in the other striatal subregions and posterior putamen (intersubregional ratio, ISR) and (ii) the interhemispheric asymmetry of dopamine depletion in the posterior putamen (asymmetric ratio, AR). RESULTS: The interaction analysis revealed a significant interaction effect of sex and serum UA levels on the ISR but not on the AR. The ISR was negatively correlated with the serum UA levels in all patients with PD (r = -0.156, P = 0.045), and this association was more prominent in male PD patients (r = -0.422, P < 0.001). However, no significant association between the AR and serum UA levels was found in any of the patients. In addition, serum UA levels were significantly associated with DAT availability in the posterior putamen on both the more affected side (r = 0.312, P = 0.005) and the less affected side (r = 0.312, P = 0.005) only in male PD patients. CONCLUSIONS: The present study demonstrated the potentially close sex-specific relationship between the serum UA levels and the anterior-posterior gradient of DAT patterns, suggesting a sex-specific protective effect of UA on nigrostriatal dopaminergic neurons in de novo PD.

Sex-specific association of urate and levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND AND PURPOSE: As a major antioxidant, uric acid (UA) is known to be associated with the clinical progression of Parkinson's disease (PD). This study investigated whether baseline UA levels are associated with the risk for levodopa-induced dyskinesia (LID) in PD in a sex-dependent manner. METHODS: In all, 152 patients with de novo PD (78 males and 74 females) who were followed up for >2 years were enrolled. The effect of baseline serum UA levels on LID-free survival was assessed by Cox regression, separately for sex, whilst being adjusted for potential confounding factors. The optimal UA level cut-off value to determine the high-risk group for LID was set using Contal and O'Quigley's method. RESULTS: Levodopa-induced dyskinesia developed in 23 (29.5%) male patients and 30 (40.5%) female patients. Cox regression showed a significant interaction between UA level and sex. Higher UA levels were associated with a higher risk for LID in male PD patients (hazard ratio 1.380; 95% confidence interval 1.038-1.835; P = 0.027), although this relationship was not observed in female PD patients. The optimal UA level cut-off for LID in male PD was 7.2 mg/dl, and the high UA group had a 5.7-fold higher risk of developing LID than the low UA group. CONCLUSIONS: Contrary to a presumptive beneficial role of UA, the present study demonstrated that higher UA levels are associated with increased risk of LID occurrence in male patients with PD, suggesting a sex-dependent role of UA in LID.

Effects of Alzheimer's disease and Lewy body disease on subcortical atrophy.

BACKGROUND AND PURPOSE: Subcortical structures are affected by neurodegeneration in Alzheimer's disease (AD) and Lewy body disease (LBD). Although the co-occurrence of AD and LBD pathologies and their possible interaction have been reported, the effect of AD and LBD on subcortical structures remains unknown. The effects of AD and LBD on subcortical atrophy and their relationship with cognitive dysfunction were investigated. METHODS: The cross-sectional study recruited 42 patients with pure AD related cognitive impairment (ADCI), 30 patients with pure LBD related cognitive impairment (LBCI), 58 patients with mixed ADCI and LBCI, and 29 normal subjects. A general linear model was used to compare subcortical volume and shape amongst the groups, to investigate the independent and interaction effects of ADCI and LBCI on subcortical shape and volume, and to analyze the relationship between subcortical volume and cognitive dysfunction in each group. RESULTS: Alzheimer's disease related cognitive impairment and LBCI were independently associated with subcortical atrophies in the hippocampus and amygdala and in the hippocampus and putamen respectively, but their interaction effect was not significant. Compared to the control group, the pure LBCI group exhibited additional local atrophies in the amygdala, caudate and thalamus. Subcortical atrophies correlated differently with cognitive dysfunction according to the underlying causes of cognitive dysfunction. CONCLUSIONS: The patterns of subcortical atrophies and their correlation with cognitive dysfunction differ according to the underlying AD, LBD or concomitant AD and LBD.

Comparative genomic evidence for the involvement of schizophrenia risk genes in antipsychotic effects.

Genome-wide association studies (GWAS) for schizophrenia have identified over 100 loci encoding >500 genes. It is unclear whether any of these genes, other than dopamine receptor D2, are immediately relevant to antipsychotic effects or represent novel antipsychotic targets. We applied an in vivo molecular approach to this question by performing RNA sequencing of brain tissue from mice chronically treated with the antipsychotic haloperidol or vehicle. We observed significant enrichments of haloperidol-regulated genes in schizophrenia GWAS loci and in schizophrenia-associated biological pathways. Our findings provide empirical support for overlap between genetic variation underlying the pathophysiology of schizophrenia and the molecular effects of a prototypical antipsychotic.

Clinical relevance of amnestic versus non-amnestic mild cognitive impairment subtyping in Parkinson's disease.

BACKGROUND AND PURPOSE: To clarify whether subtyping of amnestic and non-amnestic mild cognitive impairment (MCI) is clinically relevant in Parkinson's disease (PD) by analyzing patterns of neuroimaging and longitudinal cognitive changes. METHODS: We performed comparative analyses of cortical thickness, hippocampal volume, white matter integrity and resting-state functional connectivity between the patients with de-novo PD with amnestic MCI (PD-aMCI) (n = 50) and non-amnestic MCI (PD-naMCI) (n = 50) subtypes. Additionally, we assessed the longitudinal rate of cognitive decline in each cognitive domain over time and the rate of dementia conversion in patients with de-novo PD-aMCI (n = 125) and PD-naMCI (n = 61). RESULTS: The demographic data showed that scores in memory domains were lower in the PD-aMCI group compared with the PD-naMCI group. There were no significant differences in cortical thickness, hippocampal volume and white matter integrity between the two groups, although the PD-aMCI group exhibited more cortical thinning and hippocampal atrophy relative to the control group. The PD-aMCI group exhibited increased functional connectivity in the left posterior parietal region with the salience network relative to the PD-naMCI group. The longitudinal cognitive assessment demonstrated that patients with PD-aMCI exhibited a more rapid cognitive decline in frontal/executive function than those with PD-naMCI (P = 0.022). In addition, the PD-aMCI group had a higher risk of dementia conversion than the PD-naMCI group. CONCLUSIONS: This study suggests that the designation of PD-MCI subtypes based on memory function would highlight the heterogeneity of functional correlates as well as the longitudinal cognitive prognosis.

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

This corrects the article DOI: 10.1038/mp.2017.42.

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

Rapid eye movement sleep behaviour disorder and striatal dopamine depletion in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: Rapid eye movement sleep behaviour disorder (RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cpRBD) in patients with Parkinson's disease (PD) is associated with a specific pattern of striatal dopamine depletion. METHODS: A prospective survey was conducted using the RBD Screening Questionnaire (RBDSQ) in 122 patients with PD who had undergone dopamine transporter (DAT) positron emission tomography scan. RESULTS: Patients with cpRBD (RBDSQ ≥ 7) exhibited greater motor deficits, predominantly in the less-affected side and axial symptoms, and were prescribed higher levodopa-equivalent doses at follow-up than those without cpRBD (RBDSQ ≤ 4), despite their similar disease and treatment durations. Compared to patients without cpRBD, those with cpRBD showed lower DAT activities in the putamen, particularly in the less-affected side in all putaminal subregions, and a tendency to be lower in the ventral striatum. In addition, greater motor deficits in patients with cpRBD than in those without cpRBD remained significant after controlling for DAT binding in the putamen and other confounding variables. CONCLUSIONS: These results demonstrated that the presence of RBD in patients with PD is associated with different patterns of both motor deficit distribution and striatal DAT depletion, suggesting that the presence of RBD represents a distinct PD subtype with a malignant motor parkinsonism.

Volumetric analysis of the cerebellum in patients with progressive supranuclear palsy.

BACKGROUND AND PURPOSE: Although early cerebellar symptoms are one of the exclusive criteria in the diagnosis of progressive supranuclear palsy (PSP), cerebellar involvement in PSP is evident both clinically and pathologically. However, structural analysis focusing on the cerebellum has not been previously studied in patients with PSP. We aimed to evaluate cerebellar involvement in PSP using a magnetic resonance imaging-based segmental volumetric analysis. METHODS: We retrospectively enrolled 48 patients with PSP composed of 25 patients with PSP-Richardson's syndrome (RS) and 23 patients with pure akinesia with gait freezing, 39 patients with Parkinson's disease (PD) and 34 healthy controls. Data on both the whole and segmented cerebellar volumes were analyzed using a fully automated procedure. RESULTS: A general linear model showed that whole cerebellar volume in patients with PSP was significantly smaller compared with that of patients with PD or controls after controlling for age, sex and intracranial volume (P = 0.34). In addition, patients with PSP exhibited decreased regional volume in the crus I, lobule VIIIa and lobule VIIIb, which play roles as secondary representations of motor tasks, compared with patients with PD or controls. In subgroup analysis of PSP, volume loss in the whole and segmental cerebellum was more pronounced in patients with PSP-RS than in those with pure akinesia with gait freezing, PD or control subjects. CONCLUSION: These data demonstrate that cerebellar atrophy is evident in patients with PSP and is especially prominent in the PSP-RS group. These findings increase understanding of the clinicopathological basis of cerebellar involvement in PSP.

Normal 'heart' in Parkinson's disease: is this a distinct clinical phenotype?

BACKGROUND AND PURPOSE: Reduction of metaiodobenzylguanidine (MIBG) uptake has been observed in almost all patients with Parkinson's disease (PD), associated with hyposmia, orthostatic hypotension and rapid eye movement sleep behavioral disorder (RBD). In contrast, a subgroup of patients with PD with normal MIBG uptake have been reported to have milder disease and preserved cognition compared with those with lower MIBG. The aim of this study was to investigate whether non-motor manifestations of PD differ between patients with normal and abnormal myocardial MIBG uptake. METHODS: Among 160 de-novo cases of PD, 44 had normal MIBG uptake. Twelve candidate non-motor features were evaluated using questionnaires and laboratory tests. RESULTS: Patients with decreased MIBG uptake had more constipation, RBD, cognitive impairment, hyposmia and orthostatic hypotension than did those with normal MIBG uptake. On linear regression analysis, orthostatic hypotension, olfactory function and probable RBD were significantly associated with MIBG uptake in PD. The principal component analysis showed that the group with normal MIBG was not associated with non-motor impairments. CONCLUSIONS: These results suggest that patients with PD with normal MIBG scans have a relatively low disease burden compared with those with abnormal MIBG. Fewer synuclein pathologies in the myocardia and sympathetic ganglia in PD with preserved MIBG uptake might be associated with lower threshold patterns of Braak synuclein pathology for non-motor manifestations compared with PD with decreased MIBG.

Does serum uric acid act as a modulator of cerebrospinal fluid Alzheimer's disease biomarker related cognitive decline?

BACKGROUND AND PURPOSE: The association of serum uric acid, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) and longitudinal cognitive decline was evaluated using the AD Neuroimaging Initiative database. METHODS: In 271 healthy subjects, 596 mild cognitive impairment patients and 197 AD patients, serum uric acid and CSF AD biomarkers were measured at baseline, and Mini-Mental State Examination and AD Assessment Scale - Cognitive Subscale (ADAS-cog) were assessed serially (mean duration, 2.9 years). The effect of uric acid on longitudinal cognitive decline was evaluated using linear mixed effect models for Mini-Mental State Examination and ADAS-cog scores in female and male subjects separately, with possible confounders controlled (model 1). To determine the effects of uric acid independent of CSF biomarker (Aß1-42 or tau) and to test whether the detrimental effects of CSF biomarker differ according to uric acid, CSF biomarker and its interaction with uric acid were further included in model 1 (model 2). RESULTS: Higher levels of uric acid were associated with slower cognitive decline, particularly in the mild cognitive impairment and dementia subgroups, and more prominently in female subjects. Model 2 with CSF Aß1-42 showed that higher levels of uric acid were associated with a slower cognitive decline and alleviated the detrimental effect of Aß1-42 on cognitive decline. Model 2 with CSF tau showed that higher levels of uric acid alleviated the detrimental effect of tau on cognitive decline in female subjects but not in male subjects. CONCLUSION: Higher levels of uric acid had protective effects on longitudinal cognitive decline independent of and interactively with CSF AD biomarkers.

Association between dietary fibre intake with cancer and all-cause mortality among 15 740 adults: the National Health and Nutrition Examination Survey III.

BACKGROUND: Few prospective studies have examined the longitudinal associations of total dietary fibre intake and water insoluble and soluble fibres with cancer and all-cause mortality. The present study aimed to examine these associations. METHODS: We studied the effects of total dietary fibre intake and water insoluble and soluble fibres on cancer and all-cause mortality, using data from 15 740 adult participants [mean (SD) age: 44.53 (19.22) years, 46.60% male] in the National Health and Nutrition Examination Survey (NHANES) III, 1988-1994, who had completed a 24-h dietary recall. Death certificate data were obtained up to 2006. Participants had been followed for 13.74 years on average. Cox regression was used to estimate the hazard ratios (HRs) of total dietary, insoluble and soluble fibres on cancer and all-cause mortality, with the first quartile as the reference group, adjusted for demographics, lifestyle and dietary factors. RESULTS: Relative to those in the first quartile of total fibre intake, only the third quartile was associated with all-cause mortality, with an adjusted HR of 0.87 [95% confidence interval (CI) = 0.79, 0.97, P = 0.021], and cancer mortality, with an adjusted HR of 0.77 (95% CI = 0.61, 0.99, P = 0.05). The third quartile of insoluble fibre intake was associated with cancer mortality, with an adjusted HR of 0.76 (95% CI = 0.60, 0.96, P = 0.023), and colorectal-anal cancer mortality (in grouped data as provided for public use), with an adjusted HR of 0.42 (95% CI = 0.19, 0.91, P = 0.03). CONCLUSIONS: Dietary fibre showed protective benefits in terms of mortality risk. Investigating the mechanisms and components of dietary fibres underlying the different protective benefits remains an important consideration for research on fibre-mortality risk.

Risks and predictors of osteoporosis in patients with inflammatory bowel diseases in an Asian population: a nationwide population-based cohort study.

BACKGROUND: We investigated the inflammatory bowel disease (IBD) specific predictors of osteoporosis and pathological fracture by analysing the Taiwan National Health Insurance Research Database. METHODS: Totally, we enrolled 3141 IBD patients and 12,564 age- and sex-matched controls. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of osteoporosis and pathological fracture in both cohorts. RESULTS: Inflammatory bowel disease patients had significantly higher comorbidity-adjusted rates of osteoporosis and pathological fracture compared with controls [adjusted hazard ratio (aHR), 1.31; 95% CI, 1.09-1.60, p = 0.004]. Further analysis indicated that women (aHR, 1.36; 95% CI, 1.09-1.70, p = 0.008), middle-aged patients (aHR, 1.74; 95% CI, 1.25-2.41, p = 0.001), patients with Crohn's disease (aHR, 1.33; 95% CI, 1.09-1.64, p = 0.006) and patients without comorbidities (aHR, 1.81; 95% CI, 1.23-2.67, p = 0.003) exhibited excessive risks of osteoporosis. Moreover, patients requiring hospitalisation for IBD exhibited the highest risk of developing osteoporosis (aHR, 4.46; 95% CI, 2.74-7.27, p < 0.001) and pathological fracture (aHR, 17.1; 95% CI, 5.78-50.9, p < 0.001). CONCLUSIONS: Patients with IBD, particularly women, middle-aged patients and patients without comorbidities, are associated with a long-term risk of osteoporosis. The risks of osteoporosis and pathological fracture were highest in patients requiring hospitalisation for IBD.

The burden of white matter hyperintensities is a predictor of progressive mild cognitive impairment in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: To evaluate whether white matter hyperintensities (WMHs) may act as an independent predictor for progression of cognitive status, the authors analyzed the longitudinal effects of WMHs on cognitive dysfunction in non-demented patients with Parkinson's disease (PD). METHODS: A total of 111 patients with PD were enrolled, including subjects with mild cognitive impairment (MCI, n = 65) and cognitively normal subjects (CN, n = 46). These individuals were classified as MCI converters (n = 22) or MCI non-converters (n = 43) and CN converters (n = 18) or CN non-converters (n = 28) based on whether they were subsequently diagnosed with PD dementia or PD-MCI during a minimum 24-month follow-up. The WMH burden and the Cholinergic Pathway Hyperintensities Scale (CHIPS) and their relationships to longitudinal changes in cognitive performance were examined. RESULTS: PD-MCI converters had larger WMH volume (14421.0 vs. 5180.4, P < 0.001) and higher CHIPS score (22.6 vs. 11.2, P = 0.001) compared with PD-MCI non-converters. Logistic regression analysis revealed in patients with PD-MCI that WMH volume (odds ratio 1.616, P = 0.009) and CHIPS score (odds ratio 1.084, P = 0.007) were independently associated with PD dementia conversion. However, WMH volume and CHIPS score did not differ between PD-CN converters and PD-CN non-converters. In patients with PD-MCI, both WMH volume and CHIPS score were closely associated with longitudinal decline in general cognition, semantic fluency and Stroop test scores. CONCLUSIONS: The present study demonstrates that WMH burden is a significant predictor of conversion from PD-MCI to PD dementia and is related to ongoing decline in frontal-lobe-based cognitive performance.

Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders with overlapping susceptibility loci and symptomatology. We conducted a genome-wide association study (GWAS) of these disorders in a large Swedish sample. We report a new and independent case-control analysis of 1507 SCZ cases, 836 BD cases and 2093 controls. No single-nucleotide polymorphisms (SNPs) achieved significance in these new samples; however, combining new and previously reported SCZ samples (2111 SCZ and 2535 controls) revealed a genome-wide significant association in the major histocompatibility complex (MHC) region (rs886424, P=4.54 × 10(-8)). Imputation using multiple reference panels and meta-analysis with the Psychiatric Genomics Consortium SCZ results underscored the broad, significant association in the MHC region in the full SCZ sample. We evaluated the role of copy number variants (CNVs) in these subjects. As in prior reports, deletions were enriched in SCZ, but not BD cases compared with controls. Singleton deletions were more frequent in both case groups compared with controls (SCZ: P=0.003, BD: P=0.013), whereas the largest CNVs (>500 kb) were significantly enriched only in SCZ cases (P=0.0035). Two CNVs with previously reported SCZ associations were also overrepresented in this SCZ sample: 16p11.2 duplications (P=0.0035) and 22q11 deletions (P=0.03). These results reinforce prior reports of significant MHC and CNV associations in SCZ, but not BD.