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It remains unclear how brain metabolic activities transform in response to dopamine deficiency in the prodromal and early phases of Parkinson's disease (PD).To investigate the relationship between nigrostriatal dopaminergic denervation and brain glucose metabolism in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and early PD.This cohort study included 28 patients with polysomnography-confirmed iRBD, 24 patients with de novo PD with probable rapid eye movement sleep behavior disorder (From HCs to iRBD and finally to theOur findings suggest diverse trajectories of metabolic responses associated with dopaminergic denervation between individual brain areas in the prodromal and early PD stages. © 2022 International Parkinson and Movement Disorder Society.

Abstract Background A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. Methods Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. Results The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18–15.39). Conclusions The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

Background and ObjectivesMild cognitive impairment (MCI) in isolated REM sleep behavior disorder (iRBD) is a risk factor for subsequent neurodegeneration. We aimed to identify brain metabolism and functional connectivity changes related to MCI in patients with iRBD and the neuroimaging markers' predictive value for phenoconversion.MethodsThis is a prospective cohort study of patients with iRBD with a mean follow-up of 4.2 ± 2.6 years. At baseline, patients with iRBD and age- and sex-matched healthy controls (HCs) underwent18F-fluorodeoxyglucose (FDG)–PET and resting-state fMRI scans and a comprehensive neuropsychological test battery. Voxel-wise group comparisons for FDG-PET data were performed using a general linear model. Seed-based connectivity maps were computed using brain regions showing significant hypometabolism associated with MCI in patients with iRBD and compared between groups. A Cox regression analysis was applied to investigate the association between brain metabolism and risk of phenoconversion.ResultsForty patients with iRBD, including 21 with MCI (iRBD-MCI) and 19 with normal cognition (iRBD-NC), and 24 HCs were included in the study. The iRBD-MCI group revealed relative hypometabolism in the inferior parietal lobule, lateral and medial occipital, and middle and inferior temporal cortex bilaterally compared with HC and the iRBD-NC group. In seed-based connectivity analyses, the iRBD-MCI group exhibited decreased functional connectivity of the left angular gyrus with the occipital cortex. Of 40 patients with iRBD, 12 patients converted to Parkinson disease (PD) or dementia with Lewy bodies (DLB). Hypometabolism of the occipital pole (hazard ratio [95% CI] 6.652 [1.387–31.987]), medial occipital (4.450 [1.143–17.327]), and precuneus (3.635 [1.009–13.093]) was associated with higher phenoconversion rate to PD/DLB.DiscussionMCI in iRBD is related to functional and metabolic changes in broad brain areas, particularly the occipital and parietal areas. Moreover, hypometabolism in these brain regions was a predictor of phenoconversion to PD or DLB. Evaluation of cognitive function and neuroimaging characteristics could be useful for risk stratification in patients with iRBD.

To reveal the macular inner retinal change linked to axonal degeneration in Parkinson’s disease (PD), we performed macular optical coherence tomography scan and diffusion tensor imaging of the retrobulbar optic nerve on both eyes of 36 drug-naive PD patients. Thicknesses of inner retinal layers were automatically measured, and correlation analysis was conducted between the retinal thickness and diffusion parameters of the optic nerve. PD patients showed thinning of the inner retinal layers compared to control data. Thicknesses of the ganglion cell and inner plexiform layers were both correlated positively with fractional anisotropy and negatively with diffusivity indices of ipsilateral optic nerve (FDR-adjusted p

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer’s disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose ((18)F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer’s disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p

Cognitive impairments are prevalent in Parkinson’s disease (PD), but the underlying mechanisms of their development are unknown. In this study, we aimed to predict global cognition (GC) in PD with machine learning (ML) using structural neuroimaging, genetics and clinical and demographic characteristics. As a post-hoc analysis, we aimed to explore the connection between novel selected features and GC more precisely and to investigate whether this relationship is specific to GC or is driven by specific cognitive domains. 101 idiopathic PD patients had a cognitive assessment, structural MRI and blood draw. ML was performed on 102 input features including demographics, cortical thickness and subcortical measures, and several genetic variants (APOE, MAPT, SNCA, etc.). Using the combination of RRELIEFF and Support Vector Regression, 11 features were found to be predictive of GC including sex, rs894280, Edinburgh Handedness Inventory, UPDRS-III, education, five cortical thickness measures (R-parahippocampal, L-entorhinal, R-rostral anterior cingulate, L-middle temporal, and R-transverse temporal), and R-caudate volume. The rs894280 of SNCA gene was selected as the most novel finding of ML. Post-hoc analysis revealed a robust association between rs894280 and GC, attention, and visuospatial abilities. This variant indicates a potential role for the SNCA gene in cognitive impairments of idiopathic PD.

Background It remains unclear whether and how the isolated rapid eye movement (REM) sleep behavior disorder (iRBD)-related metabolic pattern (RBDRP) changes with disease progression in iRBD. Objective To examine longitudinal changes in RBDRP expression in iRBD patients and to explore trajectories of relative metabolic activities of individual brain regions constituting RBDRP. Methods In this cohort study, 25 iRBD patients (mean age [±standard deviation], 69.2 ± 5.3 years; 12 [48%] patients were men) and 24 age-matched healthy controls were included. The patients underwent at least two 18 F-fluorodeoxyglucose positron emission tomography scans at baseline and at the 2-year and/or 4-year follow-ups. We measured the RBDRP expression of the patients and controls which was validated by reproduction in a separate iRBD cohort (n = 13). Results At baseline, the RBDRP expression discriminated iRBD patients from healthy controls. However, the RBDRP expression z scores tended to decrease over time in the patients, especially with longer follow-ups, and this tendency was observed even in patients with high-risk of phenoconversion. Furthermore, the degree of RBDRP expression at baseline did not predict the disease conversion. The RBDRP breakdown was mainly provoked by the attenuation of relative hypermetabolism in the frontal cortex including premotor areas and relative hypometabolism in the occipital cortex. The putaminal metabolic activity increased steadily with the disease progression. Conclusions The RBDRP expression in iRBD patients was altered significantly over time. Some of the brain metabolic changes seem to represent attempted functional compensation against ongoing neurodegeneration. The RBDRP expression measurement at one time point may not be a reliable biomarker for predicting disease conversion. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Mild cognitive impairment (MCI) is a common feature of isolated rapid-eye-movement sleep behavior disorder (iRBD). Here, we assessed cognitive functions and MCI in a prospective iRBD cohort and investigated their association with disease-specific brain metabolic patterns. Methods Forty-four patients with polysomnography-confirmed iRBD performed a standardized battery of neuropsychological examinations every two years. We used previously established spatial covariance patterns from de novo drug-naive Parkinson's disease with concomitant RBD (denovoPDRBD-RP) and iRBD (iRBD-RP) using 18F-fluorodeoxyglucose PET scan. We compared those expressions between iRBD with normal cognition (iRBD-NC) and with mild cognitive impairment (iRBD-MCI), and evaluated whether they predict progressive cognitive deterioration. Results Twenty iRBD patients (45 %) had MCI at baseline and 12 patients (27 %, about 7 % per year) had clinically significant cognitive deterioration after 4 years. The iRBD-MCI and iRBD-NC groups showed similar rates of cognitive change, but iRBD-MCI consistently performed worse in the domains of verbal memory and executive function. Elevated denovoPDRBD-RP expression predicted cognitive deterioration (hazard ratio = 5.98 [1.70–21.06]), whereas iRBD-RP did not. Conclusions Increased disease-specific brain metabolic patterns are associated with iRBD-MCI and impending cognitive deterioration with the risk of progression to Lewy body dementia.

ObjectiveTo elucidate the role of Parkinson disease (PD)-related brain metabolic patterns as a biomarker in isolated REM sleep behavior disorder (iRBD) for future disease conversion.MethodsThis is a prospective cohort study consisting of 30 patients with iRBD, 25 patients with de novo PD with a premorbid history of RBD, 21 patients with longstanding PD on stable treatment, and 24 healthy controls. The iRBD group was longitudinally followed up. All participants underwent 18F-fluorodeoxyglucose (FDG) PET and were evaluated with olfaction, cognition, and the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) at baseline. From FDG-PET scans, we derived metabolic patterns from the longstanding PD group (PD-RP) and de novo PD group with RBD (dnPDRBD-RP). Subsequently, we calculated the PD-RP and dnPDRBD-RP scores in patients with iRBD. We validated the metabolic patterns in each PD group and separate iRBD cohort (n = 14).ResultsThe 2 patterns significantly correlated with each other and were spatially overlapping yet distinct. The MDS-UPDRS motor scores significantly correlated with PD-RP (p = 0.013) but not with dnPDRBD-RP (p = 0.076). In contrast, dnPDRBD-RP correlated with olfaction in butanol threshold test (p = 0.018) in patients with iRBD, but PD-RP did not (p = 0.21). High dnPDRBD-RP in patients with iRBD predicted future phenoconversion with all cutoff ranges from 1.5 to 3 SD of the control value, whereas predictability of PD-RP was only significant in a partial range of cutoff.ConclusionThe dnPDRBD-RP is an efficient neuroimaging biomarker that reflects prodromal features of PD and predicts phenoconversion in iRBD that can be applied individually.Classification of EvidenceThis study provides Class IV evidence that a de novo PD pattern on FDG-PET predicts future conversion to neurodegenerative disease in patients with iRBD.

Highlights • PD with mild behavioral impairment revealed deficits in cognitive flexibility. • Brain activities during a set-shifting task linked with MBI in PD was evaluated. • PD-MBI revealed reduced activity in the prefrontal and posterior parietal cortices. • The prefrontal activity was associated with cognitive impairment in PD-MBI. • High MBI-C score was associated with reduced deactivation in the hippocampus., Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergence of sustained neuropsychiatric symptoms, as an at-risk state for incident cognitive decline and dementia. Prior studies have reported that neuropsychiatric symptoms are associated with cognitive abilities in Parkinson’s disease (PD) patients, and we have recently found a strong correlation between MBI and cognitive performance. However, the underlying neural activity patterns of cognitive performance linked to MBI in PD are unknown. Fifty-nine non-demented PD patients and 26 healthy controls were scanned using fMRI during performance of a modified version of the Wisconsin card sorting task. MBI was evaluated using the MBI-checklist, and PD patients were divided into two groups, PD-MBI and PD-noMBI. Compared to the PD-noMBI group and healthy controls, the PD-MBI group revealed less activation in the prefrontal and posterior parietal cortices, and reduced deactivation in the medial temporal region. These results suggest that in PD, MBI reflects deficits in the frontoparietal control network and the hippocampal memory system.

ObjectiveTo evaluate the associations of mild behavioral impairment (MBI) with cognitive deficits and patterns of gray matter changes in Parkinson disease (PD).MethodsSixty patients with PD without dementia and 29 healthy controls underwent a cognitive neuropsychological evaluation and structural MRI scan. MBI was evaluated with the MBI Checklist (MBI-C), a rating scale designed to elicit emergent neuropsychiatric symptoms in accordance with MBI criteria. We divided the patients with PD into 2 groups: 1 group with high MBI-C scores (PD-MBI) and the other with low MBI-C scores (PD-noMBI).ResultsAmong 60 patients with PD, 20 were categorized as having PD-MBI (33.33%). In healthy controls, no participants met the MBI cut-point threshold. The PD-MBI group had significantly lower Montreal Cognitive Assessment and z scores in all 5 domains and the global score compared to healthy controls and those with PD-noMBI. In addition, all cognitive domains except language and global cognition negatively correlated with the MBI-C total score in all patients with PD. For cortical structures, the PD-MBI group revealed middle temporal cortex thinning and decreased volume compared with the PD-noMBI group, and decreased volume in this area negatively correlated with the MBI-C total score.ConclusionsThe impaired cognitive function over all domains and atrophy in the temporal area in the PD-MBI group are in line with posterior cortical circuit deficits in PD, which have been associated with a faster rate of progression to dementia. These initial results suggest that MBI might be an early and important marker for incident cognitive decline and dementia in patients with PD.

Although functional brain imaging has been used for the early and objective assessment of cognitive dysfunction, there is a lack of generalized image-based biomarker which can evaluate individual’s cognitive dysfunction in various disorders. To this end, we developed a deep learning-based cognitive signature of FDG brain PET adaptable for Parkinson’s disease (PD) as well as Alzheimer’s disease (AD). A deep learning model for discriminating AD from normal controls (NCs) was built by a training set consisting of 636 FDG PET obtained from Alzheimer’s Disease Neuroimaging Initiative database. The model was directly transferred to images of mild cognitive impairment (MCI) patients (n = 666) for identifying who would rapidly convert to AD and another independent cohort consisting of 62 PD patients to differentiate PD patients with dementia. The model accuracy was measured by area under curve (AUC) of receiver operating characteristic (ROC) analysis. The relationship between all images was visualized by two-dimensional projection of the deep learning-based features. The model was also designed to predict cognitive score of the subjects and validated in PD patients. Cognitive dysfunction-related regions were visualized by feature maps of the deep CNN model. AUC of ROC for differentiating AD from NC was 0.94 (95% CI 0.89–0.98). The transfer of the model could differentiate MCI patients who would convert to AD (AUC = 0.82) and PD with dementia (AUC = 0.81). The two-dimensional projection mapping visualized the degree of cognitive dysfunction compared with normal brains regardless of different disease cohorts. Predicted cognitive score, an output of the model, was highly correlated with the mini-mental status exam scores. Individual cognitive dysfunction-related regions included cingulate and high frontoparietal cortices, while they showed individual variability. The deep learning-based cognitive function evaluation model could be successfully transferred to multiple disease domains. We suggest that this approach might be extended to an objective cognitive signature that provides quantitative biomarker for cognitive dysfunction across various neurodegenerative disorders.

Background and Objectives: The incidence of visual hallucination (VH) increases with Parkinson's disease (PD) progression, and its development is thought to be related to a specific neurodegenerative process in PD. This study aimed to reveal brain degeneration related to VH in PD by analyzing neuroimaging data obtained from patients in their different stages of PD. Methods: Data from 48 PD patients - 21 nondemented without VH (PNV group), 10 nondemented with VH (PV group), and 17 demented with VH (PVD group) - and 30 age-matched healthy controls (HC group) were analyzed. Voxel-based morphometry and tract-based spatial statistics were conducted. Previous magnetic resonance volumetric studies on VH in PD were collectively reviewed. Results: The PV group showed gray matter atrophy in the right inferior parietal lobule and supramarginal gyrus compared with the HC and PNV groups. The PVD group showed a wider range of gray matter atrophies in the temporo-parieto-occipital regions than those in the PV group. White matter changes seemed to be an earlier event than gray matter changes. Fractional anisotropy values diffusely decreased in all three PD subgroups compared with the HC group without significant differences between the PD subgroups. Mean diffusivity was not different between the PNV and HC groups but increased in the parieto-temporal region in the PV group and increased diffusely in the PVD group, additionally including the fronto-occipital regions. A review of previous studies supported our observations. Conclusions: Gray matter degenerations from the parieto-temporal junction to the parieto-occipital and temporo-occipital regions may be responsible for VH on the typical timeline of PD progression.

Introduction Defective visual information processing contributes to visual hallucination in PD, for which "top-down" and "bottom-up" impairment are suggested mechanisms. This study was aimed to investigate macro- and microstructural neural changes in afferent visual pathways in relation to visual hallucination in nondemented PD patients. Methods This study included 24 nondemented, nondepressed PD patients (10 hallucinating and 14 nonhallucinating) and 15 age-matched healthy controls. We analyzed volumetric and diffusion tensor MRI data by applying region of interest analyses on the visual pathways, including the optic chiasm, bilateral optic nerves, lateral geniculate bodies, optic radiations, and primary visual cortex. Results Patients' demographic characteristics, daily medication doses, as well as duration and motor severity of PD were similar in the two PD groups. Compared to PD patients without hallucination, those with hallucination had fractional anisotropy decrease in the left optic nerve and showed atrophy of lateral geniculate bodies, especially in the left side. In addition, the PD with hallucination group had diffusivity increase in the left optic radiation compared to that in the PD without hallucination and healthy control groups. There were no differences in the primary visual cortex volume among the study groups. Conclusions We found microstructural alterations in visual pathways in nondemented PD patients with hallucination, mainly in first-order neurons and atrophy in the lateral geniculate body where the retinal ganglion cells synapse to second-order neurons. Afferent visual pathway degeneration may occur in a trans-synaptic way in PD. Further studies warrant to be conducted.

Highlights • Mild behavioral impairment in PD is linked to altered corticostriatal connectivity. • PD-MBI have less connectivity between the striatum and the DMN. • PD-MBI have increased atrophy of the SAN. • Caudate head and dorsal putamen connectivity is related to MBI-C scores in PD. • Caudate head-precuneus connectivity is linked to both MBI and MoCA scores., Background Mild behavioral impairment (MBI) is a syndrome characterized by later life onset, sustained neuropsychiatric symptoms as a marker of dementia risk. In Parkinson's disease (PD), MBI has been associated with worse cognitive abilities and increased cortical atrophy. However, the circuit level correlates of MBI have not been investigated in this population. Our objective was to investigate the relationship between MBI and corticostriatal connectivity in PD patients. This emphasis on corticostriatal connectivity was due to the significant role of these circuits in neuropsychiatric and cognitive symptoms across disease conditions. Methods Seventy-four non-demented patients with PD were administered the MBI-checklist, and classified as having high MBI (PD-MBI; n = 21) or low MBI scores (PD-noMBI; n = 53). Corticostriatal connectivity was assessed with both an atlas and seed-based analysis. The atlas analysis consisted of calculating the average connectivity between the striatal network and the default mode (DMN), central executive (CEN), and saliency networks (SAN). Structural measurements of cortical thickness and volume were also assessed. PD-MBI and PD-noMBI patients were compared, along with a group of age matched healthy control subjects (HC; n = 28). Subsequently, a seed analysis assessed the relationship of MBI scores with the connectivity of twelve seeds within the striatum while controlling for cognitive ability. A complementary analysis assessed the relationship between striatal connectivity and cognition, while controlling for MBI-C. Results PD-MBI demonstrated decreased connectivity between the striatum and both the DMN and SAN compared to PD-noMBI and HC. The decreased connectivity between the striatum and the SAN was explained partly by increased atrophy within the SAN in PD-MBI. The seed analysis revealed a relationship between higher MBI scores and lower connectivity of the left caudate head to the dorsal anterior cingulate cortex and left middle frontal gyrus. Higher MBI-C scores were also related to decreased connectivity of the right caudate head with the anterior cingulate cortex, precuneus, and left supramarginal gyrus, as well as increased connectivity to the left hippocampus and right cerebellar hemisphere. Caudate-precuneus connectivity was independently associated with both global behavioural and cognitive scores. Conclusion These results suggest PD-MBI is associated with altered corticostriatal connectivity, particularly between the head of the caudate and cortical regions associated with the DMN and SAN. In particular, caudate-precuneus connectivity is associated with both global behavioral and cognitive symptoms in PD.

OBJECTIVE It is unclear whether the decline in dopamine transporters (DAT) differs among idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with different levels of olfactory impairment. This study aimed to characterize DAT changes in relation to nonmotor features in iRBD patients by olfactory loss. METHODS This prospective cohort study consisted of three age-matched groups: 30 polysomnography-confirmed iRBD patients, 30 drug-naive Parkinson's disease patients, and 19 healthy controls without olfactory impairment. The iRBD group was divided into two groups based on olfactory testing results. Participants were evaluated for reported prodromal markers and then underwent 18F-FP-CIT positron emission tomography and 3T MRI. Tracer uptakes were analyzed in the caudate, anterior and posterior putamen, substantia nigra, and raphe nuclei. RESULTS Olfactory impairment was defined in 38.5% of iRBD patients. Mild parkinsonian signs and cognitive functions were not different between the two iRBD subgroups; however, additional prodromal features, constipation, and urinary and sexual dysfunctions were found in iRBD patients with olfactory impairment but not in those without. Tracer uptake showed significant group differences in all brain regions, except the raphe nuclei. The iRBD patients with olfactory impairment had uptake reductions in the anterior and posterior putamen, caudate, and substantia nigra (p < 0.016 in all, adjusted for age), which ranged from 0.6 to 0.8 of age-normative values. In contrast, those without olfactory impairment had insignificant changes in all regions ranging above 0.8. CONCLUSION There was a clear distinction in DAT loss and nonmotor profiles by olfactory status in iRBD.

ObjectiveTo analyze the relationship between retinal thinning and nigral dopaminergic loss in de novo Parkinson disease (PD).MethodsForty-nine patients with PD and 54 age-matched controls were analyzed. Ophthalmologic examination and macula optical coherence tomography scans were performed with additional microperimetry, N-(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane PET, and 3T MRI scans were done in patients with PD only. Retinal layer thickness and volume were measured in subfields of the 1-, 2.22-, and 3.45-mm Early Treatment of Diabetic Retinopathy Study circle and compared in patients with PD and controls. Correlation of inner retinal layer thinning with microperimetric response was examined in patients with PD, and the relationships between retinal layer thickness and dopamine transporter densities in the ipsilateral caudate, anterior and posterior putamen, and substantia nigra were analyzed.ResultsRetinal layer thinning was observed in the temporal and inferior 2.22-mm sectors (false discovery rate–adjusted p < 0.05) of drug-naive patients with PD, particularly the inner plexiform and ganglion cell layers. The thickness of these layers in the inferior 2.22-mm sector showed a negative correlation with the Hoehn and Yahr stage (p = 0.032 and 0.014, respectively). There was positive correlation between macular sensitivity and retinal layer thickness in all 3.45-mm sectors, the superior 2.22-mm sector, and 1-mm circle (p < 0.05 for all). There was an association between retinal thinning and dopaminergic loss in the left substantia nigra (false discovery rate–adjusted p < 0.001).ConclusionRetinal thinning is present in the early stages of PD, correlates with disease severity, and may be linked to nigral dopaminergic degeneration. Retinal imaging may be useful for detection of pathologic changes occurring in early PD.

Internet gaming disorder (IGD) has been conceptualized as a behavioral addiction and shares clinical, neuropsychological, and personality characteristics with alcohol use disorder (AUD), but IGD dose not entail brain exposure to toxic agents, which renders it different from AUD. To achieve a clear understanding of the neurobiological features of IGD, we aimed to identify morphological and functional changes in IGD and compare them with those in AUD. Individuals with IGD showed larger volume in the hippocampus/amygdala and precuneus than healthy controls (HCs). The volume in the hippocampus positively correlated with the symptom severity of IGD. Moreover, functional connectivity analysis with the hippocampus/amygdala cluster revealed that the left ventromedial prefrontal cortex showed stronger functional connectivity in individuals with IGD compared to those with AUD. In contrast, individuals with AUD exhibited the smaller cerebellar volume and thinner medial frontal cortex than HCs. The volume in the cerebellum correlated with impaired working memory function as well as duration of illness in AUD group. Findings suggested that altered volume and functional connectivity in the hippocampus/amygdala in IGD might be associated with abnormally enhanced memory process of gaming-related cues, while abnormal cortical changes and cognitive impairments in AUD might be associated with neurotoxic effects of alcohol.

Background and Purpose To identify a metabolic network reflecting neurodegeneration in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). Methods We recruited a prospective cohort comprising patients with de novo Parkinson's disease (PD) with probable REM sleep behavior disorder (PDRBD, n=21), polysomnography-confirmed iRBD patients (n=28), and age-matched healthy controls (HC) (n=24). PDRBD-related spatial covariance pattern (PDRBD-RP) were determined from 18F-fluorodeoxyglucose PET images of the PDRBD group and validated by reproduction in a separate PD cohort with polysomnography-confirmed REM sleep behavior disorder (n=11). We also confirmed via 18F-N-3-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)-nortropane PET that none of our iRBD patients had any loss of dopamine transporters (DATs) suggestive of PD. Differences in the PDRBD-RP across groups were compared, and the clinical significance of these metabolic patterns in iRBD patients was further evaluated based on relationships with olfactory and cognitive functions, and striatal DAT densities. Results The PDRBD-RP reflected the previously reported PD-related covariance pattern and additionally showed relative metabolic increases in the hippocampus and premotor cortex. The PDRBD-RP gradually increased from the HC to iRBD patients and to the de novo and validation PDRBD groups. In iRBD patients, the PDRBD-RP was negatively correlated with olfactory and frontal executive functions (age-controlled p

Background. It is suggested that transcranial direct current stimulation (tDCS) can produce lasting changes in corticospinal excitability and can potentially be used for the treatment of neuropathic pain. However, the detailed mechanisms underlying the effects of tDCS are unknown. Objective. We investigated the underlying neural mechanisms of tDCS for chronic pain relief using [18F]-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET). Methods. Sixteen patients with neuropathic pain (mean age 44.1 ± 8.6 years, 4 females) due to traumatic spinal cord injury received sham or active anodal stimulation of the motor cortex using tDCS for 10 days (20 minutes, 2 mA, twice a day). The effect of tDCS on regional cerebral glucose metabolism was evaluated by [18F]FDG-PET before and after tDCS sessions. Results. There was a significant decrease in the numeric rating scale scores for pain, from 7.6 ± 0.5 at baseline to 5.9 ± 1.8 after active tDCS ( P = .016). We found increased metabolism in the medulla and decreased metabolism in the left dorsolateral prefrontal cortex after active tDCS treatment compared with the changes induced by sham tDCS. Additionally, an increase in metabolism after active tDCS was observed in the subgenual anterior cingulate cortex and insula. Conclusion. The results of this study suggest that anodal stimulation of the motor cortex using tDCS can modulate emotional and cognitive components of pain and normalize excessive attention to pain and pain-related information.

Traditionally, it has been thought that probabilistic category learning, one of the implicit memory functions, is dependent on the basal ganglia. However, there is growing evidence indicating the involvement of the dorsolateral prefrontal cortex (DLPFC) in probabilistic category learning. In order to identify the causal role of DLPFC in probabilistic category learning, we investigated whether repetitive transcranial magnetic stimulation (rTMS) over the left DLPFC influences the learning ability in healthy subjects using the weather prediction task (WPT). Application of 10 Hz rTMS over the left DLPFC induced significant improvement in the total hit rate during the total trials of the WPT, compared with sham stimulation. Specifically, the improvement was significant in the early and late learning blocks of the WPT, but not in the intermediate block of learning. These results indicate that the left DLPFC may play an important role in probabilistic category learning, possibly by influencing not only on embodied information application in late stage of the learning but also on memory encoding for working memory demands in early stage of the learning via frontostriatal and frontohippocampal circuits, respectively. They also may lend support to the possibility that rTMS can improve implicit learning ability in patients with basal ganglia disorders.

Postviral olfactory loss after upper respiratory tract infection (URI) is not uncommon. However, its exact location and nature are not fully understood. Although it is likely to be caused by a direct damage of olfactory epithelium, a damage of the central pathway has also been suspected as its possible mechanism. This study will show basal metabolism in the brain of patients with postviral olfactory loss using fluorodeoxyglucose-positron emission tomography (FDG PET).Nine patients with postviral olfactory dysfunction were enrolled. All of the patients had neither apparent sinusitis nor rhinitis. All of them recalled causative URI and temporal connection with development of their olfactory loss. After olfactory function tests using the butanol threshold test and smell identification test confirmed olfactory impairment, FDG PET studies were performed during a rest state. The cerebral metabolic abnormality was compared between the patients and age/gender-matched healthy controls using a voxel-wised analysis.In comparison with healthy controls, the patients showed a significant hypometabolism in the right piriform cortex and bilateral amygdala and parahippocampal areas where the olfactory neurons primarily project. Furthermore, hypometabolism was also shown in the bilateral insular cortices, medial and lateral temporal cortex where the olfactory information is integrated to produce the sensation. Increased metabolism was not found in any brain area.This study showed that the postviral olfactory loss is likely to be associated with decreased metabolism in the specific brain regions where the olfactory information is received and integrated.

Objectives Although many preclinical studies have suggested the possible linkage between dyslipidemia and cerebral amyloid deposition, the association between serum lipid measures and cerebral amyloid-beta (Aβ) deposition in human brain is still poorly known. We aimed to investigate the association in cognitively normal (CN) elderly individuals. Design Cross-sectional study. Setting University hospital dementia clinic. Participants 59 CN elderly. Measurements The study measures included comprehensive clinical and neuropsychological assessment based on the CERAD protocol, magnetic resonance imaging and 11 C-labelled Pittsburgh Compound B positron emission tomography scans, and quantification for serum lipid biomarkers. Results Multiple linear regression analyses showed that a higher serum triglycerides level was associated with heavier global cerebral Aβ deposition even after controlling age, sex, and apolipoprotein E e4 genotype. Serum apolipoprotein B also showed significant positive association with global cerebral Aβ deposition, but the significance disappeared after controlling serum triglycerides level. No association was found between other lipid measures and global cerebral Aβ deposition. Conclusions The findings suggest that serum triglycerides are closely associated with cerebral amyloidosis, although population-based prospective studies are needed to provide further evidence of the causative effect of triglycerides on cerebral amyloidosis.

Defective visual information processing contributes to visual hallucination in PD, for which "top-down" and "bottom-up" impairment are suggested mechanisms. This study was aimed to investigate macro- and microstructural neural changes in afferent visual pathways in relation to visual hallucination in nondemented PD patients.This study included 24 nondemented, nondepressed PD patients (10 hallucinating and 14 nonhallucinating) and 15 age-matched healthy controls. We analyzed volumetric and diffusion tensor MRI data by applying region of interest analyses on the visual pathways, including the optic chiasm, bilateral optic nerves, lateral geniculate bodies, optic radiations, and primary visual cortex.Patients' demographic characteristics, daily medication doses, as well as duration and motor severity of PD were similar in the two PD groups. Compared to PD patients without hallucination, those with hallucination had fractional anisotropy decrease in the left optic nerve and showed atrophy of lateral geniculate bodies, especially in the left side. In addition, the PD with hallucination group had diffusivity increase in the left optic radiation compared to that in the PD without hallucination and healthy control groups. There were no differences in the primary visual cortex volume among the study groups.We found microstructural alterations in visual pathways in nondemented PD patients with hallucination, mainly in first-order neurons and atrophy in the lateral geniculate body where the retinal ganglion cells synapse to second-order neurons. Afferent visual pathway degeneration may occur in a trans-synaptic way in PD. Further studies warrant to be conducted.

The processing and metabolism of amyloid precursor protein (APP) is a major interest in Alzheimer disease (AD) research, because not only amyloid β (Aβ) peptide, but also cellular or mitochondrial APP are intimately involved in cellular dysfunction and AD pathogenesis. Here we demonstrate that APP is directly and efficiently cleaved by the HtrA2 serine protease in vitro and in vivo. Using several APP mutants and N-terminal amino acid sequencing, we identified that the HtrA2-mediated APP cleavage product is the C161 fragment encompassing amino acids 535-695 of APP695. The immunofluorescence and subcellular fractionation studies indicate that APP is partly colocalized with HtrA2 in the mitochondria where HtrA2 can cleave APP under normal conditions. The HtrA2-cleaved C161 fragment was detected in the cytosolic fraction; therefore, we postulate that the C161 fragment is released into the cytosol after cleavage of APP by HtrA2. Interestingly, the level of C161 was remarkably decreased in motor neuron degeneration (mnd2) mice in which the serine protease activity of HtrA2 was greatly reduced. These results show that the protease activity of HtrA2 is essential for the production of C161 and that processing of APP into C161 is a natural event occurring under normal physiological conditions. Our study suggests that the direct cleavage of mitochondrial APP by HtrA2 may prevent mitochondrial dysfunction caused by accumulation of APP and that the regulation of HtrA2 protease activity may be a therapeutic target in AD.

We describe here the synthesis of 99mTc-ciprofloxacin by four different methods and its biodistribution. All of the methods gave high radiochemical yields of > or = 90% and high stability of > or = 90% at 6 h after preparation. However HPLC analysis, bacterial binding assay, and in vivo distribution for the four 99mTc-ciprofloxacins showed different results. Among these methods, the use of formamidine sulfinic acid with microwave heating (Method A) was fast and easy, and gave more desirable biological properties than the other methods.

The dopaminergic system is involved in the regulation of food intake, which is crucial for the maintenance of body weight. We examined the relationship between striatal dopamine (DA) D2/3 receptor availability and body mass index (BMI) in 25 non-obese healthy male subjects using [(11)C]raclopride and positron emission tomography. None of [(11)C]raclopride binding potential (BP) values (measures of DA D2/3 receptor availability) in striatal subregions (dorsal caudate, dorsal putamen, and ventral striatum) in the left and right hemispheres was significantly correlated with BMI. However, there was a positive correlation between the right-left asymmetry index of [(11)C]raclopride BP in the dorsal putamen and BMI (r=0.43, p

Neuropathic pain is one of the major problems of patients with spinal cord injury (SCI), which remains refractory to treatment despite a variety of therapeutic approach. Multimodal neuroimaging could provide complementary information for brain mechanisms underlying neuropathic pain, which could be based on development of more effective treatment strategies. Ten patients suffering from chronic neuropathic pain after SCI and 10 healthy controls underwent FDG-PET, T1-anatomical MRI and diffusion tensor imaging. We found decreases of both metabolism and the gray matter volume in the left dorsolateral prefrontal cortex in patients compared to healthy controls, as well as hypometabolism in the medial prefrontal cortex and gray matter volume loss in bilateral anterior insulae and subgenual anterior cingulate cortices. These brain regions are generally known to participate in pain modulation by affective and cognitive processes. Decreases of mean diffusivity (MD) in the right internal capsule including, cerebral peduncle, pre-and post-central white matter, and prefrontal white matter as components of the corticospinal and thalamocortical tracts were demonstrated in patients. Further, lower MD value of prefrontal white matter was correlated with decreased metabolism of medial prefrontal cortex in patients. These results indicated that white matter changes imply abnormal pain modulation in patients as well as motor impairment. Our study showed the functional and structural multimodal imaging modality commonly identified the possible abnormalities in the brain regions participating pain modulation in neuropathic pain. Multifaceted imaging studies in neuropathic pain could be useful elucidating precise mechanisms of persistent pain, and providing future directions for treatment.

This study aimed to clarify whether homocysteine has independent association, not mediated by cerebral beta amyloid protein deposition and vascular burden, with whole brain or hippocampal volume in elderly individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease. Nineteen mild cognitive impairment and 24 Alzheimer's disease patients were recruited from the Dementia Clinic of the Seoul National University Hospital. Fourteen cognitively normal elderly subjects were also selected from a pool of elderly volunteers. Multiple linear regression analyses showed that plasma total homocysteine level was significantly associated with hippocampal volume even after controlling the degree of global cerebral beta amyloid deposition and vascular burden as well as other potential confounders including age, gender, education, and apolipoprotein E e4 genotype. On the contrary, plasma total homocysteine level did not show any significant association with whole brain volume. Our finding of the independent negative association between homocysteine and hippocampal volume suggests that homocysteine has a direct adverse effect, not mediated by cerebral beta amyloid deposition and vascular burden, on the hippocampus.

To better understand the functional role of cerebellum within the large-scale cerebellocerebral neural network, we investigated the changes of neuronal activity elicited by cerebellar repetitive transcranial magnetic stimulation (rTMS) using (18)F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). Twelve right-handed healthy volunteers were studied with brain FDG PET under two conditions: active rTMS of 1 Hz frequency over the left lateral cerebellum and sham stimulation. Compared to the sham condition, active rTMS induced decreased glucose metabolism in the stimulated left lateral cerebellum, the areas known to be involved in voluntary motor movement (supplementary motor area and posterior parietal cortex) in the right cerebral hemisphere, and the areas known to be involved in cognition and emotion (orbitofrontal, medial frontal, and anterior cingulate gyri) in the left cerebral hemisphere. Increased metabolism was found in cognition- and language-related brain regions such as the left inferior frontal gyrus including Broca's area, bilateral superior temporal gyri including Wernicke's area, and bilateral middle temporal gyri. Left cerebellar rTMS also led to increased metabolism in the left cerebellar dentate nucleus and pons. These results demonstrate that rTMS over the left lateral cerebellum modulates not only the target region excitability but also excitability of remote, but interconnected, motor-, language-, cognition-, and emotion-related cerebral regions. They provide further evidence that the cerebellum is involved not only in motor-related functions but also in higher cognitive abilities and emotion through the large-scale cerebellocereberal neural network.

Background: Decreased cerebral glucose metabolism has been reported in patients with sleep apnea syndrome (SAS), but it has yet to be decided whether cerebral glucose metabolism in SAS can be altered by continuous positive airway pressure (CPAP) treatment. Objective: The aim of this study was to evaluate cerebral glucose metabolism changes in patients with SAS after CPAP treatment. Methods: Thirteen middle-aged male patients with severe SAS [mean age 49.3 ± 7.2 years, mean apnea-hypopnea index (AHI) 60.4 ± 21.2] and 13 male controls (mean age 46.0 ± 9.4 years, mean AHI 4.1 ± 3.7) participated in the study. All 26 study subjects underwent fluorodeoxyglucose-positron emission tomography (FDG-PET), but SAS patients underwent FDG-PET twice, namely before and 3 months after acceptable CPAP usage. Results: Significant hypometabolism was observed in the bilateral prefrontal areas, left cuneus and left cingulate cortex of SAS patients before CPAP, and after CPAP, significant increases in cortical glucose metabolism were observed in the bilateral precentral gyri and left anterior cingulate cortex. However, these improvements in hypometabolism in both areas were insufficient to reach control levels, and hypometabolism in other regions persisted after CPAP treatment. Conclusions: Reduced cerebral glucose metabolism in the precentral gyrus and the cingulate cortex in patients with SAS was modestly improved by acceptable CPAP treatment. The findings of this study suggest that acceptable CPAP usage cannot completely reverse reduced cerebral glucose metabolism in SAS patients. Further studies are required to evaluate the long-term effects of CPAP treatment with total compliance.

To investigate the relationship between in vivo brain amyloid-beta (Aβ) burden, measured by C-labeled Pittsburgh Compound B (C-PiB) retention, and age-at-onset in patients with Alzheimer disease (AD).Cross-sectional study.University Dementia Clinic.Twenty-two AD patients including 11 early-onset AD (EOAD: onset65 years) and 11 late-onset AD (LOAD: onset ≥65years) cases with matched dementia severity, duration of illness, and apolipoprotein E ε4 allele number.C-PiB positron emission tomography scans.Both region of interest and voxel-based analyses were performed to compare C-PiB retention between EOAD and LOAD groups, and to test linear relationship between age-at-onset and C-PiB retention.Both region of interest (ROI) and voxel-based analyses revealed that EOAD patients had significantly higher C-PIB retentions than LOAD patients in diffuse brain regions including frontal, lateral parietal, lateral temporal, and occipital cortex, and basal ganglia. Subgroup analyses showed that negative correlation between age-at-onset and C-PiB retention was significant in LOAD but not in EOAD.Our finding of a heavier Aβ burden in the brain of living EOAD patients than LOAD patients is in agreement with those from postmortem studies. The inverse relationship between age-at-onset and Aβ burden is possibly associated with aging-related decrease of brain or cognitive reserve and with aging-related increase of brain vulnerability.

Introduction: Internet game overuse is an emerging disorder and features diminished impulse control and poor reward-processing. In an attempt to understand the neurobiological bases of Internet game overuse, we investigated the differences in regional cerebral glucose metabolism at resting state between young individuals with Internet game overuse and those with normal use using 18F-fluorodeoxyglucose positron emission tomography study.Methods: Twenty right-handed male participants (9 normal users: 24.7±2.4 years of age, 11 overusers: 23.5±2.9 years of age) participated. A trait measure of impulsivity was also completed after scanning.Results: Internet game overusers showed greater impulsiveness than the normal users and there was a positive correlation between the severity of Internet game overuse and impulsiveness. Imaging data showed that the overusers had increased glucose metabolism in the right middle orbitofrontal gyrus, left caudate nucleus, and right insula, and decreased metabolism in the bilateral postcentral gyrus, left precentrai gyrus, and bilateral occipital regions compared to normal users.Conclusion: Internet game overuse may be associated with abnormal neurobiological mechanisms in the orbitofrontal cortex, striatum, and sensory regions, which are implicated in impulse control, reward processing, and somatic representation of previous experiences. Our results support the idea that Internet game overuse shares psychological and neural mechanisms with other types of impulse control disorders and substance/non-substance-related addiction.