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Abstract Patients with dementia with Lewy bodies (DLB) show widespread brain metabolic changes. This study investigated whether brain hypo- and hypermetabolism in DLB have differential effects on cognition. We enrolled 55 patients with DLB (15 prodromal DLB [MCI-LB] and 40 probable DLB) and 13 healthy controls who underwent 18F-fluorodeoxyglucose positron emission tomography and detailed neuropsychological tests. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism were calculated as follows: index(-) for hypometabolism [DLB-hypo] and index(+) for hypermetabolism [DLB-hyper]. The effects of DLB-hypo or DLB-hyper on cognitive function were assessed using a multivariate linear regression model. Additionally, a linear mixed model was used to investigate the association between each index and the longitudinal cognitive decline. There was no correlation between DLB-hypo and DLB-hyper in the disease group. The multivariate linear regression model showed that DLB-hypo was associated with language, visuospatial, visual memory, and frontal/executive functions; whereas DLB-hyper was responsible for attention and verbal memory. There was significant interaction between DLB-hypo and DLB-hyper for verbal and visual memory, which was substantially affected by DLB-hyper in relatively preserved DLB-hypo status. A linear mixed model showed that DLB-hypo was associated with longitudinal cognitive outcomes, regardless of cognitive status, and DLB-hyper contributed to cognitive decline only in the MCI-LB group. The present study suggests that DLB-hypo and DLB-hyper may be independent of each other and differentially affect the baseline and longitudinal cognitive function in patients with DLB.

Abstract Background Cholesterol is an essential component of the neuronal cell membrane and is crucial for neuronal function; however, the role of cholesterol levels in Parkinson’s disease (PD) is debatable. This study investigated the complex relationship between total cholesterol (TC) levels, body mass index (BMI), and cognition in patients with PD. Methods This study included 321 drug-naïve patients with PD who underwent dopamine transporter (DAT) imaging and baseline neuropsychological tests. Multivariate linear regression and Cox regression models were used to investigate the effect of TC levels on the composite score of each cognitive domain and dementia conversion after adjusting for covariates, respectively. Interaction analyses were performed to examine the interaction effect between TC levels and BMI on baseline cognition and dementia conversion. Results TC levels and cognition showed no significant relationship after adjusting for potential confounders. A significant interaction effect between TC levels and BMI was observed in frontal/executive function and dementia conversion. Further analyses showed that TC levels were positively associated with frontal/executive function in the under-/normal weight group (β = 0.205, p = 0.013), whereas a negative relationship existed between TC levels and frontal/executive function in the obese group (β = − 0.213, p = 0.017). Cox regression analyses also showed the differential effects of TC levels on dementia conversion according to BMI (under-/normal weight group: hazard ratio [HR] = 0.550, p = 0.013; obese group: HR = 2.085, p = 0.014). Conclusions This study suggests a cross-over interaction between TC levels and BMI on cognitive symptoms in PD.

IntroductionCerebrospinal fluid (CSF) flow is involved in brain waste clearance and may be impaired in neurodegenerative diseases such as Parkinson’s disease. This study aims to investigate the relationship between the CSF pulsation and the development of dementia in Parkinson’s disease (PD) patients using EPI-based fMRI.MethodsWe measured CSF pulsation in the 4th ventricle of 17 healthy controls and 35 PD patients using a novel CSF pulsation index termed “CSFpulse” based on echo-planar imaging (EPI)-based fMRI. The PD patients were classified into a PD with dementia high-risk group (PDD-H, n = 19) and a low risk group (PDD-L, n = 16), depending on their development of dementia within 5 years after initial brain imaging. The size of the 4th ventricle was measured using intensity-based thresholding.ResultsWe found that CSF pulsation was significantly higher in PD patients than in healthy controls, and that PD patients with high risk of dementia (PDD-H) had the highest CSF pulsation. We also observed an enlargement of the 4th ventricle in PD patients compared to healthy controls.ConclusionOur results suggest that CSF pulsation may be a potential biomarker for PD progression and cognitive decline, and that EPI-based fMRI can be a useful tool for studying CSF flow and brain function in PD.

Abstract Cognitive impairment in Parkinson’s disease (PD) severely affects patients’ prognosis, and early detection of patients at high risk of dementia conversion is important for establishing treatment strategies. We aimed to investigate whether multiparametric MRI radiomics from basal ganglia can improve the prediction of dementia development in PD when integrated with clinical profiles. In this retrospective study, 262 patients with newly diagnosed PD (June 2008–July 2017, follow-up >5 years) were included. MRI radiomic features (n = 1284) were extracted from bilateral caudate and putamen. Two models were developed to predict dementia development: (1) a clinical model—age, disease duration, and cognitive composite scores, and (2) a combined clinical and radiomics model. The area under the receiver operating characteristic curve (AUC) were calculated for each model. The models’ interpretabilities were studied. Among total 262 PD patients (mean age, 68 years ± 8 [standard deviation]; 134 men), 51 (30.4%), and 24 (25.5%) patients developed dementia within 5 years of PD diagnosis in the training (n = 168) and test sets (n = 94), respectively. The combined model achieved superior predictive performance compared to the clinical model in training (AUCs 0.928 vs. 0.894, P = 0.284) and test set (AUCs 0.889 vs. 0.722, P = 0.016). The cognitive composite scores of the frontal/executive function domain contributed most to predicting dementia. Radiomics derived from the caudate were also highly associated with cognitive decline. Multiparametric MRI radiomics may have an incremental prognostic value when integrated with clinical profiles to predict future cognitive decline in PD.

Abstract Motor reserve (MR) may explain why individuals with similar pathological changes show marked differences in motor deficits in Parkinson’s disease (PD). In this study, we investigated whether estimated individual MR was linked to local striatal volume (LSV) in PD. We analyzed data obtained from 333 patients with drug naïve PD who underwent dopamine transporter scans and high-resolution 3-tesla T1-weighted structural magnetic resonance images. Using a residual model, we estimated individual MRs on the basis of initial UPDRS-III score and striatal dopamine depletion. We performed a correlation analysis between MR estimates and LSV. Furthermore, we assessed the effect of LSV, which is correlated with MR estimates, on the longitudinal increase in the levodopa-equivalent dose (LED) during the 4-year follow-up period using a linear mixed model. After controlling for intracranial volume, there was a significant positive correlation between LSV and MR estimates in the bilateral caudate, anterior putamen, and ventro-posterior putamen. The linear mixed model showed that the large local volume of anterior and ventro-posterior putamen was associated with the low requirement of LED initially and accelerated LED increment thereafter. The present study demonstrated that LSV is crucial to MR in early-stage PD, suggesting LSV as a neural correlate of MR in PD.

Abstract We evaluated the patterns of quantitative electroencephalography (EEG) in patients with Alzheimer’s disease (AD), Lewy body disease (LBD), and mixed disease. Sixteen patients with AD, 38 with LBD, 20 with mixed disease, and 17 control participants were recruited and underwent EEG. The theta/alpha ratio and theta/beta ratio were measured. The relationship of the log-transformed theta/alpha ratio (TAR) and theta/beta ratio (TBR) with the disease group, the presence of AD and LBD, and clinical symptoms were evaluated. Participants in the LBD and mixed disease groups had higher TBR in all lobes except for occipital lobe than those in the control group. The presence of LBD was independently associated with higher TBR in all lobes and higher central and parietal TAR, while the presence of AD was not. Among cognitively impaired patients, higher TAR was associated with the language, memory, and visuospatial dysfunction, while higher TBR was associated with the memory and frontal/executive dysfunction. Increased TBR in all lobar regions and temporal TAR were associated with the hallucinations, while cognitive fluctuations and the severity of Parkinsonism were not. Increased TBR could be a biomarker for LBD, independent of AD, while the presence of mixed disease could be reflected as increased TAR.

Objective To investigate whether there is a link between cognitive function and motor reserve (i.e., individual capacity to cope with nigrostriatal dopamine depletion) in patients with newly diagnosed Parkinson’s disease (PD). Methods A total of 163 patients with drug-naïve PD who underwent 18F-FP-CIT PET, brain MRI, and a detailed neuropsychological test were enrolled. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We performed correlation analyses between motor reserve estimates and cognitive composite scores. Diffusion connectometry analysis was performed to map the white matter fiber tracts, of which fractional anisotropy (FA) values were well correlated with motor reserve estimates. Additionally, Cox regression analysis was used to assess the effect of initial motor reserve on the risk of dementia conversion. Results The motor reserve estimate was positively correlated with the composite score of the verbal memory function domain (γ = 0.246) and with the years of education (γ = 0.251). Connectometry analysis showed that FA values in the left fornix were positively correlated with the motor reserve estimate, while no fiber tracts were negatively correlated with the motor reserve estimate. Cox regression analysis demonstrated that higher motor reserve estimates tended to be associated with a lower risk of dementia conversion (hazard ratio, 0.781; 95% confidence interval, 0.576–1.058). Conclusion The present study demonstrated that the motor reserve estimate was well correlated with verbal memory function and with white matter integrity in the left fornix, suggesting a possible link between cognition and motor reserve in patients with PD.

IntroductionConcomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies.MethodsWe enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status.ResultsThere was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone.DiscussionThis study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

Abstract Levodopa-induced dyskinesia (LID), a long-term motor complication in Parkinson’s disease (PD), is attributable to both presynaptic and postsynaptic mechanisms. However, no studies have evaluated the baseline structural changes associated with LID at a subcortical level in PD. A total of 116 right-handed PD patients were recruited and based on the LID latency of 5 years, we classified patients into those vulnerable to LID (PD-vLID, n = 49) and those resistant to LID (PD-rLID, n = 67). After adjusting for covariates including dopamine transporter (DAT) availability of the posterior putamen, we compared the subcortical shape between the groups and investigated its association with the onset of LID. The PD-vLID group had lower DAT availability in the posterior putamen, higher parkinsonian motor deficits, and faster increment in levodopa equivalent dose than the PD-rLID group. The PD-vLID group had significant inward deformation in the right thalamus compared to the PD-rLID group. Inward deformation in the thalamus was associated with an earlier onset of LID at baseline. This study suggests that independent of presynaptic dopamine depletion, the thalamus is a major neural substrate for LID and that a contracted thalamic shape at baseline is closely associated with an early development of LID.

Objective The Montreal Cognitive Assessment (MoCA) is recommended for assessing general cognition in Parkinson’s disease (PD). Several cutoffs of MoCA scores for diagnosing PD with cognitive impairment (PD-CI) have been proposed, with varying sensitivity and specificity. This study investigated the utility of machine learning algorithms using MoCA cognitive domain scores for improving diagnostic performance for PD-CI. Methods In total, 2,069 MoCA results were obtained from 397 patients with PD enrolled in the Parkinson’s Progression Markers Initiative database with a diagnosis of cognitive status based on comprehensive neuropsychological assessments. Using the same number of MoCA results randomly sampled from patients with PD with normal cognition or PD-CI, discriminant validity was compared between machine learning (logistic regression, support vector machine, or random forest) with domain scores and a cutoff method. Results Based on cognitive status classification using a dataset that permitted sampling of MoCA results from the same individual (n = 221 per group), no difference was observed in accuracy between the cutoff value method (0.74 ± 0.03) and machine learning (0.78 ± 0.03). Using a more stringent dataset that excluded MoCA results (n = 101 per group) from the same patients, the accuracy of the cutoff method (0.66 ± 0.05), but not that of machine learning (0.74 ± 0.07), was significantly reduced. Inclusion of cognitive complaints as an additional variable improved the accuracy of classification using the machine learning method (0.87–0.89). Conclusion Machine learning analysis using MoCA domain scores is a valid method for screening cognitive impairment in PD.

Visual hallucinations are a prevalent symptom of Parkinson’s disease. Here the authors use a structural mega-analysis to show cortical regions and networks involved in visual hallucinations and associations with receptor density maps.

Abstract To evaluate the implication of 18F-fluorodeoxyglucose (FDG)- and dopamine transporter (DAT)-positron emission tomography (PET) in the diagnosis and clinical symptoms of dementia with Lewy bodies (DLB), 55 DLB patients and 49 controls underwent neuropsychological evaluation and FDG-, DAT-, and 18F-Florbetaben (FBB) PET. DAT- and FDG-uptake and FDG/DAT ratio were measured in the anterior and posterior striatum. The first principal component (PC1) of FDG subject residual profiles was identified for each subject. Receiver operating characteristic curve analyses for the diagnosis of DLB were performed using FDG- and DAT-PET biomarkers as predictors, and general linear models for motor severity and cognitive scores were performed adding FBB standardized uptake value ratio as a predictor. Increased metabolism in the bilateral putamen, vermis, and somato-motor cortices, which characterized PC1, was observed in the DLB group, compared to the control group. A combination of posterior putamen FDG/DAT ratio and PC1 showed the highest diagnostic accuracy (91.8% sensitivity and 96.4% specificity), which was significantly greater than that obtained by DAT uptake alone. Striatal DAT uptake and PC1 independently contributed to motor severity and language, memory, frontal/executive, and general cognitive dysfunction in DLB patients, while only PC1 contributed to attention and visuospatial dysfunction.

BackgroundAdult neurogenesis is the process of generating new neurons to enter neural circuits and differentiate into functional neurons. However, it is significantly reduced in Parkinson’s disease (PD). Uric acid (UA), a natural antioxidant, has neuroprotective properties in patients with PD. This study aimed to investigate whether UA would enhance neurogenesis in PD.MethodsWe evaluated whether elevating serum UA levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mouse model would restore neurogenesis in the subventricular zone (SVZ). For a cellular model, we primary cultured neural precursor cells (NPCs) from post-natal day 1 rat and evaluated whether UA treatment promoted cell proliferation against 1-methyl-4-phenylpyridinium (MPP+).ResultsUric acid enhanced neurogenesis in both in vivo and in vitro parkinsonian model. UA-elevating therapy significantly increased the number of bromodeoxyuridine (BrdU)-positive cells in the SVZ of PD animals as compared to PD mice with normal UA levels. In a cellular model, UA treatment increased the expression of Ki-67. In the process of modulating neurogenesis, UA elevation up-regulated the expression of mitochondrial fusion markers.ConclusionIn MPTP-induced parkinsonian model, UA probably enhanced neurogenesis via regulating mitochondrial dynamics, promoting fusion machinery, and inhibiting fission process.

Abstract We investigated the efficacy of donepezil for mild cognitive impairment in Parkinson’s disease (PD-MCI). This was a prospective, non-randomized, open-label, two-arm study. Eighty PD-MCI patients were assigned to either a treatment or control group. The treatment group received donepezil for 48 weeks. The primary outcome measures were the Korean version of Mini-Mental State Exam and Montreal Cognitive Assessment scores. Secondary outcome measures were the Clinical Dementia Rating, Unified Parkinson’s Disease Rating Scale part III, Clinical Global Impression scores. Progression of dementia was assessed at 48-week. Comprehensive neuropsychological tests and electroencephalography (EEG) were performed at baseline and after 48 weeks. The spectral power ratio of the theta to beta2 band (TB2R) in the electroencephalogram was analyzed. There was no significant difference in the primary and secondary outcome measures between the two groups. However, the treatment group showed a significant decrease in TB2R at bilateral frontotemporoparietal channels compared to the control group. Although we could not demonstrate improvements in the cognitive functions, donepezil treatment had a modulatory effect on the EEG in PD-MCI patients. EEG might be a sensitive biomarker for detecting changes in PD-MCI after donepezil treatment.

The concept of cognitive reserve (CR) in Alzheimer’s disease (AD) explains the differences between individuals in their susceptibility to AD-related pathologies. An enhanced CR may lead to less cognitive deficits despite severe pathological lesions. Parkinson’s disease (PD) is also a common neurodegenerative disease and is mainly characterized by motor dysfunction related to striatal dopaminergic depletion. The degree of motor deficits in PD is closely correlated to the degree of dopamine depletion; however, significant individual variations still exist. Therefore, we hypothesized that the presence of motor reserve (MR) in PD explains the individual differences in motor deficits despite similar levels of striatal dopamine depletion. Since 2015, we have performed a series of studies investigating MR in de novo patients with PD using the data of initial clinical presentation and dopamine transporter PET scan. In this review, we summarized the results of these published studies. In particular, some premorbid experiences (i.e., physical activity and education) and modifiable factors (i.e., body mass index and white matter hyperintensity on brain image studies) could modulate an individual’s capacity to tolerate PD pathology, which can be maintained throughout disease progression.

Abstract Objective We aimed to investigate the association of the serum urate level with cortical thickness and white matter integrity in multiple system atrophy (MSA). Methods We recruited 75 MSA patients and 42 controls who underwent brain MRI and measured serum urate level at baseline. Using cortical thickness and tract‐based spatial statistics analyses, we investigated the correlation between serum urate levels and cortical thickness or diffusion tensor imaging (DTI) measures in controls and MSA patients. Interaction effects were analyzed to find different patterns of correlation according to sex and clinical subtype. We evaluated the relationship between serum urate levels, DTI measures, and total UMSARS score, using path analysis. Results Serum urate levels showed a positive correlation with FA values in the corpus callosum and a negative correlation with MD values in widespread regions including cerebellar, brainstem, and cerebral white matter in patients with MSA. Both sexes showed a negative correlation between serum urate levels and MD values without significant interaction effect. In subgroup analysis according to subtype, patients with cerebellar subtype showed a negative correlation. Serum urate levels did not correlated with cortical thickness. Path analysis showed that MD values in middle and inferior cerebellar peduncle mediated the association between serum urate level and total UMSAR score. Interpretation The present study demonstrated that serum urate levels played a pivotal role in white matter disintegrity and clinical disability in MSA. It would provide an evidence of the role of urate as a potential neuroprotective factor against white matter neurodegeneration in MSA.

Purpose To analyze the altered brain regions and intrinsic brain activity patterns in trauma-exposed firefighters without posttraumatic stress disorder (PTSD). Materials and Methods Resting-state functional MRI (rsfMRI) was performed for all subjects. Thirty-one firefighters over 40 years of age without PTSD (31 men; mean age, 49.8 ± 4.7 years) were included. Twenty-six non-traumatized healthy controls (HCs) (26 men; mean age, 65.3 ± 7.84 years) were also included. Voxel-based morphometry was performed to investigate focal differences in the brain anatomy. Seed-based functional connectivity analysis was performed to investigate differences in spontaneous brain characteristics. Results The mean z-scores of the Seoul Verbal Learning Test for immediate and delayed recall, Controlled Oral Word Association Test (COWAT) score for animals, and COWAT phonemic fluency were significantly lower in the firefighter group than in the HCs, indicating decreased neurocognitive function. Compared to HCs, firefighters showed reduced gray matter volume in the left superior parietal gyrus and left inferior temporal gyrus. Further, in contrast to HCs, firefighters showed alterations in rsfMRI values in multiple regions, including the fusiform gyrus and cerebellum. Conclusion Structural and resting-state functional abnormalities in the brain may be useful imaging biomarkers for identifying alterations in trauma-exposed firefighters without PTSD.

Objective To investigate whether baseline olfactory dysfunction in Parkinson’s disease (PD) patients is associated with baseline and longitudinal motor and cognitive function. Methods We recruited 228 drug-naïve PD patients who were followed for a mean of 6 years. Patients underwent the Cross-Cultural Smell Identification Test (CCSIT), a neuropsychological test, and N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography within 6 months of the baseline evaluation. Olfactory dysfunction was categorized as normosmia (CCSIT score ≥ 9), hyposmia (CCSIT score 5–8), and anosmia (CCSIT score ≤ 4). During the follow-up period, we investigated changes in the levodopa-equivalent dose (LED) and the occurrence of wearing-off, levodopa-induced dyskinesia, and dementia. Results Among the PD patients, 80.7% were hyposmic at the time of diagnosis, and 26.1% were anosmic. Baseline olfactory dysfunction was not associated with either initial parkinsonian motor symptoms or with the longitudinal LED increment and motor complications. Meanwhile, the anosmic group had lower baseline scores on the Korea version of the Boston Naming Test and Stroop color reading test than the normosmic and hyposmic groups. The anosmic group exhibited a higher rate of conversion to dementia than the normosmic [adjusted hazard ratio (HR) 3.99, 95% confidence interval (CI) 1.08–14.72] and hyposmic (adjusted HR 2.48, 95% CI 1.15–5.32) PD groups, regardless of baseline motor deficits and cognitive status. Conclusion Baseline olfactory dysfunction was not associated with motor deficits and complications, but it was associated with cognitive dysfunction and prognosis, suggesting that severe olfactory impairment may reflect early cortical involvement, probably in the frontotemporal region, and rapid spreading of Lewy body pathology.

Abstract Objective To investigate whether the burden of white matter hyperintensities (WMHs) is associated with the risk of developing levodopa‐induced dyskinesia (LID) in Parkinson’s disease (PD). Methods According to the Clinical Research Center for Dementia of South Korea WMH visual rating scale, 336 patients with drug‐naïve early stage PD (follow‐up >3 years) were divided into two groups of PD with minimal WMHs (PD‐WMH–; n = 227) and moderate‐to‐severe WMHs (PD‐WMH+; n = 109). The Cox regression model was used to estimate the hazard ratio for the development of LID in the PD‐WMH + group compared with the PD‐WMH– group, while adjusting for age at PD onset, sex, striatal dopamine depletion, and PD medication dose. Additionally, we assessed the effects of WMH burden rated by the Scheltens scale and regional WMH distribution on the development of LID. Results Patients in the PD‐WMH + group were older and had more severe parkinsonian motor signs despite comparable striatal dopamine transporter availability than those in the PD‐WMH– group. Patients in the PD‐WMH + group had a higher risk of developing LID (hazard ratio, 2.66; P

It is difficult to determine the pathoanatomical correlates of dystonia because of its complex pathophysiology, and most cases with secondary dystonia are associated with basal ganglia lesions. Moreover, it is a challenging issue that patients with abnormal postures accompanied by other neurological findings in the affected body part (e.g., sensory loss) can be diagnosed with true dystonia or pseudodystonia. Here, we report a case of abnormal postures with loss of proprioception in the left extremities after right dorsal pontine hemorrhage.

Abstract Objective The precise pathogenesis or neural correlates underlying levodopa‐induced dyskinesia (LID) remains poorly understood. There is growing evidence of the involvement of the cerebellum in Parkinson's disease (PD). The present study evaluated the role of motor cerebellar connectivity in determining vulnerability to LID. Methods We enrolled 25 de novo patients with PD who developed LID within 5 years of levodopa treatment, 26 propensity score‐matched PD patients who had not developed LID, and 24 age‐ and sex‐matched healthy controls. We performed a comparative analysis of resting‐state functional connectivity (FC) between the motor cerebellum and whole brain between the groups. Results The patients with PD had increased FC bewteen the motor cerebellum and posterior cortical and cerebellar regions, while no gray matter regions had decreased FC with the motor cerebellum compared to the control participant. The patients with PD who were vulnerable to the development of LID had a significantly higher FC between the motor cerebellum lobule VIIIb and the left inferior frontal gyrus than those who were resistant to LID development. The connectivity of the motor cerebellum and left inferior frontal gyrus was negatively correlated with the latency from PD onset to the occurrence of LID. Interpretation Increased FC between the motor cerebellum and left inferior frontal gyrus in de novo patients with PD could be an important determinant of vulnerability to LID.

Objective Ample evidence has suggested that age at onset of Parkinson’s disease (PD) is associated with heterogeneous clinical features in individuals. We hypothesized that this may be attributed to different patterns of nigrostriatal dopamine loss. Methods A total of 205 consecutive patients with de novo PD who underwent 18F-FP-CIT PET scans (mean follow-up duration, 6.31 years) were divided into three tertile groups according to their age at onset of parkinsonian motor symptoms. Striatal dopamine transporter (DAT) availability was compared between the old- (n = 73) and young-onset (n = 66) groups. In addition, the risk of developing freezing of gait (FOG) and longitudinal requirements for dopaminergic medications were examined. Results The old-onset PD group (mean age at onset, 72.66 years) exhibited more severe parkinsonian motor signs than the young-onset group (52.58 years), despite comparable DAT availability in the posterior putamen; moreover, the old-onset group exhibited more severely decreased DAT availability in the caudate than the young-onset group. A Cox regression model revealed that the old-onset PD group had a higher risk for developing FOG than the young-onset group [hazard ratio 2.523, 95% confidence interval (1.239–5.140)]. The old-onset group required higher doses of dopaminergic medications for symptom control than the young-onset group over time. Conclusion The present study demonstrated that the old-onset PD group exhibited more severe dopamine loss in the caudate and were more likely to develop gait freezing, suggesting that age at onset may be one of the major determinants of the pattern of striatal dopamine depletion and progression of gait disturbance in PD.

Abstract Objective We evaluated disruption of the white matter (WM) network related with Alzheimer's disease (AD) and Lewy body disease (LBD), which includes Parkinson's disease and dementia with Lewy bodies. Methods We consecutively recruited 37 controls and 77 patients with AD‐related cognitive impairment (ADCI) and/or LBD‐related cognitive impairment (LBCI). Diagnoses of ADCI and LBCI were supported by amyloid PET and dopamine transporter PET, respectively. There were 22 patients with ADCI, 19 patients with LBCI, and 36 patients with mixed ADCI/LBCI. We investigated the relationship between ADCI, LBCI, graph theory‐based network measures on diffusion tensor images, and cognitive dysfunction using general linear models after controlling for age, sex, education, deep WM hyperintensities (WMH), periventricular WMH, and intracranial volume. Results LBCI, especially mixed with ADCI, was associated with increased normalized path length and decreased normalized global efficiency. LBCI was related to the decreased nodal degree of left caudate, which was further associated with broad cognitive dysfunction. Decreased left caudate nodal degree was associated with decreased fractional anisotropy (FA) in the brain regions vulnerable to LBD. Compared with the control group, the LBCI group had an increased betweenness centrality in the occipital nodes, which was associated with decreased FA in the WM adjacent to the striatum and visuospatial dysfunction. Conclusion Concomitant ADCI and LBCI are associated with the accentuation of LBCI‐related WM network disruption centered in the left caudate nucleus. The increase of occipital betweenness centrality could be a characteristic biologic change associated with visuospatial dysfunction in LBCI.

Background. This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods. This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0×105 cells/kg; medium-dose, 6.0×105 cells/kg; high-dose, 9.0×105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results. One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion. The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Abstract Introduction Lewy body–related pathology is commonly observed at autopsy in individuals with dementia, but in vivo biomarkers for α‐synucleinopathy are lacking. Methods Baseline cerebrospinal fluid (CSF) biomarkers, polygenic risk score (PRS) for Parkinson's disease (PRS‐PD) and Alzheimer's disease (PRS‐AD), longitudinal cognitive scores, and magnetic resonance imaging were measured in 217 participants from the Alzheimer's Disease Neuroimaging Initiative. Linear mixed models were used to find the relationship of CSF biomarkers and the PRS with cognition and cortical atrophy. Results Higher PRS‐PD and PRS‐AD were associated with lower CSF α‐synuclein and amyloid beta (Aβ), respectively. Lower CSF α‐synuclein and the interaction of CSF α‐synuclein and Aβ were associated with lower cognitive scores and global cortical atrophy most prominently in the occipital cortex. Discussion Lower CSF α‐synuclein could be a biomarker for α‐synucleinopathy, and the simultaneous evaluation of CSF biomarkers for AD and CSF α‐synuclein could reveal the independent and interactive effects on cognition and cortical atrophy.

Abstract Introduction For the diagnosis of Parkinson's disease (PD) and atypical parkinsonism (AP) using neuroimaging, structural measures have been largely employed since structural abnormalities are most noticeable in the diseases. Functional abnormalities have been known as well, though less clearly seen, and thus, the addition of functional measures to structural measures is expected to be more informative for the diagnosis. Here, we aimed to assess whether multimodal neuroimaging measures of structural and functional alterations could have potential for enhancing performance in diverse diagnostic classification problems. Methods For 77 patients with PD, 86 patients with AP comprising multiple system atrophy and progressive supranuclear palsy, and 53 healthy controls (HC), structural and functional MRI data were collected. Gray matter (GM) volume was acquired as a structural measure, and GM regional homogeneity and degree centrality were acquired as functional measures. The measures were used as predictors individually or in combination in support vector machine classifiers for different problems of distinguishing between HC and each diagnostic type and between different diagnostic types. Results In statistical comparisons of the measures, structural alterations were extensively seen in all diagnostic types, whereas functional alterations were limited to specific diagnostic types. The addition of functional measures to the structural measure generally yielded statistically significant improvements to classification accuracy, compared to the use of the structural measure alone. Conclusion We suggest the fusion of multimodal neuroimaging measures as an effective strategy that could generally cope with diverse prediction problems of clinical concerns.

Depression frequently accompanies Parkinson's disease and often precedes the onset of motor symptoms. This study aimed to evaluate the impact of depression on motor compensation in patients with de novo Parkinson's disease. This retrospective cohort study analyzed data from 474 non-demented patients with de novo Parkinson's disease (mean age, 64.6±9.8 years; 242 men) who underwent both dopamine transporter PET scan and depression assessment using the Beck Depression Inventory at baseline. Patients were classified into tertiles by Beck Depression Inventory score. At baseline, high-tertile group (Beck Depression Inventory score ≥15, n = 157) showed more severe motor deficits and lower cognitive function than low-tertile group (Beck Depression Inventory score ≤7, n = 158, P = 0.034 and P = 0.008, respectively). Greater motor deficits in high-tertile group than low-tertile group remained significant after controlling for dopamine transporter binding in the posterior putamen, as well as other confounding variables. During follow-up of a median duration of 47 months, high-tertile group received higher levodopa-equivalent doses for symptom control than did low-tertile group after controlling for age, gender, and initial motor deficit severity. These results demonstrate that depression in de novo Parkinson's disease is associated with motor deficit severity at baseline and dose of PD medications during follow-up, suggesting that the presence of depression in de novo Parkinson's disease represents poor motor compensation.

Isolated middle cerebral artery (MCA) stenosis in young patients with no other medical condition may be a unique pathologic entity with a benign long-term course. Generally, moyamoya disease shows a progression of stenosis from internal cerebral artery (ICA) to other intracranial vessel. A 26-year-old woman was admitted for choreic movements of the right arm and leg. Brain magnetic resonance imaging showed no stroke. Conventional angiography revealed 48% stenosis of the left M1 without ICA stenosis. Single photon emission computed tomography revealed perfusion asymmetry after acetazolamide injection, suggesting decreased uptake in the left basal ganglia and the cerebral cortex. Her hemichorea was mildly decreased with risperidone. One year later, follow-up angiography showed complete occlusion of the left M1 with neovascularization suggestive of moyamoya disease. The patient underwent bypass surgery and her hemichorea disappeared. This may be an atypical presentation of moyamoya disease. The bypass surgery was an effective measure for restoring the vascular insufficiency and, resultantly, controlling her hemichorea.

BACKGROUND:Patients with unilateral neglect fail to respond normally to stimuli on the left side. To facilitate the evaluation of unilateral spatial neglect, we developed a new application that runs on a tablet device and investigated its feasibility in stroke patients. METHODS:We made the computerized table setting test (CTST) to run on the tablet computer. Forty acute ischemic stroke patients (20 patients with right hemispheric infarction with neglect, 10 patients with right hemispheric infarction without neglect, and 10 patients with left hemispheric infarction) and 10 healthy controls were prospectively enrolled to validate the CTST. The test requires subjects to set a table by dragging 12 dishes located below the table on the tablet screen. The horizontal deviation of the 12 dishes from the midline of the table, the selection tendency measured by the sequence of the dish selection, and the elapsed time for table setting were calculated automatically. RESULTS:Parameters measured by the CTST were correlated with the results of conventional neglect tests. The horizontal deviation was significantly higher in patients with right hemispheric infarction with neglect compared with the other groups. The selection tendency and elapsed time also were significantly different in patients with right hemispheric infarction with neglect compared with the left hemispheric infarction and control groups, but were similar to those with right hemispheric infarction without neglect. CONCLUSIONS:The CTST is feasible to administer and comparable with conventional neglect tests. This new application may be useful for the initial diagnosis and follow-up of neglect patients.

Punding, one of dopamine replacement treatment related complications, refers to aimless and stereotyped behaviors. To identify possible neural correlates of punding behavior in patients with Parkinson's disease (PD), we investigated the patterns of cognitive profiles and cortical thinning.Of the 186 subjects with PD screened during the study period, we prospectively enrolled 10 PD patients with punding and 43 without punding on the basis of a structured interview. We performed comprehensive neuropsychological tests and voxel-based and regions-of-interest (ROIs)-based cortical thickness analysis between PD patients with and without punding.The prevalence of punding in patients with PD was 5.4%. Punding behaviors were closely related to previous occupations or hobbies and showed a temporal relationship to changes of levodopa-equivalent dose (LED). Significant predisposing factors were a long duration of PD and intake of medications of PD, high total daily LED, dyskinesia, and impulse control disorder. Punding severity was correlated with LED (p = 0.029). The neurocognitive assessment revealed that PD patients with punding showed more severe cognitive deficits in the color Stroop task than did those without punding (p = 0.022). Voxel-based analysis showed that PD-punders had significant cortical thinning in the dorsolateral prefrontal area relative to controls. Additionally, ROI-based analysis revealed that cortical thinning in PD-punders relative to PD-nonpunders was localized in the prefrontal cortices, extending into orbitofrontal area.We demonstrated that PD patients with punding performed poorly on cognitive tasks in frontal executive functions and showed severe cortical thinning in the dorsolateral prefrontal and orbitofrontal areas. These findings suggest that prefrontal modulation may be an essential component in the development of punding behavior in patients with PD.

BACKGROUND: Recent studies have suggested that essential tremor (ET) is a more complex and heterogeneous clinical entity than initially thought. In the present study, we assessed the pattern of cortical thickness and diffusion tensor white matter (WM) changes in patients with ET according to the response to propranolol to explore the pathogenesis underlying the clinical heterogeneity of ET. METHODS: A total of 32 patients with drug naive ET were recruited prospectively from the Movement Disorders outpatient clinic. The patients were divided into a propranolol-responder group (n = 18) and a non-responder group (n = 14). We analyzed the pattern of cortical thickness and diffusion tensor WM changes between these two groups and performed correlation analysis between imaging and clinical parameters. RESULTS: There were no significant differences in demographic characteristics, general cognition, or results of detailed neuropsychological tests between the groups. The non-responder group showed more severe cortical atrophy in the left orbitofrontal cortex and right temporal cortex relative to responders. However, the responders exhibited significantly lower fractional anisotropy values in the bilateral frontal, corpus callosal, and right parietotemporal WM compared with the non-responder group. There were no significant clusters where the cortical thickness or WM alterations were significantly correlated with initial tremor severity or disease duration. CONCLUSIONS: The present data suggest that patients with ET have heterogeneous cortical thinning and WM alteration with respect to responsiveness to propranolol, suggesting that propranolol responsiveness may be a predictive factor to determine ET subtypes in terms of neuroanatomical heterogeneity.

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. a-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in a-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes a-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of a-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated a-synuclein clearance via ER-phagy. Overexpression of a-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of a-synuclein. [ABSTRACT FROM AUTHOR]