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The role of apolipoprotein E4 (APOE4) in the risk of Alzheimer's disease (AD) and Lewy body disease (LBD), and their relationship with β-amyloid deposition and cognitive dysfunction, remain unclear. Using amyloid and dopamine transporter imaging, we enrolled 126 controls and 208 patients with typical AD (pure AD and Lewy body variant of AD), AD with dementia with Lewy bodies, or typical LBD (dementia with Lewy bodies with amyloid deposition and pure LBD). APOE4 was associated with an increased risk of all disease subtypes except pure LBD. APOE4 was associated with increased frontal β-amyloid burden, and typical LBD was associated with increased occipital β-amyloid levels through its interaction with APOE4. APOE4 was associated with deteriorated general cognition and memory dysfunction via its interaction with typical LBD and AD, respectively. In conclusion, the impact of APOE4 on disease risk depends on its effects on β-amyloid deposition, and APOE4 is associated with β-amyloid deposition regardless of the clinical diagnosis. However, it interacts with typical LBD to cause occipital β-amyloid deposition.

Background: Sudomotor dysfunction is common in patients with multiple system atrophy (MSA). Postganglionic sudomotor dysfunction in MSA, which can be assessed using quantitative sudomotor axon reflex testing (QSART), results from the degeneration of preganglionic sympathetic neurons and direct loss of postganglionic fibers. Objective: We investigate whether abnormal QSART responses in patients with MSA are associated with disease severity. Methods: In this retrospective study, patients with probable MSA who underwent both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and autonomic function tests were included. Autonomic function test results were integrated divided into three sub-scores, including sudomotor, cardiovagal, and adrenergic sub-scores. The sudomotor sub-score represented postganglionic sudomotor function. Unified Multiple System Atrophy Rating Scale (UMSARS) Part I, Part II, and sum of Part I and II scores (Part I + II) to reflect disease severity and 18F-FDG-PET/CT results were collected. Results: Of 74 patients with MSA, 62.2%demonstrated abnormal QSART results. The UMSARS Part I + II score was significantly higher in the abnormal QSART group than in the normal QSART group (p = 0.037). In the regression analysis, both UMSARS Part I (β= 1.185, p = 0.013) and Part II (β= 1.266, p = 0.021) scores were significantly associated with the sudomotor sub-score. On 18F-FDG-PET/CT, the abnormal QSART group exhibited more severely decreased metabolic activity in the cerebellum and basal ganglia in patients with MSA-P and MSA-C, respectively. The sudomotor sub-score was significantly associated with regional metabolism in these areas. Conclusion: Patients with MSA and postganglionic sudomotor dysfunction may have worse disease severity and greater neuropathological burden than those without.

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.

To investigate the association between cognitive function at baseline and the progression of motor disability in Parkinson’s disease (PD). We consecutively enrolled 257 drug-naive patients with early-stage PD (follow-up > 2 years) who underwent a detailed neuropsychological test at initial assessment. Factor analysis was conducted to yield four cognitive function factors and composite scores thereof: Factor 1 (visual memory/visuospatial), Factor 2 (verbal memory), Factor 3 (frontal/executive), and Factor 4 (attention/working memory/language). The global cognitive composite score of each patient was calculated based on these factors. Subsequently, we assessed the effect of baseline cognitive function on long-term motor outcomes, namely levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and rate of longitudinal increases in levodopa-equivalent dose (LED). Cox regression analysis demonstrated that higher Factor 3 (frontal/executive) composite scores (i.e., better cognitive performance) were associated with early development of LID [hazard ratio (HR), 1.507; p = 0.003], whereas higher Factor 1 (visual memory/visuospatial) composite scores (i.e., better cognitive performance) were associated with a lower risk for FOG (HR 0.683; p = 0.017). We noted that higher global cognitive composite scores were associated with a lower risk for developing FOG (HR 0.455; p = 0.045). The linear mixed model demonstrated that higher global cognitive composite scores and better cognitive performance in visual memory/visuospatial function were associated with slower longitudinal increases in LED. These findings suggest that baseline cognitive profiles have prognostic implications on several motor aspects in patients with PD.

This study aimed to compare the patterns of β-amyloid deposition between patients with early-stage Alzheimer's disease (AD) with mild parkinsonism and those without parkinsonism. Sixty-one patients with early-stage AD (Clinical Dementia Rating [CDR], 0.5 or 1) who underwent 18F-florbetaben (18F-FBB) PET scans were enrolled. We performed comparative analyses of regional FBB uptake in the frontal, parietal, lateral temporal, medial temporal, occipital, anterior cingulate, and posterior cingulate cortices and in the precuneus, striatum, and thalamus between AD patients with mild parkinsonism (AD-p+; n = 23) and those without parkinsonism (AD-p−; n = 38). There was no significant difference in age, sex, years of education, Mini-Mental State Examination score, and white matter hyperintensity severity between groups. The AD-p+ group had lower composite scores in frontal/executive function domain than the AD-p− group. The AD-p+ group had a higher FBB uptake in the occipital cortex, but not in other cortical regions, than the AD-p− group. Our findings suggest that additional β-amyloid deposition in the occipital region is associated with mild parkinsonism in early-stage AD.

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.

Background White matter hyperintensities, prevalent in patients with Parkinson's disease (PD), significantly affect parkinsonian motor symptoms. The objective of this study was to investigate the relationship between white matter hyperintensities and nigrostriatal dopamine depletion and their interaction or mediating effects on motor symptoms in patients with drug-naive early-stage PD. Methods This cross-sectional study enrolled 501 patients with de novo PD who initially underwent [18 F] N-(3-fluoropropyl)-2β-carbonethoxy-3β-(4-iodophenyl) nortropane positron emission tomography and brain magnetic resonance imaging scans between April 2009 and September 2015 in a tertiary-care university hospital. We quantified dopamine transporter availability in each striatal subregion and assessed the severity of periventricular and lobar white matter hyperintensities using the Scheltens scale. The relationship between white matter hyperintensities, dopamine transporter availability in the posterior putamen, and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was assessed using multivariate linear regression and mediation analyses. Results Periventricular and frontal white matter hyperintensities were generally associated with dopamine transporter availability in striatal subregions after adjusting for age at symptom onset, sex, disease duration, and vascular risk factors. There was an interaction effect between periventricular white matter hyperintensities and dopamine transporter availability in the posterior putamen for the axial motor score. The effect of white matter hyperintensities on UPDRS total score and bradykinesia subscore was indirectly mediated by dopamine transporter availability in the posterior putamen, whereas the axial sub-score was directly affected by white matter hyperintensities. Conclusions This study suggests that the detrimental effect of white matter hyperintensities on parkinsonian motor symptoms is more relevant and independent for axial motor impairments in the status of mildly decreased striatal dopamine transporter availability. © 2021 International Parkinson and Movement Disorder Society.

Introduction To investigate whether neurodegeneration underlying Parkinson's disease (PD) accounts for a substantial proportion of cases of minimal parkinsonism in the elderly. Methods We recruited 48 consecutive subjects with minimal parkinsonism who visited the clinic with cognitive complaints. All subjects did not show findings compatible with PD on 18F-FP-CIT PET scans, and had no evidence of other neurodegenerative disorders. Striatal dopamine transporter (DAT) availability was quantified, and mean diffusivity (MD) values in the pons were calculated to characterize structural damage using diffusion tensor imaging. Additionally, 35 patients with PD and 21 healthy controls were included as reference groups. Results Individuals with minimal parkinsonism (mean age, 73.23 ± 7.03 years) exhibited mild decrease in DAT availability in the posterior putamen, which was at a level between that of healthy controls and patients with PD. DAT availability in the caudate and anterior putamen was also mildly decreased in the minimal parkinsonism group. Individuals with minimal parkinsonism also tended to have higher MD values in the pons compared to healthy controls. Conclusions Our results suggest that a substantial proportion of minimal parkinsonism is associated with nigrostriatal dopamine depletion and pontine structural damage, which may be related to the disease process of prodromal PD.

Purpose Neuropsychiatric symptoms are important and frequent nonmotor features in Parkinson disease (PD). We explored mild behavioral impairment (MBI) in drug-naive patients with PD and its clinical and dopamine transporter (DAT) correlates. Methods We recruited 275 drug-naive patients with PD who had undergone Unified Parkinson's Disease Rating Scale, a neuropsychological battery, Neuropsychiatric Inventory, and N-(3-[F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) PET within 6 months. Patients with PD were divided into groups without MBI (PD-MBI-, n = 186) and with MBI (PD-MBI+, n = 89) according to the Neuropsychiatric Inventory. We performed comparative analysis of DAT availability, cognitive function, and motor deficits between the groups. Results Mild behavioral impairment was found in 32.4% of PD patients at the time of diagnosis, and affective dysregulation and decreased motivation were the 2 most common neuropsychiatric domains. Dopamine transporter availability in the anterior caudate (odds ratio, 0.60; P = 0.016) and anterior putamen (odds ratio, 0.58; P = 0.008) was associated with the development of MBI in PD. PD-MBI+ group had a lower z-score in memory-related tests and Stroop color reading test than PD-MBI- group. PD-MBI+ group had a higher Unified Parkinson's Disease Rating Scale motor score after controlling for DAT availability in the posterior putamen than PD-MBI- group (P = 0.007). Conclusions This study suggests that early behavioral impairment is associated with more pathological involvement in the anterior striatum, memory and frontal dysfunction, and motor deficits, which could be regarded as a different phenotype in PD.

Objective To investigate the role of motor cerebellar connectivity in future development of freezing of gait, because it is a complex network disorder in Parkinson's disease (PD). Methods We recruited 26 de novo patients with PD who experienced freezing of gait within 5 years from magnetic resonance imaging acquisition (vulnerable PD group), 61 patients with PD who had not experienced freezing of gait within 5 years (resistant PD group), and 27 healthy control subjects. We compared the resting state functional connectivity between the motor cerebellum and the whole brain between the groups. In addition, we evaluated the relationship between motor cerebellar connectivity and freezing of gait latency. Results The vulnerable PD group had increased functional connectivity between the motor cerebellum and parieto-occipito-temporal association cortices compared with the control group or the resistant PD group. Connectivity between lobule VI and the right superior parietal lobule, right fusiform gyrus, and left inferior temporal gyrus; between lobule VIIb and the right superior parietal lobule, right hippocampus, and right middle temporal gyrus; and between lobule VIIIb and the bilateral fusiform gyri, right middle occipital gyrus, and bilateral parietal lobes was inversely proportional to freezing of gait latency. The freezing of gait latency-related cortical functional connectivity from the motor cerebellum was also significantly higher in the vulnerable PD group compared with the control group, as well as the resistant PD group. Conclusions The data suggest that the motor cerebellar functional connectivity with the posterior cortical areas play an important role in future development of freezing of gait in PD. © 2020 International Parkinson and Movement Disorder Society.

There are individual differences in motor deficits, despite a similar degree of dopamine neuronal loss in Parkinson's disease (PD), called motor reserve (MR). Factors enhancing MR have been documented previously, but the influence of initial MR on the long-term prognosis remains unclear. In this longitudinal study, we enrolled 205 patients with de novo PD to estimate individual MR based on initial motor deficits and striatal dopamine depletion using the residual-based approach. We assessed the risk of developing levodopa-induced dyskinesia (LID) or freezing of gait (FOG) and longitudinal increases in levodopa-equivalent dose (LED) according to MR estimates using the Cox regression model and linear mixed model, respectively. Throughout the follow-up period (≥3 years), greater MR estimates were associated with a lower risk for LID and FOG. In addition, patients with high MR received lower LED than those with low MR. These findings suggest that the initial MR, that is, individual's capacity to cope with PD-related pathologies, can be maintained with disease progression and can modulate the risk for LID or FOG.

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.

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-naive 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.

Hyposmia is common in Alzheimer's dementia (AD) and Parkinson's disease dementia (PDD). We evaluated the pattern of olfactory functional connectivity (FC) in AD and PDD to uncover neural correlates that are related to olfactory dysfunction. This study enrolled 57 patients with AD and PDD and 25 control subjects. Using a seed-based approach, we compared the resting-state network from the seed-region-of-interest in the olfactory bulb, olfactory tract, piriform cortex, and orbitofrontal cortex (OFC) between groups. The PDD group showed lower FC with striatal-thalamic-frontal regions from the olfactory bulb than the AD group. The PDD group showed lower FC from left OFC with striatal-frontal regions and lower FC from right OFC with left fronto-temporal areas than the AD group. In a correlation analysis, the FC from left OFC with right insula that differed between the PDD and control groups was positively correlated with olfactory function. The present study demonstrated that this distinct olfactory functional network pattern may represent different neural mechanisms for olfactory dysfunction in AD and PDD.

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

Objective We aimed to determine the association between striatal dopaminergic depletion, cerebral β-amyloid deposition, and cognitive dysfunction in Lewy body disease (LBD). Methods This cross-sectional study recruited 48 LBD patients (30 with dementia, 18 with mild cognitive impairment) and 15 control subjects from a university-based hospital. We measured the striatal dopamine transporter (DAT) activity and regional β-amyloid burden using N-(3-[18 F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) and 18 F-florbetaben (FBB) PET, respectively. The relationship between striatal FP-CIT uptake, regional cortical FBB uptake, and cognitive function scores was evaluated using path analyses. We also investigated the effects of striatal FP-CIT uptake and cortical FBB uptake on the interval between motor symptom and dementia onset. Results Reduced striatal FP-CIT uptake was associated with increased FBB uptake in the posterior cortical regions, most prominently in the occipital cortices. Reduced FP-CIT uptake in the anterior putamen was associated with visuospatial dysfunction with mediation of increased occipital FBB uptake. Reduced FP-CIT uptake in the posterior putamen and an increased parietal FBB uptake were independently associated with memory dysfunction. Reduced striatal FP-CIT uptake was associated with attention, language, and frontal/executive dysfunction, independent of amyloid deposition. Increased FBB uptake, especially in the parietal cortex, was associated with earlier onset of dementia. Interpretation Our results suggest that occipital β-amyloid deposition may contribute to the association between striatal dopaminergic depletion and visuospatial dysfunction in LBD patients. Although the effects of reduced DAT activity are more prominent than those of β-amyloid burden on cognitive dysfunction, the latter affects the onset of cognitive dysfunction. ANN NEUROL 2020;87:739-750.

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the 2 most common causes of dementia. We compared the regional metabolism on 18F-fluorodeoxyglucose positron emission tomography (PET) among 21 control subjects and cognitively impaired patients due to DLB (N = 63) and AD (N = 38). All participants underwent 18F-Florbetaben (FBB) PET, and all DLB patients had abnormality on dopamine transporter PET. Both the FBB-positive DLB (N = 38) and FBB-negative DLB (N = 25) groups had increased metabolism in the bilateral central cerebellum, posterior putamen, and somatomotor cortices compared with the control and AD groups. Compared with the control group, the DLB and AD groups commonly exhibited hypometabolism in the bilateral lateral temporal, temporo-parietal junction, posterior cingulate, and precuneus cortices. Both DLB groups had additional hypometabolism in the bilateral thalami and dorsolateral prefrontal cortices, whereas the AD group did in the bilateral entorhinal cortices and hippocampi. Our results suggest that hypermetabolism in the somatomotor cortex, posterior putamen, or central cerebellum could be a useful imaging biomarker for detecting DLB patients, while entorhinal/hippocampal hypometabolism could be a specific biomarker for AD.

Background The severity of motor symptoms in Parkinson's disease (PD) does not always correlate with the degree of nigral dopaminergic neuronal loss. Individuals with greater motor reserve may have milder motor signs than their striatal dopamine loss. In this study, we explored the functional brain network associated with motor reserve in early-stage PD. Methods We analyzed 134 patients with de novo PD who underwent dopamine transporter scans and resting-state functional magnetic resonance imaging. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We applied network-based statistic analysis to identify the functional brain network associated with the measure of motor reserve (ie, motor reserve network). We also assessed the effect of motor reserve network connectivity strength on the longitudinal increase in levodopa-equivalent dose during the 2-year follow-up period. Results Network-based statistic analysis identified the motor reserve network composed of the basal ganglia, inferior frontal cortex, insula, and cerebellar vermis at a primary threshold of P value 0.001. Patients with an increased degree of functional connectivity within the motor reserve network had greater motor reserve. There was a significant interaction between the motor reserve network strength and time in the linear mixed model, indicating that higher motor reserve network strength was associated with slower longitudinal increase in levodopa-equivalent dose. Conclusions The present study revealed the functional brain network associated with motor reserve in patients with early-stage PD. Functional connections within the motor reserve network are associated with the individual's capacity to cope with PD-related pathologies. © 2020 International Parkinson and Movement Disorder Society.

BACKGROUND Clinicopathological studies have demonstrated that the neuropsychological profiles and outcomes are different between two dementia subtypes, namely Alzheimer's disease (AD) and Lewy bodies-related disease. OBJECTIVE We investigated the neural correlates of cognitive dysfunction in patients with AD-related cognitive impairment (ADCI) and those with Lewy bodies-related cognitive impairment (LBCI). METHODS We enrolled 216 ADCI patients, 183 LBCI patients, and 30 controls. Cortical thickness and diffusion tensor imaging analyses were performed to correlate gray matter and white matter (WM) abnormalities to cognitive composite scores for memory, visuospatial, and attention/executive domains in the ADCI spectrum (ADCI patients and controls) and the LBCI spectrum (LBCI patients and controls) separately. RESULTS Memory dysfunction correlated with cortical thinning and increased mean diffusivity in the AD-prone regions, particularly the medial temporal region, in ADCI. Meanwhile, it only correlated with increased mean diffusivity in the WM adjacent to the anteromedial temporal, insula, and basal frontal cortices in LBCI. Visuospatial dysfunction correlated with cortical thinning in posterior brain regions in ADCI, while it correlated with decreased fractional anisotropy in the corpus callosum and widespread WM regions in LBCI. Attention/executive dysfunction correlated with cortical thinning and WM abnormalities in widespread brain regions in both disease spectra; however, ADCI had more prominent correlation with cortical thickness and LBCI did with fractional anisotropy values. CONCLUSIONS Our study demonstrated that ADCI and LBCI have different neural correlates with respect to cognitive dysfunction. Cortical thinning had greater effects on cognitive dysfunction in the ADCI, while WM disruption did in the LBCI.

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.

Background: Neuropsychiatric symptoms (NPS) are the most common non-motor symptom in Parkinson’s disease (PD). Objective: To investigate the association between the burden of NPS and motor prognosis in patients with PD. Methods: We enrolled 329 drug-naïve patients with PD, who was non-demented and followed-up≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging and neuropsychiatric inventory (NPI) scores. We performed a survival analysis and a linear mixed model analysis to assess longitudinal motor outcomes according to the NPI total score. Results: The Kaplan-Meier analysis showed no difference in the development of levodopa-induced dyskinesia and wearing-off according to the NPI total score. However, higher burden of NPI total score was associated with earlier freezing of gait (FOG) development in the time-dependent Cox regression models after adjusting for age at symptom onset, sex, disease duration, Unified PD Rating Scale motor score, baseline Mini-Mental State Examination score, DAT activity in the posterior putamen and levodopa-equivalent daily dose (LEDD) (Hazard ratio 1.047, p = 0.002). A linear mixed model analysis revealed that patients with a higher NPI total score had a more rapid LEDD increment (NPI×time, p = 0.003). Among 52 patients with PD who eventually developed FOG during the follow-up period, there was a significant correlation between the NPI total score and time with FOG development (γ= –0.472; p = 0.001) after adjusting for confounding factors. Conclusion: The present study demonstrated that the severity of NPS is a predictor of early freezing and motor progression in patients with PD.

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.

Background and purpose Associations between alterations in body mass index (BMI) and cognitive function have been reported in Parkinson's disease (PD). We investigated whether the BMI at a PD diagnosis is associated with cognitive decline and the future development of dementia. Methods We recruited 70 patients with de novo PD who underwent neuropsychological testing every 3 years and were followed up for more than 6 years. We classified patients into the following three groups based on their BMI at the diagnosis: under-/normal weight (n=21), overweight (n=22), and obese (n=27). We evaluated differences in the rate of cognitive decline over time among the groups using linear mixed models and the conversion rate to dementia using survival analysis. Results The obese patients with PD showed a slower deterioration of global cognitive function as well as language and memory functions than did the under-/normal-weight group during the 6-year follow-up. The three BMI groups showed different rates of conversion to dementia (log-rank test: p=0.026). The combined overweight and obese group showed a lower risk of developing dementia compared with the under-/normal-weight group (hazard ratio= 0.36, 95% CI=0.12-0.82, p=0.046). Conclusions We have demonstrated that a higher-than-normal BMI at the time of a PD diagnosis has a protective effect against the deterioration of cognitive function and the conversion to dementia.

This study aimed to investigate the potential beneficial effects of estrogen on nigrostriatal dopaminergic neuron degeneration in postmenopausal drug-naïve Parkinson’s disease (PD). Based on the ratio of lifetime estrogen exposure length to the total length of the estrogen exposure and deprivation period, postmenopausal women with drug-naïve PD were divided into low (n = 31) and high (n = 31) estrogen exposure ratio groups. We performed a comparative analysis of the striatal dopamine transporter (DAT) availability between the two groups. Additionally, we evaluated the longitudinal change in the levodopa equivalent dose per month using a linear mixed model. The motor symptoms were more severe in the low estrogen exposure ratio group than in the high estrogen exposure ratio group (P = 0.016). PD patients in the two groups had significantly lower DAT availability on all striatal sub-regions except for ventral striatum than did age- and sex-matched normal controls. When comparing the two groups, PD patients in the low estrogen exposure ratio group exhibited significantly lower DAT availability in the posterior putamen (P = 0.024) and in the ventral putamen (P = 0.036) than those in the high estrogen exposure ratio group. The estimated monthly levodopa equivalent dose changes were 10.9 in the low estrogen exposure ratio group and 7.1 in the high estrogen exposure ratio group with a significant interaction between the two groups (P = 0.001). These in vivo data provide indirect evidence showing that estrogen may elicit a beneficial effect on nigrostriatal dopamine neurons in PD.

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.

Little is known regarding the clinical relevance or neurobiology of subtle motor disturbance in Alzheimer’s disease (AD). This study aims to investigate the patterns of striatal 18F-FP-CIT uptake in patients with AD-related cognitive impairment (ADCI) with mild parkinsonism. We recruited 29 consecutive patients with ADCI with mild parkinsonism. All patients underwent 18F-FP-CIT PET scans and dopamine transporter (DAT) availability in striatal subregions (anterior/posterior caudate, anterior/posterior putamen, ventral putamen, ventral striatum) was quantified. Additionally, 32 patients with dementia with Lewy bodies (DLB) and 21 healthy controls were included to perform inter-group comparative analyses of the striatal DAT availability. The discriminatory power of striatal DAT availability to differentiate ADCI from DLB was assessed using receiver operating characteristics (ROC) analyses. The Spearman’s correlation coefficient was calculated to assess the relationship between motor severity and DAT availability in striatal subregions. Patients with ADCI with mild parkinsonism exhibited decreased DAT availability in the caudate that was intermediate between healthy controls and patients with DLB. The DAT availability in other striatal subregions, including the posterior putamen, did not differ between the ADCI with parkinsonism and healthy control groups. The ROC analysis showed that DAT availability of all striatal subregions, especially the whole striatum, had a fair discriminatory power. Parkinsonian motor severity did not correlate with the striatal DAT availability in ADCI with parkinsonism. The present study demonstrated that patients with ADCI with mild parkinsonism had distinct DAT scan patterns and suggests that parkinsonism is associated with the extranigral source of pathology.

ObjectiveTo investigate whether the presence of autonomic dysfunction is associated with white matter and functional connectivities and the level of cognitive performance in patients with de novo Parkinson disease (PD).MethodsSeventy-five patients with de novo PD underwent a comprehensive autonomic function test and were classified into 2 groups according to the Composite Autonomic Severity Score (CASS; 30 with moderate to severe autonomic dysfunction [CASS 4–10, PD-AUT+] and 45 without significant autonomic dysfunction [CASS 0–3, PD-AUT−]). Network-based statistics and a graph theoretical analysis were performed to assess the interregional white matter connectivity using diffusion tensor imaging. We also performed analyses of resting-state functional connectivity and compared cognitive performance between the 2 groups.ResultsThere were no significant differences in demographic characteristics and vascular risk factors between the PD-AUT+ and PD-AUT− groups. The PD-AUT+ group showed poorer cognitive performance on frontal/executive function than the PD-AUT− group. The PD-AUT+ group exhibited severely disrupted white matter connectivity in both fronto-subcortical and posterior cortical regions, which was well correlated with the severity of autonomic dysfunction assessed by the CASS. In addition, functional connectivity within the executive control network and dorsal attention network negatively correlated with the CASS.ConclusionsOur results suggest that autonomic dysfunction is associated with disrupted white matter and functional brain connectivity as well as cognitive impairment in de novo patients with PD.

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

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., We investigated structural connectivity in Alzheimer's disease (ADCI), Lewy bodies disease (LBCI), and mixed disease. LBCI, especially with ADCI, was associated with disintegration of white matter network.

Background: The relationship among amyloid-β (Aβ) deposition on amyloid positron emission tomography (PET), cortical metabolism on 18F-fluoro-2-deoxy-D-glucose (FDG)-PET, and clinical diagnosis has not been elucidated for both Alzheimer’s disease (AD) and Lewy body disease (LBD). Objective: We investigated the patterns of cerebral metabolism according to the presence of AD and LBD. Methods: A total of 178 subjects were enrolled including 42 pure AD, 32 pure LBD, 34 Lewy body variant AD (LBVAD), 15 LBD with amyloid, 26 AD with dementia with Lewy bodies (DLB), and 29 control subjects. Pure AD, LBVAD, and AD with DLB groups had biomarker-supported diagnoses of typical AD, while pure LBD, LBD with amyloid, and AD with DLB groups had biomarker-supported diagnoses of typical LBD. Typical AD and LBD with amyloid showed amyloid-positivity on 18F-florbetaben (FBB) PET, while typical LBD and LBVAD had abnormalities on dopamine transporter PET. We measured regional patterns of glucose metabolism using FDG-PET and evaluated their relationship with AD and LBD. Results: Compared with control group, typical AD and typical LBD commonly exhibited hypometabolism in the bilateral temporo-parietal junction, precuneus, and posterior cingulate cortex. Typical AD showed an additional hypometabolism in the entorhinal cortex, while patients with dopamine transporter abnormality-supported diagnosis of LBD showed diffuse hypometabolism that spared the sensory-motor cortex. Although the diffuse hypometabolism in LBD also involved the occipital cortex, prominent occipital hypometabolism was only seen in LBD with amyloid group. Conclusion: Combining clinical and metabolic evaluations may enhance the diagnostic accuracy of AD, LBD, and mixed disease cases.

Background: The different effects of white matter hyperintensity (WMH) severity and WMH-associated microstructural connectivity on cognition in the early stages of Parkinson’s disease (PD) have not been investigated. Objective: To investigate the differential effect of WMH severity and WMH-associated microstructural connectivity on cognition in early stages of PD. Methods: A total of 136 de novo PD patients were enrolled and divided into groups based on total WMH visual rating scores as follows: mild, moderate, and severe. Microstructural connectivity was measured using graph theoretical analysis according to WMH severity. Additionally, correlation coefficients between WMH-associated microstructural connectivity or WMH scores and cognitive performance were assessed. Results: Patients with severe WMHs demonstrated poorer performance in language function than those with moderate WMHs, and in frontal/executive and visual memory function than those with mild WMHs. Areas of microstructural connectivity were more extensive in patients with severe WMHs compared to those with mild and moderate WMHs, involving frontal and parieto-temporal regions. WMH-associated right fronto-temporo-parietal microstructural disintegration was correlated with cognitive dysfunction in attention, frontal/executive, and memory domains, whereas there was no correlation between WMH scores and any cognitive domains. Conclusion: These data suggest that disruption of microstructural networks by WMHs, rather than WMH burden itself, contributed more to cognitive impairment in PD.

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., The addition of functional measures (ReHo and DegCen) to the structural measure (Vol) generally yielded statistically significant improvements to classification accuracy, compared to the use of the structural measure alone, across different problems of distinguishing between healthy controls (HC) and each diagnostic type of parkinsonism (PD, MSA, and PSP) and between different diagnostic types of parkinsonism.

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.

Background: Striatal dopamine deficits play a key role in the pathogenesis of Parkinson’s disease (PD), and several non-motor symptoms (NMSs) have a dopaminergic component. Objective: To investigate the association between early NMS burden and the patterns of striatal dopamine depletion in patients with de novo PD. Methods: We consecutively recruited 255 patients with drug-naïve early-stage PD who underwent 18F-FP-CIT PET scans. The NMS burden of each patient was assessed using the NMS Questionnaire (NMSQuest), and patients were divided into the mild NMS burden (PDNMS-mild) (NMSQuest score 9; n = 90). We compared the striatal dopamine transporter (DAT) activity between the groups. Results: Patients in the PDNMS-severe group had more severe parkinsonian motor signs than those in the PDNMS-mild group, despite comparable DAT activity in the posterior putamen. DAT activity was more severely depleted in the PDNMS-severe group in the caudate and anterior putamen compared to that in the PDMNS-mild group. The inter-sub-regional ratio of the associative/limbic striatum to the sensorimotor striatum was lower in the PDNMS-severe group, although this value itself lacked fair accuracy for distinguishing between the patients with different NMS burdens. Conclusion: This study demonstrated that PD patients with severe NMS burden exhibited severe motor deficits and relatively diffuse dopamine depletion throughout the striatum. These findings suggest that the level of NMS burden could be associated with distinct patterns of striatal dopamine depletion, which could possibly indicate the overall pathological burden in PD.

This study aimed to investigate the potential of using changes in the plasma levels of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, as a biomarker in early Parkinson's disease (PD).Plasma TMAO levels were measured in 85 patients with drug-naïve early stage PD and 20 healthy controls. A linear mixed model was used to assess longitudinal changes in levodopa-equivalent dose (LED) during follow-up (2 y) in three tertile PD groups according to plasma TMAO levels. Additionally, a Cox regression analysis was performed to assess the effect of plasma TMAO levels on dementia conversion.Plasma TMAO levels of patients with PD were lower than those of healthy controls. A linear mixed model demonstrated that patients with PD and lower levels of TMAO (4.75 μmol/L; i.e., lowest tertile group) exhibited faster increases in LED over time. The Cox regression model did not reveal that plasma TMAO level was associated with the risk for dementia conversion (P = 0.488). However, when we divided patients with PD into two subgroups according to bet cutoff TMAO level to maximize the log-rank statistics, the PD group with a low plasma TMAO level (6.92 μmol/L) had a higher risk (with borderline statistical significance) for PD-dementia conversion than the group with a high TMAO level (hazard ratio: 7.565; 95% confidence interval, 1.004-57.019; P = 0.050).The results demonstrate that lower baseline plasma TMAO levels are associated with faster increases in LED and tend to increase the risk for PD-dementia conversion, suggesting the prognostic implications of TMAO in early stage PD.

Background To investigate the relationship between temporalis muscle thickness (TMT) at baseline as a surrogate marker for sarcopenia and long-term motor outcomes in patients with Parkinson’s disease (PD). Methods We enrolled 249 patients with drug-naïve early-stage PD (119 males and 130 females, follow-up > 3 years). Baseline TMT of each patient was measured on the axial plane of T1-weighted images. The association between baseline TMT and long-term motor outcomes in PD was assessed using Cox regression models for levodopa-induced dyskinesia, wearing-off, and freezing of gait and a linear mixed model for the longitudinal increases in levodopa-equivalent dose per body weight over time. Statistical analyses were performed separately for sex if an interaction effect between TMT and sex was assumed. Results TMT differed substantially between the sexes, and male PD patients had higher TMT (6.69 ± 1.39 mm) than female PD patients (5.64 ± 1.34 mm, p < .001). Cox regression models demonstrated that baseline TMT was not associated with the risk of developing levodopa-induced dyskinesia, wearing-off, or freezing of gait during the follow-up period. The linear mixed model was applied separately for sex and demonstrated that higher TMT at baseline was associated with slower increases in levodopa-equivalent dose per body weight in male PD patients, but not in female PD patients. Conclusions This study demonstrated that baseline TMT could be an indicator of the longitudinal requirement for dopaminergic medications in male patients with PD, suggesting that sarcopenia may have a detrimental effect on disease progression in PD in a sex-specific manner.

Objectives To determine whether vascular parkinsonism (VaP) patients with visually normal dopamine transporter (DAT) scans have presynaptic dopaminergic depletion. Methods We enrolled 23 VaP patients who had parkinsonism, relevant diffuse subcortical white matter hyperintensities (WMH), and visually normal DAT scans, 23 Parkinson's disease (PD) patients, and 31 control subjects. By quantitatively analyzing 18F–N-(3-fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography, we compared the pattern of striatal DAT availability among groups. The discriminatory power of striatal DAT availability to differentiate VaP patients from control subjects or PD patients was assessed using receiver operating characteristics (ROC) analyses. Additionally, correlation analysis was performed to determine whether WMH severity or Unified Parkinson Disease Rating Scale Part III (UPDRS-III) score is related to presynaptic dopaminergic depletion in VaP. Results VaP patients exhibited decreased DAT availability in all striatal subregions, including posterior putamen, compared to control subjects. VaP patients and control subjects had similar patterns of anteroposterior and ventrodorsal DAT gradients in caudate and putamen level, but VaP patients exhibited significantly different patterns at putamen level, relative to PD patients. The severity of periventricular WMH was significantly correlated with all substriatal DAT availability in VaP, but not with UPDRS-III scores. The ROC analysis showed that DAT availability in caudate and posterior putamen had a fair discriminatory power when differentiating VaP patients from control subjects. Conclusions This study demonstrates that VaP patients with WMH exhibited diffusely decreased DAT availability without any specific regional gradients of DAT patterns distinct from either control subjects or PD patients.

Purpose The aim of this study was to investigate the association between autonomic dysfunction and striatal dopamine depletion or metabolic changes in de novo Parkinson disease (PD). Methods Based on the Composite Autonomic Severity Score (CASS), patients with de novo PD were classified into PD with (PD-AUT+) and without autonomic dysfunction (PD-AUT-) groups. We compared the dopamine transporter (DAT) availability in the striatum by quantitatively measuring F-FP-CIT PET between both groups. We also assessed the association between DAT availability and the CASS. In addition, we compared regional uptake in early-phase images of F-FP-CIT PET as well as cortical thickness between the PD-AUT+ and PD-AUT- groups. Results The PD-AUT+ group had significantly lower DAT availability in all striatal subregions than did the PD-AUT- group. The total CASS was significantly correlated with DAT availability in all striatal subregions. In addition, the subscores of the adrenergic component were correlated with DAT availability in all striatal subregions. The subscores of the cardiovagal component were negatively correlated with DAT availability in the caudate and ventral striatum. In early-phase F-FP-CIT PET, the PD-AUT+ group exhibited decreased regional perfusion in the parieto-occipital areas and increased regional perfusion in the pallidothalamic, pontocerebellar, inferior frontal, and primary motor areas compared with the PD-AUT- group. There were no regions of different cortical thickness between the PD groups. Conclusions The present study revealed that autonomic dysfunction is closely linked to striatal dopamine depletion and prominent PD-related perfusion patterns in de novo PD, suggesting a greater pathological burden in patients with dysautonomia.

Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used hypoglycaemic agents and improve glucose metabolism by enhancing the bioavailability of active glucagon-like peptide-1. In this study, we hypothesized that treatment with DPP4 inhibitors may have beneficial effects on nigrostriatal dopamine and longitudinal motor performance in diabetic patients with Parkinson’s disease. We classified 697 drug naive patients with de novo Parkinson’s disease who had undergone dopamine transporter imaging into three groups according to a prior diagnosis of diabetes and use of DPP4 inhibitors: diabetic patients with Parkinson’s disease being treated with (n = 54) or without DPP4 inhibitors (n = 85), and non-diabetic patients with Parkinson’s disease (n = 558). Diabetic patients with Parkinson’s disease being treated with DPP4 inhibitors had a higher baseline dopamine transporter availability in the anterior (2.56 ± 0.74 versus 2.10 ± 0.50; P = 0.016), posterior (1.83 ± 0.69 versus 1.40 ± 0.50; P

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

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.

To investigate whether the patterns of striatal dopamine depletion could provide prognostic information on the clinical profiles of early-stage Parkinson disease (PD).Approximately 634 patients with drug-naive PD who underwent F-FP-CIT PET scans were followed up for at least 2 years. After quantifying dopamine transporter (DAT) availability in each striatal subregion, the patterns of striatal dopamine depletion of each patient were assessed based on (1) the degree of dopamine loss in the other striatal subregions compared to the posterior putamen (inter-subregional ratio [ISR]) and (2) the interhemispheric asymmetry of dopamine loss in the posterior putamen (asymmetry index [AI]). According to their patterns, we assessed the longitudinal changes in L-dopa-equivalent doses and L-dopa-induced dyskinesia (LID)-free times using the linear mixed model and Cox regression model, respectively.There was no significant correlation between the ISR and AI values (Pearson correlation coefficient, 0.150). The linear mixed model showed that higher AI values were associated with slower longitudinal increases in L-dopa-equivalent dose across time (P = 0.003), whereas ISR values were not (P = 0.154). The Cox regression model demonstrated that higher ISR values were associated with early development of LID (hazard ratio, 1.693; P = 0.010), whereas AI values were not (P = 0.269).The present study demonstrated that the pattern of anterior-to-posterior gradient and right-to-left asymmetry of striatal DAT availability predicted the development of LID and increasing doses of dopaminergic medications.

ObjectivesTo investigate which baseline neuropsychological profile predicts the risk of developing dementia in early-stage Parkinson disease (PD).MethodsWe retrospectively reviewed detailed medical records of 350 drug-naive patients with early-stage PD (follow-up >3 years) who underwent a detailed neuropsychological test at initial assessment. Factor analysis was conducted to determine cognitive profiles that yielded 4 cognitive function factors: factor 1, visual memory/visuospatial; factor 2, verbal memory; factor 3, frontal/executive; and factor 4, attention/working memory/language. Subsequently, we assessed the effect of these cognitive function factors on the risk for dementia conversion. We also constructed a nomogram to calculate the risk for developing dementia over a 5-year follow-up period based on these cognitive profiles.ResultsCox regression analysis demonstrated that a higher composite score of factor 1 (hazard ratio [HR] 0.558, 95% confidence interval [CI] 0.427–0.730), factor 2 (HR 0.768, 95% CI 0.596–0.991), and factor 3 (HR 0.425, 95% CI 0.305–0.593) was associated with a lower risk for dementia conversion, while factor 3 had the most predictive power. The nomogram had a fair ability (Heagerty integrated area under the curve 0.763) to estimate the risk for dementia conversion within 5 years. The composite scores of factor 3 contributed more to the occurrence of dementia in PD than those of the other cognitive function factors.ConclusionsThese findings suggest that these factor analysis–derived cognitive profiles can be used to predict dementia conversion in early-stage PD. In addition, frontal/executive dysfunction contributes most to the occurrence of dementia in PD.

The purpose of this study was to evaluate whether the pattern of striatal dopamine transporter (DAT) availability could differentiate between progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) in the first few years of the disease. We enrolled patients who had Parkinsonism and frontal dysfunction and/or language deficit, visited the clinic within 2 years of the onset of symptoms, and had been followed-up for longer than 5 years; thus resulting in 26 patients with PSP and 24 patients with FTD. By quantitatively analyzing N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane PET, we compared the pattern of DAT availability at the time of the baseline evaluation between the two groups. The discriminatory power of variables including DAT activity and clinical parameters was investigated by receiver operating characteristics (ROC) analyses. Additionally, we analyzed the correlation between striatal subregional DAT availability and cognitive profiles. Patients with PSP and FTD had significantly lower DAT availability than normal controls in the whole striatum and in each striatal subregion. When comparing the two groups, DAT availability was significantly lower in patients with PSP than those with FTD in all striatal subregions. The PSP and FTD groups had generally similar subregional patterns of DAT activity in terms of the anteroposterior and ventrodorsal gradients and asymmetry, except for a different preferential involvement in the caudate. The ROC analysis showed that the DAT activity of the whole striatum had an excellent discriminatory power relative to Parkinsonism or neurocognitive profiles. Correlation analysis showed that verbal memory was significantly correlated with DAT availability in the whole striatum and the putaminal subregion only in patients with PSP. DAT scans have prognostic value in determining whether patients with Parkinsonism and behavioral and/or language dysfunction will develop features of PSP or FTD later in the disease course.

Aortic atheroma is a known cause of ischemic stroke. However, it is unclear whether ischemic stroke is caused by emboli from aortic atheroma or by accompanying atherosclerosis. In this study, we evaluated lesion patterns of patients with complex aortic plaque (CAP) to assume the underlying pathophysiology. Acute ischemic stroke patients who underwent transesophageal echocardiography were included. CAP was defined as a plaque in the proximal aorta ≥ 4 mm thick or with a mobile component. The diffusion-weighted imaging lesion patterns of patients with CAP were compared to those with large arterial atherosclerosis (LAA) or cardioembolism (CE). A total of 64 CAP patients, 127 LAA patients, and 80 CE patients were included. Small cortical pattern was more common in the CAP group (45.3%) than in the LAA (7.9%, p < 0.001) or the CE group (23.8%, p = 0.018). A large cortical pattern was more common in the CE group than in the CAP group (p < 0.001), whereas subcortical only pattern tended to be more common in the CAP group than in the CE group (p = 0.057). In multinominal analysis, the CAP group was more likely to have a small cortical lesion than the LAA group [odds ratio (OR) 14.63; 95% confidence interval (CI) 4.67–45.85] or the CE (OR 3.69, 95% CI 1.19–11.39) group. In conclusion, patients with CAP frequently had small cortical lesions or subcortical single lesion. These findings imply that ischemic stroke in aortic atheroma patients is associated with either small emboli or small artery disease.

This study analyzed data from dopamine transporter (DAT) positron emission tomographic scans of 282 male patients with de novo Parkinson disease to investigate whether smoking impacts striatal dopamine neuronal degeneration. Mean DAT activity in the posterior (p = 0.016) and ventral putamen (p = 0.028) was higher in 44 current smokers in comparison to 105 ex-smokers and 133 never-smokers. The severity of baseline motor deficits and the longitudinal increases in levodopa-equivalent doses during follow-up were similar among the 3 groups. These results suggest that current smoking, but not past smoking, protects dopamine neuronal degeneration in the sensorimotor striatum with no additional clinical benefits. Ann Neurol 2017;82:850-854.

Reduced presynaptic dopaminergic activity plays an important role in the development of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD). In this study, we investigated whether dopaminergic function in the nigrostriatal system is associated with the timing of LID onset. From among 412 drug-naive PD patients who underwent a dopamine transporter (DAT) PET scan during their baseline evaluation, we enrolled 65 patients who developed LID during a follow-up period of >2 years. Based on the time from PD onset, LID was classified as early, intermediate or late onset. We then compared DAT availability in the striatal subregions of the patients in the three groups. The demographic characteristics did not differ among the three patient groups except for earlier intervention of levodopa therapy in the early LID onset group (p = 0.001). After adjusting for age at PD onset, gender, timing of levodopa therapy from PD onset, and the severity of PD motor symptoms, DAT activity in the posterior putamen was found to be significantly lower in the early LID onset group than in the late LID onset group (p = 0.017). Multivariate linear regression analysis showed that low DAT activity in the posterior putamen was significantly associated with the early appearance of LID in the early LID onset group (β = 16.039, p = 0.033). This study demonstrated that low DAT activity in the posterior putamen at baseline is a major risk factor for the early onset of LID in patients with PD, suggesting that the degree of presynaptic dopaminergic denervation plays an important role in determining the timing of LID onset.

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

ObjectiveTo investigate whether the patterns of striatal dopamine depletion on dopamine transporter (DAT) scans could provide information on the long-term prognosis in Parkinson disease (PD).MethodsWe enrolled 205 drug-naive patients with early-stage PD, who underwent 18F-FP-CIT PET scans at initial assessment and received PD medications for 3 or more years. After quantifying the DAT availability in each striatal subregion, factor analysis was conducted to simplify the identification of striatal dopamine depletion patterns and to yield 4 striatal subregion factors. We assessed the effect of these factors on the development of levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and dementia during the follow-up period (6.84 ± 1.80 years).ResultsThe 4 factors indicated which striatal subregions were relatively preserved: factor 1 (caudate), factor 2 (more-affected sensorimotor striatum), factor 3 (less-affected sensorimotor striatum), and factor 4 (anterior putamen). Cox regression analyses using the composite scores of these striatal subregion factors as covariates demonstrated that selective dopamine depletion in the sensorimotor striatum was associated with a higher risk for developing LID. Selective dopamine loss in the putamen, particularly in the anterior putamen, was associated with early development of wearing-off. Selective involvement of the anterior putamen was associated with a higher risk for dementia conversion. However, the patterns of striatal dopamine depletion did not affect the risk of FOG.ConclusionsThese findings suggested that the patterns of striatal dopaminergic denervation, which were estimated by the equation derived from the factor analysis, have a prognostic implication in patients with early-stage PD.

Objectives To investigate the potential protective influence of serum uric acid (UA) level on white matter (WM) microstructural changes in de novo Parkinson's disease (PD). Methods We enrolled a total of 184 patients with drug-naive de novo PD and 59 age and gender-matched controls that underwent diffusion tensor imaging (DTI). Based on the distribution, serum UA levels were stratified into tertiles in PD patients by gender. Using tract-based spatial statistics (TBSS) analysis, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were used to compare WM integrity between the groups. Results Interaction analysis showed that interaction effect on FA values between gender and UA levels in PD was significant in widespread WM areas, including frontal-parieto-temporal, corpus callosum, bilateral internal and external capsule, and thalamic regions. Multiple regression analysis revealed that FA values had a significantly positive correlation with UA levels across widespread WM areas in male patients. However, there was no significant correlation between DTI measures and UA levels in female patients. In a group comparison in male patients, PD with the lowest UA level (PD-L-UA) group showed significantly lower FA and higher MD and RD values in frontal-parieto-temporal WM regions than PD with the highest UA level (PD-H-UA) group. However, female patients did not show significant difference of DTI measures between PD-L-UA and PD-H-UA groups. Conclusions The present study demonstrated that the serum UA levels may have the potentially gender-specific close relationship with WM integrity in the early stage of PD.