Mun Kyung Sunwoo

Presynaptic dopamine depletion predicts levodopa-induced dyskinesia in de novo Parkinson disease

Objective: To investigate whether the magnitude of presynaptic dopamine depletion is a risk factor for the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) by quantitatively analyzing 18F-FP-CIT PET data. Methods: This retrospective cohort study enrolled a total of 127 drug-naive de novo patients with PD who completed 18F-FP-CIT PET scanning at their initial evaluation. The patients visited our outpatient clinic every 3–6 months and had been followed for a minimum of 2 years since beginning dopaminergic medication. The predictive power of the quantitatively analyzed 18F-FP-CIT uptake of striatal subregions and other clinical factors for the development of LID was evaluated using Cox proportional hazard models. Results: During a mean follow-up period of 3.4 years, 35 patients with PD (27.6%) developed LID. Patients with LID showed less dopamine transporter (DAT) activity in the putamen than did those without LID. Multivariate Cox proportional hazard models revealed that the DAT uptakes of the anterior putamen (hazard ratio [HR] 0.530; p = 0.032), posterior putamen (HR 0.302; p = 0.024), and whole putamen (HR 0.386; p = 0.022) were significant predictors of the development of LID, whereas DAT activities in the caudate and ventral striatum were not significantly correlated with the development of LID. In addition, younger age at onset of PD and higher dose of levodopa were also significant predictors of the development of LID. Conclusions: The present results provide convincing evidence that presynaptic dopaminergic denervation in PD plays a crucial role in the development of LID.

Dopaminergic modulation of resting-state functional connectivity in de novo patients with Parkinson's disease

Parkinsons disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine‐dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP‐CIT positron emission tomography imaging and resting‐state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine‐dependent functional networks. The major finding is that the patterns of dopamine‐dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine‐dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine‐dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine‐dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine‐dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian‐related motor and cognitive performance. Hum Brain Mapp 35:5431–5441, 2014.

Mesenchymal Stem Cells Inhibit Transmission of α-Synuclein by Modulating Clathrin-Mediated Endocytosis in a Parkinsonian Model

Ample evidence suggests that α-synuclein is released from cells and propagated from one area of the brain to others via cell-to-cell transmission. In terms of their prion-like behavior, α-synuclein propagation plays key roles in the pathogenesis and progression of α-synucleinopathies. Using α-synuclein-enriched models, we show that mesenchymal stem cells (MSCs) inhibited α-synuclein transmission by blocking the clathrin-mediated endocytosis of extracellular α-synuclein via modulation of the interaction with N-methyl-D-aspartate receptors, which led to a prosurvival effect on cortical and dopaminergic neurons with functional improvement of motor deficits in α-synuclein-enriched models. Furthermore, we identify that galectin-1, a soluble factor derived from MSCs, played an important role in the transmission control of aggregated α-synuclein in these models. The present data indicated that MSCs exert neuroprotective properties through inhibition of extracellular α-synuclein transmission, suggesting that the property of MSCs may act as a disease-modifying therapy in subjects with α-synucleinopathies.

Neural correlates of progressive reduction of bradykinesia in de novo Parkinson's disease

BACKGROUND A progressive reduction in the speed and amplitude of repetitive action is an essential component of bradykinesia, which is called sequence effect (SE). Because SE is specific to Parkinsons disease (PD) and is suggested to be associated with motor arrest, its features are of great interest. The aim of this study was, for the first time, to find the neural correlates of SE and to demonstrate whether dopaminergic deficit is correlated with SE. METHODS We enrolled 12 patients with de novo PD at a tertiary referral hospital. Correlations between SE severity and alterations in gray and white matter were studied. The association between severity of the SE and striatal dopaminergic deficits was also analyzed. RESULTS There was a significant negative correlation between the volumetric changes in the anterior cingulate cortex (ACC) and the inferior semilunar lobule of the cerebellum and the degree of SE. There was a significant correlation between the long association fibers (the superior longitudinal fasciculus, the uncinate fasciculus, and the inferior fronto-occipital fasciculus) connecting the frontal lobes to the temporal, parietal, and occipital lobes and SE. There was a significant negative correlation between SE in the more affected hand and the caudate dopamine transporter binding in the more affected hemisphere. CONCLUSIONS Our results suggest that the ACC and the cerebellum (inferior semilunar lobule) are associated with the severity of SE. Taken together with DTI findings, the present study proposes that ACC may have an important role. Our data show that the caudate dopaminergic activity may be related to SE.

Thalamic volume and related visual recognition are associated with freezing of gait in non-demented patients with Parkinson's disease.

BACKGROUND The pathophysiology of freezing of gait (FOG) in non-demented Parkinsons disease (PD) patients remains poorly understood. Recent studies have suggested that neurochemical alterations in the cholinergic systems play a role in the development of FOG. Here, we evaluated the association between subcortical cholinergic structures and FOG in patients with non-demented PD. METHODS We recruited 46 non-demented patients with PD, categorized into PD with (n = 16) and without FOG (n = 30) groups. We performed neuropsychological test, region-of-interest-based volumetric analysis of the substantia innominata (SI) and automatic analysis of subcortical brain structures using a computerized segmentation procedure. RESULTS The comprehensive neuropsychological assessment showed that PD patients with FOG had lower cognitive performance in the frontal executive and visual-related functions compared with those without freezing of gait. The normalized SI volume did not differ significantly between the two groups (1.65 ± 0.18 vs. 1.68 ± 0.31). The automatic analysis of subcortical structures revealed that the thalamic volumes were significantly reduced in PD patients with FOG compared with those without FOG after adjusting for age, sex, disease duration, the Unified PD Rating Scale scores and total intracranial volume (left: 6.71 vs. 7.16 cm3, p = 0.029, right: 6.47 vs. 6.91 cm3, p = 0.026). Multiple linear regression analysis revealed that thalamic volume showed significant positive correlations with visual recognition memory (left: β = 0.441, p = 0.037, right: β = 0.498, p = 0.04). CONCLUSIONS These data suggest that thalamic volume and related visual recognition, rather than the cortical cholinergic system arising from the SI, may be a major contributor to the development of freezing of gait in non-demented patients with PD.

Subjective cognitive decline predicts future deterioration in cognitively normal patients with Parkinson's disease

Increasing evidence suggests that subjective cognitive decline (SCD) is a potential predictor of future cognitive decline or dementia. We investigated whether SCD in patients with Parkinsons disease (PD) is a predictor of future cognitive decline. Forty-six cognitively normal patients with PD were selected using comprehensive neuropsychological tests, and classified depending on the presence (PD-SCD(+), n = 25) or absence of SCD (PD-SCD(-), n = 21). After a mean follow-up of 2.4 years, we repeated the cognitive assessments with the same subjects. The clinical characteristics and cognitive performance of the 2 groups did not differ at baseline. At the follow-up assessment, 11 patients in the PD-SCD(+) group (44.0%) and 2 in the PD-SCD(-) group (9.5%) were diagnosed with mild cognitive impairment (MCI), and the PD-SCD(+) patients showed more rapid decline in semantic fluency and visuospatial memory tasks than those in the PD-SCD(-) group. A multivariate logistic regression analysis showed that presence of SCD (odds ratio, 8.378; 95% confidential interval, 1.472-47.683, p = 0.017) and higher Unified PD Rating Scale motor score of 20 or more (odds ratio, 4.539; 95% confidential interval, 1.004-20.528; p = 0.049) were risk factors for incident MCI. Present results demonstrate that SCD in cognitively normal patients with PD is an independent risk factor for incident MCI and acts as a predictor for future cognitive decline.

Mesenchymal stem cells can modulate longitudinal changes in cortical thickness and its related cognitive decline in patients with multiple system atrophy

Multiple system atrophy (MSA) is an adult-onset, sporadic neurodegenerative disease. Because the prognosis of MSA is fatal, neuroprotective or regenerative strategies may be invaluable in MSA treatment. Previously, we obtained clinical and imaging evidence that mesenchymal stem cell (MSC) treatment could have a neuroprotective role in MSA patients. In the present study, we evaluated the effects of MSC therapy on longitudinal changes in subcortical deep gray matter volumes and cortical thickness and their association with cognitive performance. Clinical and imaging data were obtained from our previous randomized trial of autologous MSC in MSA patients. During 1-year follow-up, we assessed longitudinal differences in automatic segmentation-based subcortical deep gray matter volumes and vertex-wise cortical thickness between placebo (n = 15) and MSC groups (n = 11). Next, we performed correlation analysis between the changes in cortical thickness and changes in the Korean version of the Montreal Cognitive Assessment (MoCA) scores and cognitive performance of each cognitive subdomain using a multiple, comparison correction. There were no significant differences in age at baseline, age at disease onset, gender ratio, disease duration, clinical severity, MoCA score, or education level between the groups. The automated subcortical volumetric analysis revealed that the changes in subcortical deep gray matter volumes of the caudate, putamen, and thalamus did not differ significantly between the groups. The areas of cortical thinning over time in the placebo group were more extensive, including the frontal, temporal, and parietal areas, whereas these areas in the MSC group were less extensive. Correlation analysis indicated that declines in MoCA scores and phonemic fluency during the follow-up period were significantly correlated with cortical thinning of the frontal and posterior temporal areas and anterior temporal areas in MSA patients, respectively. In contrast, no significant correlations were observed in the MSC group. These results suggest that MSC treatment in patients with MSA may modulate cortical thinning over time and related cognitive performance, inferring a future therapeutic candidate for cognitive disorders.

α-Synuclein pathology is related to postoperative delirium in patients undergoing gastrectomy

Objective: The clinical characteristics of postoperative delirium are similar to core features of α-synuclein–related cognitive disorders, such as dementia with Lewy bodies or Parkinson disease dementia. We therefore investigated the α-synuclein pathology in patients who experienced postoperative delirium after gastrectomy for stomach cancer. Method: Patients with and without postoperative delirium were selected among patients undergoing total gastrectomy for primary gastric cancer from 2007 to 2011 (each n = 16) at the university hospital. Immunohistochemical staining for α-synuclein of both normal and phosphorylated form was performed in the myenteric plexus. A logistic regression analysis was applied to identify independent predictors of postoperative delirium. Results: No significant differences were observed for age, sex, operation time, or onset of delirium after total gastrectomy between patients with and without postoperative delirium. Patients with postoperative delirium had a higher frequency of intensive care unit admissions (43.8 vs 6.3%, p = 0.037) and α-synuclein–positive pathologies of normal (56.3 vs 12.5%, p = 0.023) and phosphorylated form (43.8 vs 6.3%, p = 0.037) compared with those without postoperative delirium. A logistic regression analysis revealed that immunoreactivity for normal α-synuclein (odds ratio [OR] 9.20) and intensive care unit admission (OR 11.97) were independently associated with postoperative delirium. Conclusion: These results suggest that underlying α-synuclein pathologies in the stomach are associated with postoperative delirium, implying that postoperative delirium represents a preclinical stage of α-synuclein related to cognitive disorders.

Cognitive and cortical thinning patterns of subjective cognitive decline in patients with and without Parkinson's disease

BACKGROUND Subjective cognitive decline (SCD) has gained attention as a predictor of future cognitive decline in neurodegenerative diseases. Based on the hypothesis that different pathologies may distinctly contribute to SCD, we investigated the cognitive profiles and cortical thickness of patients with SCD, with and without Parkinsons disease (PD). METHODS In total, 96 patients experiencing SCD were classified as having PD (SCD-PD(+), n = 49) or no neurological disease (SCD-PD(-), n = 47); cognitively normal subjects without SCD (n = 23) were included as controls. Neurocognitive profiles and cortical thickness were examined using standardized neuropsychological tests and magnetic resonance imaging-based analysis. RESULTS No significant differences in demographic characteristics were found among the three groups. Neuropsychological tests demonstrated that the SCD-PD(+) patients had lower semantic fluency than SCD-PD(-) patients and controls, and showed poorer performance in visual memory and confrontational naming than controls, whereas no significant difference in cognitive performance was observed between the SCD-PD(-) patients and controls. Cortical thickness analysis revealed that the SCD-PD(+) patients had focal cortical thinning in the dorsolateral prefrontal, orbitofrontal, parietal, and parahippocampal areas compared with controls. Compared with SCD-PD(-) patients, SCD-PD(+) patients had cortical thinning in the frontal, parahippocampal, and posterior cortical areas. CONCLUSION Our data show that cortical thinning and cognitive performance in patients with SCD may differ based on the presence of PD, suggesting that SCD in patients with PD reflects disease-related cortical thinning and cognitive dysfunctions more closely than SCD without PD.

Nigrostriatal dopamine-independent resting-state functional networks in Parkinson's disease

As an indicator of synchronous neural activity, resting-state functional networks are influenced by neuropathological and neurochemical changes in degenerative diseases. To further advance understanding about neurochemical and neuropathological basis for resting-state functional maps, we performed a comparative analysis of resting-state functional connectivity in patients with Parkinsons disease (PD) and drug induced parkinsonism (DIP). Resting-state neuroimaging data were analyzed with a seed-based approach to investigate striatocortical functional connectivity and cortical functional connectivity within the default mode network, executive control network, and the dorsal attention network. The striatal subregions were divided into the more or less affected sides in terms of dopamine transporter uptake. Compared with DIP, PD exhibited an increased cerebellar connectivity from the more affected side of the caudate and the less affected sides of the anterior and the posterior putamen. Additionally, PD showed increased functional connectivity in the anterior prefrontal areas from the more affected side of the anterior putamen and from the less affected side of the posterior putamen. However, PD exhibited decreased cortical functional connectivity from the posterior cingulate cortex in the left temporal area. Finally, DIP patients showed decreased cortical functional connectivity from the dorsolateral prefrontal cortex in frontal and parietal areas compared with PD patients. In summary, the present study demonstrates that PD patients exhibited a unique resting state functional connectivity that may be associated with PD-related pathological changes beyond the dopaminergic system, whereas DIP patients showed altered functional connectivity within executive control network.