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"Sohn, Young Ho"
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The role of 18F-FP-CIT PET in differentiation of progressive supranuclear palsy and frontotemporal dementia in the early stage
Purpose
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.
Methods
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-[
18
F]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.
Results
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.
Conclusions
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.
Journal Article
Presynaptic dopamine depletion determines the timing of levodopa-induced dyskinesia onset in Parkinson’s disease
Purpose
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.
Methods
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.
Results
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).
Conclusion
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.
Journal Article
Association of choroid plexus volume with motor symptoms and dopaminergic degeneration in Parkinson’s disease
BackgroundThe choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain, as a part of the glymphatic system. This study aimed to investigate the association between CP volume (CPV), nigrostriatal dopaminergic degeneration and motor outcomes in Parkinson’s disease (PD).MethodsWe retrospectively searched drug-naïve patients with early-stage PD who underwent dopamine transporter (DAT) scanning and MRI. Automatic CP segmentation was performed, and the CPV was calculated. The relationship between CPV, DAT availability and Unified PD Rating Scale Part III (UPDRS-III) scores was assessed using multivariate linear regression. We performed longitudinal analyses to assess motor outcomes according to CPV.ResultsCPV was negatively associated with DAT availability in each striatal subregion (anterior caudate, β=−0.134, p=0.012; posterior caudate, β=−0.162, p=0.002; anterior putamen, β=−0.133, p=0.024; posterior putamen, β=−0.125, p=0.039; ventral putamen, β=−0.125, p=0.035), except for the ventral striatum. CPV was positively associated with the UPDRS-III score even after adjusting for DAT availability in the posterior putamen (β=0.121; p=0.035). A larger CPV was associated with the future development of freezing of gait in the Cox regression model (HR 1.539, p=0.027) and a more rapid increase in dopaminergic medication in the linear mixed model (CPV×time, p=0.037), but was not associated with the risk of developing levodopa-induced dyskinesia or wearing off.ConclusionThese findings suggest that CPV has the potential to serve as a biomarker for baseline and longitudinal motor disabilities in PD.
Journal Article
Effects of Alzheimer’s genetic risk scores and CSF biomarkers in de novo Parkinson’s Disease
Coexisting Alzheimer’s disease (AD) pathology is common in Parkinson’s disease (PD). However, the implications of genetic risk scores (GRS) for AD have not been elucidated in PD. In 413 de novo PD and 195 healthy controls from the Parkinson’s Progression Marker Initiative database, the effects of GRS for AD (GRS-AD) and PD (GRS-PD) on the risk of PD and longitudinal CSF biomarkers and clinical outcomes were explored. Higher GRS-PD and lower baseline CSF α-synuclein were associated with an increased risk of PD. In the PD group, GRS-AD was correlated positively with CSF p-tau/Aβ and negatively with CSF α-synuclein. Higher GRS-PD was associated with faster CSF p-tau/Aβ increase, and GRS-AD and GRS-PD were interactively associated with CSF α-synuclein. In the PD group, higher GRS-AD was associated with poor visuospatial function, and baseline CSF p-tau/Aβ was associated with faster cognitive decline. Higher GRS-PD was associated with better semantic fluency and frontal-related cognition and motor function given the same levels of CSF biomarkers and dopamine transporter uptake. Taken together, our results suggest that higher GRS-AD and CSF p-tau/Aβ, reflecting AD-related pathophysiology, may be associated with cognitive decline in PD patients.
Journal Article
Parkinson's disease-related non-motor features as risk factors for post-operative delirium in spinal surgery
The clinical features of postoperative delirium are similar to the core features of alpha synuclein-related cognitive disorders, such as Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB). Therefore, we hypothesized that the non-motor symptoms (NMSs) in Parkinson's disease (PD), which precede the cardinal motor features of PD, are likely to be risk factors for developing postoperative delirium. We investigated the association between PD-related NMSs and postoperative delirium in old people undergoing elective spinal surgery.
This study was a prospective study. Participants were aged 65 years and older and scheduled to undergo elective spinal surgery. During the enrollment period, 338 individuals were screened, 104 participants were included in the analysis. We assessed eight easily-assessed and representative PD-related NMSs 1 day before the scheduled surgery using tests or questionnaires for each symptom. The presence of delirium was determined by using the short version of the Confusion Assessment Method (CAM).
Fifteen (14.4%) of the 104 participants (age, 71.7 ± 4.7 years; men, 34.6%) met the CAM criteria for post-operative delirium. Multivariate logistic analysis showed that decreased olfactory function (odds ratio [OR] 0.63, 95% CI 0.44-0.91) and exhibiting rapid eye movement sleep behavior disorder (RBD, OR 1.45, 95% CI 1.09-1.93) were significantly independent predictors of postoperative delirium.
Our study shows that hyposmia and RBD are significantly independent risk factors for postoperative delirium in general elderly population. Considering that NMSs may represent burden of alpha synuclein deposit, we postulate that an underlying alpha synucleinopathy may correlates with postoperative delirium.
This study gives a novel insight for the risk factor of postoperative delirium.
Journal Article
An interpretable multiparametric radiomics model of basal ganglia to predict dementia conversion in Parkinson’s disease
Cognitive impairment in Parkinson’s disease (PD) severely affects patients’ prognosis, and early detection of patients at high risk of dementia conversion is important for establishing treatment strategies. We aimed to investigate whether multiparametric MRI radiomics from basal ganglia can improve the prediction of dementia development in PD when integrated with clinical profiles. In this retrospective study, 262 patients with newly diagnosed PD (June 2008–July 2017, follow-up >5 years) were included. MRI radiomic features (
n
= 1284) were extracted from bilateral caudate and putamen. Two models were developed to predict dementia development: (1) a clinical model—age, disease duration, and cognitive composite scores, and (2) a combined clinical and radiomics model. The area under the receiver operating characteristic curve (AUC) were calculated for each model. The models’ interpretabilities were studied. Among total 262 PD patients (mean age, 68 years ± 8 [standard deviation]; 134 men), 51 (30.4%), and 24 (25.5%) patients developed dementia within 5 years of PD diagnosis in the training (
n
= 168) and test sets (
n
= 94), respectively. The combined model achieved superior predictive performance compared to the clinical model in training (AUCs 0.928 vs. 0.894,
P
= 0.284) and test set (AUCs 0.889 vs. 0.722,
P
= 0.016). The cognitive composite scores of the frontal/executive function domain contributed most to predicting dementia. Radiomics derived from the caudate were also highly associated with cognitive decline. Multiparametric MRI radiomics may have an incremental prognostic value when integrated with clinical profiles to predict future cognitive decline in PD.
Journal Article
Effects of dopaminergic depletion and brain atrophy on neuropsychiatric symptoms in de novo Parkinson’s disease
BackgroundNeuropsychiatric symptoms impact the patients’ quality of life and caregivers’ burdens in Parkinson’s disease (PD). We aimed to investigate the effects of striatal dopaminergic depletion and brain atrophy on the neuropsychiatric symptoms of patients with PD.MethodsTwo hundred and seven patients with de novo drug-naïve PD underwent dopamine transporter (DAT) positron emission tomography and brain MRI scanning. In addition, the patients were assessed with caregiver-administered neuropsychiatric inventory (NPI) questionnaires. To evaluate the effects of DAT uptake, subcortical volume and cortical thinning on the patients’ neuropsychiatric symptoms, we performed logistic regression and negative binomial regression analyses on the NPI data after controlling for possible confounders.ResultsFrontal cortical thinning was associated with the presence of nighttime behaviour and irritability, and the thinning correlated with the severity of the nighttime behaviour. Temporal cortical thinning was associated with the presence of aggression/agitation, and it correlated with the severity of the aggression/agitation. Subcortical atrophy in the accumbens was associated with the presence of disinhibition and correlated with the severity of the disinhibition. Putamen atrophy and insular thinning were independently associated with the presence of apathy, but only insular thinning correlated with the severity of the apathy. Of the predictors, only frontal cortical thinning correlated with the total NPI score.ConclusionsThe results of this study suggested that accumbens atrophy and frontotemporal cortical thinning, especially frontal cortical thinning, independently contributed to neuropsychiatric symptoms in patients with PD, while DAT uptake did not affect the neuropsychiatric symptoms.
Journal Article
Patterns of Neuropsychological Profile and Cortical Thinning in Parkinson’s Disease with Punding
Punding, one of dopamine replacement treatment related complications, refers to aimless and stereotyped behaviors. To identify possible neural correlates of punding behavior in patients with Parkinson's disease (PD), we investigated the patterns of cognitive profiles and cortical thinning.
Of the 186 subjects with PD screened during the study period, we prospectively enrolled 10 PD patients with punding and 43 without punding on the basis of a structured interview. We performed comprehensive neuropsychological tests and voxel-based and regions-of-interest (ROIs)-based cortical thickness analysis between PD patients with and without punding.
The prevalence of punding in patients with PD was 5.4%. Punding behaviors were closely related to previous occupations or hobbies and showed a temporal relationship to changes of levodopa-equivalent dose (LED). Significant predisposing factors were a long duration of PD and intake of medications of PD, high total daily LED, dyskinesia, and impulse control disorder. Punding severity was correlated with LED (p = 0.029). The neurocognitive assessment revealed that PD patients with punding showed more severe cognitive deficits in the color Stroop task than did those without punding (p = 0.022). Voxel-based analysis showed that PD-punders had significant cortical thinning in the dorsolateral prefrontal area relative to controls. Additionally, ROI-based analysis revealed that cortical thinning in PD-punders relative to PD-nonpunders was localized in the prefrontal cortices, extending into orbitofrontal area.
We demonstrated that PD patients with punding performed poorly on cognitive tasks in frontal executive functions and showed severe cortical thinning in the dorsolateral prefrontal and orbitofrontal areas. These findings suggest that prefrontal modulation may be an essential component in the development of punding behavior in patients with PD.
Journal Article
Neuroanatomical substrates of visual hallucinations in patients with non-demented Parkinson's disease
Background Visual hallucinations (VH), which are common in patients with Parkinson's disease (PD), lead to increased disability and are a significant predictor of the development of dementia. However, the neuroanatomical basis for VH in non-demented PD patients remains controversial. Methods A total of 110 patients with PD were classified into PD with VH (n=46) and PD without VH (n=64) groups, depending on the presence of VH assessed by the caregiver-based structured interview of the Neuropsychiatric Inventory. We performed voxel-based morphometry (VBM) for grey matter (GM) volume and a region-of-interest-based volumetric analysis of the substantia innominata (SI) between two groups. Results The comprehensive neuropsychological assessment showed that PD patients with VH showed more severe cognitive deficits in delayed visual memory and frontal executive functions compared with those without VH. A VBM analysis revealed that PD patients with VH had significantly lower GM volume in the right orbitofrontal, left temporal and left thalamic areas compared with those without VH. The normalised SI volume was significantly reduced in PD patients with VH compared with those without VH (1.28±0.22 vs 1.41±0.25, p=0.005). Conclusions The present study demonstrates that non-demented PD patients with VH exhibited a smaller volume in the frontal, temporal and thalamic areas as well as the SI, suggesting that PD hallucinators may have distinctive neuroanatomical bases relative to PD non-hallucinators.
Journal Article