Jae Jung Lee

Blood-brain barrier impairment is functionally correlated with clinical severity in patients of multiple system atrophy

Multiple system atrophy (MSA) has been regarded as a unique entity within the spectrum of oligodendrogliopathy. However, the pathomechanisms underlying the initial trigger and aggravating factors responsible for disease progression remain unknown. Even though the implication of blood-brain barrier (BBB) dysfunction has not been fully elucidated, this dysfunction may act as a modifier of disease progression in neurodegenerative disease. We evaluated the integrity of the BBB and its functional significance in patients with MSA using the CSF/serum albumin index (CSF-AI) and the volume transfer coefficient (K(trans)) in dynamic contrast-enhanced MRI (DCE-MRI). CSF-AI and K(trans) values increased significantly in patients with MSA compared to the control (5.1 μg vs 3.6 μg, p=0.02; 0.16/mim(-1) vs 0.05/mim(-1), p=0.001, respectively). There were positive relationships between both CSF-AI and K(trans) and unified MSA rating scale (UMSARS). K(trans) in the periventricular white matter was significantly correlated with the volume of white matter hyperintensities among all subjects (r=0.58, p=0.001) and within patients with MSA (r=0.58, p=0.019), but not within controls (r=0.42, p>0.05). In addition, a significant positive correlation was detected between CSF-AI and K(trans) (r=0.81, p=0.002). Multiple linear regression analysis showed that only UMSARS score was a significantly independent predisposing factor for CSF-AI (β=0.193, p=0.04). Our data suggest that BBB dysfunction is related to the underlying nature of MSA and its dysfunction is closely coupled to disease severity.

Association of body mass index and the depletion of nigrostriatal dopamine in Parkinson's disease

Several antecedent studies had reported close relationship between low body weight and Parkinsons disease (PD). However, there have been few investigations about the role of body weight to nigrostriatal dopaminergic neurodegeneration. This study enrolled 398 de novo patients with PD whom underwent [18F] N-(3-Fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scan and body mass index (BMI) measurement. The relationships between BMI and dopamine transporter (DAT) activity were analyzed using linear regression analysis. A multivariate analysis adjusted for age, gender, disease duration, smoking status, coffee and tea consumption, and residence area revealed that BMI remained independently and significantly associated with DAT activity in all striatal subregions. Moreover, multiple logistic regression analyses showed that BMI was a significant predictor for the lowest quartile of DAT activity in the anterior putamen, ventral striatum, caudate nucleus, and total striatum. The present findings suggest that a low BMI might be closely associated with low density of nigrostriatal dopaminergic neurons in PD, which could support the evidence for the role of low body weight to PD-related pathologies.

Gender Differences in Age-Related Striatal Dopamine Depletion in Parkinson’s Disease

Objective Gender differences are a well-known clinical characteristic of Parkinson’s disease (PD). In-vivo imaging studies demonstrated that women have greater striatal dopamine transporter (DAT) activity than do men, both in the normal population and in PD patients. We hypothesize that women exhibit more rapid aging-related striatal DAT reduction than do men, as the potential neuroprotective effect of estrogen wanes with age. Methods This study included 307 de novo PD patients (152 men and 155 women) who underwent DAT scans for an initial diagnostic work-up. Gender differences in age-related DAT decline were assessed in striatal sub-regions using linear regression analysis. Results Female patients exhibited greater DAT activity compared with male patients in all striatal sub-regions. The linear regression analysis revealed that age-related DAT decline was greater in the anterior and posterior caudate, and the anterior putamen in women compared with men; we did not observe this difference in other sub-regions. Conclusions This study demonstrated the presence of gender differences in age-related DAT decline in striatal sub-regions, particularly in the antero-dorsal striatum, in patients with PD, presumably due to aging-related decrease in estrogen. Because this difference was not observed in the sensorimotor striatum, this finding also suggests that women may not have a greater capacity to tolerate PD pathogenesis than do men.

Apathy and striatal dopamine defects in non-demented patients with Parkinson's disease

INTRODUCTION Apathy is a common, disabling symptom in Parkinsons disease (PD). The mechanisms underlying apathy in PD are still unclear, although they may be related to dysfunction in the meso-cortico-limbic circuit, including the ventral striatum. Thus, we performed this study to investigate whether dopamine depletion in the ventral striatum contributes to apathy in PD. METHODS We conducted a survey of the degree of apathy (using the Korean version of the Apathy Evaluation Scale, AES-S) in 108 non-demented patients with PD who underwent dopamine transporter (DAT) positron emission tomography scans as an initial diagnostic work-up. Patients with AES-S scores of 37 or higher were defined as having apathetic PD. The Beck Depression Inventory (BDI) was administered to assess the severity of depression. Patients with BDI scores of 15 or higher were regarded as having depression. RESULTS Apathetic patients (n = 34) tended to exhibit higher BDI scores than non-apathetic patients (n = 74); however, other clinical variables were comparable between the two groups. DAT activity in the striatal sub-regions was also similar between the two groups. Selecting only non-depressed patients, including 20 apathetic and 47 non-apathetic patients, did not alter the results. CONCLUSIONS This study demonstrated that the pattern of striatal dopamine depletion does not contribute to the degree of apathy in early PD. Apathy in PD may be associated with extra-striatal lesions that accompany PD rather than striatal dopaminergic deficits.

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.

Does serum uric acid act as a modulator of cerebrospinal fluid Alzheimer's disease biomarker related cognitive decline?

The association of serum uric acid, cerebrospinal fluid (CSF) biomarkers of Alzheimers disease (AD) and longitudinal cognitive decline was evaluated using the AD Neuroimaging Initiative database.

Effect of olfactory impairment and white matter hyperintensities on cognition in Parkinson's disease

INTRODUCTION Although white matter hyperintensities (WMH) and olfactory dysfunction are independently associated with the cognitive impairments in Parkinsons disease (PD), the effects of simultaneous presence of these abnormalities remain unknown. Thus, we investigated the different effects of deep WMH and periventricular WMH on olfactory and cognitive performance and evaluated the additive effects of the concurrent presence of WMH and olfactory dysfunction on cognitive performance in PD. METHODS We enrolled 171 patients with non-demented PD whose WMH scores were assessed using a semi-quantitative visual rating system. The olfactory and cognitive performance was assessed using the Cross-Cultural Smell Identification (CCSI) test and the Seoul Neuropsychological Screening Battery. Additionally, the additive effects of concurrent WMH and olfactory dysfunction on cognitive performance were investigated using binary logistic regression. RESULTS The deep WMH score exhibited a significant negative correlation with the CCSI score (p = 0.026) but the total WMH and periventricular WMH did not. A multiple regression analysis revealed that the total WMH (β = -0.109, p = 0.011) and deep WMH (β = -0.153, p = 0.020) severities had significant negative correlations with semantic fluency. A logistic regression analysis revealed that the simultaneous presence of severe olfactory dysfunction and deep WMH was associated with a greater risk for the semantic fluency impairments (odds ratio = 15.909, p = 0.0005) compared to patients with mild deep WMH or high CCSI scores. CONCLUSIONS These data indicate that deep WMH was closely coupled with olfactory impairments and cognitive decline in PD. Moreover, the concurrent presence of severe deep WMH and olfactory impairments has a greater influence on semantic fluency.

Correlation of 3D FLAIR and Dopamine Transporter Imaging in Patients With Parkinsonism

OBJECTIVE The purpose of this study is to evaluate direct in vivo visualization of nigrosome-1 in substantia nigra (SN) with 3D FLAIR imaging and its diagnostic value in predicting the intactness of presynaptic dopaminergic function of the nigrostriatal pathway. MATERIALS AND METHODS Forty-five patients showing parkinsonism who underwent both 3D FLAIR and dopamine transporter (DAT) imaging were recruited. In total, 90 SNs were reviewed on axial 3D FLAIR images. We regarded oval or linear hyperintensities on the posterolateral side of SN as intact nigrosome-1. Two neuroradiologists independently evaluated the appearance of nigrosome-1, and disagreements were settled by consensus. Kappa values for interrater agreement were calculated. Diagnostic performances of the appearance of nigrosome-1 for predicting presynaptic dopaminergic function on DAT imaging and Parkinson disease (PD) were calculated. RESULTS The diagnostic performances of a loss of nigrosome-1 on 3D FLAIR images were sensitivity of 85.7%, specificity of 85.4%, positive predictive value (PPV) of 83.7%, and negative predictive value (NPV) of 87.2% for predicting impaired presynaptic dopaminergic function on DAT imaging, and sensitivity of 94.7%, specificity of 76.9%, PPV of 85.7%, and NPV of 90.9% for predicting PD. When only oval hyperintensity was considered as intact nigrosome-1, its sensitivity and NPV were increased up to 95.2% and 91.7%, respectively, for predicting impaired presynaptic dopaminergic function on DAT imaging, and both increased to 100% for predicting PD. Interobserver agreement for the appearance of nigrosome-1 on 3D FLAIR images was substantial (κ = 0.625). CONCLUSION Nigrosome-1 could be visualized on 3D FLAIR images, and its loss can be used to predict presynaptic dopaminergic function and to diagnose PD with high accuracy.

Striatal Dopamine Depletion Patterns and Early Non-Motor Burden in Parkinsons Disease

Background The mechanism underlying non-motor symptoms in Parkinson’s disease has not yet been elucidated. In this study, we hypothesized that Parkinson patients with more non-motor symptoms have a different pattern of striatal dopamine depletion, particularly in areas other than the sensorimotor striatum, compared to those with fewer non-motor symptoms. Methods We conducted a prospective survey of the degree of non-motor symptoms (using the Korean version of the Non-Motor Symptoms Scale; K-NMSS) in 151 patients with early-stage Parkinson’s disease who had undergone a dopamine transporter PET scan as an initial diagnostic procedure. We classified the patients into two groups; high non-motor patients (HNM-PD; K-NMSS score ≥ 41) and low non-motor patients (LNM-PD). Results Patients in the HNM-PD group (n = 71) were older, had longer symptom duration, exhibited more severe motor deficits, and had been prescribed higher levodopa-equivalent doses at follow-up than those in the LNM-PD group. However, dopamine transporter binding to the striatal sub-regions and inter-sub-regional binding ratios were comparable between the two groups. A general linear model showed that the HNM-PD group had significantly more severe motor deficits than the LNM-PD group after controlling for age, gender, symptom duration, and dopamine transporter binding to the sensorimotor striatum. Conclusions This study demonstrated that the pattern of striatal dopamine depletion does not contribute to early non-motor burden in Parkinson’s disease. Our results suggest that LNM-PD patients may have a more benign course of motor symptom progression than HNM-PD patients.

Apathy and Olfactory Dysfunction in Early Parkinson’s Disease

Objective Olfactory and emotional dysfunctions are very common in patients with Parkinson’s disease (PD). Olfaction and emotions share common neuroanatomical substrates. Therefore, in this study, we evaluated the association between olfactory and emotional dysfunctions in patients with PD. Methods Parkinson’s disease patients who had been assessed for their olfactory function and neuropsychiatric symptoms including emotional dysfunction were included. A logistic regression analysis was performed to evaluate the association between low olfaction and different neuropsychiatric symptoms. Results The patients with low olfaction (cross cultural smell identification test score ≤ 6) showed a higher prevalence of apathy when compared with those with high olfaction, whereas the frequencies of other neuropsychiatric symptoms were comparable between the two groups. A multivariate logistic regression analysis revealed that the presence of apathy/indifference [odds ratio (OR) = 2.859, p = 0.007], age 70 years or more (OR = 2.281, p = 0.009), and the male gender (OR = 1.916, p = 0.030) were significantly associated with low olfaction. Conclusions Our results demonstrate that apathy/indifference is a unique emotional dysfunction associated with olfactory dysfunction in PD. The findings also suggest that PD patients with low olfaction have a high prevalence of apathy.