Olfactory performance and resting state functional connectivity in non-demented drug naïve patients with Parkinson's disease.

Olfactory performance in Parkinson's disease (PD) is closely associated with subsequent cognitive decline. In the present study, we analyzed the olfaction-dependent functional connectivity with a hypothesis that olfactory performance would influence functional connectivity within key brain areas of PD. A total of 110 nondemented drug-naïve patients with PD were subdivided into three groups of high score (PD-H, n = 23), middle score (PD-M, n = 64), and low score (PD-L, n = 23) based on olfactory performance. We performed the resting-state functional connectivity with seed region of interest in the posterior cingulate cortex (PCC) and caudate. An analysis of functional connectivity revealed that PD-L patients exhibited a significant attenuation of cortical functional connectivity with the PCC in the bilateral primary sensory areas, right frontal areas, and right parietal areas compared to PD-H or PD-M patients. Meanwhile, PD-L patients exhibited a significant enhancement of striatocortical functional connectivity in the bilateral occipital areas and right frontal areas compared to PD-H or PD-M patients. In the voxel-wise correlation analysis, olfactory performance was positively associated with cortical functional connectivity with the PCC in similar areas of attenuated cortical connectivity in PD-L patients relative to PD-H patients. On the other hand, the cortical functional connectivity with the caudate was negatively correlated with olfactory performance in similar areas of increased connectivity in PD-L patients relative to PD-H patients. The present study demonstrated that resting state functional connectivity exhibits a distinctive pattern depending on olfactory performance, which might shed light on a meaningful relationship between olfactory impairment and cognitive dysfunction in PD.

Exploratory analysis of neuropsychological and neuroanatomical correlates of progressive mild cognitive impairment in Parkinson's disease.

BACKGROUND: Parkinson's disease with mild cognitive impairment (PD-MCI) is a heterogeneous entity in terms of cognitive profiles and conversion to dementia. However, the risk factors for ongoing cognitive decline in patients with PD-MCI are not clearly defined. METHODS: 51 patients with PD-MCI were prospectively followed-up for a minimum of 2 years. Subjects were classified as MCI converters (n=15) or MCI non-converters (n=36) based on whether they were subsequently diagnosed with PD dementia. We explored cognitive profiles and neuroanatomical characteristics of PD-MCI converters using voxel based morphometry (VBM) of grey matter (GM) density and region of interest based volumetric analysis of the substantia innominata (SI). RESULTS: PD-MCI converters showed more severe cognitive deficits in frontal executive functions, immediate verbal memory and visual recognition memory compared with PD-MCI non-converters. VBM analysis revealed that PD-MCI converters had significantly lower GM density in the left prefrontal areas, left insular cortex and bilateral caudate nucleus compared with that in PD-MCI non-converters. The mean normalised SI volume was significantly smaller in both PD-MCI converters (1.19±0.35, p<0.001) and PD-MCI non-converters (1.52±0.27, p<0.001) compared with that in controls (1.87±0.19). PD-MCI converters had a significantly smaller normalised SI volume than PD-MCI non-converters (p<0.001). CONCLUSIONS: Our data show that atrophy in the frontostriatal areas and cholinergic structures, as well as frontal lobe associated cognitive performance, may act as predictors of dementia in PD-MCI patients, suggesting distinctive patterns of cognitive profiles and a neuroanatomical basis for progressive PD-MCI.

A randomized trial of mesenchymal stem cells in multiple system atrophy.

OBJECTIVE: Neuroprotective or regenerative strategies are invaluable in multiple system atrophy (MSA) due to its rapid progression with fatal prognosis. We evaluated the efficacy of autologous mesenchymal stem cells (MSC) in patients with MSA-cerebellar type (MSA-C). METHODS: Thirty-three patients with probable MSA-C and baseline unified MSA rating scale (UMSARS) scores ranging from 30 to 50 were randomly assigned to receive MSC (4 × 10(7) /injection) via intra-arterial and intravenous routes or placebo. The primary outcome was change in the total UMSARS scores from baseline throughout a 360-day follow-up period between groups. Secondary outcomes were changes in the UMSARS part II scores, cerebral glucose metabolism, gray matter density, and cognitive performance over a 360-day period. RESULTS: The mixed model analysis of neurological deficits revealed a significant interaction effect between treatment group and time, suggesting that the MSC group had a smaller increase in total and part II UMSARS scores compared with the placebo group (p = 0.047 and p = 0.008, respectively). Cerebral glucose metabolism and gray matter density at 360 days relative to the baseline were more extensively decreased in the cerebellum and the cerebral cortical areas, along with greater deterioration of frontal cognition in the placebo group compared with the MSC group. We found no serious adverse effects that were directly related to MSC treatment. However, intra-arterial infusion resulted in small ischemic lesions on magnetic resonance imaging. INTERPRETATION: MSC therapy could delay the progression of neurological deficits in patients with MSA-C, suggesting the potential of MSC therapy as a treatment candidate of MSA.

Uric acid as a potential disease modifier in patients with multiple system atrophy.

BACKGROUND: Recent studies have suggested that mitochondrial dysfunction and oxidative stress play a key role in the pathogenesis of multiple system atrophy. METHODS: We evaluated the influence of serum uric acid levels on disease progression in 52 patients with multiple system atrophy using changes in the annualized Unified Multiple System Atrophy Rating Scale scores. RESULTS: The mean annualized Unified Multiple System Atrophy Rating Scale changes were significantly lower in patients with the highest uric acid quartile compared with those with the lowest quartile (8.4 ± 5.1 vs 20.2 ± 16.0, P = .038). Serum uric acid levels had a significant negative correlation with the annualized Unified Multiple System Atrophy Rating Scale changes (r = -0.40, P = .004). Multiple linear regression analysis showed that only serum uric acid concentration was significantly correlated with the annualized Unified Multiple System Atrophy Rating Scale changes (ß = -2.687, P = .011). CONCLUSIONS: These data suggest that serum uric acid may act as a potential disease modifier in multiple system atrophy.

The pattern of cortical atrophy in patients with Parkinson's disease according to cognitive status.

BACKGROUND: Cognitive dysfunction is common in Parkinson's disease (PD), and along with PD with dementia (PDD), the concept of mild cognitive impairment in PD (PD-MCI) has been introduced. METHODS: To identify structural candidates according to cognitive status in PD, we compared gray matter (GM) density across PD-intact cognition (PD-IC, n = 23), PD-MCI (n = 27), and PDD (n = 18) using voxel-based morphometry. RESULTS: The demographic data among PD subjects were similar, however, general cognition and disease duration were more severe in PD-MCI and PDD than in PD-IC. Compared with controls, GM density was significantly decreased in the left occipital area in PD-IC; the bilateral temporal, left prefrontal and insular, and right occipital areas in PD-MCI; and in widespread brain areas in PDD. Compared with PD-IC, patients with PD-MCI had significantly decreased GM density in the right middle frontal area, and those with PDD had decreased GM density in the right parietal, middle frontal, insular, and lentiform areas. GM density in patients with PDD was significantly decreased in the bilateral middle temporal, right inferior temporal, and left middle and superior prefrontal areas. PDD patients with shorter disease duration before dementia (<5 year) showed greater GM atrophy in the posterior cingulate area than did those with longer disease duration (≥5 year). CONCLUSIONS: These data suggest that cortical atrophy in PD exhibits a greater extent with increasing levels of cognitive impairment, and different anatomical substrates would correspond to each cognitive status.

A comparative analysis of cognitive profiles and white-matter alterations using voxel-based diffusion tensor imaging between patients with Parkinson's disease dementia and dementia with Lewy bodies.

BACKGROUND: Despite clinical and neuropsychological similarities between Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), recent studies have demonstrated that structural and pathological changes are more severe in DLB than in PDD. METHODS: 19 patients with probable PDD and 18 patients with probable DLB who had a similar overall severity of dementia and demographic characteristics were examined by a standardised neuropsychological test and voxel-based analysis of fractional anisotropy (FA) using diffusion tensor imaging (DTI). RESULTS: The patients with DLB performed significantly worse in visual recognition memory, semantic fluency and ideomotor praxis than those with PDD (p<0.05). Compared with controls, the FA value in patients with PDD was significantly lower in bilateral frontal, left temporal and left parietal white matter. In patients with DLB, the pattern of FA reduction was similar to that of patients with PDD; however, white-matter abnormalities were more severe and extended into bilateral insular, bilateral posterior cingular and bilateral visual association regions. In a direct comparison between PDD and DLB, the FA value in patients with DLB was significantly decreased in bilateral posterior temporal, posterior cingular and bilateral visual association fibres extending into occipital areas. CONCLUSIONS: Despite global similarities in cognitive performance and white-matter pathology between DLB and PDD patients, those with DLB had more severely impaired frontal and temporal area-associated cognitive subsets, and more severe white-matter pathology in temporal and visual association fibres. These data suggest that differences in the underlying nature of PDD and DLB may exist with global similarities in their cognitive performance and white-matter pathology.

A comparison of gray and white matter density in patients with Parkinson's disease dementia and dementia with Lewy bodies using voxel-based morphometry.

Despite clinical and neuropsychological similarities between Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), recent studies have demonstrated that structural and pathological changes are more severe in DLB than in PDD. We used voxel-based morphometry using a 3-T MRI scanner to compare gray and white matter densities in 20 patients with probable PDD and 18 patients with probable DLB, who had similar overall severity of dementia and similar demographic characteristics. The gray matter density was significantly decreased in the left occipital, parietal, and striatal areas in patients with DLB compared with patients with PDD. The white matter density was significantly decreased in bilateral occipital and left occipito-parietal areas in patients with DLB compared with those with PDD. The degree of white and gray matter atrophy was similar in patients with DLB; in contrast, there was markedly less atrophy in the white matter than in the gray matter in patients with PDD. On analyzing the change of WM density relative to that of GM density in patients with DLB compared to those with PDD, the area of WM atrophy in the occipital areas was more extensive than that of GM atrophy. Our data demonstrate that atrophy of both gray and white matter was more severe in patients with DLB and that white matter atrophy relative to gray matter atrophy was less severe in patients with PDD. These data may reflect a difference in the underlying nature of PDD and DLB.

A case-control study of multiple system atrophy in Korean patients.

A few case-control studies of multiple system atrophy (MSA) have been reported in Western populations. In this study, we included various epidemiological factors to evaluate whether the risk factors for MSA differed in Korean and Western populations. A total of 100 consecutive MSA patients and 104 controls at two referral hospitals participated. Information was obtained through face-to-face interviews using a structured questionnaire: history of living area, occupational history, food habits, alcohol and tobacco consumption, and use of drugs. Odds ratios and 95% confident intervals (OR [95% CI]) were computed using logistic regression. The multivariate logistic regression analysis revealed that use of antihypertensive medication (OR = 0.30 [0.12-0.78]) and vitamins (OR = 0.30 [0.14-0.64]) and consumption of meat and poultry (OR = 0.27 [0.13-0.56]) were associated with decreasing risk for MSA, whereas use of herbal medications (OR = 3.17 [1.28-7.84]) was associated with increasing risk for MSA. In univariate analysis adjusted for age, sex, education level, and recruitment center, use of aspirin (OR = 0.21 [0.07-0.61]) and coffee consumption (OR = 0.44 [0.23-0.84]) were significantly less frequent in MSA patients than in controls, whereas heavy smoking (≥40 pack-years) was significantly more prevalent in MSA patients than in controls (OR = 3.44 [1.05-11.23]). There was no difference in living area, participation in farming, or exposure to agrichemicals and solvents between groups. This study showed that MSA in Korea is characterized by risk factors that are both similar to and different from those affecting Western populations and that herbal medicines constitute a new MSA risk factor for the Korean population.

Mesenchymal stem cells stabilize the blood-brain barrier through regulation of astrocytes.

INTRODUCTION: The blood-brain barrier (BBB) protects the brain against potentially neurotoxic molecules in the circulation, and loss of its integrity may contribute to disease progression in neurodegenerative conditions. Recently, the active role of reactive astrocytes in BBB disruption has become evident in the inflamed brain. In the present study, we investigated whether mesenchymal stem cell (MSC) treatment might modulate reactive astrocytes and thus stabilize BBB integrity through vascular endothelial growth factor A (VEGF-A) signaling in inflammatory conditions. METHODS: For the inflamed brain, we injected LPS using a stereotaxic apparatus and MSCs were injected into the tail vein. At 6 hours and 7 days after LPS injection, we analyzed modulatory effects of MSCs on the change of BBB permeability through VEGF-A signaling using immunochemistry and western blot. To determine the effects of MSCs on VEGF-A-related signaling in cellular system, we had used endothelial cells treated with VEGF-A and co-cultured astrocyte and BV 2 cells treated with lipopolysaccharide (LPS) and then these cells were co-cultured with MSCs. RESULTS: In LPS-treated rats, MSCs restored Evans blue infiltration and the number of endothelial-barrier antigen (EBA) and P-glycoprotein (p-gp)-expressing cells, which were significantly altered in LPS-treated animals. Additionally, MSC administration following LPS treatment markedly increased the density of astrocytic filaments around vessels and reversed LPS-induced elevations in VEGF-A levels as well as endothelial nitric oxide synthase (eNOS)-dependent downregulation of tight junction proteins in the endothelium. Consequently, MSC treatment reduced neutrophil infiltration and enhanced survival of midbrain dopaminergic neurons in LPS-treated animals. In cellular system, MSC treatment led to a significant reversion of VEGF-A-induced eNOS and tight junction protein expression in endothelial cells, which led to increased EBA expressing cells. Additionally, MSC treatment significantly attenuated LPS-induced increased expressions of IL-1ß in microglia and VEGF-A in astrocytes with an increase in IL-10 levels. CONCLUSION: The present study indicated that MSCs may stabilize BBB permeability by modulating astrocytic endfeet and VEGF-A signaling, which may be relevant to the treatment of Parkinsonian diseases as a candidate for disease modifying therapeutics.

Olfactory performance acts as a cognitive reserve in non-demented patients with Parkinson's disease.

OBJECTIVE: To explore whether olfactory performance acts as a cognitive reserve in non-demented patients with Parkinson's disease (PD). METHODS: Patients with non-demented PD (n = 119) underwent T1-weighted MRI and olfactory identification tests. According to their olfactory performance, PD patients were subdivided into three groups of high score (PD-H, n = 38), middle score (PD-M, n = 48), and low score (PD-L, n = 33). We investigated the pattern of gray matter (GM) density according to olfactory performance using voxel-based morphometry (VBM) and analyzed the correlation between GM density and olfactory performance. RESULTS: No significant differences in demographic characteristics were observed among the groups. A neuropsychological test showed that cognitive deficits in verbal memory function were more severe in the PD-L group than in the PD-H group. However, a VBM analysis revealed that patients in the PD-H group possessed significantly decreased GM density in the bilateral temporal areas, orbitofrontal areas, mesiofrontal areas extending into the cingulate gyrus, and prefrontal areas, compared with patients in the PD-L group. No areas exhibiting a significant difference in GM density were observed between the PD-H and PD-M groups. Olfactory performance in patients with PD was negatively correlated with both the brain GM volume and intracerebral volume; in particular, GM density in the caudate nucleus and putamen exhibited a negative correlation with olfactory performance. CONCLUSIONS: Our data show that a high olfactory performance may compensate GM volume loss in order to minimize the exhibition of cognitive impairment and thus may act as a cognitive reserve in non-demented patients with PD.

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.

Changes in the blood-brain barrier status closely correlate with the rate of disease progression in patients with multiple system atrophy: a longitudinal study.

BACKGROUND: The pathomechanisms responsible for disease progression in multiple system atrophy are unknown. The blood-brain barrier status may act as a modifier of disease progression in neurodegenerative diseases. METHODS: We evaluated the 12-month longitudinal change of the blood-brain barrier in 16 multiple system atrophy patients and analyzed its correlation with changes in clinical severity. RESULTS: The baseline blood-brain barrier index did not correlate significantly with change in disease severity. However, changes in the blood-brain barrier indices over 12 months had significant positive correlations with changes in total unified multiple system atrophy rating scale (r = 0.56, p = 0.024) and part II scores (r = 0.56, p = 0.025). These correlation coefficients were higher after adjusting for baseline neurological deficits. CONCLUSIONS: These data suggest that changes in the blood-brain barrier status are closely coupled with the rate of disease progression in multiple system atrophy, potentially acting as a contributor to disease progression.

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 (ß=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.