Ji E. Lee

A randomized trial of mesenchymal stem cells in multiple system atrophy

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).

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

Background: Cognitive dysfunction is common in Parkinsons 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 Parkinsons 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.

Factors contributing to the development of restless legs syndrome in patients with Parkinson disease

Although restless legs syndrome (RLS) commonly accompanies Parkinson disease (PD), the mechanism of RLS development in PD is still unclear. We investigated the prevalence of RLS in Korean patients with PD, and the possible contributing factors to the development of RLS in those patients. Four hundred forty‐seven consecutive patients with PD were interviewed and examined. Among them, 73 patients (16.3%) were diagnosed with RLS. PD patients with RLS had a longer duration of PD symptoms, more severe PD disability, a greater degree of cognitive decline, and a longer duration of antiparkinson therapy than those without RLS. Multivariate logistic regression analysis revealed that the duration of antiparkinson therapy was the most significant factor contributing to the development of RLS in patients with PD. The present results support a higher prevalence of RLS in patients with PD and suggest that long‐term antiparkinson therapy, rather than PD itself, may contribute to the development of RLS.

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

Background Parkinsons 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.

Factors related to clinically probable REM sleep behavior disorder in Parkinson disease

Rapid eye movement sleep behavior disorder (RBD) is commonly accompanied in Parkinson disease (PD). However, the underlying mechanism linking RBD to PD remains unclear. We interviewed and examined 447 consecutive patients with PD to investigate factors associated with the presence of RBD in PD patients. Using the minimal diagnostic criteria for parasomnias provided in the International Classification of Sleep Disorders-Revised (ICSD-R), 164 patients (36.5%) were diagnosed with clinically probable RBD (cpRBD). PD patients with cpRBD were older, had a longer duration of PD, a more severe level of disability, a longer duration of antiparkinsonian medication, and a lower proportion of their Unified Parkinson Disease Rating Scale (UPDRS) scores accounted for by tremor than those without RBD. Multivariate and univariate logistic regression analyses revealed that patient age, PD symptom duration (and, accordingly, more severe motor disability), tremor score, and proportion of the UPDRS score accounted for by tremor were significant factors associated with the presence of RBD in PD patients. The results of the present study support previous observations that PD with RBD may result from a different underlying pattern of neurodegeneration than PD without RBD.

Volumetric analysis of the substantia innominata in patients with Parkinson's disease according to cognitive status

The cholinergic system arising from the substantia innominata (SI) of the basal forebrain has an important role in the cognitive functions of Parkinsons disease (PD). We performed magnetic resonance imaging based volumetric analysis to evaluate the SI volume in patients with PD-intact cognition (PD-IC), PD-mild cognitive impairment (PD-MCI), and PD dementia (PDD). The mean normalized SI volume was significantly decreased in patients with PD-IC (1.54 ± 0.12, p < 0.001), PD-MCI (1.49 ± 0.12, p < 0.001), and PDD (1.39 ± 0.12, p < 0.001) compared with that of control subjects (1.68 ± 0.11). The normalized SI volume did not differ between patients with PD-IC and PD-MCI; however, the normalized SI volume was significantly decreased in patients with PDD compared with that in those with PD-IC (p < 0.001) or PD-MCI (p = 0.016). The normalized SI volume was significantly correlated with general cognitive status (r = 0.51, p < 0.001) as well as with performance in each cognitive subdomain, with a particularly significant independent association with attention (β = 0.33, p = 0.003) and object naming (β = 0.26, p = 0.017). The present study demonstrated that the SI volume in PD differs depending on cognitive status and is significantly correlated with cognitive performance.

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.

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 Parkinsons 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.

Subcortical white matter hyperintensities within the cholinergic pathways of Parkinson's disease patients according to cognitive status

Background White matter hyperintensities (WMH) in the cholinergic pathways show a stronger correlation with cognitive performance than general WMH in Alzheimers disease. However, the role of WMH within the cholinergic pathways in cognitive dysfunction has not been investigated in Parkinsons disease (PD). Method The severity of WMH within the cholinergic pathways of PD subgroups with intact cognition (PD-IC, n=44), mild cognitive impairment (PD-MCI, n=87) and dementia (PDD, n=40) were compared using the Cholinergic Pathways Hyperintensities Scale (CHIPS), and the correlation between the CHIPS score and performance on individual tests of cognitive subdomains were analysed. Results The mean CHIPS score was significantly higher in patients with PDD compared with those with PD-IC (p=0.03) or PD-MCI (p=0.015). The CHIPS score in patients with PD was negatively correlated with general cognition assessed using the Mini-Mental State Examination (r=−0.28, p<0.001) and positively with the Unified Parkinsons Disease Rating Scale motor score (r=0.24, p=0.002). The CHIPS score showed a significant correlation with cognitive performance on individual cognitive subdomains and had the highest independent correlations with contrasting programme (β=−0.33, p<0.001) and forward digit span (β=−0.17, p=0.04). Conclusions This study demonstrated that the burden of WMH within cholinergic pathways was significantly higher in patients with PDD relative to other groups, and that cholinergic WMH was significantly correlated with a decline in frontal executive function and attention.