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Background and purpose: Olfactory dysfunction or dysautonomia is one of the earliest prodromal nonmotor symptoms of Parkinson's disease (PD). We aimed to investigate whether PD patients with dysautonomia and hyposmia at the de novo stage present different prognoses regarding PD dementia (PDD) conversion, motor complication development, and change in levodopa-equivalent doses (LED). Methods: In this retrograde cohort study, we included 105 patients with newly diagnosed PD patients who underwent cross-cultural smell identification test (CC-SIT), autonomic function tests (AFT), and dopamine transporter (DAT) scan at the de novo stage. PD patients were divided into Hyposmia + /Dysautonomia + (H + /D +) and Hyposmia − /Dysautonomia − (H − /D −) groups depending on the result of AFT and CC-SIT. Baseline clinical, cognitive, imaging characteristics, longitudinal risks of PDD development and motor complication occurrence, and longitudinal LED changes were compared between the two groups. Results: When compared with the H − /D − group, the H + /D + group showed lower standardized uptake value ratios in all subregions, lower asymmetry index, and steeper ventral − dorsal gradient in the DAT scan. The H + /D + group exhibited poorer performance in frontal/executive function and a higher risk of PDD development. The risk of motor complications including levodopa-induced dyskinesia, wearing off, and freezing of gait, was comparable between the two groups. The analysis of longitudinal changes in LED using a linear mixed model showed that the increase of LED in the H + /D + group was more rapid. Conclusions: Our results suggest that PD patients with dysautonomia and hyposmia at the de novo stage show a higher risk of PD dementia conversion and rapid progression of motor symptoms. [ABSTRACT FROM AUTHOR]

The background of this study is to investigate whether striatal dopamine depletion patterns (selective involvement in the sensorimotor striatum or asymmetry) are associated with motor deficits in Parkinson's disease (PD). We enrolled 404 drug-naïve patients with early stage PD who underwent dopamine transporter (DAT) imaging. After quantifying DAT availability in each striatal sub-region, principal component (PC) analysis was conducted to yield PCs representing the spatial patterns of striatal dopamine depletion. Subsequently, multivariate linear regression analysis was conducted to investigate the relationship between striatal dopamine depletion patterns and motor deficits assessed using the Unified PD Rating Scale Part III (UPDRS-III). Mediation analyses were used to evaluate whether dopamine deficiency in the posterior putamen mediated the association between striatal dopamine depletion patterns and parkinsonian motor deficits. Three PCs indicated patterns of striatal dopamine depletion: PC1 (overall striatal dopamine deficiency), PC2 (selective dopamine loss in the sensorimotor striatum), and PC3 (symmetric dopamine loss in the striatum). Multivariate linear regression analysis revealed that PC1 (β = − 1.605, p < 0.001) and PC2 (β = 3.201, p < 0.001) were associated with motor deficits (i.e., higher UPDRS-III scores in subjects with severe dopamine depletion throughout the whole striatum or more selective dopamine loss in the sensorimotor striatum), whereas PC3 was not (β = − 0.016, p = 0.992). Mediation analyses demonstrated that the effects of PC1 and PC2 on UPDRS-III scores were indirectly mediated by DAT availability in the posterior putamen, with a non-significant direct effect. Dopamine deficiency in the posterior putamen was most relevant to the severity of motor deficits in patients with PD, while the spatial patterns of striatal dopamine depletion were not a key determinant. [ABSTRACT FROM AUTHOR]

We evaluated the patterns of quantitative electroencephalography (EEG) in patients with Alzheimer's disease (AD), Lewy body disease (LBD), and mixed disease. Sixteen patients with AD, 38 with LBD, 20 with mixed disease, and 17 control participants were recruited and underwent EEG. The theta/alpha ratio and theta/beta ratio were measured. The relationship of the log-transformed theta/alpha ratio (TAR) and theta/beta ratio (TBR) with the disease group, the presence of AD and LBD, and clinical symptoms were evaluated. Participants in the LBD and mixed disease groups had higher TBR in all lobes except for occipital lobe than those in the control group. The presence of LBD was independently associated with higher TBR in all lobes and higher central and parietal TAR, while the presence of AD was not. Among cognitively impaired patients, higher TAR was associated with the language, memory, and visuospatial dysfunction, while higher TBR was associated with the memory and frontal/executive dysfunction. Increased TBR in all lobar regions and temporal TAR were associated with the hallucinations, while cognitive fluctuations and the severity of Parkinsonism were not. Increased TBR could be a biomarker for LBD, independent of AD, while the presence of mixed disease could be reflected as increased TAR. [ABSTRACT FROM AUTHOR]

Levodopa-induced dyskinesia (LID), a long-term motor complication in Parkinson's disease (PD), is attributable to both presynaptic and postsynaptic mechanisms. However, no studies have evaluated the baseline structural changes associated with LID at a subcortical level in PD. A total of 116 right-handed PD patients were recruited and based on the LID latency of 5 years, we classified patients into those vulnerable to LID (PD-vLID, n = 49) and those resistant to LID (PD-rLID, n = 67). After adjusting for covariates including dopamine transporter (DAT) availability of the posterior putamen, we compared the subcortical shape between the groups and investigated its association with the onset of LID. The PD-vLID group had lower DAT availability in the posterior putamen, higher parkinsonian motor deficits, and faster increment in levodopa equivalent dose than the PD-rLID group. The PD-vLID group had significant inward deformation in the right thalamus compared to the PD-rLID group. Inward deformation in the thalamus was associated with an earlier onset of LID at baseline. This study suggests that independent of presynaptic dopamine depletion, the thalamus is a major neural substrate for LID and that a contracted thalamic shape at baseline is closely associated with an early development of LID. [ABSTRACT FROM AUTHOR]

Background: Although levodopa-induced dyskinesia-relevant white matter change has been evaluated, it is uncertain whether these changes may reflect the underlying predisposing conditions leading to the development of levodopa-induced dyskinesia. Objective: To elucidate the role of white matter connectivity networks in the development of levodopa-induced dyskinesia in drug-naïve Parkinson's disease. Methods: We recruited 30 patients who developed levodopa-induced dyskinesia within 5 years from MRI acquisition (vulnerable-group), 47 patients who had not developed levodopa-induced dyskinesia within 5 years (resistant-group), and 28 controls. We performed comparative analyses of whole-brain white matter integrity and connectivity using tract-based spatial and network- and degree-based statistics. We evaluated the predictability of levodopa-induced dyskinesia development and relationship with its latency, using the average connectivity strength as a predictor in Cox- and linear-regression, respectively. Results: Mean-diffusivity was lower mainly at the left frontal region in the vulnerable-group compared to the resistant-group. Network-based statistics identified a subnetwork consisting of the bilateral fronto-striato-pallido-thalamic and lateral parietal regions (subnetwork A) and degree-based statistics identified four subnetworks (hub-subnetwork) consisting of edges centered on the left superior frontal gyrus, left putamen, left insular, or left precentral gyrus, where the vulnerable-group had stronger connectivity compared to the resistant-group. Stronger connectivity within the subnetwork A and hub-subnetwork centered on the left superior frontal gyrus was a predictor of levodopa-induced dyskinesia development independent of known risk factors and had an inverse relationship with its latency. Conclusions: Our data suggest that white matter connectivity subnetworks within corticostriatal regions play a pivotal role in the development of levodopa-induced dyskinesia. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between cognitive function at baseline and the progression of motor disability in Parkinson's disease (PD). Methods: We consecutively enrolled 257 drug-naïve patients with early-stage PD (follow-up > 2 years) who underwent a detailed neuropsychological test at initial assessment. Factor analysis was conducted to yield four cognitive function factors and composite scores thereof: Factor 1 (visual memory/visuospatial), Factor 2 (verbal memory), Factor 3 (frontal/executive), and Factor 4 (attention/working memory/language). The global cognitive composite score of each patient was calculated based on these factors. Subsequently, we assessed the effect of baseline cognitive function on long-term motor outcomes, namely levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and rate of longitudinal increases in levodopa-equivalent dose (LED). Results: Cox regression analysis demonstrated that higher Factor 3 (frontal/executive) composite scores (i.e., better cognitive performance) were associated with early development of LID [hazard ratio (HR), 1.507; p = 0.003], whereas higher Factor 1 (visual memory/visuospatial) composite scores (i.e., better cognitive performance) were associated with a lower risk for FOG (HR 0.683; p = 0.017). We noted that higher global cognitive composite scores were associated with a lower risk for developing FOG (HR 0.455; p = 0.045). The linear mixed model demonstrated that higher global cognitive composite scores and better cognitive performance in visual memory/visuospatial function were associated with slower longitudinal increases in LED. Conclusions: These findings suggest that baseline cognitive profiles have prognostic implications on several motor aspects in patients with PD. [ABSTRACT FROM AUTHOR]

To evaluate the implication of 18F-fluorodeoxyglucose (FDG)- and dopamine transporter (DAT)-positron emission tomography (PET) in the diagnosis and clinical symptoms of dementia with Lewy bodies (DLB), 55 DLB patients and 49 controls underwent neuropsychological evaluation and FDG-, DAT-, and 18F-Florbetaben (FBB) PET. DAT- and FDG-uptake and FDG/DAT ratio were measured in the anterior and posterior striatum. The first principal component (PC1) of FDG subject residual profiles was identified for each subject. Receiver operating characteristic curve analyses for the diagnosis of DLB were performed using FDG- and DAT-PET biomarkers as predictors, and general linear models for motor severity and cognitive scores were performed adding FBB standardized uptake value ratio as a predictor. Increased metabolism in the bilateral putamen, vermis, and somato-motor cortices, which characterized PC1, was observed in the DLB group, compared to the control group. A combination of posterior putamen FDG/DAT ratio and PC1 showed the highest diagnostic accuracy (91.8% sensitivity and 96.4% specificity), which was significantly greater than that obtained by DAT uptake alone. Striatal DAT uptake and PC1 independently contributed to motor severity and language, memory, frontal/executive, and general cognitive dysfunction in DLB patients, while only PC1 contributed to attention and visuospatial dysfunction. [ABSTRACT FROM AUTHOR]

We investigated the efficacy of donepezil for mild cognitive impairment in Parkinson's disease (PD-MCI). This was a prospective, non-randomized, open-label, two-arm study. Eighty PD-MCI patients were assigned to either a treatment or control group. The treatment group received donepezil for 48 weeks. The primary outcome measures were the Korean version of Mini-Mental State Exam and Montreal Cognitive Assessment scores. Secondary outcome measures were the Clinical Dementia Rating, Unified Parkinson's Disease Rating Scale part III, Clinical Global Impression scores. Progression of dementia was assessed at 48-week. Comprehensive neuropsychological tests and electroencephalography (EEG) were performed at baseline and after 48 weeks. The spectral power ratio of the theta to beta2 band (TB2R) in the electroencephalogram was analyzed. There was no significant difference in the primary and secondary outcome measures between the two groups. However, the treatment group showed a significant decrease in TB2R at bilateral frontotemporoparietal channels compared to the control group. Although we could not demonstrate improvements in the cognitive functions, donepezil treatment had a modulatory effect on the EEG in PD-MCI patients. EEG might be a sensitive biomarker for detecting changes in PD-MCI after donepezil treatment. [ABSTRACT FROM AUTHOR]

Lysosomal dysfunction has been associated with Parkinson's disease (PD). However, the activity of lysosomal enzymes is heterogeneously observed in PD. We investigated whether arylsulfatase A (ARSA) level can be used as a fluid biomarker of PD and can reflect disease progression. Plasma ARSA level was measured in 55 patients with early and drug-naïve PD, 13 patients with late PD, and 14 healthy controls. We compared the plasma ARSA level among the groups and assessed its correlation to clinical parameters and striatal dopamine transporter (DAT) activity. Plasma ARSA level was not correlated with age. The early PD group had higher plasma ARSA level than the control and late PD groups. In a generalized additive model including all patients with PD, the plasma ARSA level showed an inverted U-shape according to disease duration, peaking at 2.19 years. In patients with early PD, plasma ARSA level was positively correlated to parkinsonian motor score and negatively to striatal DAT activity. In summary, plasma ARSA level was elevated in early stage of PD, and elevated plasma ARSA level was correlated to the clinical and imaging markers of nigrostriatal degeneration. These results suggest that ARSA level is a potential biomarker of compensation in early PD. [ABSTRACT FROM AUTHOR]

Purpose: Little is known regarding the clinical relevance or neurobiology of subtle motor disturbance in Alzheimer's disease (AD). This study aims to investigate the patterns of striatal 18F-FP-CIT uptake in patients with AD-related cognitive impairment (ADCI) with mild parkinsonism. Methods: We recruited 29 consecutive patients with ADCI with mild parkinsonism. All patients underwent 18F-FP-CIT PET scans and dopamine transporter (DAT) availability in striatal subregions (anterior/posterior caudate, anterior/posterior putamen, ventral putamen, ventral striatum) was quantified. Additionally, 32 patients with dementia with Lewy bodies (DLB) and 21 healthy controls were included to perform inter-group comparative analyses of the striatal DAT availability. The discriminatory power of striatal DAT availability to differentiate ADCI from DLB was assessed using receiver operating characteristics (ROC) analyses. The Spearman's correlation coefficient was calculated to assess the relationship between motor severity and DAT availability in striatal subregions. Results: Patients with ADCI with mild parkinsonism exhibited decreased DAT availability in the caudate that was intermediate between healthy controls and patients with DLB. The DAT availability in other striatal subregions, including the posterior putamen, did not differ between the ADCI with parkinsonism and healthy control groups. The ROC analysis showed that DAT availability of all striatal subregions, especially the whole striatum, had a fair discriminatory power. Parkinsonian motor severity did not correlate with the striatal DAT availability in ADCI with parkinsonism. Conclusions: The present study demonstrated that patients with ADCI with mild parkinsonism had distinct DAT scan patterns and suggests that parkinsonism is associated with the extranigral source of pathology. [ABSTRACT FROM AUTHOR]

Objective: Parkinson's disease (PD) patients are often unaware of olfactory deficits despite having hyposmia from the early stages. We aimed to evaluate whether olfactory anosognosia is a predictor of cognitive decline in PD. Methods: In this retrospective cohort study, we recruited 77 PD patients who underwent both olfactory and neuropsychological tests and were followed-up for over 5 years. Based on the degree of olfactory dysfunction and awareness of its presence, patients were classified as normosmic patients (Normosmia group, n = 15), hyposmic patients without olfactory anosognosia (Hyposmia-OA−, n = 40), or hyposmic patients with olfactory anosognosia (Hyposmia-OA+, n = 22). We compared the rates of cognitive decline using linear mixed model and dementia conversion using a survival analysis among the groups. Results: A higher proportion of patients in the Hyposmia-OA+ group had mild cognitive impairment at baseline (77.3%) and dementia converter at follow-up (50.0%). The Hyposmia-OA+ group exhibited a faster decline in frontal executive and global cognitive function than did the Normosmia and Hyposmia-OA− groups. A Kaplan–Meier analysis demonstrated that the conversion rate to dementia was significantly higher in the Hyposmia-OA+ group than in the Normosmia (P = 0.007) and Hyposmia-OA− (P = 0.038) groups. A Cox regression analysis showed that olfactory anosognosia remained a significant predictor of time to develop dementia in the Hyposmia-OA+ group compared to the Normosmia group (adjusted hazard ratio 3.30; 95% confidence interval 1.10–8.21). Conclusion: This study suggests that olfactory anosognosia is a predictor of cognitive decline and dementia conversion in PD. [ABSTRACT FROM AUTHOR]

Background: It remains controversial whether late levodopa administration is a reasonable approach to reducing the risk of levodopa-induced dyskinesia in Parkinson's disease.Objective: This study aimed to investigate the effects of levodopa sparing on the development of levodopa-induced dyskinesia.Methods: We retrospectively reviewed medical records for patients with de novo Parkinson's disease who visited the Yonsei Parkinson Center between April 2009 and June 2015 and received at least 2 years of treatment. Among 657 patients with drug-naïve Parkinson's disease who met the study criteria, 90 were initially treated with dopamine agonists (levodopa-sparing group; levodopa supplementation after 2.15 years). Another 90 patients who were initially treated with levodopa (levodopa group) were matched to the 90 patients for age, sex, follow-up duration, Parkinson's disease duration, Unified Parkinson's Disease Rating Scale Part III scores, and baseline dopamine transporter availability in the posterior putamen. The effects of levodopa sparing on dyskinesia development were assessed with Kaplan-Meier estimates and a stratified Cox regression model adjusted for age of onset, sex, dopamine transporter availability, and daily levodopa dose per weight.Results: The levodopa-sparing group had a comparable age of onset (54.80 ± 7.36 years) to the levodopa group (56.53 ± 6.16 years). The Kaplan-Meier analysis revealed that the risk of levodopa-induced dyskinesia after treatment initiation was similar between the groups. Once the levodopa-sparing group started levodopa supplementation, they had a higher risk of developing levodopa-induced dyskinesia. However, a stratified Cox regression model indicated that hazard ratios for levodopa sparing to levodopa-induced dyskinesia development were 0.138 (95% confidence interval 0.024-0.785) after treatment initiation and 0.438 (95% confidence interval 0.105-1.832) after levodopa initiation.Conclusion: Late levodopa administration was associated with a low risk of dyskinesia after adjusting for confounding effects and may be a reasonable strategy for prolonging the levodopa-induced dyskinesia-free period in Parkinson's disease. [ABSTRACT FROM AUTHOR]

When attempting to perform two tasks simultaneously, the human motor as well as the cognitive system shows interference. Such interference often causes altered activation of the cortical area representing each task compared to the single task condition. We investigated changes in corticospinal inhibition during dual action by transcranial magnetic stimulation (TMS). Single-pulse TMS was applied to the left motor cortex, triggered by right leg movement (tibialis anterior muscle) while the right abductor digiti minimi (ADM) muscle was moderately activated (10-20% of the maximal voluntary contraction). The background electromyography (EMG) activity of ADM was measured before and during the leg movement. The silent period (SP) and amplitude of motor evoked potential (MEP) following magnetic stimulation in active ADM were compared for the conditions with and without leg movement. The mean area of the rectified EMG activity of ADM did not alter, while the SP was significantly shortened during leg movement compared to that without leg movement. MEP amplitude was comparable between the two conditions. These results suggest that corticospinal inhibition tested by the SP duration is reduced during the movement of another body part, presumably in order to help maintain muscle force by compensating interference-related alteration in motor cortical activation. [ABSTRACT FROM AUTHOR]

In sensory systems, a neural mechanism called surround inhibition (SI) sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, the functional operation of SI remains to be demonstrated, although it has been hypothesized to contribute to the selection of voluntary movements. Here we test this hypothesis by using transcranial magnetic stimulation of the human motor cortex. The motor evoked potential of the little finger muscle is suppressed or unchanged during self-paced, voluntary movements of the index finger, mouth or leg, despite an increase in spinal excitability. This result indicates that motor excitability related to little finger movement is suppressed at the supraspinal level during these movements, and supports the idea that SI is an organizational principle of the motor system. [ABSTRACT FROM AUTHOR]

We investigated the influence of self-paced, phasic voluntary hand movement on the excitability of the ipsilateral motor cortex. Single- and paired-pulse transcranial magnetic stimulation (TMS) was applied to the right motor cortex triggered by EMG onset of self-paced movements of individual right hand fingers at intervals ranging from 13 to 2,000 ms. Motor evoked potentials (MEPs) were evaluated in several left arm muscles. Significant suppression of MEP amplitudes was observed when TMS was applied between 35 and 70 ms after EMG onset. This inhibition was diffuse, affecting "adjacent" muscles (those near the homologous muscle in the same extremity) as well as homologous muscles, but more inhibition was observed in adjacent and distal muscles than homologous and proximal muscles. Significant inhibition of ipsilateral motor cortex was produced by index finger movements (both the extensor indicis proprius and the first dorsal interosseus), but not by little finger movement (the abductor digiti minimi). Paired-pulse TMS (at 2- and 10-ms interstimulus intervals) showed a significant increase in intracortical facilitation (ICF) selectively in the homologous muscle when triggered by self-paced movement of the opposite hand, but no change was observed in intracortical inhibition. When stimulation was triggered by self-paced movements, the silent period of the homologous muscle was significantly shortened, but the F-wave and compound muscle action potential were unchanged. Our findings demonstrate that voluntary hand movement exerts an inhibitory influence on a diffuse area of the ipsilateral motor cortex. This inhibitory influence is both time and movement dependent. The inhibitory influence is nonselective, while the facilitatory influence (enhancing ICF) appears to act selectively on the homologous muscles. These effects are most likely mediated by a transcallosal pathway. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the potential beneficial effects of estrogen on nigrostriatal dopaminergic neuron degeneration in postmenopausal drug-naïve Parkinson's disease (PD). Based on the ratio of lifetime estrogen exposure length to the total length of the estrogen exposure and deprivation period, postmenopausal women with drug-naïve PD were divided into low (n = 31) and high (n = 31) estrogen exposure ratio groups. We performed a comparative analysis of the striatal dopamine transporter (DAT) availability between the two groups. Additionally, we evaluated the longitudinal change in the levodopa equivalent dose per month using a linear mixed model. The motor symptoms were more severe in the low estrogen exposure ratio group than in the high estrogen exposure ratio group (P = 0.016). PD patients in the two groups had significantly lower DAT availability on all striatal sub-regions except for ventral striatum than did age- and sex-matched normal controls. When comparing the two groups, PD patients in the low estrogen exposure ratio group exhibited significantly lower DAT availability in the posterior putamen (P = 0.024) and in the ventral putamen (P = 0.036) than those in the high estrogen exposure ratio group. The estimated monthly levodopa equivalent dose changes were 10.9 in the low estrogen exposure ratio group and 7.1 in the high estrogen exposure ratio group with a significant interaction between the two groups (P = 0.001). These in vivo data provide indirect evidence showing that estrogen may elicit a beneficial effect on nigrostriatal dopamine neurons in PD. [ABSTRACT FROM AUTHOR]