Effects of Dihydropyridines on the Motor and Cognitive Outcomes of Patients with Parkinson's Disease.

BACKGROUND: Dihydropyridines (DHPs) may have neuroprotective effects against Parkinson's disease (PD). OBJECTIVE: This study investigated the effects of DHPs on nigrostriatal dopaminergic denervation and longitudinal motor and cognitive outcomes in PD. METHODS: We classified 476 patients with drug-naive PD who had undergone dopamine transporter imaging into three groups. They were selected according to a prior diagnosis of hypertension and use of DHPs and were matched using propensity scores: patients without hypertension (HTN-; n = 50) and patients with hypertension treated without DHP (HTN+/DHP-; n = 50) or with DHP (HTN+/DHP+; n = 50). Multiple linear regression and linear mixed model analyses were performed to determine intergroup differences in baseline dopamine transporter availability and longitudinal changes in the levodopa-equivalent dose, respectively. Using Kaplan-Meier analyses, we compared the risks of levodopa-induced dyskinesia, wearing off, and dementia-free survival during the 5.06 years of the mean follow-up period. The Cox regression model determined the independent effects of DHPs on dementia conversion. RESULTS: Dopamine transporter availability in all striatal subregions was comparable between the HTN-, HTN+/DHP-, and HTN+/DHP+ groups. The risks of levodopa-induced dyskinesia and wearing off, as well as longitudinal changes in the levodopa-equivalent dose, did not differ between the groups. The HTN+/DHP+ group had a lower risk of developing dementia than the HTN+/DHP- (Bonferroni-corrected Plog-rank  = 0.036) group. The use of DHP was independently associated with a lower risk of dementia conversion after controlling for other antihypertensive drugs and confounding factors (hazard ratio, 0.242; 95% confidence interval, 0.087-0.668; P = 0.006). CONCLUSIONS: DHPs may be associated with better long-term cognitive outcomes in hypertensive patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Effects of statins on dopamine loss and prognosis in Parkinson's disease.

Statins are more widely used not only for the primary and secondary prevention of cardiovascular disease by blocking cholesterol biosynthesis but also for the potential neuroprotective agents during neurological disorders due to their pleiotropic effects. In this study, we investigate whether the previous use of statins affect baseline nigrostriatal dopamine loss at the time of diagnosis and longitudinal motor and cognitive outcomes in patients with Parkinson's disease. Five hundred drug-naïve patients with Parkinson's disease who underwent dopamine transporter imaging were classified into two groups according to the prior use of statins: patients with and without statin use. Multivariate linear regression was used to determine intergroup differences in dopamine transporter availability. We evaluated the longitudinal changes in levodopa-equivalent dose and dementia conversion between the groups using a linear mixed model and survival analysis, respectively. In addition, mediation analysis was applied to examine the effect of total cholesterol. Patients with Parkinson's disease treated with statins had a lower baseline dopamine transporter availability in the anterior (2.13 ± 0.55 versus 2.37 ± 0.67; P = 0.002), posterior (1.31 ± 0.43 versus 1.49 ± 0.54; P = 0.003) and ventral putamina (1.40 ± 0.39 versus 1.56 ± 0.47; P = 0.002) than that in matched patients with Parkinson's disease without statins. After adjusting for age at symptom onset, sex, disease duration and vascular risk factors, linear regression models showed that a previous treatment with statins remained significantly and independently associated with more severely decreased dopamine transporter availability in the anterior putamen (Beta = -0.140, P = 0.004), posterior putamen (Beta = -0.162, P = 0.001) and ventral putamen (Beta = -0.140, P = 0.004). A linear mixed model revealed that patients with Parkinson's disease being treated with statins had a faster longitudinal increase in levodopa-equivalent dose than those without. A survival analysis showed that the rate of dementia conversion was significantly higher in patients with Parkinson's disease with statins (hazard ratio, 2.019; 95% confidence interval, 1.108-3.678; P = 0.022) than those without. Mediation analyses revealed that the effect of statin treatment on baseline dopamine transporter availability and longitudinal outcome was not mediated by total cholesterol levels. This study suggests that statin use may have a detrimental effect on baseline nigrostriatal dopamine degeneration and long-term outcomes in patients with Parkinson's disease.

Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson's disease.

Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used hypoglycaemic agents and improve glucose metabolism by enhancing the bioavailability of active glucagon-like peptide-1. In this study, we hypothesized that treatment with DPP4 inhibitors may have beneficial effects on nigrostriatal dopamine and longitudinal motor performance in diabetic patients with Parkinson's disease. We classified 697 drug naive patients with de novo Parkinson's disease who had undergone dopamine transporter imaging into three groups according to a prior diagnosis of diabetes and use of DPP4 inhibitors: diabetic patients with Parkinson's disease being treated with (n = 54) or without DPP4 inhibitors (n = 85), and non-diabetic patients with Parkinson's disease (n = 558). Diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had a higher baseline dopamine transporter availability in the anterior (2.56 ± 0.74 versus 2.10 ± 0.50; P = 0.016), posterior (1.83 ± 0.69 versus 1.40 ± 0.50; P < 0.001), and ventral putamina (1.72 ± 0.58 versus 1.35 ± 0.37; P = 0.001) than that in diabetic patients with Parkinson's disease without DPP4 inhibitors. Additionally, diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had higher dopamine transporter availability in the posterior putamen than that in non-diabetic patients with Parkinson's disease (1.83 ± 0.69 versus 1.43 ± 0.59; P < 0.001). After adjusting for age, sex, disease duration, and vascular risk factors, linear regression models showed that a prior treatment of DPP4 inhibitors remained independently and significantly associated with dopamine transporter availability in the anterior (ß = -0.186, P = 0.012; ß = -0.207, P = 0.003), posterior (ß = -0.336, P < 0.001; ß = -0.286, P < 0.001), and ventral putamina (ß = -0.204, P = 0.005; ß = -0.250, P < 0.001). A linear mixed model revealed that the diabetic group with Parkinson's disease being treated with DPP4 inhibitors had a slower longitudinal increase in levodopa-equivalent dose than the other groups (P = 0.003). Survival analyses showed that the rate of levodopa-induced dyskinesia was significantly lower in the diabetic group with a prior treatment with DPP4 inhibitors than the diabetic group without DPP4 inhibitors (hazard ratio = 0.194, P = 0.037). These findings suggest that DPP4 inhibitors may confer beneficial effects on the baseline nigrostriatal dopamine degeneration and long-term motor outcomes in diabetic patients with Parkinson's disease and may extend its role into non-diabetic patients with Parkinson's disease.

Diffusion tensor imaging-based pontine damage as a degeneration marker in synucleinopathy.

The pons is one of the earliest affected regions in patients with synucleinopathies. We aimed to investigate the diagnostic value of measuring pontine damage using diffusion tensor imaging (DTI) in these patients. We enrolled 49 patients with Parkinson's disease (PD), 16 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD), 23 patients with multiple system atrophy (MSA), and 39 healthy controls in this study. All the participants underwent high-resolution T1-weighted imaging and DTI. Mean diffusivity (MD) and fraction anisotropy (FA) values in the pons were calculated to characterize structural damage. The discriminatory power of pontine MD and FA values to differentiate patients with synucleinopathies from healthy controls was examined using receiver operating characteristics (ROC) analyses. Compared to healthy controls, patients with PD, iRBD, and MSA had increased MD values and decreased FA values in the pons, although no correlation was observed between these DTI measures and disease severity. The ROC analyses showed that MD values in the pons had a fair discriminatory power to differentiate healthy controls from patients with PD (area under the curve [AUC], 0.813), iRBD (AUC, 0.779), and MSA (AUC, 0.951). The AUC for pontine FA values was smaller than that for pontine MD values when differentiating healthy controls from patients with PD (AUC, 0.713; p = 0.054) and iRBD (AUC, 0.686; p = 0.045). Our results suggest that MD values in the pons may be a useful marker of brain stem neurodegeneration in patients with synucleinopathies.

Dopaminergic Depletion, ß-Amyloid Burden, and Cognition in Lewy Body Disease.

OBJECTIVE: We aimed to determine the association between striatal dopaminergic depletion, cerebral ß-amyloid deposition, and cognitive dysfunction in Lewy body disease (LBD). METHODS: This cross-sectional study recruited 48 LBD patients (30 with dementia, 18 with mild cognitive impairment) and 15 control subjects from a university-based hospital. We measured the striatal dopamine transporter (DAT) activity and regional ß-amyloid burden using N-(3-[18 F]fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET) and 18 F-florbetaben (FBB) PET, respectively. The relationship between striatal FP-CIT uptake, regional cortical FBB uptake, and cognitive function scores was evaluated using path analyses. We also investigated the effects of striatal FP-CIT uptake and cortical FBB uptake on the interval between motor symptom and dementia onset. RESULTS: Reduced striatal FP-CIT uptake was associated with increased FBB uptake in the posterior cortical regions, most prominently in the occipital cortices. Reduced FP-CIT uptake in the anterior putamen was associated with visuospatial dysfunction with mediation of increased occipital FBB uptake. Reduced FP-CIT uptake in the posterior putamen and an increased parietal FBB uptake were independently associated with memory dysfunction. Reduced striatal FP-CIT uptake was associated with attention, language, and frontal/executive dysfunction, independent of amyloid deposition. Increased FBB uptake, especially in the parietal cortex, was associated with earlier onset of dementia. INTERPRETATION: Our results suggest that occipital ß-amyloid deposition may contribute to the association between striatal dopaminergic depletion and visuospatial dysfunction in LBD patients. Although the effects of reduced DAT activity are more prominent than those of ß-amyloid burden on cognitive dysfunction, the latter affects the onset of cognitive dysfunction. ANN NEUROL 2020;87:739-750.

White Matter Hyperintensities, Dopamine Loss, and Motor Deficits in De Novo Parkinson's Disease.

BACKGROUND: White matter hyperintensities, prevalent in patients with Parkinson's disease (PD), significantly affect parkinsonian motor symptoms. The objective of this study was to investigate the relationship between white matter hyperintensities and nigrostriatal dopamine depletion and their interaction or mediating effects on motor symptoms in patients with drug-naive early-stage PD. METHODS: This cross-sectional study enrolled 501 patients with de novo PD who initially underwent [18 F] N-(3-fluoropropyl)-2ß-carbonethoxy-3ß-(4-iodophenyl) nortropane positron emission tomography and brain magnetic resonance imaging scans between April 2009 and September 2015 in a tertiary-care university hospital. We quantified dopamine transporter availability in each striatal subregion and assessed the severity of periventricular and lobar white matter hyperintensities using the Scheltens scale. The relationship between white matter hyperintensities, dopamine transporter availability in the posterior putamen, and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was assessed using multivariate linear regression and mediation analyses. RESULTS: Periventricular and frontal white matter hyperintensities were generally associated with dopamine transporter availability in striatal subregions after adjusting for age at symptom onset, sex, disease duration, and vascular risk factors. There was an interaction effect between periventricular white matter hyperintensities and dopamine transporter availability in the posterior putamen for the axial motor score. The effect of white matter hyperintensities on UPDRS total score and bradykinesia subscore was indirectly mediated by dopamine transporter availability in the posterior putamen, whereas the axial sub-score was directly affected by white matter hyperintensities. CONCLUSIONS: This study suggests that the detrimental effect of white matter hyperintensities on parkinsonian motor symptoms is more relevant and independent for axial motor impairments in the status of mildly decreased striatal dopamine transporter availability. © 2021 International Parkinson and Movement Disorder Society.

Motor Cerebellar Connectivity and Future Development of Freezing of Gait in De Novo Parkinson's Disease.

OBJECTIVE: To investigate the role of motor cerebellar connectivity in future development of freezing of gait, because it is a complex network disorder in Parkinson's disease (PD). METHODS: We recruited 26 de novo patients with PD who experienced freezing of gait within 5 years from magnetic resonance imaging acquisition (vulnerable PD group), 61 patients with PD who had not experienced freezing of gait within 5 years (resistant PD group), and 27 healthy control subjects. We compared the resting state functional connectivity between the motor cerebellum and the whole brain between the groups. In addition, we evaluated the relationship between motor cerebellar connectivity and freezing of gait latency. RESULTS: The vulnerable PD group had increased functional connectivity between the motor cerebellum and parieto-occipito-temporal association cortices compared with the control group or the resistant PD group. Connectivity between lobule VI and the right superior parietal lobule, right fusiform gyrus, and left inferior temporal gyrus; between lobule VIIb and the right superior parietal lobule, right hippocampus, and right middle temporal gyrus; and between lobule VIIIb and the bilateral fusiform gyri, right middle occipital gyrus, and bilateral parietal lobes was inversely proportional to freezing of gait latency. The freezing of gait latency-related cortical functional connectivity from the motor cerebellum was also significantly higher in the vulnerable PD group compared with the control group, as well as the resistant PD group. CONCLUSIONS: The data suggest that the motor cerebellar functional connectivity with the posterior cortical areas play an important role in future development of freezing of gait in PD. © 2020 International Parkinson and Movement Disorder Society.

Frontal atrophy as a marker for dementia conversion in Parkinson's disease with mild cognitive impairment.

This study aimed to investigate the cortical neural correlates of dementia conversion in Parkinson's disease with mild cognitive impairment (PD-MCI). We classified 112 patients with drug-naïve early stage PD meeting criteria for PD-MCI into either PD with dementia (PDD) converters (n = 34) or nonconverters (n = 78), depending on whether they developed dementia within 4 years of PD diagnosis. Cortical thickness analyses were performed in 34 PDD converters and 34 matched nonconverters. Additionally, a linear discriminant analysis was performed to distinguish PDD converters from nonconverters using cortical thickness of the regions that differed between the two groups. The PDD converters had higher frequencies of multiple domain MCI and amnestic MCI with storage failure, and poorer cognitive performances on frontal/executive, memory, and language function domains than did the nonconverters. Cortical thinning extending from the posterior cortical area into the frontal region was observed in PDD converters relative to nonconverters. The discriminant analysis showed that the prediction model with two cortical thickness variables in the right medial superior frontal and left olfactory cortices optimally distinguished PDD converters from nonconverters. Our data suggest that cortical thinning in the frontal areas including the olfactory cortex is a marker for early dementia conversion in PD-MCI.

Distinct FP-CIT PET patterns of Alzheimer's disease with parkinsonism and dementia with Lewy bodies.

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.

Premorbid Educational Attainment and Long-Term Motor Prognosis in Parkinson's Disease.

BACKGROUND: Premorbid educational attainment is a well-known proxy of reserve, not only with regard to cognition, but also to motor symptoms. OBJECTIVE: In the present study, we investigated the relationship between educational attainment and long-term motor prognosis in patients with Parkinson's disease (PD). METHODS: We analyzed 466 patients with de novo PD without dementia who underwent dopamine transporter (DAT) scans and were followed up more than 2 years. Patients were divided into three groups: low education (years-of-education ≤6, n = 125), intermediate education (6 

White matter connectivity networks predict levodopa-induced dyskinesia in Parkinson's disease.

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.

The pattern of FP-CIT PET in pure white matter hyperintensities-related vascular parkinsonism.

OBJECTIVES: To determine whether vascular parkinsonism (VaP) patients with visually normal dopamine transporter (DAT) scans have presynaptic dopaminergic depletion. METHODS: We enrolled 23 VaP patients who had parkinsonism, relevant diffuse subcortical white matter hyperintensities (WMH), and visually normal DAT scans, 23 Parkinson's disease (PD) patients, and 31 control subjects. By quantitatively analyzing 18F-N-(3-fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography, we compared the pattern of striatal DAT availability among groups. The discriminatory power of striatal DAT availability to differentiate VaP patients from control subjects or PD patients was assessed using receiver operating characteristics (ROC) analyses. Additionally, correlation analysis was performed to determine whether WMH severity or Unified Parkinson Disease Rating Scale Part III (UPDRS-III) score is related to presynaptic dopaminergic depletion in VaP. RESULTS: VaP patients exhibited decreased DAT availability in all striatal subregions, including posterior putamen, compared to control subjects. VaP patients and control subjects had similar patterns of anteroposterior and ventrodorsal DAT gradients in caudate and putamen level, but VaP patients exhibited significantly different patterns at putamen level, relative to PD patients. The severity of periventricular WMH was significantly correlated with all substriatal DAT availability in VaP, but not with UPDRS-III scores. The ROC analysis showed that DAT availability in caudate and posterior putamen had a fair discriminatory power when differentiating VaP patients from control subjects. CONCLUSIONS: This study demonstrates that VaP patients with WMH exhibited diffusely decreased DAT availability without any specific regional gradients of DAT patterns distinct from either control subjects or PD patients.

Effect of Alzheimer's Disease and Lewy Body Disease on Metabolic Changes.

BACKGROUND: The relationship among amyloid-ß (Aß) deposition on amyloid positron emission tomography (PET), cortical metabolism on 18F-fluoro-2-deoxy-D-glucose (FDG)-PET, and clinical diagnosis has not been elucidated for both Alzheimer's disease (AD) and Lewy body disease (LBD). OBJECTIVE: We investigated the patterns of cerebral metabolism according to the presence of AD and LBD. METHODS: A total of 178 subjects were enrolled including 42 pure AD, 32 pure LBD, 34 Lewy body variant AD (LBVAD), 15 LBD with amyloid, 26 AD with dementia with Lewy bodies (DLB), and 29 control subjects. Pure AD, LBVAD, and AD with DLB groups had biomarker-supported diagnoses of typical AD, while pure LBD, LBD with amyloid, and AD with DLB groups had biomarker-supported diagnoses of typical LBD. Typical AD and LBD with amyloid showed amyloid-positivity on 18F-florbetaben (FBB) PET, while typical LBD and LBVAD had abnormalities on dopamine transporter PET. We measured regional patterns of glucose metabolism using FDG-PET and evaluated their relationship with AD and LBD. RESULTS: Compared with control group, typical AD and typical LBD commonly exhibited hypometabolism in the bilateral temporo-parietal junction, precuneus, and posterior cingulate cortex. Typical AD showed an additional hypometabolism in the entorhinal cortex, while patients with dopamine transporter abnormality-supported diagnosis of LBD showed diffuse hypometabolism that spared the sensory-motor cortex. Although the diffuse hypometabolism in LBD also involved the occipital cortex, prominent occipital hypometabolism was only seen in LBD with amyloid group. CONCLUSION: Combining clinical and metabolic evaluations may enhance the diagnostic accuracy of AD, LBD, and mixed disease cases.

Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy.

BACKGROUND: This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). METHODS: This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 105 cells/kg; medium-dose, 6.0 × 105 cells/kg; high-dose, 9.0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. RESULTS: One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. CONCLUSION: The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Donepezil for mild cognitive impairment in Parkinson's disease.

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.

Structural connectivity networks in Alzheimer's disease and Lewy body disease.

OBJECTIVE: We evaluated disruption of the white matter (WM) network related with Alzheimer's disease (AD) and Lewy body disease (LBD), which includes Parkinson's disease and dementia with Lewy bodies. METHODS: We consecutively recruited 37 controls and 77 patients with AD-related cognitive impairment (ADCI) and/or LBD-related cognitive impairment (LBCI). Diagnoses of ADCI and LBCI were supported by amyloid PET and dopamine transporter PET, respectively. There were 22 patients with ADCI, 19 patients with LBCI, and 36 patients with mixed ADCI/LBCI. We investigated the relationship between ADCI, LBCI, graph theory-based network measures on diffusion tensor images, and cognitive dysfunction using general linear models after controlling for age, sex, education, deep WM hyperintensities (WMH), periventricular WMH, and intracranial volume. RESULTS: LBCI, especially mixed with ADCI, was associated with increased normalized path length and decreased normalized global efficiency. LBCI was related to the decreased nodal degree of left caudate, which was further associated with broad cognitive dysfunction. Decreased left caudate nodal degree was associated with decreased fractional anisotropy (FA) in the brain regions vulnerable to LBD. Compared with the control group, the LBCI group had an increased betweenness centrality in the occipital nodes, which was associated with decreased FA in the WM adjacent to the striatum and visuospatial dysfunction. CONCLUSION: Concomitant ADCI and LBCI are associated with the accentuation of LBCI-related WM network disruption centered in the left caudate nucleus. The increase of occipital betweenness centrality could be a characteristic biologic change associated with visuospatial dysfunction in LBCI.

Temporalis Muscle Thickness as an Indicator of Sarcopenia Is Associated With Long-term Motor Outcomes in Parkinson's Disease.

BACKGROUND: To investigate the relationship between temporalis muscle thickness (TMT) at baseline as a surrogate marker for sarcopenia and long-term motor outcomes in patients with Parkinson's disease (PD). METHODS: We enrolled 249 patients with drug-naïve early-stage PD (119 males and 130 females, follow-up > 3 years). Baseline TMT of each patient was measured on the axial plane of T1-weighted images. The association between baseline TMT and long-term motor outcomes in PD was assessed using Cox regression models for levodopa-induced dyskinesia, wearing-off, and freezing of gait and a linear mixed model for the longitudinal increases in levodopa-equivalent dose per body weight over time. Statistical analyses were performed separately for sex if an interaction effect between TMT and sex was assumed. RESULTS: TMT differed substantially between the sexes, and male PD patients had higher TMT (6.69 ± 1.39 mm) than female PD patients (5.64 ± 1.34 mm, p < .001). Cox regression models demonstrated that baseline TMT was not associated with the risk of developing levodopa-induced dyskinesia, wearing-off, or freezing of gait during the follow-up period. The linear mixed model was applied separately for sex and demonstrated that higher TMT at baseline was associated with slower increases in levodopa-equivalent dose per body weight in male PD patients, but not in female PD patients. CONCLUSIONS: This study demonstrated that baseline TMT could be an indicator of the longitudinal requirement for dopaminergic medications in male patients with PD, suggesting that sarcopenia may have a detrimental effect on disease progression in PD in a sex-specific manner.

Neuropsychiatric Burden Is a Predictor of Early Freezing and Motor Progression in Drug-Naïve Parkinson's Disease.

BACKGROUND: Neuropsychiatric symptoms (NPS) are the most common non-motor symptom in Parkinson's disease (PD). OBJECTIVE: To investigate the association between the burden of NPS and motor prognosis in patients with PD. METHODS: We enrolled 329 drug-naïve patients with PD, who was non-demented and followed-up≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging and neuropsychiatric inventory (NPI) scores. We performed a survival analysis and a linear mixed model analysis to assess longitudinal motor outcomes according to the NPI total score. RESULTS: The Kaplan-Meier analysis showed no difference in the development of levodopa-induced dyskinesia and wearing-off according to the NPI total score. However, higher burden of NPI total score was associated with earlier freezing of gait (FOG) development in the time-dependent Cox regression models after adjusting for age at symptom onset, sex, disease duration, Unified PD Rating Scale motor score, baseline Mini-Mental State Examination score, DAT activity in the posterior putamen and levodopa-equivalent daily dose (LEDD) (Hazard ratio 1.047, p = 0.002). A linear mixed model analysis revealed that patients with a higher NPI total score had a more rapid LEDD increment (NPI×time, p = 0.003). Among 52 patients with PD who eventually developed FOG during the follow-up period, there was a significant correlation between the NPI total score and time with FOG development (γ= -0.472; p = 0.001) after adjusting for confounding factors. CONCLUSION: The present study demonstrated that the severity of NPS is a predictor of early freezing and motor progression in patients with PD.

Apolipoprotein E4, amyloid, and cognition in Alzheimer's and Lewy body disease.

The role of apolipoprotein E4 (APOE4) in the risk of Alzheimer's disease (AD) and Lewy body disease (LBD), and their relationship with ß-amyloid deposition and cognitive dysfunction, remain unclear. Using amyloid and dopamine transporter imaging, we enrolled 126 controls and 208 patients with typical AD (pure AD and Lewy body variant of AD), AD with dementia with Lewy bodies, or typical LBD (dementia with Lewy bodies with amyloid deposition and pure LBD). APOE4 was associated with an increased risk of all disease subtypes except pure LBD. APOE4 was associated with increased frontal ß-amyloid burden, and typical LBD was associated with increased occipital ß-amyloid levels through its interaction with APOE4. APOE4 was associated with deteriorated general cognition and memory dysfunction via its interaction with typical LBD and AD, respectively. In conclusion, the impact of APOE4 on disease risk depends on its effects on ß-amyloid deposition, and APOE4 is associated with ß-amyloid deposition regardless of the clinical diagnosis. However, it interacts with typical LBD to cause occipital ß-amyloid deposition.