A selective ER-phagy exerts neuroprotective effects via modulation of α-synuclein clearance in parkinsonian models.

The endoplasmic reticulum (ER) is selectively degraded by ER-phagy to maintain cell homeostasis. α-synuclein accumulates in the ER, causing ER stress that contributes to neurodegeneration in Parkinson's disease (PD), but the role of ER-phagy in α-synuclein modulation is largely unknown. Here, we investigated the mechanisms by which ER-phagy selectively recognizes α-synuclein for degradation in the ER. We found that ER-phagy played an important role in the degradation of α-synuclein and recovery of ER function through interaction with FAM134B, where calnexin is required for the selective FAM134B-mediated α-synuclein clearance via ER-phagy. Overexpression of α-synuclein in the ER of the substantia nigra (SN) resulted in marked loss of dopaminergic neurons and motor deficits, mimicking PD characteristics. However, enhancement of ER-phagy using FAM134B overexpression in the SN exerted neuroprotective effects on dopaminergic neurons and recovered motor performance. These data suggest that ER-phagy represents a specific ER clearance mechanism for the degradation of α-synuclein.

Hippocampal Perfusion Affects Motor and Cognitive Functions in Parkinson Disease: An Early Phase 18 F-FP-CIT Positron Emission Tomography Study.

OBJECTIVE: We investigated whether hippocampal perfusion changes are associated with cognitive decline, motor deficits, and the risk of dementia conversion in patients with Parkinson disease (PD). METHODS: We recruited patients with newly diagnosed and nonmedicated PD and healthy participants who underwent dual phase 18 F-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane positron emission tomography scans. Patients were classified into 3 groups according to hippocampal perfusion measured by standard uptake value ratios (SUVRs): (1) PD hippocampal hypoperfusion group (1 standard deviation [SD] below the mean hippocampal SUVR of healthy controls; PD-hippo-hypo), (2) PD hippocampal hyperperfusion group (1 SD above the mean; PD-hippo-hyper), and (3) the remaining patients (PD-hippo-normal). We compared the baseline cognitive performance, severity of motor deficits, hippocampal volume, striatal dopamine transporter (DAT) availability, and risk of dementia conversion among the groups. RESULTS: We included 235 patients (PD-hippo-hypo, n = 21; PD-hippo-normal, n = 157; PD-hippo-hyper, n = 57) and 48 healthy participants. Patients in the PD-hippo-hypo group were older and had smaller hippocampal volumes than those in the other PD groups. The PD-hippo-hypo group showed less severely decreased DAT availability in the putamen than the other groups despite similar severities of motor deficit. The PD-hippo-hypo group had a higher risk of dementia conversion compared to the PD-hippo-normal (hazard ratio = 2.59, p = 0.013) and PD-hippo-hyper (hazard ratio = 3.73, p = 0.006) groups, despite similar cognitive performance at initial assessment between groups. INTERPRETATION: Hippocampal hypoperfusion may indicate a reduced capacity to cope with neurodegenerative processes in terms of the development of motor deficits and cognitive decline in patients with PD. ANN NEUROL 2024;95:388-399.

Nanoscale Magneto-mechanical-genetics of Deep Brain Neurons Reversing Motor Deficits in Parkinsonian Mice.

Here, we introduce the magneto-mechanical-genetic (MMG)-driven wireless deep brain stimulation (DBS) using magnetic nanostructures for therapeutic benefits in the mouse model of Parkinson's disease (PD). Electrical DBS of the subthalamic nucleus (STN) is an effective therapy for mitigating Parkinson's motor symptoms. However, its broader application is hampered by the requirement for implanted electrodes and the lack of anatomical and cellular specificity. Using the nanoscale magnetic force actuators (m-Torquer), which deliver torque force under rotating magnetic fields to activate pre-encoded Piezo1 ion channels on target neurons, our system enables wireless and STN-specific DBS without implants, addressing key unmet challenges in the DBS field. In both late- and early-stage PD mice, MMG-DBS significantly improved locomotor activity and motor balance by 2-fold compared to untreated PD mice. Moreover, MMG-DBS enabled sustained therapeutic effects. This approach provides a non-invasive and implant-free DBS with cellular targeting capability for the effective treatment of Parkinsonian symptoms.

Increases in anterograde axoplasmic transport in neurons of the hyper-glutamatergic, glutamate dehydrogenase 1 (Glud1) transgenic mouse: Effects of glutamate receptors on transport.

The excitatory neurotransmitter glutamate has a role in neuronal migration and process elongation in the central nervous system (CNS). The effects of chronic glutamate hyperactivity on vesicular and protein transport within CNS neurons, that is, processes necessary for neurite growth, have not been examined previously. In this study, we measured the effects of lifelong hyperactivity of glutamate neurotransmission on axoplasmic transport in CNS neurons. We compared wild-type (wt) to transgenic (Tg) mice over-expressing the glutamate dehydrogenase gene Glud1 in CNS neurons and exhibiting increases in glutamate transmitter formation, release, and synaptic activation in brain throughout the lifespan. We found that Glud1 Tg as compared with wt mice exhibited increases in the rate of anterograde axoplasmic transport in neurons of the hippocampus measured in brain slices ex vivo, and in olfactory neurons measured in vivo. We also showed that the in vitro pharmacologic activation of glutamate synapses in wt mice led to moderate increases in axoplasmic transport, while exposure to selective inhibitors of ion channel forming glutamate receptors very significantly suppressed anterograde transport, suggesting a link between synaptic glutamate receptor activation and axoplasmic transport. Finally, axoplasmic transport in olfactory neurons of Tg mice in vivo was partially inhibited following 14-day intake of ethanol, a known suppressor of axoplasmic transport and of glutamate neurotransmission. The same was true for transport in hippocampal neurons in slices from Glud1 Tg mice exposed to ethanol for 2 h ex vivo. In conclusion, endogenous activity at glutamate synapses regulates and glutamate synaptic hyperactivity increases intraneuronal transport rates in CNS neurons.

Energy Transfer Between i-Motif DNA Encapsulated Silver Nanoclusters and Fluorescein Amidite Efficiently Visualizes the Redox State of Live Cells.

The redox regulation, maintaining a balance between oxidation and reduction in living cells, is vital for cellular homeostasis, intricate signaling networks, and appropriate responses to physiological and environmental cues. Here, a novel redox sensor, based on DNA-encapsulated silver nanoclusters (DNA/AgNCs) and well-defined chemical fluorophores, effectively illustrating cellular redox states in live cells is introduced. Among various i-motif DNAs, the photophysical property of poly-cytosines (C20)-encapsulated AgNCs that sense reactive oxygen species (ROS) is adopted. However, the sensitivity of C20/AgNCs is insufficient for evaluating ROS levels in live cells. To overcome this drawback, the ROS sensing mechanism of C20/AgNCs through gel electrophoresis, mass spectrometry, and small-angle X-ray scattering is primarily defined. Then, by tethering fluorescein amidite (FAM) and Cyanine 5 (Cy5) dyes to each end of the C20/AgNCs sensor, an Energy Transfer (ET) between AgNCs and FAM is achieved, resulting in intensified green fluorescence upon ROS detection. Taken together, the FAM-C20/AgNCs-Cy5 redox sensor enables dynamic visualization of intracellular redox states, yielding insights into oxidative stress-related processes in live cells.

Functional Brain Networks of Minor and Well-Structured Major Hallucinations in Parkinson's Disease.

BACKGROUND: Minor hallucinations (mHs) and well-structured major hallucinations (MHs) are common symptoms of Parkinson's disease (PD) psychosis. OBJECTIVES: To investigate the resting-state networks (RSNs) in patients with PD without hallucinations (PD-nH), with mH (PD-mH), and with MH (PD-MH). METHODS: A total of 73 patients with PD were enrolled (27 PD-nH, 23 PD-mH, and 23 PD-MH). Using seed-based functional connectivity analyses, we investigated the RSNs supposedly related to hallucinations in PD: the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), ventral attention network (VAN), and visual network (VN). We compared the cognitive function and RSN connectivity among the three groups. In addition, we performed a seed-to-seed analysis to examine the inter-network connectivity within each group using the corresponding RSN seeds. RESULTS: PD-MH group had lower test scores for attention and visuospatial functions compared with those in the other groups. The connectivity of the right intracalcarine cortex within the DAN was lower in the PD-MH group than in the others. The PD-mH and PD-MH groups showed higher connectivity in the left orbitofrontal cortex within DMN compared with the PD-nH group, whereas the connectivity was lower in the right middle frontal gyrus (MFG) within ECN, precuneus cortex within VAN, right middle temporal gyrus and precuneus cortex within DAN, and left MFG within VN. The PD-mH and PD-MH groups showed different inter-network connectivity between the five RSNs, especially regarding DAN connectivity. CONCLUSIONS: DAN dysfunction may be a key factor in the progression from mH to MH in patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Association between striatal amyloid deposition and motor prognosis in Parkinson's disease.

BACKGROUND AND PURPOSE: The co-occurrence of amyloid-ß pathology in Parkinson's disease (PD) is common; however, the role of amyloid-ß deposition in motor prognosis remains elusive. This study aimed to investigate the association between striatal amyloid deposition, motor complications and motor prognosis in patients with PD. METHODS: Ninety-six patients with PD who underwent 18F florbetaben (FBB) positron emission tomography were retrospectively assessed. The ratio of the striatum to global (STG) FBB uptake was obtained for each individual, and patients were allotted into low and high STG groups according to the median value. The effect of STG group on regional amyloid deposition, the occurrence of motor complications and longitudinal change in levodopa equivalent dose (LED) requirement were investigated after controlling for age, sex, LED and disease duration at FBB scan. RESULTS: The high STG group was associated with lower cortical FBB uptake in the parietal, occipital and posterior cingulate cortices and higher striatal FBB uptake compared to the low STG group. Patients in the high STG group had a higher risk of developing wearing off and levodopa-induced dyskinesia than those in the low STG group, whereas the risk for freezing of gait was comparable between the two groups. The high STG group showed a more rapid increase in LED requirements over time than the low STG group. CONCLUSIONS: These findings suggest that relatively high striatal amyloid deposition is associated with poor motor outcomes in patients with PD.

Non-invasive in vivo measurements of metabolic alterations in the type 2 diabetic brain by 1 H magnetic resonance spectroscopy.

Type 2 diabetes (T2D) is a complex chronic metabolic disorder characterized by hyperglycemia because of insulin resistance. Diabetes with chronic hyperglycemia may alter brain metabolism, including brain glucose and neurotransmitter levels; however, detailed, longitudinal studies of metabolic alterations in T2D are lacking. To shed insight, here, we characterized the consequences of poorly controlled hyperglycemia on neurochemical profiles that reflect metabolic alterations of the brain in both humans and animal models of T2D. Using in vivo 1 H magnetic resonance spectroscopy, we quantified 12 metabolites cross-sectionally in T2D patients and 20 metabolites longitudinally in T2D db/db mice versus db+ controls. We found significantly elevated brain glucose (91%, p < 0.001), taurine (22%, p = 0.02), glucose+taurine (56%, p < 0.001), myo-inositol (12%, p = 0.02), and choline-containing compounds (10%, p = 0.01) in T2D patients versus age- and sex-matched controls, findings consistent with measures in T2D db/db versus control db+ littermates. In mice, hippocampal and striatal neurochemical alterations in brain glucose, ascorbate, creatine, phosphocreatine, γ-aminobutyric acid, glutamate, glutamine, glutathione, glycerophosphoryl-choline, lactate, myo-inositol, and taurine persisted in db/db mice with chronic disease progression from 16 to 48 weeks of age, which were distinct from control db+ mice. Overall, our study demonstrates the utility of 1 H magnetic resonance spectroscopy as a non-invasive tool for characterizing and monitoring brain metabolic changes with T2D progression.

Effects of Alzheimer and Lewy Body Disease Pathologies on Brain Metabolism.

OBJECTIVE: This study aimed to determine the pattern of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) related to postmortem Lewy body disease (LBD) pathology in clinical Alzheimer disease (AD). METHODS: FDG-PET scans were analyzed in 62 autopsy-confirmed patients and 110 controls in the Alzheimer's Disease Neuroimaging Initiative. Based on neuropathologic evaluations on Braak stage for neurofibrillary tangle, Consortium to Establish a Registry for AD score for neuritic plaque, and Lewy-related pathology, subjects were classified into AD(-)/LBD(-), AD(-)/LBD(+), AD(+)/LBD(-), and AD(+)/LBD(+) groups. The association between postmortem LBD and AD pathologies and antemortem brain metabolism was evaluated. RESULTS: AD and LBD pathologies had significant interaction effects to decrease metabolism in the cerebellar vermis, bilateral caudate, putamen, basal frontal cortex, and anterior cingulate cortex in addition to the left side of the entorhinal cortex and amygdala, and significant interaction effects to increase metabolism in the bilateral parietal and occipital cortices. LBD pathology was associated with hypermetabolism in the cerebellar vermis, bilateral putamen, anterior cingulate cortex, and basal frontal cortex, corresponding to the Lewy body-related hypermetabolic patterns. AD pathology was associated with hypometabolism in the bilateral hippocampus, entorhinal cortex, and posterior cingulate cortex regardless of LBD pathology, whereas LBD pathology was associated with hypermetabolism in the bilateral putamen and anterior cingulate cortex regardless of AD pathology. INTERPRETATION: Postmortem LBD and AD pathologies had significant interaction effects on the antemortem brain metabolism in clinical AD patients. Specific metabolic patterns related to AD and LBD pathologies could be elucidated when simultaneously considering the two pathologies. ANN NEUROL 2022;91:853-863.

Association of choroid plexus volume with motor symptoms and dopaminergic degeneration in Parkinson's disease.

BACKGROUND: The choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain, as a part of the glymphatic system. This study aimed to investigate the association between CP volume (CPV), nigrostriatal dopaminergic degeneration and motor outcomes in Parkinson's disease (PD). METHODS: We retrospectively searched drug-naïve patients with early-stage PD who underwent dopamine transporter (DAT) scanning and MRI. Automatic CP segmentation was performed, and the CPV was calculated. The relationship between CPV, DAT availability and Unified PD Rating Scale Part III (UPDRS-III) scores was assessed using multivariate linear regression. We performed longitudinal analyses to assess motor outcomes according to CPV. RESULTS: CPV was negatively associated with DAT availability in each striatal subregion (anterior caudate, ß=-0.134, p=0.012; posterior caudate, ß=-0.162, p=0.002; anterior putamen, ß=-0.133, p=0.024; posterior putamen, ß=-0.125, p=0.039; ventral putamen, ß=-0.125, p=0.035), except for the ventral striatum. CPV was positively associated with the UPDRS-III score even after adjusting for DAT availability in the posterior putamen (ß=0.121; p=0.035). A larger CPV was associated with the future development of freezing of gait in the Cox regression model (HR 1.539, p=0.027) and a more rapid increase in dopaminergic medication in the linear mixed model (CPV×time, p=0.037), but was not associated with the risk of developing levodopa-induced dyskinesia or wearing off. CONCLUSION: These findings suggest that CPV has the potential to serve as a biomarker for baseline and longitudinal motor disabilities in PD.

Effect of Amyloid on Cognitive Performance in Parkinson's Disease and Dementia with Lewy Bodies.

BACKGROUND: Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs). OBJECTIVE: The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis. RESULTS: In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B = -2.03; P = 0.010) and memory functions (B = -1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group. CONCLUSIONS: Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society.

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.

Differential Implications of Cerebral Hypoperfusion and Hyperperfusion in Parkinson's Disease.

BACKGROUND: Patients with Parkinson's disease (PD) exhibit widespread brain perfusion changes. OBJECTIVE: This study investigated whether cerebral regions with hypoperfusion and hyperperfusion have differential effects on motor and cognitive symptoms in PD using early-phase 18 F-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (18 F-FP-CIT) positron emission tomography (PET) scans. METHODS: We enrolled 394 patients with newly diagnosed PD who underwent dual-phase 18 F-FP-CIT PET scans. Indices reflecting associated changes in regional cerebral hypoperfusion and hyperperfusion on early-phase 18 F-FP-CIT PET scans were calculated as PD[hypo] and PD[hyper] , respectively. The associations of PD[hypo] and PD[hyper] on motor and cognitive symptoms at baseline were assessed using multivariate linear regression. Also, Cox regression and linear mixed models were performed to investigate the effects of baseline PD[hypo] and PD[hyper] on longitudinal outcomes. RESULTS: There was a weak correlation between PD[hypo] and PD[hyper] (γ = -0.19, P < 0.001). PD[hypo] was associated with baseline Unified Parkinson's Disease Rating Scale Part III scores (ß = -1.02, P = 0.045), rapid increases in dopaminergic medications (ß = -18.02, P < 0.001), and a higher risk for developing freezing of gait (hazard ratio [HR] = 0.67, P = 0.019), whereas PD[hyper] was not associated. Regarding cognitive function, PD[hypo] was more relevant to the baseline cognitive performance levels of visuospatial, memory, and frontal/executive function than PD[hyper] . However, greater PD[hyper] was associated with future dementia conversion (HR = 1.43, P = 0.004), whereas PD[hypo] was not associated. CONCLUSIONS: These findings suggest that PD[hypo] and PD[hyper] may differentially affect motor and cognitive functions in patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Patterns of striatal dopamine depletion and motor deficits in de novo Parkinson's disease.

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 (ß = - 1.605, p < 0.001) and PC2 (ß = 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 (ß = - 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.

Is the cingulate island sign a marker for early dementia conversion in Parkinson's disease?

BACKGROUND: To investigate whether the cingulate island sign (CIS) ratio (i.e., the ratio of regional uptake in the posterior cingulate cortex relative to the precuneus and cuneus on cerebral perfusion scans) is associated with early dementia conversion in Parkinson's disease (PD). METHODS: We enrolled 226 patients with newly diagnosed PD and 48 healthy controls who underwent dual-phase 18 F-FP-CIT PET scans. Patients with PD were classified into three groups according to the CIS ratio on early-phase 18 F-FP-CIT PET images: a PD group with CIS or high CIS ratios (PD-CIS; n = 96), a PD group with inverse CIS or low CIS ratios (PD-iCIS; n = 40), and a PD group consisting of the remaining patients with normal CIS ratios (PD-nCIS; n = 90). We compared the risk of dementia conversion within a 5-year time point between the groups. RESULTS: There were no significant differences in age, sex, education, or baseline cognitive function between the PD groups. The PD-CIS group had higher Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and more severely decreased dopamine transporter availability in the putamen. The PD-iCIS group had a smaller hippocampal volume compared with the other groups. The risk of dementia conversion in the PD-CIS group did not differ from that in the PD-iCIS and PD-nCIS groups. Meanwhile, the PD-iCIS group had a higher risk of dementia conversion than the PD-nCIS group. CONCLUSION: The results of this study suggest that inverse CIS, rather than CIS, is relevant to early dementia conversion in patients with PD.

Association between choroid plexus volume and cognition in Parkinson disease.

BACKGROUND AND PURPOSE: The choroid plexus (CP) clears harmful metabolites from the central nervous system as part of the glymphatic system. We investigated the association of CP volume (CPV) with baseline and longitudinal cognitive decline in patients with Parkinson disease (PD). METHODS: We retrospectively reviewed the medical records of 240 patients with newly diagnosed PD who had undergone detailed neuropsychological tests and high-resolution T1-weighted structural magnetic resonance imaging during the initial assessment. The CPV of each patient was automatically segmented, and the intracranial volume ratio was used in subsequent analyses. The relationship between CPV and baseline composite scores of each cognitive domain was assessed using multivariate linear regression analyses. A Cox proportional hazards model was used to compare the risk of dementia conversion with CPV. RESULTS: CPV negatively correlated with composite scores of the frontal/executive function domain (ß = -0.375, p = 0.002) after adjusting for age, sex, years of education, and parkinsonian symptom duration. The Cox regression model revealed that a larger CPV was associated with a higher risk of dementia conversion (hazard ratio [HR] = 1.509, p = 0.038), which was no longer significant after adjusting for the composite scores of the frontal/executive function domain. A mediation analysis demonstrated that the effect of CPV on the risk of dementia conversion was completely mediated by frontal/executive function (direct effect: HR = 1.203, p = 0.396; indirect effect: HR = 1.400, p = 0.015). CONCLUSIONS: Baseline CPV is associated with baseline frontal/executive function, which subsequently influences dementia conversion risk in patients with PD.

Association of cholesterol level with dopamine loss and motor deficits in Parkinson disease: A cross-sectional study.

BACKGROUND AND PURPOSE: Cholesterol is vital in neuronal function; however, the influence of cholesterol levels on parkinsonism is unclear. This study investigated the relationship between baseline total cholesterol (TC) levels, dopamine loss, and motor symptoms in drug-naïve Parkinson disease (PD). METHODS: This cross-sectional study enrolled 447 drug-naïve patients with PD who underwent dopamine transporter (DAT) imaging. Multivariate linear regression was used to investigate the effect of cholesterol levels on Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) total score and each subscore after adjusting for the covariates. An interaction analysis was performed to examine the interaction between TC levels and statin use on the UPDRS-III scores. RESULTS: No significant correlation was found between TC levels and DAT availability after adjusting for potential confounders. Multivariate linear regression showed that TC levels were significantly and negatively associated with the UPDRS-III total score (ß = -0.116, p = 0.013) and bradykinesia subscore (ß = -0.145, p = 0.011). Dichotomized analysis according to TC levels showed that TC levels were significantly associated with UPDRS-III total score, and rigidity, bradykinesia, and axial subscores only in the low TC group. There was an interaction effect between TC levels and statin use for the axial subscores (ß = -0.523, p = 0.025). Subgroup analysis showed that TC levels were significantly and negatively associated with the axial subscore in statin users; however, no association was found in statin nonusers. CONCLUSIONS: This study suggests that TC levels affect parkinsonian motor symptoms, especially in subjects with low cholesterol status, whereas the severity of axial motor symptoms is negatively associated with TC levels only in statin users.

Iridium(III)-Catalyzed C-H Cyclization of Sulfoximines with Diazo Meldrum's Acids for the Synthesis of Cyclic Sulfoximines.

Iridium(III)-catalyzed C-H cyclization of sulfoximines with diazo Meldrum's acid provided cyclic sulfoximines with a carbonyl group in good to excellent yields. These compounds were easily converted into unsubstituted and arylated sulfoximines. Moreover, the vinyl triflates obtained from the cyclic sulfoximines underwent palladium(II)-catalyzed cross-coupling reactions with a variety of aryl, arylalkynyl, and heteroatom (N and S) nucleophiles, affording a wide range of monosubstituted sulfoximines in high yields.

Interrelation of striatal dopamine, brain metabolism and cognition in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB), the second most common neurodegenerative dementia, is characterized by cognitive decline, fluctuation of cognition and alertness, visual hallucinations, rapid eye movement sleep behaviour disorder and parkinsonism. Imaging biomarkers are of great importance in diagnosing patients with DLB and associated with characteristic clinical features including cognitive decline. In this study, we investigate interrelation between nigrostriatal dopamine depletion, brain metabolism and cognition in DLB. We enrolled 55 patients with probable DLB (15 with prodromal DLB and 40 with DLB) and 13 healthy controls. All subjects underwent N-(3-[18F]fluoropropyl)-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane PET/CT, 18F-fluorodeoxyglucose PET/CT, 18F-florbetaben PET/CT and detailed neuropsychological testing. The relationship between striatal dopamine transporter availability and regional brain metabolism was assessed using general linear models, and the effect of striatal dopamine transporter availability and brain metabolism on specific cognitive function was evaluated by multivariate linear regression analysis. Path analyses were used to evaluate the relationship between striatal dopamine transporter availability, fluorodeoxyglucose uptake and cognitive function scores. Additionally, a linear mixed model was used to investigate the association between baseline dopamine transporter availability or brain metabolism and longitudinal cognitive decline. Independent of amyloid deposition, caudate and putamen dopamine transporter availabilities were positively correlated with brain metabolism in the DLB-specific hypometabolic regions, most prominently in the occipital and lateral parietal cortices. Both reduced caudate dopamine and brain hypometabolism were associated with low z-scores of Rey-Osterrieth Complex Figure Test copy, Seoul Verbal Learning Test immediate recall and Controlled Oral Word Association Test (COWAT)-animal. Path analyses showed that the effect of reduced caudate dopamine on the Rey-Osterrieth Complex Figure Test copy z-score was completely mediated by brain hypometabolism, whereas it affected the Seoul Verbal Learning Test immediate recall z-score both directly and via the mediation of brain hypometabolism. Caudate dopamine depletion was directly associated with the COWAT-animal z-score, not mediated by brain hypometabolism. Both baseline caudate dopamine transporter availability and brain hypometabolism were associated with longitudinal cognitive decline, with brain hypometabolism being more relevant. Our findings suggest that in DLB, striatal dopaminergic depletion and brain hypometabolism are closely related, and they differentially affect cognitive dysfunction in an item-specific manner. Additionally, brain hypometabolism would be more relevant to longitudinal cognitive outcomes than striatal dopaminergic degeneration.

COMMUTE: Communication-efficient transfer learning for multi-site risk prediction.

OBJECTIVES: We propose a communication-efficient transfer learning approach (COMMUTE) that effectively incorporates multi-site healthcare data for training a risk prediction model in a target population of interest, accounting for challenges including population heterogeneity and data sharing constraints across sites. METHODS: We first train population-specific source models locally within each site. Using data from a given target population, COMMUTE learns a calibration term for each source model, which adjusts for potential data heterogeneity through flexible distance-based regularizations. In a centralized setting where multi-site data can be directly pooled, all data are combined to train the target model after calibration. When individual-level data are not shareable in some sites, COMMUTE requests only the locally trained models from these sites, with which, COMMUTE generates heterogeneity-adjusted synthetic data for training the target model. We evaluate COMMUTE via extensive simulation studies and an application to multi-site data from the electronic Medical Records and Genomics (eMERGE) Network to predict extreme obesity. RESULTS: Simulation studies show that COMMUTE outperforms methods without adjusting for population heterogeneity and methods trained in a single population over a broad spectrum of settings. Using eMERGE data, COMMUTE achieves an area under the receiver operating characteristic curve (AUC) around 0.80, which outperforms other benchmark methods with AUC ranging from 0.51 to 0.70. CONCLUSION: COMMUTE improves the risk prediction in a target population with limited samples and safeguards against negative transfer when some source populations are highly different from the target. In a federated setting, it is highly communication efficient as it only requires each site to share model parameter estimates once, and no iterative communication or higher-order terms are needed.