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.

Immunosuppressive therapy in elderly patients with neuromyelitis optica spectrum disorder: a retrospective multicentre study.

BACKGROUND: The risk-benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of IST in elderly patients with NMOSD. METHODS: This retrospective study analysed IST efficacy and safety in 101 patients with aquaporin-4 antibody-positive NMOSD aged over 65 years, treated for at least 6 months at five Korean referral centres, focusing on relapse rates, infection events and discontinuation due to adverse outcomes. RESULTS: The mean age at disease onset was 59.8 years, and female-to-male ratio was 4:1. Concomitant comorbidities at NMOSD diagnosis were found in 87 patients (86%). The median Expanded Disability Status Scale score at the initiation of IST was 3.5. The administered ISTs included azathioprine (n=61, 60%), mycophenolate mofetil (MMF) (n=48, 48%) and rituximab (n=41, 41%). Over a median of 5.8 years of IST, 58% of patients were relapse-free. The median annualised relapse rate decreased from 0.76 to 0 (p<0.001), and 81% experienced improved or stabilised disability. Patients treated with rituximab had a higher relapse-free rate than those treated with azathioprine or MMF (p=0.022). During IST, 21 patients experienced 25 severe infection events (SIEs) over the age of 65 years, and 3 died from pneumonia. 14 patients (14%) experienced 17 adverse events that led to switching or discontinuation of IST. When comparing the incidence rates of SIEs and adverse events, no differences were observed among patients receiving azathioprine, MMF and rituximab. CONCLUSION: In elderly patients with NMOSD, IST offers potential benefits in reducing relapse rates alongside a tolerable risk of adverse events.

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.

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.

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.

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.

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.

Anatomical Reconstruction of Extensive Inferomedial Blow-Out Fractures Involving the Inferomedial Orbital Strut Using a Single Fan-shaped Titanium-Reinforced Porous Polyethylene Plate.

Extensive inferomedial blow-out fractures involving the inferomedial orbit strut frequently result in severe ophthalmic complications. Therefore, anatomical reconstruction is essential but is still technically challenging. Thus, the authors have used a novel technique using a combination of single fan-shaped titanium-reinforced porous polyethylene (TR-PPE) implants and a bidirectionally extended transconjunctival approach. Herein, the authors describe our surgical technique and discuss its effectiveness. First, the transconjunctival approach was performed and was subsequently extended medially using the transcaruncular approach and laterally using lateral blepharotomy. After the origin of the inferior oblique muscle was identified, a trimmed fan-shaped TR-PPE implant was inserted into the orbital floor. It was subsequently rotated and bent at the site of origin of the IO muscle and moved upward to cover the superior bony ledge of the medial wall. Finally, the implant was fixed to the orbital rim. Anatomical orbital reconstruction was confirmed by a computed tomographic scan. The preoperative diplopia in 19 patients, resolved within 1 week in 16 patients and in 3 to 6 months in the remaining 3 patients. Preoperative enophthalmos >2 mm in all patients improved to <2 mm in 67 patients and 3 mm in 2 patients (>7 mm preoperatively). The postoperative course was uneventful, and no severe complications were observed. The authors believe that the placement of a fan-shaped TR-PEE implant into the orbit through the bidirectionally extended transconjunctival approach could be a viable option for the anatomical reconstruction of extensive inferomedial blow-out fractures involving the inferomedial orbital strut.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

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.

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.

Folded Cymba Concha: Is It Large and Stable Enough for Caudal Septal Extension Graft in Asian Rhinoplasty?

BACKGROUND: Septal extension grafting (SEG) is used for nasal tip projection and positioning. Often, insufficient quadrangular cartilage is available for grafting in Asians, and in most secondary cases the septum is already harvested. We utilized the folded cymba concha as an alternative for caudal SEG (CSEG) by modifying a tongue-in-groove technique. OBJECTIVES: The aim of this study was to evaluate the physical suitability of the cymba concha for CSEG and compare its outcomes with those of septal quadrangular cartilage. METHODS: The mean length and width of 311 harvested consecutive folded cymba conchae were measured from intraoperative photographs. Data from 220 patients with >12 months of follow-up were retrospectively reviewed for clinical outcomes. Clinical demography was determined based on the need for additional spreader grafts. For clinical reliability, anthropometric photographs of patients in whom folded cymba conchae were used were compared with those in whom quadrangular cartilage was used. RESULTS: Mean [standard deviation] lengths and widths of the folded cymba conchae in men and women were 24.2 [3.9] and 22.4 [3.7] mm, and 7.8 [1.9] and 7.2 [1.9] mm, respectively. Use of the folded cymba concha graft significantly increased nasal tip projection by 28.9% and columellar-labial angle by 9.7%, improving both aspects postoperatively. Anthropometric comparison revealed no significant differences between folded cymba conchae and septal cartilage in terms of nasal tip projection (P = 0.264) and postoperative columellar-labial angle (P = 0.182). CONCLUSIONS: Folded cymba conchal cartilage can be a primary option for CSEG in Asian septorhinoplasty cases or for individuals with insufficient septal cartilage remnants.

Effects of Granulocyte Macrophage Colony-Stimulating Factor Inhibition on the Skin/Nerve Cell Model In Vitro.

The present study is based on the concept of neuro-aging and how it may affect surrounding skin cells. It has been shown that many factors play a significant role in skin homeostasis by interfering with various cytokines, either through activation or inhibition. Granulocyte macrophage colony-stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine, and our previous study has shown its effects on neuronal senescence after ultraviolet (UV) irradiation of skin cells. Following our previous work, this study was performed to investigate the neuroprotective effects of a GM-CSF antagonist, and how it may play an essential role in mediating anti-senescence and anti-inflammatory effects in the keratinocyte/nerve aging model. When human blastoma cells (SH-SY5Y) were treated with 10 ng/ml of GM-CSF, the levels of regulatory RNAs associated with aging, such as matrix metalloproteinase-9 (MMP9), nuclear factor NF-kappa-B p50 subunit (NFKB), inducible nitric oxide synthase (iNOS), and interleukin 1 beta (IL-1ß) increased, whereas GM-CSF inhibition caused their expression to decrease. A decrease in the antioxidant, glutathione (GSH) was observed after SH-SY5Y cells were treated with GM-CSF. This study confirms that this GM-CSF antagonist may play an important role in neural senescence, where inhibition may be a new target in the skin/nerve aging model.

Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.

The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity.

Comparative Biological Effects of Human Amnion and Chorion Membrane Extracts on Human Adipose-Derived Stromal Cells.

Although therapies with human amnion/chorion are used to ameliorate acute and chronic wounds, it is unclear which component of the amnion/chorion tissue promotes wound healing. To characterize the comparative effects of amnion and chorion in wound healing, we used human adipose-derived stromal cells to assess cell viability, migration, and gel contraction after treatment with amnion membrane extract (AME) or chorion membrane extract (CME). We then correlated the possible effectors via AME and CME protein profiling, and compared them by enzyme-linked immunosorbent assay (ELISA), western blotting, and immunocytochemistry. Cell viability was significantly increased with 50 and 100 µg/mL AME treatment, but with CME treatment, a significant increase was only observed with 100 µg/mL. With CME treatment, cell migration was 2.22-fold greater than the control, and collagen gels showed 20% greater contraction. Compared to control, the expression levels of α-smooth muscle actin (SMA) and smooth muscle protein 22-alpha (SM22α) increased both with AME and CME treatments, whereas calponin expression decreased. Protein profiling revealed significantly higher tissue inhibitor of metalloproteinase-1 (TIMP-1), interleukin-8, exotoxin, and adiponectin levels in CME than in AME, and ELISA revealed 8-fold higher adiponectin levels in cells treated with CME than those treated with AME. Immunocytochemistry revealed that α-SMA, SM22α, and calponin were significantly higher in CME- than AME-treated cells; however, adiponectin treatment did not enhance α-SMA, SM22α, or calponin expression. In conclusion, amnion and chorion membrane extracts exerted differential effects on proliferation and contraction of human adipose-derived stromal cells. Amnion extract was superior at inducing cell proliferation and migration, whereas CME was superior at inducing cell contraction.

Effects of Ultraviolet Irradiation on Cellular Senescence in Keratinocytes Versus Fibroblasts.

Aging is a biologic process characterized by time-dependent functional declines that are influenced by oxidative stress-induced inflammatory reactions. In particular, ultraviolet (UV) irradiation plays a key role in cellular senescence in photo-aged skin. However, the cellular senescence of epidermal keratinocytes and dermal fibroblasts by UV irradiation may differ depending on the exposure time and dosage of UV irradiation. Therefore, the purpose of the study was to evaluate and compare the effects of UV irradiation on cellular senescence in human epidermal keratinocytes (HaCaT) and human dermal fibroblasts (HDFs). After cell viability test, 200 mJ/cm UV irradiation was used in this study. To evaluate the reactive oxygen species and reactive nitrogen species production, the levels of glutathione (GSH) and nitrite (NO2) were measured. We also performed reverse transcription-polymerase chain reaction, Western blot analysis, and senescence-associated beta-galactosidase assay. An overall decrease in GSH and an increase in NO2 were observed in the HaCaT and HDF cells. However, the time-line and dose-dependent effects varied. Higher expressions of tumor necrosis factor-α, inducible nitric oxide synthase, and interleukin-1ß than that of the control group were observed in both cells. The HDF cells showed high levels of matrix metallopeptidase 9 and neutral endopeptidase protein but low levels of SIRT1 and procollagen I. The expression of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) was increased in the HaCaT cells, but not in the HDF cells. The NF-κB peaked at 1 hour after UV irradiation in the HaCaT cells. The "turning-on" signal was faster in the irradiated HaCaT cells.