Treatment Of PD Research Articles

(424) A Contemporary Assessment of Patients Presenting to a Tertiary Medical Center with Peyronie’s Disease

Abstract Introduction Peyronie’s disease (PD) is a progressive wound-healing disorder resulting in plaque formation within the tunica albuginea. PD continues to be poorly understood and an area of investigation, with increased awareness by patients and clinicians. Most commonly, PD patients will have a singular plaque and uniplanar curvature in the dorsal or lateral direction. However, previous studies have categorized less common deformities as “atypical”, which includes ventral curvature, multiplanar curvatures, unilateral indentations, hourglass deformity, and severe loss of penile length. Objective We aim to characterize the presenting features of PD within a large cohort of patients presenting to a tertiary referral center. Furthermore, we seek to elucidate the pre-operative factors that correlate with subsequent surgical intervention. Methods 1483 consecutive patients presenting with PD from 2016 to 2021 were retrospectively identified. Patients were excluded if they only had virtual visits, refused penile duplex evaluation, or had PD surgical correction prior to presentation. Baseline demographics, prior treatments, physical exam findings, penile duplex assessment (PDDU), subsequent interventions, and clinical outcomes were documented. Univariate and multivariate analyses were performed to assess pre-operative predictors of subsequent surgical intervention. Results In total, 1263 patients met inclusion criteria. Mean age at presentation was 55.4 ± 11.1 years with a mean duration of PD at presentation of 33.2 ± 42.5 months. Mean primary curvature was 49.8 ± 20.8°. Primary ventral curvature was present in 11.4% and 36.5% of patients had a multiplanar curvature. Mean composite curvature was 60.4 ± 28.2°. Subjective penile shortening was reported by 64.8% of patients with a mean reported loss of 3.8 ± 2.1 cm. During PDDU, indentation/narrowing deformities was appreciated in 73.7%, hourglass deformity in 10.1%, and hinge effect in 33.0% of patients. Calcification was seen in 30.1% of patients. Operative intervention occurred in 35.3% of patients. Hypogonadism (1.56 OR, p=0.04), severity of primary curvature (1.03 OR, p<0.001), hourglass deformity (1.82 OR, p=0.01), decreased tunical elasticity (1.20 OR, p=0.03), and prior intralesional Xiaflex injections (2.94 OR, p <0.001) predicted subsequent surgical correction. Negative predictors of surgical intervention included use of any oral PD treatment (0.43 OR, <0.001) and ability to perform penetrative sex (0.72 OR, p=0.04). 446 (35.3%) patients underwent surgical intervention with 170 (38.1%) plaque incision/excision and grafting, 110 (24.7%) tunical plication, and 166 (37.2%) inflatable penile prosthesis cases. Conclusions Peyronie’s disease remains an incompletely understood disease and presenting features may be changing as a result of more sophisticated evaluation and physician experience. Ventral curvature, multiplanar curvatures, indentation deformity, hourglass deformity, and severe loss of penile length have been described as “atypical”, but these changes are not rare in our cohort of referred patients. Patients with worse erectile function and more severe PD characteristics were predictors of surgical intervention. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific.

(481) Experience with Plaque Excision and Dermal Grafting in the Surgical Treatment of Peyronie's Disease

Abstract Introduction Plaque incision and grafting (PIG) is indicated for men with complex or severe penile curvature, several surgical options to treat PD have been performed. Surgical treatment use graft, as these procedures aim to maintain penile length. Objective To assess outcomes following plaque excision and dermal grafting in the surgical treatment of Peyronie's disease. Methods A prospective study, was performed at Binh Dan Hospital (Ho Chi Minh City – VietNam), from 1/2016 – 12/2020. Surgical correction for curvature is indicated when the PD duration is >12 months, and when the stable phase of PD is >6 months, all case use plaque excision and dermal grafting technique. Results our study have 52 patients, - History illnes: 42.1% diabetes, 26.3% hypertension, 36.84% hyperlipid. - Age mean: 58.31 ± 8.5 years (min: 48 – max 72). - Chief complaine: penile deformities (36.8%), pain (31.6%), palpable lumps (26.3%). - 52.6% have psychological effects. - Fibrous plaque on corpus: Anterior (5.2%), Mid (47.37%), Posterior (47.37%). - Plaque size: 72.59 ± 75.78mm2 (15.51 mm2 – 207 mm2). + Primary outcome measures - Complications (follow one month): alter sensation (16.7%), edema (21.05%), infection (1.9%), pain (10.53%) - Penile straightening: 89%. - Penile length: no changes (82.7%), shorter (17.3%). + Secondary outcome measures - Recurrent curvature: 3 cases – 01 case need operation second time. - Post-operative erectile dysfunction: 7 cases (13.46%). - Patient satisfaction: 82.3% Conclusions Surgical correction of penile curvature is the mainstay for PD treatment. Dermal graft: effectiveness in terms of satisfaction, length change, straightening, economic efficiency and complications. Suitable for patients with underlying medical conditions. Adequate preoperative patient counseling. Disclosure No

Morin exhibits a neuroprotective effect in MPTP-induced Parkinson's disease model via TFEB/AMPK-mediated mitophagy

BackgroundParkinson's disease (PD) is one of the most common neurodegenerative diseases in the world. Mitophagy has been implicated in PD etiology for decades and its pharmacological activation is recognized as a promising treatment strategy for PD. For mitophagy initiation, low mitochondrial membrane potential (ΔΨm) is essential. We identified a natural compound morin that could induce mitophagy without affecting ΔΨm. Morin is a flavonoid that can be isolated from fruits like mulberry. PurposeTo reveal the effect of morin on the PD mice model and their potential underlying molecular mechanism. MethodsMitophagy process induced by morin in N2a cells meditation were measured using flow cytometry and immunofluorescence. JC-1 fluorescence dye used to detect the mitochondrial membrane potential (ΔΨm). The TFEB nuclear translocation were examined by immunofluorescence staining and western blot assay. The PD mice model was induced by MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) intraperitoneal administration. ResultsWe found that morin also promoted nuclear translocation of the mitophagy regulator TFEB and activated the AMPK-ULK1 pathway. In MPTP-induced PD in vivo models, morin protected DA neurons from MPTP neurotoxicity and ameliorated behavioral deficit. ConclusionAlthough morin was previously reported to be neuroprotective in PD, the detailed molecular mechanisms remain to be elucidated. For the first time, we report morin served as a novel and safe mitophagy enhancer underlying AMPK-ULK1 pathway and exhibited anti-Parkinsonian effects indicating its potential as a clinical drug for PD treatment.

Art therapy as a comprehensive complementary treatment for Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease. Complementary and alternative therapies are increasingly utilized to address its complex multisystem symptomatology. Art therapy involves motoric action and visuospatial processing while promoting broad biopsychosocial wellness. The process involves hedonic absorption, which provides an escape from otherwise persistent and cumulative PD symptoms, refreshing internal resources. It involves the expression in nonverbal form of multilayered psychological and somatic phenomena; once these are externalized in a symbolic arts medium, they can be explored, understood, integrated, and reorganized through verbal dialogue, effecting relief and positive change. 42 participants with mild to moderate PD were treated with 20 sessions of group art therapy. They were assessed before and after therapy with a novel arts-based instrument developed to match the treatment modality for maximum sensitivity. The House-Tree-Person PD Scale (HTP-PDS) assesses motoric and visuospatial processing-core PD symptoms-as well as cognition (thought and logic), affect/mood, motivation, self (including body-image, self-image, and self- efficacy), interpersonal functioning, creativity, and overall level of functioning. It was hypothesized that art therapy will ameliorate core PD symptoms and that this will correlate with improvements in all other variables. HTP-PDS scores across all symptoms and variables improved significantly, though causality among variables was indeterminate. Art therapy is a clinically efficacious complementary treatment for PD. Further research is warranted to disentangle causal pathways among the aforementioned variables, and additionally, to isolate and examine the multiple, discrete healing mechanisms believed to operate simultaneously in art therapy.

Parkinson Disease: review

Parkinson’s sickness (PD) is a neurodegenerative ailment precipitated by the death of a kind of neuron that plays an integral function in the production of dopamine in the brain. The pathophysiology of this sickness is based totally on the formation of alpha syncline folds that generate Lewy bodies, which are cytotoxic and minimize dopamine levels. Most pharmacological redress for PD goal alphasynuclein to limit the symptoms. However, the therapeutic method to this pathology includes combination of pharmacological and non-pharmacological strategies to maximize results and improve symptomatological manipulate in these patients. It is therefore essential to delve deeper into the pathophysiology of the ailment in order to enhance these remedies and consequently the exceptional of life of the patients. Therefore, we urgently want to analyze every cutting-edge clinical trial’s status and therapeutic approach to find out new therapeutic tactics for PD treatment. We hope this evaluate can supply new ideas and insights for PD remedy development.

Blockade of sodium-glucose co-transporters improves peritoneal ultrafiltration in uraemic rodent models.

The most used PD fluids contain glucose as a primary osmotic agent. Glucose peritoneal absorption during dwell decreases the osmotic gradient of peritoneal fluids and causes undesirable metabolic consequences. Inhibitors of sodium-glucose co-transporter (SGLT) type 2 are wildly used for the treatment of diabetes, heart and kidney failure. Previous attempts to use SGLT2 blockers in experimental peritoneal dialysis yielded contrasting results. We studied whether peritoneal SGLTs blockade may improve ultrafiltration (UF) via partial inhibition of glucose uptake from dialysis fluids. Kidney failure was induced in mice and rats by bilateral ureteral ligation, and dwell was performed by injection of glucose-containing dialysis fluids. The effect of SGLT inhibitors on glucose absorption during fluid dwell and UF was measured in vivo. Diffusion of glucose from dialysis fluid into the blood appeared to be sodium-dependent, and blockade of SGLTs by phlorizin and sotagliflozin attenuated blood glucose increment thereby decreasing fluid absorption. Specific SGLT2 inhibitors failed to reduce glucose and fluid absorption from the peritoneal cavity in a rodent kidney failure model. Our study suggests that peritoneal non-type 2 SGLTs facilitate glucose diffusion from dialysis solutions, and we propose that limiting glucose reabsorption by specific SGLT inhibitors may emerge as a novel strategy in PD treatment to enhance UF and mitigate the deleterious effects of hyperglycaemia.

RIPK1-Induced A1 Reactive Astrocytes in Brain in MPTP-Treated Murine Model of Parkinson's Disease.

Neuroinflammation is one of the hallmarks of Parkinson's disease, including the massive activation of microglia and astrocytes and the release of inflammatory factors. Receptor-interacting protein kinase 1 (RIPK1) is reported to mediate cell death and inflammatory signaling, and is markedly elevated in the brain in PD mouse models. Here, we aim to explore the role of RIPK1 in regulating the neuroinflammation of PD. C57BL/6J mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 20 mg/kg four times/day), followed by necrostatin-1 treatment (Nec-1, RIPK1 inhibitor; 1.65 mg/kg once daily for seven days. Notably, the first Nec-1 was given 12 h before MPTP modeling). Behavioral tests indicated that inhibition of RIPK1 greatly relieved motor dysfunction and anxiety-like behaviors of PD mice. It also increased striatal TH expression, rescue the loss of dopaminergic neurons, and reduce activation of astrocytes in the striatum of PD mice. Furthermore, inhibition of RIPK1 expression reduced A1 astrocytes' relative gene expression (CFB, H2-T23) and inflammatory cytokine or chemokine production (CCL2, TNF-α, IL-1β) in the striatum of PD mice. Collectively, inhibition of RIPK1 expression can provide neuroprotection to PD mice, probably through inhibition of the astrocyte A1 phenotype, and thus RIPK1 might be an important target in PD treatment.

Transcriptomic analysis: the protection of over-expression thioredoxin reductase 1 in Parkinson’s disease

BackgroundParkinson’s disease (PD) is the second most common neurodegenerative disease. The pathologic characteristic feature is the loss of dopaminergic neurons in the substantia nigra (SN). However, the biochemical mechanisms are unclear.A large number of studies have shown that oxidative damage is the primary cause of PD. Hence, antioxidants could become a suitable option to treat PD. The thioredoxin (Trx) system represents a useful, potentially disease-relevant oxidation–reduction system. Thioredoxin reductase 1 (TR1) is a significant component of the Trx system.MethodsThe overexpression lentivirus (LV) or LV-TR1 in the TR1-A53T model of PD by the stereotactic brain, and successful overexpression of LV or LV-TR1 in the MPP+-induced cellular model by LV or LV-TR1 transfection.ResultsWe confirmed that interleukin-7 mRNA levels increased in MPP+ compared to that in the control and MPP+-TR1 groups using quantitative polymerase chain reaction. The γ-H2AX level was increased in the Tg-A53T group compared to that in the TR1-A53T group by western blotting. The expression of Na+-K+-ATP was decreased in the MPP+ group compared to that in the control and MPP+-TR1 groups by high content screening. Tg-A53T(the C57BL/6 mice transferred with mutant human a-syn); TR1-A53T(A53T mice which were injected TR1-LV 2 µl in SNc on two sides with minipump).The mice were fed for 10 months. control (the N2a cells cultivated with DMEM); MPP+(the N2a cells dealt with MPP+(1 mM) 48 h), MPP+-LV (the N2a cells over-expressed LV for 24 h then dealt with MPP+(1 mM) 48 h). MPP+-TR1(the N2a cell over-expressed TR1-LV for 24 h then dealt with MPP+(1 mM) 48 h).From the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we confirmed that the overexpression of TR1 in SN pars compacta cells decreased oxidative stress, apoptosis, DNA damage, and inflammatory response and increased NADPH, Na+-K+-ATP, and immune response in this PD model.ConclusionsOur study shows that overexpressed TR1 can be developed as a neuroprotective agent for PD. Therefore, our findings demonstrate a new targeted protein for the treatment of PD.

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Ketone Bodies and Brain Metabolism: New Insights and Perspectives for Neurological Diseases.

Design, synthesis and evaluation of novel monoamine oxidase B (MAO-B) inhibitors with improved pharmacokinetic properties for Parkinson's disease

A series of novel ((benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide derivatives were designed, synthesized and evaluated as MAO-B inhibitors. SAR studies indicated that cyclizing benzyl ether into benzofuran ring resulted in the most potent MAO-B inhibitor (IC50 = 0.037 μM), (2S,4S)-4-fluoro-1-((2-(4-fluorophenyl) benzofuran-5-yl)methyl)pyrrolidine-2-carboxamide (C14). PK properties of C14 in rats and mice were significantly improved compared to our previous candidate and safinamide, indicating that benzofuran moiety is essential for improving PK properties. Moreover, C14 displayed good metabolic stability and brain-blood barrier permeability, as well as favorable in vitro properties. Finally, C14 significantly inhibited MAO-B in the mouse brain. C14 exhibited a potential efficacy for DA deficits in the MPTP-induced mouse model and significantly increased DA concentration in the striatum. Thus, we identified that C14 may be a promising drug candidate for PD treatment.

Neuroprotective effect of engineered Clostridiumbutyricum-pMTL007-GLP-1 on Parkinson's disease mice models via promoting mitophagy.

Parkinson's disease (PD) is a common neurodegenerative disease with limited treatment and no cure, hence, broadening PD drug spectrum is of great significance. At present, engineered microorganisms are attracting increasing attention. In this study, we constructed an engineered strain of Clostridium butyricum-GLP-1, a C. butyricum (a probiotic) that consistently expresses glucagon-like peptide-1 (GLP-1, a peptide-based hormone with neurological advantage) in anticipation of its use in PD treatment. We further investigated the neuroprotective mechanism of C. butyricum-GLP-1 on PD mice models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The results indicated that C. butyricum-GLP-1 could improve motor dysfunction and ameliorate neuropathological changes by increasing TH expression and reducing the expression of α-syn. Moreover, we confirmed that C. butyricum-GLP-1 improved microbiome imbalance of PD mice by decreasing the relative abundance of Bifidobacterium at the genus level, improved gut integrity, and upregulated the levels of GPR41/43. Surprisingly, we found it could exert its neuroprotective effects via promoting PINK1/Parkin mediated mitophagy and attenuating oxidative stress. Together, our work showed that C. butyricum-GLP-1 improves PD by promoting mitophagy, which provides an alternative therapeutic modality for PD.

Quality of Life and Related Factors in Patients Undergoing Renal Replacement Therapy at the Hospital General Universitario de Ciudad Real: Cross Sectional Descriptive Observational Study.

Background: The aim of the present study was to determine the relationship between the quality of life of patients on renal replacement therapy and the Symptomatology they presented. Methods: Cross-sectional descriptive observational study: quality of life was assessed by means of the KDQOL-SF questionnaire, Symptomatology by the Palliative Care Outcome Scale-Symptoms Renal questionnaire, and sociodemographic and clinical data of patients in the Hemodialysis Unit (HD) of the Hospital General Universitario de Ciudad Real (HGUCR) by means of personal interviews and clinical history data. Results: A total of 105 patients participated in the study, 63 (60.57%) men and 42 (40.38%) female. The mean age was 62.5 dt (14.84) years. Of these, 43 (41%) were on peritoneal dialysis and 62 (59%) were on hemodialysis. The mean quality of life score was 44.89 dt (9.73). People on hemodialysis treatment presented a better quality of life than those on PD treatment: 49.66 dt (9.73) vs. 38.13 dt (9.12) t = 7.302, p < 0.001. A higher score on the symptom impairment scale (post-renal) correlated with worse scores on the total quality of life score: r = -0.807, p < 0.001. It was observed that those who improved the distress symptom scored better on the total quality of life questionnaire: 50.22 dt (8.44) vs. 46.42 dt (9.05), p < 0.001. Conclusions: The presence and management of the large number of symptoms that appear as side effects, such as distress or depression, could determine changes in some components of quality of life.

Integrated analysis of metabolomic and transcriptomic profiling reveals the effect of Buyang Huanwu decoction on Parkinson's disease in mice

BackgroundParkinson's disease (PD) is a common, complex, and chronic neurodegenerative disorder involved in multi-system. At present, medicine for PD has many limitations. Buyang Huanwu decoction (BHD), a famous traditional Chinese medicinal (TCM) formulae, is used in the treatment of PD clinically in China. However, the therapeutic mechanism is still unknown. PurposeWe aimed to explore the pharmacological mechanism of BHD alleviating PD through an integrated liver metabolome and brain transcriptome analysis. MethodsThe mice with PD were induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral tests and immunohistochemistry were used to evaluate the neuroprotective effects of BHD. The non-targeted metabolomics analysis was conducted to profile differentially accumulated metabolites (DAMs) in the liver using a UHPLC-Q-Exactive MS/MS method. The differentially expressed genes (DEGs) in the brain were investigated by transcriptomic analysis on an Illumina sequencing platform. The correlations of DAMs and DEGs were investigated using an integrated metabolomic and transcriptomic approach. ResultsThe results of behavioral tests and immunohistochemistry proved the alleviated effects of BHD on PD symptoms. A total of 14 and 36 DAMs were detected in the groups treated with low- (L group) and high-dose (H group) BHD respectively under the positive ion mode. Compared with the PD model group (M group), three enriched pathways including metabolic pathways, ABC transporters, and biosynthesis of amino acids were common in the L and H group. Transcriptomic analysis proved that BHD could regulate the expression of numerous genes, some of which were targeted by Ben-Ldopa such as Creb5, Gm45623, Ccer2, Cd180, Fosl2, Crip3, and Noxred1. Based on the integrated metabolomic and transcriptomic analysis, 7 metabolite-gene pairs were found in four comparisons, including C vs M, M vs P, M vs L, and M vs H, and 6 enriched pathways containing purine metabolism, glycine/serine/threonine metabolism, phenylalanine metabolism, carbon fixation in photosynthetic organisms, thiamine metabolism, and ABC transporters were overlapped. ConclusionsThough the underlying pharmacological mechanism of BHD is still lacking, we provided evidence that BHD could improve dopaminergic neurons in MPTP-induced PD mice by regulating liver metabolism and brain transcriptome. The correlation between the liver and the brain was preliminarily revealed in this study.

Effect of probiotic supplementation on gastrointestinal motility, inflammation, motor, non-motor symptoms and mental health in Parkinson’s disease: a meta-analysis of randomized controlled trials

BackgroundParkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Gut dysbiosis is hypothesized to cause PD; therefore, whether probiotics can be used as adjuvants in the treatment of PD is being actively investigated.AimsWe performed a systematic review and meta-analysis to evaluate the effectiveness of probiotic therapy in PD patients.MethodsPUBMED/MEDLINE, EMBASE, Cochrane, Scopus, PsycINFO and Web of Science databases were searched till February 20, 2023. The meta-analysis used a random effects model and the effect size was calculated as mean difference or standardized mean difference. We assessed the quality of the evidence using the Grade of Recommendations Assessment, Development and Evaluation (GRADE) approach.ResultsEleven studies involving 840 participants were included in the final analysis. This meta-analysis showed high-quality evidence of improvement in Unified PD Rating Scale Part III motor scale (standardized mean difference [95% confidence interval]) (− 0.65 [− 1.11 to − 0.19]), non-motor symptom (− 0.81 [− 1.12 to − 0.51]), and depression scale (− 0.70 [− 0.93 to -0.46]). Moderate to low quality evidence of significant improvement was observed in gastrointestinal motility (0.83 [0.45–1.10]), quality of life (− 1.02 [− 1.66 to − 0.37]), anxiety scale (− 0.72 [− 1.10 to − 0.35]), serum inflammatory markers (− 5.98 [− 9.20 to − 2.75]), and diabetes risk (− 3.46 [− 4.72 to − 2.20]). However, there were no significant improvements in Bristol Stool Scale scores, constipation, antioxidant capacity, and risk of dyslipidemia. In a subgroup analysis, probiotic capsules improved gastrointestinal motility compared to fermented milk.ConclusionProbiotic supplements may be suitable for improving the motor and non-motor symptoms of PD and reducing depression. Further research is warranted to determine the mechanism of action of probiotics and to determine the optimal treatment protocol.

Ultrasound ablation treatment for PD.

Ultrasound ablation treatment for PD.

Prediction of drug amount in Parkinson's disease using hybrid machine learning systems and radiomics features

AbstractParkinson's disease (PD) is progressive and heterogeneous. Levodopa is widely prescribed to control PD, and its long‐term‐treatment leads to dyskinesia in a dose‐dependent manner. Interpretation of clinical trials comparing different drug treatments for PD is complicated by different dose intensities employed: higher doses of levodopa produce better symptomatic control but more late complications. Thus, the dose must be recalibrated and reduced gradually. Since recommendations for gradually reducing Levodopa are currently lacking and estimation of Levodopa amount can help doctor to correctly prescribe drug amount, this study aims to predict Levodopa amount and incremental doses using Hybrid Machine Learning Systems (HMLS) and a mixture of radiomics and clinical features. We selected 264 patients from PPMI and obtained 950 features including imaging and nominating features. We generated seven datasets constructed from the dataset in years 0 and 1, which linked with outcomes, (O1) patients being on/off drug in year 1, (O2) dose amount in year 1, and (O3‐8) incremental dose from 1st to 2nd, 2nd to 3rd, 3rd to 4th, 4th to 5th, 1st to 4th, 1st to 5th year. HMLSs included 10 feature extraction/9 feature selection algorithms followed by 10 prediction algorithms. To predict O1, timeless dataset + Random Forest + ReliefA had the highest accuracy~88.5% ± 2.2%, and external testing~91.6%. Furthermore, to predict O2, timeless dataset + Minimum Redundancy Maximum Relevance Algorithm (MRMR) + K Nearest Neighbor Regressor (KNN‐R) achieved a mean absolute error (MAE) ~ 47.5 ± 13.6 ([30.3:850 milligram]) and external testing~31.9. To predict dose increments (O3‐8), HMLSs: Unsupervised Feature Selection with Ordinal Locality + KNNR, ReliefA + KNNR, ReliefA + KNNR, Local Learning‐based Clustering Feature Selection + KNNR, MRMR + KNNR, and MRMR + KNNR applied to timeless datasets resulted in MAEs ~ 0.42 ± 0.18, 0.10 ± 0.09, 0.04 ± 0.01, 0.24 ± 0.15, 0.25 ± 0.05, and 0.33 ± 0.26 ([0.23:29.7]), respectively. Moreover, their external testing confirmed our findings. We demonstrated that timeless datasets including a mixture of clinical and imaging features, linked with appropriate HMLSs, significantly improve prediction performances.

Immunotherapeutic Approaches for the Treatment of Neurodegenerative Diseases: Challenges and Outcomes.

Neurodegenerative diseases, being rapidly increasing disorders and the seventh leading cause of death worldwide, have been a great challenge for researchers, affecting cognition, motor activity and other body functioning due to neurodegeneration. Several neurodegenerative diseases are caused by aggregation of proteins which induce the alteration of neuronal function leading to cell death. These proteins are amyloid-β peptide, tau, α-synuclein, and mHTT, which cause Alzheimer's disease, Frontotemporal dementia, Corticobasal degeneration, Progressive supranuclear palsy, Parkinson's disease, Multiple system atrophy, Dementia with Lewy-body and Huntington's disease. Currently available treatments only reduce symptoms and increase life sustainability; however, they possess side effects and are ineffective in curing the diseases. Literature survey of neurodegenerative diseases and immunotherapeutic approaches is used to evaluate their pharmacological effects and future endeavours. A literature search was performed to find the relevant articles related to neurodegenerative diseases and immunotherapies. Clinical trials data were analysed from clinicaltrial.com. According to the literature study, it was found that researchers have explored the effect of active and passive vaccines generated against amyloid-β, tau, α-synuclein and mHTT. Few clinical trials have shown severe side effects and terminated, despite that, few of them produced desirable effects for the treatment of AD and PD. Several immunotherapeutic trials have shown promising outcomes against amyloid-β, tau and α-synuclein. In addition, various preclinical studies against mHTT and prion proteins are under scrutinization. These clinical outcomes indicate a promising role of immunotherapies against neurodegenerative diseases.

Comparison of Parkinson’s patients with and without COVID-19 in terms of prognosis

Background &amp; Objectives: This study aimed to compare PD patients with and without COVID-19 and to evaluate the associated factors about prognosis. Methods: The data of 37 hospitalized PD patients associated with COVID-19 pneumonia were evaluated. It was compared with the data of 40 PD patients who did not have COVID-19 in the same period. Clinical findings, prognosis, mortality and other related factors were compared in PD patients with and without COVID-19. Results: Hypertension was higher comorbid disease in PD patients with COVID-19 (p = 0.005). The duration of PD was longer in patients without COVID-19 disease (6.02 ± 2.80 vs 5.08 ± 4.59) (p = 0.028). In PD patients with COVID-19, the most common symptoms were myalgia-arthralgia (73.0%) and fatigue (48.6%). Intensive care was required in 17 (45.9%) patients, and invasive mechanical ventilation (IMV) was required in 9 (24.3%) patients. The in-hospital mortality rate was 29.7% (n = 11). Mortality and IMV requirement were higher in patients whose initial symptom was diarrhea (p = 0.004, p = 0.008, respectively). No correlation was detected between PD stage, treatment options and prognosis (p &lt; 0.05). Conclusion: Mortality rate and IMV requirement are higher in PD patients with COVID-19 pneumonia, particularly in patients with initial symptoms of diarrhea. These patients should be followed more carefully in terms of probable poor prognosis.

Abstract P1-13-18: EGFR signaling contributes to acquired resistance to CDK4/6 inhibitors in ER+ breast cancer cells in vitro and in vivo

Abstract Breast cancer driven by different hormone receptors, including estrogen receptor (ER+), is responsible for approximately 70-80% of cases among women. While endocrine therapy (ET) of ER+ primary tumors with antiestrogens or aromatase inhibitors is an effective first-line therapy, its success is limited by intrinsic and acquired resistance. Response to ET can be limited due to overexpression of cyclin D1, which promotes the activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Selective inhibition of CDK4/6 and ER signaling is now standard-of-care therapy for ER+ metastatic breast cancer. CDK4/6 inhibitors (CDK4/6i), including palbociclib (PD), ribociclib, and abemaciclib, used in combination with ET, have shown improvement in progression-free survival compared to ET alone in the metastatic setting. However, the inevitable development of acquired resistance significantly limits the efficacy of this targeted therapy. Rewired signaling driven by different oncogenes, including the epidermal growth factor receptor (EGFR), overcomes the targeted inhibition of CDK4/6, which, in turn, allows cell cycle progression contributing to acquired resistance. We evaluated the expression and activity of EGFR in the panel of different matching pairs of ER- and ER+ CDK4/6i-sensitive (pS) and CDK4/6i-resistant (pR) breast cancer cell lines in vitro. Increased EGFR expression in ER+ MCF7/pR cells correlated with elevated ER phosphorylation, suggesting a direct cross-talk between EGFR and ER signaling in PD-resistant cells. Stimulation with EGF promoted ER activation, whereas estrogen stimulation promoted EGFR activation in ER+ pS and pR cell lines, indicating a direct cross-regulation between these molecular targets. Treatment of MCF7/pR cells with CDK4/6i resulted in elevated EGFR mRNA expression, confirming the dependency of resistant cells on EGFR signaling. Moreover, exposure to the EGFR inhibitors dramatically inhibited the proliferation of MCF7/pR cells compared to the parental cells, suggesting that EGFR could be an essential bypass signaling regulator contributing to resistance to CDK4/6i. We found that combined treatment with EGFRi and CDK4/6i significantly inhibited Rb phosphorylation in pR cells improving the effect of CDK4/6i on cell cycle arrest. We evaluated EGFR expression in MCF7/pS and pR mouse xenograft models in vivo. We observed a significant elevation in EGFR expression and phosphorylation in response to PD treatment, confirming the importance of EGFR signaling in maintaining the acquired resistance to CDK4/6i in ER+ breast cancer cells. Taken together, our findings suggest that EGFR signaling plays an important role in acquired resistance to CDK4/6i in ER+ breast cancer cells in vitro and in vivo and targeting EGFR with small-molecule inhibitors (like erlotinib or gefitinib) or chimeric monoclonal antibodies (i.e. cetuximab) can be a promising approach to improve CDK4/6i efficacy in breast cancer patients. Citation Format: Nadiia Lypova, Lilibeth Lanceta, Susan Daugherty, Jason Chesney, Yoannis Imbert-Fernandez. EGFR signaling contributes to acquired resistance to CDK4/6 inhibitors in ER+ breast cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-18.

The Relationship between Rem Sleep Behaviour Disorder and Parkinson’s Disease Revisited – Are They One and the Same?

This paper reviews the relationship between RBD and PD and the pathophysiology. Most RBD patients develop PD within 14 years. PD pathophysiology is α-synucleinopathy with dopamine degeneration in nigrostriatal pathways. RBD pathology is poorly understood. Anomalies suggest RBD and PD are different, evidenced by smoking. RBD and PD are associated with glucocerebrosidase gene mutations (GBA gene), suggesting RDB with GBA gene mutation predicts PD. PET imaging, assessing vesicular monoamine transporter 2 (VMAT2), indexing nigrostriatal dopamine innervation, is lower in PD and RBD, in the putamen, ventral striatum and globus pallidus but not substantia nigra or subthalamus, compared with controls. VMAT2 may not contribute to pathophysiology of RBD in PD. Treatments for RBD and PD differ. PD with RBD had more depression, compared to PD without RBD. Only PD with RBD had statistically significant increased depression, compared with controls, and non-significant lowered cognition. PD patients, with and without RBD, had decreased ligand binding, compared to healthy controls, indicating no difference in VMAT2 within the caudate and putamen. Research showed differences in cholinergic levels, noradrenaline and glucose metabolism for PD with and without RBD. RBD with PD, is multi-systematic, affecting regions beyond dopaminergic pathways. Treatment of RBD does not affects PD neurodegeneration. Researchers continue to search for neuro-protective intervention. There is a relationship between PD and RBD but it is not absolute. PD nigrostriatal degeneration is independent of RBD. Pathophysiological differences may explain why treatment of RBD does not alter its natural history.