Male Parkinson's Disease Patients Research Articles

Sex-dependent associations of serum BDNF, glycolipid metabolism and cognitive impairments in Parkinson's disease with depression: a comprehensive analysis.

Brain-derived neurotrophic factor (BDNF) and glycolipid metabolism have been implicated in cognitive impairments and depression among Parkinson's disease (PD). However, the role of sex differences in this relationship remains elusive. This study aimed to investigate the potential sex differences in the link between serum BDNF levels, glycolipid metabolism and cognitive performance among depressive PD patients. PD patients comprising 108 individuals with depression and 108 without depression were recruited for this study. Cognitive function was assessed using the Montreal Cognitive Assessment Beijing version (MOCA-BJ). The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HAMD-17), while motor symptoms were evaluated using the Revised Hoehn and Yahr rating scale (H-Y) and the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). Laboratory testing and enzyme-linked immunosorbent assay (ELISA) are used to measure serum levels of glycolipid metabolism and BDNF. Females showed superior performance in delayed recall (all p < 0.05), male PD patients exhibited higher scores in naming tasks compared to females in non-depression group. There was no sex differences in serum BDNF levels between depression and non-depression groups. Liner regression analysis indicated BDNF as an independent risk factor for language deficits in male PD patients with depression (p < 0.05), while cholesterol (CHOL) emerged as a cognitive influencing factor, particularly in delayed recall among male PD patients with depression (p < 0.05). Our study reveals extensive cognitive impairments in PD patients with depression. Moreover, BDNF and CHOL may contribute to the pathological mechanisms underlying cognitive deficits, particularly in male patients with depression.

Quantification of Circulating Cell-Free DNA in Idiopathic Parkinson's Disease Patients.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders globally and leads to an excessive loss of dopaminergic neurons in the substantia nigra of the brain. Circulating cell-free DNA (ccf-DNA) are double-stranded DNA fragments of different sizes and origins that are released into the serum and cerebrospinal fluid (CSF) due to cell death (i.e., necrosis and apoptosis) or are actively released by viable cells via exocytosis and NETosis. Using droplet digital polymerase chain reaction (ddPCR), we comprehensively analyzed and distinguished circulating cell-free mitochondrial DNA (ccf mtDNA) and circulating cell-free nuclear DNA (ccfDNA) in the serum and CSF of PD and control patients. The quantitative analysis of serum ccf-DNA in PD patients demonstrated a significant increase in ccf mtDNA and ccfDNA compared to that in healthy control patients and a significantly higher copy of ccf mtDNA when compared to ccfDNA. Next, the serum ccf mtDNA levels significantly increased in male PD patients compared to those in healthy male controls. Furthermore, CSF ccf mtDNA in PD patients increased significantly compared to ccfDNA, and ccf mtDNA decreased in PD patients more than it did in healthy controls. These decreases were not statistically significant but were in agreement with previous data. Interestingly, ccf mtDNA increased in healthy control patients in both serum and CSF as compared to ccfDNA. The small sample size of serum and CSF were the main limitations of this study. To the best of our knowledge, this is the first comprehensive study on serum and CSF of PD patients using ddPCR to indicate the distribution of the copy number of ccf mtDNA as well as ccfDNA. If validated, we suggest that ccf mtDNA has greater potential than ccfDNA to lead the development of novel treatments for PD patients.

Generation of the iPSC line FINi002-A from a male Parkinson's disease patient carrying compound heterozygous mutations in the PRKN gene

The most common cause of autosomal recessive familial Parkinson’s disease (PD) are mutations in the PRKN/PARK2 gene encoding an E3 ubiquitin protein-ligase PARKIN. We report the generation of an iPSC cell line from the fibroblasts of a male PD patient carrying a common missense variant in exon 7 (p.Arg275Trp), and a 133 kb deletion encompassing exon 8, using transiently-present Sendai virus. The established line displays typical human primed iPSC morphology and expression of pluripotency-associated markers, normal karyotype without SNP array-detectable copy number variations and can give rise to derivatives of all three embryonic germ layers. We envisage the usefulness of this iPSC line, carrying a common and well-studied missense mutation in the RING1 domain of the PARKIN protein, for the elucidation of PARKIN-dependent mechanisms of PD using in vitro and in vivo models.

The value of ultrasound measurement of muscle thickness at different sites and shear wave elastography in Parkinson's disease with sarcopenia: a pilot study.

Patients with Parkinson's disease (PD) and sarcopenia often exhibit resilience, frailty, disability, and depression, highlighting the complex and interrelated nature of these conditions. Despite the presence of clinical manifestations of muscle atrophy in both PD and sarcopenia, accurately discerning the coexistence of sarcopenia in PD patients remains a challenging task with significant implications for treatment strategies and prognostic assessments. This study aims to elucidate the specific ultrasonic diagnostic parameters associated with PD accompanied by sarcopenia through a comparative analysis of muscle ultrasound parameters in patients with PD, thereby presenting a novel approach for rapid identification of this condition. A total of 110 participants were enrolled in this study, including patients with PD and control subjects. Demographic data, clinical characteristics, physical performance tests, appendicular skeletal muscle mass index (ASMI), bioelectrical impedance analysis and muscle ultrasound measurements were collected from all participants. The muscle ultrasound measurements encompassed assessments of muscle thickness, pennation angle and shear wave elastography at various anatomical sites. Parkinson's disease patients exhibited decreased muscle strength and physical performance, and increased shear wave elastography value. In PD patients with sarcopenia, body circumference, including calf circumference, mid-arm circumference, Waist-to-Hip Ratio and body mass index (BMI) were all significantly decreased. Biceps brachii muscle thickness (MT) and gastrocnemius MT decreased in PD patients with sarcopenia and low ASMI. Binary logistic regression analysis revealed that male PD patients, BMI and gastrocnemius MT were predictive factors for ASMI in PD patients. Biceps brachii MT and gastrocnemius MT are important indicators for distinguishing whether PD patients have sarcopenia. Male patients, low BMI and gastrocnemius MT were identified as valid predictors of low ASMI in PD patients. The findings of this study provide important insights into the use of muscle ultrasound in the diagnosis of PD with sarcopenia.

Evaluation of the role of FMR1 CGG repeat allele in Parkinson's disease from the Chinese population.

There is controversial evidence that FMR1 premutation or "gray zone" (GZ) allele (small CGG expansion, 45-54 repeats) was associated with Parkinson's disease (PD). We aimed to explore further the association between FMR1 CGG repeat expansions and PD in a large sample of Chinese origin. We included a cohort of 2,362 PD patients and 1,072 controls from the Parkinson's Disease and Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) in this study and conducted repeat-primed polymerase chain reaction (RP-PCR) for the size of FMR1 CGG repeat expansions. Two PD patients were detected with FMR1 premutation (61 and 56 repeats), and the other eleven PD patients were detected with the GZ allele of FMR1 CGG repeat expansions. Those thirteen PD patients responded well to levodopa and were diagnosed with clinically established PD. Specifically, one female PD patient with GZ allele was also found with premature ovarian failure. However, compared to healthy controls, we found no significant enrichment of GZ allele carriers in PD patients or other subgroups of PD cases, including the subgroups of female, male, early-onset, and late-onset PD patients. Furthermore, we did not find any correlation between the FMR1 gene CGG repeat sizes and age at onset of PD. It suggested that FMR1 premutation was related to PD, but the GZ allele of FMR1 CGG repeat expansions was not significantly enriched in PD cases of Chinese origin. Further larger multiple ethnic studies are needed to determine further the role of the FMR1 GZ allele in PD.

Sex Differences in Brain Structure in de novo Parkinson's Disease: A Cross-Sectional and Longitudinal Neuroimaging Study.

Parkinson's disease (PD) varies in occurrence, presentation, and severity between males and females. However, the sex effects on the patterns of brain structure, cross-sectionally and longitudinally, are still unclear. We aimed to compare sex differences in brain features cross-sectionally and longitudinally using grey matter volume (GMV) and cortical thickness in a large sample of newly diagnosed drug-naive PD patients. Cognitive assessments and structural MR images of 262 PD patients (171 males) and 113 healthy controls (68 males) were selected from the Parkinson's Progression Markers Initiative. Of these, 97 PD patients (66 males) completed 12- and 24-month follow-up examinations. After regressing out the expected effects of age and sex, brain maps of GMV and cortical thickness were compared using two-sample t tests cross-sectionally and were compared using repeated measurement analyses of variance longitudinally. At baseline, male PD patients exhibited a greater extent of brain atrophy and cortical thickness reduction than females, which mainly occurred in the cerebellum, frontal lobe, parietal lobe, and temporal lobe. At follow-up, female and male PD patients showed similar dynamics of disease progression, as both groups declined over time while the females maintained the advantage. The cortical thickness of the right precentral gyrus at baseline was negatively associated with the longitudinal changes of motor function in male PD patients. The current findings might demonstrate sex effect in neuroanatomy during the course of PD, provide new insights into the neurodegenerative process, and facilitate the development of more effective sex-specific therapeutic strategies.

Exploring the alteration of gut microbiota and brain function in gender-specific Parkinson's disease based on metagenomic sequencing.

The role of the microbiota-gut-brain axis in Parkinson's disease (PD) has received increasing attention. Although gender differences are known to an essential role in the epidemiology and clinical course of PD, there are no studies on the sex specificity of the microbiota-gut-brain axis in the development and progression of PD. Fresh fecal samples from 24 PD patients (13 males, 11 females) were collected for metagenomic sequencing. The composition and function of the gut microbiota were analyzed by resting-state functional magnetic resonance imaging (fMRI). Gender-dependent differences in brain ALFF values and their correlation with microbiota were further analyzed. The relative abundance of Propionivibrio, Thermosediminibacter, and Flavobacteriaceae_noname was increased in male PD patients. LEfse analysis showed that Verrucomicrobial, Akkermansiaceae, and Akkermansia were dominant in the males. In female patients, the relative abundance of Propionicicella was decreased and Escherichia, Escherichia_coli, and Lachnospiraceae were predominant. The expression of the sesquiterpenoid and triterpenoid biosynthesis pathways was increased in male PD patients and was statistically different from females. Compared to the Male PD patients, female patients showed decreased ALFF values in the left inferior parietal regions, and the relative abundance of Propionivibrio was positively correlated with the regional ALFF values. Our study provides novel clinical evidence of the gender-specific relationship between gut microbiota alterations and brain function in PD patients, highlighting the critical role of the microbiota-gut-brain axis in gender differences in PD.

Sex hormones differentially contribute to Parkinson disease in males: A multimodal biomarker study.

Parkinson disease (PD) presents relevant sex-related differences in epidemiology, pathophysiology, and clinical features, with males being more vulnerable to the disease. Sex hormones might have a role, as the experimental models suggest; however, human-based evidence is scarce. Here, we integrated multimodal biomarkers to investigate the relationships between circulating sex hormones and clinical-pathological features in male PD patients. A cohort of 63 male PD patients underwent comprehensive clinical evaluation of motor and nonmotor disturbances; measurement of estradiol, testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) blood levels; and cerebrospinal fluid (CSF) assay of total α-synuclein, amyloid-β-42, amyloid-β-40, total tau, and phosphorylated-181 tau levels. A subgroup of 47 PD patients underwent brain volumetry by 3-T magnetic resonance imaging for further correlations. A control group of 56 age-matched individuals was enrolled for comparative analyses. Male PD patients had higher estradiol and testosterone levels than controls. Estradiol had independent inverse associations with Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part 3 score and disease duration; it was also lower in nonfluctuating patients. Testosterone had inverse independent correlations with CSF α-synuclein and right globus pallidus volume. FSH and LH had age-dependent correlations with cognitive impairment and CSF amyloid-β-42/amyloid-β-40 ratio. The study suggested that sex hormones could differentially contribute to clinical-pathological features of PD in male patients. Whereas estradiol might have a protective role in motor impairment, testosterone might be involved in male vulnerability to PD neuropathology. Gonadotropins instead might mediate age-dependent phenomena of amyloidopathy and cognitive decline.

Voltage-Gated Proton Channel Hv1 Regulates Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson's Disease Models.

Although the precise mechanisms for neurodegeneration in Parkinson's disease (PD) are unknown, evidence suggests that neuroinflammation is a critical factor in the pathogenic process. Here, we sought to determine whether the voltage-gated proton channel, Hv1 (HVCN1), which is expressed in microglia and regulates NADPH oxidase, is associated with dopaminergic neurodegeneration. We utilized data mining to evaluate the mRNA expression of HVCN1 in the brains of PD patients and controls and uncovered increased expression of the gene encoding Hv1, HVCN1, in the brains of PD patients compared to controls, specifically in male PD patients. In an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 × 16 mg/kg) mouse model of PD, Hvcn1 gene expression was increased 2-fold in the striatum. MPTP administration to wild-type (WT) mice resulted in a ~65% loss of tyrosine hydroxylase positive neurons (TH+) in the substantia nigra (SN), while a ~39% loss was observed in Hv1 knockout (KO) mice. Comparable neuroprotective effects of Hv1 deficiency were found in a repeated-dose LPS model. Neuroprotection was associated with decreased pro-inflammatory cytokine levels and pro-oxidant factors in both neurotoxicant animal models. These in vivo results were confirmed in primary microglial cultures, with LPS treatment increasing Hvcn1 mRNA levels and Hv1 KO microglia failing to exhibit the LPS-mediated inflammatory response. Conditioned media from Hv1 KO microglia treated with LPS resulted in an attenuated loss of cultured dopamine neuron cell viability compared to WT microglia. Taken together, these data suggest that Hv1 is upregulated and mediates microglial pro-inflammatory cytokine production in parkinsonian models and therefore represents a novel target for neuroprotection.

Does dopamine deficiency affect sex-dependent prognosis in Parkinson's disease?

IntroductionA bundle of evidence indicates that biological sex is an important factor for clinical phenotypes as well as prognosis in Parkinson's disease (PD). We investigated the effect of nigrostriatal dopaminergic degeneration on longitudinal outcomes according to sex in patients with PD. MethodsWe recruited 571 consecutive drug-naïve PD patients (279 men and 292 women) who were followed up for ≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging. A Cox proportional hazard model was used to compare the risk of developing levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), or PD dementia (PDD) between male and female PD patients. A mediation analysis was used to determine the relationship between biological sex, striatal dopamine deficiency, and longitudinal outcomes. ResultsFemale PD patients exhibited less severely decreased DAT availability in all striatal subregions than male PD patients. The future development of wearing-off and FOG did not differ according to sex. LID developed more frequently in female PD patients than in male PD patients, while the risk of PDD conversion was higher in male PD patients than in female PD patients. In the mediation analyses, the direct effect of biological sex on the development of LID or PDD was major, while the mediating effect through the striatal DAT availability was minimal. ConclusionDifferences in longitudinal outcomes according to biological sex may be ascribed to a non-dopaminergic basis. This study suggests that therapeutic strategies targeting the extra-nigrostriatal pathway should be considered in future trials.

The protective role of cigarette smoking against Parkinson's disease via moderation of the interaction between iron deposition in the nigrostriatal pathway and clinical symptoms.

Although cigarette smoking is a risk factor for multiple disorders, it has long been thought to protect against Parkinson's disease (PD). Quantitative susceptibility mapping (QSM) is a novel magnetic resonance imaging (MRI)-based technique for assessing iron accumulation in vivo that has been widely applied in PD studies. This study aimed to investigate how cigarette smoking affects clinical performance of PD using quantified iron deposition as a proxy for PD pathology. In this observational study, we enrolled 35 male PD patients and 47 male healthy controls (HCs) and divided them into four groups. We performed an enhanced T2 star-weighted angiography (ESWAN) MRI sequence to measure the iron content of the nuclei within the nigrostriatal pathway. With the age and total intracranial volume (TIV) controlled as covariates, we performed inter-group comparisons of QSM values and moderation analyses for PD patients using smoking status and the smoking index (SI), respectively, as moderator variables. The 2-way multivariate analysis of covariance (MANCOVA) results showed higher QSM values in the left red nucleus (P=0.024) in PD patients compared with those in HCs, and in the bilateral globi pallidi [left/right (L/R): P=0.009/0.003], substantia nigra pars compacta (SNc; L/R: P=0.001/0.037), and right substantia nigra pars reticulata (SNr; P=0.002) in non-smokers compared with smokers, with no marked interaction effect between PD and smoking status observed when applying the Bonferroni adjustment for multiple comparisons. Using cigarette smoking status and the SI as separate moderator variables, the moderation was shown up by a significant interaction effect in a disordinal and double-edged form. In our results, smoking-moderated protection for PD movement deficits emerged when PD was progressed. Among the affected deep brain nuclei, the nuclei most moderated by the impact of cigarette smoking on the interaction between brain iron and PD symptoms were the thalamus [smoking status associated with the Unified Parkinson's Disease Rating Scale (UPDRS) total score, P=0.04 (L); rigidity, P=0.03 (L); SI associated with UPDRS-III, P (L/R) =0.049/0.0497; rigidity, P (L/R) =0.01/0.02; bradykinesia, P (L/R) =0.048/0.04], the right red nucleus (SI associated with rigidity, P=0.04; bradykinesia, P=0.02), and the left SNc [smoking status associated with the Hoehn and Yahr (H&Y) stage, P=0.01]. This was the first study investigating the impacts of current cigarette smoking on PD using quantified iron deposition. Our study confirmed the protective role of cigarette smoking against PD, consistent with the findings of previous studies. Furthermore, neuroprotection was present only when the PD pathology had progressed to a certain extent. In the interaction between iron deposition and clinical PD symptoms, our findings suggest that the thalamus, red nucleus, and SNc are likely to be the most affected nuclei moderated by cigarette smoking.

Expression of BDNF-Associated lncRNAs in Parkinson's disease.

Decreased level of neurotrophic factor brain-derived neurotrophic factor (BDNF) has been supposed to participate in the pathoetiology of Parkinson's disease (PD). However, the underlying mechanisms of its dysregulation and the functional network between this factor and other transcripts have not been elucidated. In the current study, we measured expressions of BDNF, and four related long non-coding RNAs, namely BDNF-AS, MIR137HG, MIAT and PNKY in blood of PD patients and normal controls to find their expression levels in these patients and propose a possible mechanism for dysregulation of BDNF in PD patients. Notably, we detected down-regulation of all transcripts in the circulation of PD patients compared with controls. There was no significant difference in expression of either gene between male and female PD patients or patients receiving L-Dopa versus those receiving other drugs. Expression of none of genes was correlated with age, disease duration, disease stage, MMSE or UPDRS. Dynamic principal component analysis showed that expression levels of these genes almost clearly separated samples collected from healthy controls and PD patients into their respective groups. This suggests that the observed lncRNAs differences are associated with the pathophysiology of PD, and these lncRNAs might constitute an important biomarker signature for PD.

CSF and Serum Levels of Inflammatory Markers in PD: Sparse Correlation, Sex Differences and Association With Neurodegenerative Biomarkers.

BackgroundAn involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established.ObjectivesWe face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers?MethodsUsing a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aβ1−42, t-Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences.ResultsCorrelations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum.InterpretationLevels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system.

Prevalence, clinical presentations and impact on relationship of sexual dysfunction in Parkinson's Disease

Sexual dysfunction is one of the commonest non-motor symptoms in Parkinson's disease (PD) and has been found about twice as high in PD patients compared to age-matched controls. The quality of sexual life is reduced in PD patients compared to healthy peers and impairment affects wide aspects of physical sexual function as well as sexual desire, sexual satisfaction and sexual partnership. Overall, male PD patients are more frequently affected by sexual disorders than females and seem to suffer more from sexual impairment. The reported frequencies and presentations of various sexual dysfunctions vary widely in the literature, which is likely related to the patient cohorts examined, in particular with regard to age and gender, duration and severity of disease and applied measurement instruments. This chapter gives an overview of the prevalence, phenotype and clinical presentation of sexual dysfunction in PD and its influence on the partnership.

The VDR FokI (rs2228570) polymorphism is involved in Parkinson's disease

The etiology of Parkinson's disease (PD) is presumably multifactorial and likely involves interactions between genetic and environmental factors, as well as mitochondrial dysfunction, oxidative stress and inflammation. Among environmental factors, Vitamin D was reported to associate with the risk of PD. Vitamin D activity is mediated by its binding to the vitamin D Receptor (VDR), a transcriptional factor for almost 3% of human genes. We genotyped for ApaI, BsmI, TaqI, FokI and rs1989969 VDR single nucleotide polymorphisms (SNPs) a cohort of 406 PD and 800 healthy controls (HC) and found a strong association between the FokI (rs2228570) VDR SNP and PD. Thus, the TT genotype and the T allele resulted associated with PD in the overall analyzed PD population. Gender-based stratification of data indicated that results were maintained for FokI TT genotype and T allele in male PD patients, whereas the FokI T allele alone was confirmed as a risk factor for PD in females. Co-segregation analyses indicated the TaqI ApaI FokI rs1989969 GCTG as a “risk” haplotype for PD. In a subgroup of patients and controls neural Vitamin D and VDR concentration was analyzed in extravesicles (NDEVs) isolated from peripheral blood: no differences emerged between PD and HC. NDEVs results will need to be validated in ampler cohort but we can speculate that, if at neuronal level the amounts of Vitamin D and of VDR are comparable, than the bioavailability of vitamin D and the efficacy of the vitamin D/VDR axis is differentially modulated in PD by VDR SNPs.

A mitochondria-targeted caffeic acid derivative reverts cellular and mitochondrial defects in human skin fibroblasts from male sporadic Parkinson's disease patients

Parkinson's Disease (PD) is a neurodegenerative disorder affecting more than 10 million people worldwide. Currently, PD has no cure and no early diagnostics methods exist. Mitochondrial dysfunction is presented in the early stages of PD, and it is considered an important pathophysiology component. We have previously developed mitochondria-targeted hydroxycinnamic acid derivatives, presenting antioxidant and iron-chelating properties, and preventing oxidative stress in several biological models of disease. We have also demonstrated that skin fibroblasts from male sporadic PD patients (sPD) presented cellular and mitochondrial alterations, including increased oxidative stress, hyperpolarized and elongated mitochondria and decreased respiration and ATP levels. We also showed that forcing mitochondrial oxidative phosphorylation (OXPHOS) in sPD fibroblasts uncovers metabolic defects that were otherwise hidden. In this work, we tested the hypothesis that a lead mitochondria-targeted hydroxycinnamic acid derivative would revert the phenotype found in skin fibroblasts from sPD patients.Our results demonstrated that treating human skin fibroblasts from sPD patients with non-toxic concentrations of AntiOxCIN4 restored mitochondrial membrane potential and mitochondrial fission, decreased autophagic flux, and enhanced cellular responses to stress by improving the cellular redox state and decreasing reactive oxygen species (ROS) levels. Besides, fibroblasts from sPD patients treated with AntiOxCIN4 showed increased maximal respiration and metabolic activity, converting sPD fibroblasts physiologically more similar to their sex- and age-matched healthy controls. The positive compound effect was reinforced using a supervised machine learning model, confirming that AntiOxCIN4 treatment converted treated fibroblasts from sPD patients closer to the phenotype of control fibroblasts.Our data points out a possible mechanism of AntiOxCIN4 action contributing to a deeper understanding of how the use of mitochondria-targeted antioxidants based on a polyphenol scaffold can be used as potential drug candidates for delaying PD progression, validating the use of fibroblasts from sPD patients with more active OXPHOS as platforms for mitochondria-based drug development.

Association of CLU gene polymorphism with Parkinson's disease in the Chinese Han population.

Clusterin (CLU) plays important role in the pathology of neurodegenerative disorders. Recently, a genetic variant of CLU rs9331896 has been reported as a risk estimate for Alzheimer's disease (AD). However, the association between this variant and the risk of Parkinson's disease (PD) in the Chinese Han population remains elusive. We sequenced CLU rs9331896 in 353 PD patients and 326 healthy-matched individuals of the Chinese Han population. The genotypes of rs9331896 were analyzed using MassArray (Agena Bioscience, San Diego, CA, USA) in accordance with the manufacturer's instructions. The distribution of genotypes and allelic frequencies was analyzed by a chi-squared test. Additionally, the expression of CLU protein in plasma was evaluated by an enzyme-linked immunosorbent assay and analysed with a t-test. The TT genotype in rs9331896 in a recessive model was found to be associated with the increased risk of PD (odds ratio = 1.408, 95% confidence interval = 1.034-1.916, p = 0.029). Subgroup analysis indicated that TT genotype carriers showed a significantly higher risk in male PD patients compared to male healthy controls (odds ratio = 1.611, 95% confidence interval = 1.046-2.483, p = 0.030). In addition, CLU levels in the plasma of PD patients were significantly higher than controls (p = 0.024). The CLU-rs9331896-TT genotype was a risk factor for PD, particularly in males. PD patients also expressed a high level of CLU in plasma.

Can sex influence the neurocognition of language? Evidence from Parkinson's disease

Parkinson's disease (PD), which involves basal ganglia degeneration, affects language as well as motor function. However, which aspects of language are impaired in PD and under what circumstances remains unclear. We examined whether lexical and grammatical aspects of language are differentially affected in PD, and whether this dissociation is moderated by sex as well as the degree of basal ganglia degeneration. Our predictions were based on the declarative/procedural model of language. The model posits that grammatical composition, including in regular inflection, depends importantly on left basal ganglia procedural memory circuits, whereas irregular and other lexicalized forms are memorized in declarative memory. Since females tend to show declarative memory advantages as compared to males, the model further posits that females should tend to rely on this system for regulars, which can be stored as lexicalized chunks. We tested non-demented male and female PD patients and healthy control participants on the intensively studied paradigm of English regular and irregular past-tense production. Mixed-effects regression revealed PD deficits only at regular inflection, only in male patients. The degree of left basal ganglia degeneration, as reflected by right-side hypokinesia, predicted only regular inflection, and only in male patients. Left-side hypokinesia did not show this pattern. Past-tense frequency effects suggested that the female patients retrieved regular as well as irregular past-tense forms from declarative memory, whereas the males retrieved only irregulars. Sensitivity analyses showed that the pattern of findings was robust. The results, which are consistent with the declarative/procedural model, suggest a grammatical deficit in PD due to left basal ganglia degeneration, with a relative sparing of lexical retrieval. Female patients appear to compensate for this deficit by relying on chunks stored in declarative memory. More generally, the study elucidates the neurocognition of inflectional morphology and provides evidence that sex can influence how language is computed in the mind and brain.

Investigation on sleep and mental health of patients with Parkinson's disease during the Coronavirus disease 2019 pandemic

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic is adversely affecting sleep quality and mental health, especially in individuals with chronic disease such as Parkinson's disease (PD). MethodsWe conducted a quantitative study, which included 119 Chinese PD patients who had been treated in an outpatient neurology clinic in Wuhan and 169 age- and sex-matched healthy controls. The questionnaire survey focused on the impact of the COVID-19 pandemic on sleep, mental status, symptoms, and daily life and medical treatment of PD patients. ResultsCompared to healthy controls, PD patients had significantly higher scores in both the Pittsburgh Sleep Quality Index (PSQI) (8.13 vs 5.36, p < 0.001) and the Hospital Anxiety and Depression Scale (HADS) -Depression (4.89 vs 3.82, p = 0.022), as well as a higher prevalence of sleep disturbances with PSQI > 5 points (68.9% vs 44.4%, p < 0.001). Sleep disturbance was identified in 68.9% of PD patients. A logistic regression analysis showed that sleep disturbance of PD patients was independently associated with exacerbation of PD symptoms (OR = 3.616, 95%CI= (1.479, 8.844), p = 0.005) and anxiety (OR = 1.379, 95%CI= (1.157, 1.642), p < 0.001). Compared to male PD patients, female ones had higher PSQI scores (9.28 ± 4.41 vs 7.03 ± 4.01, p = 0.009) and anxiety (32.8% vs 0.1%, p = 0.002) and depression prevalence (34.5% vs 11.5%, p = 0.003). ConclusionThe findings of the present study emphasize the importance of mental and sleep health interventions in PD patients during the COVID-19 pandemic. Additional attention should be paid to the difficulty encountered by PD patients in seeking medical treatment.

Sacral Nerve Stimulation in Parkinson's Disease Patients With Overactive Bladder Symptoms

ObjectiveTo assess the efficacy, safety, and outcomes of sacral nerve stimulation (SNS) for Parkinson's disease (PD) patients with overactive bladder symptoms. MethodsWe retrospectively reviewed PD patients who underwent Stage I SNS. Demographics, urodynamic data, and baseline voiding function were analyzed. Efficacy and safety of treatment were determined by rate of progression to Stage II, explantation, and surgical revision. Long-term outcomes were assessed using voiding diaries and/or clinic notes. ResultsSixty percent (9/15) experienced ≥50% improvement in urinary parameters and proceeded to Stage II. There was no significant difference in age, body mass index, comorbidities, PD disease duration, or levodopa equivalent daily dose between successful and nonsuccessful Stage I patients. However, 100% of female patients experienced Stage I success compared to 44% of male PD patients (P = .04). Individuals with >12-month follow-up experienced an average reduction of 6 voids/day. No patients required revision or explantation of their device at latest clinic follow-up (22.2 ± 7.8 months). Higher maximal urethral closure pressures, detrusor pressure at maximum flow rate (PdetQmax), post-void residual volume, and mean bladder outlet obstruction index were observed in the Stage I trial failures. ConclusionAt our institution, PD patients have a similar rate of progression to Stage II compared to the general population. SNS is an effective therapy that should be considered among the treatment options for PD patients with overactive bladder symptoms. Urodynamic parameters associated with obstruction may be predictive of SNS failure in PD patients and may help guide patient selection, however further studies are needed.