Exploring Responsiveness to Highly Challenging Balance and Gait Training in Parkinson's Disease.

BACKGROUND: Exercise potentially improves gait, balance, and habitual physical activity in Parkinson's disease (PD). However, given the heterogeneous nature of the disease, it is likely that people respond differently to exercise interventions. Factors determining responsiveness to exercise interventions remain unclear. OBJECTIVES: To address this uncertainty, we explored the responsiveness to our highly challenging balance and gait intervention (HiBalance) in people with PD. METHODS: Thirty-nine participants with mild-moderate PD who underwent the HiBalance intervention from our randomized controlled trial were included. We defined response in three domains: (1) balance based on Mini-BESTest, (2) gait based on gait velocity, and (3) physical activity based on accelerometry-derived steps per day. In each domain, we explored three responsiveness levels: high, low, or non-responders according to the change from pre- to post-intervention. Separate Random Forests for each responder domain classified these responsiveness levels and identified variable importance. RESULTS: Only the Random Forest for the balance domain classified all responsiveness levels above the chance level indicated by a Cohen's kappa of "slight" agreement. Variable importance differed among the responsiveness levels. Slow gait velocity indicated high responders in the balance domain but showed low probabilities for low and non-responders. For low and non-responders, fall history or no falls, respectively, were more important. CONCLUSIONS: Among three responder domains and responsiveness levels, we could moderately classify responders in the balance domain, but not for the gait or physical activity domain. This can guide inclusion criteria for balance-targeted, personalized intervention studies in people with PD.

AOP Report: An Upstream Network for Reduced Androgen Signaling Leading to Altered Gene Expression of Androgen Receptor-Responsive Genes in Target Tissues.

Adverse outcome pathways (AOPs) can aid with chemical risk assessment by providing plausible links between chemical activity at the molecular level and effect outcomes in intact organisms. Because AOPs can be used to infer causality between upstream and downstream events in toxicological pathways, the AOP framework can also facilitate increased uptake of alternative methods and new approach methodologies to help inform hazard identification. However, a prevailing challenge is the limited number of fully developed and endorsed AOPs, primarily due to the substantial amount of work required by AOP developers and reviewers. Consequently, a more pragmatic approach to AOP development has been proposed where smaller units of knowledge are developed and reviewed independent of full AOPs. In this context, we have developed an upstream network comprising key events (KEs) and KE relationships related to decreased androgen signaling, converging at a nodal KE that can branch out to numerous adverse outcomes (AOs) relevant to androgen-sensitive toxicological pathways. Androgen signaling represents an extensively studied pathway for endocrine disruption. It is linked to numerous disease outcomes and can be affected by many different endocrine-disrupting chemicals. Still, pathways related to disrupted androgen signaling remain underrepresented in the AOP-wiki, and endorsed AOPs are lacking. Given the pivotal role of androgen signaling in development and function across vertebrate taxa and life stages of both sexes, this upstream AOP network serves as a foundational element for developing numerous AOPs. By connecting the upstream network with various downstream AOs, encompassing different species, it can also facilitate cross-species extrapolations for hazard and risk assessment of chemicals. Environ Toxicol Chem 2024;00:1-9. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Validation of fNIRS measurement of executive demand during walking with and without dual-task in younger and older adults and people with Parkinson's disease.

BACKGROUND: Walking with a concurrent cognitive task (dual-task walking) can pose a challenge to some populations due to aging or neurodegenerative disease. These tasks require cognitive resources involving the prefrontal cortex and can be studied using functional near-infrared spectroscopy (fNIRS). An important step in understanding fNIRS measures during such walking tasks is validating that measures reflect the demands of the tasks and not confounding sources or movement artifacts. AIM: This study aimed to investigate the validity of fNIRS measures of prefrontal cortex activity as an indicator of executive demand during usual walking (single-task) and dual-task walking against clinical and objective measures of motor behavior in young adults, older adults, and people with Parkinson's disease (PD), by evaluating several validation hypotheses. METHODS: In total, 133 participants were recruited from younger adults (18-50 years, n = 42), older adults (≥60 years, n = 49) and people with PD (≥60 years, n = 42). Activity in the prefrontal cortex during walking with and without an auditory Stroop task was measured with fNIRS. A combined hemoglobin measure (correlation-based signal improvement, CBSI) was calculated for use in a region of interest analysis in the dorsolateral prefrontal cortex (dlPFC). Pre-registered hypotheses regarding convergent validity, discriminant validity and known group validity were tested. An exploratory analysis of different hemoglobin measures was also performed. RESULTS: Increases in dlPFC activity were found from single- to dual-task walking in the younger adults group and from rest to single-task walking in the older adults and PD groups. In line with hypotheses, a positive relationship was found between between dlPFC activity during dual-task walking and dual-task cost in the younger adults group, as well as a positive relationship to step time variability during single-task walking and a negative relationship to walking speed during single-task walking in the PD group. However, several clinical and gait measures lacked a relationship with dlPFC activity. CONCLUSION: The fNIRS results point towards the CBSI measure of dlPFC activity being a valid measure of executive demand during both single and dual-task walking. Some relationships between clinical and gait measures and brain activity during walking need further investigation.

Enhanced identification of endocrine disruptors through integration of science-based regulatory practices and innovative methodologies: The MERLON Project.

The prevalence of hormone-related health issues caused by exposure to endocrine disrupting chemicals (EDCs) is a significant, and increasing, societal challenge. Declining fertility rates together with rising incidence rates of reproductive disorders and other endocrine-related diseases underscores the urgency in taking more action. Addressing the growing threat of EDCs in our environment demands robust and reliable test methods to assess a broad variety of endpoints relevant for endocrine disruption. EDCs also require effective regulatory frameworks, especially as the current move towards greater reliance on non-animal methods in chemical testing puts to test the current paradigm for EDC identification, which requires that an adverse effect is observed in an intact organism. Although great advances have been made in the field of predictive toxicology, disruption to the endocrine system and subsequent adverse health effects may prove particularly difficult to predict without traditional animal models. The MERLON project seeks to expedite progress by integrating multispecies molecular research, new approach methodologies (NAMs), human clinical epidemiology, and systems biology to furnish mechanistic insights and explore ways forward for NAM-based identification of EDCs. The focus is on sexual development and function, from foetal sex differentiation of the reproductive system through mini-puberty and puberty to sexual maturity. The project aims are geared towards closing existing knowledge gaps in understanding the effects of EDCs on human health to ultimately support effective regulation of EDCs in the European Union and beyond.

Investigating underlying brain structures and influence of mild and subjective cognitive impairment on dual-task performance in people with Parkinson's disease.

Cognitive impairment can affect dual-task abilities in Parkinson's disease (PD), but it remains unclear whether this is also driven by gray matter alterations across different cognitive classifications. Therefore, we investigated associations between dual-task performance during gait and functional mobility and gray matter alterations and explored whether these associations differed according to the degree of cognitive impairment. Participants with PD were classified according to their cognitive function with 22 as mild cognitive impairment (PD-MCI), 14 as subjective cognitive impairment (PD-SCI), and 20 as normal cognition (PD-NC). Multiple regression models associated dual-task absolute and interference values of gait speed, step-time variability, and reaction time, as well as dual-task absolute and difference values for Timed Up and Go (TUG) with PD cognitive classification. We repeated these regressions including the nucleus basalis of Meynert, dorsolateral prefrontal cortex, and hippocampus. We additionally explored whole-brain regressions with dual-task measures to identify dual-task-related regions. There was a trend that cerebellar alterations were associated with worse TUG dual-task in PD-SCI, but also with higher dual-task gait speed and higher dual-task step-time variability in PD-NC. After multiple comparison corrections, no effects of interest were significant. In summary, no clear set of variables associated with dual-task performance was found that distinguished between PD cognitive classifications in our cohort. Promising but non-significant trends, in particular regarding the TUG dual-task, do however warrant further investigation in future large-scale studies.

Building an adverse outcome pathway network for estrogen-, androgen- and steroidogenesis-mediated reproductive toxicity.

Introduction: Adverse Outcome Pathways (AOPs) can support both testing and assessment of endocrine disruptors (EDs). There is, however, a need for further development of the AOP framework to improve its applicability in a regulatory context. Here we have inventoried the AOP-wiki to identify all existing AOPs related to mammalian reproductive toxicity arising from disruption to the estrogen, androgen, and steroidogenesis modalities. Core key events (KEs) shared between relevant AOPs were also identified to aid in further AOP network (AOPN) development. Methods: A systematic approach using two different methods was applied to screen and search the entire AOP-wiki library. An AOPN was visualized using Cytoscape. Manual refinement was performed to remove AOPS devoid of any KEs and/or KERs. Results: Fifty-eight AOPs relevant for mammalian reproductive toxicity were originally identified, with 42 AOPs included in the final AOPN. Several of the KEs and KE relationships (KERs) described similar events and were thus merged to optimize AOPN construction. Sixteen sub-networks related to effects on hormone levels or hormone activity, cancer outcomes, male and female reproductive systems, and overall effects on fertility and reproduction were identified within the AOPN. Twenty-six KEs and 11 KERs were identified as core blocks of knowledge in the AOPN, of which 19 core KEs are already included as parameters in current OECD and US EPA test guidelines. Discussion: The AOPN highlights knowledge gaps that can be targeted for further development of a more complete AOPN that can support the identification and assessment of EDs.

Feasibility of a novel eHealth intervention for Parkinson's disease targeting motor-cognitive function in the home.

BACKGROUND: Parkinson's disease (PD) drastically affects motor and cognitive function, but evidence shows that motor-cognitive training improves disease symptoms. Motor-cognitive training in the home is scarcely investigated and eHealth methods can provide continual support for PD self-management. Feasibility testing is however required. OBJECTIVE: To assess the feasibility (i) Recruitment capability (ii) Acceptability and Suitability (iii) Demand and Safety of a home-based motor-cognitive eHealth exercise intervention in PD. METHODS: The 10-week intervention was delivered using the ExorLive® application and exercises were individually adapted and systematically progressed and targeted functional strength, cardiovascular fitness, flexibility, and motor-cognitive function. People with mild-to moderate PD were assessed before and after the intervention regarding; gait performance in single and dual-task conditions; functional mobility; dual-task performance; balance performance; physical activity level; health related quality of life and perceived balance confidence and walking ability; global cognition and executive function. Feasibility outcomes were continuously measured using a home-exercise diary and contact with a physiotherapist. Changes from pre- and post-intervention are reported descriptively. RESULTS: Fifteen participants (mean age 68.5 years) commenced and 14 completed the 10-week intervention. In relation to intervention Acceptability, 64% of the motor sessions and 52% of motor-cognitive sessions were rated as "enjoyable". Concerning Suitability, the average level of exertion (Borg RPE scale) was light (11-12). Adherence was high, with 86% of all (420) sessions reported as completed. No falls or other adverse events occurred in conjunction with the intervention. CONCLUSIONS: This motor-cognitive eHealth home exercise intervention for PD was safe and feasible in terms of Recruitment capability, Acceptability, Safety and Demand. The intensity of physical challenge needs to be increased before testing in an efficacy trial. TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT05027620).

Skating on thin ice? Mental health and well-being in women's ice hockey.

Objectives: First, to map the prevalence of symptoms of positive mental health, anxiety, depression and sleep difficulties, along with the coexistence of these symptoms, among players in the Swedish Women's Hockey League (SDHL). Second, to investigate relationships between these mental health symptoms and demographic variables (ie, age, injuries, dual careers), social support and psychological flexibility. Methods: Players from nine teams in SDHL (n=182; mean age 22.3±SD 4.8, range 16-35) participated in this cross-sectional study. An online survey, including validated self-assessment questionnaires, conducted data collection. The questionnaires were distributed just before the play-offs started in the 2022-2023 season. Mental health variables were presented as descriptive statistics, and associations were investigated through multivariate binary logistic regression analyses. Results: The response rate was 91%. Moderate or severe symptoms were reported among 29.7% for sleep difficulties, 20.9% for anxiety and 18.1% for depression. Nineteen per cent reported comorbidities. Sixty percent reported flourishing mental health. Lower psychological flexibility was associated with lower odds of flourishing mental health and higher odds of symptoms of anxiety, depression and sleep difficulties. Social support was associated with higher odds of flourishing mental health and lower odds of sleep difficulties. Conclusion: 6 of every 10 players reported not reaching the ideal state of mental health (ie, flourishing mental health without mental illness). Mental health symptoms were statistically significantly associated with psychological flexibility and social support, suggesting that these factors will be beneficial to consider when preventing mental illness and promoting mental health in this population.

Comparison of female rat reproductive effects of pubertal versus adult exposure to known endocrine disruptors.

A prevailing challenge when testing chemicals for their potential to cause female reproductive toxicity is the lack of appropriate toxicological test methods. We hypothesized that starting a 28-day in vivo toxicity study already at weaning, instead of in adulthood, would increase the sensitivity to detect endocrine disruptors due to the possibility of including assessment of pubertal onset. We compared the sensitivity of two rat studies using pubertal or adult exposure. We exposed the rats to two well-known human endocrine disruptors, the estrogen diethylstilbestrol (DES; 0.003, 0.012, 0.048 mg/kg bw/day) and the steroid synthesis inhibitor ketoconazole (KTZ; 3, 12, 48 mg/kg bw/day). Specifically, we addressed the impact on established endocrine-sensitive endpoints including day of vaginal opening (VO), estrous cyclicity, weights of reproductive organs and ovarian histology. After 28 days of exposure, starting either at weaning or at 9 weeks of age, DES exposure altered estrous cyclicity, reduced ovary weight as well as number of antral follicles and corpora lutea. By starting exposure at weaning, we could detect advanced day of VO in DES-exposed animals despite a lower body weight. Some endpoints were affected mainly with adult exposure, as DES increased liver weights in adulthood only. For KTZ, no effects were seen on time of VO, but adrenal and liver weights were increased in both exposure scenarios, and adult KTZ exposure also stimulated ovarian follicle growth. At first glance, this would indicate that a pubertal exposure scenario would be preferrable as timing of VO may serve as sensitive indicator of endocrine disruption by estrogenic mode of action. However, a higher sensitivity for other endocrine targets may be seen starting exposure in adulthood. Overall, starting a 28-day study at weaning with inclusion of VO assessment would mainly be recommended for substances showing estrogenic potential e.g., in vitro, whereas for other substances an adult exposure scenario may be recommended.

Design of the STEPS trial: a phase II randomized controlled trial evaluating eHealth-supported motor-cognitive home training for Parkinson's disease.

BACKGROUND: Electronic health (eHealth) technology offers the potential to support and motivate physical activity for symptom management in Parkinson's disease (PD). It is also recommended that motor exercise in PD be complemented with cognitive training aimed at attentional or executive functions. This paper describes the protocol for a double-blind randomized controlled trial to evaluate the effects of motor-cognitive training in the home environment, supported by eHealth. METHODS/DESIGN: The Support for home Training using Ehealth in Parkinsons diseaSe (STEPS) is a double-blind single center randomized controlled trial. Two parallel groups will include in total 120 participants with mild to moderate PD who will receive either (i) the intervention (a progressive 10-week individualized motor-cognitive eHealth training with cognitive behavioral elements to increase physical activity levels) or (ii) an active control group (an individualized 10-week paper-based home exercise program). The active control group will not receive motor-cognitive exercises or cognitive behavioral approaches to increase physical activity level. The primary outcome is walking capacity assessed by the six-minute walk test (6MWT). Secondary outcomes will include gait performance during single and dual task conditions, gait speed, functional mobility and lower limb strength, balance, physical activity behavior and a range of patient reported outcome measures relevant in PD. DISCUSSION: The STEPS trial will answer the question whether 10 weeks of eHealth supported motor-cognitive exercise in the home environment can improve walking capacity in PD when compared to a standard paper exercise program. Findings from this study will also strengthen the evidence concerning the efficacy of PD-specific eHealth interventions with a view meeting future health care demands by addressing issues of inaccessibility to specialized neurological rehabilitation in PD. TRIAL REGISTRATION: ClinicalTrials.gov August 2022, NCT05510739.

Quantitative analysis of ovarian surface photographs as a tool for assessment of chemical effects on folliculogenesis and ovulation in rats.

Female reproductive toxicity assessments rely on histological evaluation of ovaries by hematoxylin & eosin (H&E)-stained cross-sections. This is time-consuming, labor-intensive and costly, thus alternative methods for ovarian toxicity assessment could be valuable. Here, we report on an improved method based on quantification of antral follicles (AF) and corpora lutea (CL) using ovarian surface photographs, called 'surface photo counting' (SPC). To validate a potential utility for the method to detect effects on folliculogenesis in toxicity studies, we investigated ovaries from rats exposed to two well-known endocrine disrupting chemicals (EDCs), diethylstilbestrol (DES) and ketoconazole (KTZ). Animals were exposed to DES (0.003, 0.012, 0.048 mg/kg body weight (bw)/day) or KTZ (3, 12, 48 mg/kg bw/day) during puberty or adulthood. At the end of the exposure, ovaries were photographed under stereomicroscope and subsequently processed for histological assessments to allow for direct comparison between the two methods by quantifying AF and CL. There was a significant correlation between the SPC and histology methods, albeit CL counts correlated better than AF counts, potentially due to their larger size. Effects of DES and KTZ were found by both methods, suggesting applicability of the SPC method to chemical hazard and risk assessment. Based on our study, we propose that SPC can be employed as a fast and cheap tool for assessment of ovarian toxicity in in vivo studies to prioritize chemical exposure groups for further histological assessment.

The Swedish King's Parkinson's disease Pain Scale: Validation and pain prevalence in persons with mild-moderate severity Parkinson's disease.

OBJECTIVES: To examine convergent and divergent validity of the King's Parkinson's disease Pain Scale - Swedish translated version, and to determine the prevalence of pain according to scale domains in persons with Parkinson's disease. DESIGN: Cross-sectional, validation study. PATIENTS: Ninety-seven persons with Parkinson's disease. METHODS: The pain scale was translated into Swedish by an accredited company, and permission was granted to use the resultant version. Participants completed the rater-administered The King's Parkinson's disease Pain Scale - Swedish version, the visual analogue scale (pain), Parkinson's Disease Questionnaire (bodily discomfort subscale), MiniBESTest and Walk-12G. Spearman's rank correlation coefficient was used to assess the strength of associations. RESULTS: The mean (standard deviation) age of participants was 71 (6.1) years, 63% were male, and 76% presented with mild disease severity. The mean (standard deviation) The King's Parkinson's disease Pain Scale - Swedish version score was 7.84 (12.8). A strong (r = 0.65) and moderate (r = 0.45) association was found between the newly-translated version and visual analogue scale (pain) and Parkinson's Disease Questionnaire - bodily discomfort subscale, respectively. Weak associations were found between the newly translated version and divergent measures. Overall pain prevalence was 57%, with musculoskeletal pain being the most common, followed by chronic and radicular pain. CONCLUSION: This study affirms aspects of validity of the Swedish King's Parkinson's disease Pain Scale. Most participants presented with 1 or more types of pain, highlighting the need for targeted interventions.

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats.

Introduction: Estrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats. Design: Female rats were exposed to KTZ or DES during perinatal (DES 3-6-12µg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48µg/kg.d; KTZ 3-12-48mg/kg.d). Results: Ex vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with Ingenuity Pathway Analysis predicted "Creb signaling in Neurons" and "IGF-1 signaling" among the most downregulated pathways by all doses of KTZ and DES before puberty, and "PPARg" as a common upstream regulator driving gene expression changes. Deeper screening ofRNAseq datasets indicated that a high number of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood. Conclusion: nRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation.

Using functional near-infrared spectroscopy to measure prefrontal cortex activity during dual-task walking and navigated walking: A feasibility study.

INTRODUCTION: While functional near-infrared spectroscopy (fNIRS) can provide insight into motor-cognitive deficits during ecologically valid gait conditions, the feasibility of using fNIRS during complex walking remains unknown. We tested the process and scientific feasibility of using an fNIRS device to measure cortical activity during complex walking tasks consisting of straight walking and navigated walking under single and dual-task (DT) conditions. METHODS: Nineteen healthy people from 18 to 64 years (mean age: 45.7 years) participated in this study which consisted of three complex walking protocols: (i) straight walking, DT walking (walking while performing an auditory Stroop task) and single-task auditory Stroop, (ii) straight and navigated walking, and (iii) navigated walking and navigated DT walking. A rest condition (standing still) was also included in each protocol. Process feasibility outcomes included evaluation of the test procedures and participant experience during and after each protocol. Scientific feasibility outcomes included signal quality measures, and the ability to measure changes in concentration of deoxygenated and oxygenated hemoglobin in the prefrontal cortex. RESULTS: All participants were able to complete the three protocols with most agreeing that the equipment was comfortable (57.9%) and that the testing duration was adequate (73.7%). Most participants did not feel tired (94.7%) with some experiencing pain (42.1%) during the protocols. The signal qualities were high for each protocol. Compared to the rest condition, there was an increase in oxygenated hemoglobin in the prefrontal cortex when performing dual-task walking and navigation. CONCLUSION: We showed that our experimental setup was feasible for assessing activity in the prefrontal cortex with fNIRS during complex walking. The experimental setup was deemed acceptable and practicable. Signal quality was good during complex walking conditions and findings suggest that the different tasks elicit a differential brain activity, supporting scientific feasibility.

Effects of motor-cognitive training on dual-task performance in people with Parkinson's disease: a systematic review and meta-analysis.

Motor-cognitive training in Parkinson's disease (PD) can positively affect gait and balance, but whether motor-cognitive (dual-task) performance improves is unknown. This meta-analysis, therefore, aimed to establish the current evidence on the effects of motor-cognitive training on dual-task performance in PD. Systematic searches were conducted in five databases and 11 studies with a total of 597 people (mean age: 68.9 years; mean PD duration: 6.8 years) were included. We found a mean difference in dual-task gait speed (0.12 m/s (95% CI 0.08, 0.17)), dual-task cadence (2.91 steps/min (95% CI 0.08, 5.73)), dual-task stride length (10.12 cm (95% CI 4.86, 15.38)) and dual-task cost on gait speed (- 8.75% (95% CI - 14.57, - 2.92)) in favor of motor-cognitive training compared to controls. The GRADE analysis revealed that the findings were based on high certainty evidence. Thus, we can for the first time systematically show that people with PD can improve their dual-task ability through motor-cognitive training.

Transcriptional profiling of the developing rat ovary following intrauterine exposure to the endocrine disruptors diethylstilbestrol and ketoconazole.

Exposure to endocrine-disrupting chemicals (EDCs) during development may cause reproductive disorders in women. Although female reproductive endpoints are assessed in rodent toxicity studies, a concern is that typical endpoints are not sensitive enough to detect chemicals of concern to human health. If so, measured endpoints must be improved or new biomarkers of effects included. Herein, we have characterized the dynamic transcriptional landscape of developing rat ovaries exposed to two well-known EDCs, diethylstilbestrol (DES) and ketoconazole (KTZ), by 3' RNA sequencing. Rats were orally exposed from day 7 of gestation until birth, and from postnatal day 1 until days 6, 14 or 22. Three exposure doses for each chemical were used: 3, 6 and 12 µg/kg bw/day of DES; 3, 6, 12 mg/kg bw/day of KTZ. The transcriptome changed dynamically during perinatal development in control ovaries, with 1137 differentially expressed genes (DEGs) partitioned into 3 broad expression patterns. A cross-species deconvolution strategy based on a mouse ovary developmental cell atlas was used to map any changes to ovarian cellularity across the perinatal period to allow for characterization of actual changes to gene transcript levels. A total of 184 DEGs were observed across dose groups and developmental stages in DES-exposed ovaries, and 111 DEGs in KTZ-exposed ovaries across dose groups and developmental stages. Based on our analyses, we have identified new candidate biomarkers for female reproductive toxicity induced by EDC, including Kcne2, Calb2 and Insl3.

Exposure to the pesticides linuron, dimethomorph and imazalil alters steroid hormone profiles and gene expression in developing rat ovaries.

Inhibition of androgen signaling during critical stages of ovary development can disrupt folliculogenesis with potential consequences for reproductive function later in life. Many environmental chemicals can inhibit the androgen signaling pathway, which raises the question if developmental exposure to anti-androgenic chemicals can negatively impact female fertility. Here, we report on altered reproductive hormone profiles in prepubertal female rats following developmental exposure to three pesticides with anti-androgenic potential: linuron (25 and 50 mg/kg bw/d), dimethomorph (60 and 180 mg/kg bw/d) and imazalil (8 and 24 mg/kg bw/d). Dams were orally exposed from gestational day 7 (dimethomorph and imazalil) or 13 (linuron) until birth, then until end of dosing at early postnatal life. Linuron and dimethomorph induced dose-related reductions to plasma corticosterone levels, whereas imazalil mainly suppressed gonadotropin levels. In the ovaries, expression levels of target genes were affected by linuron and dimethomorph, suggesting impaired follicle growth. Based on our results, we propose that anti-androgenic chemicals can negatively impact female reproductive development. This highlights a need to integrate data from all levels of the hypothalamic-pituitary-gonadal axis, as well as the hypothalamic-pituitary-adrenal axis, when investigating the potential impact of endocrine disruptors on female reproductive development and function.

Unraveling Parkinson's disease heterogeneity using subtypes based on multimodal data.

BACKGROUND: Parkinson's disease (PD) is a clinically and neuroanatomically heterogeneous neurodegenerative disease characterized by different subtypes. To this date, no studies have used multimodal data that combines clinical, motor, cognitive and neuroimaging assessments to identify these subtypes, which may provide complementary, clinically relevant information. To address this limitation, we subtyped participants with mild-moderate PD based on a rich, multimodal dataset of clinical, cognitive, motor, and neuroimaging variables. METHODS: Cross-sectional data from 95 PD participants from our randomized EXPANd (EXercise in PArkinson's disease and Neuroplasticity) controlled trial were included. Participants were subtyped using clinical, motor, and cognitive assessments as well as structural and resting-state MRI data. Subtyping was done by random forest clustering. We extracted information about the subtypes by inspecting their neuroimaging profiles and descriptive statistics. RESULTS: Our multimodal subtyping analysis yielded three PD subtypes: a motor-cognitive subtype characterized by widespread alterations in brain structure and function as well as impairment in motor and cognitive abilities; a cognitive dominant subtype mainly impaired in cognitive function that showed frontoparietal structural and functional changes; and a motor dominant subtype impaired in motor variables without any brain alterations. Motor variables were most important for the subtyping, followed by gray matter volume in the right medial postcentral gyrus. CONCLUSIONS: Three distinct PD subtypes were identified in our multimodal dataset. The most important features to subtype PD participants were motor variables in addition to structural MRI in the sensorimotor region. These findings have the potential to improve our understanding of PD heterogeneity, which in turn can lead to personalized interventions and rehabilitation.

The impact of aerobic and resistance training intensity on markers of neuroplasticity in health and disease.

OBJECTIVE: To determine the effects of low- vs. high-intensity aerobic and resistance training on motor and cognitive function, brain activation, brain structure, and neurochemical markers of neuroplasticity and the association thereof in healthy young and older adults and in patients with multiple sclerosis, Parkinson's disease, and stroke. DESIGN: Systematic review and robust variance estimation meta-analysis with meta-regression. DATA SOURCES: Systematic search of MEDLINE, Web of Science, and CINAHL databases. RESULTS: Fifty studies with 60 intervention arms and 2283 in-analyses participants were included. Due to the low number of studies, the three patient groups were combined and analyzed as a single group. Overall, low- (g=0.19, p = 0.024) and high-intensity exercise (g=0.40, p = 0.001) improved neuroplasticity. Exercise intensity scaled with neuroplasticity only in healthy young adults but not in healthy older adults or patient groups. Exercise-induced improvements in neuroplasticity were associated with changes in motor but not cognitive outcomes. CONCLUSION: Exercise intensity is an important variable to dose and individualize the exercise stimulus for healthy young individuals but not necessarily for healthy older adults and neurological patients. This conclusion warrants caution because studies are needed that directly compare the effects of low- vs. high-intensity exercise on neuroplasticity to determine if such changes are mechanistically and incrementally linked to improved cognition and motor function.

Using alternative test methods to predict endocrine disruption and reproductive adverse outcomes: do we have enough knowledge?

Endocrine disrupting chemicals (EDCs) are a matter of great concern. They are ubiquitous in the environment, are considered harmful to humans and wildlife, yet remain challenging to identify based on current international test guidelines and regulatory frameworks. For a compound to be identified as an EDC within the EU regulatory system, a plausible link between an endocrine mode-of-action and an adverse effect outcome in an intact organism must be established. This requires in-depth knowledge about molecular pathways regulating normal development and function in animals and humans in order to elucidate causes for disease. Although our knowledge about the role of the endocrine system in animal development and function is substantial, it remains challenging to predict endocrine-related disease outcomes in intact animals based on non-animal test data. A main reason for this is that our knowledge about mechanism-of-action are still lacking for essential causal components, coupled with the sizeable challenge of mimicking the complex multi-organ endocrine system by methodological reductionism. Herein, we highlight this challenge by drawing examples from male reproductive toxicity, which is an area that has been at the forefront of EDC research since its inception. We discuss the importance of increased focus on characterizing mechanism-of-action for EDC-induced adverse health effects. This is so we can design more robust and reliable testing strategies using non-animal test methods for predictive toxicology; both to improve chemical risk assessment in general, but also to allow for considerable reduction and replacement of animal experiments in chemicals testing of the 21st Century.