Bidirectional Interplay between Deep Brain Stimulation and Cognition in Parkinson's Disease: A Systematic Review.

BACKGROUND: Deep brain stimulation (DBS) is efficacious for treating motor symptoms in Parkinson's disease (PD). OBJECTIVES: The aim is to evaluate the evidence regarding DBS effectiveness after postoperative cognitive deterioration, the impact of preoperative cognition on DBS effectiveness, and the impact of DBS on cognition. METHODS: Literature searches were performed on MEDLINE, EMBASE, and CENTRAL (Cochrane library). Primary outcomes were OFF-drug Unified Parkinson Disease Rating Scale Part III score and cognitive test scores. RESULTS: DBS effectiveness did not differ in patients with postoperative declining compared to stable cognition (n = 5 studies). Preoperative cognition did not influence DBS effectiveness (n = 1 study). DBS moderately decreased verbal fluency compared to the best medical treatment (n = 24 studies), which may be transient. CONCLUSION: DBS motor effectiveness in PD does not appear to be influenced by cognition. DBS in PD seems cognitively safe, except for a moderate decline in verbal fluency. Further research is warranted. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Quality of athlete screening for high-risk cardiovascular conditions-A systematic review.

BACKGROUND: Sudden cardiac death (SCD) is the leading medical cause of death in athletes. To prevent SCD, screening for high-risk cardiovascular conditions (HRCC) is recommended. Screening strategies are based on a limited number of studies and expert consensus. However, evidence and efficacy of athlete HRCC screening is unclear. OBJECTIVE: To determine methodological quality and quality of evidence of athlete screening, and screening efficacy to detect HRCC in a systematic review. METHODS: We performed a systematic search of Medline, Embase, Scopus and Cochrane Library up to June 2021. We included articles containing original data of athlete cardiovascular screening, providing details of screening strategies, test results and HRCC detection. We assessed methodological quality of the included articles by QUADAS-2, quality of evidence of athlete HRCC screening by GRADE, and athlete HRCC screening efficacy by SWiM. RESULTS: Of 2720 citations, we included 33 articles (1991-2018), comprising 82 417 athletes (26.7% elite, 73.4% competitive, 21.7% women, 75.2% aged ≤35). Methodological quality was 'very low' (33 articles), caused by absence of data blinding and inappropriate statistical analysis. Quality of evidence was 'very low' (33 articles), due to observational designs and population heterogeneity. Screening efficacy could not be reliably established. The prevalence of HRCC was 0.43% with false positive rate (FPR) 13.0%. CONCLUSIONS: Methodological quality and quality of evidence on athlete screening are suboptimal. Efficacy could not be reliably established. The prevalence of screen detected HRCC was very low and FPR high. Given the limitations of the evidence, individual recommendations need to be prudent.

Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment.

BACKGROUND: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. OBJECTIVES: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. METHODS: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. RESULTS: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. CONCLUSION: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.

Comparison of multiplex platforms for cytokine assessments and their potential use for biomarker profiling in multiple sclerosis.

BACKGROUND: The levels of pro and anti-inflammatory cytokines can be altered in different autoimmune pathologies, such as multiple sclerosis (MS). It is likely that cytokines in bodily fluids can provide a good reflection of ongoing disease patho-physiology. In this study we aimed to validate multiplex cytokine platforms and evaluate whether these cytokines are differentially expressed in MS. METHODS: Assay validation for simultaneous quantification of IL-1ß, IL-6, IL-8 and TNF-α in serum and CSF were performed using both the Luminex-xMAP (Luminex) and Meso Scale Discovery (MSD) platforms. Next, the relation of the pro-inflammatory cytokine 4-plex with disease progression, symptoms and subtypes was studied in paired serum and CSF of MS patients (n=56), and compared with healthy controls (n=203), with the use of the MSD-platform. RESULTS: The MSD-platform showed overall better assay characteristics such as, sensitivity, recovery and linearity compared to the Luminex for the 4-plex cytokines in CSF and serum. IL-6, IL-8 and TNF-α (p<0.001) levels were significantly increased in MS serum compared to healthy controls. Moreover, serum IL-1ß levels correlated with expanded disability status scale (EDSS) scores (r=-0.34, p<0.05). Additionally, IL-6 and IL-8 CSF levels were both significantly decreased in MS patients compared to non-inflammatory neurological disease controls. Noteworthy, higher IL-8 CSF levels than IL-8 serum levels were observed for MS patients, indicating intrathecal activation of macrophages in MS. CONCLUSION: We have demonstrated that the pro-inflammatory 4-plex kit of the MSD-platform shows better assay characteristics in comparison with Luminex kit for quantification of these cytokines in serum and CSF. Overall, the increased levels of IL-6, IL-8 and TNF-α in serum of MS patients compared to healthy controls, support the use of multiple cytokines for future MS biomarker and disease progression research.

How Information Affects Patients with Parkinson's Disease: A Scoping Review of the Literature.

Background: Patients with Parkinson's disease (PD) need to receive adequate information to manage their disease. However, little is known about how information provision affects patients. Objective: To conduct a scoping review of the literature on the relationship between content, timing, manner of delivery, and source of PD-specific information on the one hand, and patient outcomes on the other. Methods: All literature reporting about original data and published until April 2024 in peer-reviewed journals was searched in MEDLINE (Ovid), Embase (Ovid) and PsychInfo (Ovid). Subsequently, data were extracted and synthesized. Results: 40 publications describing the effects of information provision or patients' evaluation thereof were retrieved. Four categories of patient outcomes were described, namely 1) evaluation and experience of information provision; 2) physical functioning; 3) psychosocial well-being; and 4) quality of life. In intervention studies, patients generally valued the provided information. Findings from cross-sectional and qualitative studies showed the importance of tailoring information to individuals' needs and capabilities. Due to variation in study designs and outcomes, no unambiguous conclusions could be drawn regarding the relationship between information and outcomes. Conclusions: This scoping review identified how PD patients acquire information and revealed a lack of systematic research into the effect of information on patient outcomes. Future studies should assess 1) what information is currently provided by clinicians; 2) what additional information might be beneficial to provide; and 3) how information can be effectively aligned to benefit patients. This will eventually yield insight into how information might optimally empower PD patients.

Analysis of Serum Free Thyroxine Concentrations in Healthy Term Neonates Underlines Need for Local and Laboratory-Specific Reference Interval: A Systematic Review and Meta-Analysis of Individual Participant Data.

Background: Initial evaluation of the hypothalamus-pituitary-thyroid axis is done by measuring serum free thyroxine (fT4) and thyrotropin concentrations. For correct interpretation of these measurements, reliable age-specific reference intervals (RIs) are fundamental. Since neonatal fT4 RIs conforming to the Clinical and Laboratory Standards Institute guidelines are not available for all assays, we set out to create literature-based uniform age-specific neonatal fT4 RIs that may be used for every assay. Methods: For meta-analysis of individual participant fT4 concentrations, we systematically searched MEDLINE and Embase (search date December 6, 2023; PROSPERO registration CRD42016041871). We searched for studies reporting fT4 concentrations in healthy term newborns aged 2-27 days, born to mothers without thyroid disease in iodine-sufficient regions. Authors were invited to supply data. Due to standardization differences between assays, data could not be combined for meta-analysis directly, and we attempted to normalize the data using two distinct methods. Results: We obtained 4206 fT4 concentrations from 20 studies that used 13 different assays from 6 manufacturers. First, we set out to normalize fT4 data using the mean and standard deviation of (assay-specific) adult RIs. fT4 concentrations were transformed into Z-scores, assuming a normal distribution. Using a linear mixed-effects model (LMM), we still found a significant difference between fT4 concentration across studies (p < 0.001), after this normalization. As a second approach, we normalized the fT4 concentrations using data from a method/assay comparison study. We used the relationship between the Cobas assay and the other assays as a reference point to convert all values to Cobas values. However, this method also failed to produce consistent results, with significant differences between the normalized data (LMM p < 0.001). Conclusions: We conclude that our attempts at normalizing fT4 assay results were unsuccessful. Confounders related to our unsuccessful analysis may be assay related and/or biological. These findings have significant implications for patient care, since relying on RIs from literature may result in erroneous interpretation of results. Therefore, we strongly recommend to establish local RIs for accurate interpretation of serum fT4 concentrations in neonates.

Electrocardiographic and morphological cardiac remodeling in competitive female athletes - a scoping review.

AIMS: To quantitatively analyse exercise-induced cardiac remodeling (EICR) data in female athletes. METHODS: This scoping review included from the databases Medline, Embase, and Google Scholar, peer-reviewed original English-language articles on female athlete-populations aged ≥18 years containing data on electrocardiography (ECG), echocardiography or cardiac magnetic resonance (CMR), and excluded athletes with cardiovascular conditions. From the extracted ECG data, we calculated prevalence percentages, and from the imaging data we compared the results with the upper reference limits of the general female population (URL). RESULTS: We included 31 articles comprising 4,896 female athletes, aged mean 22.2±4.6 years. On ECG (n=889), most prevalent findings were increased QRS voltages for LV hypertrophy (LVH, n=97), J-point elevation (JPE, n=108), and T-wave inversion (TWI, n=104). On echocardiography (n=4,644), we found increased mean of means BSA-indexed volumes for the LV 67.3 mL/m2 (95%CI 66.8-67.8; URL=61) and right ventricle (RV) 82.7 mL/m2 (95%CI 79.5-86.0; URL=74), while atrial volumes, septal wall thickness and LV mass were within the upper reference limits of the general population (URL). On CMR (n=309), the mean of means volumes of LA (62.0 mL/m2, 95%CI 58.8-65.2; URL=61), LV (103.4 mL/m2, 95%Ci 101.8-105.0; URL=96), and RV (105.3 mL/m2, 95%CI 103.3-110.6; URL=107.2) were >URL. CONCLUSION: Female athletes demonstrate distinct features of electrical (increased QRS voltages for LVH, JPE and TWI) and morphological EICR (biventricular dilatation). On CMR, LA was borderline dilated. Extensive studies on female athletes are needed to understand sex specific EICR.

Prolonged and repetitive exercise induces changes in the heart, both electrical (as seen on the ECG) and in size and shape (as seen on echocardiography or cardiac magnetic resonance imaging. These changes may include wall thickening and increase in chamber volumes. These changes are well-described in male athletes, but not in female athletes. This review highlights the changes in the hearts of healthy female athletes including electrical signs of increased cardiac muscle mass and of altered electrical reloading, and shape changes that include increases in left and right sided chamber volumes with normal ventricular wall thickness and mass.

Challenges in multi-plex and mono-plex platforms for the discovery of inflammatory profiles in neurodegenerative diseases.

Pro and anti-inflammatory cytokines are involved in disease onset and pathophysiology of multiple sclerosis, Alzheimer's disease and Parkinson's disease. It is likely that panels of multiple cytokines provide a good reflection of disease status and can be used as biological markers in body fluids. Different multi-plex platforms, Luminex-xMAP and Meso Scale Discovery, are able to detect multiple analytes in the same sample at the same time. In this literature based review, we offer an overview of the multi-plex platforms and compare them with the golden standard ELISA in their ability to accurately and sensitively detect cytokines in cerebrospinal fluid (CSF) and blood (serum/plasma). The detectability and levels of cytokines in multiple sclerosis, Alzheimer's disease and Parkinson's disease are promising but also show discrepancies between studies. The current immuno-assays lack sensitivity for detection of various cytokines that have low concentrations of cytokines in CSF and blood, and therefore technical improvements are needed. With such improvements the use of large panels of cytokines as inflammatory profiles may offer additional value in diagnosis, prognosis and therapeutic response in neurodegenerative diseases.

Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis.

BACKGROUND: Blood glucose regulation in women with diabetes may change during and after menopause, which could be attributed, in part, to decreased estrogen levels. PURPOSE: To determine the effect of postmenopausal hormone therapy (HT) on HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering drugs in women with type 1 and women with type 2 diabetes. DATA SOURCES: We conducted a systematic search of MEDLINE, Embase, Scopus, the Cochrane Library, and the ClinicalTrials.gov registry to identify randomized controlled trials (RCTs). STUDY SELECTION: We selected RCTs on the effect of HT containing estrogen therapy in postmenopausal women (≥12 months since final menstrual period) with type 1 or type 2 diabetes. DATA EXTRACTION: Data were extracted for the following outcomes: HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering medication. DATA SYNTHESIS: Nineteen RCTs were included (12 parallel-group trials and 7 crossover trials), with a total of 1,412 participants, of whom 4.0% had type 1 diabetes. HT reduced HbA1c (mean difference -0.56% [95% CI -0.80, -0.31], -6.08 mmol/mol [95% CI -8.80, -3.36]) and fasting glucose (mean difference -1.15 mmol/L [95% CI -1.78, -0.51]). LIMITATIONS: Of included studies, 50% were at high risk of bias. CONCLUSIONS: When postmenopausal HT is considered for menopausal symptoms in women with type 2 diabetes, HT is expected to have a neutral-to-beneficial impact on glucose regulation. Evidence for the effect of postmenopausal HT in women with type 1 diabetes was limited.

Effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation on offspring outcomes: a systematic review of the evidence.

Aims/hypothesis: Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation. Methods: We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17th 2023 and the Teratology Information Service (TIS) of Switzerland on February 6th 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion. Results: We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available. Conclusion/interpretation: We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies. Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.