Search Results (39)

Background/Objectives: Overall priorities of the international pediatric-onset spinal cord injury (SCI) population are unknown. The purpose was to describe and compare Life and Health (L&H) domain overall priorities of European youth with SCI and their parents and caregivers (P&C). Methods: A survey with a cross-sectional design, prepared by the PEPSCI Collaboration, was conducted in six European countries. In total, 202 participants, including youth with SCI (n = 101) and their P&C (n = 101), were included. Overall priorities were calculated based on unhappiness, importance, and research. Results: The sample included youth aged 8–12 years (30.7%) and 13–25 years (69.3%; 38.6% 13–17-year-olds and 30.7% youth aged 18–25 years), in addition to their P&C. The top three L&H priorities highlighted by P&C of the youth aged 8–12 years were “bladder” function (78%), “leg/foot movement” (77%), or “bowel” function (74%), compared with “leg/foot movement” (79%), “sit-to-stand” (76%), or “walking/ability to move” (75%) reported by P&C of the youth aged 13–25 years. The youth aged 13–25 years considered “leg/foot movement” (68%), “bowel” (66%), or “bladder” function (65%) as priorities. The top 10 priorities highlighted by the youth aged 13–25 years compared to the top 10 priorities rated by P&C were issues related to “personal needs”. Nevertheless, “pressure injuries”, “pain”, “bowel function”, or “mobility in the community” were highlighted as top preferences of priorities for the youth aged 13–25 years compared to their P&C. Conclusions: Adolescents/young adults highlighted health domain priorities compared with their P&C, who equally considered L&H domains. Life domains, which were previously unaddressed, were highlighted by P&C, including “adulthood expectations” and “parenthood expectations”. This survey will promote the involvement of stakeholders for comprehensive rehabilitation management for this population. Full article

Endometrial disorders, such as infertility and endometriosis, significantly impact reproductive health, thus necessitating better models to study endometrial function. Current in vitro models fail to replicate the complexity of the human endometrium throughout the entire menstrual cycle. This study aimed to assess the physiological response of human endometrial organoids (hEOs) to in vitro hormonal treatments designed to mimic the hormonal fluctuations of the menstrual cycle. Endometrial biopsies from three healthy women were used to develop hEOs, which were treated over 28 days with three hormonal stimulation strategies: (1) estrogen only (E) to mimic the proliferative phase, (2) the addition of progesterone (EP) to simulate the secretory phase, and (3) the further addition of cAMP (EPC) to enhance the secretory functions of hEOs. Gene and protein expression were analyzed using qPCR, IHC, and ELISA. The hEOs exhibited proliferation, gland formation, and appropriate expression of markers such as E-cadherin and Ki67. The hormonal treatments induced significant changes in PR, HSD17B1, PAEP, SPP1, and other genes relevant to endometrial function, closely mirroring in vivo physiological responses. The prominent changes were observed in EPC-treated hEOs (week 4) with significantly high expression of uterine milk components such as glycodelin (PAEP) and osteopontin (SPP1), reflecting mid- to late-secretory phase physiology. This model successfully recapitulates human menstrual cycle dynamics and offers a promising platform for studying endometrial disorders and advancing personalized treatments in gynecology. Full article

Glial cell line-derived neurotrophic factor (GDNF) is among the strongest dopamine neuron function- and survival-promoting factors known. Due to this reason, it has clinical relevance in dopamine disorders such as Parkinson’s disease and schizophrenia. In the striatum, GDNF is exclusively expressed in interneurons, which make up only about 0.6% of striatal cells. Despite clinical significance, histological analysis of striatal GDNF system arborization and relevance to incoming dopamine axons, which bear its receptor RET, has remained enigmatic. This is mainly due to the lack of antibodies able to visualize GDNF- and RET-positive cellular processes; here, we overcome this problem by using knock-in marker alleles. We find that GDNF neurons chemoattract RET+ axons at least seven times farther in distance than medium spiny neurons (MSNs), which make up 95% of striatal neurons. Furthermore, we provide evidence that tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, is enriched towards GDNF neurons in the dopamine axons. Finally, we find that GDNF neuron arborizations occupy approximately only twelve times less striatal volume than 135 times more abundant MSNs. Collectively, our results improve our understanding of how endogenous GDNF affects striatal dopamine system function. Full article

As little evidence is available, we report the oral health of neurogeriatric inpatients and the association with hematological parameters representing systemic health. We performed a cross-sectional investigation of 30 patients undergoing neurogeriatric early rehabilitation and excluded systemic inflammation as a trigger for oral infection (C-reactive protein >5 mg/dL). Outcomes included oral health and hygiene status and routine laboratory parameters. Patients (mean age 79 ± 6 years, mean comorbidities 7 ± 3, and mean Barthel Index at hospital admission 31 ± 18) had impaired oral health (mean 18 ± 7 of their own teeth, elevated plaque indices (2.5 ± 0.4), and bleeding on probing (26 ± 17)), representing short- and long-term reduced oral hygiene. Twenty-four (80%) patients had periodontitis. Laboratory parameters for inflammation, nutrition, and anemia did not correlate with oral health parameters (p > 0.05). The number of teeth correlated moderately with total protein (Spearman’s rank correlation coefficient (r_s) = 0.524; p = 0.003). Plaque indices correlated weakly with number of teeth (r_s = −0.460; p = 0.010) and periodontitis diagnosis (r_s = 0.488; p = 0.006). Thus, highly vulnerable neurogeriatric inpatients had reduced oral health and hygiene independent of laboratory parameters, representing a high-risk population for oral health problems even without clinically proven systemic infection. This should be considered in future interprofessional therapy planning. Full article

At the time of diagnosis, Alzheimer’s disease (AD) patients already suffer from significant neuronal loss. The identification of proteins that influence disease progression before the onset of symptoms is thus an essential part of the development of new effective drugs and biomarkers. Here, we used an unbiased ¹⁸O labelling proteomics approach to identify proteins showing altered levels in the AD brain. We studied the relationship between the protein with the highest increase in hippocampus, DEAD box Helicase 24 (DDX24), and AD pathology. We visualised DDX24 in the human brain and in a mouse model for Aβ42-induced AD pathology—App^NL-F—and studied the interaction between Aβ and DDX24 in primary neurons. Immunohistochemistry in the AD brain confirmed the increased levels and indicated an altered subcellular distribution of DDX24. Immunohistochemical studies in App^NL-F mice showed that the increase of DDX24 starts before amyloid pathology or memory impairment is observed. Immunocytochemistry in App^NL-F primary hippocampal neurons showed increased DDX24 intensity in the soma, nucleus and nucleolus. Furthermore, siRNA targeting of DDX24 in neurons decreased APP and Aβ42 levels, and the addition of Aβ42 to the medium reduced DDX24. In conclusion, we have identified DDX24 as a protein with a potential role in Aβ-induced AD pathology. Full article

Background: Dynamic technological development and its enormous impact on modern societies are posing new challenges for 21st-century neuroscience. A special place is occupied by technologies based on virtual reality (VR). VR tools have already played a significant role in both basic and clinical neuroscience due to their high accuracy, sensitivity and specificity and, above all, high ecological value. Objective: Being in a digital world affects the functioning of the body as a whole and its individual systems. The data obtained so far, both from experimental and modeling studies, as well as (clinical) observations, indicate their great and promising potential, but apart from the benefits, there are also losses and negative consequences for users. Methods: This review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework across electronic databases (such as Web of Science Core Collection; PubMed; and Scopus, Taylor & Francis Online and Wiley Online Library) to identify beneficial effects and applications, as well as adverse impacts, especially on brain health in human neuroscience. Results: More than half of these articles were published within the last five years and represent state-of-the-art approaches and results (e.g., 54.7% in Web of Sciences and 63.4% in PubMed), with review papers accounting for approximately 16%. The results show that in addition to proposed novel devices and systems, various methods or procedures for testing, validation and standardization are presented (about 1% of articles). Also included are virtual developers and experts, (bio)(neuro)informatics specialists, neuroscientists and medical professionals. Conclusions: VR environments allow for expanding the field of research on perception and cognitive and motor imagery, both in healthy and patient populations. In this context, research on neuroplasticity phenomena, including mirror neuron networks and the effects of applied virtual (mirror) tasks and training, is of interest in virtual prevention and neurogeriatrics, especially in neurotherapy and neurorehabilitation in basic/clinical and digital neuroscience. Full article

This study explored the physical, social, and psychological benefits of an active rehabilitation (AR) camp as experienced by participants with spinal cord injury (SCI), and perceived fitness and mastery of being physically active six months after the camp. The study used a mixed-method design with pre- (n = 23), post- (n = 23), and follow-up questionnaires (n = 18) and individual interviews (n = 8). Fuzzy qualitative comparative analysis (fsQCA) was used to analyze the quantitative data and qualitative content analysis was used to analyze the qualitative data. Results showed that benefits were mainly experienced in the social and psychological domains. As for the physical domain, younger and more recently injured persons with tetraplegia reported more benefits. Six months after the camp, being in the preparation stage of change and being somewhat physically active were necessary and sufficient conditions for experiencing mastery of physical activity regardless of injury type, but only persons with paraplegia experienced fitness benefits. Qualitative data shed further light on the perceived benefits of the camp. The knowledge gained from this study might help practitioners to tailor interventions to individual needs and researchers to ask questions that take into consideration the complexity of active rehabilitation and changes in physical activity behavior for people with SCI. Full article

Incorporating and sustaining engaging everyday activities (EEAs) in everyday life holds potential for improving health and wellbeing; thus, there is reason to explore EEAs as a behavioral change technique in stroke prevention. The aim of this study was to evaluate the feasibility of the stroke prevention program Make My Day (MMD) for people with moderate-to-high risk for stroke in a primary healthcare setting, where EEAs are utilized to promote healthy activity patterns. A randomized controlled pilot trial was designed to evaluate the feasibility of MMD. Twenty-nine persons at risk for stroke were recruited and randomized into either an intervention group (n = 14) receiving MMD or a control group (n = 15) receiving brief health advice and support with goal setting. The results suggest that MMD is feasible, with timely recruitment, overall high response rates and study completion, and sensitivity to change in key outcome measures. Moreover, the results demonstrate that the application of EEAs can be useful for promoting behavioral change in stroke prevention. Recommendations for improvements for a full-scale trial include recruiting a relevant sample, using reliability- and validity-tested outcome measures, and implementing strategies to limit missing data. Full article

The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on Gdnf and its receptors, Gfra1 and Ret, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases Gdnf expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors Gfra1 and Ret. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists. Full article

The accumulation and aggregation of alpha-synuclein (α-Syn) are pathological processes associated with Parkinson’s disease, indicating that the regulation of protein is a crucial etiopathological mechanism. Interestingly, human serum and cerebrospinal fluid contain autoantibodies that recognize α-Syn. This potentially demonstrates an already existing, naturally decomposing, and protective system. Thus, quantitative or qualitative alterations, such as the modified antigen binding of so-called naturally occurring autoantibodies against α-Syn (nAbs-α-Syn), may induce disease onset and/or progression. We investigated the serum titers and binding characteristics of nAbs-α-Syn in patients suffering from sporadic Parkinson’s disease (n = 38), LRRK2 mutation carriers (n = 25), and healthy controls (n = 22). Methods: Titers of nAbs-α-Syn were assessed with ELISA and binding affinities and kinetics with SPR. Within the patient cohort, we discriminated between idiopathic and genetic (LRRK2-mutated) variants. Results: ELISA experiments revealed no significant differences in nAbs-α-Syn serum titers among the three cohorts. Moreover, the α-Syn avidity of nAbs-α-Syn was also unchanged. Conclusions: Our findings indicate that nAbs-α-Syn concentrations or affinities in healthy and diseased persons do not differ, independent of mutations in LRRK2. Full article

The introduction of anti-amyloid monoclonal antibodies against Alzheimer’s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect can possibly increase over time, there is still a need for alternative treatments that will improve cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease-modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons, or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells, and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1/2, showed a neuroprotective effect against amyloid-beta or energy-deprivation-induced neurotoxicity, and increased the levels of brain-derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase in BDNF in the brains of 21 months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect, which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD. Full article

Background: The endocannabinoid system (ECS) and associated lipid transmitter-based signaling systems play an important role in modulating brain neuroinflammation. ECS is affected in neurodegenerative disorders, such as Alzheimer’s disease (AD). Here we have evaluated the non-psychotropic endocannabinoid receptor type 2 (CB2) and lysophosphatidylinositol G-protein-coupled receptor 55 (GPR55) localization and expression during Aβ-pathology progression. Methods: Hippocampal gene expression of CB2 and GPR55 was explored by qPCR analysis, and brain distribution was evaluated by immunofluorescence in the wild type (WT) and APP knock-in App^NL-G-F AD mouse model. Furthermore, the effects of Aβ42 on CB2 and GPR55 expression were assessed in primary cell cultures. Results: CB2 and GPR55 mRNA levels were significantly upregulated in App^NL-G-F mice at 6 and 12 months of age, compared to WT. CB2 was highly expressed in the microglia and astrocytes surrounding the Aβ plaques. Differently, GPR55 staining was mainly detected in neurons and microglia but not in astrocytes. In vitro, Aβ42 treatment enhanced CB2 receptor expression mainly in astrocytes and microglia cells, whereas GPR55 expression was enhanced primarily in neurons. Conclusions: These data show that Aβ pathology progression, particularly Aβ42, plays a crucial role in increasing the expression of CB2 and GPR55 receptors, supporting CB2 and GPR55 implications in AD. Full article

Cocaine addiction is a serious condition with potentially lethal complications and no current pharmacological approaches towards treatment. Perturbations of the mesolimbic dopamine system are crucial to the establishment of cocaine-induced conditioned place preference and reward. As a potent neurotrophic factor modulating the function of dopamine neurons, glial cell line-derived neurotrophic factor (GDNF) acting through its receptor RET on dopamine neurons may provide a novel therapeutic avenue towards psychostimulant addiction. However, current knowledge on endogenous GDNF and RET function after the onset of addiction is scarce. Here, we utilized a conditional knockout approach to reduce the expression of the GDNF receptor tyrosine kinase RET from dopamine neurons in the ventral tegmental area (VTA) after the onset of cocaine-induced conditioned place preference. Similarly, after establishing cocaine-induced conditioned place preference, we studied the effect of conditionally reducing GDNF in the ventral striatum nucleus accumbens (NAc), the target of mesolimbic dopaminergic innervation. We find that the reduction of RET within the VTA hastens cocaine-induced conditioned place preference extinction and reduces reinstatement, while the reduction of GDNF within the NAc does the opposite: prolongs cocaine-induced conditioned place preference and increases preference during reinstatement. In addition, the brain-derived neurotrophic factor (BDNF) was increased and key dopamine-related genes were reduced in the GDNF cKO mutant animals after cocaine administration. Thus, RET antagonism in the VTA coupled with intact or enhanced accumbal GDNF function may provide a new approach towards cocaine addiction treatment. Full article

Clinical gait analysis has a long-standing tradition in biomechanics. However, the use of kinematic data or segment coordination has not been reported based on wearable sensors in “real-life” environments. In this work, the skeletal kinematics of 21 healthy and 24 neurogeriatric participants was collected in a magnetically disturbed environment with inertial measurement units (IMUs) using an accelerometer-based functional calibration method. The system consists of seven IMUs attached to the lower back, the thighs, the shanks, and the feet to acquire and process the raw sensor data. The Short Physical Performance Battery (SPPB) test was performed to relate joint kinematics and segment coordination to the overall SPPB score. Participants were then divided into three subgroups based on low (0–6), moderate (7–9), or high (10–12) SPPB scores. The main finding of this study is that most IMU-based parameters significantly correlated with the SPPB score and the parameters significantly differed between the SPPB subgroups. Lower limb range of motion and joint segment coordination correlated positively with the SPPB score, and the segment coordination variability correlated negatively. The results suggest that segment coordination impairments become more pronounced with a decreasing SPPB score, indicating that participants with low overall SPPB scores produce a peculiar inconsistent walking pattern to counteract lower extremity impairment in strength, balance, and mobility. Our findings confirm the usefulness of SPPB through objectively measured parameters, which may be relevant for the design of future studies and clinical routines. Full article

Although SRPKs were discovered nearly 30 years ago, our understanding of their mode of regulation is still limited. Regarded as constitutively active enzymes known to participate in diverse biological processes, their prominent mode of regulation mainly depends on their intracellular localization. Molecular chaperones associate with a large internal spacer sequence that separates the bipartite kinase catalytic core and modulates the kinases’ partitioning between the cytoplasm and nucleus. Besides molecular chaperones that function as anchoring proteins, a few other proteins were shown to interact directly with SRPK1, the most-studied member of SRPKs, and alter its activity. In this study, we identified TAF15, which has been involved in transcription initiation, splicing, DNA repair, and RNA maturation, as a novel SRPK1-interacting protein. The C-terminal RGG domain of TAF15 was able to associate with SRPK1 and downregulate its activity. Furthermore, overexpression of this domain partially relocalized SRPK1 to the nucleus and resulted in hypophosphorylation of SR proteins, inhibition of splicing of a reporter minigene, and inhibition of Lamin B receptor phosphorylation. We further demonstrated that peptides comprising the RGG repeats of nucleolin, HNRPU, and HNRNPA2B1, were also able to inhibit SRPK1 activity, suggesting that negative regulation of SRPK1 activity might be a key biochemical property of RGG motif-containing proteins. Full article