Search Results (3,320)

Background: The influence of gait speed on lower-extremity coordination while walking in people with Parkinson’s disease (pwPD) is poorly understood. This study sought to investigate the relationship between gait speed and hip–knee coordination and coordination variability in older adults and pwPD. Methods: A total of 27 pwPD and 21 healthy older adults were recruited. Participants walked in a straight line at slow, preferred, and fast walking speeds. Gait data were collected using inertial measurement units, and the kinematics of the hip and knee were calculated. Coordination and coordination variability at the hip–knee joint pair were determined using continuous relative phase. A repeated measures two-way ANCOVA tested the impact of gait speed on coordination and coordination variability, while group differences were evaluated using statistical parametric mapping (SPM). Results: Neither the healthy older adults nor the pwPD adjusted their hip–knee coordination in response to changes in gait speed. pwPD also displayed a trend towards restricted hip and knee joint excursion compared to older adults, which may further limit their ability to adapt gait strategies. Conclusions: These findings suggest that interventions addressing both joint excursion and motor adaptability may be important for improving gait function in individuals with Parkinson’s disease. Real-world applicability can be found in the potential of wearable sensors to become a valuable tool in routine clinical practice for both diagnosis and ongoing management. Trial registration: The study is registered in the German Clinical Trials Register (DRKS00022998). Full article

Nucleocytoplasmic transport is crucial for neuronal cell physiology and defects are involved in neurodegenerative diseases like amyotrophic lateral sclerosis and Alzheimer’s disease, but also in ageing. Recent studies have suggested, that the classic nuclear import factor adapters KPNA3 (also named importin alpha4) and KPNA4 (also named importin alpha3) could be associated with the development of motor neuron diseases, a condition specifically affecting the neurons projecting from brain to spinal cord or from spinal cord to the muscles. Here we set out to analyze the neuronal function of mice deficient in KPNA3 (Kpna3-KO) or KPNA4 (Kpna4-KO). The motoric abilities and locomotion at different time points in ageing were tested to study the role of these two genes on motor neuron function. While we did not find deficits related to motor neurons in both mouse models, we discovered a hypermotoric phenotype in KPNA4-deficient mice. Attention deficit/hyperactivity disorder (ADHD) is caused by a combination of genetic, environmental and neurobiological factors and a number of genes have been suggested in genome-wide association studies to contribute to ADHD, including KPNA4. Here we provide supportive evidence for KPNA4 as a candidate pathogenic factor in ADHD, by analysing Kpna4-KO mice which show ADHD-like symptoms. Full article

This publication aims to present the preliminary results of research on an innovative device designed to support the rehabilitation of drivers with neurological disorders, developed as part of a multidisciplinary project. The device was designed for individuals recovering from neurological diseases, injuries, and COVID-19-related complications, who experience difficulties with coordination and the speed of performing motor exercises. Its goal is to improve the quality of life for patients and increase their chances of safely driving vehicles, which also contributes to the safety of all road users. The device allows for controlled upper limb exercises using a diagnostic module, exercise program, and biofeedback system. The main component is a mechatronic driving simulator, enhanced with dedicated software to support the rehabilitation of individuals with neurological disorders and older adults. Through driving simulations and rehabilitation tasks, patients perform exercises that improve their health, facilitating a faster recovery. The innovation of the solution is confirmed by a submitted patent application, and preliminary research results indicate its effectiveness in rehabilitation and improving mobility for individuals with neurological disorders. Full article

Clinicopathological studies and the effectiveness of dopaminergic replacement therapy establish that dopamine loss is the key pathology causing motor symptoms in Parkinson’s disease. The dopamine neurons that are impaired in Parkinson’s disease reside in the substantia nigra and ventral tegmental area in the midbrain. These neurons project into the striatum, where dopamine axons bifurcate repeatedly and form dense axon networks (the striatum is separated into the caudate nucleus and putamen by the internal capsule). Midbrain dopamine neurons also innervate many other areas of the brain, including the cerebral cortex. Therefore, there are preclinical and clinical studies investigating extrastriatal dopamine mechanisms in motor control and Parkinson’s disease pathophysiology and treatment. While extrastriatal dopamine can contribute, this contribution needs to be compared with the contribution of the striatal dopamine system. An isolated view of the extrastriatal dopamine system is like examining only the ear of an elephant and may lead to distorted assessments for preclinical and clinical research and diagnostic work. Thus, photographs of the whole brain dopamine system are important. For these reasons, we photographed the dopamine systems in whole mouse brain sagittal sections, showing clearly that, under identical imaging conditions, dopamine innervation is highly concentrated and intense in the striatum but sparse and weak in the cerebral cortex. Full article

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann–Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases. Full article

Background/Objectives: Technological approaches for the objective, quantitative assessment of motor functions have the potential to improve the medical management of people with Parkinson’s disease (PwPD), offering more precise, data-driven insights to enhance diagnosis, monitoring, and treatment. Markerless motion capture (MMC) is a promising approach for the integration of biomechanical analysis into clinical practice. The aims of this project were to evaluate a commercially available MMC system, develop and validate a custom MMC data processing algorithm, and evaluate the effectiveness of the algorithm in discriminating fine motor performance between PwPD and healthy controls (HCs). Methods: A total of 58 PwPD and 25 HCs completed finger-tapping assessments, administered and recorded by a self-worn augmented reality headset. Fine motor performance was evaluated using the headset’s built-in hand tracking software (Native-MMC) and a custom algorithm (CART-MMC). Outcomes from each were compared against a gold-standard motion capture system (Traditional-MC) to determine the equivalence. Known-group validity was evaluated using CART-MMC. Results: A total of 82 trials were analyzed for equivalence against the Traditional-MC, and 152 trials were analyzed for known-group validity. The CART-MMC outcomes were statistically equivalent to Traditional-MC (within 5%) for tap count, frequency, amplitude, and opening velocity metrics. The Native-MMC did not meet equivalence with the Traditional-MC, deviating by an average of 24% across all outcomes. The CART-MMC captured significant differences between PwPD and HCs for tapping amplitude, amplitude variability, frequency variability, finger opening and closing velocities, and their respective variabilities, and normalized path length. Conclusions: The biomechanical data gathered using a commercially available augmented reality device and analyzed via a custom algorithm accurately characterize fine motor performance in PwPD. Full article

Background: The retina plays a vital role in vision, and its impairment can cause significant visual deficits. Current retinal disease treatments range from conventional anti-inflammatory drugs to advanced anti-VEGF therapies and monoclonal antibodies. TnP, a novel synthetic peptide in preclinical development, has demonstrated therapeutic potential in chronic inflammatory conditions such as multiple sclerosis and asthma due to its immunomodulatory properties. Using zebrafish—which share significant genetic homology with humans—we investigated TnP’s effects on retinopathy models mimicking diabetic retinopathy (DR) through either cobalt chloride (CoCl₂)-induced hypoxia or light-induced retinal damage (LIRD). Methods: We employed two retinal injury models (CoCl₂-induced hypoxia and LIRD) and subjected them to TnP treatment, assessing the outcomes through visual–motor response testing and histological examination. Results: CoCl₂ exposure impaired swimming activity, while light damage reduced the movement distance. Both models induced distinct retinal morphological changes. Although TnP failed to reverse most injury effects, it specifically restored the inner plexiform layer (IPL)’s thickness. Conclusions: Our findings suggest that TnP may enhance neuronal plasticity by promoting cell proliferation and synaptic connectivity. While showing promise as a therapeutic candidate for retinal and neurodegenerative disorders, TnP might achieve optimal efficacy when combined with complementary treatments. Full article

This review focuses on the complexities of amyotrophic lateral sclerosis (ALS) onset, highlighting the insidious nature of the disease and the challenges in defining its precise origin and early pathogenic mechanisms. The clinical presentation of ALS is characterised by progressive muscle weakness and wasting, often with widespread fasciculations, reflecting lower motor neuron hyperexcitability. The disease’s pathogenesis involves a prolonged preclinical phase of neuronal proteinopathy, particularly TDP-43 accumulation, which eventually leads to motor neuron death and overt ALS. This review discusses the difficulties in detecting this transition and the implications for early therapeutic intervention. It also addresses the involvement of both the upper and lower motor neuron systems, as well as the importance of following presymptomatic patients with genetic mutations. The significance of understanding the distinct processes of TDP-43 deposition and subsequent neuronal degeneration in developing effective treatments is emphasised. Full article

Retinoic acid (RA) exerts biological effects through RA receptors (RARs) to regulate transcription. RA also elicits rapid, RAR-independent (noncanonical) activities mediated by Cellular RA Binding Protein 1 (CRABP1) to modulate cytosolic signaling. CRABP1 functions by forming protein complexes, named CRABP1 signalosomes, to modulate signal propagation in a cell type-specific manner. This review summarizes multiple CRABP1 signalosomes and their physiological functions. CRABP1 knockout (CKO) mice develop multiple phenotypes progressively throughout the lifespan. These include altered brain function, obesity, and insulin resistance starting at young adult stages, increased vulnerability to heart failure and altered serum exosome profiles in midlife, and motor deterioration and thyroid dysfunction (hypothyroidism) in later life. The mouse Crabp1 gene is tightly regulated by multiple epigenetic mechanisms, whereas human CRABP1 gene dysregulation is associated with multiple human diseases in which age is an important factor. Further, CRABP1 expression in human and mouse thyroid glands gradually increases with aging. This underscores the clinical relevance of CRABP1 signalosomes in maintaining health and the functions of certain cells/organ systems, especially in the thyroid and during the aging process. The CRABP1 sequence is highly conserved, likely due to its functional constraint in forming various signalosomes; its tight regulation ensures proper expression of CRABP1 required for the forming of various signalosomes critical to the health and functions of multiple cell types/organ systems. Finally, CRABP1-specific (without activating RARs) signaling pathway-selective compounds have been designed. It may be an attractive therapeutic strategy to exploit these CRABP1-specific compounds to modulate selective signaling pathways in certain disease conditions, such as thyroid dysfunction, to maximize efficacy while minimizing retinoid toxicity. Full article

Cognitive impairment is common but often overlooked in patients with inflammatory demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorder. The conventional assessments may fail to detect subtle deficits and require substantial time and expertise. We collected neuropsychological scores and real-time handwriting data across nine drawing tasks and tasks from the Symbol Digit Modalities Test in 93 patients. Temporal, pressure, and kinematic features were extracted, and machine learning classifiers were trained using five-fold cross-validation with bootstrap confidence intervals. The response timing and pen pressure metrics correlated significantly with global cognitive scores (|r| = 0.30–0.37, p < 0.01). A support vector machine using eight selected features achieved an area under the receiver-operating characteristic curve (AUC) of 0.910, and a streamlined five-feature variant maintained an equivalent performance (AUC = 0.921) while reducing the assessment time by 35%. These results indicate that digital handwriting metrics can complement the standard screening by capturing fine motor and temporal characteristics overlooked in conventional testing. Validation in larger, disease-balanced, and longitudinal cohorts is needed to confirm their clinical utility. Full article

(1) Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by dopaminergic neuronal loss. Tissue stem cell-based therapies have emerged as promising candidates for disease modification and symptomatic relief. This scoping review aims to systematically synthesise the literature on tissue stem cell therapies for PD across cellular, animal, and human studies, with a focus on transplantation strategies, mechanisms of action, and therapeutic outcomes. (2) Methods: We identified 1017 records by querying PubMed, Scopus, Cochrane, and the Virtual Health Library. After screening and applying eligibility criteria, 33 experimental studies were included. Data were extracted on study design, tissue stem cell source, type of subject, and therapeutic effects. (3) Results: Most studies (n = 25) involved animal models, with a minority (n = 8) focusing on human applications. Tissue stem cell therapies showed potential to promote dopaminergic differentiation, reduce inflammation and apoptosis, and improve behavioural and motor outcomes. Autologous transplants yielded a higher safety and efficacy compared to allogeneic ones. The beneficial mechanisms of tissue stem cells included neurotrophic support, mitochondrial protection, modulation of the gut–brain axis, and α-synuclein clearance. (4) Conclusions: Tissue stem cell therapies represent a promising approach for PD. However, standardised protocols and long-term safety assessments are essential to optimise their translational potential. Full article

Parkinson’s disease (PD) causes attentional deficits and worse dual-task (DT) performance, which increases the risk of being run over. In addition to motor deficits, the decision-making ability and the response to external stimuli are impaired. The aim of this study was to evaluate the spatiotemporal parameters of gait during everyday tasks of individuals with PD, specifically during street crossing simulation, obstacle circumvention, and motor DT. People with PD (PG) and matched controls (CG) were distributed into two groups and were evaluated under six different gait and randomized conditions: without a concomitant task (NW); with obstacle circumvention (OC); and four other conditions under simulation of street crossing (without concomitant task (SC); with obstacle circumvention (SC_OC); carrying bags (SC_B); and carrying bags concomitant to obstacle circumvention (SC_OC+B)). The CG group had greater values for all parameters compared to PG, except for double support time. This study’s results found that individuals with PD took smaller, narrower, slower, and shorter steps when compared to neurologically healthy older people and that there was a change in the spatiotemporal gait parameters of all individuals, except for the step-duration parameter under the most difficult crossing conditions. Full article

Purpose: The skeletal muscle has been proposed to contribute to the progressive loss of motor neurons typical of amyotrophic lateral sclerosis (ALS). However, this mechanism has not yet been clarified due to the lack of suitable imaging tools. Here, we aimed to verify whether PET imaging of the translocator protein 18 kDa (TSPO) can detect a muscular abnormality in an experimental model of ALS. Methods: In vivo biodistribution and kinetics of [¹⁸F]DPA-714 were analyzed in skeletal muscle and brain of SOD1^G93A transgenic mice and in wildtype (WT) littermates. Both cohorts were divided into three groups (n = 6 each) to be studied at 60, 90 and 120 days. After microPET imaging, animals were sacrificed to evaluate inflammatory infiltrates by hematoxylin/eosin staining and TSPO expression by immunohistochemistry and Western blot in both quadriceps and brain. Results: [¹⁸F]DPA-714 uptake was higher in the skeletal muscles of SOD1^G93A than in WT mice in the preclinical phase (60 and 90 days) and further increased up to the symptomatic late stage (120 days). Inflammatory cells were absent in the quadriceps of SOD1^G93A mice whose myocytes, instead, showed a progressive increase in TSPO expression with advancing age. By contrast, brain tracer uptake and TSPO expression were comparably low in both groups, regardless of age and genotype. Conclusion: Upregulation of TSPO expression is characteristic of skeletal muscle, but not the brain, in the experimental SOD1^G93A mouse model of ALS. Tracers targeting this pathway have been mostly proposed for the evaluation of inflammatory processes within the central nervous system. Nevertheless, the ubiquitous nature of TSPO expression and its responsiveness to various signals may broaden the diagnostic potential of these tracers to include disease conditions beyond inflammation. Full article

Emerging evidence highlights the gut microbiota as a pivotal determinant of pharmacological efficacy. While Enterococcus faecalis (E. faecalis)-derived tyrosine decarboxylases (tyrDCs) are known to decarboxylate levodopa (L-dopa), compromising systemic bioavailability, the causal mechanisms underlying microbiota-mediated pharmacodynamic variability remain unresolved. In our study, we employed antibiotic-induced microbiota depletion and fecal microbiota transplantation (FMT) to interrogate microbiota-L-dopa interactions in MPTP-induced Parkinson’s disease (PD) mice. The study demonstrated that antibiotic-mediated microbiota depletion enhances L-dopa bioavailability and striatal dopamine (DA) level, correlating with improved motor function. To dissect clinical heterogeneity in the L-dopa response, PD patients were stratified into moderate responders and good responders following standardized L-dopa challenges. In vitro bioconversion assays revealed greater L-dopa-to-DA conversion in fecal samples from moderate responders versus good responders. FMT experiments confirmed mice receiving good-responder microbiota exhibited enhanced L-dopa bioavailability, higher striatal DA concentrations, and a heightened therapeutic effect of L-dopa relative to moderate-responder recipients. Collectively, our study provided evidence that the gut microbiota directly modulates L-dopa metabolism and microbial composition determines interindividual therapeutic heterogeneity. Targeted microbial modulation—through precision antibiotics or donor-matched FMT—is a viable strategy to optimize PD pharmacotherapy, supporting the potential for microbiota-targeted adjuvant therapies in PD management. Full article

Background/Objectives: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. MS lesions can affect the motor, sensory, and visual nerves, leading to impaired balance, muscle tension, and pain. The occurrence of the above can significantly affect quality of life. There is therefore a need to use objective methods of functional assessment for balance and gait disorders in patients with MS. The aim of the study was to assess the functional status and quality of life in people with multiple sclerosis with the simultaneous use of an accelerometer and baropodometric mat. Methodology: The research was conducted using functional tests: Tinetti test, Tandem Pivot Test, timed up and go test, and the Berg Balance Scale. In addition, the Sensor Medica baropodometric mat and the Baiobit balance and gait assessment system were used to objectively assess balance and gait. The assessment was performed once. The study involved 34 participants diagnosed with relapsing–remitting multiple sclerosis compared to a control group consisting of healthy individuals with similar demographic data to the study group. Results: Significant differences were found between the study and control groups in both functional and baropodometric assessments as well as when using an accelerometer in the pelvic area. Conclusions: Higher disturbances and differences are detected in the pelvic area; therefore, it is necessary to consider assessment using the simultaneous measurement of the displacement of the center of gravity located both on the pelvis and on the feet during the performance of different tasks—static and dynamic. Full article