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Stroke Jul 2024GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089...
BACKGROUND
GPR65 (G protein-coupled receptor 65) can sense extracellular acidic environment to regulate pathophysiological processes. Pretreatment with the GPR65 agonist BTB09089 has been proven to produce neuroprotection in acute ischemic stroke. However, whether delayed BTB09089 treatment and neuronal GPR65 activation promote neurorestoration remains unknown.
METHODS
Ischemic stroke was induced in wild-type (WT) or GPR65 knockout (GPR65) mice by photothrombotic ischemia. Male mice were injected intraperitoneally with BTB09089 every other day at days 3, 7, or 14 poststroke. AAV-Syn-GPR65 (adenoassociated virus-synapsin-GPR65) was utilized to overexpress GPR65 in the peri-infarct cortical neurons of GPR65 and WT mice. Motor function was monitored by grid-walk and cylinder tests. The neurorestorative effects of BTB09089 were observed by immunohistochemistry, Golgi-Cox staining, and Western blotting.
RESULTS
BTB09089 significantly promoted motor outcomes in WT but not in GPR65 mice, even when BTB09089 was delayed for 3 to 7 days. BTB09089 inhibited the activation of microglia and glial scar progression in WT but not in GPR65 mice. Meanwhile, BTB09089 reduced the decrease in neuronal density in WT mice, but this benefit was abolished in GPR65 mice and reemerged by overexpressing GPR65 in peri-infarct cortical neurons. Furthermore, BTB09089 increased the GAP43 (growth-associated protein-43) and synaptophysin puncta density, dendritic spine density, dendritic branch length, and dendritic complexity by overexpressing GPR65 in the peri-infarct cortical neurons of GPR65 mice, which was accompanied by increased levels of p-CREB (phosphorylated cAMP-responsive element-binding protein). In addition, the therapeutic window of BTB09089 was extended to day 14 by overexpressing GPR65 in the peri-infarct cortical neurons of WT mice.
CONCLUSIONS
Our findings indicated that delayed BTB09089 treatment improved neurological functional recovery and brain tissue repair poststroke through activating neuronal GRP65. GPR65 overexpression may be a potential strategy to expand the therapeutic time window of GPR65 agonists for neurorehabilitation after ischemic stroke.
PubMed: 38946544
DOI: 10.1161/STROKEAHA.124.046954 -
Clinical Neurology and Neurosurgery Jun 2024Parkinson's disease (PD) is the second most prevalent neurodegenerative condition after Alzheimer's disease and it represents one of the fastest emerging neurological... (Review)
Review
Parkinson's disease (PD) is the second most prevalent neurodegenerative condition after Alzheimer's disease and it represents one of the fastest emerging neurological diseases worldwide. PD is usually diagnosed after the third decade of life with symptoms like tremors at rest and muscle stiffness. Rapid Eye Movement sleep behavioral disorder (RBD) is another disorder that is caused by a loss of typical muscle relaxation during sleep with a lot of motor activity. Usually, RBD is strongly associated with PD. Recent studies have demonstrated that PD reduces the life expectancy of patients to 10 and 20 years after being diagnosed. In addition, delayed diagnosis and treatment of these neurological disorders have significant socio-economic impacts on patients, their partners and on the general public. Often, it is not clear about PD associated financial burdens both in low and high-income countries. On the other hand, PD triggers neurological variations that affect differences in the dopamine transporter (DAT) and in glucose metabolism. Therefore, positron emission tomography (PET) using specific DAT radiotracers and fluorine-18 labeled desoxyglucose (FDG) has being considered a key imaging technique that could be applied clinically for the very early diagnosis of RBD and in PD. However, a few myths about PET is that it is very expensive. Here, we looked at the cost of treatment of PD and RBD in relation to early PET imaging. Our finding suggests that PET imaging might also be a cost sparing diagnostic option in the management of patients with PD and RBD, not only for first world countries as it is the case now but also for the third world countries. Therefore, PET is a cost-effective imaging technique for very early diagnostic of RBD and PD.
PubMed: 38944021
DOI: 10.1016/j.clineuro.2024.108404 -
Trials Jun 2024Isolated REM sleep behavior disorder (iRBD) is an early α-synucleinopathy often accompanied by incipient cognitive impairment. As executive dysfunctions predict earlier...
Cognitive training and promoting a healthy lifestyle for individuals with isolated REM sleep behavior disorder: study protocol of the delayed-start randomized controlled trial CogTrAiL-RBD.
BACKGROUND
Isolated REM sleep behavior disorder (iRBD) is an early α-synucleinopathy often accompanied by incipient cognitive impairment. As executive dysfunctions predict earlier phenotypic conversion from iRBD to Parkinson's disease and Lewy body dementia, cognitive training focusing on executive functions could have disease-modifying effects for individuals with iRBD.
METHODS
The study CogTrAiL-RBD investigates the short- and long-term effectiveness and the feasibility and underlying neural mechanisms of a cognitive training intervention for individuals with iRBD. The intervention consists of a 5-week digital cognitive training accompanied by a module promoting a healthy, active lifestyle. In this monocentric, single-blinded, delayed-start randomized controlled trial, the intervention's effectiveness will be evaluated compared to an initially passive control group that receives the intervention in the second, open-label phase of the study. Eighty individuals with iRBD confirmed by polysomnography will be consecutively recruited from the continuously expanding iRBD cohort at the University Hospital Cologne. The evaluation will focus on cognition and additional neuropsychological and motor variables. Furthermore, the study will examine the feasibility of the intervention, effects on physical activity assessed by accelerometry, and interrogate the intervention's neural effects using magnetic resonance imaging and polysomnography. Besides, a healthy, age-matched control group (HC) will be examined at the first assessment time point, enabling a cross-sectional comparison between individuals with iRBD and HC.
DISCUSSION
This study will provide insights into whether cognitive training and psychoeducation on a healthy, active lifestyle have short- and long-term (neuro-)protective effects for individuals with iRBD.
TRIAL REGISTRATION
The study was prospectively registered in the German Clinical Trial Register (DRKS00024898) on 2022-03-11, https://drks.de/search/de/trial/DRKS00024898 .
PROTOCOL VERSION
V5 2023-04-24.
Topics: Humans; Single-Blind Method; REM Sleep Behavior Disorder; Healthy Lifestyle; Randomized Controlled Trials as Topic; Executive Function; Cognition; Time Factors; Polysomnography; Treatment Outcome; Cognitive Behavioral Therapy; Male; Germany; Middle Aged; Exercise; Female; Aged; Feasibility Studies; Cognitive Training
PubMed: 38943191
DOI: 10.1186/s13063-024-08265-9 -
Annals of Agricultural and... Jun 2024The NAA10 gene encodes N-alpha-acetyltransferase 10 which plays an important role in cell growth, differentiation, DNA damage, metastasis, apoptosis, stress response and... (Review)
Review
The NAA10 gene encodes N-alpha-acetyltransferase 10 which plays an important role in cell growth, differentiation, DNA damage, metastasis, apoptosis, stress response and autophagy. Defects in the NAA10 gene correlate with the diagnosis of NAA10-related syndrome (Ogden syndrome). The most common symptoms of NAA10-related syndrome are: global developmental delay, non-verbal or limited speech, autism spectrum disorder, feeding difficulties, motor delay, muscle tone disturbances, and long QT syndrome. To-date, there are about 100 patients who have been reported with this condition. The case report presents the clinical study of a girl aged 4 years and 3 months diagnosed with Ogden syndrome. She had many characteristic features of the disorder, as well as precocious puberty. This girl represents the case of a patient with p.Arg83Cys mutation in NAA10 gene as well as precocious puberty.
Topics: Humans; Female; Puberty, Precocious; N-Terminal Acetyltransferase A; N-Terminal Acetyltransferase E; Child, Preschool; Mutation
PubMed: 38940118
DOI: 10.26444/aaem/171758 -
Clinical and Translational Radiation... Jul 2024Preoperative radiosurgery (SRS) of brain metastases (BM) aims to achieve cavity local control with a reduction in leptomeningeal relapse (LMD) and without additional...
PURPOSE
Preoperative radiosurgery (SRS) of brain metastases (BM) aims to achieve cavity local control with a reduction in leptomeningeal relapse (LMD) and without additional radionecrosis compared to postoperative SRS. We present the final results of a prospective feasibility trial of linac-based stereotactic radiosurgery (SRS) prior to neurosurgical resection of a brain metastasis (PREOP-1).
METHODS
Eligibility criteria included a BM up to 4 cm in diameter for elective resection. The primary endpoint was the feasibility of delivering linac-based preoperative SRS in all patients prior to anticipated gross tumour resection. Secondary endpoints included rates of LMD, local control and overall survival. Exploratory endpoints were the level of expression of immunological and proliferative markers.
RESULTS
Thirteen patients of median age 65 years (range 41-77) were recruited. Twelve patients (92 %) received preoperative radiosurgery and metastasectomy and one patient went directly to surgery and received postoperative SRS, thus the primary endpoint was not met. The median time between referral and preoperative SRS was 6.5 working days (1-10) and from SRS to neurosurgery was 1 day (0-5). The median prescribed dose was 16 Gy (14-19) to a median planning target volume of 12.7 cm (5.9-26.1). Five patients completed 12-month follow-up after preoperative SRS without local recurrence or leptomeningeal disease. The patient who received postoperative FSRT developed LMD after six months. There was one transient toxicity (grade 2 alopecia) and nine patients have died from extracranial causes. Patients reported significant improvement in motor weakness at 6 months (P = 0.04). No pattern in changes of marker expression was observed.
CONCLUSION
In patients with large brain metastasis without raised intracranial pressure, linac-based preoperative SRS was feasible in 12/13 patients and safe in 12/12 patients without any surgical delay or intracranial complications.
PubMed: 38938931
DOI: 10.1016/j.ctro.2024.100798 -
Chinese Journal of Traumatology =... Jun 2024To assess the relationship between dislocation and functional outcomes in supination-external rotation (SER) ankle fractures.
PURPOSE
To assess the relationship between dislocation and functional outcomes in supination-external rotation (SER) ankle fractures.
METHODS
A retrospective case series study was performed on patients with ankle fractures treated surgically at a large trauma center from January 2015 to December 2021. The inclusion criteria were young and middle-aged patients of 18-65 years with SER ankle fractures that can be classified by Lauge-Hansen classification and underwent surgery at our trauma center. Exclusion criteria were serious life-threatening diseases, open fractures, fractures delayed for more than 3 weeks, fracture sites ≥2, etc. Then patients were divided into dislocation and no-dislocation groups. Patient demographics, injury characteristics, surgery-related outcomes, and postoperative functional outcomes were collected and analyzed. The functional outcomes of SER ankle fractures were assessed postoperatively at 1-year face-to-face follow-up using the foot and ankle outcome score (FAOS) and American orthopedic foot and ankle society score and by 2 experienced orthopedic physicians. Relevant data were analyzed using SPSS version 22.0 by Chi-square or t-test.
RESULTS
During the study period, there were 371 ankle fractures. Among them, 190 (51.2%) were SER patterns with 69 (36.3%) combined with dislocations. Compared with the no-dislocation group, the dislocation group showed no statistically significant differences in gender, age composition, fracture type, preoperative complications with diabetes, smoking history, preoperative waiting time, operation time, and length of hospital stay (all p > 0.05), but a significantly higher Lauge-Hansen injury grade (p < 0.001) and syndesmotic screw fixation rate (p = 0.033). Moreover, the functional recovery was poorer, revealing a significantly lower FAOS in the sport/rec scale (p < 0.001). Subgroup analysis showed that among SER IV ankle fracture patients, FAOS was much lower in pain (p = 0.042) and sport/rec scales (p < 0.001) for those with dislocations. American orthopedic foot and ankle society score revealed no significant difference between dislocation and no-dislocation patients.
CONCLUSION
Dislocation in SER ankle fractures suggests more severe injury and negatively affects functional recovery, mainly manifested as more pain and poorer motor function, especially in SER IV ankle cases.
PubMed: 38937167
DOI: 10.1016/j.cjtee.2024.06.001 -
IEEE Transactions on Neural Systems and... Jun 2024Robotic rehabilitation has been shown to match the effects of conventional physical therapy on motor function for patients with neurological diseases. Rehabilitation...
Robotic rehabilitation has been shown to match the effects of conventional physical therapy on motor function for patients with neurological diseases. Rehabilitation robots have the potential to reduce therapists' workload in time-intensive training programs as well as perform actions that are not replicable by human therapists. We investigated the effects of one such modality that cannot be achieved by a human therapist: assistance and resistance within the electromechanical delay between muscle activation and muscle contraction during arm extension. We found increased muscle activation when providing robotic assistance within this electromechanical delay. Assistance provided within this delay moves the participant's arm quicker than their own muscle and increases the subsequent peak voluntary muscle activation compared to normal arm extension by 68.97 ± 80.05% (SE = 0.021; p = 0.007). This is surprising since all previous literature shows that muscle activation either decreases or does not change when participants receive robotic assistance. As a consequence, traditional robotic rehabilitation incrementally reduces assistance as the patient improves to maintain levels of muscle activation which is suggested to be important for neuronal repair. The present result may enable therapists to no longer have to choose between providing assistance or increasing muscle activation. Instead, therapists may be able to provide assistance while also increasing muscle activation.
PubMed: 38935467
DOI: 10.1109/TNSRE.2024.3419688 -
Journal of Neurochemistry Jun 2024Deregulated cyclin-dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous...
Deregulated cyclin-dependent kinase 5 (Cdk5) activity closely correlates with hyperphosphorylated tau, a common pathology found in neurodegenerative diseases. Previous postmortem studies had revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS); hence, we investigated the effects of Cdk5 inhibition on ALS model mice and neurons in this study. For the in vitro study, motor neuron cell lines with wild-type superoxide dismutase 1 (SOD1) or SOD1 and primary neuronal cultures from SOD1 transgenic (TG) mice or non-TG mice were compared for the expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth by applying Cdk5-small interfering RNA or Cdk5-short hairpin RNA (shRNA). For the in vivo study, SOD1 mice and non-TG mice were intrathecally injected with adeno-associated virus 9 (AAV9)-scramble (SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Weight and motor function were measured three times per week from 60 days of age, longevity was evaluated, and the tissues were collected from 90-day-old or 120-day-old mice. Neurons with SOD1 showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, and enhanced neuroinflammation and apoptosis, all of which were reversed by Cdk5 inhibition. Weights did not show significant differences among non-TG and SOD1 mice with or without Cdk5 silencing. SOD1 mice treated with AAV9-Cdk5-shRNA showed significantly delayed disease onset, delayed rotarod failure, and prolonged survival compared with those treated with AAV9-SCR-shRNA. The brain and spinal cord of SOD1 mice intrathecally injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis, and an increased number of motor neurons compared to those of SOD1 mice injected with AAV9-SCR-shRNA. Cdk5 inhibition could be an important mechanism in the development of a new therapeutic strategy for ALS.
PubMed: 38934222
DOI: 10.1111/jnc.16160 -
Cureus Jun 2024Although rare, acute compartment syndrome may develop as a simple elbow dislocation after reduction without initial motor, sensory, or peripheral circulatory...
Although rare, acute compartment syndrome may develop as a simple elbow dislocation after reduction without initial motor, sensory, or peripheral circulatory abnormalities. This report describes a rare case of this condition. Acute compartment syndrome remains a potential complication, even in a simple elbow dislocation without apparent initial abnormalities, and should be explained to patients. A peripheral nerve block during reduction may mask symptoms and delay recognition of acute compartment syndrome. This case highlights the importance of vigilant monitoring for acute compartment syndrome following reduction of simple elbow dislocations, especially when a peripheral nerve block is used during reduction.
PubMed: 38933345
DOI: 10.7759/cureus.63145 -
Neurology. Clinical Practice Jun 2024Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients...
BACKGROUND AND OBJECTIVES
Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020.
METHODS
This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected.
RESULTS
Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH ( = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH ( = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up.
DISCUSSION
This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned.
CLASSIFICATION OF EVIDENCE
This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.
PubMed: 38932995
DOI: 10.1212/CPJ.0000000000200298