Iron Chelators and Alzheimer's Disease Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-ß (Aß) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aß plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research.

Cross-sectional examination of current and future trends and attributes of the presidents of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons societies.

Objective: The present study aimed to analyze the academic attributes of the presidents of the American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) over the past four decades to elucidate the trajectories of these societies' leaderships. Methods: Forty-three AANS and 43 CNS presidents of the past four decades were identified. Demographic and research productivity data were collected from publicly available sources. Results: Compared to AANS presidents, CNS presidents were younger (median = 48 years vs. 59.5 years; p < 0.001), had fewer years of practice prior to their election (15 years vs. 28 years; p < 0.001), had higher NIH funding rate (37.2% vs. 11.6%; p = 0.01), and higher rate of practicing at academic institutions (93% vs. 74.4%; p = 0.04). The CNS presidents had a comparable median number of publications at election (AANS: 72 vs. CNS: 94 publications, p = 0.78) but a higher median h-index scores (AANS: 28 vs. CNS: 59; p = 0.04). In the multiple linear regression analysis, vascular subspecialty (ß = 0.21 [95% CI: 0.09-0.34]; p = 0.002) and practicing in a non-academic institution (ß = 0.23 [95% CI: 0.08-0.39]; p = 0.007) were predictors for later election for AANS presidency. Conclusions: We characterized the attributes of AANS and CNS presidents to serve as useful references for career trajectories for junior neurosurgeons and trainees. Research and academic presence seem to be associated with early election to both societies.

Atypical cervical radiculopathy presenting with brachioradial pruritus: illustrative cases.

BACKGROUND: Brachioradial pruritus (BRP) is a rare form of chronic dysesthesia characterized by persistent itching, burning, or tingling commonly involving the dorsolateral upper extremities. Although the exact pathophysiology remains unclear, the condition may be a manifestation of atypical cervical radiculopathy. OBSERVATIONS: The authors describe two patients with BRP, a 44-year-old female and a 51-year-old male, both of whom benefited from surgical intervention for atypical cervical radiculopathy, while also highlighting their presentation, diagnostic testing, treatment, and outcomes. LESSONS: The cases demonstrate the potential relationship between cervical spondylosis and BRP while examining the role of surgical intervention as a treatment option.

Glutathione Depletion and Concomitant Elevation of Susceptibility in Patients with Parkinson's Disease: State-of-the-Art MR Spectroscopy and Neuropsychological Study.

Parkinson's disease (PD) is characterized by extrapyramidal motor disturbances and nonmotor cognitive impairments which impact activities of daily living. Although the etiology of PD is still obscure, autopsy reports suggest that oxidative stress (OS) is one of the important factors in the pathophysiology of PD. In the current study, we have investigated the impact of OS in PD by measuring the antioxidant glutathione (GSH) levels from the substantia nigra (SN), left hippocampus (LH) and neurotransmitter γ-amino butyric acid (GABA) levels from SN region. Concomitant quantitative susceptibility mapping (QSM) from SN and LH was also acquired from thirty-eight PD patients and 30 age-matched healthy controls (HC). Glutathione levels in the SN region decreased significantly and susceptibility increased significantly in PD compared to HC. Nonsignificant depletion of GABA was observed in the SN region. GSH levels in the LH region were depleted significantly, but LH susceptibility did not alter in the PD cohort compared to HC. Neuropsychological and physical assessment demonstrated significant impairment of cognitive functioning in PD patients compared to HC. GSH depletion was negatively correlated to motor function performance. Multivariate receiver operating characteristic (ROC) curve analysis on the combined effect of GSH, GABA, and susceptibility in the SN region yielded an improved diagnostic accuracy of 86.1% compared to individual diagnostic accuracy based on GSH (65.8%), GABA (57.5%), and susceptibility (69.6%). This is the first comprehensive report in PD demonstrating significant GSH depletion as well as concomitant iron enhancement in the SN region.

SWADESH: a multimodal multi-disease brain imaging and neuropsychological database and data analytics platform.

Multimodal neuroimaging data of various brain disorders provides valuable information to understand brain function in health and disease. Various neuroimaging-based databases have been developed that mainly consist of volumetric magnetic resonance imaging (MRI) data. We present the comprehensive web-based neuroimaging platform "SWADESH" for hosting multi-disease, multimodal neuroimaging, and neuropsychological data along with analytical pipelines. This novel initiative includes neurochemical and magnetic susceptibility data for healthy and diseased conditions, acquired using MR spectroscopy (MRS) and quantitative susceptibility mapping (QSM) respectively. The SWADESH architecture also provides a neuroimaging database which includes MRI, MRS, functional MRI (fMRI), diffusion weighted imaging (DWI), QSM, neuropsychological data and associated data analysis pipelines. Our final objective is to provide a master database of major brain disease states (neurodegenerative, neuropsychiatric, neurodevelopmental, and others) and to identify characteristic features and biomarkers associated with such disorders.

Blood Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. The characteristic pathological manifestation of AD includes the deposition of extracellular insoluble ß amyloid plaques and intracellular neurofibrillary tangles formed from hyperphosphorylated tau protein. Cost effective and minimally invasive peripheral blood-based biomarkers are critical for early AD diagnosis. Currently, the plasma based two fraction of ß amyloid peptide ratio (Aß42/40) and phosphorylated tau (p-tau) are considered as blood-based biomarkers for AD diagnosis. Recent research indicates that oxidative stress (OS) occurs prior to amyloid plaque (Aß) formation and abnormal tau phosphorylation in AD. The imbalance of the master antioxidant, glutathione (GSH), and prooxidants (iron, zinc, and copper)─plays a crucial role in AD neurodegeneration. We present peripheral blood-based OS related biomarkers that are mechanistically involved in the disease process and may serve as a novel screening tool for early detection of AD onset. This OS based approach may also provide a quick and cost efficient method to monitor the effects of disease-modifying therapies in AD clinical trials.

An answered call for aid? Cannabinoid clinical framework for the opioid epidemic.

BACKGROUND: The opioid crisis continues in full force, as physicians and caregivers are desperate for resources to help patients with opioid use and chronic pain disorders find safer and more accessible non-opioid tools. MAIN BODY: The purpose of this article is to review the current state of the opioid epidemic; the shifting picture of cannabinoids; and the research, policy, and current events that make opioid risk reduction an urgent public health challenge. The provided table contains an evidence-based clinical framework for the utilization of cannabinoids to treat patients with chronic pain who are dependent on opioids, seeking alternatives to opioids, and tapering opioids. CONCLUSION: Based on a comprehensive review of the literature and epidemiological evidence to date, cannabinoids stand to be one of the most interesting, safe, and accessible tools available to attenuate the devastation resulting from the misuse and abuse of opioid narcotics. Considering the urgency of the opioid epidemic and broadening of cannabinoid accessibility amidst absent prescribing guidelines, the authors recommend use of this clinical framework in the contexts of both clinical research continuity and patient care.

Oxidative Stress Occurs Prior to Amyloid Aß Plaque Formation and Tau Phosphorylation in Alzheimer's Disease: Role of Glutathione and Metal Ions.

Alzheimer's disease (AD) is an insidious and progressive neurodegenerative disorder that affects millions of people worldwide. Although the pathogenesis remains obscure, there are two dominant causal hypotheses. Since last three decades, amyloid beta (Aß) deposition was the most prominent hypothesis, and the other is the tau hyperphosphorylation hypothesis. The confirmed diagnostic criterion for AD is the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and the deposition of toxic oligomeric Aß in the autopsied brain. Consistent with these hypotheses, oxidative stress (OS) is garnering major attention in AD research. OS results from an imbalance of pro-oxidants and antioxidants. There is a considerable debate in the scientific community on which process occurs first, OS or plaque deposition/tau hyperphosphorylation. Based on recent scientific observations of various laboratories including ours along with critical analysis of those information, we believe that OS is the early event that leads to oligomeric Aß deposition as well as dimerization of tau protein and its subsequent hyperphosphorylation. This OS hypothesis immediately suggests the consideration of novel therapeutic approaches to include antioxidants involving glutathione enrichment in the brain by supplementation with or without an iron chelator.

Brain Imaging Databases.

The availability of neuroimaging-based databases is helping immensely to understand the brain function in healthy and diseased conditions. This viewpoint highlights the objectives, commonalities, and differences within these existing databases and pointers for researchers to choose a particular database. We introduce a multimodal multidisease database, SWADESH, and its comparison with the existing databases. A futuristic database blueprint is proposed for housing multidisease, multimodal, and longitudinal brain imaging data systematically organized in a matrix form along with neuropsychological assessment scores for the identification of causal disease processes. The information-rich databases will ultimately assist with the systematic identification of prime features linked to causal disease processes, leading to the design of appropriate clinical trials for successful therapeutic interventions.

Quantitation of Brain and Blood Glutathione and Iron in Healthy Age Groups Using Biophysical and In Vivo MR Spectroscopy: Potential Clinical Application.

The antioxidant glutathione (GSH) and pro-oxidant iron levels play a balancing role in the modulation of oxidative stress (OS). There is a significant depletion of GSH in the left hippocampus (LH) in patients with Alzheimer's disease (AD) with concomitant elevation of iron level. However, the correlation of GSH and iron distribution patterns between the brain and the peripheral system (blood) is not yet known. We measured GSH and magnetic susceptibility (e.g., iron) in the LH region along with GSH in plasma and iron in serum across four age groups consisting of healthy volunteers (age range 18-72 y, n = 70). We report non-variability of the mean GSH in the plasma and LH region across mentioned age groups. The mean iron level in the LH region does not change, but the iron level in the serum in the 51-72 y age group increases non-significantly. Regression analysis of our data indicated that GSH and iron levels (both in blood and in brain) are not related to age. This research pave the way for the identification of a risk/susceptibility biomarker for AD and Parkinson's disease from the evaluation of GSH (in plasma) and iron (in serum) levels concomitantly.

A Proprietary Herbal Blend Containing Extracts of Punica granatum Fruit Rind and Theobroma cocoa Seeds Increases Serum Testosterone Level in Healthy Young Males: A Randomized, Double-Blind Placebo-Controlled Study.

LN18178 is a proprietary herbal blend containing extracts of Punica granatum fruit rind and Theobroma cocoa seeds. The objective of the present study was to evaluate the effect of LN18178 on serum testosterone levels in healthy young adults in a randomized, double-blind, placebo-controlled study. One hundred and twenty male volunteers (age 21-35 years) were randomized into three groups. Each group (n = 40) received a daily dose of either placebo or 200 or 400 mg LN18178 for fifty-six days. An increase in serum testosterone (free and total) was the primary efficacy measure of the study. The secondary measures included dihydrotestosterone (DHT), cortisol, Luteinizing hormone (LH), 17ß-Estradiol (E2), hand grip strength, and the mid-upper arm circumferences (MUAC). The vital signs and clinical chemistry parameters in blood and urine were performed to determine product safety. Post-intervention, both doses of LN18178 significantly increased free testosterone (p < 0.0001 vs. baseline; p = 0.0268 and p < 0.0001, respectively vs. placebo). The high dose group showed significant increases in total testosterone (p < 0.0001 vs. baseline; p = 0.0184 vs. placebo) and luteinizing hormone (p < 0.0007 vs. baseline; p = 0.0470 vs. placebo). The changes in other hormones were not significant. At post-trial, the LN18178-400 group showed significant improvements in the hand grip strength and mid-upper arm circumference. The hemato-biochemical parameters, urinalysis, and vital signs of the participants were within the normal range. Together, these observations suggest that LN18178 is a safe and tolerable herbal blend; it increases testosterone level and increases muscle strength and MUAC in young, healthy males.Supplemental data for this article is available online at https://doi.org/10.1080/19390211.2022.2035037 .

Hippocampal glutathione depletion with enhanced iron level in patients with mild cognitive impairment and Alzheimer's disease compared with healthy elderly participants.

Oxidative stress has been implicated in Alzheimer's disease, and it is potentially driven by the depletion of primary antioxidant, glutathione, as well as elevation of the pro-oxidant, iron. Present study evaluates glutathione level by magnetic resonance spectroscopy, iron deposition by quantitative susceptibility mapping in left hippocampus, as well as the neuropsychological scores of healthy old participants (N = 25), mild cognitive impairment (N = 16) and Alzheimer's disease patients (N = 31). Glutathione was found to be significantly depleted in mild cognitive impaired (P < 0.05) and Alzheimer's disease patients (P < 0.001) as compared with healthy old participants. A significant higher level of iron was observed in left hippocampus region for Alzheimer's disease patients as compared with healthy old (P < 0.05) and mild cognitive impairment (P < 0.05). Multivariate receiver-operating curve analysis for combined glutathione and iron in left hippocampus region provided diagnostic accuracy of 82.1%, with 81.8% sensitivity and 82.4% specificity for diagnosing Alzheimer's disease patients from healthy old participants. We conclude that tandem glutathione and iron provides novel avenue to investigate further research in Alzheimer's disease.

Metabolic management of microenvironment acidity in glioblastoma.

Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.

The effect of hyperbaric oxygen therapy on cognition, performance, proteomics, and telomere length-The difference between zero and one: A case report.

Introduction: Hyperbaric oxygen (HBO2) therapy has recently been suggested for the treatment of different brain injuries as well as for physical and cognitive enhancement. The author recently carried out a self-experiment to obtain objective information on the effects of HBO2 therapy on neurocognition, cardiopulmonary function, neuroimaging and its effect on novel biomarkers such as telomere length and proteomics. In the following case report, the author will present and discuss the results and the differences between zero and one. Methods: This is a personal case report on a single subject, myself, who underwent a protocol of 60 daily HBO2 therapy sessions within 3 months. Pre- and post-therapy objective evaluation measured included computerized cognitive assessment, brain imaging, cardiopulmonary exercise test, physical assessments and blood tests including telomere length and proteomics. Results: Neurocognitive results showed a 3.1-3.8% improvements in global cognitive function as well as all other cognitive function domains. In the perfusion MRI, there was a relative increase ranging from 43.3 to 52.3% in cerebral perfusion in various areas subserving memory, coordination, and visual motor cortex function. Similar improvements in cerebral perfusion were seen in the SPECT scans, which ranged from 8.79 to 16.12% increased perfusion in the temporal pole and entorhinal cortex subserving memory, as well as in the subcallosal area and lingual gyrus. MRI-DTI showed prominent increases in fractional anisotropy in several white matter areas including 9% in the body of the corpus callosum, 16.85% in for the fornix and 22.06% in the tapetum. In the physical domains, there were improvements in both anaerobic threshold, exercise endurance, muscle strength, gait speed and grip strength in the 7-15% range. The telomeres length was doubled and clusters of inflammatory proteins dropped around the 40th session and remained low at the 60th session. Conclusion: The difference between zero and one in this single case study of HBO2 therapy confirmed improvement in objective biomarkers which measured cognition, memory, brain processing speed, athletic performance and neuroimaging modalities measuring cerebral perfusion, blood flow and tractography. Additional studies with larger sample size and randomized clinical trials using similar biomarkers are needed to confirm the results and to delineate the longevity of these improvements.

In Vivo 13C Magnetic Resonance Spectroscopy for Assessing Brain Biochemistry in Health and Disease.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique that contributes to the elucidation of brain biochemistry. 13C MRS enables the detection of specific neurochemicals and their neuroenergetic correlation with neuronal function. The synergistic outcome of 13C MRS and the infusion of 13C-labeled substrates provide an understanding of neurometabolism and the role of glutamate/gamma-aminobutyric acid (GABA) neurotransmission in diseases, such as Alzheimer's disease, schizophrenia, and bipolar disorder. Moreover, 13C MRS provides a window into the altered flux rate of different pathways, including the tricarboxylic acid cycle (TCA) and the glutamate/glutamine/GABA cycle, in health and in various diseases. Notably, the metabolic flux rate of the TCA cycle often decreases in neurodegenerative diseases. Additionally, 13C MRS can be used to investigate several psychiatric and neurological disorders as it directly reflects the real-time production and alterations of key brain metabolites. This review aims to highlight the chronology, the technological advancements, and the applications of 13C MRS in various brain diseases.

The application of augmented reality-based navigation for accurate target acquisition of deep brain sites: advances in neurosurgical guidance.

OBJECTIVE: The objective of this study is to quantify the navigational accuracy of an advanced augmented reality (AR)-based guidance system for neurological surgery, biopsy, and/or other minimally invasive neurological surgical procedures. METHODS: Five burr holes were drilled through a plastic cranium, and 5 optical fiducials (AprilTags) printed with CT-visible ink were placed on the frontal, temporal, and parietal bones of a human skull model. Three 0.5-mm-diameter targets were mounted in the interior of the skull on nylon posts near the level of the tentorium cerebelli and the pituitary fossa. The skull was filled with ballistic gelatin to simulate brain tissue. A CT scan was taken and virtual needle tracts were annotated on the preoperative 3D workstation for the combination of 3 targets and 5 access holes (15 target tracts). The resulting annotated study was uploaded to and launched by VisAR software operating on the HoloLens 2 holographic visor by viewing an encrypted, printed QR code assigned to the study by the preoperative workstation. The DICOM images were converted to 3D holograms and registered to the skull by alignment of the holographic fiducials with the AprilTags attached to the skull. Five volunteers, familiar with the VisAR, used the software/visor combination to navigate an 18-gauge needle/trocar through the series of burr holes to the target, resulting in 70 data points (15 for 4 users and 10 for 1 user). After each attempt the needle was left in the skull, supported by the ballistic gelatin, and a high-resolution CT was taken. Radial error and angle of error were determined using vector coordinates. Summary statistics were calculated individually and collectively. RESULTS: The combined angle of error of was 2.30° ± 1.28°. The mean radial error for users was 3.62 ± 1.71 mm. The mean target depth was 85.41 mm. CONCLUSIONS: The mean radial error and angle of error with the associated variance measures demonstrates that VisAR navigation may have utility for guiding a small needle to neural lesions, or targets within an accuracy of 3.62 mm. These values are sufficiently accurate for the navigation of many neurological procedures such as ventriculostomy.

AD Hypotheses and Suggested Clinical Trials.

Alzheimer's disease (AD) is a major neurodegenerative disorder that impairs cognitive reserve impacting activities of daily living. The prime pathological characteristics of AD include the deposition of neurofibrillary tangles of hyperphosphorylated tau (τ) proteins, accumulation of amyloid-ß (Aß), and neuronal loss. Expanding literature suggests that oxidative stress (OS) is a vital factor contributing to the pathogenesis of AD such that biometals (e.g., iron, zinc, copper) are believed to play a crucial role in Aß formation and neurodegeneration. Growing evidence indicates the impact of OS in AD, and clinical trials with antioxidative therapeutic interventions are in the frontline of AD research. We discuss various AD hypotheses and associated clinical trials. We present a case for future therapeutic intervention for AD by putting forth postulated hypotheses and trials.

Return to Play Guidelines After Cervical Spine Injuries in American Football Athletes: A Literature-Based Review.

STUDY DESIGN: Literature-based review. OBJECTIVE: We sought to evaluate clinical and case studies related to return to play (RTP) after cervical spine injuries in elite American football athletes and to formulate guidelines to help health care practitioners manage these conditions. SUMMARY OF BACKGROUND DATA: American football athletes are at unique risk of cervical spine injury and appropriate case-by-case management of cervical spine injuries is necessary for these athletes. Despite this need, no standardized guidelines exist for RTP after cervical spine injury. METHODS: Observational or case-based articles relating to RTP after cervical spine injury in American football athletes were curated from PubMed/EMBASE databases. Primary literature published before December 1, 2019 involving National Football League (NFL) or National Collegiate Athletic Association (NCAA) athletes met inclusion criteria. RESULTS: The data acquisition process yielded 28 studies addressing cervical spine injuries and RTP in American football athletes. Stingers/burners were the most common injury and placed athletes at higher risk of a more severe re-injury. Transient quadriplegia, cervical stenosis, cervical disc herniation (CDH), and cervical fractures have a more significant impact on the long-term health and career longevity of the American football athlete. As such, the literature offers some guidance for management of these athletes, including average time for RTP in patients treated nonoperatively, thresholds involving cervical stenosis, and postoperative recommendations after spinal decompression and/or fusion surgery. CONCLUSION: Elite American football athletes are at high risk for cervical spine injury due to the nature of their sport. The decision to allow these athletes to return to play should involve an understanding of the average RTP time, the potential risks of recurrence or re-injury, and individual characteristics such as position played and pathology on imaging.Level of Evidence: 3.