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A promising direction in the research on Alzheimer's Disease (AD) is the identification of biomarkers that better inform the disease progression of AD. However, the performance of amyloid-based biomarkers in predicting cognitive performance has been shown to be suboptimal. We hypothesise that neuronal loss could better inform cognitive impairment. We have utilised the 5xFAD transgenic mouse model that displays AD pathology at an early phase, already fully manifested after 6 months. We have evaluated the relationships between cognitive impairment, amyloid deposition, and neuronal loss in the hippocampus in both male and female mice. We observed the onset of disease characterized by the emergence of cognitive impairment in 6-month-old 5xFAD mice coinciding with the emergence of neuronal loss in the subiculum, but not amyloid pathology. We also showed that female mice exhibited significantly increased amyloid deposition in the hippocampus and entorhinal cortex, highlighting sex-related differences in the amyloid pathology of this model. Therefore, parameters based on neuronal loss might more accurately reflect disease onset and progression compared to amyloid-based biomarkers in AD patients. Moreover, sex-related differences should be considered in studies involving 5xFAD mouse models.

Alzheimer's disease (AD) is the most common form of dementia. Although previous studies have selectively investigated the localization of amyloid-beta (Aβ) deposition in certain brain regions, a comprehensive characterization of the rostro-caudal distribution of Aβ plaques in the brain and their inter-regional correlation remain unexplored. Our results demonstrated remarkable working and spatial memory deficits in 9-month-old 5xFAD mice compared to wildtype mice. High Aβ plaque load was detected in the somatosensory cortex, piriform cortex, thalamus, and dorsal/ventral hippocampus; moderate levels of Aβ plaques were observed in the motor cortex, orbital cortex, visual cortex, and retrosplenial dysgranular cortex; and low levels of Aβ plaques were located in the amygdala, and the cerebellum; but no Aβ plaques were found in the hypothalamus, raphe nuclei, vestibular nucleus, and cuneate nucleus. Interestingly, the deposition of Aβ plaques was positively associated with brain inter-regions including the prefrontal cortex, somatosensory cortex, medial amygdala, thalamus, and the hippocampus. In conclusion, this study provides a comprehensive morphological profile of Aβ deposition in the brain and its inter-regional correlation. This suggests an association between Aβ plaque deposition and specific brain regions in AD pathogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tsui, Roy, Chau, Wong, Shi, Poon, Wang, Strekalova, Aquili, Chang, Fung, Song and Lim.)

Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and progressive functional disabilities lead to reduced lifespan. There is currently no cure for ARCAs, likely attributed to the lack of understanding of the multifaceted roles of antioxidant defense and the underlying mechanisms. This systematic review aims to evaluate the extant literature on the current developments of therapeutic strategies that target oxidative stress for the management of ARCAs. We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs.

Anxiety is characteristic comorbidity of noise-induced hearing loss (NIHL), which causes physiological changes within the dentate gyrus (DG), a subfield of the hippocampus that modulates anxiety. However, which DG circuit underlies hearing loss-induced anxiety remains unknown. We utilize an NIHL mouse model to investigate short- and long-term synaptic plasticity in DG networks. The recently discovered longitudinal DG-DG network is a collateral of DG neurons synaptically connected with neighboring DG neurons and displays robust synaptic efficacy and plasticity. Furthermore, animals with NIHL demonstrate increased anxiety-like behaviors similar to a response to chronic restraint stress. These behaviors are concurrent with enhanced synaptic responsiveness and suppressed short- and long-term synaptic plasticity in the longitudinal DG-DG network but not in the transverse DG-CA3 connection. These findings suggest that DG-related anxiety is typified by synaptic alteration in the longitudinal DG-DG network., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Melatonin and novel melatonin-based therapies such as melatonin-containing hybrid molecules, melatonin analogues, and melatonin derivatives have been investigated as potential therapeutics against Alzheimer's disease (AD) pathogenesis. In this review, we examine the developmental trends of melatonin therapies for AD from 1997 to 2021. We then highlight the neuroprotective mechanisms of melatonin therapy derived from preclinical studies. These mechanisms include the alleviation of amyloid-related burden, neurofibrillary tangle accumulation, oxidative stress, neuroinflammation, apoptosis, mitochondrial dysfunction, and impaired neuroplasticity and neurotransmission. We further illustrate the beneficial effects of melatonin on behavior in animal models of AD. Next, we discuss the clinical effects of melatonin on sleep, cognition, behavior, psychiatric symptoms, electroencephalography findings, and molecular biomarkers in patients with mild cognitive impairment and AD. We then explore the effectiveness of novel melatonin-based therapies. Lastly, we discuss the limitations of current melatonin therapies for AD and suggest two emerging research themes for future study., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Depression is a severe neuropsychiatric disorder that affects more than 264 million people worldwide. The efficacy of conventional antidepressants are barely adequate and many have side effects. Hericium erinaceus (HE) is a medicinal mushroom that has been reported to have therapeutic potential for treating depression., Methods: Animals subjected to chronic restraint stress were given 4 weeks HE treatment. Animals were then screened for anxiety and depressive-like behaviours. Gene and protein assays, as well as histological analysis were performed to probe the role of neurogenesis in mediating the therapeutic effect of HE. Temozolomide was administered to validate the neurogenesis-dependent mechanism of HE., Results: The results showed that 4 weeks of HE treatment ameliorated depressive-like behaviours in mice subjected to 14 days of restraint stress. Further molecular assays demonstrated the 4-week HE treatment elevated the expression of several neurogenesis-related genes and proteins, including doublecortin, nestin, synaptophysin, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), phosphorylated extracellular signal-regulated kinase, and phosphorylated cAMP response element-binding protein (pCREB). Increased bromodeoxyuridine-positive cells were also observed in the dentate gyrus of the hippocampus, indicating enhanced neurogenesis. Neurogenesis blocker temozolomide completely abolished the antidepressant-like effects of HE, confirming a neurogenesis-dependent mechanism. Moreover, HE induced anti-neuroinflammatory effects through reducing astrocyte activation in the hippocampus, which was also abolished with temozolomide administration., Conclusion: HE exerts antidepressant effects by promoting neurogenesis and reducing neuroinflammation through enhancing the BDNF-TrkB-CREB signalling pathway., (© 2021. The Author(s).)

Alzheimer's disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.

Alzheimer's disease is a neurodegenerative disorder associated with age, and is characterized by pathological markers such as amyloid-beta plaques and neurofibrillary tangles. Symptoms of AD include cognitive impairments, anxiety and depression. It has also been shown that individuals with AD have impaired neurotransmission, which may result from the accumulation of amyloid plaques and neurofibrillary tangles. Preclinical studies showed that melatonin, a monoaminergic neurotransmitter released from the pineal gland, is able to ameliorate AD pathologies and restore cognitive impairments. Theoretically, inhibition of the pathological progression of AD by melatonin treatment should also restore the impaired neurotransmission. This review aims to explore the impact of AD on neurotransmission, and whether and how melatonin can enhance neurotransmission via improving AD pathology.

Melatonin (MLT) is a neurohormone that is regulated by the circadian clock and plays multifunctional roles in numerous neurodegenerative disorders, such as Alzheimer's disease (AD). AD is the most common form of dementia and is associated with the degradation of axons and synapses resulting in memory loss and cognitive impairment. Despite extensive research, there is still no effective cure or specific treatment to prevent the progression of AD. The pathogenesis of AD involves atrophic alterations in the brain that also result in circadian alterations, sleep disruption, and autophagic dysfunction. In this scenario, MLT and autophagy play a central role in removing the misfolded protein aggregations. MLT also promotes autophagy through inhibiting methamphetamine toxicity to protect against neuronal cell death in AD brain. Besides, MLT plays critical roles as either a pro-autophagic indicator or anti-autophagic regulator depending on the phase of autophagy. MLT also has antioxidant properties that can counteract mitochondrial damage, oxidative stress, and apoptosis. Aging, a major risk factor for AD, can change sleep patterns and sleep quality, and MLT can improve sleep quality through regulating sleep cycles. The primary purpose of this review is to explore the putative mechanisms of the beneficial effects of MLT in AD patients. Furthermore, we also summarize the findings from preclinical and clinical studies on the multifunctional roles of MLT on autophagic regulation, the control of the circadian clock-associated genes, and sleep regulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Besides extracellular deposition of amyloid beta and formation of phosphorylated tau in the brains of patients with Alzheimer's disease (AD), the pathogenesis of AD is also thought to involve mitochondrial dysfunctions and altered neurotransmission systems. However, none of these components can describe the diverse cognitive, behavioural, and psychiatric symptoms of AD without the pathologies interacting with one another. The purpose of this review is to understand the relationships between mitochondrial and neurotransmission dysfunctions in terms of (1) how mitochondrial alterations affect cholinergic and monoaminergic systems via disruption of energy metabolism, oxidative stress, and apoptosis; and (2) how different neurotransmission systems drive mitochondrial dysfunction via increasing amyloid beta internalisation, oxidative stress, disruption of mitochondrial permeabilisation, and mitochondrial trafficking. All these interactions are separately discussed in terms of neurotransmission systems. The association of mitochondrial dysfunctions with alterations in dopamine, norepinephrine, and histamine is the prospective goal in this research field. By unfolding the complex interactions surrounding mitochondrial dysfunction in AD, we can better develop potential treatments to delay, prevent, or cure this devastating disease., Competing Interests: Declaration of Competing Interest None., (copyright: © 2020 Wong et al.)

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the hallmark pathologies of amyloid-beta plaques and neurofibrillary tangles. Symptoms of this devastating disease include behavioral changes and deterioration of higher cognitive functions. Impairment of neurogenesis has also been shown to occur in AD, which adversely impacts new neuronal cell growth, differentiation, and survival. This impairment possibly results from the cumulative effects of the various pathologies of AD. Preclinical studies have suggested that the administration of melatonin-the pineal hormone primarily responsible for the regulation of the circadian rhythm-targets the effects of AD pathologies and improves cognitive impairment. It is postulated that by mitigating the effect of these pathologies, melatonin can also rescue neurogenesis impairment. This review aims to explore the effect of AD pathologies on neurogenesis, as well as the mechanisms by which melatonin is able to ameliorate AD pathologies to potentially promote neurogenesis., (© 2020 New York Academy of Sciences.)

AIDS is a global infection involving several complications and its increasing prevalence every year has prioritized our study. Therapy associated with HIV has led to emergence of multidrug resistance and toxicity. Thus, the development of a potent, affordable and safe anti-HIV drug is a global concern. Among the different targets developed, inhibition of non-nucleoside reverse transcriptase (NNRT) is found to be effective and promising. Etravirine, efavirenz, nevirapine, rilpivirine and delavirdine are the marketed NNRTIs available. This study is focused on computational prediction of hit molecules as well as repurposing of various FDA-approved drugs as potential NNRTIs. A synthetic database from ZINCpharmer, publicly available natural databases of coumarins, chromones and chalcones, and two databases of FDA-approved drugs for repurposing were screened to check for the possibility of these compounds to possess anti-HIV activity. Study utilizes a structure-based approach with the generated pharmacophore of target protein (PDB ID: 3MEC), screening of selected datasets is carried out using the Phase tool of Schrodinger. The top filtered compounds with good fitness score were proceeded to molecular docking studies to study their binding affinity to the target. Energy-based calculations using Prime MM-GBSA of Schrodinger was performed to determine free binding energy of the complexes. Prediction of pharmacokinetic parameters of top compounds is further carried out and reported. All the results obtained from different databases are compiled, interpreted and five molecules were subjected to molecular dynamic studies to further confirm the prediction and identified hit molecules for in vitro screening as potential NNRTIs.Communicated by Ramaswamy H. Sarma.

Acquired Immuno Defficiency Syndrome (AIDS) is one of the major global life threatening condition caused by Human Immunodeficiency Virus (HIV) and its prevalence has been increasing every year. Hence, this study has put its emphasis on HIV. Inhibition of Non-Nucleoside Reverse Transcriptase (NNRT) is considered as a well-developed target for HIV. Structure-based pharmacophore model was generated using the Phase tool of Schrodinger and screened database of metronidazole derivatives, flavonoids and metronidazole-flavonoid hybrid molecules. Compounds having good fitness score with similar pharmacophoric features as that of the Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) in market or clinical trials and metronidazole derivatives with reported anti-HIV activity are taken for molecular docking and rescoring by Glide and Prime tools. Hybrid molecules demonstrated good docking score and similar binding interactions as that of reference drugs. From Prime MM-GBSA rescoring, free binding energy was found less and protein-ligand complexes were stabilized with van der Waals free energy and nonpolar solvation terms. Further, atom-based QSAR model of reported metronidazole derivatives as NNRTIs was developed with good statistical values to further refine the database. Pharmacokinetic and toxicity prediction of the top compounds using some free wares like pkCSM and SwissADME reported that identified top compounds have good ADMET profile for oral administration, safe excretion and less toxicity. Study suggests that metronidazole-flavonoid hybrid molecules can be taken as lead molecule for further biological screening and has scope in future drug discovery as safe and potential NNRTIs.Communicated by Ramaswamy H. Sarma.

Purpose: This paper presents an overview of multisource inverse-geometry computed tomography (IGCT) as well as the development of a gantry-based research prototype system. The development of the distributed x-ray source is covered in a companion paper [V. B. Neculaes et al., "Multisource inverse-geometry CT. Part II. X-ray source design and prototype," Med. Phys. 43, 4617-4627 (2016)]. While progress updates of this development have been presented at conferences and in journal papers, this paper is the first comprehensive overview of the multisource inverse-geometry CT concept and prototype. The authors also provide a review of all previous IGCT related publications., Methods: The authors designed and implemented a gantry-based 32-source IGCT scanner with 22 cm field-of-view, 16 cm z-coverage, 1 s rotation time, 1.09 × 1.024 mm detector cell size, as low as 0.4 × 0.8 mm focal spot size and 80-140 kVp x-ray source voltage. The system is built using commercially available CT components and a custom made distributed x-ray source. The authors developed dedicated controls, calibrations, and reconstruction algorithms and evaluated the system performance using phantoms and small animals., Results: The authors performed IGCT system experiments and demonstrated tube current up to 125 mA with up to 32 focal spots. The authors measured a spatial resolution of 13 lp/cm at 5% cutoff. The scatter-to-primary ratio is estimated 62% for a 32 cm water phantom at 140 kVp. The authors scanned several phantoms and small animals. The initial images have relatively high noise due to the low x-ray flux levels but minimal artifacts., Conclusions: IGCT has unique benefits in terms of dose-efficiency and cone-beam artifacts, but comes with challenges in terms of scattered radiation and x-ray flux limits. To the authors' knowledge, their prototype is the first gantry-based IGCT scanner. The authors summarized the design and implementation of the scanner and the authors presented results with phantoms and small animals.

Objectives: Two steps in stapedotomy are particularly challenging: (1) micropick fenestration of the stapes footplate (SF) and (2) crimping of the stapes prosthesis (SP) to the incus. We conducted trials to determine if experience correlates with differences in performance for these tasks., Methods: In a surgical model of stapedotomy, performance was measured for 3 experienced and 3 novice surgeons. For fenestration, we measured ability to target the fenestration and force applied to the SF. For crimping, we measured crimp quality, movement of the SP during crimping, and force applied to the SF., Results: Experienced surgeons demonstrated significantly better ability to target the fenestration and, during crimping, caused less SP movement and a significantly lower rate of SP dislodgment., Conclusions: Clear differences in task performance are measurable between more and less experienced surgeons during critical steps of stapedotomy., Clinical Significance: The observed differences in task performance may contribute to an understanding of maneuvers that increase the risk of inadequate prosthesis placement and cochlear trauma-factors likely responsible for variable hearing results with strapedotomy.

Objective: Micropick fenestration of the stapes footplate, a difficult step in stapedotomy, was selected for trials evaluating the potential for robotic assistance (RA) to improve clinical measures of surgical performance., Study Design: In a surgical model of stapedotomy, we measured accuracy of fenestration to a desired point location and force applied to the stapes footplate. Performance variables were measured for 3 experienced and 3 less-experienced surgeons., Results: RA significantly reduced the maximum force applied to the stapes footplate. For fenestration targeting, RA significantly improved accuracy for less-experienced surgeons and significantly worsened targeting for more-experienced surgeons., Conclusions: RA significantly improves performance for micropick fenestration in a surgical model of stapedotomy. For certain tasks, RA differentially affects performance for users of different experience levels., Clinical Significance: These are the first results showing quantitative improvements in performance during simulated ear surgery using RA and differential effects of RA on performance for users of different experience levels.