Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug...Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.展开更多
Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathologic...Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathological changes,such as amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.展开更多
A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit...A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.展开更多
Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diver...Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diverse and complex human diseases such as neurodegenerative diseases,cancers,myopathies,premature aging,and metabolic syndromes（Nunnari and Suomalainen,2012）.展开更多
BACKGROUND： Numerous studies have shown that tumor necrosis factor α （TNF-α） is closely correlated with spinal cord injury （SCI）, but the mechanisms of TNF-α and therapeutic treatments for SCI are still poorly...BACKGROUND： Numerous studies have shown that tumor necrosis factor α （TNF-α） is closely correlated with spinal cord injury （SCI）, but the mechanisms of TNF-α and therapeutic treatments for SCI are still poorly understood. OBJECTIVE： To determine the role of TNF-α in the pathogenesis of SCI. DESIGN, TIME AND SETTING： An in vivo experiment based on genetically engineered animals was performed at the Medical University of South Carolina, Charleston, South Carolina, USA, between June 2007 and October 2008. MATERIALS： TNF-α transgenic rats （Xenogen Biosciences in Cranbury, New Jersey, USA） were utilized in this study. METHODS： TNF-α transgenic （tg） and wild-type （WT） rats underwent a complete single-level laminectomy at the 10^th thoracic vertebra （T10）. MAIN OUTCOME MEASURES： Motor function of rat hindlimb was assessed using the Basso, Beattie, and Bresnahan hindlimb locomotor rating scale. Histological evaluation of spinal cord tissue loss was conducted. Immunohistochemistry for astrocytes, microglia/macrophages, and TNF receptors （TNFRs） was performed on spinal cord tissue sections. TNF-α mRNA expression was detected by real-time polymerase chain reaction. The concentrations of nerve growth factor （NGF） and brain-derived neurotrophic factor （BDNF） in the supernatant were determined using an enzyme-linked immunosorbent assay kit for rat NGF or BDNF, respectively. The rats were injected subcutaneously with etanercept to verify that TNF-α was the direct effect of the modulation of behavioral and neurodegenerative outcomes in the TNF-α tg rats. RESULTS： TNF-α tg rats showed higher expression of TNF-α mRNA in the spinal cord prior to SCI. TNF-α tg rats showed worse motor deficits than WT rats in the acute period （〈 3 days） after SCI （P 〈 0.01）, while in the chronic period, TNF-α tg rats exhibited persistent elevated baseline levels of TNF-α mRNA and improved recovery in motor function and tissue healing compared to WT rats （P 〈 0.01 ）. Following SCI, the number of microglia/macrophages in TNF-α tg rat was always greater than in WT rat （P 〈 0.01）. There were no significant differences in NGF and BDNF levels in the supernatant of spinal cord homogenates. TNFR1 expression was significantly greater in the TNF-α tg rats compared to the WT rats （P 〈 0.01）. However, TNFR2 expression did not reveal a significant increase in the TNF-α tg rats compared to the WT rats. Finally, treatment with etanercept reduced injury acutely, but exacerbated the injury chronically. CONCLUSION： Overexpression of TNF-α is deleterious in the acute phase, but beneficial in the chronic phase in the response to SCI. The role of TNF-α post-injury may depend on TNF-α expression in the spinal cord and its differential binding to TNFRI. Our observations may have clinical relevance that antagonists or inhibitors of TNF-α could be administered within the early time window post-injury, and appropriate amounts of TNF-α could be administered during the chronic stage, in order to improve the final neurological recovery in patients with SCI.展开更多
Objective:Since concussion is the most common injury in ice hockey,the objective of the current study was to elucidate risk factors,specific mechanisms,and clinical presentations of concussion in men’s and women’s i...Objective:Since concussion is the most common injury in ice hockey,the objective of the current study was to elucidate risk factors,specific mechanisms,and clinical presentations of concussion in men’s and women’s ice hockey.Methods:Ice hockey players from 5 institutions participating in the Concussion Assessment,Research,and Education Consortium were eligible for the current study.Participants who sustained a concussion outside of this sport were excluded.There were 332(250 males,82 females)athletes who participated in ice hockey,and 47(36 males,11 females)who sustained a concussion.Results:Previous concussion(odds ratio(OR)=2.00;95%confidence interval(95%CI):1.02‒3.91)was associated with increased incident concussion odds,while wearing a mouthguard was protective against incident concussion(OR=0.43;95%CI:0.22‒0.85).Overall,concussion mechanisms did not significantly differ between sexes.There were specific differences in how concussions presented clinically across male and female ice hockey players,however.Females(9.09%)were less likely than males(41.67%)to have a delayed symptom onset(p=0.045).Additionally,females took significantly longer to reach asymptomatic(p=0.015)and return-to-play clearance(p=0.005).Within the first 2 weeks post-concussion,86.11%of males reached asymptomatic,while only 45.50%of females reached the same phase of recovery.Most males(91.67%)were cleared for return to play within 3 weeks of their concussion,compared to less than half(45.50%)of females.Conclusion:The current study proposes possible risk factors,mechanisms,and clinical profiles to be validated in future concussions studies with larger female sample sizes.Understanding specific risk factors,concussion mechanisms,and clinical profiles of concussion in collegiate ice hockey may generate ideas for future concussion prevention or intervention studies.展开更多
Objective: To define the neuropathologic findings in amnestic mild cognitive impairment (MCI) and early Alzheimer disease (EAD). Methods: The mean numbers of diffuse plaques, neuritic plaques (NPs), and neurofibrillar...Objective: To define the neuropathologic findings in amnestic mild cognitive impairment (MCI) and early Alzheimer disease (EAD). Methods: The mean numbers of diffuse plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs) in 4 neocortical regions and 4 ventromedial temporal lobe regions were counted in 10 patients with amnestic MCI and compared with the mean numbers in 23 normal control subjects and 10 patients with EAD, and then were compared with memory performance. All of the controls and patients were followed longitudinally. Results: Patients with MCI showed no significant difference (P >.05) in the number of diffuse plaques from that in normal controls or patients with EAD. In patients with MCI, the number of NPs was significantly elevated in all 4 neocortical regions and amygdala compared with controls (P < .01 to < .001). There were no significant differences (P >.05) in the number of NPs between MCI and EAD cerebral cortex, but significant increases were present for NPs in EAD amygdala and subiculum compared with MCI (P< .01). In patients with MCI compared with controls, the only significant increase in NFTs in the neocortex was in the parietal lobe. However, the number of NFTs was significantly elevated in MCI in all 4 ventromedial temporal lobe structures compared with controls (P < .01 to < .001). In comparing MCI with EAD, there were significant increases in NFTs in EAD in frontal and temporal lobes, amygdala, and subiculum (P < .01). The numbers of NPs and NFTs were significantly elevated in all of the neocortical regions and ventromedial temporal lobe regions in patients with EAD compared with controls (P < .001). Memory function was significantly correlated with NFTs in CA1 of the hippocampus (P < .01) and the entorhinal cortex (P < .05). Conclusions: In patients with amnestic MCI who were followed longitudinally, the early changes of Alzheimer disease were present. The NFTs were slightly more prominent than β -amyloid peptide deposition in the progression from normal to MCI to EAD. Ventromedial temporal lobe NFTs probably represent the substrate for memory decline in MCI. From a neuropathologic perspective, it appears that amnestic MCI is, in reality, EAD.展开更多
The miR-15/107 family comprises a group of 10 paralogous microRNAs （miRNAs）,sharing a 5＇ AGCAGC sequence.These miRNAs have overlapping targets.In order to characterize the expression of miR-15/107 family miRNAs,we ...The miR-15/107 family comprises a group of 10 paralogous microRNAs （miRNAs）,sharing a 5＇ AGCAGC sequence.These miRNAs have overlapping targets.In order to characterize the expression of miR-15/107 family miRNAs,we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR-15/107 family members,and other selected miRNAs,in 11 human tissues obtained at autopsy including the cerebral cortex,frontal cortex,primary visual cortex,thalamus,heart,lung,liver,kidney,spleen,stomach and skeletal muscle.miR-103,miR-195 and miR-497 were expressed at similar levels across various tissues,whereas miR-107 is enriched in brain samples.We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations （enriched for cortical neurons,astrocytes and microglia,respectively）.In primary cultures of rat brain cells,several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system （CNS）.In addition to mature miRNAs,we also examined the expression of precursors （pri-miRNAs）.Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors.In summary,we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes.展开更多
Background:Down syndrome(DS)individuals,by the age of 40s,are at increased risk to develop Alzheimer-like dementia,with deposition in brain of senile plaques and neurofibrillary tangles.Our laboratory recently demonst...Background:Down syndrome(DS)individuals,by the age of 40s,are at increased risk to develop Alzheimer-like dementia,with deposition in brain of senile plaques and neurofibrillary tangles.Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain,prior and after the development of Alzheimer Disease(AD).The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways,including insulin signaling and autophagy,involved in pathology onset and progression.Within this context,the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena.By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol(InRapa)that maximizes brain delivery and reduce systemic side effects.Methods:Ts65Dn mice were administered with InRapa for 12 weeks,starting at 6 months of age demonstrating,at the end of the treatment by radial arms maze and novel object recognition testing,rescued cognition.Results:The analysis of mTOR signalling,after InRapa,demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR(reduced to physiological levels),which led,through the rescue of autophagy and insulin signalling,to reduced APP levels,APP processing and APP metabolites production,as well as,to reduced tau hyperphosphorylation.In addition,a reduction of oxidative stress markers was also observed.Discussion:These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis,thus ultimately resulting in improved cognition.Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.展开更多
Uncontrolled and chronic microglia activation has been implicated in the process of dopaminergic neuron degeneration in sporadic Parkinson＇s disease （PD）. Elevated proinflammatory mediators, presumably from activat...Uncontrolled and chronic microglia activation has been implicated in the process of dopaminergic neuron degeneration in sporadic Parkinson＇s disease （PD）. Elevated proinflammatory mediators, presumably from activated microglia （e.g., cytokines, PGE2, nitric oxide, and superoxide radical）, have been observed in PD patients and are accompanied by dopaminergic neuronal loss. Preclinical studies have demonstrated the deleterious effects of proinflammatory mediators in various in vivo and in vitro models of PD. The use of in vitro studies provides a unique tool to investigate the interaction between neurons and microglia and is especially valuable when considering the role of activated microglia in neuronal death. Here we summarize findings highlighting the potential mechanisms of microglia- mediated neurodegeneration in PD.展开更多
Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet ...Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet promising dis-ease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta(Aβ)is a toxic species contributing to AD through synaptic damage and neuronal toxicity[1].展开更多
基金Funding for the canine atorvastatin study was through the Alzheimer's Association IIRG-03-5673 to Elizabeth Head
文摘Alzheimer’s disease is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathology. Recent preclinical and epidemiological studies proposed statins as a possible therapeutic drug for Alzheimer’s disease, but the exact mechanisms of action are still unknown. Biliverdin reductase-A is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but its serine/threonine/ tyrosine kinase activity is able to modulate cell signaling networks. We previously reported the beneficial effects of atorvastatin treatment on biliverdin reductase-A and heme oxygenase-1 in the brains of a well characterized pre-clinical model of Alzheimer’s disease, aged beagles, together with observed improvement in cognition. Here we extend our knowledge of the effects of atorvastatin on inducible nitric oxide synthase in parietal cortex, cerebellum and liver of the same animals. We demonstrated that atorvastatin treatment （80 mg/day for 14.5 months） to aged beagles selectively increased inducible nitric oxide synthase in the parietal cortex but not in the cerebellum. In contrast, inducible nitric oxide synthase protein levels were significantly decreased in the liver. Significant positive correlations were found between biliverdin reductase-A and inducible nitric oxide synthase as well as heme oxygenase-1 protein levels in the parietal cortex. The opposite was observed in the liver. Inducible nitric oxide synthase up-regulation in the parietal cortex was positively associated with improved biliverdin reductase-A functions, whereas the oxidative-induced impairment of biliverdin reductase-A in the liver negatively affected inducible nitric oxide synthase expression, thus suggesting a role for biliverdin reductase-A in atorvastatin-dependent inducible nitric oxide synthase changes. Interestingly, increased inducible nitric oxide synthase levels in the parietal cortex were not associated with higher oxidative/nitrosative stress levels. We hypothesize that biliverdin reductase-A-dependent inducible nitric oxide synthase regulation strongly contributes to the cognitive improvement observed following atorvastatin treatment.
文摘Alzheimer's disease (AD) is the most common form of dementia,affecting millions worldwide.It is cha racterized by progressive cognitive decline and changes in behavior and personality,attributed to neuropathological changes,such as amyloid-beta (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.
基金supported in part by a Kentucky Spinal and Head Injury Trust trainee fellowshipsupported by National Institutes of Health under award numbers R00 AG044445(to ADB)P30 GM110787(to ADB)
文摘A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury（TBI）. Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life.
基金Supported by an endowment to JES from Cardinal Hill Rehabilitation Hospital
文摘Mitochondria serve as the powerhouse of cells,respond to cellular demands and stressors,and play an essential role in cell signaling,differentiation,and survival.Aberrant mitochondria function has been linked to diverse and complex human diseases such as neurodegenerative diseases,cancers,myopathies,premature aging,and metabolic syndromes（Nunnari and Suomalainen,2012）.
基金the ES016774-01A1VA Merit Award and National Science Foundation EPSCoR grant, No. EPS-0132573+1 种基金EPS-0447660 (MSK)NS050452-05 (JJH)
文摘BACKGROUND： Numerous studies have shown that tumor necrosis factor α （TNF-α） is closely correlated with spinal cord injury （SCI）, but the mechanisms of TNF-α and therapeutic treatments for SCI are still poorly understood. OBJECTIVE： To determine the role of TNF-α in the pathogenesis of SCI. DESIGN, TIME AND SETTING： An in vivo experiment based on genetically engineered animals was performed at the Medical University of South Carolina, Charleston, South Carolina, USA, between June 2007 and October 2008. MATERIALS： TNF-α transgenic rats （Xenogen Biosciences in Cranbury, New Jersey, USA） were utilized in this study. METHODS： TNF-α transgenic （tg） and wild-type （WT） rats underwent a complete single-level laminectomy at the 10^th thoracic vertebra （T10）. MAIN OUTCOME MEASURES： Motor function of rat hindlimb was assessed using the Basso, Beattie, and Bresnahan hindlimb locomotor rating scale. Histological evaluation of spinal cord tissue loss was conducted. Immunohistochemistry for astrocytes, microglia/macrophages, and TNF receptors （TNFRs） was performed on spinal cord tissue sections. TNF-α mRNA expression was detected by real-time polymerase chain reaction. The concentrations of nerve growth factor （NGF） and brain-derived neurotrophic factor （BDNF） in the supernatant were determined using an enzyme-linked immunosorbent assay kit for rat NGF or BDNF, respectively. The rats were injected subcutaneously with etanercept to verify that TNF-α was the direct effect of the modulation of behavioral and neurodegenerative outcomes in the TNF-α tg rats. RESULTS： TNF-α tg rats showed higher expression of TNF-α mRNA in the spinal cord prior to SCI. TNF-α tg rats showed worse motor deficits than WT rats in the acute period （〈 3 days） after SCI （P 〈 0.01）, while in the chronic period, TNF-α tg rats exhibited persistent elevated baseline levels of TNF-α mRNA and improved recovery in motor function and tissue healing compared to WT rats （P 〈 0.01 ）. Following SCI, the number of microglia/macrophages in TNF-α tg rat was always greater than in WT rat （P 〈 0.01）. There were no significant differences in NGF and BDNF levels in the supernatant of spinal cord homogenates. TNFR1 expression was significantly greater in the TNF-α tg rats compared to the WT rats （P 〈 0.01）. However, TNFR2 expression did not reveal a significant increase in the TNF-α tg rats compared to the WT rats. Finally, treatment with etanercept reduced injury acutely, but exacerbated the injury chronically. CONCLUSION： Overexpression of TNF-α is deleterious in the acute phase, but beneficial in the chronic phase in the response to SCI. The role of TNF-α post-injury may depend on TNF-α expression in the spinal cord and its differential binding to TNFRI. Our observations may have clinical relevance that antagonists or inhibitors of TNF-α could be administered within the early time window post-injury, and appropriate amounts of TNF-α could be administered during the chronic stage, in order to improve the final neurological recovery in patients with SCI.
文摘Objective:Since concussion is the most common injury in ice hockey,the objective of the current study was to elucidate risk factors,specific mechanisms,and clinical presentations of concussion in men’s and women’s ice hockey.Methods:Ice hockey players from 5 institutions participating in the Concussion Assessment,Research,and Education Consortium were eligible for the current study.Participants who sustained a concussion outside of this sport were excluded.There were 332(250 males,82 females)athletes who participated in ice hockey,and 47(36 males,11 females)who sustained a concussion.Results:Previous concussion(odds ratio(OR)=2.00;95%confidence interval(95%CI):1.02‒3.91)was associated with increased incident concussion odds,while wearing a mouthguard was protective against incident concussion(OR=0.43;95%CI:0.22‒0.85).Overall,concussion mechanisms did not significantly differ between sexes.There were specific differences in how concussions presented clinically across male and female ice hockey players,however.Females(9.09%)were less likely than males(41.67%)to have a delayed symptom onset(p=0.045).Additionally,females took significantly longer to reach asymptomatic(p=0.015)and return-to-play clearance(p=0.005).Within the first 2 weeks post-concussion,86.11%of males reached asymptomatic,while only 45.50%of females reached the same phase of recovery.Most males(91.67%)were cleared for return to play within 3 weeks of their concussion,compared to less than half(45.50%)of females.Conclusion:The current study proposes possible risk factors,mechanisms,and clinical profiles to be validated in future concussions studies with larger female sample sizes.Understanding specific risk factors,concussion mechanisms,and clinical profiles of concussion in collegiate ice hockey may generate ideas for future concussion prevention or intervention studies.
文摘Objective: To define the neuropathologic findings in amnestic mild cognitive impairment (MCI) and early Alzheimer disease (EAD). Methods: The mean numbers of diffuse plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs) in 4 neocortical regions and 4 ventromedial temporal lobe regions were counted in 10 patients with amnestic MCI and compared with the mean numbers in 23 normal control subjects and 10 patients with EAD, and then were compared with memory performance. All of the controls and patients were followed longitudinally. Results: Patients with MCI showed no significant difference (P >.05) in the number of diffuse plaques from that in normal controls or patients with EAD. In patients with MCI, the number of NPs was significantly elevated in all 4 neocortical regions and amygdala compared with controls (P < .01 to < .001). There were no significant differences (P >.05) in the number of NPs between MCI and EAD cerebral cortex, but significant increases were present for NPs in EAD amygdala and subiculum compared with MCI (P< .01). In patients with MCI compared with controls, the only significant increase in NFTs in the neocortex was in the parietal lobe. However, the number of NFTs was significantly elevated in MCI in all 4 ventromedial temporal lobe structures compared with controls (P < .01 to < .001). In comparing MCI with EAD, there were significant increases in NFTs in EAD in frontal and temporal lobes, amygdala, and subiculum (P < .01). The numbers of NPs and NFTs were significantly elevated in all of the neocortical regions and ventromedial temporal lobe regions in patients with EAD compared with controls (P < .001). Memory function was significantly correlated with NFTs in CA1 of the hippocampus (P < .01) and the entorhinal cortex (P < .05). Conclusions: In patients with amnestic MCI who were followed longitudinally, the early changes of Alzheimer disease were present. The NFTs were slightly more prominent than β -amyloid peptide deposition in the progression from normal to MCI to EAD. Ventromedial temporal lobe NFTs probably represent the substrate for memory decline in MCI. From a neuropathologic perspective, it appears that amnestic MCI is, in reality, EAD.
基金supported by the National Institutes of Health,USA(Grant Nos.AG042419,NS085830 and AG028 383)
文摘The miR-15/107 family comprises a group of 10 paralogous microRNAs （miRNAs）,sharing a 5＇ AGCAGC sequence.These miRNAs have overlapping targets.In order to characterize the expression of miR-15/107 family miRNAs,we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR-15/107 family members,and other selected miRNAs,in 11 human tissues obtained at autopsy including the cerebral cortex,frontal cortex,primary visual cortex,thalamus,heart,lung,liver,kidney,spleen,stomach and skeletal muscle.miR-103,miR-195 and miR-497 were expressed at similar levels across various tissues,whereas miR-107 is enriched in brain samples.We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations （enriched for cortical neurons,astrocytes and microglia,respectively）.In primary cultures of rat brain cells,several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system （CNS）.In addition to mature miRNAs,we also examined the expression of precursors （pri-miRNAs）.Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors.In summary,we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes.
基金This work was supported by the Ministry of Instruction,Universities and Research(MIUR)under the SIR program n°RBSI144MT to FDD,Jerome Lejeune Foundation with the grant#PERLUIGI/1484-PM2016A to MP and Fondi di Ateneo Progetti Grandi#RG116154C9214D1A from Sapienza University of Rome to FDD.
文摘Background:Down syndrome(DS)individuals,by the age of 40s,are at increased risk to develop Alzheimer-like dementia,with deposition in brain of senile plaques and neurofibrillary tangles.Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain,prior and after the development of Alzheimer Disease(AD).The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways,including insulin signaling and autophagy,involved in pathology onset and progression.Within this context,the therapeutic use of mTOR-inhibitors may prevent/attenuate the neurodegenerative phenomena.By our work we aimed to rescue mTOR signalling in DS mice by a novel rapamycin intranasal administration protocol(InRapa)that maximizes brain delivery and reduce systemic side effects.Methods:Ts65Dn mice were administered with InRapa for 12 weeks,starting at 6 months of age demonstrating,at the end of the treatment by radial arms maze and novel object recognition testing,rescued cognition.Results:The analysis of mTOR signalling,after InRapa,demonstrated in Ts65Dn mice hippocampus the inhibition of mTOR(reduced to physiological levels),which led,through the rescue of autophagy and insulin signalling,to reduced APP levels,APP processing and APP metabolites production,as well as,to reduced tau hyperphosphorylation.In addition,a reduction of oxidative stress markers was also observed.Discussion:These findings demonstrate that chronic InRapa administration is able to exert a neuroprotective effect on Ts65Dn hippocampus by reducing AD pathological hallmarks and by restoring protein homeostasis,thus ultimately resulting in improved cognition.Results are discussed in term of a potential novel targeted therapeutic approach to reduce cognitive decline and AD-like neuropathology in DS individuals.
文摘Uncontrolled and chronic microglia activation has been implicated in the process of dopaminergic neuron degeneration in sporadic Parkinson＇s disease （PD）. Elevated proinflammatory mediators, presumably from activated microglia （e.g., cytokines, PGE2, nitric oxide, and superoxide radical）, have been observed in PD patients and are accompanied by dopaminergic neuronal loss. Preclinical studies have demonstrated the deleterious effects of proinflammatory mediators in various in vivo and in vitro models of PD. The use of in vitro studies provides a unique tool to investigate the interaction between neurons and microglia and is especially valuable when considering the role of activated microglia in neuronal death. Here we summarize findings highlighting the potential mechanisms of microglia- mediated neurodegeneration in PD.
基金supported by grants from the National Institute on Aging(AG057780 to SMC)and by Cognition Therapeutics,Inc.
文摘Trial Registration:May 11th,2018 ClinicalTrials.gov Identifier:NCT03522129 https://clini caltr ials.gov/ct2/show/NCT03522129.Investigational therapies for Alzheimer’s disease(AD)target a wide range of mechanisms,yet promising dis-ease-modifying therapies remain a huge unmet need.Much evidence indicates that the oligomeric form of amyloid-beta(Aβ)is a toxic species contributing to AD through synaptic damage and neuronal toxicity[1].
