1   965 113 CHRONIC NEURODEGENERATIVE CONSEQUENCES OF TRAUMATIC BRAIN INJURY. TRAUMATIC BRAIN INJURY (TBI) IS A SERIOUS PUBLIC HEALTH CONCERN AND A MAJOR CAUSE OF DEATH AND DISABILITY WORLDWIDE. EACH YEAR, AN ESTIMATED 1.7 MILLION AMERICANS SUSTAIN TBI OF WHICH ~52,000 PEOPLE DIE, ~275,000 PEOPLE ARE HOSPITALIZED AND 1,365,000 PEOPLE ARE TREATED AS EMERGENCY OUTPATIENTS. CURRENTLY THERE ARE ~5.3 MILLION AMERICANS LIVING WITH TBI. TBI IS MORE OF A DISEASE PROCESS THAN OF AN EVENT THAT IS ASSOCIATED WITH IMMEDIATE AND LONG-TERM SENSOMOTOR, PSYCHOLOGICAL AND COGNITIVE IMPAIRMENTS. TBI IS THE BEST KNOWN ESTABLISHED EPIGENETIC RISK FACTOR FOR LATER DEVELOPMENT OF NEURODEGENERATIVE DISEASES AND DEMENTIA. PEOPLE SUSTAINING TBI ARE ~4 TIMES MORE LIKELY TO DEVELOP DEMENTIA AT A LATER STAGE THAN PEOPLE WITHOUT TBI. SINGLE BRAIN INJURY IS LINKED TO LATER DEVELOPMENT OF SYMPTOMS RESEMBLING ALZHEIMER'S DISEASE WHILE REPETITIVE BRAIN INJURIES ARE LINKED TO LATER DEVELOPMENT OF CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE) AND/OR DEMENTIA PUGILISTICA (DP). FURTHERMORE, GENETIC BACKGROUND OF SS-AMYLOID PRECURSOR PROTEIN (APP), APOLIPOPROTEIN E (APOE), PRESENILIN (PS) AND NEPRILYSIN (NEP) GENES IS ASSOCIATED WITH EXACERBATION OF NEURODEGENERATIVE PROCESS AFTER TBI. THIS REVIEW ENCOMPASSES ACUTE EFFECTS AND CHRONIC NEURODEGENERATIVE CONSEQUENCES AFTER TBI.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  1344  25 DETECTION OF BRAIN AMYLOID BETA DEPOSITION IN PATIENTS WITH NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TRAUMATIC BRAIN INJURY: PET EVALUATION USING PITTSBURGH COMPOUND-B. OBJECTIVE: TRAUMATIC BRAIN INJURY (TBI) IS AN EPIGENETIC RISK FACTOR FOR ALZHEIMER'S DISEASE (AD) AND AMYLOID BETA (ABETA) DEPOSITION IS OBSERVED HISTOPATHOLOGICALLY IN THE TRAUMATIZED BRAIN. THIS STUDY WAS CONDUCTED TO DETECT CEREBRAL ABETA DEPOSITION USING AMYLOID POSITRON EMISSION TOMOGRAPHY (PET) IN PATIENTS WITH NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TBI. METHODS: TWELVE PATIENTS WITH POST-TRAUMATIC NEUROPSYCHOLOGICAL IMPAIRMENT (11 MEN AND ONE WOMAN, AGE RANGE = 21-78 YEARS) WERE EXAMINED USING PITTSBURGH COMPOUND B ((11)C-PIB) PET AT THE CHRONIC STAGE AFTER TBI (RANGE = 5-129 MONTHS). RESULTS: (11)C-PIB WAS POSITIVE IN THREE PATIENTS AND NEGATIVE IN THE OTHER NINE PATIENTS. THERE WAS NO CORRELATION BETWEEN (11)C-PIB DEPOSITION AND THE SEVERITY OF INJURY; INITIAL CT FINDINGS; ELAPSED TIME FROM THE INJURY; AND NEUROPSYCHOLOGICAL TEST SCORES. CONCLUSIONS: THE ABSENCE OF ABETA DEPOSITION IN MANY PATIENTS WITH CHRONIC NEUROPSYCHOLOGICAL IMPAIRMENT AFTER TBI DOES NOT SUPPORT THE PREMISE THAT ABETA PATHOLOGY PROGRESSES OVER TIME IN THE TRAUMATIZED BRAIN. EARLY AND SEQUENTIAL (11)C-PIB PET EXAMINATION MAY CLARIFY THE TIME COURSE OF ABETA DEPOSITION IN THE TRAUMATIZED BRAIN AND THE RELATIONSHIP BETWEEN TRAUMATIC BRAIN INSULT AND SUBSEQUENT NEUROPSYCHOLOGICAL IMPAIRMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3  1459  35 DISORDERED APP METABOLISM AND NEUROVASCULATURE IN TRAUMA AND AGING: COMBINED RISKS FOR CHRONIC NEURODEGENERATIVE DISORDERS. TRAUMATIC BRAIN INJURY (TBI), ADVANCED AGE, AND CEREBRAL VASCULAR DISEASE ARE FACTORS CONFERRING INCREASED RISK FOR LATE ONSET ALZHEIMER'S DISEASE (AD). THESE CONDITIONS ARE ALSO RELATED PATHOLOGICALLY THROUGH MULTIPLE INTERACTING MECHANISMS. THE HALLMARK PATHOLOGY OF AD CONSISTS OF PATHOLOGICAL AGGREGATES OF AMYLOID-BETA (ABETA) PEPTIDES AND TAU PROTEINS. THESE MOLECULES ARE ALSO INVOLVED IN NEUROPATHOLOGY OF SEVERAL OTHER CHRONIC NEURODEGENERATIVE DISEASES, AND ARE UNDER INTENSE INVESTIGATION IN THE AFTERMATH OF TBI AS POTENTIAL CONTRIBUTORS TO THE RISK FOR DEVELOPING AD AND CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE). THE PATHOLOGY OF TBI IS COMPLEX AND DEPENDENT ON INJURY SEVERITY, AGE-AT-INJURY, AND LENGTH OF TIME BETWEEN INJURY AND NEUROPATHOLOGICAL EVALUATION. IN ADDITION, THE MECHANISMS INFLUENCING PATHOLOGY AND RECOVERY AFTER TBI LIKELY INVOLVE GENETIC/EPIGENETIC FACTORS AS WELL AS ADDITIONAL DISORDERS OR COMORBID STATES RELATED TO AGE AND CENTRAL AND PERIPHERAL VASCULAR HEALTH. IN THIS REGARD, DYSFUNCTION OF THE AGING NEUROVASCULAR SYSTEM COULD BE AN IMPORTANT LINK BETWEEN TBI AND CHRONIC NEURODEGENERATIVE DISEASES, EITHER AS A PRECIPITATING EVENT OR RELATED TO ACCUMULATION OF AD-LIKE PATHOLOGY WHICH IS AMPLIFIED IN THE CONTEXT OF AGING. THUS WITH ADVANCED AGE AND VASCULAR DYSFUNCTION, TBI CAN TRIGGER SELF-PROPAGATING CYCLES OF NEURONAL INJURY, PATHOLOGICAL PROTEIN AGGREGATION, AND SYNAPTIC LOSS RESULTING IN CHRONIC NEURODEGENERATIVE DISEASE. IN THIS REVIEW WE DISCUSS EVIDENCE SUPPORTING TBI AND AGING AS DUAL, INTERACTING RISK FACTORS FOR AD, AND THE ROLE OF ABETA AND CEREBRAL VASCULAR DYSFUNCTION IN THIS RELATIONSHIP. EVIDENCE IS DISCUSSED THAT ABETA IS INVOLVED IN CYTO- AND SYNAPTO-TOXICITY AFTER SEVERE TBI, AND THAT ITS CHRONIC EFFECTS ARE POTENTIATED BY AGING AND IMPAIRED CEREBRAL VASCULAR FUNCTION. FROM A THERAPEUTIC PERSPECTIVE, WE EMPHASIZE THAT IN THE FIELDS OF TBI- AND AGING-RELATED NEURODEGENERATION PROTECTIVE STRATEGIES SHOULD INCLUDE PRESERVATION OF NEUROVASCULAR FUNCTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  6039  25 THE CHEMOKINE RECEPTOR CXCR2 SUPPORTS NOCICEPTIVE SENSITIZATION AFTER TRAUMATIC BRAIN INJURY. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. CHEMOKINE RECEPTORS PLAY AN IMPORTANT ROLE IN BOTH PAIN AND BRAIN INJURY. IN THE CURRENT WORK, WE PURSUED THE HYPOTHESIS THAT THE EPIGENETICALLY REGULATED CXC CHEMOKINE RECEPTOR 2 (CXCR2) IS A CRUCIAL MODULATOR OF NOCICEPTIVE SENSITIZATION INDUCED BY TBI. FOR THESE STUDIES, WE USED THE RAT LATERAL FLUID PERCUSSION MODEL OF TBI. HISTONE ACTYLTRANSFERASE ACTIVITY WAS BLOCKED USING ANACARDIC ACID BEGINNING IMMEDIATELY FOLLOWING INJURY, OR DELAYED FOR SEVEN DAYS PRIOR TO ADMINISTRATION. THE SELECTIVE CXCR2 ANTAGONIST SCH527123 ADMINISTERED SYSTEMICALLY OR INTRATHECALLY WAS USED TO PROBE THE ROLE OF CHEMOKINE SIGNALING ON MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE EXPRESSION OF THE CXCR2 RECEPTOR WAS ACCOMPLISHED USING REAL-TIME PCR, IMMUNOHISTOCHEMISTRY, AND WESTERN BLOTTING, WHILE EPIGENETIC REGULATION WAS ASSESSED USING CHROMATIN IMMUNOPRECIPITATION ASSAY. THE SPINAL LEVELS OF SEVERAL PAIN-RELATED MEDIATORS INCLUDING CXCL1, AN ENDOGENOUS LIGAND FOR CXCR2, AS WELL AS BRAIN-DERIVED NEUROTROPHIC FACTOR AND PRODYNORPHIN WERE MEASURED BY ENZYME-LINKED IMMUNOSORBENT ASSAY. WE OBSERVED THAT ANACARDIC ACID POTENTLY BLOCKED AND REVERSED MECHANICAL HINDPAW SENSITIZATION AFTER TBI. THE SAME DRUG WAS ABLE TO PREVENT THE UPREGULATION OF CXCR2 AFTER TBI, BUT DID NOT AFFECT THE SPINAL EXPRESSION OF OTHER PAIN MEDIATORS. ON THE OTHER HAND, BOTH SYSTEMICALLY AND INTRATHECALLY ADMINISTERED SCH527123 REVERSED HINDPAW ALLODYNIA AFTER TBI. MOST OF THE SPINAL CXCR2 APPEARED TO BE EXPRESSED BY SPINAL CORD NEURONS. CHROMATIN IMMUNOPRECIPITATION EXPERIMENTS DEMONSTRATED TBI-ENHANCED ASSOCIATION OF THE CXCR2 PROMOTER WITH ACETYLATED-H3K9 HISTONE PROTEIN THAT WAS ALSO REVERSIBLE USING ANACARDIC ACID. TAKEN TOGETHER, OUR FINDINGS SUGGESTED THAT TBI CAUSES THE UPREGULATION OF SPINAL CXCR2 THROUGH AN EPIGENETIC MECHANISM ULTIMATELY SUPPORTING NOCICEPTIVE SENSITIZATION. THE USE OF CXCR2 ANTAGONISTS MAY, THEREFORE, BE USEFUL IN PAIN RESULTING FROM TBI.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  5954  23 TBI-INDUCED NOCICEPTIVE SENSITIZATION IS REGULATED BY HISTONE ACETYLATION. CHRONIC PAIN AFTER TRAUMATIC BRAIN INJURY (TBI) IS VERY COMMON, BUT THE MECHANISMS LINKING TBI TO PAIN AND THE PAIN-RELATED INTERACTIONS OF TBI WITH PERIPHERAL INJURIES ARE POORLY UNDERSTOOD. IN THESE STUDIES WE PURSUED THE HYPOTHESIS THAT TBI PAIN SENSITIZATION IS ASSOCIATED WITH HISTONE ACETYLATION IN THE RAT LATERAL FLUID PERCUSSION MODEL. SOME ANIMALS RECEIVED HINDPAW INCISIONS IN ADDITION TO TBI TO MIMIC POLYTRAUMA. NEUROPATHOLOGICAL ANALYSIS OF BRAIN TISSUE FROM SHAM AND TBI ANIMALS REVEALED EVIDENCE OF BLEEDING, BREAKDOWN OF THE BLOOD BRAIN BARRIER, IN THE CORTEX, HIPPOCAMPUS, THALAMUS AND OTHER STRUCTURES RELATED TO PAIN SIGNAL PROCESSING. MECHANICAL ALLODYNIA WAS MEASURED IN THESE ANIMALS FOR UP TO EIGHT WEEKS POST-INJURY. INHIBITORS OF HISTONE ACETYLTRANSFERASE (HAT) AND HISTONE DEACETYLASE (HDAC) WERE USED TO PROBE THE ROLE OF HISTONE ACETYLATION IN SUCH PAIN PROCESSING. WE FOLLOWED SERUM MARKERS INCLUDING GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP), NEURON-SPECIFIC ENOLASE 2 (NSE) MYELIN BASIC PROTEIN (MBP) AND S100BETA TO GAUGE TBI INJURY SEVERITY. OUR RESULTS SHOWED THAT TBI CAUSED MECHANICAL ALLODYNIA IN THE HINDPAWS OF THE RATS LASTING SEVERAL WEEKS. HINDPAWS CONTRALATERAL TO TBI SHOWED MORE RAPID AND PROFOUND SENSITIZATION THAN IPSILATERAL HINDPAWS. THE INHIBITION OF HAT USING CURCUMIN 50 MG/KG S.C REDUCED MECHANICAL SENSITIZATION WHILE THE HDAC INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID 50 MG/KG I.P. PROLONGED SENSITIZATION IN THE TBI RATS. IMMUNOHISTOCHEMICAL ANALYSES OF SPINAL CORD TISSUE LOCALIZED CHANGES IN THE LEVEL OF ACETYLATION OF THE H3K9 HISTONE MARK TO DORSAL HORN NEURONS. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE THAT TBI INDUCES SUSTAINED NOCICEPTIVE SENSITIZATION, AND CHANGES IN SPINAL NEURONAL HISTONE PROTEINS MAY PLAY AN IMPORTANT ROLE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  2827  22 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7  6367  32 THE ROLE OF MICROGLIA IN THE ETIOLOGY AND EVOLUTION OF CHRONIC TRAUMATIC ENCEPHALOPATHY. CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE) IS A PROGRESSIVE NEURODEGENERATIVE DISEASE THAT PRESENTS AS A LATE SEQUELA FROM TRAUMATIC BRAIN INJURY (TBI). TBI IS A GROWING AND UNDER-RECOGNIZED PUBLIC HEALTH CONCERN WITH A HIGH DEGREE OF MORBIDITY AND LARGE ASSOCIATED GLOBAL COSTS. WHILE THE IMMUNE RESPONSE TO TBI IS COMPLEX, ITS CONTRIBUTION TO THE DEVELOPMENT OF CTE REMAINS LARGELY UNKNOWN. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE LINK BETWEEN CTE AND THE RESIDENT INNATE IMMUNE SYSTEM OF THE BRAIN-MICROGLIA. WE DISCUSS THE NEUROPATHOLOGY UNDERLYING CTE INCLUDING THE CREATION AND AGGREGATION OF PHOSPHORYLATED TAU PROTEIN INTO NEUROFIBRILLARY TANGLES AND THE FORMATION OF AMYLOID BETA DEPOSITS. WE ALSO PRESENT HOW MICROGLIA, THE RESIDENT INNATE IMMUNE CELLS OF THE BRAIN, DRIVE THE CONTINUOUS LOW-LEVEL INFLAMMATION ASSOCIATED WITH THE INSIDIOUS ONSET OF CTE. IN THIS REVIEW, WE CONCLUDE THAT THE LATENCY PERIOD BETWEEN THE INDEX BRAIN INJURY AND THE LONG-TERM DEVELOPMENT OF CTE PRESENTS AN OPPORTUNITY FOR THERAPEUTIC INTERVENTION. ENCOURAGING ADVANCES WITH MICROTUBULE STABILIZERS, CIS P-TAU ANTIBODIES, AND THE ABILITY TO THERAPEUTICALLY ALTER THE INFLAMMATORY STATE OF MICROGLIA HAVE SHOWN POSITIVE RESULTS IN BOTH ANIMAL AND HUMAN TRIALS. LOOKING FORWARD, RECENT ADVANCEMENTS IN NEXT-GENERATION SEQUENCING TECHNOLOGY FOR THE STUDY OF GENOMIC, TRANSCRIPTOMIC, AND EPIGENETIC INFORMATION WILL PROVIDE AN OPPORTUNITY FOR SIGNIFICANT ADVANCEMENT IN OUR UNDERSTANDING OF PROREPAIR AND PRO-INJURY GENE SIGNATURES ALLOWING FOR TARGETED INTERVENTION IN THIS HIGHLY MORBID INJURY PROCESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  4640  25 NEURONAL NUCLEAR CALCIUM SIGNALING SUPPRESSION OF MICROGLIAL REACTIVITY IS MEDIATED BY OSTEOPROTEGERIN AFTER TRAUMATIC BRAIN INJURY. BACKGROUND: TRAUMATIC BRAIN INJURY (TBI) IS CHARACTERIZED BY MASSIVE CHANGES IN NEURONAL EXCITATION, FROM ACUTE EXCITOTOXICITY TO CHRONIC HYPER- OR HYPOEXCITABILITY. NUCLEAR CALCIUM SIGNALING PATHWAYS ARE INVOLVED IN TRANSLATING CHANGES IN SYNAPTIC INPUTS AND NEURONAL ACTIVITY INTO DISCRETE TRANSCRIPTIONAL PROGRAMS WHICH NOT ONLY AFFECT NEURONAL SURVIVAL AND SYNAPTIC INTEGRITY, BUT ALSO THE CROSSTALK BETWEEN NEURONS AND GLIAL CELLS. HERE, WE REPORT THE EFFECTS OF BLUNTING NEURONAL NUCLEAR CALCIUM SIGNALS IN THE CONTEXT OF TBI. METHODS: WE USED AAV VECTORS TO EXPRESS THE GENETICALLY ENCODED AND NUCLEAR-TARGETED CALCIUM BUFFER PARVALBUMIN (PV.NLS.MCHERRY) OR THE CALCIUM/CALMODULIN BUFFER CAMBP4.MCHERRY IN NEURONS ONLY. UPON TBI, THE EXTENT OF NEUROINFLAMMATION, NEURONAL DEATH AND SYNAPTIC LOSS WERE ASSESSED BY IMMUNOHISTOCHEMISTRY AND TARGETED TRANSCRIPTOME ANALYSIS. MODULATION OF THE OVERALL LEVEL OF NEURONAL ACTIVITY WAS ACHIEVED BY PSAM/PSEM CHEMOGENETICS TARGETED TO PARVALBUMIN INTERNEURONS. THE FUNCTIONAL IMPACT OF NEURONAL NUCLEAR CALCIUM BUFFERING IN TBI WAS ASSESSED BY QUANTIFICATION OF SPONTANEOUS WHISKING. RESULTS: BUFFERING NEURONAL NUCLEAR CALCIUM UNEXPECTEDLY RESULTED IN A MASSIVE AND LONG-LASTING INCREASE IN THE RECRUITMENT OF REACTIVE MICROGLIA TO THE INJURY SITE, WHICH WAS CHARACTERIZED BY A DISEASE-ASSOCIATED AND PHAGOCYTIC PHENOTYPE. THIS EFFECT WAS ACCOMPANIED BY A SUBSTANTIAL SURGE IN SYNAPTIC LOSS AND SIGNIFICANTLY REDUCED WHISKING ACTIVITY. TRANSCRIPTOME ANALYSIS REVEALED A COMPLEX EFFECT OF TBI IN THE CONTEXT OF NEURONAL NUCLEAR CALCIUM BUFFERING, WITH UPREGULATION OF COMPLEMENT FACTORS, CHEMOKINES AND INTERFERON-RESPONSE GENES, AS WELL AS THE DOWNREGULATION OF SYNAPTIC GENES AND EPIGENETIC REGULATORS COMPARED TO CONTROL CONDITIONS. NOTABLY, NUCLEAR CALCIUM BUFFERING LED TO A SUBSTANTIAL LOSS IN NEURONAL OSTEOPROTEGERIN (OPG), WHEREAS STIMULATION OF NEURONAL FIRING INDUCED OPG EXPRESSION. VIRAL RE-EXPRESSION OF OPG RESULTED IN DECREASED MICROGLIAL RECRUITMENT AND SYNAPTIC LOSS. OPG UPREGULATION WAS ALSO OBSERVED IN THE CSF OF HUMAN TBI PATIENTS, UNDERSCORING ITS TRANSLATIONAL VALUE. CONCLUSION: NEURONAL NUCLEAR CALCIUM SIGNALS REGULATE THE DEGREE OF MICROGLIAL RECRUITMENT AND REACTIVITY UPON TBI VIA, AMONG OTHERS, OSTEOPROTEGERIN SIGNALS. OUR FINDINGS SUPPORT A MODEL WHEREBY NEURONAL ACTIVITY ALTERED AFTER TBI EXERTS A POWERFUL IMPACT ON THE NEUROINFLAMMATORY CASCADE, WHICH IN TURN CONTRIBUTES TO THE OVERALL LOSS OF SYNAPSES AND FUNCTIONAL IMPAIRMENT.	2022	
                                                                                                                                                                                                                                                                                                             
9  4525  20 MULTIFACTORIAL CAUSES OF PARANOID SCHIZOPHRENIA WITH AUDITORY-VISUAL HALLUCINATIONS IN A 31-YEAR-OLD MALE WITH HISTORY OF TRAUMATIC BRAIN INJURY AND SUBSTANCE ABUSE. SCHIZOPHRENIA IS A CHRONIC PSYCHIATRIC DISORDER THAT CLASSICALLY PRESENTS WITH DISTORTIONS OF THOUGHT, BEHAVIOR, AND PERCEPTIONS THAT ARE OFTEN MISDIAGNOSED. ONE DIFFICULTY IN DIAGNOSING SCHIZOPHRENIA IS DUE TO ITS PHENOTYPICALLY HETEROGENEOUS CONDITION THAT CAN BE PRECIPITATED BY A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. THE PREVALENCE OF SCHIZOPHRENIA IS ROUGHLY 1%, BUT IT IS OFTEN MISDIAGNOSED. POSSIBLE DIFFERENTIAL DIAGNOSES INCLUDE DEPRESSION OR BIPOLAR DISORDER WITH PSYCHOSIS, PSYCHOSIS DUE TO A MEDICAL CONDITION, SCHIZOTYPAL AND SCHIZOID PERSONALITY DISORDERS, AND NEUROCOGNITIVE DISORDERS. IN THIS CASE REPORT, A 31-YEAR-OLD MALE PRESENTS WITH THOUGHTS OF SUICIDE FOLLOWING A RECENT EXACERBATION OF HIS HALLUCINATIONS. ON PRESENTATION, THE PATIENT PRESENTED WITH A HISTORICAL DIAGNOSIS OF "PARANOID SCHIZOPHRENIA" AS WELL AS A HISTORY OF TRAUMATIC BRAIN INJURY (TBI), POLY-SUBSTANCE USE DISORDER, AND A FAMILY HISTORY OF SCHIZOPHRENIA. THIS CASE SERVES TO HIGHLIGHT THE DIFFICULTIES OF MAKING AN ACCURATE DIAGNOSIS AND PROVIDING EVIDENCED-BASED TREATMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10   103  25 A REHABILOMICS FRAMEWORK FOR PERSONALIZED AND TRANSLATIONAL REHABILITATION RESEARCH AND CARE FOR INDIVIDUALS WITH DISABILITIES: PERSPECTIVES AND CONSIDERATIONS FOR SPINAL CORD INJURY. DESPITE MANY PEOPLE HAVING SIMILAR CLINICAL PRESENTATION, DEMOGRAPHIC FACTORS, AND CLINICAL CARE, OUTCOME CAN DIFFER FOR THOSE SUSTAINING SIGNIFICANT INJURY SUCH AS SPINAL CORD INJURY (SCI) AND TRAUMATIC BRAIN INJURY (TBI). IN ADDITION TO TRADITIONAL DEMOGRAPHIC, SOCIAL, AND CLINICAL FACTORS, VARIABILITY ALSO MAY BE ATTRIBUTABLE TO INNATE (INCLUDING GENETIC, TRANSCRIPTOMIC PROTEOMIC, EPIGENETIC) BIOLOGICAL VARIATION THAT INDIVIDUALS BRING TO RECOVERY AND THEIR UNIQUE RESPONSE TO THEIR CARE AND ENVIRONMENT. TECHNOLOGIES COLLECTIVELY CALLED "-OMICS" ENABLE SIMULTANEOUS MEASUREMENT OF AN ENORMOUS NUMBER OF BIOMOLECULES THAT CAN CAPTURE MANY POTENTIAL BIOLOGICAL CONTRIBUTORS TO HETEROGENEITY OF INJURY/DISEASE COURSE AND OUTCOME. DUE TO THE NATURE OF INJURY AND COMPLEX DISEASE, AND ITS ASSOCIATIONS WITH IMPAIRMENT, DISABILITY, AND RECOVERY, REHABILITATION DOES NOT LEND ITSELF TO A SINGULAR "PROTOCOLIZED" PLAN OF THERAPY. YET, BY NATURE AND BY NECESSITY, REHABILITATION MEDICINE OPERATES AS A FUNCTIONAL MODEL OF "PERSONALIZED CARE". THUS, THE CHALLENGE FOR SUCCESSFUL PROGRAMS OF TRANSLATIONAL REHABILITATION CARE AND RESEARCH IS TO IDENTIFY VIABLE APPROACHES TO EXAMINE BROAD POPULATIONS, WITH VARIED IMPAIRMENTS AND FUNCTIONAL LIMITATIONS, AND TO IDENTIFY EFFECTIVE TREATMENT RESPONSES THAT INCORPORATE PERSONALIZED PROTOCOLS TO OPTIMIZE FUNCTIONAL RECOVERY. THE REHABILOMICS FRAMEWORK IS A TRANSLATIONAL MODEL THAT PROVIDES AN "-OMICS" OVERLAY TO THE SCIENTIFIC STUDY OF REHABILITATION PROCESSES AND MULTIDIMENSIONAL OUTCOMES. REHABILOMICS RESEARCH PROVIDES NOVEL OPPORTUNITIES TO EVALUATE THE NEUROBIOLOGY OF COMPLEX INJURY OR CHRONIC DISEASE AND CAN BE USED TO EXAMINE METHODS AND TREATMENTS FOR PERSON-CENTERED CARE AMONG POPULATIONS WITH DISABILITIES. EXEMPLARS FOR APPLICATION IN SCI AND OTHER NEUROREHABILITATION POPULATIONS ARE DISCUSSED.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  1829  19 EFFECTS OF INHIBITING ASTROCYTES AND BET/BRD4 CHROMATIN READER ON SPATIAL MEMORY AND SYNAPTIC PROTEINS IN RATS WITH ALZHEIMER'S DISEASE. COMMUNICATION BETWEEN ASTROCYTES AND NEURONS HAS A PROFOUND EFFECT ON THE PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE (AD). ASTROCYTES REGULATE HOMEOSTASIS AND INCREASE SYNAPTIC PLASTICITY IN PHYSIOLOGICAL SITUATIONS, HOWEVER, THEY BECOME ACTIVATED DURING THE PROGRESSION OF AD. WHETHER OR NOT THESE REACTIONS ARE SUPPORTIVE OR DETRIMENTAL FOR THE CENTRAL NERVOUS SYSTEM HAVE NOT BEEN UNDERSTOOD YET. CONSIDERING EPIGENETIC REGULATION OF NEUROINFLAMMATORY GENES BY CHROMATIN READERS, PARTICULARLY BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) FAMILY, HERE WE EXAMINED THE EFFECT OF CHRONIC CO-INHIBITION OF ASTROCYTES METABOLISM (WITH FLUOROCITRATE) AND ALSO BRD4 (WITH JQ1) ON COGNITION DEFICIT AT EARLY STAGES OF AD. FORTY ADULT MALE WISTAR RATS UNDERWENT STEREOTAXIC CANNULATION FOR INDUCING AD BY INTRAHIPPOCAMPAL INJECTION OF ABETA(1-42) (4 MUG/8 MUL/RAT). THEN ANIMALS WERE DIVIDED INTO FIVE GROUPS OF SALINE+DMSO, ABETA + SALINE+DMSO, ABETA + JQ1, ABETA + FC (FLUOROCITRATE), AND ABETA + JQ1 + FC AND RECEIVED THE RELATED TREATMENTS. TWO WEEKS LATER, SPATIAL MEMORY WAS RECORDED BY MORRIS WATER MAZE (MWM), AND THE LEVELS OF PHOSPHORYLATED CYCLIC-AMP RESPONSE ELEMENT BINDING PROTEIN (CREB), POSTSYNAPTIC DENSITY 95 (PSD95), SYNAPTOPHYSIN (SYP), AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) WERE MEASURED IN THE HIPPOCAMPUS BY WESTERN BLOTTING AND RT-QPCR. ADMINISTRATION OF JQ1 SIGNIFICANTLY IMPROVED BOTH ACQUISITION AND RETRIEVAL OF SPATIAL MEMORY, WHICH WERE EVIDENT BY DECREASED ESCAPE LATENCY AND INCREASED TOTAL TIME SPENT (TTS) IN TARGET QUADRANT, AND SIGNIFICANT RISE IN P-CREB, PSD95, AND SYNAPTOPHYSIN COMPARED WITH ABETA + SALINE+DMSO GROUP. IN CONTRAST, BOTH GROUPS RECEIVING FC DEMONSTRATED MEMORY DECLINE, AND REDUCTION IN P-CREB, PSD95 AND SYNAPTOPHYSIN IN PARALLEL WITH INCREASE IN TNF-ALPHA. OUR DATA INDICATE THAT CHRONIC INHIBITION OF BRD4 SIGNIFICANTLY RESTORES MEMORY IMPAIRED BY AMYLOID BETA PARTLY VIA CREB SIGNALING AND UPREGULATING SYNAPTIC PROTEINS OF PSD95 AND SYNAPTOPHYSIN. HOWEVER, INHIBITION OF ASTROCYTES NULLIFIES THE MEMORY-BOOSTING EFFECTS OF JQ1 AND REDUCES CREB/PSD95/SYNAPTOPHYSIN LEVELS IN HIPPOCAMPUS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12  6108  24 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS.	2019	

13  6893  22 [SLEEP AND DEMENTIA]. AGING IS ASSOCIATED WITH CHANGES IN SLEEP STRUCTURE AND CEREBRAL DEPOSITION OF AMYLOID BETA AND TAU PROTEINS. SLEEP DISTURBANCES PRECEDE THE ONSET OF DEMENTIA BY YEARS. COMORBID SLEEP DISORDERS, SUCH AS INSOMNIA AND SLEEP-DISORDERED BREATHING, A FAMILY HISTORY OF DEMENTIA AND EPIGENETIC FACTORS CAN CONTRIBUTE TO THE DEVELOPMENT OF DEMENTIA. THIS ARTICLE EXPLORES THE QUESTION OF THE INTERACTION BETWEEN SLEEP AND DEMENTIA BASED ON THE EXISTING LITERATURE. ALTERATIONS CAUSED BY SLOW WAVE SLEEP LEAD TO CHANGES IN THE GLYMPHATIC CLEARANCE OF AMYLOID BETA, TAU PROTEINS AND OTHER PROTEINS. TRANSIENT AND CHRONIC SLEEP DISORDERS CAUSE DISTURBANCES IN THE BRAIN AREAS RESPONSIBLE FOR COGNITION AND BEHAVIOR. SLEEP-REGULATING BRAIN AREAS ARE THE FIRST TO BE AFFECTED IN THE NEURODEGENERATIVE PROCESS AND ACCELERATE THE RISK OF DEMENTIA. CIRCADIAN AGE-RELATED CHANGES IN AMYLOID BETA AND TAU PROTEINS AFFECT THE AMOUNT AND DEPTH OF SLEEP AND VICE VERSA. AMYLOID BETA IN CEREBROSPINAL FLUID SHOWS AN INVERSE CORRELATION WITH SLEEP. OREXINS MODULATE AMYLOID BETA AND SLEEP.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  3559  31 IMPACT OF CHRONIC CONDITIONS AND DEMENTIA IN RURAL WEST TEXAS: A HEALTHY AGING STUDY. ALZHEIMER'S DISEASE (AD) IS A DEVASTATING ILLNESS IN ELDERLY INDIVIDUALS, THAT CURRENTLY HAS NO KNOWN CURE. CAUSAL GENETIC FACTORS ONLY ACCOUNT FOR 1-2% OF AD PATIENTS. HOWEVER, OTHER CAUSAL FACTORS ARE STILL UNKNOWN FOR A MAJORITY OF AD PATIENTS. CURRENTLY, MULTIPLE FACTORS ARE IMPLICATED IN LATE-ONSET AD, INCLUDING UNHEALTHY DIET, PHYSICAL INACTIVITY, TRAUMATIC BRAIN INJURY, CHRONIC CONDITIONS, EPIGENETIC FACTORS, AND ENVIRONMENTAL EXPOSURES. ALTHOUGH CLINICAL SYMPTOMS OF DEMENTIA ARE COMMON TO ALL RACES AND ETHNIC GROUPS, CONDITIONS THAT LEAD TO DEMENTIA ARE DIFFERENT IN TERMS OF LIFESTYLE, GENETIC PROFILE, AND SOCIO-ECONOMIC CONDITIONS. INCREASING EVIDENCE ALSO SUGGESTS THAT SOME ELDERLY INDIVIDUALS AGE WITHOUT COGNITIVE IMPAIRMENTS IN THEIR 60-90S AS SEEN IN RURAL WEST TEXAS, WHILE SOME INDIVIDUALS PROGRESS WITH CHRONIC CONDITIONS AND COGNITIVE IMPAIRMENTS INTO THEIR 60S. TO UNDERSTAND THESE DISCRIMINATIONS, WE ASSESSED CURRENT LITERATURE ON DEMOGRAPHIC FEATURES OF HEALTH IN RURAL WEST TEXAS. THIS PAPER ALSO OUTLINES OUR INITIATED CLINICAL STUDY WITH A PURPOSE OF UNDERSTANDING THE FACTORS THAT ALLOW SOME INDIVIDUALS TO LIVE WITHOUT COGNITIVE IMPAIRMENTS AT THE AGE OF 60-90 YEARS, WHEREAS OTHERS DEVELOP DEFICITS IN COGNITIVE FUNCTION AROUND OR ABOVE 60 YEARS. OUR ONGOING STUDY HOPES TO DETERMINE THE FACTORS THAT DELAY AGING IN SOME INDIVIDUALS BY INVESTIGATING VARIOUS ASPECTS INCLUDING GENETICS, EPIGENETICS, ETHNICITY, BIOLOGY, CULTURE, AND LIFESTYLE. THIS WILL BE ACHIEVED BY GATHERING INFORMATION ABOUT PARTICIPANTS' ETHNOGRAPHIC PROFILES, COGNITIVE ASSESSMENTS, BLOOD-PROFILES, BRAIN SCANS, AND BLOOD-BASED GENOMIC ANALYSES IN RELATION TO LIFESTYLE. THE OUTCOMES OF OUR STUDY WILL PROVIDE INSIGHTS INTO HEALTHY AGING IN RURAL WEST TEXAS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15   190  16 ACETYL-L-CARNITINE IN PAINFUL PERIPHERAL NEUROPATHY: A SYSTEMATIC REVIEW. ACETYL-L-CARNITINE (ALC) HAS SHOWN A NEUROPROTECTIVE EFFECT IN PATIENTS WITH PERIPHERAL NEUROPATHIES OF DIFFERENT ETIOLOGIES. PRECLINICAL STUDIES DEMONSTRATED A CENTRAL ANTI-NOCICEPTIVE ACTION, BOTH IN NEUROPATHIC AND NOCICEPTIVE PAIN MODELS. THE PRESENT REVIEW AIMS TO PROVIDE THE KNOWLEDGE ON THE EFFICACY OF ALC IN PATIENTS WITH PAINFUL PERIPHERAL NEUROPATHY, BASED ON THE EVIDENCE. CONSISTENT WITH THE PRISMA STATEMENT, AUTHORS SEARCHED PUBMED, EMBASE AND THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS FOR RELEVANT PAPERS, INCLUDING THOSE ISSUED BEFORE APRIL 2018. TWO AUTHORS INDEPENDENTLY SELECTED STUDIES FOR INCLUSION AND DATA EXTRACTION: ONLY TRIALS INCLUDING PATIENTS WITH A DIAGNOSIS OF PERIPHERAL NEUROPATHY AND INVOLVING AT LEAST 10 PATIENTS WERE CONSIDERED FOR THE PURPOSES OF THIS REVIEW. FOURTEEN CLINICAL TRIALS WERE REVISED, TO PROVIDE THE LEVEL OF EVIDENCE FOR NEUROPATHY. TO ASSESS THE GLOBAL EFFICACY OF ALC IN PAINFUL PERIPHERAL NEUROPATHY, A META-ANALYSIS OF FOUR RANDOMIZED CONTROLLED TRIALS WAS PERFORMED. MEAN DIFFERENCE IN PAIN REDUCTION AS MEASURED ON A 10-CM VAS, AND 95% CIS WERE USED FOR POOLING CONTINUOUS DATA FROM EACH TRIAL. FOUR RANDOMIZED CONTROLLED TRIALS TESTED ALC IN PATIENTS WITH NEUROPATHY SECONDARY TO DIABETES AND TO ANTIRETROVIRAL THERAPY FOR HIV. COMPARED TO PLACEBO, ALC PRODUCED A SIGNIFICANT PAIN REDUCTION EQUAL TO 20.2% (95% CI: 8.3%-32.1%, P<0.0001) WITH RESPECT TO BASELINE. CLINICAL TRIALS ALSO SHOWED BENEFICIAL EFFECTS ON NERVE CONDUCTION PARAMETERS AND NERVE FIBER REGENERATION, WITH A GOOD SAFETY PROFILE. THESE DATA INDICATE THAT ALC PROVIDES AN EFFECTIVE AND SAFE TREATMENT IN PATIENTS WITH PAINFUL PERIPHERAL NEUROPATHY. WE RECOMMEND FURTHER STUDIES TO ASSESS THE OPTIMAL DOSE AND DURATION OF THE THERAPEUTIC EFFECT (ALSO AFTER TREATMENT WITHDRAWAL).	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16  5766  34 SPECIAL ISSUE: ALZHEIMER'S DISEASE. MORE THAN 45 MILLION PEOPLE WORLDWIDE HAVE ALZHEIMER'S DISEASE (AD), A DETERIORATION OF MEMORY AND OTHER COGNITIVE DOMAINS THAT LEADS TO DEATH WITHIN 3 TO 9 YEARS AFTER DIAGNOSIS. THE PRINCIPAL RISK FACTOR FOR AD IS AGE. AS THE AGING POPULATION INCREASES, THE PREVALENCE WILL APPROACH 131 MILLION CASES WORLDWIDE IN 2050. AD IS THEREFORE A GLOBAL PROBLEM CREATING A RAPIDLY GROWING EPIDEMIC AND BECOMING A MAJOR THREAT TO HEALTHCARE IN OUR SOCIETIES. IT HAS BEEN MORE THAN 20 YEARS SINCE IT WAS FIRST PROPOSED THAT THE NEURODEGENERATION IN AD MAY BE CAUSED BY DEPOSITION OF AMYLOID-BETA (ABETA) PEPTIDES IN PLAQUES IN BRAIN TISSUE. ACCORDING TO THE AMYLOID HYPOTHESIS, ACCUMULATION OF ABETA PEPTIDES, RESULTING FROM A CHRONIC IMBALANCE BETWEEN ABETA PRODUCTION AND ABETA CLEARANCE IN THE BRAIN, IS THE PRIMARY INFLUENCE DRIVING AD PATHOGENESIS. CURRENT AVAILABLE MEDICATIONS APPEAR TO BE ABLE TO PRODUCE MODERATE SYMPTOMATIC BENEFITS BUT NOT TO STOP DISEASE PROGRESSION. THE SEARCH FOR BIOMARKERS AS WELL AS NOVEL THERAPEUTIC APPROACHES FOR AD HAS BEEN A MAJOR FOCUS OF RESEARCH. RECENT FINDINGS, HOWEVER, SHOW THAT NEURONAL-INJURY BIOMARKERS ARE INDEPENDENT OF ABETA SUGGESTING EPIGENETIC MODIFICATIONS, GENE-GENE AND/OR GENE-ENVIRONMENT INTERACTIONS IN THE DISEASE ETIOLOGY, AND CALLING FOR RECONSIDERATION OF THE PATHOLOGICAL CASCADE AND ASSESSMENT OF ALTERNATIVE THERAPEUTIC STRATEGIES. IN ADDITION, RECENT RESEARCH RESULTS REGARDING THE EXPRESSION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP) GENE RESULTING IN THE PRESENCE OF VARIOUS APP-MRNA ISOFORMS AND THEIR QUANTIFICATION, ESPECIALLY FOR IDENTIFYING THE MOST ABUNDANT ONE THAT MAY DECISIVE FOR THE NORMAL STATUS OR DISEASE RISK, HAVE BEEN REPORTED. AS SUCH, A MORE COMPLETE UNDERSTANDING OF AD PATHOGENESIS WILL LIKELY REQUIRE GREATER INSIGHTS INTO THE PHYSIOLOGICAL FUNCTION OF THE BETA-AMYLOID PRECURSOR PROTEIN (APP).	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17   747  24 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
18  5497  25 REVIEW: ANIMAL MODELS OF ACQUIRED EPILEPSY: INSIGHTS INTO MECHANISMS OF HUMAN EPILEPTOGENESIS. IN MANY PATIENTS WHO SUFFER FROM EPILEPSIES, RECURRENT EPILEPTIC SEIZURES DO NOT START AT BIRTH BUT DEVELOP LATER IN LIFE. THIS HOLDS PARTICULARLY TRUE FOR EPILEPSIES WITH A FOCAL SEIZURE ORIGIN INCLUDING FOCAL CORTICAL DYSPLASIAS AND TEMPORAL LOBE EPILEPSY (TLE). TLE MOST FREQUENTLY HAS ITS SEIZURE ONSET IN THE HIPPOCAMPAL FORMATION. HIPPOCAMPAL BIOPSIES OF PHARMACORESISTANT TLE PATIENTS UNDERGOING EPILEPSY SURGERY FOR SEIZURE CONTROL MOST FREQUENTLY REVEAL THE DAMAGE PATTERN OF HIPPOCAMPAL SCLEROSIS, THAT IS, SEGMENTAL NEURONAL CELL LOSS AND CONCOMITANT ASTROGLIOSIS. MANY TLE PATIENTS REPORT ON TRANSIENT BRAIN INSULTS EARLY IN LIFE, WHICH IS FOLLOWED BY A 'LATENCY' PERIOD LACKING SEIZURE ACTIVITY OF MONTHS OR EVEN YEARS BEFORE CHRONIC RECURRENT SEIZURES START. THE PLETHORA OF STRUCTURAL AND CELLULAR MECHANISMS THAT CONVERT THE HIPPOCAMPAL FORMATION TO BECOME CHRONICALLY HYPEREXCITABLE AFTER A TRANSIENT INSULT TO THE BRAIN ARE SUMMARIZED UNDER THE TERM EPILEPTOGENESIS. IN CONTRAST TO THE OBSTACLES ARISING FOR EXPERIMENTAL STUDIES OF EPILEPTOGENESIS ASPECTS IN HUMAN SURGICAL HIPPOCAMPAL TISSUE, RECENT ANIMAL MODEL APPROACHES ALLOW INSIGHTS INTO MECHANISMS OF EPILEPTOGENESIS. RELEVANT MODELS OF TRANSIENT BRAIN INSULTS IN THIS CONTEXT COMPRISE SEVERAL DISTINCT TYPES OF LESIONS INCLUDING EXCITOXIC STATUS EPILEPTICUS (SE), ELECTRICAL SEIZURE INDUCTION, TRAUMATIC BRAIN INJURY, INDUCTION OF INFLAMMATORY PROCESSES BY HYPERTHERMIA AND VIRAL INFLAMMATION AND OTHERS. IN PATHOGENETIC TERMS, ABERRANT TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING, ACQUIRED CHANNEL- AND SYNAPTOPATHIES, NEURONAL NETWORK AND BLOOD-BRAIN BARRIER DYSFUNCTION AS WELL AS INNATE AND ADAPTIVE IMMUNITY-MEDIATED DAMAGE PLAY MAJOR ROLES. IN SUBSEQUENT STEPS, RESPECTIVE ANIMAL MODELS HAVE BEEN USED IN ORDER TO TEST WHETHER THIS DYNAMIC PROCESS CAN BE EITHER RETARDED OR EVEN ABOLISHED BY INTERFERING WITH EPILEPTOGENIC MECHANISMS. WELL-CONTROLLED SUBSEQUENT ANALYSES OF EPILEPTOGENIC CASCADES CHARACTERIZED IN ANIMAL MODELS USING CAREFULLY STRATIFIED HUMAN HIPPOCAMPAL BIOPSIES TO EXPLOIT THE UNIQUE OPPORTUNITIES GIVEN BY THESE RARE AND PRECIOUS BRAIN TISSUE SAMPLES AIM TO TRANSLATE INTO NOVEL ANTIEPILEPTOGENIC APPROACHES. RESPECTIVE PRECLINICAL TESTS CAN OPEN ENTIRELY NEW PERSPECTIVES FOR TAILOR-MADE TREATMENTS IN PATIENTS WITH THE POTENTIAL TO AVOID THE EMERGENCE OF CHRONIC FOCAL SEIZURE EVENTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
19   524  29 ASSOCIATIONS OF BDNF GENOTYPE AND PROMOTER METHYLATION WITH ACUTE AND LONG-TERM STROKE OUTCOMES IN AN EAST ASIAN COHORT. BACKGROUND: BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN POSTSTROKE RECOVERY. BDNF SECRETION IS INFLUENCED BY GENETIC AND EPIGENETIC PROFILES. THIS STUDY AIMED TO INVESTIGATE WHETHER BDNF VAL66MET POLYMORPHISM AND PROMOTER METHYLATION STATUS WERE ASSOCIATED WITH OUTCOMES AT TWO WEEKS AND ONE YEAR AFTER STROKE. METHODS AND FINDINGS: A TOTAL OF 286 PATIENTS WERE EVALUATED AT THE TIME OF ADMISSION AND TWO WEEKS AFTER STROKE, AND 222 (78%) WERE FOLLOWED ONE YEAR LATER IN ORDER TO EVALUATE CONSEQUENCES OF STROKE AT BOTH ACUTE AND CHRONIC STAGES. STROKE OUTCOMES WERE DICHOTOMISED INTO GOOD AND POOR BY THE MODIFIED RANKIN SCALE. STROKE SEVERITY (NATIONAL INSTITUTES OF HEALTH STROKE SCALE), PHYSICAL DISABILITY (BARTHEL INDEX), AND COGNITIVE FUNCTION (MINI-MENTAL STATE EXAMINATION) WERE MEASURED. ASSOCIATIONS OF BDNF GENOTYPE AND METHYLATION STATUS ON STROKE OUTCOMES AND ASSESSMENT SCALE SCORES WERE INVESTIGATED USING LOGISTIC REGRESSION, REPEATED MEASURES ANOVA AND PARTIAL CORRELATION TESTS. BDNF VAL66MET POLYMORPHISM WAS INDEPENDENTLY ASSOCIATED WITH POOR OUTCOME AT 2 WEEKS AND AT 1 YEAR, AND WITH WORSENING PHYSICAL DISABILITY AND COGNITIVE FUNCTION OVER THAT PERIOD. HIGHER BDNF PROMOTER METHYLATION STATUS WAS INDEPENDENTLY ASSOCIATED WITH WORSE OUTCOMES AT 1 YEAR, AND WITH THE WORSENING OF PHYSICAL DISABILITY AND COGNITIVE FUNCTION. NO SIGNIFICANT GENOTYPE-METHYLATION INTERACTIONS WERE FOUND. CONCLUSIONS: A ROLE FOR BDNF IN POSTSTROKE RECOVERY WAS SUPPORTED, AND CLINICAL UTILITY OF BDNF GENETIC AND EPIGENETIC PROFILE AS PROGNOSTIC BIOMARKERS AND A TARGET FOR DRUG DEVELOPMENT WAS SUGGESTED.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  5006  30 PERIPHERAL NERVE INJURY IS ACCOMPANIED BY CHRONIC TRANSCRIPTOME-WIDE CHANGES IN THE MOUSE PREFRONTAL CORTEX. BACKGROUND: PERIPHERAL NERVE INJURY CAN HAVE LONG-TERM CONSEQUENCES INCLUDING PAIN-RELATED MANIFESTATIONS, SUCH AS HYPERSENSITIVITY TO CUTANEOUS STIMULI, AS WELL AS AFFECTIVE AND COGNITIVE DISTURBANCES, SUGGESTING THE INVOLVEMENT OF SUPRASPINAL MECHANISMS. CHANGES IN BRAIN STRUCTURE AND CORTICAL FUNCTION ASSOCIATED WITH MANY CHRONIC PAIN CONDITIONS HAVE BEEN REPORTED IN THE PREFRONTAL CORTEX (PFC). THE PFC IS IMPLICATED IN PAIN-RELATED CO-MORBIDITIES SUCH AS DEPRESSION, ANXIETY AND IMPAIRED EMOTIONAL DECISION-MAKING ABILITY. WE RECENTLY REPORTED THAT THIS REGION IS SUBJECT TO SIGNIFICANT EPIGENETIC REPROGRAMMING FOLLOWING PERIPHERAL NERVE INJURY, AND NORMALIZATION OF PAIN-RELATED STRUCTURAL, FUNCTIONAL AND EPIGENETIC ABNORMALITIES IN THE PFC ARE ALL ASSOCIATED WITH EFFECTIVE PAIN REDUCTION. IN THIS STUDY, WE USED THE SPARED NERVE INJURY (SNI) MODEL OF NEUROPATHIC PAIN TO TEST THE HYPOTHESIS THAT PERIPHERAL NERVE INJURY TRIGGERS PERSISTENT LONG-LASTING CHANGES IN GENE EXPRESSION IN THE PFC, WHICH ALTER FUNCTIONAL GENE NETWORKS, THUS PROVIDING A POSSIBLE EXPLANATION FOR CHRONIC PAIN ASSOCIATED BEHAVIORS. RESULTS: SNI OR SHAM SURGERY WHERE PERFORMED IN MALE CD1 MICE AT THREE MONTHS OF AGE. SIX MONTHS AFTER INJURY, WE PERFORMED TRANSCRIPTOME-WIDE SEQUENCING (RNASEQ), WHICH REVEALED 1147 DIFFERENTIALLY REGULATED TRANSCRIPTS IN THE PFC IN NERVE-INJURED VS. CONTROL MICE. CHANGES IN GENE EXPRESSION OCCURRED ACROSS A NUMBER OF FUNCTIONAL GENE CLUSTERS ENCODING CARDINAL BIOLOGICAL PROCESSES AS REVEALED BY INGENUITY PATHWAY ANALYSIS. SIGNIFICANTLY ALTERED BIOLOGICAL PROCESSES INCLUDED NEUROLOGICAL DISEASE, SKELETAL MUSCULAR DISORDERS, BEHAVIOR, AND PSYCHOLOGICAL DISORDERS. SEVERAL OF THE CHANGES DETECTED BY RNASEQ WERE VALIDATED BY RT-QPCR AND INCLUDED TRANSCRIPTS WITH KNOWN ROLES IN CHRONIC PAIN AND/OR NEURONAL PLASTICITY INCLUDING THE NMDA RECEPTOR (GLUTAMATE RECEPTOR, IONOTROPIC, NMDA; GRIN1), NEURITE OUTGROWTH (ROUNDABOUT 3; ROBO3), GLIOSIS (GLIAL FIBRILLARY ACIDIC PROTEIN; GFAP), VESICULAR RELEASE (SYNAPTOTAGMIN 2; SYT2), AND NEURONAL EXCITABILITY (VOLTAGE-GATED SODIUM CHANNEL, TYPE I; SCN1A). CONCLUSIONS: THIS STUDY USED AN UNBIASED APPROACH TO DOCUMENT LONG-TERM ALTERATIONS IN GENE EXPRESSION IN THE BRAIN FOLLOWING PERIPHERAL NERVE INJURY. WE PROPOSE THAT THESE CHANGES ARE MAINTAINED AS A MEMORY OF AN INSULT THAT IS TEMPORALLY AND SPATIALLY DISTANT FROM THE INITIAL INJURY.	2013