S W Scheff

University of Kentucky, Lexington, Kentucky, United States

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Publications (192)899.41 Total impact

  • Mubeen A Ansari, Kelly N Roberts, Stephen W Scheff
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    ABSTRACT: Nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase; NOX) is a complex enzyme responsible for increased levels of reactive oxygen species (ROS), superoxide (O2•(-)). NOX derived O2•(-) is a key player in oxidative stress and inflammation mediated multiple secondary injury cascades (SIC) following traumatic brain injury (TBI). The O2•(-) reacts with nitric oxide (NO), produces various reactive nitrogen species (RNS), and contributes to apoptotic cell death. Following a unilateral cortical contusion, young adult rats were killed at various times post injury (1, 3, 6, 12, 24, 48, 72, and 96h). Fresh tissue from the hippocampus was analyzed for NOX activity, and level of O2•(-). In addition we evaluated the translocation of cytosolic NOX proteins (p67(Phox), p47(Phox) and p40(Phox)) to the membrane, along with total NO and the activation (phosphorylation) of endothelial nitric oxide synthase (p-eNOS). Results show that both enzymes and levels of O2•(-) and NO have time dependent injury effects in the hippocampus. Translocation of cytosolic NOX proteins into membrane, NOX activity and O2•(-) were also increased in a time dependent fashion. Both, NOX activity and O2•(-) were increased at 6h. Levels of p-eNOS increased within 1h, with significant elevation of NO at 12h post TBI. Levels of NO failed to show a significant association with p-eNOS, but did associate with O2•(-). NOX up-regulation strongly associated with both the levels of O2•(-) and also total NO. The initial 12hours post TBI are very important as a possible window of opportunity to interrupt SIC. It may be important to selectively target the translocation of cytosolic subunits for the modulation of NOX function.
    Free radical biology & medicine. 09/2014;
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    ABSTRACT: Mild cognitive impairment (MCI) is considered to be an early stage in the progression of Alzheimer's disease (AD) providing an opportunity to investigate brain pathogenesis prior to the onset of dementia. Neuroimaging studies have identified the posterior cingulate gyrus (PostC) as a cortical region affected early in the onset of AD. This association cortex is involved in a variety of different cognitive tasks and is intimately connected with the hippocampal/entorhinal cortex region, a component of the medial temporal memory circuit that displays early AD pathology. We quantified the total number of synapses in lamina 3 of the PostC using unbiased stereology coupled with electron microscopy from short postmortem autopsy tissue harvested from cases at different stage of AD progression. Individuals in the early stages of AD showed a significant decline in synaptic numbers compared to individuals with no cognitive impairment (NCI). Subjects with MCI exhibited synaptic numbers that were between the AD and NCI cohorts. Adjacent tissue was evaluated for changes in both pre and postsynaptic proteins levels. Individuals with MCI demonstrated a significant loss in presynaptic markers synapsin-1 and synaptophysin and postsynaptic markers PSD-95 and SAP-97. Levels of [3H]PiB binding was significantly increased in MCI and AD and correlated strongly with levels of synaptic proteins. All synaptic markers showed a significant association with Mini-Mental Status Examination scores. These results support the idea that the PostC synaptic function is affected during the prodromal stage of the disease and may underlie some of the early clinical sequelae associated with AD.
    Journal of Alzheimer's disease: JAD 08/2014; · 4.17 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is associated with alterations in the distribution, number, and size of inputs to hippocampal neurons. Some of these changes are thought to be neurodegenerative, whereas others are conceptualized as compensatory, plasticity-like responses, wherein the remaining inputs reactively innervate vulnerable dendritic regions. Here, we provide evidence that the axospinous synapses of human AD cases and mice harboring AD-linked genetic mutations (the 5XFAD line) exhibit both, in the form of synapse loss and compensatory changes in the synapses that remain. Using array tomography, quantitative conventional electron microscopy, immunogold electron microscopy for AMPARs, and whole-cell patch-clamp physiology, we find that hippocampal CA1 pyramidal neurons in transgenic mice are host to an age-related synapse loss in their distal dendrites, and that the remaining synapses express more AMPA-type glutamate receptors. Moreover, the number of axonal boutons that synapse with multiple spines is significantly reduced in the transgenic mice. Through serial section electron microscopic analyses of human hippocampal tissue, we further show that putative compensatory changes in synapse strength are also detectable in axospinous synapses of proximal and distal dendrites in human AD cases, and that their multiple synapse boutons may be more powerful than those in non-cognitively impaired human cases. Such findings are consistent with the notion that the pathophysiology of AD is a multivariate product of both neurodegenerative and neuroplastic processes, which may produce adaptive and/or maladaptive responses in hippocampal synaptic strength and plasticity.
    Brain Structure and Function 07/2014; · 7.84 Impact Factor
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    ABSTRACT: The positron emitting (PET) (11) C-labeled Pittsburgh Compound B (PIB) ligand is used to image β-amyloid (Aβ) deposits in the brains of living subjects with the intent of detecting early stages of Alzheimer's disease (AD). However, deposits of human-sequence Aβ in APP transgenic mice and nonhuman primates bind very little PIB. The high stoichiometry of PIB:Aβ binding in human AD suggests that the PIB binding site may represent a particularly pathogenic entity and/or report local pathologic conditions. In this study, (3) H-PIB was employed to track purification of the PIB binding site in > 90% yield from frontal cortical tissue of autopsy-diagnosed AD subjects. The purified PIB binding site comprises a distinct, highly insoluble subfraction of the Aβ in AD brain with low buoyant density due to an SDS-resistant association with a limited subset of brain proteins and lipids with physical properties similar to lipid rafts and to a ganglioside:Aβ complex in AD and Down Syndrome brain. Both the protein and lipid components are required for PIB binding. Elucidation of human-specific biological components and pathways will be important in guiding improvement of the animal models of AD and in identifying new potential therapeutic avenues. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; · 3.97 Impact Factor
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    ABSTRACT: Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.
    Acta Neuropathologica 04/2014; · 9.73 Impact Factor
  • Stephen W Scheff, Janna H Neltner, Peter T Nelson
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    ABSTRACT: Synapses may represent a key nidus for dementia including Alzheimer's disease (AD) pathogenesis. Here we review published studies and present new ideas related to the question of the specificity of synapse loss in AD. Currently, AD is defined by the regional presence of neuritic plaques and neurofibrillary tangles in the brain. The severity of involvement by those pathological hallmarks tends to correlate both with antemortem cognitive status, and also with synapse loss in multiple brain areas. Recent studies from large autopsy series have led to a new standard of excellence with regard to clinical-pathological correlation and to improved comprehension of the numerous brain diseases of the elderly. These studies have provided evidence that it is the rule rather than the exception for brains of aged individuals to demonstrate pathologies (often multiple) other than AD plaques and tangles. For many of these comorbid pathologies, the extent of synapse loss is imperfectly understood but could be substantial. These findings indicate that synapse loss is probably not a hallmark specific to AD but rather a change common to many diseases associated with dementia.
    Biochemical pharmacology 01/2014; · 4.25 Impact Factor
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    ABSTRACT: Background Precuneus choline acetyltransferase activity reduction co-occurs with greater β-amyloid (Aβ) in Alzheimer's disease (AD). Whether this cholinergic deficit associates with alterations in nerve growth factor (NGF) signaling and its relation to Aβ plaque and neurofibrillary tangle (NFT) pathology during disease onset is unknown. Methods Precuneus NGF up and down stream signaling levels relative to Aβ and NFT pathology were evaluated using biochemistry and histochemistry in 62 subjects diagnosed premortem as non cognitively impaired (NCI, n=23), mild cognitively impaired (MCI, n=21) and mild to moderate Alzheimer’s disease (AD, n=18) Results Immunoblots revealed increased levels of proNGF in AD but not MCI, whereas its cognate receptors were unchanged. There were no significant differences in protein level for the downstream survival kinase-signaling proteins Erk and phospho-Erk among groups. Apoptotic phospho-JNK, phospho-JNK/JNK ratio and Bcl-2 were significantly elevated in AD. Soluble Aβ 1-42 and fibrillar Aβ measured by [3H] Pittsburgh compound-B (PiB) binding were significantly higher in AD compared to MCI and NCI. The density of plaques showed a trend to increase, but only 6-CN-PiB positive plaques reached significance in AD. AT8, TOC-1 and Tau C3 positive NFT density were unchanged, whereas only AT8 positive neuropil thread density was statistically higher in AD. A negative correlation was found between proNGF, phospho-JNK, Bcl-2 levels and phospho-JNK/JNK ratio and cognition, whereas proNGF correlated positively with 6-CN-PiB positive plaques during disease progression. Conclusions Data indicate that precuneus neurotrophin pathways are resilient to amyloid toxicity during the onset of AD.
    Biological psychiatry 01/2014; · 8.93 Impact Factor
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    ABSTRACT: Hippocampal sclerosis of aging (HS-Aging) is a causative factor in a large proportion of elderly dementia cases. The current definition of HS-Aging rests on pathologic criteria: neuronal loss and gliosis in the hippocampal formation that is out of proportion to AD-type pathology. HS-Aging is also strongly associated with TDP-43 pathology. HS-Aging pathology appears to be most prevalent in the oldest-old: autopsy series indicate that 5-30 % of nonagenarians have HS-Aging pathology. Among prior studies, differences in study design have contributed to the study-to-study variability in reported disease prevalence. The presence of HS-Aging pathology correlates with significant cognitive impairment which is often misdiagnosed as AD clinically. The antemortem diagnosis is further confounded by other diseases linked to hippocampal atrophy including frontotemporal lobar degeneration and cerebrovascular pathologies. Recent advances characterizing the neurocognitive profile of HS-Aging patients have begun to provide clues that may help identify living individuals with HS-Aging pathology. Structural brain imaging studies of research subjects followed to autopsy reveal hippocampal atrophy that is substantially greater in people with eventual HS-Aging pathology, compared to those with AD pathology alone. Data are presented from individuals who were followed with neurocognitive and neuroradiologic measurements, followed by neuropathologic evaluation at the University of Kentucky. Finally, we discuss factors that are hypothesized to cause or modify the disease. We conclude that the published literature on HS-Aging provides strong evidence of an important and under-appreciated brain disease of aging. Unfortunately, there is no therapy or preventive strategy currently available.
    Acta Neuropathologica 07/2013; · 9.73 Impact Factor
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    ABSTRACT: Following traumatic brain injury (TBI), both primary and secondary injury cascades are initiated leading to neuronal death and cognitive dysfunction. We have previously shown that the combinational bioflavonoid, Pycnogenol® (PYC), alters some secondary injury cascades and protects synaptic proteins when administered immediately following trauma. The purpose of the present study was to further explore the beneficial effects of PYC and to test whether it can be used in a more clinically relevant fashion. Young adult male Sprague-Dawley rats were subjected to a unilateral moderate/severe cortical contusion. Subjects received a single intravenous (i.v.) injection of PYC (1, 5 & 10mg/kg) or vehicle, with treatment initiated at 15 min, 2 h or 4 h post injury. All rats were killed at 96 h post TBI. Both the cortex and hippocampus ipsilateral and contralateral to the injury were evaluated for possible changes in oxidative stress (thiobarbituric acid reactive species; TBARS) and both pre- and post-synaptic proteins (synapsin-I, synaptophysin, drebrin, post synaptic density protein-95, and synapse associated protein-97). Following TBI, TBARS were significantly increased in both the injured cortex and ipsilateral hippocampus. Regardless of the dose and delay in treatment, PYC treatment significantly lowered TBARS. PYC treatment significantly protected both the cortex and hippocampus from injury-related declines in pre- and post-synaptic proteins. These results demonstrate that a single i.v. treatment of PYC is neuroprotective after TBI with a therapeutic window of at least 4h post trauma. The natural bioflavonoid PYC may provide a possible therapeutic intervention in neurotrauma.
    Journal of neurotrauma 04/2013; · 4.25 Impact Factor
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    ABSTRACT: Amnestic mild cognitive impairment (aMCI) is considered to be one of the early stages in the progression from no cognitive impairment (NCI) to Alzheimer's disease (AD). Individuals with aMCI have increased levels of AD-type neuropathology in multiple regions of the neocortex and hippocampus and demonstrate a loss of synaptic connectivity. Recent neuroimaging studies have reported increased levels of 11C-PiB (Pittsburgh, compound B) in regions of the neocortex including the precuneus region of the medial parietal lobe. This cortical region has been implicated in episodic memory, which is disrupted early in the progression of AD. In this study, unbiased stereology coupled with electron microscopy was used to quantify total synaptic numbers in lamina 3 of the precuneus from short postmortem autopsy tissue harvested from subjects who died at different cognitive stages during the progression of AD. Individuals with aMCI did not reveal a statistically significant decline in total synapses compared to the NCI cohort while the AD group did show a modest but significant decline. Synaptic numbers failed to correlate with several different cognitive tasks including the Mini-Mental State Examination scores and episodic memory scores. Although levels of [3H]PiB binding were elevated in both the aMCI and AD groups, it did not strongly correlate with synaptic counts. These results support the idea that despite increased amyloid load, the precuneus region does not show early changes in synaptic decline during the progression of AD.
    Journal of Alzheimer's disease: JAD 03/2013; · 4.17 Impact Factor
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    ABSTRACT: Hippocampal precursor of nerve growth factor (proNGF)/NGF signaling occurs in conjunction with β-amyloid (Aβ) accumulations in Alzheimer disease (AD). To assess the involvement of this pathway in AD progression, we quantified these proteins and their downstream pathway activators in postmortem tissues from the brains of subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD using immunoblotting and ELISA. Hippocampal proNGF was significantly greater in AD cases compared with those in NCI and MCI cases. TrkA was significantly reduced in MCI compared with those in NCI and AD, whereas p75 neurotrophin receptor, sortilin, and neurotrophin receptor homolog 2 remained stable. Akt decreased from NCI to MCI to AD, whereas phospho-Akt and phospho-Akt-to-Akt ratio were elevated in AD compared with those in MCI and NCI. No differences were found in phospho-Erk, Erk, or their ratio across groups. Although c-jun kinase (JNK) remained stable across groups, phospho-JNK and the phospho-JNK-to-JNK ratio increased significantly in AD compared with those in NCI and MCI. Expression levels of Aβ1-40, Aβ1-42, and Aβ40/42 ratio were stable. Statistical analysis revealed a strong positive correlation between proNGF and phospho-JNK, although only proNGF was negatively correlated with cognitive function and only TrkA was negatively associated with pathologic criteria. These findings suggest that alterations in the hippocampal NGF signaling pathway in MCI and AD favor proNGF-mediated proapoptotic pathways, and that this is independent of Aβ accumulation during AD progression.
    Journal of Neuropathology and Experimental Neurology 11/2012; 71(11):1018-1029. · 4.35 Impact Factor
  • Stephen W Scheff, Mubeen A Ansari, Kelly N Roberts
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    ABSTRACT: Traumatic brain injury (TBI) involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Oxidative stress is one of the most celebrated secondary injury mechanisms. A close relationship exists between levels of oxidative stress and the pathogenesis of TBI. However, other cascades, such as an increase in proinflammatory cytokines, also play important roles in the overall response to the trauma. Pharmacologic intervention, in order to be successful, requires a multifaceted approach. Naturally occurring flavonoids are unique in possessing not only tremendous free radical scavenging properties but also the ability to modulate cellular homeostasis leading to a reduction in inflammation and cell toxicity. This study evaluated the therapeutic role of Pycnogenol (PYC), a patented combinational bioflavonoid. Young adult Sprague-Dawley rats were subjected to a unilateral moderate cortical contusion and treated post injury with PYC or vehicle. At either 48 or 96h post trauma, the animals were killed and the cortex and hippocampus analyzed for changes in enzymatic and non-enzymatic oxidative stress markers. In addition, possible changes in both pre- and post-synaptic proteins (synapsin-1, PSD-95, drebrin, synapse associated protein-97) were analyzed. Finally, a separate cohort of the animals was used to evaluate two proinflammatory cytokines (IL-6, TNF-α). Following the trauma there was a significant increase in oxidative stress in both the injured cortex and the ipsilateral hippocampus. Animals treated with PYC significantly ameliorated levels of protein carbonyls, lipid peroxidation, and protein nitration. The PYC treatment also significantly reduced the loss of key pre- and post-synaptic proteins with some levels in the hippocampus of PYC treated animals not significantly different from sham operated controls. Although levels of the proinflammatory cytokines were significantly elevated in both injury groups, the cohort treated with PYC showed a significant reduction compared to the vehicle treated controls. These results are the first to show a neuroprotective effect of PYC following TBI. They also suggest that the diverse effects of bioflavonoids may provide a unique avenue for possible therapeutic intervention following head trauma.
    Experimental Neurology 10/2012; · 4.65 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI) induces a cascade of primary and secondary events resulting in impairment of neuronal networks that eventually determines clinical outcome. The dynorphins, endogenous opioid peptides, have been implicated in secondary injury and neurodegeneration in rodent and human brain. To gain insight into the role of dynorphins in the brain's response to trauma, we analyzed short-term (1-day) and long-term (7-day) changes in dynorphin A (Dyn A) levels in the frontal cortex, hippocampus, and striatum, induced by unilateral left-side or right-side cortical TBI in mice. The effects of TBI were significantly different from those of sham surgery (Sham), while the sham surgery also produced noticeable effects. Both sham and TBI induced short-term changes and long-term changes in all three regions. Two types of responses were generally observed. In the hippocampus, Dyn A levels were predominantly altered ipsilateral to the injury. In the striatum and frontal cortex, injury to the right (R) hemisphere affected Dyn A levels to a greater extent than that seen in the left (L) hemisphere. The R-TBI but not L-TBI produced Dyn A changes in the striatum and frontal cortex at 7 days after injury. Effects of the R-side injury were similar in the two hemispheres. In naive animals, Dyn A was symmetrically distributed between the two hemispheres. Thus, trauma may reveal a lateralization in the mechanism mediating the response of Dyn A-expressing neuronal networks in the brain. These networks may differentially mediate effects of left and right brain injury on lateralized brain functions.
    Journal of neurotrauma 04/2012; 29(9):1785-93. · 4.25 Impact Factor
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    ABSTRACT: Cognitively intact elderly research volunteers at the University of Kentucky have been recruited, followed longitudinally, and autopsied with extensive neuropathological evaluations since 1989. To date, the cohort has recruited 1,030 individuals with 552 participants being actively followed, 363 deceased, and 273 autopsied. An extensive database has been constructed with continuous updates that include textured clinical, neuropsychological, neuroimaging, and pathological information. The history, demographics, clinical observations, and pathological features of this research cohort are described. We also explain some of the evolving methodologies and the academic contributions that have been made due to this motivated group of older Kentuckians.
    Current Alzheimer research 04/2012; 9(6):724-33. · 4.97 Impact Factor
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    ABSTRACT: Alterations in the relative abundance of synaptic proteins may contribute to hippocampal synaptic dysfunction in Alzheimer's disease (AD). The extent to which perturbations in synaptic protein expression occur during the earliest stages of cognitive decline remains unclear. We examined protein levels of presynaptic synaptophysin (SYP) and synaptotagmin (SYT), and postsynaptic drebrin (DRB), a marker for dendritic spine plasticity, in the hippocampus of people with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) or mild/moderate AD. Although normalized SYP and SYT levels were preserved, DRB was reduced by approximately 40% in the hippocampus of MCI and AD compared to NCI subjects. This differential alteration of synaptic markers in MCI suggests a selective impairment in hippocampal postsynaptic dendritic plasticity in prodromal AD that likely heralds the onset of memory impairment in symptomatic disease.
    Neurodegenerative Diseases 02/2012; 10(1-4):216-9. · 3.41 Impact Factor
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    ABSTRACT: The role of tumor necrosis factor α (TNF) in neural function has been investigated extensively in several neurodegenerative conditions, but rarely in brain aging, where cognitive and physiologic changes are milder and more variable. Here, we show that protein levels for TNF receptor 1 (TNFR1) are significantly elevated in the hippocampus relative to TNF receptor 2 (TNFR2) in aged (22 months) but not young adult (6 months) Fischer 344 rats. To determine if altered TNF/TNFR1 interactions contribute to key brain aging biomarkers, aged rats received chronic (4-6 week) intracranial infusions of XPro1595: a soluble dominant negative TNF that preferentially inhibits TNFR1 signaling. Aged rats treated with XPro1595 showed improved Morris Water Maze performance, reduced microglial activation, reduced susceptibility to hippocampal long-term depression, increased protein levels for the GluR1 type glutamate receptor, and lower L-type voltage sensitive Ca(2+) channel (VSCC) activity in hippocampal CA1 neurons. The results suggest that diverse functional changes associated with brain aging may arise, in part, from selective alterations in TNF signaling.
    PLoS ONE 01/2012; 7(5):e38170. · 3.53 Impact Factor
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    ABSTRACT: Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly. The pathologic and molecular substrate of people diagnosed with MCI is not well established. Since MCI is a human specific disorder and neither the clinical nor the neuropathological course appears to follow a direct linear path, it is imperative to characterize neuropathology changes in the brains of people who came to autopsy with a well-characterized clinical diagnosis of MCI. Herein, we discuss findings derived from clinical pathologic studies of autopsy cases who died with a clinical diagnosis of MCI. The heterogeneity of clinical MCI imparts significant challenges to any review of this subject. The pathologic substrate of MCI is equally complex and must take into account not only conventional plaque and tangle pathology but also a wide range of cellular, biochemical and molecular deficits, many of which relate to cognitive decline as well as compensatory responses to the progressive disease process. The multifaceted nature of the neuronal disconnection syndrome associated with MCI suggests that there is no single event which precipitates this prodromal stage of AD. In fact, it can be argued that neuronal degeneration initiated at different levels of the central nervous system drives cognitive decline as a final common pathway at this stage of the dementing disease process.
    Acta Neuropathologica 11/2011; 123(1):13-30. · 9.73 Impact Factor
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    ABSTRACT: Controlled cortical impact injury was used to examine relationships between focal posttraumatic cortical damage and mossy fiber sprouting (MFS) in the dentate gyrus in three mouse strains. Posttraumatic MFS was more robust when cortical injury impinged upon the hippocampus, versus contusions restricted to neocortex, and was qualitatively similar among CD-1, C57BL/6, and FVB/N background strains. Impact parameters influencing injury severity may be critical in reproducing epilepsy-related changes in neurotrauma models.
    Epilepsy research 10/2011; 99(1-2):167-70. · 2.48 Impact Factor
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    ABSTRACT: This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD). Choline acetyltransferase (ChAT) activity, [(3)H]PiB binding, and soluble amyloid-β(1-42) (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging-Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage. Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [(3)H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [(3)H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology. Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.
    Neurology 06/2011; 77(1):39-47. · 8.30 Impact Factor
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    Robert F Hunt, Stephen W Scheff, Bret N Smith
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    ABSTRACT: Functional plasticity of synaptic networks in the dentate gyrus has been implicated in the development of posttraumatic epilepsy and in cognitive dysfunction after traumatic brain injury, but little is known about potentially pathogenic changes in inhibitory circuits. We examined synaptic inhibition of dentate granule cells and excitability of surviving GABAergic hilar interneurons 8-13 weeks after cortical contusion brain injury in transgenic mice that express enhanced green fluorescent protein in a subpopulation of inhibitory neurons. Whole-cell voltage-clamp recordings in granule cells revealed a reduction in spontaneous and miniature IPSC frequency after head injury; no concurrent change in paired-pulse ratio was found in granule cells after paired electrical stimulation of the hilus. Despite reduced inhibitory input to granule cells, action potential and EPSC frequencies were increased in hilar GABA neurons from slices ipsilateral to the injury versus those from control or contralateral slices. Furthermore, increased excitatory synaptic activity was detected in hilar GABA neurons ipsilateral to the injury after glutamate photostimulation of either the granule cell or CA3 pyramidal cell layers. Together, these findings suggest that excitatory drive to surviving hilar GABA neurons is enhanced by convergent input from both pyramidal and granule cells, but synaptic inhibition of granule cells is not fully restored after injury. This rewiring of circuitry regulating hilar inhibitory neurons may reflect an important compensatory mechanism, but it may also contribute to network destabilization by increasing the relative impact of surviving individual interneurons in controlling granule cell excitability in the posttraumatic dentate gyrus.
    Journal of Neuroscience 05/2011; 31(18):6880-90. · 6.91 Impact Factor

Publication Stats

9k Citations
899.41 Total Impact Points

Institutions

  • 1982–2014
    • University of Kentucky
      • • Sanders-Brown Center on Aging
      • • Department of Anatomy & Neurobiology
      • • Department of Pharmaceutical Sciences
      • • Department of Psychology
      • • Sanders-Brown Center on Aging/Alzheimer’s Disease Research Center
      Lexington, Kentucky, United States
  • 2011–2012
    • Rush University Medical Center
      • Department of Neurological Sciences
      Chicago, IL, United States
    • University of Pittsburgh
      • Department of Neurology
      Pittsburgh, PA, United States
  • 2008
    • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
  • 1999
    • The Ohio State University
      Columbus, Ohio, United States
  • 1994
    • University of Cologne
      • Institute for Genetics
      Köln, North Rhine-Westphalia, Germany
  • 1990
    • Lexington Medical Center
      West Columbia, South Carolina, United States
  • 1983–1987
    • Lexington VA Medical Center
      Washington, Washington, D.C., United States
  • 1977–1982
    • University of California, Irvine
      • Department of Neurology
      Irvine, California, United States