Robert E. Mrak

University of Toledo, Toledo, Ohio, United States

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Publications (162)596.52 Total impact

  • Dmitry Romanovsky · Robert E Mrak · Maxim Dobretsov
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    ABSTRACT: Ambulatory instability and falls are a major source of morbidity in the elderly. Age-related loss of tendon reflexes is a major contributing factor to this morbidity, and deterioration of the afferent limb of the stretch reflex is a potential contributing factor to such age-dependent loss of tendon reflexes. To evaluate this, we assessed the number and distribution of muscle spindle afferent fibers in human sacral spinal ganglia (S1) and tibial nerve samples obtained at autopsy, using immunohistochemical staining for the α 3 isoform of Na(+),K(+)-ATPase (α 3NKA), a marker of muscle spindle afferents. Across all age groups, an average of 26±4% of myelinated fibers of tibial nerve and 17±2% of ganglion neuronal profiles were α 3NKA-positive (n=8 per group). Subject age explained 85% of the variability in these counts. The relative frequency of α 3NKA-labeled fibers/neurons starts to decline during the 5(th) decade of life, approaching half that of young adult values in 65-year-old subjects. At all ages, α 3NKA-positive neurons were among the largest of spinal ganglia neurons. However, as compared to younger subjects, the population of α 3NKA-positive neurons from advanced-age subjects showed diminished numbers of large (both moderately and strongly labeled), and medium-sized (strongly labeled) profiles. Considering the critical significance of ion transport by NKA for neuronal activity, our data suggest that functional impairment and, also, most likely atrophy and/or degeneration of muscle spindle afferents, are mechanisms underlying loss of tendon reflexes with age. The larger and more strongly α 3NKA-expressing spindle afferents appear to be proportionally more vulnerable.
    No preview · Article · Sep 2015 · Neuroscience
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    ABSTRACT: Reports from neural cell cultures and experimental animal studies provide evidence of age- and disease-related changes in retrograde transport of spent or misfolded proteins destined for degradation or recycling. However, few studies address these issues in human brain from those who either age without dementia and overt neuropathology, or succumb to Alzheimer's; especially as such propensity may be influenced by APOE genotype. We studied the expression and distribution of the dynein subunit dynactin-P50, the β amyloid precursor protein (βAPP), and hyperphosphorylated tau (P-tau) in tissues and tissue sections of brains from non-demented, neuropathology-free patients and from Alzheimer patients, with either APOE ε3,3 or APOE ε4,4. We found that advanced age in patients without dementia or neuropathological change was associated with coordinated increases in dynactin-P50 and βAPP in neurons in pyramidal layers of the hippocampus. In contrast, in Alzheimer's, βAPP and dynactin were significantly reduced. Furthermore, the dynactin-P50 and βAPP that was present was located primarily in dystrophic neurites in Aβ plaques. Tissues from Alzheimer patients with APOE ε3,3 had less P-tau, more βAPP, dynactin-P50, and synaptophysin than did tissues from Alzheimer patients carrying APOE ε4,4. It is logical to conclude, then, that as neurons age successfully, there is coordination between retrograde delivery and maintenance and repair, as well as between retrograde delivery and degradation and/or recycling of spent proteins. The buildup of proteins slated for repair, synaptic viability, transport, and re-cycling in neuron soma and dystrophic neurites suggest a loss of this coordination in Alzheimer neurons. Inheritance of APOE ε3,3 rather than APOE ε4,4, is associated with neuronal resilience, suggestive of better repair capabilities, more synapses, more efficient transport, and less hyperphosphorylation of tau. We conclude that even in disease the ε3 allele is neuroprotective.
    Preview · Article · Mar 2015 · Frontiers in Cellular Neuroscience
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    ABSTRACT: Frontotemporal lobar degeneration with τ pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick’s disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8 % of non-diseased controls, we found grains, coiled bodies, and/or τ-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age-related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau.
    No preview · Article · Jan 2015 · Journal of Neural Transmission
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    ABSTRACT: Alzheimer's disease (AD) is characterized neuropathologically by the presence of amyloid plaques, neuritic plaques, and neurofibrillary tangles (NFTs). These lesions occur not only in demented individuals with AD but also in non-demented persons. In non-demented individuals, amyloid and neuritic plaques are usually accompanied with NFTs and are considered to represent asymptomatic or preclinical AD (pre-AD) pathology. Here, we defined and characterized neuropathological differences between clinical AD, non-demented pre-AD, and non-AD control cases. Our results show that clinical AD may be defined as cases exhibiting late stages of NFT, amyloid, and neuritic plaque pathology. This is in contrast to the neuropathological changes characteristic of pre-AD, which display early stages of these lesions. Both AD and pre-AD cases often exhibit cerebral amyloid angiopathy (CAA) and granulovacuolar degeneration (GVD), and when they do, these AD-related pathologies were at early stages in pre-AD cases and at late stages in symptomatic AD. Importantly, NFTs, GVD, and CAA were also observed in non-AD cases, i.e., in cases without amyloid plaque pathology. Moreover, soluble and dispersible, high-molecular-weight amyloid β-protein (Aβ) aggregates detected by blue-native polyacrylamide gel electrophoresis were elevated in clinical AD compared to that in pre-AD and non-AD cases. Detection of NFTs, GVD, and CAA in cases without amyloid plaques, presently classified as non-AD, is consistent with the idea that NFTs, GVD, and CAA may precede amyloid plaque pathology and may represent a pre-amyloid plaque stage of pre-AD not yet considered in the current recommendations for the neuropathological diagnosis of AD. Our finding of early stages of AD-related NFT, amyloid, and GVD pathology provides a more clear definition of pre-AD cases that is in contrast to the changes in clinical AD, which is characterized by late stages of these AD-related pathologies. The observed elevation of soluble/dispersible Aβ aggregates from pre-AD compared to that in AD cases suggests that, in addition to more widespread AD-related pathologies, soluble/dispersible Aβ aggregates in the neuropil play a role in the conversion of pre-AD to clinical AD.
    No preview · Article · Sep 2013 · European Archives of Psychiatry and Clinical Neuroscience
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    ABSTRACT: Intradural and intratumorous ossification in spinal meningiomas are rare compared to their cranial counterparts. Extradural extension of the spinal meningioma is not uncommon. To the best of our knowledge, the ossification in an extra-intradural spinal meningioma is not yet reported in the literature. The authors report a rare case of an extra-intradural spinal meningioma with ossification and calcification. The review of literature including the surgical challenges and the histologic variations as well as histogenesis of the ossified spinal meningioma is discussed. Case report and review of the literature. A 61-year-old woman presented with complaints of numbness and weakness for 3 years, and gait disturbances for 6 months. Magnetic resonance imaging revealed a mass compressing the spinal cord at the T4 level. Complete resection of the tumor was achieved with coagulation and partial resection of the dura. Histopathological examination demonstrated a psammomatous spinal meningioma with intratumorous and intradural mature lamellar bone formation, complete with marrow and hematopoietic cells. The patient is asymptomatic at 3-year postoperative follow-up. Despite adherence of the ossified mass to the dura, arachnoid, and spinal cord, complete atraumatic resection of the mass was possible with favorable surgical outcome. In addition to calcification as a likely forerunner of ossification in the psammomatous subtype of meningioma, metaplastic differentiation of neoplastic cells to osseous and hematopoietic component might play a crucial role.
    No preview · Article · Sep 2013 · The spine journal: official journal of the North American Spine Society
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    ABSTRACT: Precocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE ϵ4,4 carriers is well known, but not the ways in which other APOE allelic combinations influence this outcome. Frozen and paraffin-embedded tissue samples resected from superior temporal lobes of 92 patients undergoing temporal lobectomies as a treatment for medication-resistant temporal lobe epilepsy were used in this study. To determine if epilepsy-related changes reflect those in another neurological condition, analogous tissue samples harvested from 10 autopsy-verified Alzheimer brains, and from 10 neurologically and neuropathologically normal control patients were analyzed using immunofluorescence histochemistry, western immunoblot, and real-time PCR to determine genotype effects on neuronal number and size, neuronal and glial expressions of amyloid β (Aβ) precursor protein (βAPP), Aβ, apolipoprotein E (ApoE), S100B, interleukin-1α and β, and α and β secretases; and on markers of neuronal stress, including DNA/RNA damage and caspase 3 expression. Allelic combinations of APOE influenced each epilepsy-related neuronal and glial response measured as well as neuropathological change. APOE ϵ3,3 conferred greatest neuronal resilience denoted as greatest production of the acute phase proteins and low neuronal stress as assessed by DNA/RNA damage and caspase-3 expression. Among patients having an APOE ϵ2 allele, none had Aβ plaques; their neuronal sizes, like those with APOE ϵ3,3 genotype were larger than those with other genotypes. APOE ϵ4,4 conferred the weakest neuronal resilience in epilepsy as well as in Alzheimer patients, but there were no APOE genotype-dependent differences in these parameters in neurologically normal patients. Our findings provide evidence that the strength of the neuronal stress response is more related to patient APOE genotype than to either the etiology of the stress or to the age of the patient, suggesting that APOE genotyping may be a useful tool in treatment decisions.
    Full-text · Article · Jul 2013
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    Sue T Griffin · Robert E Mrak
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    ABSTRACT: Contributing reviewers The editors of Journal of Neuroinflammation would like to thank all the reviewers who have contributed to the journal in Volume 9 (2012).
    Preview · Article · Feb 2013 · Journal of Neuroinflammation
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    Robert E Mrak
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    ABSTRACT: Microglia have long been noted to be present and activated in Alzheimer brain. Demonstrations that these microglia are associated with the specific lesions of Alzheimer disease-Aβ plaques and neurofibrillary tangles-and that these microglia overexpress the potent proinflammatory cytokine interleukin-1 led to the recognition of a potential pathogenic role for these cells in initiation and progression of disease. Activated, cytokine-overexpressing microglia are near-universal components of Aβ plaques at early (diffuse) and mid (neuritic) stages of progression in Alzheimer brain, and only decline in end-stage, dense core plaques. They correlate with plaque distribution across cerebral cortical cytoarchitectonic layers and across brain regions. They also show close associations with tangle-bearing neurons in Alzheimer brain. Microglial activation is a consistent feature in conditions that confer increased risk for Alzheimer disease or that are associated with accelerated appearance of Alzheimer-type neuropathological changes. These include normal ageing, head injury, diabetes, heart disease, and chronic intractable epilepsy. The neuropathological demonstration of microglial activation in Alzheimer brain and in Alzheimer-related conditions opened the field of basic and applied investigations centered on the idea of a pathogenically important neuroinflammatory process in Alzheimer disease.
    Preview · Article · May 2012 · International Journal of Alzheimer's Disease
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    Orwa Aboud · Robert E Mrak · Frederick Boop · Sue T Griffin
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    ABSTRACT: Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of APOE ε4 allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to APOE genotype. With an eye toward defining ways in which APOE ε3 alleles may foster neuronal well-being in epilepsy and/or APOE ε4 alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either APOE ε4,4 or APOE ε3,3 genotype. Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 APOE ε3,3 and 7 APOE ε4,4 (0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry. Tissue levels of IL-1α were elevated in patients of both APOE ε3,3 and APOE ε4,4 genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (APOE ε3,3 vs APOE ε4,4 = 3.7 ± 1.2 vs 1.5 ± 0.4; P < 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that APOE ε4,4 genotype was associated with smaller neuron size (APOE ε4,4 vs APOE ε3,3 = 173 ± 27 vs 356 ± 45; P ≤ 0.01) and greater DNA damage (APOE ε4,4 vs APOE ε3,3 = 67 ± 10 vs 39 ± 2; P = 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of APOE genotype (APOE ε4,4 age 10; APOE ε3,3 age 17). Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of APOE ε3,3 genotype compared to APOE ε4,4 genotype carriers, are consistent with the idea that the APOE ε3,3 genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).Please see related article:
    Full-text · Article · Apr 2012 · BMC Medicine
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    ABSTRACT: We have previously outlined functional interactions, including feedback cycles, between several of the gene products implicated in the pathogenesis of Alzheimer's disease. A number of Alzheimer-related stressors induce neuronal expression of apolipoprotein E (ApoE), β-amyloid precursor protein (βAPP), and fragments of the latter such as amyloid β-peptide (Aβ) and secreted APP (sAPP). These stressors include interleukin-1 (IL-1)-mediated neuroinflammation and glutamate-mediated excitotoxicity. Such circumstances are especially powerful when they transpire in the context of an APOE ε4 allele. Semi-quantitative immunofluorescence imaging was used to analyze rat brains implanted with IL-1β slow-release pellets, sham pellets, or no pellets. Primary neuronal or NT2 cell cultures were treated with IL-1β, glutamate, Aβ, or sAPP; relative levels of ApoE mRNA and protein were measured by RT-PCR, qRT-PCR, and western immunoblot analysis. Cultures were also treated with inhibitors of multi-lineage kinases--in particular MAPK-p38 (SB203580), ERK (U0126), or JNK (SP600125)--prior to exposure of cultures to IL-1β, Aβ, sAPP, or glutamate. Immunofluorescence of tissue sections from pellet-implanted rats showed that IL-1β induces expression of βAPP, IL-1α, and ApoE; the latter was confirmed by western blot analysis. These protein changes were mirrored by increases in their mRNAs, as well as in those encoding IL-1β, IL-1β-converting enzyme (ICE), and tumor necrosis factor (TNF). IL-1β also increased ApoE expression in neuronal cultures. It stimulated release of sAPP and glutamate in these cultures too, and both of these agents--as well as Aβ--stimulated ApoE expression themselves, suggesting that they may contribute to the effect of IL-1β on ApoE levels. Inhibitors of MAPK-p38, ERK, and JNK inhibited ApoE induction by all these agents except glutamate, which was sensitive only to inhibitors of ERK and JNK. Conditions of glial activation and hyperexcitation can elevate proinflammatory cytokines, ApoE, glutamate, βAPP, and its secreted fragments. Because each of these factors promotes glial activation and neuronal hyperexcitation, these relationships have the potential to sustain self-propagating neurodegenerative cycles that could culminate in a progressive neurodegenerative disorder such as Alzheimer's disease.
    Preview · Article · Dec 2011 · Journal of Neuroinflammation

  • No preview · Article · Jan 2011 · Neuropathology and Applied Neurobiology
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    K E Funk · R E Mrak · J Kuret
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    ABSTRACT: Granulovacuolar degeneration involves the accumulation of large, double membrane-bound bodies within certain neurones during the course of Alzheimer's disease (AD) and other adult-onset dementias. Because of the two-layer membrane morphology, it has been proposed that the bodies are related to autophagic organelles. The aim of this study was to test this hypothesis, and determine the approximate stage at which the pathway stalls in AD. Spatial colocalization of autophagic and endocytic markers with casein kinase 1 delta, a marker for granulovacuolar degeneration (GVD) bodies, was evaluated in hippocampal sections prepared from post mortem Braak stage IV and V AD cases using double-label confocal fluorescence microscopy. GVD bodies colocalized weakly with early-stage autophagy markers LC3 and p62, but strongly with late-stage marker lysosome-associated membrane protein 1 (LAMP1), which decorated their surrounding membranes. GVD bodies also colocalized strongly with charged multivesicular body protein 2B (CHMP2B), which colocalized with the core granule, but less strongly with lysosomal marker cathepsin D. The resultant immunohistochemical signature suggests that granulovacuolar degeneration bodies (GVBs) do contain late-stage autophagic markers, and accumulate at the nexus of autophagic and endocytic pathways. The data further suggest that failure to complete autolysosome formation may be an important correlate of GVB accumulation.
    Full-text · Article · Oct 2010 · Neuropathology and Applied Neurobiology

  • No preview · Article · Sep 2010 · Brain Pathology
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    ABSTRACT: The deposition of amyloid beta-protein (Abeta) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer's disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Abeta-deposits. In addition, as in Alzheimer's disease, risk for capillary CAA is associated with the apolipoprotein E (APOE) epsilon4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Abeta-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Abeta-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE epsilon4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the alpha(2)macroglobulin receptor/low-density lipoprotein receptor-related protein-1 (LRP-1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE epsilon4-associated subtype of AD.
    Full-text · Article · Aug 2010 · Acta Neuropathologica
  • Shimin Hu · Robert E Mrak · Peter J Goldblatt
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    ABSTRACT: We report an unusual case of hepatocellular carcinoma with three histologically and immunohistochemically distinct components, arising in a noncirrhotic liver, with a pulmonary tumor embolus from one of the three components. The histological patterns of the three components were fibrolamellar, well-differentiated nodular, and pleomorphic. The immunophenotypes were, respectively CK7- /CK20- /Hep Par1+, CK7+ /CK20- /Hep Par1+, and CK7+ /CK20+ /Hep Par1-. The tumor in the pulmonary embolus showed only the morphological and immunohistochemical features of the pleomorphic component. This unusual case ofmetastasizing hepatocellular carcinoma with three distinct histologic components suggests that the histological and immunophenotype of the tumor might be useful in predicting metastatic potential.
    No preview · Article · Feb 2010 · Connecticut medicine
  • W. Sue T. Griffin · Robert E. Mrak
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    ABSTRACT: Improvements in modern hygiene and public health have resulted in decreased human contact with organisms associated with so-called ‘dirtier’ environs. These changes, in turn have led to an appreciation of the potential importance of such ‘friendly’ organisms toward proper development of the human immune system. Based on this, a novel hypothesis (the hygiene hypothesis) has been formulated. This idea suggests that a paucity of exposure to environmental pathogens retards proper immune system development, and consequently decreases its ability to effectively thwart a variety of effectors with degenerative consequences, such as those associated with chronic inflammatory responses in diseases as seemingly diverse as those of the gut and the brain. In this chapter, we review current information, including the potential contribution of inheritance to development of hypotheses regarding the pathogenesis of chronic neurodegenerative diseases, especially Alzheimer’s disease. We further explore ways in which the hygiene hypothesis and ideas in Darwinian medicine may play a role in the neuropathogenesis of these diseases.
    No preview · Chapter · Dec 2009
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    Kelly K Ball · Nancy F Cruz · Robert E Mrak · Gerald A Dienel
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    ABSTRACT: Metabolic brain imaging is widely used to evaluate brain function and disease, and quantitative assays require local retention of compounds used to register changes in cellular activity. As labeled metabolites of [1- and 6-(14)C]glucose are rapidly released in large quantities during brain activation, this study evaluated release of metabolites and proteins through perivascular fluid flow, a pathway that carries solutes from brain to peripheral lymphatic drainage sites. Assays with [3,4-(14)C]glucose ruled out local oxidation of glucose-derived lactate as a major contributor of label loss. Brief infusion of [1-(14)C]glucose and D-[(14)C]lactate into the inferior colliculus of conscious rats during acoustic stimulation labeled the meninges, consistent with perivascular clearance of [(14)C]metabolites from interstitial fluid. Microinfusion of Evans blue albumin and amyloid-beta(1-40) (Abeta) caused perivascular labeling in the inferior colliculus, labeled the surrounding meninges, and Abeta-labeled-specific blood vessels in the caudate and olfactory bulb and was deposited in cervical lymph nodes. Efflux of extracellular glucose, lactate, and Abeta into perivascular fluid pathways is a normal route for clearance of material from the inferior colliculus that contributes to underestimates of brain energetics. Convergence of 'watershed' drainage to common pathways may facilitate perivascular amyloid plaque formation and pathway obstruction in Alzheimer's disease.
    Preview · Article · Sep 2009 · Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism
  • Robert E Mrak
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    ABSTRACT: A role for innate immunity in neurodegenerative diseases is now widely accepted, although debate continues over the relative contributions of these processes to disease progression and/or to disease amelioration. The idea that microglia and cytokines are important in neurodegeneration arose from neuropathological observations, especially in Alzheimer's disease. Microglia are invariant components of the Abeta plaques of Alzheimer's disease, where they show a waxing and waning of numbers, activation state, and cytokine expression during plaque progression. This is in contrast to diffuse Abeta deposits sometimes found in abundance in the brain of non-demented elderly individuals, which do not contain activated microglia. In Alzheimer's disease, plaque-associated astrocytes, which also produce paracrine mediators, show a pattern similar to that of microglia; and the associated plaque progression is accompanied by progressive damage to and loss of adjacent neurons. Further, activated microglia and astrocytes show a progressive pattern of association with neurofibrillary tangles. These observations, together with known functions of the involved cytokines, originally suggested a central role for immunological phenomena in driving disease progression in Alzheimer's disease. Further observations have extended these ideas to alpha-synuclein-based diseases (Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy) as well as other neurodegenerative diseases and conditions.
    No preview · Article · Aug 2009 · Journal of Alzheimer's disease: JAD
  • Murat Gokden · Robert E Mrak
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    ABSTRACT: Neoplasms consisting of pituitary adenoma and craniopharyngioma components are rare and are being increasingly recognized. Their histogenesis is not clear. Most represent collision tumors; others are difficult to assess. Here, we describe a pituitary adenoma with an intermingled craniopharyngioma component, without forming 2 distinct mass lesions or histologic delineation. Areas that suggest a transition between the 2 components were also present. It was clinically a nonfunctioning adenoma, which was also negative for pituitary hormones by immunohistochemistry. Its histogenesis and implications are discussed with a review of the literature.
    No preview · Article · Jun 2009 · Human pathology
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    John M Pearce · Richard A Komoroski · Robert E Mrak
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    ABSTRACT: Cell membrane abnormalities due to changes in phospholipid (PL) composition and metabolism have been implicated in schizophrenia pathogenesis. That work has generally assessed membrane phospholipids from nonneural tissues such as erythrocytes and platelets. High-resolution (31)P NMR spectroscopy was used to characterize PLs of gray matter in postmortem brain for 20 schizophrenics, 20 controls, and 7 patients with other mental illnesses (psychiatric controls). Tissues from frontal, temporal, and occipital cortices were extracted with hexane-isopropanol, and (31)P NMR spectra were obtained in an organic-solvent system to resolve the major PL classes (based on headgroups) and subclasses (based on linkage at the sn - 1 position). Surprisingly, repeated-measures multivariate analysis of variance revealed no overall differences among the groups. There were no significant differences (P < .05) among the three groups for any individual PL subclass, including lysophospholipids. The sum of all phosphatidylethanolamine headgroups was significantly lower for schizophrenics than for controls or psychiatric controls in the frontal cortex. The present results are minimally correlated with previous results for aqueous PL metabolites on these same samples. The metabolite changes measured by in vivo (31)P MRS in schizophrenia do not appear to reflect PL concentration changes. The present results offer very little support for the phospholipid hypothesis of schizophrenia.
    Full-text · Article · Jan 2009 · Magnetic Resonance in Medicine

Publication Stats

10k Citations
596.52 Total Impact Points


  • 2008-2015
    • University of Toledo
      • Department of Pathology
      Toledo, Ohio, United States
  • 1988-2015
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 2009
    • Medical University of Ohio at Toledo
      Toledo, Ohio, United States
  • 1993-2008
    • University of Arkansas for Medical Sciences
      • • Department of Anesthesiology
      • • Department of Dermatology
      • • Department of Radiology
      Little Rock, Arkansas, United States
  • 2001
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
  • 2000
    • Banner Sun Health Research Institute
      Sun City, Arizona, United States
  • 1990-1999
    • Arkansas Children's Hospital
      Little Rock, Arkansas, United States
  • 1997-1998
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
  • 1989
    • University of Cincinnati Medical Center
      Cincinnati, Ohio, United States