George Godsey | Rowan University (original) (raw)

Papers by George Godsey

Innovation in Aging

AD-related pathological changes begin in the brain long before symptoms emerge. In the present st... more AD-related pathological changes begin in the brain long before symptoms emerge. In the present study, we demonstrate the utility of a panel of AD-related autoantibodies capable of detecting AD at the earliest points along the AD continuum, including preclinical AD, years before the onset of symptoms, and prodromal AD (mild cognitive impairment, MCI). Using a customized panel of AD-specific autoantibody biomarkers and Luminex xMAP® technology, sera from ADNI subjects with preclinical AD or MCI were screened to demonstrate preclinical and prodromal AD detection. A panel of eight autoantibodies with increased titer in MCI and preclinical AD relative to controls was evaluated using Random Forest and Receiver Characteristic Operating curves for their ability to distinguish diseased subjects from age- and sex-matched controls, as well as from individuals with other neurodegenerative and non-neurodegenerative diseases. Results showed that this panel of biomarkers was capable of differentia...

Alzheimer's & Dementia

Journal of Alzheimer's Disease, 2020

Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD).... more Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-␤ 1-42 (A␤ 42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (␣7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of A␤ 42, IgG, GluR2/3, and ␣7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble A␤ 42 peptide and serum from AD and control subjects. The rate and extent of A␤ 42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for ␣7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM A␤ 42. Initial co-localization of IgG, ␣7nAChR, and A␤ 42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). A␤ 42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then

Scientific Reports, 2019

Regulating the intrinsic interactions between blood vessels and nerve cells has the potential to ... more Regulating the intrinsic interactions between blood vessels and nerve cells has the potential to enhance repair and regeneration of the central nervous system. Here, we evaluate the efficacy of aligned microvessels to induce and control directional axon growth from neural progenitor cells in vitro and host axons in a rat spinal cord injury model. Interstitial fluid flow aligned microvessels generated from co-cultures of cerebral-derived endothelial cells and pericytes in a three-dimensional scaffold. The endothelial barrier function was evaluated by immunostaining for tight junction proteins and quantifying the permeability coefficient (~10−7 cm/s). Addition of neural progenitor cells to the co-culture resulted in the extension of Tuj-positive axons in the direction of the microvessels. To validate these findings in vivo, scaffolds were transplanted into an acute spinal cord hemisection injury with microvessels aligned with the rostral-caudal direction. At three weeks post-surgery, ...

Journal of Neuroimmunology, 2017

The goal of this preliminary proof-of-concept study was to use human protein microarrays to ident... more The goal of this preliminary proof-of-concept study was to use human protein microarrays to identify bloodbased autoantibody biomarkers capable of diagnosing multiple sclerosis (MS). Using sera from 112 subjects, including 51 MS subjects, autoantibody biomarkers effectively differentiated MS subjects from age-and gendermatched normal and breast cancer controls with 95.0% and 100% overall accuracy, but not from subjects with Parkinson's disease. Autoantibody biomarkers were also useful in distinguishing subjects with the relapsingremitting form of MS from those with the secondary progressive subtype. These results demonstrate that autoantibodies can be used as noninvasive blood-based biomarkers for the detection and subtyping of MS.

Biomaterials, 2017

Transport of fluid and solutes is tightly controlled within the brain, where vasculature exhibits... more Transport of fluid and solutes is tightly controlled within the brain, where vasculature exhibits a bloodbrain barrier and there is no organized lymphatic network facilitating waste transport from the interstitial space. Here, using a compliant, three-dimensional co-culture model of the blood-brain barrier, we show that mechanical stimuli exerted by blood flow mediate both the permeability of the endothelial barrier and waste transport along the basement membrane. Application of both shear stress and cyclic strain facilitates tight junction formation in the endothelial monolayer, with and without the presence of astrocyte endfeet in the surrounding matrix. We use both dextran perfusion and TEER measurements to assess the initiation and maintenance of the endothelial barrier, and microparticle image velocimetry to characterize the fluid dynamics within the in vitro vessels. Application of pulsatile flow to the in vitro vessels induces pulsatile strain to the vascular wall, providing an opportunity to investigate stretchinduced transport along the basement membrane. We find that a pulsatile wave speed of approximately 1 mm/s with Womersley number of 0.004 facilitates retrograde transport of high molecular weight dextran along the basement membrane between the basal endothelium and surrounding astrocytes. Together, these findings indicate that the mechanical stress exerted by blood flow is an important regulator of transport both across and along the walls of cerebral microvasculature.

Diabetes & vascular disease research, May 1, 2017

Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that d... more Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood-brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42 peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood-retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in Müller cells, all of which were curtailed by treatment with Dar...

Journal of Alzheimer's Disease, 2016

Alzheimer's disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating ... more Alzheimer's disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating disorders that afflict people throughout the world. Although typically associated with older demographics, recent epidemiologic studies have reported parallel trends in decreasing age of onset and increasing incidence of these conditions. Promising research continues to implicate the cerebrovasculature and blood-brain barrier (BBB) as playing key roles in AD pathoetiology. Similarly, complications accompanying DM, such as diabetic nephropathy/retinopathy, cardiovascular disease, and stroke, have been rooted in vascular compromise. Not surprisingly, DM is now considered a major risk factor for AD. The purpose of this review is to highlight investigations into the role of the cerebrovasculature in the development and progression of AD. We give particular attention to studies on humans and a variety of animal model systems that have demonstrated a link between BBB dysfunction and pathological changes in the brain consistent with aging and AD. Together, these studies suggest that the vascular complications associated with chronic, poorly managed DM can lead to subclinical BBB breakdown that precedes and drives the pathological changes progressing to symptomatic AD, providing a common mechanistic thread connecting these two disorders. Furthermore, this emphasizes the need to focus on the vasculature as a potential therapeutic target with the intent of limiting BBB breakdown involved in disease initiation and progression. In conclusion, AD may be more than just an associated comorbidity of DM, and instead another manifestation of the underlying vascular pathology that is common to both.

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 2016

Introduction: There is an urgent need to identify biomarkers that can accurately detect and diagn... more Introduction: There is an urgent need to identify biomarkers that can accurately detect and diagnose Alzheimer's disease (AD). Autoantibodies are abundant and ubiquitous in human sera and have been previously demonstrated as disease-specific biomarkers capable of accurately diagnosing mildmoderate stages of AD and Parkinson's disease. Methods: Sera from 236 subjects, including 50 mild cognitive impairment (MCI) subjects with confirmed low CSF Ab42 levels, were screened with human protein microarrays to identify potential biomarkers for MCI. Autoantibody biomarker performance was evaluated using Random Forest and Receiver Operating Characteristic curves. Results: Autoantibody biomarkers can differentiate MCI patients from age-matched and gendermatched controls with an overall accuracy, sensitivity, and specificity of 100.0%. They were also capable of differentiating MCI patients from those with mild-moderate AD and other neurologic and non-neurologic controls with high accuracy. Discussion: Autoantibodies can be used as noninvasive and effective blood-based biomarkers for early diagnosis and staging of AD.

Immunology Letters, 2015

Introduction: There is a great need to identify readily accessible, blood-based biomarkers for Pa... more Introduction: There is a great need to identify readily accessible, blood-based biomarkers for Parkinson's disease (PD) that are useful for accurate early detection and diagnosis. This advancement would allow early patient treatment and enrollment into clinical trials, both of which would greatly facilitate the development of new therapies for PD. Methods: Sera from a total of 398 subjects, including 103 early-stage PD subjects derived from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, were screened with human protein microarrays containing 9,486 potential antigen targets to identify autoantibodies potentially useful as biomarkers for PD. A panel of selected autoantibodies with a higher prevalence in early-stage PD was identified and tested using Random Forest for its ability to distinguish early-stage PD subjects from controls and from individuals with other neurodegenerative and non-neurodegenerative diseases. Results: Results demonstrate that a panel of selected, blood-borne autoantibody biomarkers can distinguish early-stage PD subjects (90% confidence in diagnosis) from age-and sex-matched controls with an overall accuracy of 87.9%, a sensitivity of 94.1% and specificity of 85.5%. These biomarkers were also capable of differentiating patients with early-stage PD from those with more advanced (mild-moderate) PD with an overall accuracy of 97.5%, and could distinguish subjects with early-stage PD from those with other neurological (e.g., Alzheimer's disease and multiple sclerosis) and non-neurological (e.g., breast cancer) diseases. Conclusion: These results demonstrate, for the first time, that a panel of selected autoantibodies may prove to be useful as effective blood-based biomarkers for the diagnosis of early-stage PD.

International Review of Neurobiology, 2015

Autoantibodies are self-reactive antibodies that have been widely implicated as causal agents of ... more Autoantibodies are self-reactive antibodies that have been widely implicated as causal agents of autoimmune diseases. They are found in the blood of all human sera, regardless of age, gender, or the presence or absence of disease. While the underlying reason for their ubiquity remains unknown, it has been hypothesized that they participate in the clearance of blood-borne cell and tissue debris generated in both healthy and diseased individuals on a daily basis. Although much evidence supports this debris clearance role, recent studies also suggest a causal role for autoantibodies in disease. This chapter first presents well-known examples of autoimmune diseases that emphasize a direct causal role for autoantibodies and then discusses the veritable explosion of evidence now supporting their involvement in a wide variety of other diseases, including cancers and several types of neurological and neurodegenerative diseases. Lastly, translational strategies that take advantage of the &amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;cause and/or effect&amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; role of autoantibodies and recent technological advancements in their detection to exploit autoantibodies as sensitive and specific biomarkers useful for the detection and diagnosis of disease are outlined. Their use in the diagnosis and staging of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s and Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s diseases is presented, and future applications in clinical medicine and basic science are highlighted.

Brain Research, 2015

Please cite this article as: Acharya, N.K., et al., Sevoflurane and Isoflurane induce structural ... more Please cite this article as: Acharya, N.K., et al., Sevoflurane and Isoflurane induce structural changes in brain vascular endothelial cells and increase bloodÀbrain barrier permeability: Possible link to postoperative delirium and cognitive decline. Brain Research (2015), http://dx.doi.org/10.1016/j.brainres.2015.04.054 membrane, which may weaken or disrupt their BBB-associated tight junctions. Disruption of brain homeostasis due to plasma influx into the brain parenchyma and binding of plasma components (e.g., immunoglobulins) to neurons may contribute to POD. We propose that, in the elderly, exposure to some IAs can cause BBB compromise that disrupts brain homeostasis, perturbs neuronal function and thereby contributes to POD. If unresolved, this may progress to postoperative cognitive decline and later dementia.

Journal of Alzheimer's Disease

Background: Evidence for the universal presence of IgG autoantibodies in blood and their potentia... more Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer’s disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. Methods: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP ® technology to predict ...