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Sun City, AZ, United States

Banner Sun Health Research Institute Sun City

Sun City, AZ, United States
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PubMed | Barrow Neurological Institute, Midwestern UniversityGlendale, Banner Sun Health Research Institute Sun City and Midwestern University
Type: Journal Article | Journal: American journal of neurodegenerative disease | Year: 2016

Based on the amyloid cascade hypothesis of Alzheimers disease (AD) pathogenesis, a series of clinical trials involving immunotherapies have been undertaken including infusion with the IgG1 monoclonal anti-A antibody solanezumab directed against the middle of the soluble A peptide. In this report, we give an account of the clinical history, psychometric testing, gross and microscopic neuropathology as well as immunochemical quantitation of soluble and insoluble A peptides and other proteins of interest related to AD pathophysiology in a patient treated with solanezumab.The solanezumab-treated AD case (SOLA-AD) was compared to non-demented control (NDC, n = 5) and non-immunized AD (NI-AD, n = 5) subjects. Brain sections were stained with H&E, Thioflavine-S, Campbell-Switzer and Gallyas methods. ELISA and Western blots were used for quantification of proteins of interest.The SOLA-AD subjects neuropathology and biochemistry differed sharply from the NDC and NI-AD groups. The SOLA-AD case had copious numbers of amyloid laden blood vessels in all areas of the cerebral cortex, from leptomeningeal perforating arteries to arteriolar deposits which attained the cerebral amyloid angiopathy (CAA) maximum score of 12. In contrast, the maximum CAA for the NI-AD cases averaged a total of 3.6, while the NDC cases only reached 0.75. The SOLA-AD subject had 4.4-fold more soluble A40 and 5.6-fold more insoluble A40 in the frontal lobe compared to NI-AD cases. In the temporal lobe of the SOLA-AD case, the soluble A40 was 80-fold increased, and the insoluble A40 was 13-fold more abundant compared to the non-immunized AD cases. Both soluble and insoluble A42 levels were not dramatically different between the SOLA-AD and NI-AD cohort.Solanezumab immunotherapy provided no apparent relief in the clinical evolution of dementia in this particular AD patient, since there was a continuous cognitive deterioration and full expression of amyloid deposition and neuropathology.


PubMed | Banner Sun Health Research Institute Sun City
Type: Journal Article | Journal: American journal of neurodegenerative disease | Year: 2013

Alzheimers disease (AD) dementia impacts all facets of higher order cognitive function and is characterized by the presence of distinctive pathological lesions in the gray matter (GM). The profound alterations in GM structure and function have fostered the view that AD impacts are primarily a consequence of GM damage. However, the white matter (WM) represents about 50% of the cerebrum and this area of the brain is substantially atrophied and profoundly abnormal in both sporadic AD (SAD) and familial AD (FAD). We examined the WM biochemistry by ELISA and Western blot analyses of key proteins in 10 FAD cases harboring mutations in the presenilin genes PSEN1 and PSEN2 as well as in 4 non-demented control (NDC) individuals and 4 subjects with SAD. The molecules examined were direct substrates of PSEN1 such as Notch-1 and amyloid precursor protein (APP). In addition, apolipoproteins, axonal transport molecules, cytoskeletal and structural proteins, neurotrophic factors and synaptic proteins were examined. PSEN-FAD subjects had, on average, higher amounts of WM amyloid-beta (A) peptides compared to SAD, which may play a role in the devastating dysfunction of the brain. However, the PSEN-FAD mutations we examined did not produce uniform increases in the relative proportions of A42 and exhibited substantial variability in total A levels. These observations suggest that neurodegeneration and dementia do not depend solely on enhanced A42 levels. Our data revealed additional complexities in PSEN-FAD individuals. Some direct substrates of -secretase, such as Notch, N-cadherin, Erb-B4 and APP, deviated substantially from the NDC group baseline for some, but not all, mutation types. Proteins that were not direct -secretase substrates, but play key structural and functional roles in the WM, likewise exhibited varied concentrations in the distinct PSEN mutation backgrounds. Detailing the diverse biochemical pathology spectrum of PSEN mutations may offer valuable insights into dementia progression and the design of effective therapeutic interventions for both SAD and FAD.


PubMed | Mayo Medical School, Arizona State University and Banner Sun Health Research Institute Sun City
Type: | Journal: Frontiers in neuroscience | Year: 2016

Evidence of inflammation has been consistently associated with pathology in Parkinsons disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains. It is not known whether inflammatory changes occur first in striatum or SN. Many animal models of PD have implicated certain inflammatory molecules with dopaminergic cell neuronal loss; however, there have been few studies to validate these findings by measuring the levels of these and other inflammatory factors in human PD brain samples. This study also included samples from incidental Lewy body disease (ILBD) cases, since ILBD is considered a non-symptomatic precursor to PD, with subjects having significant loss of tyrosine hydroxylase-producing neurons. We hypothesized that there may be a progressive change in key inflammatory factors in ILBD samples intermediate between neurologically normal and PD. To address this, we used a quantitative antibody-array platform (Raybiotech-Quantibody arrays) to measure the levels of 160 different inflammation-associated cytokines, chemokines, growth factors, and related molecules in extracts of SN and striatum from clinically and neuropathologically characterized PD, ILBD, and normal control cases. Patterns of changes in inflammation and related molecules were distinctly different between SN and striatum. Our results showed significantly different levels of interleukin (IL)-5, IL-15, monokine induced by gamma interferon, and IL-6 soluble receptor in SN between disease groups. A different panel of 13 proteins with significant changes in striatum, with IL-15 as the common feature, was identified. Although the ability to detect some proteins was limited by sensitivity, patterns of expression indicated involvement of certain T-cell cytokines, vascular changes, and loss of certain growth factors, with disease progression. The results demonstrate the feasibility of profiling inflammatory molecules using diseased human brain samples, and have provided additional targets to validate in relation to PD pathology.


PubMed | Banner Sun Health Research Institute Sun City
Type: Journal Article | Journal: American journal of neurodegenerative disease | Year: 2013

We have previously reported that increased numbers of Alz-50-reactive (apoptotic) neurons occurred in young DS subjects compared to controls, but increased in density with increasing age, and in advance of identifiable senile plaques (SP) in DS. The purpose of the study was to determine if there are further differences in Alzheimers disease (AD)-like neuropathology with increasing age among individuals with Downs syndrome (DS) compared to cognitively normal age-matched controls. The two populations compared were age-matched normal controls (N = 14) between 11 months and 61 years of age and individuals with DS (N = 8) between 1 and 54 years of age. There were 7 cognitively intact DS and 10 control subjects under 35 years of age. The single demented 54 year old DS subject was compared to 4 non-demented controls between 48 and 61 years of age. 50 m Vibratome sections of formalin fixed hippocampal formations were immunohistochemically stained for amyloid- (6E10), APP (22C11) and phosphorylated tau (AT8) using standard methods. AT8 immunoreactive features were found only in the oldest DS subject. In contrast, the number and intensity of amyloid--immunoreactive neurons were maximal in the youngest DS subjects (1-24 years), reduced in the young adults (25-35 years) synchronous with the appearance of only diffuse-form SP, and were further reduced in the 54 year-old DS subject exhibiting abundant multiform SP. Distribution of APP immunoreactivity (22C11) was distinct from amyloid- (6E10) in appearance and by location and age in both DS and normal controls. The data indicates that the earliest observable neuropathologic feature in DS may be neuronal accumulation of amyloid-. Such accumulation of amyloid- occurs decades in advance of deposition as SP, which in turn occurs decades before cognitive decline.

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