Browsing by Subject "Alzheimer Disease"
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Item Changes in Brain Functional Connectivity Following Donepezil Treatment in Alzheimer's Disease(2006-05-16) Zaidel, Liam; Allen, GregThis study used resting state functional connectivity magnetic resonance imaging (fcMRI) to explore changes in brain connectivity and their behavior correlates in nine regions of interest (ROIs) in eleven patients with mild Alzheimer's disease (AD) following treatment with the cholinesterase inhibitor, donepezil. The ROIs were selected on the basis of their association with cholinergic neurotransmission, AD neuropathology, and neurocognitive deficits in AD. These ROIs included the medial septal nuclei, left and right hippocampi, left Broca's area and its right hemisphere homologue, left and right dorsolateral prefrontal cortices, and left and right primary visual cortices. Changes in connectivity were also related to changes in performance on neurocognitive tests of verbal fluency and episodic memory. Among the ROIs, the effects of the drug were selective. Only the connection between left and right DLPFC increased significantly after treatment. However, ten of the eighteen connections measured showed significant relationships between connectivity and behavior. The significant correlations centered around left hippocampus, left Broca's area, and dorsolateral prefrontal cortex bilaterally. Connections originating in the left hippocampus showed mostly inverse relationships with behavior. Predictions of selective increases in connectivity in networks associated with the neurochemical, the neuropathological, and neurocognitive profiles of AD were generally not supported. A separate, whole-brain, exploratory, analysis measured changes in connectivity throughout the brain with each of the nine regions of interest (ROIs). There were increases in connectivity among bilateral frontal areas in language circuits, including the left IFG, left superior temporal gyrus, and left supramarginal gyrus, and in the sensory-motor integrative network. Further connections were noted between the left inferior frontal gyrus and caudate nucleus. The data suggest that the drug had selective effects on executive networks of attention.Item Characterization and Differences Between Possible and Probable Mild Cognitive Impairment(2009-06-15) Denney, David Austin; Lacritz, LauraMild Cognitive Impairment (MCI) is the period of subtle cognitive decline that occurs between normal aging and clinical Alzheimer's Disease (AD). Patients' subjective memory complaints (SMCs) are essential to the diagnosis of MCI. In cases where memory complaints are not verifiable by objective measures, patients are left without a formal diagnosis of cognitive impairment. The current proposal describes a study designed to compare the cognitive features and risk factors of AD in subgroups of patients with SMCs with (Probable MCI) and without (Possible MCI) objective memory deficits in relation to controls. It is predicted that the Probable MCI group will demonstrate lower performance and have a greater decline on neuropsychological measures than patients diagnosed with Possible MCI, who will demonstrate lower performance and have a greater decline on those measures than controls. Also, it is predicted that Probable MCI patients will have greater incidence of vascular risk factors and presence of the apolipoprotein element 4 (APOE-4) allele than the Possible MCI patients, who will have higher incidence of these variables than controls. There is also a demographic analysis designed to identify any differences in age, education, and gender between the groups. Implications of possible outcomes of the study are then discussed.Item A Comparison of the Frontal Variant of Alzheimer's Disease with Typical Alzheimer's Disease and Frontotemporal Dementia(2005-08-11) Ninman, Erin Taylor; Lacritz, LauraA frontal variant of Alzheimer's Disease (FvAD) has been described in the literature in which prominent frontal lobe dysfunction accompanies typical temporal and parietal lobe dysfunction in the early stages of the illness. However, no study has investigated how executive deficits and neuropsychiatric symptoms of the FvAD subgroup differ from those seen in frontotemporal dementias. The current proposal describes a study designed to examine neuropsychological and behavioral functioning in groups of AD, FvAD and FTD patients. It is predicted that the FvAD group will have an older age of onset and a lower ratio of males to females than the FTD group, and will perform similar to the AD group on measures of memory, language and visuospatial abilities. The FvAD group is also expected to perform similar to the FTD group on measures of executive functioning and exhibit a greater degree of behavioral symptoms than the AD group. Implications of possible outcomes of the study are then discussed.Item Evaluation of F-18 Labeled Hydroxy Quinoline Derivative as a Potential PET Imaging Agent for Early Detection of Alzheimer’s Disease(2012-07-17) Alhasan, Mustafa; Kulkarni, PadmakarAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive cognitive decline in the elderly people older than 65 years of age. The pathological hallmarks of the disease include extracellular senile plaques and intracellular tangles developing during the pre-symptomatic stage. Although the definite diagnosis of AD is only possible post-mortem, non-invasive imaging has provided an important tool for early detection, and has helped in planning for an effective treatment. Targeted molecular imaging using positron emission tomography (PET) has provided the insight into understanding different disease mechanisms with high sensitivity. Based on the amyloid cascade hypothesis, congo red and thioflavine derivatives have been investigated as potential PET ligands that bind specifically to the amyloid plaques. Another hypothesis, the metal hypothesis, suggested that elevated level of metals particularly zinc, copper and iron, can interact with amyloid beta proteins to form metal complexes. The use of metal chelation therapy has emphasized the involvement of metals in the aggregation of plaques and has shown promising results in clinical and animal studies through dissolving plaques and restoring the metals balance in the affected brains. In this study, based on the metal hypothesis, 18F-labeled 8-hydroxy quinoline was investigated as a potential PET imaging agent for early detection of AD in APP/PS1 mouse model. This agent demonstrated high binding affinity to the plaque aggregates (1.5 nM), and increased fluorescence intensity upon binding to zinc. In addition, in vivo studies showed the feasibility of differentiating mice with AD from normal control mice (p < 0.05), and the ability to detect different plaque densities at different ages of AD (4, 6, and 12 months). Good correlations were found between autoradiography, histology and PET images. The biodistribution data demonstrated rapid uptake and clearance of this compound in the normal brain of wild-type mice.Item Familial Alzheimer's Disease Mutations in Presenilins disrupt Endoplasmic Reticulum Calcium leak(2009-06-19) Nelson, Omar Lloyd; Bezprovanny, IlyaAlzheimer disease (AD) is the most common form of progressive dementia in adults over the age of 65 years. AD is a fatal brain disease and it currently affects about 27 million people worldwide. It is speculated that the number of people affected by AD will quadruple by 2050. The presence of amyloid beta plaque serves a pathological hallmark for AD, since it was first described by Alois Alzheimer's in 1906. The major risk factors for developing AD are age, mutations in presenilins (PS1 and PS2), mutations in the amyloid precursor protein (APP), cardiovascular diseases, open heart surgery, diabetes, brain injury/head trauma, Apolipoprotein E-e4 (APOE-e4) and the (P86L) mutation in the CALHM1(Calcium homeostasis modulator 1) gene. Multiple missense mutations have been reported in presenilin-1 (PS1), presenilin-2 (PS2) and the amyloid precursor proteins (APP), which are linked to familial AD (FAD). Presenilins are known to function as the catalytic subunit of the (-secretase complex and FAD mutations in presenilins affect APP processing, leading to the accumulation of Aᴲ peptide and amyloid plaque formation in AD brains. In addition to abnormal APP processing, several FAD mutations in presenilins have been linked to abnormal calcium (Ca2+) signaling. Our laboratory recently discovered that presenilin holoproteins function as endoplasmic reticulum (ER) Ca2+ leak channels and that FAD mutations in presenilns affected this function. Our findings potentially provided an explanation for Ca2+ signaling abnormalities resulting from FAD mutations in presenilins. The goal of my thesis project is to establish a connection between presenilins FAD mutations and ER Ca2+ signaling. For these studies we utilized the lipid bilayer reconstitution technique and Ca2+ imaging experiments. In order to establish such a connection I examined the effects of FAD PS1 mutation, FAD PS2 mutation, FAD APP mutation, a mutation in tau and sporadic AD cases on ER Ca2+ leak. In addition, I will map the conductance pore of PS1 using cysteine substitution in transmembrane 6, 7 and 9. These data will help to evaluate the "Ca2+ hypothesis of AD" and will contribute to selecting optimal strategies for treatment of AD.Item Functional Connectivity of Entorhinal Cortex in Alzheimer's disease(2008-09-12) Long, Sally Ferdon; Allen, GregAlzheimer's disease (AD) is a progressive neurodegenerative disease characterized by prominent memory impairment, executive dysfunction, language, construction, and visuospatial deficits. In AD, the accumulation of neurofibrillary tangles neuritic plaques, and other associated neuropathology, results in widespread disruption of cortical connections. The entorhinal cortex (EC) is a region of cortical gray matter in the medial temporal lobe important in memory processing, and has been identified as the first structure affected in AD. The current study investigated the functional connectivity of the EC in AD and normal control (NC) subjects using functional connectivity magnetic resonance imaging (fcMRI). Additional goals of the study were to examine relationships between EC functional connectivity, EC volume, and neuropsychological measures of episodic memory and global cognitive ability. Nine NC and seven AD subjects were imaged using a 3.0 Tesla magnetic resonance scanner while resting quietly. Compared to the NC group, AD subjects exhibited significantly reduced functional connectivity with the EC in prefrontal cortex (BA 47, 10, 6, 9,&8), right superior temporal areas (BA 22&39), right fusiform gyrus (BA 37), and right perirhinal/entorhinal cortex (BA 35) extending into the hippocampus. Areas of significantly increased functional connectivity in AD subjects included bilateral inferior frontal gyrus (BA 47), left middle frontal gyrus (BA 46), left entorhinal/parahippocampal cortex (BA 28), and the left putamen. No significant relationships were detected among EC functional connectivity, EC volume, and cognitive measures. The findings of reduced EC connectivity in frontal and temporal association areas in AD are consistent with what is known about the progression of pathophysiology of AD, and provide support for the use of fcMRI in examining cortical connectivity patterns. Increased EC connectivity in prefrontal cortex may reflect the presence of compensatory mechanisms in the neural connections of AD patients. The lack of correlations among EC connectivity, EC volume, and neuropsychological measures suggests that more complex relationships among the variable may exist than was hypothesized. Future research investigating the relationships between functional integrity and structural volume, and how these variables relate to cognitive performance is needed.Item Functional Connectivity of the Posterior Cingulate in Mild Cognitive Impairment and Alzheimer's Disease(2008-09-12) Fields, Julie A.; Allen, GregMild cognitive impairment (MCI) has been implicated as an early stage of Alzheimer's disease (AD) by some, while others argue this is not necessarily the case. While controversy around this issue continues, it is undisputed that MCI is a risk factor for AD. Finding a biomarker of AD would lead to early intervention that could potentially slow the progression of the disease and guide further research towards targets for a cure. Recent findings suggest that reduced connectivity between the posterior cingulate cortex (PCC) and associated brain regions may make an important contribution in this regard, as changes in the PCC/precuneus and entorhinal cortex are implicated as early biomarkers for AD. The current study used functional connectivity magnetic resonance imaging (fcMRI) to examine the posterior cingulate's connectivity with other brain regions in subjects with AD (n=10), MCI (n=9), and age-matched elderly normal controls (NC; n=10). As hypothesized, results revealed that subjects with AD showed decreased connectivity in regions of the frontal lobe, temporal lobe, and cingulate gyrus when compared to NC, and in the frontal and temporal gyri when compared to MCI. When MCI was compared to NC, decreased connectivity was observed in the cingulate gyrus and parahippocampal gyrus while increased connectivity was found in prefrontal cortex and cerebellar regions. The latter finding of increased connectivity in the MCI group in the prefrontal cortex and cerebellum was interpreted as evidence of compensatory recruitment of alternate brain regions in the face of deficient processing in parahippocampal regions in the early stage of disease. It is possible that the connectivity between the PCC and cerebello-frontal structures in MCI may be helping to sustain episodic memory and executive functions that deteriorate in AD. This study showed that fcMRI may be sensitive enough to detect subtle changes in brain structure, and while it is premature to say that fcMRI might prove to be a biomarker of AD, these preliminary findings are encouraging and may serve as an impetus for further research.Item Genetic Reduction of Cholesterol Synthesis in the Mouse Brain Does Not Affect Amyloid Formation in an Alzheimer’s Disease Model, but Does Extend Lifespan(2011-08-26T17:35:30Z) Warren, Rebekkah Lynn; Russell, David W.In vitro alterations in cellular cholesterol content or synthesis affect the cleavage of amyloid precursor protein (APP) to amyloidogenic peptides characteristic of Alzheimer’s disease (AD). To determine whether a decrease in cholesterol synthesis would affect APP processing in vivo, we crossed cholesterol 24-hydroxylase knockout (KO) mice, which exhibit a 50 percent reduction in sterol synthesis, with transgenic mice (B6.Cg-Tg(APPswe, PSEN1E9)85Dbo/J) that develop AD and followed progression of the disease and lipid metabolism in the offspring. APP expression and amyloid plaque deposition in the cortex and hippocampus of 3- to 15-month-old male and female AD mice were similar in the presence and absence of cholesterol 24-hydroxylase. At 15 months of age, a modest but statistically significant decline in insoluble A-beta 40 and A-beta 42 peptide levels was detected in the hippocampus but not cortex of KO/AD mice versus WT/AD mice. Amyloid plaque accumulation did not affect brain sterol or fatty acid synthesis rates in 24-hydroxylase WT or KO mice. Unexpectedly, loss of one or two 24-hydroxylase alleles increased longevity in AD mice. These studies suggest that reducing de novo cholesterol synthesis in the brain will not substantially alter the course of AD, but may confer a survival advantage.Item Molecular Imaging of Amyloid-Beta Proteins by Polymeric Anoparticles in Mouse Models of Alzheimer's Disease(2006-12-20) Roney, Celeste Anita; Bonte, Frederick J.Alzheimer's disease (AD) is the most common cause of dementia among the elderly, affecting 5% of Americans over age 65, and 20% over age 80. An excess of senile plaques (beta -amyloid protein) and neurofibrillary tangles (tau protein), ventricular enlargement, and cortical atrophy characterizes it. In vivo detection of aggregated amyloid peptides (Abeta ) (amyloid plaques) presents targets for development of biological markers for Alzheimer's disease. In an effort to fabricate in vivo probes, polymeric n-butyl-2-cyanoacrylate (BCA) nanoparticles (NPs) were encapsulated with the radiolabelled amyloid affinity drug 125Iclioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline). 125ICQ was initially selected as a tracer of interest because it chelates transition metals, crosses the BBB, and is easily labeled with radioisotopes of iodine (e.g. 123I, 124I and 125I). Preliminary studies with 125ICQ showed that the agent crossed the BBB, but was retained too briefly for effective chelation. Therefore, a drug carrier is required to improve the extravascular retention of 125ICQ; BCA NPs were chosen as the drug carrier. 125I-CQ discriminately binds to AD post-mortem brain tissue homogenates, versus control. Additionally, 125I-CQ-BCA NPs labeled the Abeta plaques from AD human post-mortem frontal cortical sections, on paraffin-fixed slides. Storage phosphor imaging verified preferential uptake by the AD brain sections, compared to cortical control sections. Additionally, 125I-CQ-BCA NPs cross the BBB in the wild type mouse, with an enhanced brain uptake (%ID/g, significant with 95% confidence (p=0.05)), compared to 125I-CQ. Moreover, brain uptake of 125I-CQ-BCA NPs is enhanced in AD transgenic mice (APP/PS1 and APP/PS1/Tau), and in mice intracranially injected with the aggregated Abeta peptide, versus age-matched wild type controls. Thus, 125I-CQ-BCA NPs act as targeted drug carriers with an affinity for amyloid plaques. Brain entry of 125I-CQBCA NPs was rapid, demonstrating ideal in vivo imaging characteristics for small animal modalities; good clearance of free and non-specifically bound radioisotope affords high-quality temporal resolution, and good signal-to-noise. 125I-CQ-BCA NPs have specificity for the Abeta plaques in post-mortem tissue, and have a rapid brain entry. This combination makes radioiodinated CQ-BCA NPs a promising candidate as an in vivo SPECT (123I), or PET (124I) amyloid imaging agent.Item Neurophysiological Correlates of Leukoaraiosis in Alzheimer's Disease, Mild Cognitive Impairment, and Nondemented Elderly(2005-8-11) McDonald, Noelle Kristen; Lacritz, LauraLeukoaraiosis (LA) refers to neurodegenerative white matter changes that are associated with age and appear as areas of hyperintensity on magnetic resonance imaging (Hachinski, Potter, and Merskey, 1987). Leukoaraiosis has been associated with cognitive impairment and vascular risk factors in nondemented elderly (DeCarli et al., 1995; deGroot et al., 2000), while the relationship with demented elderly is unclear. The current study examined the severity of LA, the relationship between vascular risk factors and LA, and associations between neuropsychological functioning and LA across three groups with varied levels of cognitive functioning. Total LA was more severe among subjects with Alzheimer's Disease (AD, n = 30) than those with Mild Cognitive Impairment (MCI, n = 30) and nondemented elderly (NE, n = 30), but MCI did not have more severe LA than NE. Periventricular and subcortical LA were more severe in AD than MCI, but not NE. Age was a significant predictor of both periventricular and subcortical LA, but hypertension and homocysteine were not independently related to LA. Total LA was inversely associated with neuropsychological performance for all subjects, though correlations were low to moderate (r = -.23 to r = -.36), and were not significant after controlling for the effects of age and cerebral atrophy. Within the AD group, several significant positive correlations between LA and neuropsychological measures emerged, but were reduced when controlling for age, but not atrophy. Results for periventricular LA were similar to total LA findings, while subcortical LA had fewer correlations with neuropsychological measures. Neuropsychological measures of general cognitive functioning, verbal fluency, memory, and executive functioning were associated with increased total and periventricular LA, while measures assessing confrontation naming, visuoconstructional ability, and attention were less affected. Across all subjects, age and cerebral atrophy contributed to associations between neuropsychological performance and LA. Despite greater atrophy and LA in the AD group, neuropsychological functioning was not associated with increased LA within the AD group in the current study. This suggests that relationships between LA and neuropsychological functioning may be identifiable in normal controls, but that disease characteristics play a larger role in cognition in dementia populations such as Alzheimer's disease.Item Predicting the Rate of Decline in Early Alzheimer Disease: the Role of Neurocognitive Performance Features(2013-07-25) Parikh, Mili R; Cullum, C. Munro; Lacritz, Laura H; Hynan, Linda S; Weiner, Myron; Ringe, WendyAlzheimer disease (AD) is a neurodegenerative disorder that characteristically begins with episodic memory impairment followed by other cognitive deficits over time; however, the course of illness varies, with significant variability in terms of the rate of cognitive decline across affected individuals. Several studies have examined demographic, clinical, biological, and neurocognitive performance markers to predict rate of AD progression, but findings are mixed. The current study utilized neurocognitive performance features along with disease-specific and health features to determine the best prediction model for the rate of future cognitive decline in subjects with mild AD. Ninety-six subjects with mild AD at baseline were administered a comprehensive battery of neurocognitive tests and clinical measures. Based on Clinical Dementia Ratings (CDR) of functional and cognitive decline within two years, subjects were determined to be Faster (n = 45) or Slower Progressors (n = 51). Stepwise logistic regressions using neurocognitive performance features, disease-specific, health, and demographic variables were performed in a hierarchical fashion to determine optimal predictors of rate of progression. Several individual neurocognitive measures distinguished Faster from Slower Progressors at baseline, including Trail Making Test - A, Digit Symbol, California Verbal Learning Test (CVLT) Total Learned, CVLT Primacy Recall, and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Neuropsychological Battery Total Score. No disease-specific, health, or demographic variables predicted rate of progression; however, history of cardiac illness showed a trend. In a stepwise logistic regression of neurocognitive performance features alone, a combination model of three measures (Trail Making Test - A, Semantic Fluency, and CERAD Total) distinguished Faster from Slower Progressors with 76% accuracy. In an omnibus model including neurocognitive, disease-specific, health, and demographic variables, only Trail Making Test - A distinguished groups (68% correct classification). Several neurocognitive performance features may play a role in predicting rate of decline in mild AD. Notably, three relatively brief and commonly used measures were found to predict differences in rate progression with good accuracy. Results from the current research provide important advances in understanding the role of neurocognitive measures in predicting rate of decline in AD.Item Regulatory role of ApoE and Apoer 2 in symaptic activity: A new insight into Alzheimer's disease(2008-09-12) Chen, Ying; Herz, JoachimApolipoprotein E (ApoE) genotype is the major genetic modifier of late-onset Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly. By unknown mechanisms, ApoE4 isoform is strongly associated with a substantially earlier age of onset of AD. A synaptic ApoE receptor, Apoer2, activates Dab1 and Src family tyrosine kinases (SFKs) upon binding to the extracellular ligand Reelin. Here, we show that this Reelin-Apoer2-Dab1-SFKs signaling complex greatly enhances the tyrosine phosphorylation as well as the calcium conductance of NMDA receptor, a calcium-permeable postsynaptic glutamate receptor that is critical for synaptic plasticity. The simultaneous interaction of Apoer2 with both Dab1 and postsynaptic scaffolding protein PSD-95 is required for Apoer2 to activate NMDA receptor in response to Reelin. Through this NMDAR-dependent mechanism, Reelin also stimulates the phosphorylation of CREB, a transcription factor that is necessary for neuronal survival and synaptic plasticity. In addition, Reelin can potently counteract the surpression of surface NMDA receptor expression induced by Abeta peptide, the accepted causative factor in the pathogenic process of AD. These results indicate that Apoer2-mediated signaling, by counteracting depressive effect on synapses, is critical for proper function of synaptic network. Last, we show that ApoE4 impairs the trafficking and reduces the surface expression of Apoer2. Consequently, ApoE4 critically diminishes the ability of Reelin to enhance NMDA receptor activity or CREB phosphorylation in primary neurons. As a result, the ability of Reelin to enhance long-term potentiation (LTP), a form of synaptic plasticity involved in learning and memory formation, is significantly impaired in the hippocampus of mice expressing the human ApoE4 isoform. Taken together, in this thesis, we identified a novel synaptic function of Apoer2, which is to enhance NMDA receptor activity, and thereby to enhance synaptic plasticity and maintain the integrity of synaptic network. ApoE4 impairs the function of synapses by suppressing the synaptic function of Apoer2. These findings suggest a novel rational mechanism by which ApoE4 may accelerate the destabilization of synaptic network, neuronal degeneration, and eventually the progression of AD.Item The Relationship of Inflammatory Markers to Cognitive Function in a Population-Based Sample(2010-11-02T18:10:17Z) Bernardo, Keith Alan; Lacritz, Laura Ph.D., ABPPC-reactive protein (CRP), Interleukin-18 (IL-18), Monocyte chemoattractant protein (MCP-1), and Lipoprotein-associated phospholipase (Lp-PLA2) are pro-inflammatory blood markers that appear to play critical roles in atherosclerosis and vascular disease, and have been linked to Alzheimer’s Disease, vascular dementia, and subclinical levels of cognitive decline. The present study investigated the relationship of these four inflammatory markers to cognitive function prospectively, and examined the potential impact of vascular risk factors (i.e., hypertension, hyperlipidemia, smoking status, alchol intake, diabetes mellitus, waist circumference, Cystatin C) and APOE 4 as mediators of cognitive function. METHOD AND RESULTS: Participants include 1904 individuals with CRP, IL-18, MCP-1, and Lp-PLA2, vascular risk factor and APOE 4 data collected as part of the Dallas Heart Study I initiated in 1999, who returned to the Dallas Heart Study II (8 years later) who completed the Montreal Cognitive Assessment (MoCA) as part of a larger clinical research protocol. A significant yet weak correlation was found for Lp-PLA2 (r=.09, p<.01) and MoCA scores, with significant correlations only for men (r=.24, p<.01). None of the other inflammatory markers were associated with MoCA scores. An increased number of vascular risk factors was not related to lower MoCA total scores [F(5,1621)=1.56, p=.168)]. The presence of the APOE 4 allele did not impact the relationship between concentrations of blood markers and cognitive function as hypothesized. In logistic regression analysis, only the demographic variables of Caucasian race and education were significant, and decreased the odds of membership into lowest MoCA tertile group. CONCLUSIONS: Results did not support a relationship between mid-life inflammation and vascular risk factors and later cognitive function in this healthy, middle-aged sample. Demographic factors were the only consistent variables associated with cognitive performance. The minimum level of significant inflammation in this sample may have attenuated the results. Follow-up studies to examine progression of inflammation and vascular risk in relation to cognitive function will help to further examine these relationships.Item The Role of TNF Signaling In Regulating Beta-Amyloid Burden in the 3xtgad Mouse Model of Alzheimer's Disease(2008-05-13) McAlpine, Fiona E.; Tansey, MaluMicroglial activation and overproduction of inflammatory mediators in the CNS have been implicated in Alzheimer's Disease (AD), but the precise nature of the key molecular mediators of neurotoxicity that directly contribute to neurodegeneration or loss of specific neuronal populations is less clear. The pro-inflammatory cytokine Tumor Necrosis Factor (TNF) has been implicated in AD by its elevated presence in serum and post-mortem brains of patients with AD. To test the hypothesis that TNF-dependent neuroinflammation and neurotoxicity contributes to the increased microglial burden and exacerbated pathology observed in the hippocampus and cortex of 3xTgAD mice (transgenic mouse expressing human familial AD mutations in APP, PS1, and a familial frontotemporal dementia mutation in tau) after chronic systemic LPS exposure, we inhibited TNF signaling with novel engineered dominant negative TNF inhibitors (DN-TNF) selective for soluble TNF (solTNF) or lentiviral-derived DN-TNF to achieve long-term inhibition of TNF activity and halt or delay the early stages of amyloid-associated neuropathology. In vitro, cells infected with lenti-pro-DN-TNF-IRES-GFP produce sufficient levels of DN-TNF protein to block nuclear translocation of p65 in response to stimulation by TNF. Infection with lenti-DN-TNF also blocks solTNF-induced activation of primary microglia. Results from in vivo studies indicate that short-term pharmacological inhibition as well as long-term lentiviral-driven inhibition of soluble TNF signaling decreases the accumulation of intraneuronal full length APP in hippocampus and cortex induced by chronic systemic inflammation. To our knowledge, this is the first study that selectively inhibits soluble TNF signaling in an acute manner using a pharmacologic agent, thereby directly linking endogenous TNF activity in vivo to accumulation of APP in a model of Alzheimer's disease. Targeted inhibition of soluble TNF in the central nervous system may represent a new therapeutic approach to slow the appearance of amyloid pathology, cognitive deficits, and possibly the progressive loss of neurons in AD.Item Subclinical Atherosclerosis and Cognitive Functioning in a Population-Based Sample(2010-11-02T18:18:59Z) Rossetti, Heidi Christine; Lacritz, LauraClinical risk factors for and signs of atherosclerosis have been linked to Alzheimer disease and milder forms of cognitive impairment. This study examines the relationship between subclinical atherosclerosis and cognition in a sample from the Dallas Heart Study (DHS), a population-based study of cardiovascular disease, who were followed 8 years later (DHS-II); N = 1904, mean age = 42.9, SD = 10.5, range 8-65. Weanalyzed atherosclerosis data from DHS-I participants who had completed the Montreal Cognitive Assessment (MoCA) in DHS-II. The relationship between MoCA scores, coronary artery calcium (CAC), abdominal aortic plaque, and abdominal aortic wall thickness (AWT) was examined in the group as a whole, and in relation to age and ApoE4 allele status. Indirect measures of atherosclerosis (diabetes, hypertension, hypercholesterolemia, abdominal obesity) were also examined. Logistic regression was used to examine the association between direct and indirect measures of subclinical atherosclerosis and cognitive function, adjusting for other correlates of cognition. CAC (N = 1414, rho = -.06), abdominal AWT (N = 1284, rho = -.04), and abdominal aortic plaque (N = 1286, rho = -.06) did not correlate with MoCA Total Score (p ≥.048). Though MoCA scores were successively lower with increasing numbers of both direct atherosclerotic indicators [F(2, 633) = 1.40)] and indirect atherosclerotic indicators [F(2, 1048) = 1.09], the differences were not significant (p ≥ .248).The factors that most related to lower MoCA performance were race, gender, and education. There was no difference in MoCA Total Scores or measures of atherosclerosis between participants with an E4 allele and those without the E4 allele. There was no significant relationship between positive CAC, elevated abdominal AWT, and abdominal aortic plaque to MoCA scores obtained 7-8 years later. This relationship did not significantly increase with age and was not influenced by the presence of one or more apolipoprotein E4 alleles. This study does not support an association between direct or indirect measures of atherosclerosis in middle age and global cognition assessed 8 years later in this ethnically diverse population-based sample.Item Substrate Selection by the 20s Proteasome and Implications in Disease Pathogenesis(2013-01-16) Ritchie, Caroline Marie; Thomas, Philip J., Ph.D.Alpha-synuclein is a major component of Lewy bodies, large insoluble protein aggregates, found in various regions of the brain in patients with Parkinson’s disease, diffuse Lewy body disease, and the Lewy body variant of Alzheimer’s disease. Within Lewy bodies, several modifications of alpha-synuclein have been identified, including truncations from either terminus. Several observations support a role for C-terminally truncated forms of alpha-synuclein in disease pathogenesis. While multiple proteases have been implicated in the metabolism of alpha-synuclein, C-terminally truncated forms of alpha-synuclein produced by the 20S proteasome in vitro, through a ubiquitin-independent mechanism, are similar to those found in the cingulate cortex of patients with Lewy body diseases. The work presented here describes an investigation into the mechanism by which alpha-synuclein is recognized and degraded by the 20S proteasome, aimed at the properties of both the substrate and the enzyme required for activity. The results shown reveal a previously unappreciated mechanism by which the 20S proteasome selects its substrates, and this activity is coupled to gate opening in mammalian proteasomes. Additionally, a post-translational modification of the 20S proteasome was identified that correlates with activity of the enzyme against alpha-synuclein.Item Utility of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Battery Total Score in the Progression of Alzheimer's Disease(2007-08-08) Rossetti, Heidi Christine; Lacritz, LauraThe Consortium to Establish a Registry for Alzheimer's Disease (CERAD) created a neuropsychological battery that is both brief and sensitive to dementia (Morris et al., 1989). Chandler et al. (2005) put forth a method of calculating a Total Score for the CERAD along with normative data. The objective of this study was to determine the utility of the Total Score as a measure of progression of Alzheimer's disease (AD). Subjects included CERAD registry normal controls (NC; N = 383) and AD subjects (N = 655) with a baseline assessment and at least one follow-up assessment. Change Scores were calculated along with Reliable Change Indexes (RCI). The AD sample declined an average of -7.2 points per year, compared to a 1.0 point annual increase obtained by the NC sample. By the third annual assessment, the majority of AD subjects (65.2%) exceeded the confidence interval established by the RCI. Annualized CERAD Change Scores significantly correlated with change scores on the MMSE (r = .66), CDR Sum of Boxes (r = -.42), and BDRS (r = -.38). The impact of race, gender, education, and age-at-baseline on AD progression was examined with analysis of covariance and multiple regression. Demographic variables accounted for only 4% of the variance in annualized change in CERAD performance, with greater annualized decline in Total Score observed in Caucasians (M = -7.64, SD = 6.82) versus African- Americans (M = -4.60, SD = 7.03); males (M = -8.22, SD = 6.70) versus females (M = 6-.44, SD = 7.04); and younger age-at-baseline (M = -8.72, SD = 6.44) versus older age-at-baseline (M = -6.85, SD = 7.01). Neither education nor dementia severity significantly impacted annualized Change Scores. The current study provides support for the validity of the CERAD Total Score as a measure of progression in AD.