Browsing by Subject "Alzheimer Disease"
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Item AB1-42 Antibody Producing Plasma Cells in DNA AB42 Trimer Immunized Mice Reside Predominantly in the Bone Marrow(2013-01-22) Zacharias, Tresa; Langworthy, Suzanna; Fu, Min; Anderson, Larry; Stuve, Olaf; Rosenburg, Roger; Lambracht-Washington, DorisAlzheimer's disease (AD) is the most common form of age-related dementia and affects nearly 40 million people worldwide. Immunotherapy provides a possible avenue for prophylaxis of AD, but a clinical trial (AN1792) in which patients with early AD were immunized with Aβ1-42 peptide was halted after the occurrence of meningoencephalitis in 6% of the immunized people which was attributed to a T cell autoimmune response. DNA vaccination has been shown to have a polarized Th2 immune response that lacks many of the features responsible for inflammation seen in peptide immunizations. In this study, we show a new feature of the DNA Aβ42 trimer elicited B cell immune response and present data for the presence of a long lived plasma cell pool residing within the bone marrow in DNA immunized mice but not in peptide immunized mice. Two groups of mice were analyzed: one group of B6C3F1 mice (n=20) were studied 4 months after the last DNA vaccination, and a second group of BALB/c mice (n=14), which received DNA or peptide immunizations, were analyzed 10 days following the last immunization. The comparison of antibody producing cells in bone marrow and spleen for the DNA and peptide immunized mice with an Antibody Forming Cell (AFC) ELISPOT assay and subsequent ELISAs showed that bone marrow plasma cells from DNA immunized mice produced more anti-Aβ42 IgG producing cells and higher levels of secreted IgG antibodies. In peptide immunized mice, more IgG antibody producing cells were found to reside in the spleen. These data indicate that the bone marrow may be an important reservoir for B cells following DNA Aβ42 immunization and is in line with studies showing that the bone marrow represents an excellent niche for the survival of long lived plasma cells and a lifetime source for antibody producing B cells which are independent of continuous antigen specific stimulation. Further studies are needed to show whether it is possible to define additional phenotypic characteristics for the antigen specific B cell immune response in DNA Aβ42 trimer immunized mice or differences in the TH subsets directly involved in initial signaling events to B cells in the germinal center reactions.Item Adapting Behavioral Interventions to Better Support Alzheimer's Disease and Lewy Body Dementia Care Partners Based on Their Unique Needs and Differences(2021-12-16) Kew, Chung Lin; Krumwiede, Kimberly Hoggatt; Juengst, Shannon B.; Osborne, Candice L.; Tzen, Yi-Ting; Kelley, Brendan; Smith, Scott AlanCare partners of individuals with Alzheimer's disease (AD) and Lewy body dementia (LBD) are typically family members or friends. They often experience physical and psychological strain associated with caregiving. Hence, the long-term goal is to improve the physical and psychological health and well-being of care partners of individuals with AD and LBD through the provision of a self-management intervention, problem-solving training (PST). To achieve this goal, the following gap in literature has to be addressed. Firstly, although AD and LBD have different symptom presentations, little is known about challenges specific to LBD care partners and how these challenges differ between AD and LBD care partners. Next, research to date has yet to identify specific care partner characteristics that could impact uptake and outcomes of behavioral interventions that promote self-management, like PST. Therefore, this (ORBIT model Phase I) study aims to (1) identify differences between the challenges faced by care partners of AD and LBD patients to support the transferability of care partner interventions to all care partners, and (2) identify whether PST needs to be adapted (i.e., optimized) to account for unique individual differences that may affect how much a person benefits from the intervention. Results of both these aims will provide a concrete understanding of both AD and LBD care partner experiences and specific care partner characteristics and intervention components that could impact how we can better support care partners.Item Alzheimer's Disease and disordered cholesterol metabolism another illness to treat with statins?(2000-06-22) Dietschy, John M.Item Analyses of the Link Between Amyloid and Tau Pathology in an AD Mouse Model (3xtg-AD): Disease Progression with Increased Levels of Abeta and Tau Peptides(2018-01-23) Zapata, Lucio, Jr.; Ismail, Hannah; Lambracht-Washington, DorisINTRODUCTION: Pathological features of Alzheimer's disease (AD) include the accumulation of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptide and intracellular neurofibrillary tangles consisting of phosphorylated tau protein. Mutations in the genes that encode amyloid precursor protein (APP), and presenilin 1 and 2 (PS1/PS2) have been shown to cause familial AD in humans. Studies provided evidence that Aβ accumulation may initiate phosphorylation of tau protein, via the Ras/MEK/Extracellular Signal-regulated Kinase (ERK) signaling cascade, activation of the mitogen-activated protein kinase (p38 MAPK), Cyclin dependent kinase 5 (CDK5) and/or glycogen synthase kinase-3β (GSK3β). We studied distribution of Aβ and tau oligomers, Erk activity in different brain lysate fractions from different age groups of a triple transgenic mouse model (3xTg-AD) and wild-type mice, and Erk activity in DNA Abeta42 immunized mice. METHODS: Brain lysates of 4-, 6-, 12-, and 20-month-old 3xTg-AD and wild-type mice were prepared via a 4-step extraction protocol in TBS (soluble), TBS-T, SDS, and formic acid. DNA Abeta42 vaccination administered via gene gun. Abeta and Tau concentrations and Tau phosphorylation levels were monitored by Dot blot, Semidenaturing detergent agarose gel electrophoresis (SDD-AGE), and ELISA using anti-Abeta and anti-Tau antibodies. Erk1/2 levels were monitored by Western blot using monoclonal antibodies. RESULTS: There was a significant increase of total tau concentrations with increasing age and we found also an increasing insolubility (more tau in the non-soluble brain lysate fractions). 4- and 20-month-old 3xTg-AD soluble brain lysates indicated the presence of aggregated tau peptide, which was not present in wild-type control mice. Kinases involved with tau phosphorylation were measured and showed an increase of activated/phosphorylated Erk1/2 with increasing age, with a drop in concentration at 12 months in half of the mice analyzed (n=5). Immunized 3xTg-AD mice showed a decrease in activated Erk1/2 when compared to non-immunized, age matched mice. DISCUSSION: The 3xTg-AD mouse model provides a good model to study pathologies and possible treatments for human Alzheimer's disease. Abeta 42 peptide and tau increase due to age in this mouse model. A link between the amyloid pathology is likely found in the wide spectrum of cellular kinases which are upregulated due to Abeta in Alzheimer's disease. Therefore, immunization against Abeta and generation of anti-Abeta antibody will indirectly reduce tau pathology.Item ApoE Receptors in Alzheimer's and CNS Function(2017-03-24) Lane-Donovan, Courtney; Powell, Craig M.; Herz, Joachim; Eisch, Amelia J.; Huber, Kimberly M.Alzheimer's disease (AD) is a currently incurable neurodegenerative disorder and the most common form of dementia over age 65. The predominant genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4). Other genes related to lipid metabolism and lipoprotein receptor signaling have also been identified as risk modifiers for AD. Despite nearly two decades of research, the mechanisms by which lipid transport proteins cause central nervous system (CNS) disease are not completely understood. Here, the ApoE receptor family and its ligands and their roles in CNS function and neurological disease were explored. It has been previously shown that ApoE4 renders neurons resistant to the neuromodulator and ApoE receptor ligand Reelin, which enhances synaptic plasticity and protects against amyloid β (Aβ) oligomer-induced synaptic toxicity in vitro. Here, mice with reduced Reelin expression were more sensitive to amyloid-induced synaptic suppression, and had memory and learning disabilities at very low amyloid levels. However, this effect of Reelin loss did not extend to other forms a neurological insult, since the Reelin conditional knockout mice were not more susceptible to transient middle cerebral artery occlusions. Together, these findings highlight the specific physiological importance of Reelin for protecting the brain against Aβ-induced synaptic dysfunction and memory impairment. One of the continuing debates in the AD field is whether ApoE is required for synaptic function. ApoE knockout mice have synaptic loss; however, they also have severely increased plasma lipids, which could independently contribute to CNS dysfunction. A novel mouse with normal plasma ApoE, but severely depleted brain ApoE, shares a similar synaptic phenotype as ApoE knockout mice, suggesting central ApoE is required for brain function. To determine if diet can modulate ApoE levels, wildtype, ApoE3, and ApoE4 targeted replacement mice were fed a chow, high-fat, or ketogenic (high-fat, very-low-carb) diet. Surprisingly, high-fat diet reduced hippocampal ApoE levels in ApoE3 TR mice, indicating an intersection of genetic (ApoE isoform) and lifestyle (diet) risk factors on AD pathogenesis. Taken together, these findings highlight the importance of ApoE receptors and their ligands in AD biology, and future studies will have to determine how to target these mechanisms to treat AD and improve patient outcomes.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, Laura H.Mild 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, Laura H.A 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 Distinct Tau Strains: Exploring Variability in Cell Uptake and Seeding(2019-03-15) Prueitt, William Lloyd; Diamond, Marc; Stopschinski, Barbara; Joachimiak, LukaszBACKGROUND: Tauopathies are neurodegenerative diseases characterized by the pathological aggregation of the microtubule-associated protein tau in neurons and glia. These conditions are incurable, progressive, and deadly. Alzheimer's Disease, the most common tauopathy, affects more than 30 million people worldwide and will afflict more than 120 million by 2050. Evidence suggests that tau aggregates spread pathology as do prions, infectious proteins that transmit a pathologic conformation to native proteins via disease-specific conformers (strains). Various tau strains have been identified which propagate stably in cultured cells over many generations. Additionally, evidence shows that tau aggregates enter cells through heparan sulfate proteoglycan (HSPG) mediated macropinocytosis. However, it is unknown if: 1) different tau strains bind HSPGs uniquely or generically to trigger uptake; 2) which HSPG size and sulfation patters are important for cellular uptake of tau. OBJECTIVE: Test for differential inhibition of cellular uptake using heparin, heparinoids, and HSPG modifications; and test effects of HSPG size and sulfation patterns on binding to tau. METHODS: A "biosensor" cell line responsive to tau aggregates was used to measure intracellular tau aggregation based on fluorescence resonance energy transfer (FRET). The biosensors were HEK-293T cells which overexpress the tau repeat domain (RD) with the disease-associated P301S mutation and were tagged with cyan or yellow fluorescent proteins (RD-CFP/YFP). Cell lysate from various strains of tau was used as source material for pathologic tau seeds to induce aggregation of native tau protein within the biosensors. Lysate was incubated with heparin or heparinoids (heparin-derived molecules of varying length and sulfation patterns) for 24-hours and then added to biosensor cells in culture. When incubated in this way, heparin and heparinoids block cellular uptake of tau by preventing its binding to HSPGs. In a separate assay, lysate was added to cultured biosensor cells with CRISPR/Cas9 knockouts of important genes in the HSPG synthesis pathway. In both assays, cells were harvested 48 hours after lysate/lysate-heparinoid addition and seeding was quantified using FRET flow cytometry. RESULTS: All tau strains tested (DS 5, 6, 8, 9, 10, 13, 14, 15, 16, 17) were highly sensitive to heparin inhibition of seeding and most maintained a highly similar dose response (IC50 of ~100 nM). Some strains, however, showed subtle differences. At maximal heparin concentrations (200 ug/mL), noticeably higher seeding vs baseline was observed in DS 5 and 6 (17%, 9%) as compared to the other strains (<5%). When using heparinoids of 4, 8, 12, and 16 disaccharide units to inhibit tau uptake, similar patterns were seen in DS 9 and 10 (seeding reduction: dp4 = 21% vs 19%; dp8 = 27% vs 33%; dp12 = 70% vs 64%; dp16 = 63% vs 46%). Heparinoids that were desulfated at the 2-O, 6-O, and N positions also showed similar patterns of tau uptake inhibition in DS 9 and 10 (De-2-O = 65% vs 53%; De-6-O = 52% vs 25%; De-N = 35% vs 13%). Finally, seeding in HSPG genetic knockout cells was reduced substantially across strains tested in two knockout cell lines (for genes EXT1 and NDST1). Interestingly, DS 5, DS 6, and DS 15 showed less reduction than the other strains in the knockout cell lines (-38%, -50%, and -51% respectively vs roughly -65% for other strains). Finally, seeding in the third knockout cell line (HS6ST2) increased across all strains tested ranging from +13% to +58%. CONCLUSIONS: Cellular uptake of many tau strains is similarly inhibited by heparin, hinting that the same heparinoid (or small molecule analog) could be used to treat diverse tauopathies. However, the unique behavior of some strains suggests that a one-size-fits-all treatment approach may not always be sufficient. Additionally, certain heparin size and sulfation patterns have specific importance for tau binding. Larger heparinoids better inhibited tau seeding (dp16 & dp12 > dp8 & dp4). Regarding sulfation patterns, the relative importance for tau binding of the sulfate moieties tested is: N-sulfation > 6-O-sulfation > 2-O-sulfation. This pattern remains consistent in recombinant tau, DS 9, DS 10, and in the genetic knockout data gathered in this project (using strains) and by others in the laboratory (using recombinant tau). Overall, this data shows many similarities and some differences in cellular uptake between strains of tau. Additional research to further characterize these differences could have important implications for understanding the diversity of tauopathies and finding unique approaches to diagnosis and treatment.Item Donald W. Seldin, M.D., Research Symposium finalist presentations(2022-04-29) Almonte, Matthew; Duvalyan, Angela; McAdams, Meredith; Onyirioha, Kristeen; Saez-Calveras, Nil; Triana, TaylorThis edition of the UT Southwestern Internal Medicine Grand Rounds features presentations by the six Foster Fellows selected as finalists from the Seventh Annual Donald W. Seldin, M.D. Research Symposium, which was held on April 21, 2022. These Foster Fellows presented work that spanned the breadth and depth of scholarly activity across the department, and at the close of Grand Rounds, one will be selected as the 2022 Seldin Scholar, in honor of Dr. Donald W. Seldin. The Grand Rounds presentation includes additional award presentations recognizing Clinical Vignettes, as well as the Award for Research in Quality and Education at Parkland Hospital and the Social Impact Award.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; Bezprozvanny, 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 basis of Alzheimer's Disease: death from cerebral indigestion(1995-11-30) Brown, Michael S.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(2011-08-10) 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 Lifestyle Factors Related to Cognitive Aging(2020-08-01T05:00:00.000Z) Smith, Emily Elaine; Rossetti, Heidi; Lacritz, Laura; Hynan, Linda S.; Lamar, Melissa; Smernoff, Eric; Valvano, AbbeyCognitive changes are a hallmark feature of Alzheimer's disease (AD) and lifestyle behaviors have been associated with a reduced risk of disease onset and slower rate of cognitive decline. Research examining the relationship of lifestyle factors (LFs) to brain health has typically focused on individual factors in isolation (more physical activity (PA) and reduced risk of AD); however, few studies have examined the combined effects of multiple LFs on cognition. The current study aimed to 1) determine which LFs best predict cognition cross-sectionally; 2) derive and compare different approaches to developing a Health Score (HS) to help predict cognition; and 3) discern if a healthy lifestyle was associated with slower rate of cognitive decline. This study included 467 older adults (Mage=83; No Cognitive Impairment=361, Mild Cognitive Impairment (MCI=94), Alzheimer's dementia (AD=12)) enrolled in a longitudinal (Myears=3.72) aging study with yearly evaluations, including neuropsychological testing, clinical evaluation, and detailed assessment of lifestyle behaviors: diet, PA, sleep, social activities, stress, depression, alcohol, smoking, body mass index (BMI), and APOE genotyping. Cognitive z-scores were derived for global cognition, verbal memory, processing speed, and working memory. HS based on a Scientific (i.e., data driven), Lifestyle/Health (i.e., only healthy lifestyle behaviors), Risk/Disease (i.e., only unhealthy behaviors), or Comprehensive (i.e., all healthy/unhealthy behaviors) approaches were calculated and categorized (Unfavorable, Minimally Favorable, Moderately Favorable, Favorable) based on quartiles. Rate of cognitive change was also calculated. Multiple linear regression analyses in the full sample revealed demographic and lifestyle (i.e., social activities, diet) factors consistently predicted cognition cross-sectionally. In the MCI/AD group, diet, PA and BMI were significant predictors with minimal demographic predictors. HS comparisons via Meng's test revealed a Lifestyle/Health approach as the best predictor of cognition compared to the other approaches. In addition, individuals with HSs in the Favorable category had significantly slower rates of cognitive decline than individuals in other categories. Overall, LFs better predicted cognition than risk factors commonly used in clinical and research settings. Results from this study corroborate prior findings and encourage continued support and resources for lifestyle research and intervention programs to help prevent and slow cognitive decline and AD.Item Losing it: mild cognitive impairment, is it Alzheimers?(1999-07-15) Vicioso, Belinda A.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(2005-08-11) McDonald, Noelle Kristen; Lacritz, Laura H.Leukoaraiosis (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.