Neurology Commons^™

Preventive And Therapeutic Reduction Of Amyloid Deposition And Behavioral Impairments In A Model Of Alzheimer’S Disease By Whole Blood Exchange, Akihiko Urayama, Ines Moreno-Gonzalez, Diego Morales-Scheihing, Vineetkumar Kharat, Sandra Pritzkow, Claudio Soto

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD. In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) …

Loss Of Lamp5 Interneurons Drives Neuronal Network Dysfunction In Alzheimer’S Disease, Yuanyuan Deng, Mian Bi, Fabien Delerue, Shelley L Forrest, Gabriella Chan, Julia Van Der Hoven, Annika Van Hummel, Astrid F Feiten, Seojin Lee, Ivan Martinez-Valbuena, Tim Karl, Gabor G Kovacs, Grant Morahan, Yazi D Ke, Lars M Ittner

Faculty, Staff and Student Publications

In Alzheimer's disease (AD), where amyloid-β (Aβ) and tau deposits in the brain, hyperexcitation of neuronal networks is an underlying disease mechanism, but its cause remains unclear. Here, we used the Collaborative Cross (CC) forward genetics mouse platform to identify modifier genes of neuronal hyperexcitation. We found LAMP5 as a novel regulator of hyperexcitation in mice, critical for the survival of distinct interneuron populations. Interestingly, synaptic LAMP5 was lost in AD brains and LAMP5 interneurons degenerated in different AD mouse models. Genetic reduction of LAMP5 augmented functional deficits and neuronal network hypersynchronicity in both Aβ- and tau-driven AD mouse models. …

‘Fly-Ing’ From Rare To Common Neurodegenerative Disease Mechanisms, Mengqi Ma, Matthew J Moulton, Shenzhao Lu, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Genome sequencing advances have enabled researchers and clinicians to probe vast numbers of human variants to distinguish pathogenic from benign variation. Model organisms have been critical in variant assessment and delineating molecular mechanisms of some of the diseases caused by these variants. The fruit fly, Drosophila melanogaster, has played a valuable role in this endeavor, taking advantage of its genetic technologies and established biological knowledge. In this review, we highlight the utility of the fly in studying the function of genes associated with rare neurological diseases that have led to a better understanding of common disease mechanisms. We emphasize …

Risk Of Alzheimer’S Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching, Avram S Bukhbinder, Yaobin Ling, Omar Hasan, Xiaoqian Jiang, Yejin Kim, Kamal N Phelps, Rosemarie E Schmandt, Albert Amran, Ryan Coburn, Srivathsan Ramesh, Qian Xiao, Paul E Schulz

Faculty, Staff and Student Publications

BACKGROUND: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized.

OBJECTIVE: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database.

METHODS: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years …

Association Of Rare Apoe Missense Variants V236e And R251g With Risk Of Alzheimer Disease, Yann Le Guen, Michael E Belloy, Benjamin Grenier-Boley, Itziar De Rojas, Atahualpa Castillo-Morales, Iris Jansen, Aude Nicolas, Céline Bellenguez, Carolina Dalmasso, Fahri Küçükali, Sarah J Eger, Katrine Laura Rasmussen, Jesper Qvist Thomassen, Jean-François Deleuze, Zihuai He, Valerio Napolioni, Philippe Amouyel, Frank Jessen, Patrick G Kehoe, Cornelia Van Duijn, Magda Tsolaki, Pascual Sánchez-Juan, Kristel Sleegers, Martin Ingelsson, Giacomina Rossi, Mikko Hiltunen, Rebecca Sims, Wiesje M Van Der Flier, Alfredo Ramirez, Ole A Andreassen, Ruth Frikke-Schmidt, Julie Williams, Agustín Ruiz, Jean-Charles Lambert, Michael D Greicius, Members Of The Eadb, Gr@Ace, Degesco, Demgene, Gerad, And Eadi Groups, Beatrice Arosio, Luisa Benussi, Anne Boland, Barbara Borroni, Paolo Caffarra, Delphine Daian, Antonio Daniele, Stéphanie Debette, Carole Dufouil, Emrah Düzel, Daniela Galimberti, Vilmantas Giedraitis, Timo Grimmer, Caroline Graff, Edna Grünblatt, Olivier Hanon, Lucrezia Hausner, Stefanie Heilmann-Heimbach, Henne Holstege, Jakub Hort, Deckert Jürgen, Teemu Kuulasmaa, Aad Van Der Lugt, Carlo Masullo, Patrizia Mecocci, Shima Mehrabian, Alexandre De Mendonça, Susanne Moebus, Benedetta Nacmias, Gael Nicolas, Robert Olaso, Goran Papenberg, Lucilla Parnetti, Florence Pasquier, Oliver Peters, Yolande A L Pijnenburg, Julius Popp, Innocenzo Rainero, Inez Ramakers, Steffi Riedel-Heller, Nikolaos Scarmeas, Philip Scheltens, Norbert Scherbaum, Anja Schneider, Davide Seripa, Hilkka Soininen, Vincenzo Solfrizzi, Gianfranco Spalletta, Alessio Squassina, John Van Swieten, Thomas J Tegos, Lucio Tremolizzo, Frans Verhey, Martin Vyhnalek, Jens Wiltfang, Mercè Boada, Pablo García-González, Raquel Puerta, Luis M Real, Victoria Álvarez, María J Bullido, Jordi Clarimon, José María García-Alberca, Pablo Mir, Fermin Moreno, Pau Pastor, Gerard Piñol-Ripoll, Laura Molina-Porcel, Jordi Pérez-Tur, Eloy Rodríguez-Rodríguez, Jose Luís Royo, Raquel Sánchez-Valle, Martin Dichgans, Dan Rujescu

Faculty, Staff and Students Publications

IMPORTANCE: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly.

OBJECTIVE: To determine whether rare missense variants on APOE are associated with AD risk.

DESIGN, SETTING, …

Changes In Measures Of Vestibular And Balance Function And Hippocampus Volume In Alzheimer's Disease And Mild Cognitive Impairment, Helen S Cohen, Christie M Lincoln, Valory N Pavlik, Haleh Sangi-Haghpeykar

Faculty, Staff and Students Publications

OBJECTIVE: To test the hypotheses that people with Alzheimer's disease and mild cognitive impairment have increased frequency of vestibular impairments and decreased hippocampal volume compared with healthy age-matched controls.

STUDY DESIGN: Retrospective, with some historical controls.

SETTING: Out-patient, tertiary care center.

SUBJECTS: People with mild to moderate dementia diagnosed with Alzheimer's disease and with mild cognitive impairment. Main Outcome Measures: A standard clinical battery of objective tests of the vestibular system, and screening for balance; available clinical diagnostic magnetic resonance imaging (MRIs) were reviewed and postprocessed to quantify the left and right hippocampal volumes utilizing both manual segmentation and computer …

Gut Dysbiosis And Age-Related Neurological Diseases In Females, Janelle M Korf, Bhanu P Ganesh, Louise D Mccullough

Faculty, Staff and Student Publications

Historically, females have been underrepresented in biological research. With increased interest in the gut microbiome and the gut-brain axis, it is important for researchers to pursue studies that consider sex as a biological variable. The composition of the gut microbiome is influenced by environmental factors, disease, diet, and varies with age and by sex. Detrimental changes in the gut microbiome, referred to as dysbiosis, is believed to influence the development and progression of age-related neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and stroke. Many are investigating the changes in microbial populations in order or to better understand …

A Peptide Blocking The Adora1-Neurabin Interaction Is Anticonvulsant And Inhibits Epilepsy In An Alzheimer's Model, Shalini Saggu, Yunjia Chen, Liping Chen, Diana Pizarro, Sandipan Pati, Wen Jing Law, Lori Mcmahon, Kai Jiao, Qin Wang

Faculty, Staff and Student Publications

Epileptic seizures are common sequelae of stroke, acute brain injury, and chronic neurodegenerative diseases, including Alzheimer's disease (AD), and cannot be effectively controlled in approximately 40% of patients, necessitating the development of novel therapeutic agents. Activation of the A1 receptor (A1R) by endogenous adenosine is an intrinsic mechanism to self-terminate seizures and protect neurons from excitotoxicity. However, targeting A1R for neurological disorders has been hindered by side effects associated with its broad expression outside the nervous system. Here we aim to target the neural-specific A1R/neurabin/regulator of G protein signaling 4 (A1R/neurabin/RGS4) complex that dictates A1R signaling strength and response outcome …

Plasmalogen Deficiency: A Risk Factor For Dementias And Potential Treatment Target, Mitchel A. Kling, Mallika Mendu, Rima F. Kaddurah-Daouk, Sheldon Jordan, Dayan B. Goodenowe

Rowan-Virtua Research Day

Altered lipid metabolism is implicated in the risk of sporadic Alzheimer’s disease (AD) and related dementias (ADRD); however, the precise mechanisms accounting for findings from observational studies remains to be fully elucidated.

Plasmalogens are a subclass of integral membrane phospholipids with unique properties that appear to play important roles relevant to the pathophysiology of AD and ADRD, including vesicle fusion necessary for synaptic neurotransmitter release, modulation of membrane fluidity and microdomain dynamics, membrane antioxidant functions, and neuroprotection. Like the more familiar phosphatides, plasmalogens are synthesized on a 3-carbon glycerol backbone; however, they differ from phosphatides by the presence of a …

Recent Insights Into The Role Of Glia And Oxidative Stress In Alzheimer’S Disease Gained From Drosophila, Lindsey D Goodman, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Here, we discuss findings made using Drosophila on Alzheimer's disease (AD) risk and progression. Recent studies have investigated the mechanisms underlying glia-mediated neuroprotection in AD. First, we discuss a novel mechanism of glial lipid droplet formation that occurs in response to elevated reactive oxygen species in neurons. The data suggest that disruptions to this process contribute to AD risk. We further discuss novel mechanistic insights into glia-mediated Aβ42-clearance made using the fly. Finally, we highlight work that provides evidence that the aberrant accumulation of reactive oxygen species in AD may not just be a consequence of disease but contribute to …

Macrocyclic Immunoproteasome Inhibitors As A Potential Therapy For Alzheimer's Disease, Min Jae Lee, Deepak Bhattarai, Hyeryung Jang, Ahreum Baek, In Jun Yeo, Seongsoo Lee, Zachary Miller, Sukyeong Lee, Jin Tae Hong, Dong-Eun Kim, Wooin Lee, Kyung Bo Kim

Faculty, Staff and Students Publications

Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (

Amylin As A Potential Link Between Type 2 Diabetes And Alzheimer Disease, Florin Despa, Larry B. Goldstein, Geert Jan Biessels

Pharmacology and Nutritional Sciences Faculty Publications

No abstract provided.

Review Of Alterations In Perlecan-Associated Vascular Risk Factors In Dementia, Amanda L. Trout, Ibolya Rutkai, Ifechukwude J. Biose, Gregory J. Bix

Neurology Faculty Publications

Perlecan is a heparan sulfate proteoglycan protein in the extracellular matrix that structurally and biochemically supports the cerebrovasculature by dynamically responding to changes in cerebral blood flow. These changes in perlecan expression seem to be contradictory, ranging from neuroprotective and angiogenic to thrombotic and linked to lipid retention. This review investigates perlecan's influence on risk factors such as diabetes, hypertension, and amyloid that effect Vascular contributions to Cognitive Impairment and Dementia (VCID). VCID, a comorbidity with diverse etiology in sporadic Alzheimer's disease (AD), is thought to be a major factor that drives the overall clinical burden of dementia. Accordingly, changes …

Intervention For Cognitive Reserve Enhancement In Delaying The Onset Of Alzheimer's Symptomatic Expression (Increase), A Randomized Controlled Trial: Rationale, Study Design, And Protocol, Daniela C. Moga, Brooke F. Beech, Erin L. Abner, Frederick A. Schmitt, Riham H. El Khouli, Ashley I. Martinez, Lynne Eckmann, Mark Huffmyer, Rosmy George, Gregory A. Jicha

Pharmacy Practice and Science Faculty Publications

BACKGROUND: The course of Alzheimer's disease (AD) includes a 10-20-year preclinical period with progressive accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles in the absence of symptomatic cognitive or functional decline. The duration of this preclinical stage in part depends on the rate of pathologic progression, which is offset by compensatory mechanisms, referred to as cognitive reserve (CR). Comorbid medical conditions, psychosocial stressors, and inappropriate medication use may lower CR, hastening the onset of symptomatic AD. Here, we describe a randomized controlled trial (RCT) designed to test the efficacy of a medication therapy management (MTM) intervention to reduce inappropriate …

Distinct Patterns Of Default Mode And Executive Control Network Circuitry Contribute To Present And Future Executive Function In Older Adults, Christopher A. Brown, Frederick A. Schmitt, Charles D. Smith, Brian T. Gold

Neuroscience Faculty Publications

Executive function (EF) performance in older adults has been linked with functional and structural profiles within the executive control network (ECN) and default mode network (DMN), white matter hyperintensities (WMH) burden and levels of Alzheimer's disease (AD) pathology. Here, we simultaneously explored the unique contributions of these factors to baseline and longitudinal EF performance in older adults. Thirty-two cognitively normal (CN) older adults underwent neuropsychological testing at baseline and annually for three years. Neuroimaging and AD pathology measures were collected at baseline. Separate linear regression models were used to determine which of these variables predicted composite EF scores at baseline …

Rationale And Methods For A Multicenter Clinical Trial Assessing Exercise And Intensive Vascular Risk Reduction In Preventing Dementia (Rrad Study), Amanda N. Szabo-Reed, Eric Vidoni, Ellen F. Binder, Jeffrey Burns, C. Munro Cullum, William P. Gahan, Aditi Gupta, Linda S. Hynan, Diana R. Kerwin, Heidi Rossetti, Ann M. Stowe, Wanpen Vongpatanasin, David C. Zhu, Rong Zhang, Jeffrey N. Keller

Neurology Faculty Publications

Alzheimer's Disease (AD) is an age-related disease with modifiable risk factors such as hypertension, hypercholesterolemia, obesity, and physical inactivity influencing the onset and progression. There is however, no direct evidence that reducing these risk factors prevents or slows AD. The Risk Reduction for Alzheimer's Disease (rrAD) trial is designed to study the independent and combined effects of intensive pharmacological control of blood pressure and cholesterol and exercise training on neurocognitive function. Six hundred and forty cognitively normal older adults age 60 to 85 years with hypertension and increased risk for dementia will be enrolled. Participants are randomized into one of …

Distinct White Matter Changes Associated With Cerebrospinal Fluid Amyloid-Β1-42 And Hypertension, Omar M. Al-Janabi, Christopher A. Brown, Ahmed A. Bahrani, Erin L. Abner, Justin M. Barber, Brian T. Gold, Larry B. Goldstein, Richard R. Murphy, Peter T. Nelson, Nathan F. Johnson, Leslie M. Shaw, Charles D. Smith, John Q. Trojanowski, Donna M. Wilcock, Gregory A. Jicha

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults.

OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations.

METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ_1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess …

Conserved Brain Myelination Networks Are Altered In Alzheimer's And Other Neurodegenerative Diseases., Mariet Allen, Xue Wang, Jeremy D Burgess, Jens Watzlawik, Daniel J Serie, Curtis S Younkin, Thuy Nguyen, Kimberly G Malphrus, Sarah Lincoln, Minerva M Carrasquillo, Charlotte Ho, Paramita Chakrabarty, Samantha Strickland, Melissa E Murray, Vivek Swarup, Daniel H Geschwind, Nicholas T Seyfried, Eric B Dammer, James J Lah, Allan I Levey, Todd E Golde, Cory Funk, Hongdong Li, Nathan D Price, Ronald C Petersen, Neill R Graff-Radford, Steven G Younkin, Dennis W Dickson, Julia R Crook, Yan W Asmann, Nilüfer Ertekin-Taner

Articles, Abstracts, and Reports

INTRODUCTION: Comparative transcriptome analyses in Alzheimer's disease (AD) and other neurodegenerative proteinopathies can uncover both shared and distinct disease pathways.

METHODS: We analyzed 940 brain transcriptomes including patients with AD, progressive supranuclear palsy (PSP; a primary tauopathy), and control subjects.

RESULTS: We identified transcriptional coexpression networks implicated in myelination, which were lower in PSP temporal cortex (TCX) compared with AD. Some of these associations were retained even after adjustments for brain cell population changes. These TCX myelination network structures were preserved in cerebellum but they were not differentially expressed in cerebellum between AD and PSP. Myelination networks were downregulated in …

Brain-Derived Neurotrophic Factor As A Biomarker For Aging And Dementia, Krishna Lajwanti Bharani

MUSC Theses and Dissertations

The number of people with dementia due to Alzheimer’s disease (AD) is increasing worldwide. Although AD pathology begins well before clinical symptoms are apparent, identifying individuals at risk of developing AD to provide early interventions is still a challenge. Brain-derived neurotrophic factor (BDNF) is produced by neurons and glial cells and has complex interactions with AD pathology. BDNF also crosses the blood-brain barrier and can be measured in serum or plasma. In this dissertation, I investigated the biomarker potential of serum BDNF for AD using post mortem human samples, an aged rat model of cognitive impairment, and blood samples from …

Genotype-Phenotype Study In Patients With Valosin-Containing Protein Mutations Associated With Multisystem Proteinopathy, Ebaa Al-Obeidi, Sejad Al-Tahan, Abhilasha Surampalli, Namita Goyal, Annabel K. Wang, Andreas Hermann, Molly Omizo, Charles D. Smith, Tahseen Mozaffar, Virginia Kimonis

Neurology Faculty Publications

Mutations in valosin‐containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in …

Incidence Of Cognitively Defined Late-Onset Alzheimer's Dementia Subgroups From A Prospective Cohort Study., Paul K Crane, Emily Trittschuh, Shubhabrata Mukherjee, Andrew J Saykin, R Elizabeth Sanders, Eric B Larson, Susan M Mccurry, Wayne Mccormick, J D Bowen, Thomas Grabowski, Mackenzie Moore, Julianna Bauman, Alden L Gross, C Dirk Keene, Thomas D Bird, Laura E Gibbons, Jesse Mez

Articles, Abstracts, and Reports

INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia.

METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments.

RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), …

Does Music Therapy Intervention Have An Effect On The Emotional Behavior Of Alzheimer Patients?, Alexandra P. Lahurd

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: The objective of this selective EBM review is to determine whether or not music therapy intervention have an effect on emotional behavior of Alzheimer patients. Behavior variables measuring are agitation and anxiety.

STUDY DESIGN: Systematic review of two randomized, controlled trials published in 2009 and 2014, respectively, and one randomized control case study published in 2006.

DATA SOURCE: Three published studies comparing music therapy intervention on behavioral modifications with Alzheimer patients were found using PubMed and Medline

OUTCOMES MEASURES: All three studies measure behavior in Alzheimer patients based on a variety of well validated …

Linkage, Whole Genome Sequence, And Biological Data Implicate Variants In Rab10 In Alzheimer's Disease Resilience., Perry G Ridge, Celeste M Karch, Simon Hsu, Ivan Arano, Craig C Teerlink, Mark T W Ebbert, Josue D Gonzalez Murcia, James M Farnham, Anna R Damato, Mariet Allen, Xue Wang, Oscar Harari, Victoria M Fernandez, Rita Guerreiro, Jose Bras, John Hardy, Ronald Munger, Maria Norton, Celeste Sassi, Andrew Singleton, Steven G Younkin, Dennis W Dickson, Todd E Golde, Nathan D Price, Nilüfer Ertekin-Taner, Carlos Cruchaga, Alison M Goate, Christopher Corcoran, Joann Tschanz, Lisa A Cannon-Albright, John S K Kauwe

Articles, Abstracts, and Reports

BACKGROUND: While age and the APOE ε4 allele are major risk factors for Alzheimer's disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.

METHODS: We used over 200 "AD resilient" individuals and an innovative, pedigree-based approach to identify genetic variants that segregate with AD resilience. First, we performed linkage analyses in pedigrees with resilient individuals and a statistical excess of AD deaths. Second, we used whole genome sequences to identify candidate SNPs in significant linkage regions. Third, we replicated SNPs …

Impact Of Home Visit Capacity On Genetic Association Studies Of Late-Onset Alzheimer's Disease., David W Fardo, Laura E Gibbons, Shubhabrata Mukherjee, M Maria Glymour, Wayne Mccormick, Susan M Mccurry, James D Bowen, Eric B Larson, Paul K Crane

Articles, Abstracts, and Reports

INTRODUCTION: Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits.

METHODS: We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators.

RESULTS: …

Risk Of Incident Clinical Diagnosis Of Alzheimer's Disease-Type Dementia Attributable To Pathology-Confirmed Vascular Disease, Hiroko H. Dodge, Jian Zhu, Randy Woltjer, Peter T. Nelson, David A. Bennett, Nigel J. Cairns, David W. Fardo, Jeffrey A. Kaye, Deniz-Erten Lyons, Nora Mattek, Julie A. Schneider, Lisa C. Silbert, Chengjie Xiong, Lei Yu, Frederick A. Schmitt, Richard J. Kryscio, Erin L. Abner, Smart Data Consortium

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD).

METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with …

Outcomes After Diagnosis Of Mild Cognitive Impairment In A Large Autopsy Series, Erin L. Abner, Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo, Daniela C. Moga, Eseosa T. Ighodaro, Gregory A. Jicha, Lei Yu, Hiroko H. Dodge, Chengjie Xiong, Randall L. Woltjer, Julie A. Schneider, Nigel J. Cairns, David A. Bennett, Peter T. Nelson

Epidemiology and Environmental Health Faculty Publications

OBJECTIVE: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI).

METHODS: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States.

RESULTS: Mean follow‐up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical …

Self-Reported Sleep Apnea And Dementia Risk: Findings From The Prevention Of Alzheimer's Disease With Vitamin E And Selenium Trial, Xiuhua Ding, Richard J. Kryscio, Joshua Turner, Gregory A. Jicha, Gregory E. Cooper, Allison M. Caban-Holt, Frederick A. Schmitt, Erin L. Abner

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVES: To investigate the association between baseline sleep apnea and risk of incident dementia in the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADViSE) study and to explore whether the association depends on apolipoprotein E (APOE) ɛ4 allele status.

DESIGN: Secondary analysis based on data collected during PREADViSE.

SETTING: Participants were assessed at 128 local clinical study sites during the clinical trial phase and later were followed by telephone from a centralized location.

PARTICIPANTS: Men enrolled in PREADViSE (without dementia or other active neurological conditions that affect cognition such as major psychiatric disorders, including depression; N = …

Network-Driven Plasma Proteomics Expose Molecular Changes In The Alzheimer's Brain, Philipp A. Jaeger, Kurt M. Lucin, Markus Britschgi, Badri Vardarajan, Ruo-Pan Huang, Elizabeth D. Kirby, Rachelle Abbey, Bradley F. Boeve, Adam L. Boxer, Lindsay A. Farrer, Nicole Finch, Neill R. Graff-Radford, Elizabeth Head, Matan Hofree, Ruochun Huang, Hudson Johns, Anna Karydas, David S. Knopman, Andrey Loboda, Eliezer Masliah, Ramya Narasimhan, Ronald C. Petersen, Alexei Podtelezhnikov, Suraj Pradhan, Rosa Rademakers, Chung-Huan Sun, Steven G. Younkin, Bruce L. Miller, Trey Ideker, Tony Wyss-Coray

Pharmacology and Nutritional Sciences Faculty Publications

Background: Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.

Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using …

Peripheral (Deep) But Not Periventricular Mri White Matter Hyperintensities Are Increased In Clinical Vascular Dementia Compared To Alzheimer's Disease, Charles D. Smith, Eleanor S. Johnson, Linda J. Van Eldik, Gregory A. Jicha, Frederick A. Schmitt, Peter T. Nelson, Richard J. Kryscio, Richard R. Murphy, Clinton V. Wellnitz

Neurology Faculty Publications

Background and purpose: Vascular dementia (VAD) is a complex diagnosis at times difficult to distinguish from Alzheimer's disease (AD). MRI scans often show white matter hyperintensities (WMH) in both conditions. WMH increase with age, and both VAD and AD are associated with aging, thus presenting an attribution conundrum. In this study, we sought to show whether the amount of WMH in deep white matter (dWMH), versus periventricular white matter (PVH), would aid in the distinction between VAD and AD, independent of age. Methods: Blinded semiquantitative ratings of WMH validated by objective quantitation of WMH volume from standardized MRI image acquisitions. …

The Role Of Capillaries In The Lesser Ailments Of Old Age And In Alzheimer's Disease And Vascular Dementia: The Potential Of Pro-Therapeutic Angiogenesis, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Apart from chronic diseases (arthritis, diabetes, etc.), old age is generally characterized by three lesser ailments: muscle weakness, minor memory lapses, and cold intolerance. This trio of complaints may have a common, underlying cause, namely, the age-associated reduced microcirculation in muscles, brain, skin, and elsewhere in the body. The Angiogenesis Hypothesis proposes that old age is in part a deficiency disease due to the decline in angiogenic (AG) factors, resulting in a reduced capillary density (CD) throughout the body. Over fifty published papers document waning levels of AG factors and/or decreased CD in various organ systems of aged animals and …