Medicine and Health Sciences Commons^™

The Trend Of Disruption In The Functional Brain Network Topology Of Alzheimer’S Disease, Alireza Fathian, Yousef Jamali, Mohammad Reza Raoufy, The Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Norbert Schuf, Howard J. Rosen, Bruce L. Miller, Thomas Neylan, Jacqueline Hayess, Shannon Finley, Paul Aisen, Zaven Khachaturian, Ronald G. Thomas, Charles D. Smith, Gregory A. Jicha, Peter A. Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) is a progressive disorder associated with cognitive dysfunction that alters the brain’s functional connectivity. Assessing these alterations has become a topic of increasing interest. However, a few studies have examined different stages of AD from a complex network perspective that cover different topological scales. This study used resting state fMRI data to analyze the trend of functional connectivity alterations from a cognitively normal (CN) state through early and late mild cognitive impairment (EMCI and LMCI) and to Alzheimer’s disease. The analyses had been done at the local (hubs and activated links and areas), meso (clustering, assortativity, and …

New Insights Into The Genetic Etiology Of Alzheimer’S Disease And Related Dementias, Céline Bellenguez, Fahri Küçükali, Iris Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C. Naj, Rafael Campos-Martin, David W. Fardo, Yuriko Kastumata, Erin L. Abner, Radb, Gr@Ace, Degesco, Eadi, Gerad, Demgene, Finngen, Adgc, Charge

Sanders-Brown Center on Aging Faculty Publications

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly …

Sensory Processing Abnormalities In Community-Dwelling Older Adults With Cognitive Impairment: A Mixed Methods Study, Elizabeth K. Rhodus, Elizabeth G. Hunter, Graham D. Rowles, Shoshana H. Bardach, Kelly Parsons, Justin M. Barber, Maryellen Thompson, Gregory A. Jicha

Sanders-Brown Center on Aging Faculty Publications

Mild cognitive impairment (MCI) or dementia often leads to behavioral and psychiatric symptoms of dementia (BPSD). Sensory processing abnormalities may be associated with BPSD. The purpose of this study was to explore relationships among sensory processing, behavior, and environmental features within the homes of people with MCI or dementia. This project used mixed methods to assess participants’ sensory processing, care partner perspectives on behaviors, and in situ observations of the home environment. Nine participants with cognitive impairment (MCI n = 8, early dementia = 1) and their care partners were included. Seven participants with cognitive impairment were reported to have …

Dementia Risk Reduction: Why Haven't The Pharmacological Risk Reduction Trials Worked? An In-Depth Exploration Of Seven Established Risk Factors, Ruth Peters, John Breitner, Sarah James, Gregory A. Jicha, Pierre-Francois Meyer, Marcus Richards, A. David Smith, Hussein N. Yassine, Erin L. Abner, Atticus H. Hainsworth, Patrick G. Kehoe, Nigel Beckett, Christopher Weber, Craig Anderson, Kaarin J. Anstey, Hiroko H. Dodge

Neurology Faculty Publications

Identifying the leading health and lifestyle factors for the risk of incident dementia and Alzheimer's disease has yet to translate to risk reduction. To understand why, we examined the discrepancies between observational and clinical trial evidence for seven modifiable risk factors: type 2 diabetes, dyslipidemia, hypertension, estrogens, inflammation, omega-3 fatty acids, and hyperhomocysteinemia. Sample heterogeneity and paucity of intervention details (dose, timing, formulation) were common themes. Epidemiological evidence is more mature for some interventions (eg, non-steroidal anti-inflammatory drugs [NSAIDs]) than others. Trial data are promising for anti-hypertensives and B vitamin supplementation. Taken together, these risk factors highlight a future need …

Committee On High-Quality Alzheimer’S Disease Studies (Chads) Consensus Report, Gregory A. Jicha, Erin L. Abner, Steven E. Arnold, Maria C. Carrillo, Hiroko H. Dodge, Steven D. Edland, Keith N. Fargo, Howard H. Feldman, Larry B. Goldstein, James A. Hendrix, Ruth Peters, Julie M. Robillard, Lon S. Schneider, Jodi R. Titiner, Christopher J. Weber

Sanders-Brown Center on Aging Faculty Publications

Background: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials.

Methods: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations.

Results: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement …

Dysregulation Of Systemic Immunity In Aging And Dementia, Jenny Lutshumba, Barbara S. Nikolajczyk, Adam D. Bachstetter

Pharmacology and Nutritional Sciences Faculty Publications

Neuroinflammation and the tissue-resident innate immune cells, the microglia, respond and contribute to neurodegenerative pathology. Although microglia have been the focus of work linking neuroinflammation and associated dementias like Alzheimer’s Disease, the inflammatory milieu of brain is a conglomerate of cross-talk amongst microglia, systemic immune cells and soluble mediators like cytokines. Age-related changes in the inflammatory profile at the levels of both the brain and periphery are largely orchestrated by immune system cells. Strong evidence indicates that both innate and adaptive immune cells, the latter including T cells and B cells, contribute to chronic neuroinflammation and thus dementia. Neurodegenerative hallmarks …

Q134r: Small Chemical Compound With Nfat Inhibitory Properties Improves Behavioral Performance And Synapse Function In Mouse Models Of Amyloid Pathology, Pradoldej Sompol, Jenna L. Gollihue, Susan D. Kraner, Irina A. Artiushin, Ryan A. Cloyd, Emad Chishti, Shon A. Koren, Grant K. Nation, Jose F. Abisambra, Orsolya Huzian, Lajos I. Nagy, Miklos Santha, Laszlo Hackler Jr., Laszlo G. Puskas, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. However, small chemical inhibitors of NFATs have only rarely been described. Here, we investigate a newly developed neuroprotective hydroxyquinoline derivative (Q134R) that suppresses NFAT signaling, without inhibiting CN activity. …

Sex, Diabetes Status And Cognition: Findings From The Study Of Longevity In Diabetes, Chris Moran, Paola Gilsanz, Michal S. Beeri, Rachel A. Whitmer, Mary E. Lacy

Epidemiology and Environmental Health Faculty Publications

INTRODUCTION: Women comprise two-thirds of people with dementia, making female sex a significant dementia risk factor. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) are known dementia risk factors with an increasing global incidence. Understanding whether subtle sex differences persist in cognitive function prior to dementia in the context of diabetes may help elucidate the magnitude of sex effects on dementia risk.

RESEARCH DESIGN AND METHODS: We examined cross-sectional data from the Study of Longevity in Diabetes (SOLID), a prospective cohort study of members of Kaiser Permanente Northern California aged 60 years and older with T1D (n=758), T2D …

The Bach1/Nrf2 Axis In Brain In Down Syndrome And Transition To Alzheimer Disease-Like Neuropathology And Dementia, Marzia Perluigi, Antonella Tramutola, Sara Pagnotta, Eugenio Barone, D. Allan Butterfield

Chemistry Faculty Publications

Down syndrome (DS) is the most common genetic cause of intellectual disability that is associated with an increased risk to develop early-onset Alzheimer-like dementia (AD). The brain neuropathological features include alteration of redox homeostasis, mitochondrial deficits, inflammation, accumulation of both amyloid beta-peptide oligomers and senile plaques, as well as aggregated hyperphosphorylated tau protein-containing neurofibrillary tangles, among others. It is worth mentioning that some of the triplicated genes encoded are likely to cause increased oxidative stress (OS) conditions that are also associated with reduced cellular responses. Published studies from our laboratories propose that increased oxidative damage occurs early in life in …

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 …

Frontotemporal Dementia Nonsense Mutation Of Progranulin Rescued By Aminoglycosides, Lisha Kuang, Kei Hashimoto, Eric J. Huang, Matthew S. Gentry, Haining Zhu

Molecular and Cellular Biochemistry Faculty Publications

Frontotemporal dementia (FTD) is an early onset dementia and is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD is highly heritable with mutations in progranulin accounting for 5-26% of cases in different populations. Progranulin is involved in endocytosis, secretion and lysosomal processes, but its function under physiological and pathological conditions remains to be defined. Many FTD-causing nonsense progranulin mutations contain a premature termination codon (PTC), thus progranulin haploinsufficiency has been proposed as a major disease mechanism. Currently, there is no effective FTD treatment or therapy.

Aminoglycosides are a class of antibiotics that possess a less known function …

Contributing Factors To Diabetic Brain Injury And Cognitive Decline, Nirmal Verma, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

The link of diabetes with co-occurring disorders in the brain involves complex and multifactorial pathways. Genetically engineered rodents that express familial Alzheimer's disease-associated mutant forms of amyloid precursor protein and presenilin 1 (PSEN1) genes provided invaluable insights into the mechanisms and consequences of amyloid deposition in the brain. Adding diabetes factors (obesity, insulin impairment) to these animal models to predict success in translation to clinic have proven useful at some extent only. Here, we focus on contributing factors to diabetic brain injury with the aim of identifying appropriate animal models that can be used to mechanistically dissect the …

Diabetes-Related Amylin Dyshomeostasis: A Contributing Factor To Cerebrovascular Pathology And Dementia, Han Ly, Florin Despa

Pharmacology and Nutritional Sciences Faculty Publications

Type 2 diabetes (T2D) increases the risk for cerebrovascular disease (CVD) and dementia. The underlying molecular mechanisms remain elusive, which hampers the development of treatment or/and effective prevention strategies. Recent studies suggest that dyshomeostasis of amylin, a satiety hormone that forms pancreatic amyloid in patients with T2D, promotes accumulation of amylin in cerebral small blood vessels and interaction with Alzheimer's disease (AD) pathology. Overexpression of human amylin in rodents (rodent amylin does not form amyloid) leads to late-life onset T2D and neurologic deficits. In this Review, we discuss clinical evidence of amylin pathology in CVD and AD and identify critical …

Hyperhomocysteinemia As A Risk Factor For Vascular Contributions To Cognitive Impairment And Dementia, Brittani R. Price, Donna M. Wilcock, Erica M. Weekman

Physiology Faculty Publications

Behind only Alzheimer’s disease, vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia, affecting roughly 10–40% of dementia patients. While there is no cure for VCID, several risk factors for VCID, such as diabetes, hypertension, and stroke, have been identified. Elevated plasma levels of homocysteine, termed hyperhomocysteinemia (HHcy), are a major, yet underrecognized, risk factor for VCID. B vitamin deficiency, which is the most common cause of HHcy, is common in the elderly. With B vitamin supplementation being a relatively safe and inexpensive therapeutic, the treatment of HHcy-induced VCID would seem straightforward; however, …

Ca2+, Astrocyte Activation And Calcineurin/Nfat Signaling In Age-Related Neurodegenerative Diseases, Pradoldej Sompol, Christopher M. Norris

Sanders-Brown Center on Aging Faculty Publications

Mounting evidence supports a fundamental role for Ca²⁺ dysregulation in astrocyte activation. Though the activated astrocyte phenotype is complex, cell-type targeting approaches have revealed a number of detrimental roles of activated astrocytes involving neuroinflammation, release of synaptotoxic factors and loss of glutamate regulation. Work from our lab and others has suggested that the Ca²⁺/calmodulin dependent protein phosphatase, calcineurin (CN), provides a critical link between Ca²⁺ dysregulation and the activated astrocyte phenotype. A proteolyzed, hyperactivated form of CN appears at high levels in activated astrocytes in both human tissue and rodent tissue around regions of amyloid and …

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 …

Csf Protein Changes Associated With Hippocampal Sclerosis Risk Gene Variants Highlight Impact Of Grn/Pgrn, David W. Fardo, Yuriko Katsumata, John S. K. Kauwe, Yuetiva Deming, Oscar Harari, Carlos Cruchaga, Alzheimer’S Disease Neuroimaging Initiative, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Objective—Hippocampal sclerosis of aging (HS-Aging) is a common cause of dementia in older adults. We tested the variability in cerebrospinal fluid (CSF) proteins associated with previously identified HS-Aging risk single nucleotide polymorphisms (SNPs).

Methods—Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI; n=237) data, combining both multiplexed proteomics CSF and genotype data, were used to assess the association between CSF analytes and risk SNPs in four genes (SNPs): GRN (rs5848), TMEM106B (rs1990622), ABCC9 (rs704180), and KCNMB2 (rs9637454). For controls, non-HS-Aging SNPs in APOE (rs429358/rs7412) and MAPT (rs8070723) were also analyzed against Aβ1-42 and total tau CSF analytes.

Results—The GRN risk …

Neurovascular Astrocyte Degeneration In The Hyperhomocysteinemia Model Of Vascular Cognitive Impairment And Dementia (Vcid), Tiffany L. Sudduth, Erica M. Weekman, Brittani Rae Price, Jennifer L. Gooch, Abigail E. Woolums, Christopher M. Norris, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer’s disease (AD) and is a frequent co-morbidity with AD. Despite its prevalence, little is known about the molecular mechanisms underlying the cognitive dysfunction resulting from cerebrovascular disease. Astrocytic end-feet almost completely surround intraparenchymal blood vessels in the brain and express a variety of channels and markers indicative of their specialized functions in the maintenance of ionic and osmotic homeostasis and gliovascular signaling. These functions are mediated by end-foot enrichment of the aquaporin 4 water channel (AQP4), the inward rectifying potassium channel Kir4.1 and the calcium-dependent …

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 = …

White Matter Diffusion Alterations In Normal Women At Risk Of Alzheimer's Disease, Charles D. Smith, Himachandra Chebrolu, Anders H. Andersen, David A. Powell, Mark A. Lovell, Shuling Xiong, Brian T. Gold

Neurology Faculty Publications

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal …