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Mielke M.M.,Mayo Medical School | Zetterberg H.,Gothenburg University | Zetterberg H.,University College London | Blennow K.,Gothenburg University | And 23 more authors.
Neurobiology of Aging | Year: 2014

Cellular studies suggest sphingolipids may cause or accelerate amyloid-beta (Aβ) and tau pathology but invivo human studies are lacking. We determined cerebrospinal fluid levels of sphingolipids (ceramides and sphingomyelins), amyloid-beta (Aβ1-42, AβX-38, AβX-40, and AβX-42) and tau (T-tau and p-tau181) in 91 cognitively normal individuals, aged 36-69years, with a parental history of Alzheimer's disease. The 18-carbon acyl chain length ceramide species was associated with AβX-38 (. r= 0.312, p= 0.003), AβX-40 (. r= 0.327, p= 0.002), and T-tau (. r= 0.313, p= 0.003) but not with AβX-42 (. r= 0.171, p= 0.106) or p-tau (. r= 0.086, p= 0.418). All sphingomyelin species correlated (most p < 0.001) with all Aβ species and T-tau many also correlated with p-tau. Results remained in regression models after controlling for age and APOE genotype. These results suggest invivo relationships between cerebrospinal fluid ceramides and sphingomyelins and Aβ and tau levels in cognitively normal individuals at increased risk for Alzheimer's disease, indicating these sphingolipids may be associated with early pathogenesis. © 2014 Elsevier Inc.


Wichmann M.A.,U.S. National Institute on Aging | Wichmann M.A.,Wisconsin Alzheimers Disease Research Center | Carlsson C.M.,University of Wisconsin - Madison | Carlsson C.M.,Wisconsin Alzheimers Disease Research Center | And 3 more authors.
Alzheimer Disease and Associated Disorders | Year: 2016

Nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent dementia, but previous studies have yielded conflicting results. This study estimated the association of prior NSAID use with incident cognitive impairment in the population-based Epidemiology of Hearing Loss Study (EHLS, n=2422 without cognitive impairment in 1998-2000). Prospectively collected medication data from 1988-1990, 1993-1995, and 1998-2000 were used to categorize NSAID use history at the cognitive baseline (1998-2000). Aspirin use and nonaspirin NSAID use were separately examined. Cox regression models were used to estimate the associations between NSAID use history at baseline and incident cognitive impairment in 2003-2005 or 2009-2010. Logistic regression analyses were used to estimate associations with a second outcome, mild cognitive impairment/dementia, available in 2009-2010. Participants using aspirin at baseline but not 5 years prior were more likely to develop cognitive impairment (adjusted hazard ratio=1.77; 95% confidence interval=1.11, 2.82; model 2), with nonsignificant associations for longer term use. Nonaspirin NSAID use was not associated with incident cognitive impairment or mild cognitive impairment/dementia odds. These results provided no evidence to support a potential protective effect of NSAIDs against dementia. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Gleason C.E.,University of Wisconsin - Madison | Gleason C.E.,William S Middleton Memorial Veterans Hospital | Gleason C.E.,Wisconsin Alzheimers Disease Research Center | Dowling N.M.,University of Wisconsin - Madison | And 26 more authors.
PLoS Medicine | Year: 2015

Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2(95% CI, −8.27 × 10−2to −2.44 × 10−2;ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2(95% CI, −5.09 × 10−2to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. ClinicalTrials.gov NCT00154180


Wichmann M.A.,University of Wisconsin - Madison | Cruickshanks K.J.,University of Wisconsin - Madison | Carlsson C.M.,University of Wisconsin - Madison | Carlsson C.M.,Wisconsin Alzheimers Disease Research Center | And 8 more authors.
Journal of the American Geriatrics Society | Year: 2014

Objectives Evidence suggests inflammation is associated with cognitive impairment, but previous epidemiological studies have reported conflicting results. Design Prospective population-based cohort. Setting Epidemiology of Hearing Loss Study participants. Participants Individuals without cognitive impairment in 1998-2000 (N = 2,422; 1,947 with necessary data). Measurements Cognitive impairment (Mini-Mental State Examination score <24 or diagnosis of dementia) was ascertained in 1998-2000, 2003-2005, and 2009-2010. Serum C-reactive protein (CRP) and interleukin-6 (IL-6) were measured in 1988-1990, 1998-2000, and 2009-2010; tumor necrosis factor-alpha was measured from 1998-2000. Results Participants with high CRP in 1988-1990 and 1998-2000 had lower risk of cognitive impairment than those with low CRP at both time points (hazard ratio (HR) = 0.46, 95% confidence interval (CI) = 0.26-0.80). Risk did not differ according to 10-year IL-6 profile or baseline inflammation category in the whole cohort. In sensitivity analyses restricted to statin nonusers, those with high IL-6 at both times had greater risk of cognitive impairment than those with low IL-6 at both times (HR = 3.35, 95% CI = 1.09-10.30). In secondary analyses, each doubling of IL-6 change over 20 years was associated with greater odds of cognitive impairment in 2009-2010 in the whole cohort (odds ratio (OR) = 1.40, 95% CI = 1.04-1.89), whereas a doubling of CRP change over 20 years was associated with cognitive impairment only in statin nonusers (OR = 1.32, 95% CI = 1.06-1.65). Conclusion With data collected over 20 years, this study demonstrated greater likelihood of cognitive impairment in individuals with repeated high or increasing IL-6. The inconsistent CRP findings may reflect effects of statin medications, survival effects, or adverse effects associated with chronically low CRP. Further studies of long-term inflammation and cognitive impairment are needed. © 2014, The American Geriatrics Society.


Ithapu V.,University of Wisconsin - Madison | Ithapu V.,Wisconsin Alzheimers Disease Research Center | Singh V.,University of Wisconsin - Madison | Singh V.,Wisconsin Alzheimers Disease Research Center | And 11 more authors.
Human Brain Mapping | Year: 2014

Precise detection and quantification of white matter hyperintensities (WMH) observed in T2-weighted Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Images (MRI) is of substantial interest in aging, and age-related neurological disorders such as Alzheimer's disease (AD). This is mainly because WMH may reflect co-morbid neural injury or cerebral vascular disease burden. WMH in the older population may be small, diffuse, and irregular in shape, and sufficiently heterogeneous within and across subjects. Here, we pose hyperintensity detection as a supervised inference problem and adapt two learning models, specifically, Support Vector Machines and Random Forests, for this task. Using texture features engineered by texton filter banks, we provide a suite of effective segmentation methods for this problem. Through extensive evaluations on healthy middle-aged and older adults who vary in AD risk, we show that our methods are reliable and robust in segmenting hyperintense regions. A measure of hyperintensity accumulation, referred to as normalized effective WMH volume, is shown to be associated with dementia in older adults and parental family history in cognitively normal subjects. We provide an open source library for hyperintensity detection and accumulation (interfaced with existing neuroimaging tools), that can be adapted for segmentation problems in other neuroimaging studies. © 2014 Wiley Periodicals, Inc.


Wharton W.,University of Wisconsin - Madison | Wharton W.,Wisconsin Alzheimers Disease Research Center | Gleason C.E.,University of Wisconsin - Madison | Gleason C.E.,William S Middleton Memorial Veterans Hospital | And 5 more authors.
Brain Research | Year: 2013

This manuscript describes the study design and rationalle for the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective ancillary study (KEEPS Cog). KEEPS is a multicenter, randomized, double-blinded, placebo-controlled trial, designed to test the hypothesis that low-dose hormone therapy (HT) initiated in recently postmenopausal women will reduce the progression of subclinical atherosclerosis as measured by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC) over four years. The KEEPS Cog ancillary study was designed to assess potential estrogenic treatment effects on cognition and mood. We present the KEEPS trial in the context of issues raised by the Women's Health Initiative (WHI) and the Women's Health Initiative Memory Study (WHIMS). Here we also describe the most recent results and ongoing HT-related research studies designed to address similar issues. This article is part of a Special Issue entitled Hormone Therapy. © 2013 Elsevier B.V.


O'Hagan T.S.,University of Bristol | Wharton W.,University of Wisconsin - Madison | Wharton W.,William S Middleton Memorial Veterans Hospital | Wharton W.,Wisconsin Alzheimers Disease Research Center | Kehoe P.G.,University of Bristol
American Journal of Neurodegenerative Diseases | Year: 2012

Interactions between oestrogen and the renin angiotensin system (RAS) are reviewed and explored from the perspective where these interactions may modulate risk of developing Alzheimer’s disease (AD). AD is more prevalent in women than men, partly attributed to women’s increased life expectancy; however underlying vascular differences may also contribute to AD risk. The RAS is a key regulator of blood pressure (BP). Pharmacological inhibition of angiotensin converting enzyme (ACE) and blockade of angiotensin II type 1 receptors (AT1R) are widely used to treat hypertension. Variation in components of the RAS such as ACE, neprilysin (NEP) and AT1R have been reported in AD, some of which may also directly alter AD neuropathology with changes in amyloid beta (Aβ) levels, cognitive decline and neuroinflammation. Recently, RAS inhibiting drugs have been shown to attenuate the incidence, progression and pathology of AD. Oestrogen is also thought to prevent hypertension by reducing the vasoconstrictive actions of the RAS. Reduced oestrogen levels in women during the menopausal transition may therefore increase their risk of hypertension and/or RAS-mediated changes to cerebrovascular or AD pathology. Specifically, oestrogen prevents the production and action of angiotensin II (Ang II), thought to exert harmful effects of the RAS in both hypertension and AD, while also potentially facilitating RAS-mediated Aβ degradation. These oestrogen-RAS interactions may partly explain current conflicting findings regarding oestrogen depletion and hormone therapy with respect to AD risk. Clinical trials targeting either the RAS or oestrogen systems for AD prevention and treatment should perhaps give closer attention to key biochemical components of these pathways as potential confounders to primary and secondary outcome measures. © 2012, E-Century Publishing Corporation. All rights reserved.


Carlsson C.M.,University of Wisconsin - Madison | Carlsson C.M.,William S Middleton Memorial Veterans Hospital Geriatric Research | Carlsson C.M.,Wisconsin Alzheimers Disease Research Center
Journal of Alzheimer's Disease | Year: 2010

The prevalence of Alzheimer's disease (AD) is increasing rapidly, heightening the importance of finding effective preventive therapies for this devastating disease. Midlife vascular risk factors, including type 2 diabetes mellitus (T2DM), have been associated with increased risk of AD decades later and may serve as targets for AD prevention. Studies to date suggest that T2DM and hyperinsulinemia increase risk for AD, possibly through their effects on amyloid-β metabolism and cerebrovascular dysfunction - two early findings in preclinical AD pathology. This paper reviews the evidence supporting a relationship between T2DM, hyperinsulinemia, and diabetic dyslipidemia on the development of AD, discusses DM treatment trials and their preliminary results on cognitive function, and proposes some strategies for optimizing future AD prevention trial design. © 2010 - IOS Press and the authors.


Fischer B.,William S Middleton Memorial Veterans Affairs Hospital | Gleason C.,William S Middleton Memorial Veterans Affairs Hospital | Gleason C.,Wisconsin Alzheimers Disease Research Center | Gleason C.,University of Wisconsin - Madison | And 3 more authors.
Fertility and Sterility | Year: 2014

Objective Results of the Women's Health Initiative (WHI) and Women's Health Initiative Memory Study (WHIMS) suggested that hormone therapy (HT) may be detrimental to cognitive health. This article reviews clinical studies that address issues relevant to those results. Design Literature review. Intervention(s) A search of Pubmed and Web of Science was conducted using the search terms HT and cognition, HT and mood. Clinical and observational studies were selected if they were published after the year 2000. Theories of HT mechanisms of action, pharmacology, biology, and observational and clinical trials are discussed. Result(s) Although observational and clinical trials show conflicting findings, methodologic considerations must be acknowledged. HT formulation and dose, route of administration, timing of initiation, length of treatment, and health of participants all contribute to inconsistencies in results. Transdermal estradiol and micronized progesterone administered at time of menopause are generally associated with cognitive and affective benefit. Conclusion(s) At the present time, results from existing studies are equivocal regarding the benefits of HT on cognition and affect. Future studies, such as the Kronos Early Estrogen Prevention Study (KEEPS), should address methodologic inconsistencies to provide clearer answers to this important question. © 2014 American Society for Reproductive Medicine, Published by Elsevier Inc. All rights reserved.


Dowling N.M.,University of Wisconsin - Madison | Dowling N.M.,Wisconsin Alzheimers Disease Research Center | Olson N.,University of Wisconsin - Madison | Olson N.,Wisconsin Alzheimers Disease Research Center | And 5 more authors.
Clinical Trials | Year: 2012

Background The identification and enlistment of suitable participants into clinical studies is often challenging, requiring a large commitment of time and staff resources. The recruitment and retention of populations typically underrepresented in research present additional challenges to enrollment of sufficient numbers of participants in clinical studies. Inadequate participation may undermine the pace and direction of new treatment discoveries.Purpose Registries of potential research participants are powerful tools to support research by providing a framework to streamline screening and recruitment and to maintain a communication history with potential research participants. The authors present a model for the development and implementation of a web-based database system to support recruitment, enrollment, and retention of potential study participants in close alignment with the goals of the Wisconsin Alzheimer's Disease Research Center (ADRC).Methods The required data elements and major information domains for the registry were identified using a structured problem-solving and system design approach and the collaboration of a multidisciplinary team of stakeholders. The system performance, utility, and usability were assessed through multiple iterations with the users.Results The process-oriented approach culminated in a multifaceted tool that combined contact management and potential research participant registration to assist with the challenges of recruitment and retention in clinical research. A unique feature of the registry design model was its contact management capabilities for efficient tracking of all contacts with registrants.Limitations We have focused on the development and implementation of a system for the recruitment of older adults with specific cognitive and medical characteristics. However, our procedures for identifying data needs and database system utility and functionality can be transferred easily to other populations and settings. As with any multipurpose registry database system, careful management and training are essential to optimize efficiency.Conclusion Adding a contact management element to the registry design significantly improved the efficiency of communication between clinical study coordinators and potential research participants, as well as the communication among coordinators. © 2011 The Author(s).

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