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Neuroimage  2012;61(3):525-532.
Children of Alzheimer's Disease (AD) patients are at heightened risk of developing AD due to genetic influences, including the apolipoprotein E4 (ApoE4) allele. In this study, we assessed the earliest cortical changes associated with AD in 71 cognitively healthy, adult children of AD patients (AD offspring) as compared with 69 with no family history of AD (non-AD offspring). Cortical thickness measures were obtained using FreeSurfer from 1.5T magnetic resonance (MR) scans. ApoE genotyping was obtained. Primary analyses examined family history and ApoeE4 effects on cortical thickness. Secondary analyses examined age effects within groups. All comparisons were adjusted using False Discovery Rate at a significance threshold of p < 0.05. There were no statistically significant differences between family history and ApoE4 groups. Within AD offspring, increasing age was related to reduced cortical thickness (atrophy) over large areas of the precuneus, superior frontal and superior temporal gyri, starting at around age 60. Further, these patterns existed within female and maternal AD offspring, but were absent in male and paternal AD offspring. Within non-AD offspring, negative correlations existed over small regions of the superior temporal, insula and lingual cortices. These results suggest that as AD offspring age, cortical atrophy is more prominent, particularly if the parent with AD is mother or if the AD offspring is female.
PMCID: PMC3358455  PMID: 22503937
Antecedent biomarker; Familial risk; Alzheimer’s Disease; Dementia; Adult Children Study; Cortical thickness; Maternal risk
2.  Operationalizing diagnostic criteria for Alzheimer’s disease and other age-related cognitive impairment—Part 1* 
Population studies strive to determine the prevalence of Alzheimer dementia but prevalence estimates vary widely. The challenges faced by several noted population studies for Alzheimer dementia in operationalizing current clinical diagnostic criteria for Alzheimer’s disease (AD) are reviewed. Differences in case ascertainment, methodological biases, cultural and educational influences on test performance, inclusion of special populations such as underrepresented minorities and the oldest old, and detection of the earliest symptomatic stages of underlying AD are considered. Classification of Alzheimer dementia may be improved by the incorporation of biomarkers for AD if the sensitivity, specificity, and predictive value of the biomarkers are established and if they are appropriate for epidemiological studies as may occur should a plasma biomarker be developed. Biomarkers for AD also could facilitate studies of the interactions of various forms of neurodegenerative disorders with cerebrovascular disease, resulting in “mixed dementia”.
PMCID: PMC3063444  PMID: 21255741
3.  Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions 
Van Deerlin, Vivianna M. | Sleiman, Patrick M. A. | Martinez-Lage, Maria | Chen-Plotkin, Alice | Wang, Li-San | Graff-Radford, Neill R | Dickson, Dennis W. | Rademakers, Rosa | Boeve, Bradley F. | Grossman, Murray | Arnold, Steven E. | Mann, David M.A. | Pickering-Brown, Stuart M. | Seelaar, Harro | Heutink, Peter | van Swieten, John C. | Murrell, Jill R. | Ghetti, Bernardino | Spina, Salvatore | Grafman, Jordan | Hodges, John | Spillantini, Maria Grazia | Gilman, Sid' | Lieberman, Andrew P. | Kaye, Jeffrey A. | Woltjer, Randall L. | Bigio, Eileen H | Mesulam, Marsel | al-Sarraj, Safa | Troakes, Claire | Rosenberg, Roger N. | White, Charles L. | Ferrer, Isidro | Lladó, Albert | Neumann, Manuela | Kretzschmar, Hans A. | Hulette, Christine Marie | Welsh-Bohmer, Kathleen A. | Miller, Bruce L | Alzualde, Ainhoa | de Munain, Adolfo Lopez | McKee, Ann C. | Gearing, Marla | Levey, Allan I. | Lah, James J. | Hardy, John | Rohrer, Jonathan D. | Lashley, Tammaryn | Mackenzie, Ian R.A. | Feldman, Howard H. | Hamilton, Ronald L. | Dekosky, Steven T. | van der Zee, Julie | Kumar-Singh, Samir | Van Broeckhoven, Christine | Mayeux, Richard | Vonsattel, Jean Paul G. | Troncoso, Juan C. | Kril, Jillian J | Kwok, John B.J. | Halliday, Glenda M. | Bird, Thomas D. | Ince, Paul G. | Shaw, Pamela J. | Cairns, Nigel J. | Morris, John C. | McLean, Catriona Ann | DeCarli, Charles | Ellis, William G. | Freeman, Stefanie H. | Frosch, Matthew P. | Growdon, John H. | Perl, Daniel P. | Sano, Mary | Bennett, David A. | Schneider, Julie A. | Beach, Thomas G. | Reiman, Eric M. | Woodruff, Bryan K. | Cummings, Jeffrey | Vinters, Harry V. | Miller, Carol A. | Chui, Helena C. | Alafuzoff, Irina | Hartikainen, Päivi | Seilhean, Danielle | Galasko, Douglas | Masliah, Eliezer | Cotman, Carl W. | Tuñón, M. Teresa | Martínez, M. Cristina Caballero | Munoz, David G. | Carroll, Steven L. | Marson, Daniel | Riederer, Peter F. | Bogdanovic, Nenad | Schellenberg, Gerard D. | Hakonarson, Hakon | Trojanowski, John Q. | Lee, Virginia M.-Y.
Nature genetics  2010;42(3):234-239.
Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP)1. FTLD-TDP is frequently familial resulting from progranulin (GRN) mutations. We assembled an international collaboration to identify susceptibility loci for FTLD-TDP, using genome-wide association (GWA). We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium (LD) block on 7p21 that contains TMEM106B in a GWA study (GWAS) on 515 FTLD-TDP cases. Three SNPs retained genome-wide significance following Bonferroni correction; top SNP rs1990622 (P=1.08×10−11; odds ratio (OR) minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P=2×10−4). TMEM106B variants may confer risk by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in patients with GRN mutations. Our data implicate TMEM106B as a strong risk factor for FTLD-TDP suggesting an underlying pathogenic mechanism.
PMCID: PMC2828525  PMID: 20154673
4.  Clinical and Psychological Characteristics of Initial Cohort of the Dominantly Inherited Alzheimer Network (DIAN) 
Neuropsychology  2013;28(1):10.1037/neu0000030.
To describe clinical, cognitive, and personality characteristics at baseline assessment of 249 participants 19 to 60 years of age in a multinational longitudinal study (DIAN) of autosomal dominant Alzheimer disease (ADAD).
Participants (74% cognitively normal) were from ADAD families with mutations in one of three genes (APP, PSEN1, or PSEN2). Mixed model analyses including family as a random variable and controlling for years from expected time of symptomatic onset of ADAD based on parental age at onset compared three groups (cognitively normal mutation noncarriers, cognitively normal mutation carriers, very mildly impaired mutation carriers).
Global cognitive deficits similar to those observed in late-life sporadic Alzheimer disease (AD) existed in very mild ADAD compared with cognitively normal carriers and noncarriers on all but two measures (Digit Span Backward, Letter Fluency for FAS) of episodic memory, semantic memory, working memory, attention, and speeded visuospatial abilities. Demented individuals were less extraverted, open, and conscientious than cognitively normal participants on the International Personality Item Pool. Differences in the relation between three measures (Logical Memory, Digit Symbol, attention switching) and time to expected age at symptomatic onset indicate that cognitive deficits on some measures can be detected in mutation carriers prior to symptomatic AD and hence should be useful markers in subsequent longitudinal follow-up.
Overall cognitive and personality deficits in very mild ADAD are similar to those seen in sporadic AD. Cognitive deficits also occur in asymptomatic mutation carriers who are closer to the expected time of dementia onset.
PMCID: PMC3877741  PMID: 24219606
Alzheimer disease; early onset; preclinical; cognition; personality
5.  Objective Assessment of Image Quality VI: Imaging in Radiation Therapy 
Physics in medicine and biology  2013;58(22):8197-8213.
Earlier work on Objective Assessment of Image Quality (OAIQ) focused largely on estimation or classification tasks in which the desired outcome of imaging is accurate diagnosis. This paper develops a general framework for assessing imaging quality on the basis of therapeutic outcomes rather than diagnostic performance. By analogy to Receiver Operating Characteristic (ROC) curves and their variants as used in diagnostic OAIQ, the method proposed here utilizes the Therapy Operating Characteristic or TOC curves, which are plots of the probability of tumor control vs. the probability of normal-tissue complications as the overall dose level of a radiotherapy treatment is varied. The proposed figure of merit is the area under the TOC curve, denoted AUTOC. This paper reviews an earlier exposition of the theory of TOC and AUTOC, which was specific to the assessment of image-segmentation algorithms, and extends it to other applications of imaging in external-beam radiation treatment as well as in treatment with internal radioactive sources. For each application, a methodology for computing the TOC is presented. A key difference between ROC and TOC is that the latter can be defined for a single patient rather than a population of patients.
PMCID: PMC4326059  PMID: 24200954
6.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
7.  Optimizing parameters in clinical trials with a randomized start or withdrawal design 
Disease-modifying (DM) trials on chronic diseases such as Alzheimer’s disease (AD) require a randomized start or withdrawal design. The analysis and optimization of such trials remain poorly understood, even for the simplest scenario in which only three repeated efficacy assessments are planned for each subject: one at the baseline, one at the end of the trial, and the other at the time when the treatments are switched. Under the assumption that the repeated measures across subjects follow a trivariate distribution whose mean and covariance matrix exist, the DM efficacy hypothesis is formulated by comparing the change of efficacy outcome between treatment arms with and without a treatment switch. Using a minimax criterion, a methodology is developed to optimally determine the sample size allocations to individual treatment arms as well as the optimum time when treatments are switched. The sensitivity of the optimum designs with respect to various model parameters is further assessed. An intersection-union test (IUT) is proposed to test the DM hypothesis, and determine the asymptotic size and the power of the IUT. Finally, the proposed methodology is demonstrated by using reported statistics on the placebo arms from several recently published symptomatic trials on AD to estimate necessary parameters and then deriving the optimum sample sizes and the time of treatment switch for future DM trials on AD.
PMCID: PMC3804275  PMID: 24159249
Alzheimer’s disease; Disease-modifying trials; Intersection-union test; Minimax criterion; Random intercept and slope models; Randomized start design
8.  Physical Activity and Cognitive Trajectories in Cognitively Normal Adults: The Adult Children Study 
Increased physical activity may protect against cognitive decline, the primary symptom of Alzheimer's disease (AD). In this study, we examined the relationship between physical activity and trajectories of cognitive functioning over serial assessments. Cognitively normal (Clinical Dementia Rating 0) middle aged and older adults (N=173, mean age 60.7 +/- 7.8 years) completed a self-report measure of physical activity and a battery of standard neuropsychological tests assessing processing speed, attention, executive functioning, and verbal memory. At baseline, individuals with higher physical activity levels performed better on tests of episodic memory and visuospatial functioning. Over subsequent follow-up visits, higher physical activity was associated with small performance gains on executive functioning and working memory tasks in participants with one or more copy of the apolipoprotein ε4 allele (APOE4). In APOE4 non-carriers, slopes of cognitive performance over time were not related to baseline physical activity. Our results suggest that cognitively normal older adults who report higher levels of physical activity may have slightly better cognitive performance, but the potential cognitive benefits of higher levels of physical activity over time may be most evident in individuals at genetic risk for AD.
PMCID: PMC3778080  PMID: 23739296
Alzheimer's disease; dementia; memory; physical activity; exercise; apolipoprotein E
9.  An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice 
Science translational medicine  2014;6(236):236re4.
Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased Aβ in brain interstitial fluid (ISF) in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of pre-existing plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable-isotope labeling kinetics (SILK), with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.
PMCID: PMC4269372  PMID: 24828079
10.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs.
Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers.
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process.
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
11.  Exploration of 100 commonly used drugs and supplements on cognition in older adults 
There are conflicting reports and a lack of evidence-based data regarding effects of medications on cognition in cognitively normal older adults. We explored whether use of 100 common medications taken by older adults is associated with longitudinal cognitive performance.
A longitudinal observational cohort was used with analysis of data collected September 2005 through May 2011 and maintained in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. Participants were aged 50 years or older and cognitively normal (N=4414). Composite scores were constructed from 10 psychometric tests. Scores for each participant reflecting change in the psychometric composite score from the baseline clinical assessment to the next assessment were calculated. General linear models were used to test whether the mean composite change score differed for participants who reported starting, stopping, continuing, or not taking each of the 100 most frequently-used medications in the NACC sample.
The average time between assessments was 1.2 years (SD=0.42). Nine medications showed a difference (p<0.05) across the four participant groups in mean psychometric change scores from the first to the second assessment. Medications associated with improved psychometric performance were: naproxen, calcium-vitamin D, ferrous sulfate, potassium chloride, flax, and sertraline. Medications associated with declining psychometric performance were: bupropion, oxybutynin, and furosemide.
Reported use of common medications is associated with cognitive performance in older adults, but studies are needed to investigate the mechanisms underlying these effects.
PMCID: PMC3823812  PMID: 23954027
cognition; medications; psychometric tests; National Alzheimer’s Coordinating Center
12.  Genome-Wide Association Study of CSF Levels of 59 Alzheimer's Disease Candidate Proteins: Significant Associations with Proteins Involved in Amyloid Processing and Inflammation 
PLoS Genetics  2014;10(10):e1004758.
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10−10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.
Author Summary
The use of quantitative endophenotypes from cerebrospinal fluid has led to the identification of several genetic variants that alter risk or rate of progression of Alzheimer's disease. Here we have analyzed the levels of 58 disease-related proteins in the cerebrospinal fluid for association with millions of variants across the human genome. We have identified significant, replicable associations with 5 analytes, Angiotensin-converting enzyme, Chemokine (C-C motif) ligand 2, Chemokine (C-C motif) ligand 4, Interleukin 6 receptor and Matrix metalloproteinase-3. Our results suggest that these variants play a regulatory role in the respective protein levels and are relevant to the inflammatory and amyloid processing pathways. Variants in associated with ACE and those associated with MMP3 levels also show association with risk for Alzheimer's disease in the expected directions. These associations are consistent in cerebrospinal fluid and plasma and in samples with only cognitively normal individuals suggesting that they are relevant in the regulation of these protein levels beyond the context of Alzheimer's disease.
PMCID: PMC4207667  PMID: 25340798
13.  Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study 
Lancet neurology  2013;12(10):957-965.
New research criteria for preclinical Alzheimer’s disease (AD)have been proposed by the National Institute on Aging and Alzheimer’s Association. They include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and injury markers (stage 2) and abnormal amyloid and injury markers and subtle cognitive changes (stage 3). We investigated the occurrence and long-term outcome of these stages.
Cerebrospinal fluidamyloid-β1–42 and tau levels and a memory composite score were used to classify 311 cognitively normal(Clinical Dementia Rating [CDR]=0) research participants ≥65 years as normal (both markers normal), preclinical AD stage 1–3, or Suspected Non-Alzheimer Pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). Outcome measures were progression to CDR≥0·5 symptomatic AD and mortality up to 15 years after baseline (average=4 years).
129 (41·5%) of participants were normal, 47 (15%)were in stage 1, 36 (12%) in stage 2, 13 (4%)in stage 3, 72 (23%) had SNAP, and 14 (4·5%) remained unclassified. The proportion of preclinical AD (stage 1–3) in our cohort was higher in individuals older than 72 years and in APOE-ε4 carriers. The 5-year progression rate to CDR≥0·5 symptomatic AD was 2% for normal participants, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with normal individuals, participants with preclinical AD had an increased risk of death (HR=6·2, p=0·0396).
Preclinical AD is common in cognitively normal elderly and strongly associated with future cognitive decline and mortality. Preclinical AD thus should be an important target for therapeutic interventions.
PMCID: PMC3904678  PMID: 24012374
14.  Vaccination with Tumor Cells Expressing IL-15 and IL-15Rα Inhibit Murine Breast and Prostate Cancer 
Gene therapy  2014;21(4):393-401.
A number of antitumor vaccines have shown recent promise up-regulating immune responses against tumor antigens and improving patient survival. In this study we examine the effectiveness of vaccination using IL-15 expressing tumor cells and examined their ability to up-regulate immune responses to tumor antigens. We demonstrated that the co-expression of IL-15 with its receptor, IL-15Rα, increased the cell-surface expression and secretion of IL-15. We show that a gene transfer approach using recombinant adenovirus to express IL-15 and IL-15Rα in murine TRAMP-C2 prostate or TS/A breast tumors induced antitumor immune responses. From this we developed a vaccine platform, consisting of TRAMP-C2 prostate cancer cells or TS/A breast cancer cells co-expressing IL-15 and IL-15Rα that inhibited tumor formation when mice were challenged with tumor. Inhibition of tumor growth led to improved survival when compared to animals receiving cells expressing IL-15 alone or unmodified tumor cells. Animals vaccinated with tumor cells co-expressing IL-15 and IL-15Rα showed greater tumor infiltration with CD8+ T and NK cells, as well as increased antitumor CD8+ T-cell responses. Vaccination with IL-15/IL-15Rα-modified TS/A breast cancer cells provided a survival advantage to mice challenged with unrelated murine TUBO breast cancer cells indicating the potential for allogeneic IL-15/IL-15Rα expressing vaccines.
PMCID: PMC3976433  PMID: 24572789
Cancer; gene therapy; interleukin-15; interleukin-15 receptor-alpha; vaccine
15.  Genetic Heterogeneity in Alzheimer Disease and Implications for Treatment Strategies 
Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer’s disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
PMCID: PMC4162987  PMID: 25217249
Alzheimer’s disease; Genetic; Heterogeneity; Presenilin; Amyloid precursor protein; Apolipoprotein E
16.  Relationship Between Stroop Performance and Resting State Functional Connectivity in Cognitively Normal Older Adults 
Neuropsychology  2013;27(5):10.1037/a0033402.
Early biomarkers of Alzheimer’s disease (AD) are needed for developing therapeutic interventions. Measures of attentional control in Stroop-type tasks discriminate healthy aging from early stage AD (Hutchison et al., 2010) and predict future development of AD (Balota et al., 2010) in cognitively normal individuals. Disruption in resting state functional connectivity magnetic resonance imaging (rs-fcMRI) has been reported in AD (Greicius et al., 2004), and in healthy controls at risk for AD (Sheline et al, 2010a). We explored the relationship among Stroop performance, rs-fcMRI, and CSF Aβ42 levels in cognitively normal older adults.
A computerized Stroop task (along with standard neuropsychological measures), rs-fcMRI, and CSF were obtained in 237 cognitively normal older adults. We compared the relationship between Stroop performance, including measures from reaction distributional analyses, and composite scores from four resting state networks (RSNs) [default mode (DMN), salience (SAL), dorsal attention (DAN), and sensory motor (SMN)], and the modulatory influence of CSF Aβ42 levels.
A larger Stroop effect in errors was associated with reduced rs-fcMRI within the DMN and SAL. Reaction time distributional analyses indicated the slow tail of the reaction time distribution was related to reduced rs-fcMRI functional connectivity within the SAL. Standard psychometric measures were not related to RSN composite scores. A relationship between Stroop performance and DMN (but not SAL) functional connectivity was stronger in CSF Aβ42 positive individuals.
A link exists between RSN composite scores and specific attentional performance measures. Both measures may be sensitive biomarkers for AD.
PMCID: PMC3837537  PMID: 24040929
resting state functional connectivity; Stroop; Alzheimer’s disease
17.  The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception 
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.
PMCID: PMC4108198  PMID: 23932184
Alzheimer's disease; Mild cognitive impairment; Amyloid; Tau; Biomarker
18.  The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer’s Disease 
Gerrish, Amy | Russo, Giancarlo | Richards, Alexander | Moskvina, Valentina | Ivanov, Dobril | Harold, Denise | Sims, Rebecca | Abraham, Richard | Hollingworth, Paul | Chapman, Jade | Hamshere, Marian | Pahwa, Jaspreet Singh | Dowzell, Kimberley | Williams, Amy | Jones, Nicola | Thomas, Charlene | Stretton, Alexandra | Morgan, Angharad R. | Lovestone, Simon | Powell, John | Proitsi, Petroula | Lupton, Michelle K. | Brayne, Carol | Rubinsztein, David C. | Gill, Michael | Lawlor, Brian | Lynch, Aoibhinn | Morgan, Kevin | Brown, Kristelle S. | Passmore, Peter A. | Craig, David | McGuinness, Bernadette | Todd, Stephen | Johnston, Janet A. | Holmes, Clive | Mann, David | Smith, A. David | Love, Seth | Kehoe, Patrick G. | Hardy, John | Mead, Simon | Fox, Nick | Rossor, Martin | Collinge, John | Maier, Wolfgang | Jessen, Frank | Kölsch, Heike | Heun, Reinhard | Schürmann, Britta | van den Bussche, Hendrik | Heuser, Isabella | Kornhuber, Johannes | Wiltfang, Jens | Dichgans, Martin | Frölich, Lutz | Hampel, Harald | Hüll, Michael | Rujescu, Dan | Goate, Alison M. | Kauwe, John S. K. | Cruchaga, Carlos | Nowotny, Petra | Morris, John C. | Mayo, Kevin | Livingston, Gill | Bass, Nicholas J. | Gurling, Hugh | McQuillin, Andrew | Gwilliam, Rhian | Deloukas, Panagiotis | Davies, Gail | Harris, Sarah E. | Starr, John M. | Deary, Ian J. | Al-Chalabi, Ammar | Shaw, Christopher E. | Tsolaki, Magda | Singleton, Andrew B. | Guerreiro, Rita | Mühleisen, Thomas W. | Nöthen, Markus M. | Moebus, Susanne | Jöckel, Karl-Heinz | Klopp, Norman | Wichmann, H-Erich | Carrasquillo, Minerva M | Pankratz, V Shane | Younkin, Steven G. | Jones, Lesley | Holmans, Peter A. | O’Donovan, Michael C. | Owen, Michael J. | Williams, Julie
Rare mutations in AβPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer’s disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson’s disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AβPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.
PMCID: PMC4118466  PMID: 22027014
Alzheimer’s disease; amyloid-β protein precursor; genetics; human; MAPT protein; PSEN1 protein; PSEN2 protein
19.  Increased uptake of [123I]-meta-iodobenzylguanidine and [18F]-dopamine in mouse pheochromocytoma cells and tumors after treatment with the histone deacetylase inhibitors romidepsin and trichostatin A 
Endocrine-related cancer  2011;18(1):143-157.
[131I]-meta-iodobenzylguanidine ([131I]-MIBG) is the most commonly employed treatment for metastatic pheochromocytoma and paraganglioma; however, its success is limited. Its efficacy depends on the [131I]-MIBG concentration reached within the tumor through its uptake via the norepinephrine transporter and retention in neurosecretory granules. Purpose is to enhance [123I]-MIBG uptake in cells and liver pheochromocytoma tumors.
Experimental Design
We report the in vitro effects of two histone deacetylase (HDAC) inhibitors, romidepsin and trichostatin A, on increased uptake of [3H]-norepinephrine and [123I]-MIBG in mouse pheochromocytoma (MPC) cells, and the effect of romidepsin on [18F]-fluorodopamine and [123I]-MIBG uptake in a mouse model of metastatic pheochromocytoma. The effects of both inhibitors on norepinephrine transporter activity were assessed in MPC cells by [123I]-MIBG uptake studies with and without the transporter blocking agent desipramine and the vesicular blocking agent reserpine.
Both HDAC inhibitors increased [3H]-norepinephrine, [123I]-MIBG, and [18F]-fluorodopamine uptake through the norepinephrine transporter in MPC cells. In vivo, inhibitor treatment resulted in increased uptake of [18F]-fluorodopamine and in pheochromocytoma liver metastases as measured by maximal standardized uptake values on PET imaging (p < 0.001). Analysis of biodistribution after inhibitor treatment confirmed the PET results in that uptake of [123I]-MIBG was significantly increased in liver metastases (p < 0.05). Therefore, HDAC inhibitor treatment increased radioisotope uptake in MPC cells in vitro and in liver metastases in vivo, through increased norepinephrine transporter activity.
These results suggest that HDAC inhibitors could enhance the therapeutic efficacy of [131I]-MIBG treatment in patients with malignant pheochromocytoma.
PMCID: PMC4110720  PMID: 21098082
histone deacetylase; meta-iodobenzylguanidine; pheochromocytoma; romidepsin; trichostatin A
20.  Rare coding variants in Phospholipase D3 (PLD3) confer risk for Alzheimer's disease 
Nature  2013;505(7484):550-554.
Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimer's disease (LOAD)1,2. These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low frequency coding variants with large effects on LOAD risk, we performed whole exome-sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large case-control datasets. A rare variant in PLD3 (phospholipase-D family, member 3, rs145999145; V232M) segregated with disease status in two independent families and doubled risk for AD in seven independent case-control series (V232M meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354 cases and controls of European-descent). Gene-based burden analyses in 4,387 cases and controls of European-descent and 302 African American cases and controls, with complete sequence data for PLD3, indicate that several variants in this gene increase risk for AD in both populations (EA: OR= 2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92; p=1.40×10-3). PLD3 is highly expressed in brain regions vulnerable to AD pathology, including hippocampus and cortex, and is expressed at lower levels in neurons from AD brains compared to control brains (p=8.10×10-10). Over-expression of PLD3 leads to a significant decrease in intracellular APP and extracellular Aβ42 and Aβ40, while knock-down of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a two-fold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may be used to identify rare variants with large effects on risk for disease or other complex traits.
PMCID: PMC4050701  PMID: 24336208
21.  The effects of aging and Alzheimer's disease on cerebral cortical anatomy: Specificity and differential relationships with cognition 
NeuroImage  2013;76:332-344.
Although both normal aging and Alzheimer's disease (AD) are associated with regional cortical atrophy, few studies have directly compared the spatial patterns and magnitude of effects of these two processes. The extant literature has not addressed two important questions: 1) Is the pattern of age-related cortical atrophy different if cognitively intact elderly individuals with silent AD pathology are excluded? and 2) Does the age- or AD-related atrophy relate to cognitive function? Here we studied 142 young controls, 87 older controls, and 28 mild AD patients. In addition, we studied 35 older controls with neuroimaging data indicating the absence of brain amyloid. Whole-cortex analyses identified regions of interest (ROIs) of cortical atrophy in aging and in AD. Results showed that some regions are predominantly affected by age with relatively little additional atrophy in patients with AD, e.g., calcarine cortex; other regions are predominantly affected by AD with much less of an effect of age, e.g., medial temporal cortex. Finally, other regions are affected by both aging and AD, e.g., dorsolateral prefrontal cortex and inferior parietal lobule. Thus, the processes of aging and AD have both differential and partially overlapping effects on specific regions of the cerebral cortex. In particular, some frontoparietal regions are affected by both processes, most temporal lobe regions are affected much more prominently by AD than aging, while sensorimotor and some prefrontal regions are affected specifically by aging and minimally more by AD. Within normal older adults, atrophy in aging-specific cortical regions relates to cognitive performance, while in AD patients atrophy in AD-specific regions relates to cognitive performance. Further work is warranted to investigate the behavioral and clinical relevance of these findings in additional detail, as well as their histological basis; ROIs generated from the present study could be used strategically in such investigations.
PMCID: PMC4098706  PMID: 23507382
Magnetic resonance imaging; Cerebral cortex; Aging; Alzheimer' disease; Parietal lobe; Frontal lobe; Temporal lobe
22.  Mild Physical Impairment Predicts Future Diagnosis of Dementia of the Alzheimer Type 
Journal of the American Geriatrics Society  2013;61(7):10.1111/jgs.12255.
To determine whether mildly impaired physical function (based on performance-based assessment) is associated with the development of dementia of the Alzheimer type (DAT) in cognitively normal older adults.
Longitudinal, observational study with yearly assessments of physical and cognitive function. Mean follow-up was 5 years.
Knight Alzheimer’s Disease Research Center at Washington University, St. Louis, Missouri.
Four hundred thirty-five cognitively normal adults, age 60 years or older participating in longitudinal studies of aging.
Survival analyses were used to examine whether scores on the 9-item Physical Performance Test (PPT) predicted time to DAT diagnosis. Cox proportional hazards models were used to examine associations between the PPT total scores and time to cognitive impairment and DAT; as well as the association of time to these events while adjusting for, and simultaneously testing the effects of age, gender, education, and presence of at least one apolipoprotein (APOE) ε4 allele.
During the follow-up period, 81 participants developed DAT. Compared to those who remained cognitively normal, participants diagnosed with DAT were older (81 vs 74.2 years; p=.001) and had worse performance on the PPT (25.5 vs 28.1; p=.009). Time to DAT diagnosis was associated with total scores on the PPT (hazard ratio [HR] =.89, 95% CI=.86–.93, p<.001) such that time to a DAT diagnosis was slower for participants with higher physical performance scores. In the adjusted analysis, the PPT scores significantly predicted time to a DAT diagnosis (HR =.94, 95% CI=.89–.99, p<.022).
The presence of mild physical impairment in cognitively normal older adults is associated with subsequent development of DAT. Although the physical impairment may be sufficiently mild that it is recognized only with performance-based assessments, its presence may predate clinically detectable cognitive decline.
PMCID: PMC3809089  PMID: 23647233
Dementia of Alzheimer type; physical performance; predictors; frailty
23.  Clinicopathologic Study of Alzheimer’s Disease: Alzheimer mimics 
A definite diagnosis of Alzheimer disease (AD) can only be made at autopsy. Even at expert research centers, diagnostic accuracy is relatively low. We conducted this study to examine the accuracy of clinical diagnosis of AD and present a list of clinical and neuropsychological findings that could render the clinical diagnosis difficult. Using the National Alzheimer’s Coordinating Center database, the records of 533 patients who had been diagnosed clinically with AD and later underwent autopsy, were reviewed retrospectively. Since the pathologic results of 119 subjects did not meet the criteria for definite AD, we labeled them as Alzheimer “mimics”. The neuropathological diagnoses of Alzheimer mimics consisted of dementia with Lewy body (n=35, 29%), insufficient AD (n=22, 18%), vascular disease (n=15, 13%), frontotemporal lobar degeneration (n=14, 12%) and hippocampal sclerosis (n=10, 8%). History of pacemaker insertion (10.92% vs. 4.11%, p=0.005), congestive heart failure (13.45% vs. 6.04% p=0.007), hypertension (56.30% vs. 47.83%, p=0.037) and resting tremor (14.29% vs. 10.87%, p=0.170) was more prevalent in Alzheimer mimics. Clinical Dementia Rating score and frequency of Neuropsychiatric Inventory Questionnaire items reflecting delusions, agitation, depression and motor disturbance were more severe in confirmed AD. In addition to Mini-Mental State Examination (16.97±8.29 vs. 12.74±15.26, p<0.001), Logical Memory, Animal Fluency, Boston Naming Test and Digit Span scores showed more severe impairment in confirmed AD. Continuing systematic comparisons of the current criteria for the clinical and pathological dementia diagnoses are essential to clinical practice and research, and may also lead to further improvement of the diagnostic procedure.
PMCID: PMC3725959  PMID: 23481687
Alzheimer’s disease; diagnosis; pathology; dementia with Lewy bodies
24.  Improving dementia care: The role of screening and detection of cognitive impairment 
The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia.
PMCID: PMC4049530  PMID: 23375564
Alzheimer; Dementia; Screening; Detection; Health care; Policy; Priority; Quality; Medicare; Annual wellness visit; Cognitive impairment; Cost-benefit analysis; Management; Patient-centered
25.  Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology 
Neurology  2013;80(23):2121-2129.
We sought to identify demographic and clinical features that were associated with expression of symptoms in the presence of Alzheimer disease (AD) neuropathologic changes.
We studied 82 asymptomatic (Clinical Dementia Rating global score = 0) and 824 symptomatic subjects (Clinical Dementia Rating score >0) with low to high AD neuropathologic changes at autopsy who were assessed at 1 of 34 National Institute on Aging–funded Alzheimer’s Disease Centers. All subjects underwent a clinical examination within 1 year of death. Logistic regression was used to evaluate factors associated with the odds of being asymptomatic vs symptomatic.
Asymptomatic subjects tended to have low neurofibrillary tangle scores but a wide range of neuritic plaque frequencies. There were, however, a few asymptomatic subjects with very high tangle and neuritic plaque burden, as well as symptomatic subjects with few changes. In the multivariable model, asymptomatic subjects were older (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.01–1.07), had lower clinical Hachinski Ischemic Score (OR = 0.82; 95% CI = 0.69–0.97), were less likely to have an APOE ε4 allele (OR = 0.36; 95% CI = 0.16–0.83), and had lower neurofibrillary tangle score (OR = 0.28; 95% CI = 0.17–0.45) compared with symptomatic subjects.
Dissociating clinical symptoms from pathologic findings better allows for investigation of preclinical AD. Our results suggest that although the severity of the pathology, particularly neurofibrillary tangles, has a large role in determining the extent of symptoms, other factors, including age, APOE status, and comorbidities such as cerebrovascular disease also explain differences in clinical presentation.
PMCID: PMC3716351  PMID: 23645594

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