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1.  Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline 
Neurology  2012;79(16):1636-1644.
Objectives:
Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.
Methods:
A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.
Results:
In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10).
Conclusions:
Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.
doi:10.1212/WNL.0b013e3182661f74
PMCID: PMC3468774  PMID: 22786606
2.  APOE & Neuroenergetics: an Emerging Paradigm in Alzheimer's Disease 
Neurobiology of aging  2012;34(4):1007-1017.
APOE is the major known genetic risk factor for late-onset Alzheimer's disease (AD). While relationships between APOE-encoded apoE and β-amyloid are increasingly well described, mounting evidence supports wide-ranging effects of APOE on the brain. Specifically, APOE appears to impact brain network activity and closely related neuroenergetic functions that may be involved in vulnerability to neurodegenerative pathophysiology. These effects highlight the salience of further investigation into the diverse influences of APOE. Therefore, this article reviews the interplay between APOE and neuroenergetics and proposes areas for further investigation. This research may lead to the identification of novel therapeutic targets for the treatment and/or prevention of AD.
doi:10.1016/j.neurobiolaging.2012.10.011
PMCID: PMC3545040  PMID: 23159550
APOE; apolipoprotein E; mitochondria; neuroenergetics; brain imaging; fMRI; FDG PET; cytochrome oxidase; biomarkers; Alzheimer's disease; energy metabolism; neurodegeneration
3.  Amyloid deposition detected with florbetapir F 18 (18F-AV-45) is related to lower episodic memory performance in clinically normal older individuals 
Neurobiology of aging  2012;34(3):822-831.
The objective of this study was to evaluate the relationship of amyloid burden, as assessed by florbetapir F 18 (18F-AV-45) amyloid PET, and cognition in healthy older control subjects (HC). Seventy-eight HC subjects were assessed with a brief cognitive test battery and PET imaging with florbetapir F 18. A standard uptake value ratio (SUVr) was computed for mean data from six cortical regions using a whole cerebellum reference region. Scans were also visually rated as amyloid positive (Aβ+) or amyloid negative (Aβ−) by three readers. Higher SUVr correlated with lower immediate memory (r=−0.33; p=0.003) and delayed recall scores (r=−0.25; p=0.027). Performance on immediate recall was also lower in the visually rated Aβ+ compared to Aβ− HC (p=0.04), with a similar trend observed in delayed recall (p=0.06). These findings support the hypothesis that higher amyloid burden is associated with lower memory performance among clinically normal older subjects. Longitudinal follow-up is ongoing to determine whether florbetapir F 18 may also predict subsequent cognitive decline.
doi:10.1016/j.neurobiolaging.2012.06.014
PMCID: PMC3518678  PMID: 22878163
4.  Initial Assessment of the Pathogenic Mechanisms of the recently identified Alzheimer Risk Loci 
Annals of human genetics  2013;77(2):85-105.
SUMMARY
Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer’s disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology.
Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer’s disease.
doi:10.1111/ahg.12000
PMCID: PMC3578142  PMID: 23360175
Alzheimer’s disease; genetic risk; GWAS
5.  A Sparse Structure Learning Algorithm for Gaussian Bayesian Network Identification from High-Dimensional Data 
Structure learning of Bayesian Networks (BNs) is an important topic in machine learning. Driven by modern applications in genetics and brain sciences, accurate and efficient learning of large-scale BN structures from high-dimensional data becomes a challenging problem. To tackle this challenge, we propose a Sparse Bayesian Network (SBN) structure learning algorithm that employs a novel formulation involving one L1-norm penalty term to impose sparsity and another penalty term to ensure that the learned BN is a Directed Acyclic Graph (DAG)—a required property of BNs. Through both theoretical analysis and extensive experiments on 11 moderate and large benchmark networks with various sample sizes, we show that SBN leads to improved learning accuracy, scalability, and efficiency as compared with 10 existing popular BN learning algorithms. We apply SBN to a real-world application of brain connectivity modeling for Alzheimer’s disease (AD) and reveal findings that could lead to advancements in AD research.
doi:10.1109/TPAMI.2012.129
PMCID: PMC3924722  PMID: 22665720
Bayesian network; machine learning; data mining
6.  Imaging markers for Alzheimer disease 
Neurology  2013;81(5):487-500.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
doi:10.1212/WNL.0b013e31829d86e8
PMCID: PMC3776529  PMID: 23897875
7.  Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study 
Lancet neurology  2012;11(12):10.1016/S1474-4422(12)70227-2.
Summary
Background
Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer’s disease. By assessing the accumulation of Aβ in people at risk of genetic forms of Alzheimer’s disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease.
Methods
Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer’s disease Colombian kindred aged 18–60 years were recruited from the Alzheimer’s Prevention Initiative’s registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer’s Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions. was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition.
Findings
We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. 18F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions.
Interpretation
These findings contribute to the understanding of preclinical familial Alzheimer’s disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer’s disease.
Funding
Avid Radiopharmaceuticals, Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
doi:10.1016/S1474-4422(12)70227-2
PMCID: PMC3515078  PMID: 23137949
8.  Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults 
Neurobiology of aging  2012;33(12):2723-2732.
The apolipoprotein E (APOE) ε4 allele increases the risk for late-onset Alzheimer's disease (AD) and age-related cognitive decline. We investigated whether ε4 carriers show reductions in gray matter volume compared to ε4 non-carriers decades prior to the potential onset of AD dementia or healthy cognitive aging. Fourteen cognitively normal ε4 carriers, ages 26 to 45, were compared with 10 age-matched, ε4 non-carriers using T1-weighted volumetric magnetic resonance imaging (MRI) scans. All had reported first or second-degree family histories of dementia. Group differences in gray matter were tested using voxel-based morphometry (VBM) and a multivariate model of regional covariance, the Scaled Subprofile Model (SSM). A combination of the first two SSM MRI gray matter patterns distinguished the APOE ε4 carriers from non-carriers. This combined pattern showed gray matter reductions in bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal cortices with co-varying relative increases in cerebellum, occipital, fusiform, and hippocampal regions. With these gray matter differences occurring decades prior to the potential onset of dementia or cognitive aging, the results suggest longstanding, gene-associated differences in brain morphology that may lead to preferential vulnerability for the later effects of late onset AD or healthy brain aging.
doi:10.1016/j.neurobiolaging.2012.01.014
PMCID: PMC3398228  PMID: 22405043
Apolipoprotein E; Late-Onset Alzheimer's Disease; Magnetic Resonance Imaging; Voxel-Based Morphometry; Multivariate Analysis; Gray Matter Volume
9.  Longitudinal Modeling of Cognitive Aging and the TOMM40 Effect 
Background
TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21–29 T residues) poly-T variants within intron 6 of TOMM40 while APOE e3 can be associated with either with a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer’s disease (AD) onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.
Methods
An APOE e4 enriched cohort of 639 cognitively normal individuals age 21–97 years of known TOMM40 genotype underwent longitudinal neuropsychological testing every two years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross sectional and longitudinal effects of age on the auditory verbal learning test long term memory score (AVLT) by APOE, TOMM40, and the interaction between the two.
Results
There were significant effects overall for both TOMM40 (p=0.04 linear effect, p=0.03 quadratic effect) and APOE (p=0.06 linear effect, p=0.008 quadratic effect) with no significant interaction (p=0.63). These differences were age-dependent: there was a significant TOMM40 effect prior to age 60 (p=0.009) characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect; and a significant APOE effect after age 60 (p=0.006) characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.
Conclusion
Both TOMM40 and APOE significantly influence age-related memory performance, but appear to do so independently of each other.
doi:10.1016/j.jalz.2011.11.006
PMCID: PMC3483561  PMID: 23102119
TOMM40; APOE; preclinical Alzheimer’s disease; cognitive aging; age-related memory loss; mitochondria; very long term memory; test-retest effects
10.  Clinical and multimodal biomarker correlates of ADNI neuropathological findings 
Background
Autopsy series commonly report a high percentage of coincident pathologies in demented patients, including patients with a clinical diagnosis of dementia of the Alzheimer type (DAT). However many clinical and biomarker studies report cases with a single neurodegenerative disease. We examined multimodal biomarker correlates of the consecutive series of the first 22 Alzheimer’s Disease Neuroimaging Initiative autopsies. Clinical data, neuropsychological measures, cerebrospinal fluid Aβ, total and phosphorylated tau and α-synuclein and MRI and FDG-PET scans.
Results
Clinical diagnosis was either probable DAT or Alzheimer’s disease (AD)-type mild cognitive impairment (MCI) at last evaluation prior to death. All patients had a pathological diagnosis of AD, but only four had pure AD. A coincident pathological diagnosis of dementia with Lewy bodies (DLB), medial temporal lobe pathology (TDP-43 proteinopathy, argyrophilic grain disease and hippocampal sclerosis), referred to collectively here as MTL, and vascular pathology were present in 45.5%, 40.0% and 22.7% of these patients, respectively. Hallucinations were a strong predictor of coincident DLB (100% specificity) and a more severe dysexecutive profile was also a useful predictor of coincident DLB (80.0% sensitivity and 83.3% specificity). Occipital FDG-PET hypometabolism accurately classified coincident DLB (80% sensitivity and 100% specificity). Subjects with coincident MTL showed lower hippocampal volume.
Conclusions
Biomarkers can be used to independently predict coincident AD and DLB pathology, a common finding in amnestic MCI and DAT patients. Cohorts with comprehensive neuropathological assessments and multimodal biomarkers are needed to characterize independent predictors for the different neuropathological substrates of cognitive impairment.
doi:10.1186/2051-5960-1-65
PMCID: PMC3893373  PMID: 24252435
Alzheimer’s disease; Mild cognitive impairment; CSF; MRI; Autopsy; Neuropathology; Dementia; Biomarkers; Amyloid; Tau
11.  Apolipoprotein E as a β-amyloid-independent factor in Alzheimer’s disease 
APOE, which encodes apolipoprotein E, is the most prevalent and best established genetic risk factor for late-onset Alzheimer’s disease. Current understanding of Alzheimer’s disease pathophysiology posits an important role for apolipoprotein E in the disease cascade via its interplay with β-amyloid. However, evidence is also emerging for roles of apolipoprotein E in the disease process that are independent of β-amyloid. Particular areas of interest are lipid metabolism, tau pathology, neuroenergetics, neurodevelopment, synaptic plasticity, the neurovasculature, and neuroinflammation. The intent of this article is to review the literature in each of these areas.
doi:10.1186/alzrt204
PMCID: PMC3979087  PMID: 23998393
12.  Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease 
JAMA neurology  2013;70(3):320-325.
Objective
To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease.
Design
Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxy-glucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers.
Setting
Academic medical center.
Participants
A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level.
Main Outcome Measures
The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume.
Results
Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P=.001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r=0.29, P=.0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P<.05, determined by use of pairwise Fisher z tests).
Conclusions
Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.
doi:10.1001/2013.jamaneurol.286
PMCID: PMC3745014  PMID: 23599929
13.  Multicenter Standardized 18F-FDG PET Diagnosis of Mild Cognitive Impairment, Alzheimer’s Disease, and Other Dementias 
This multicenter study examined 18F-FDG PET measures in the differential diagnosis of Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI).
Methods
We examined the 18F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals (“normals” or NLs), 114 MCI, 199 AD,98FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal 18F-FDG uptake that were then applied to characterize MCI.
Results
Standardized disease-specific PET patterns were developed that correctly classified 95%AD, 92% DLB,94%FTD,and 94%NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. 18F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns.
Conclusion
Standardized automated analysis of 18F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia.
doi:10.2967/jnumed.107.045385
PMCID: PMC3703818  PMID: 18287270
18F-FDG PET; Alzheimer’s disease; frontotemporal dementia; Lewy body dementia; mild cognitive impairment; normal aging; hippocampus
14.  Considerations in the Design of Clinical Trials for Cognitive Aging 
What will it take to develop interventions for the treatment of age-related cognitive decline? Session V of the Summit provided perspectives on the design of clinical trials to evaluate promising but unproven interventions, and some of the steps needed to accelerate the discovery and evaluation of promising treatments. It considered strategies to further characterize the biological and cognitive changes associated with normal aging and their translation into the development of new treatments. It provided regulatory, scientific, and clinical perspectives about neurocognitive aging treatments, their potential benefits and risks, and the strategies and endpoints needed to evaluate them in the most rapid, rigorous, and clinically meaningful way. It considered lessons learned from the study of Alzheimer's disease, the promising roles of biomarkers in neurocognitive aging research, and ways to help galvanize the scientific study and treatment of neurocognitive aging.
doi:10.1093/gerona/gls124
PMCID: PMC3391068  PMID: 22573913
Cognition; Clinical trials; Aging
15.  Association between an Alzheimer’s Disease-Related Index and APOE ε4 Gene Dose 
PLoS ONE  2013;8(6):e67163.
Background
We introduced a hypometabolic convergence index (HCI) to characterize in a single measurement the extent to which a person’s fluorodeoxyglucose positron emission tomogram (FDG PET) corresponds to that in Alzheimer’s disease (AD). Apolipoprotein E ε4 (APOE ε4) gene dose is associated with three levels of risk for late-onset AD. We explored the association between gene dose and HCI in cognitively normal ε4 homozygotes, heterozygotes, and non-carriers.
Methods
An algorithm was used to characterize and compare AD-related HCIs in cognitively normal individuals, including 36 ε4 homozygotes, 46 heterozygotes, and 78 non-carriers.
Results
These three groups differed significantly in their HCIs (ANOVA, p = 0.004), and there was a significant association between HCIs and gene dose (linear trend, p = 0.001).
Conclusions
The HCI is associated with three levels of genetic risk for late-onset AD. This supports the possibility of using a single FDG PET measurement to help in the preclinical detection and tracking of AD.
doi:10.1371/journal.pone.0067163
PMCID: PMC3694066  PMID: 23840615
16.  BRAIN IMAGING IN THE STUDY OF ALZHEIMER'S DISEASE 
Neuroimage  2011;61(2):505-516.
Over the last 20 years, there has been extraordinary progress in brain imaging research and its application to the study of Alzheimer's disease (AD). Brain imaging researchers have contributed to the scientific understanding, early detection and tracking of AD. They have set the stage for imaging techniques to play growing roles in the clinical setting, the evaluation of disease-modifying treatments, and the identification of demonstrably effective prevention therapies. They have developed ground-breaking methods, including positron emission tomography (PET) ligands to measure fibrillar amyloid-β (Aβ) deposition, new magnetic resonance imaging (MRI) pulse sequences, and powerful image analysis techniques, to help in these endeavors. Additional work is needed to develop even more powerful imaging methods, to further clarify the relationship and time course of Aβ and other disease processes in the predisposition to AD, to establish the role of brain imaging methods in the clinical setting, and to provide the scientific means and regulatory approval pathway needed to evaluate the range of promising disease-modifying and prevention therapies as quickly as possible. Twenty years from now, AD may not yet be a distant memory, but the best is yet to come.
doi:10.1016/j.neuroimage.2011.11.075
PMCID: PMC3351556  PMID: 22173295
Alzheimer's disease; dementia; mild cognitive impairment; MRI; PET; amyloid; diagnosis; prevention
17.  A coding variant in CR1 interacts with APOE-ɛ4 to influence cognitive decline 
Human Molecular Genetics  2012;21(10):2377-2388.
Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D′ = 1, r2= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ɛ4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q.
doi:10.1093/hmg/dds054
PMCID: PMC3335317  PMID: 22343410
18.  A method of generating image derived input function in quantitative 18F-FDG PET study based on the monotonicity of the input and output function curve 
Nuclear medicine communications  2012;33(4):10.1097/MNM.0b013e32834f262e.
Objective
A method for defining image-derived input function (IDIF) has been introduced and evaluated for the quantification of the regional cerebral metabolic rate of glucose in positron emission tomography studies.
Methods
The voxels in the brain vasculature are extracted based on the different monotonicity between the input and output function curves. The TACs of such voxels are averaged to get the uncorrected TAC of the brain vasculature. The IDIF was obtained from the raw TAC after correcting for the partial volume and spillover effects by an empirical formula in conjunction with single blood sample and the TAC of the brain tissue. Data from 16 human subjects were used to test the proposed method. The Patlak approach is used to calculate the net FDG clearance with plasma-derived input function (PDIF) and our generated IDIF, respectively.
Results
the net FDG clearances calculated with the image-derived input function generated by our approach are not only highly correlated (correlation coefficients close to 1) to, but also highly comparable (regression slopes close to 1, and intercepts close to 0) with those calculated with plasma-derived input function.
Conclusion
The method used in the present work is feasible and accurate.
doi:10.1097/MNM.0b013e32834f262e
PMCID: PMC3654793  PMID: 22262245
regional cerebral metabolic rate of glucose; 18F-fluoro-2-deoxyglucose; image derived input function; positron emission tomography
19.  A genome-wide scan for common variants affecting the rate of age-related cognitive decline 
Neurobiology of Aging  2011;33(5):1017.e1-1017.e15.
Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Since common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in three independent replication cohorts, consisting of 2,279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer’s disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (PDISC=5.6×10−9; PJOINT=3.7×10−27). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (PDISC=6.7×10−5; PREP=9.4×10−3; PJOINT=2.3×10−5). This variant influences the expression of two adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type II diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.
doi:10.1016/j.neurobiolaging.2011.09.033
PMCID: PMC3307898  PMID: 22054870
20.  Correlations between FDG PET glucose uptake-MRI gray matter volume scores and apolipoprotein E ε4 gene dose in cognitively normal adults: a cross-validation study using voxel-based multi-modal partial least squares 
Neuroimage  2012;60(4):2316-2322.
We previously introduced a voxel-based, multi-modal application of the partial least square algorithm (MMPLS) to characterize the linkage between patterns in a person’s complementary complex datasets without the need to correct for multiple regional comparisons. Here we used it to demonstrate a strong correlation between MMPLS scores to characterize the linkage between the covarying patterns of fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism and magnetic resonance imaging (MRI) measurements of regional gray matter associated with apolipoprotein E (APOE) ε4 gene dose (i.e., three levels of genetic risk for late-onset Alzheimer’s disease (AD)) in cognitively normal, late-middle-aged persons. Coregistered and spatially normalized FDG PET and MRI images from 70% of the subjects (27 ε4 homozygotes, 36 ε4 heterozygotes and 67 ε4 non-carriers) were used in a hypothesis-generating MMPLS analysis to characterize the covarying pattern of regional gray matter volume and cerebral glucose metabolism most strongly correlated with APOE-ε4 gene dose. Coregistered and spatially normalized FDG PET and MRI images from the remaining 30% of the subjects were used in a hypothesis-testing MMPLS analysis to generate FDG PET-MRI gray matter MMPLS scores blind to their APOE genotype and characterize their relationship to APOE-ε4 gene dose. The hypothesis-generating analysis revealed covarying regional gray matter volume and cerebral glucose metabolism patterns that resembled those in traditional univariate analyses of AD and APOE-ε4 gene dose and PET-MRI scores that were strongly correlated with APOE-ε4 gene dose (p<1×10−16). The hypothesis-testing analysis results showed strong correlations between FDG PET-MRI gray matter scores and APOE-ε4 gene dose (p=8.7×10−4). Our findings support the possibility of using the MMPLS to analyze complementary datasets from the same person in the presymptomatic detection and tracking of AD.
doi:10.1016/j.neuroimage.2012.02.005
PMCID: PMC3325642  PMID: 22348880
21.  Characterizing the Preclinical Stages of Alzheimer’s Disease and the Prospect of Presymptomatic Intervention 
Journal of Alzheimer's disease : JAD  2013;33(0 1):S405-S416.
Studies of asymptomatic carriers of genes that are known to predispose to Alzheimer’s disease (AD) have facilitated the characterization of preclinical AD. The most prevalent genetic risk factor is the e4 allele of apolipoprotein E (APOE). Neuropathological studies of young deceased e4 carriers have shown modest but abnormal amounts of neocortical amyloid and medial temporal neurofibrillary tangles that is also reflected in cerebrospinal fluid (CSF) biomarkers, abeta-amyloid and phosphotau in particular. MRI studies have shown progressive hippocampal and gray matter atrophy with the advent of mild cognitive impairment (MCI), and fluorodeoxyglucose PET scans show reduced cerebral metabolism in posterior cingulate and related AD regions evident even in 30 year olds. Cerebral amyloidosis disclosed by more recent amyloid ligand PET studies in asymptomatic 60 year olds increases in parallel with e4 gene dose. Longitudinal neuropsychological studies have revealed accelerated memory decline in e4 carriers beginning around age 55–60 years whose severity again parallels e4 gene dose. The clinico-pathological correlation of declining memory and AD-like neuropathological change defines preclinical AD and has set the stage for the accelerated evaluation of presymptomatic AD treatments. In this article, we briefly consider some of the earliest detectable changes associated with the predisposition to AD, and some of the prevention trial strategies that have been proposed to help find treatments to reduce the risk, postpone the onset of, or completely prevent AD symptoms as soon as possible.
doi:10.3233/JAD-2012-129026
PMCID: PMC3628721  PMID: 22695623
preclinical; APOE; normal aging; prevention
22.  Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers☆ 
NeuroImage : Clinical  2013;2:512-520.
Aside from apolipoprotein E (APOE), genetic risk factors for β amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects β amyloid burden and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of 18F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of β amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against β amyloid-related effects on cognition.
Highlights
•Codon 66 BDNF polymorphisms have been associated with various cerebral effects.•Community-recruited cognitively intact older adults underwent amyloid PET.•Recruitment was stratified factorially with APOE and BDNF as factors.•Aβ load in BDNF met carriers was higher but only in the presence of APOE ε4.•Aβ load was associated with worse episodic memory but only in BDNF met/APOE ε4.
doi:10.1016/j.nicl.2013.04.001
PMCID: PMC3777754  PMID: 24179803
BDNF, brain-derived neurotrophic factor; APOE, apolipoprotein E; SUVR, standardized uptake value ratio; SUVRcomp, SUVR in composite cortical volume of interest; val, valine; met, methionine; MRI, magnetic resonance imaging; PET, positron emission tomography; VOI, volume-of-interest; AD, Alzheimer's disease; PVC, partial volume correction; BDNF; APOE; Amyloid PET; Alzheimer; Flutemetamol
23.  Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons 
Neurobiology of Aging  2011;33(4):827.e11-827.e19.
Epidemiological studies suggest that elevated blood pressure (BP) in mid-life is associated with increased risk of Alzheimer’s disease (AD) in late-life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid-beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late-middle-aged to older adult apolipoprotein E (APOE) ε4 homozygotes, heterozygotes and non-carriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB DVRs and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower CMRgl in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late-mid-life may be associated with increased risk of presymptomatic AD.
doi:10.1016/j.neurobiolaging.2011.06.020
PMCID: PMC3236809  PMID: 21821316
APOE; blood pressure; arterial stiffness; brain imaging; PET; Alzheimer’s disease; amyloid; PiB; Pittsburgh Compound-B
24.  Analysis of Copy Number Variation in Alzheimer’s Disease in a Cohort of Clinically Characterized and Neuropathologically Verified Individuals 
PLoS ONE  2012;7(12):e50640.
Copy number variations (CNVs) are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap genes affecting their function and have been shown to be associated with disease. We previously investigated the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment using Alzheimer’s Disease Neuroimaging Initiative (ADNI) and National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study participants, and identified a number of genes overlapped by CNV calls. To confirm the findings and identify other potential candidate regions, we analyzed array data from a unique cohort of 1617 Caucasian participants (1022 AD cases and 595 controls) who were clinically characterized and whose diagnosis was neuropathologically verified. All DNA samples were extracted from brain tissue. CNV calls were generated and subjected to quality control (QC). 728 cases and 438 controls who passed all QC measures were included in case/control association analyses including candidate gene and genome-wide approaches. Rates of deletions and duplications did not significantly differ between cases and controls. Case-control association identified a number of previously reported regions (CHRFAM7A, RELN and DOPEY2) as well as a new gene (HLA-DRA). Meta-analysis of CHRFAM7A indicated a significant association of the gene with AD and/or MCI risk (P = 0.006, odds ratio = 3.986 (95% confidence interval 1.490–10.667)). A novel APP gene duplication was observed in one case sample. Further investigation of the identified genes in independent and larger samples is warranted.
doi:10.1371/journal.pone.0050640
PMCID: PMC3515604  PMID: 23227193
25.  Fluorodeoxyglucose Positron Emission Tomography: Emerging Roles in the Evaluation of Putative Alzheimer’s Disease-Modifying Treatments 
Neurobiology of Aging  2011;32(Suppl 1):S44-S47.
Alzheimer’s disease (AD) is associated with characteristic and progressive reductions in flourodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate for glucose. These reductions begin years before the onset of symptoms, are correlated with clinical severity, and may help predict an affected patient’s clinical course and neuropathological diagnosis. Like several other AD biomarkers, FDG PET has the potential to accelerate the evaluation of these treatments, particularly in the earliest clinical and preclinical stages. This article considers FDG PET’s role in the detection and tracking of AD, its emerging roles in the evaluation of disease-slowing treatments, some of the issues involved in the acquisition, analysis, and interpretation of FDG PET data, and the evidence needed to help qualify FDG PET and other biomarkers for use in the accelerated approval of AD-slowing treatments. It recommends scientific strategies and public policies to further establish the role of FDG PET and other AD biomarkers in therapeutic trials and find demonstrably effective disease-modifying and presymptomatic AD treatments as quickly as possible.
doi:10.1016/j.neurobiolaging.2011.09.007
PMCID: PMC3343736  PMID: 21983241
Alzheimer’s disease; brain imaging; biomarkers; clinical trials; positron emission tomography; magnetic resonance imaging; cerebrospinal fluid; dementia; mild cognitive impairment; preclinical; presymptomatic; treatment; prevention

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