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1.  Age-specific population frequencies of amyloidosis and neurodegeneration among cognitively normal people age 50-89 years: a cross-sectional study 
The Lancet. Neurology  2014;13(10):997-1005.
As treatment of pre-clinical Alzheimer's disease (AD) becomes a focus of therapeutic intervention, observational research studies should recognize the overlap between imaging abnormalities associated with typical aging vs those associated with AD. Our objective was to characterize how typical aging and pre-clinical AD blend together with advancing age in terms of neurodegeneration and b-amyloidosis.
We measured age-specific frequencies of amyloidosis and neurodegeneration in 985 cognitively normal subjects age 50 to 89 from a population-based study of cognitive aging. Potential participants were randomly selected from the Olmsted County, Minnesota population by age- and sex-stratification and invited to participate in cognitive evaluations and undergo multimodality imaging. To be eligible for inclusion, subjects must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, FDG PET and MRI. Imaging studies were obtained from March 2006 to December 2013. Amyloid positive/negative status (A+/A−) was determined by amyloid PET using Pittsburgh Compound B. Neurodegeneration positive/negative status (N+/N−) was determined by an AD-signature FDG PET measure and/or hippocampal volume on MRI. We labeled subjects positive or negative for neurodegeneration (FDG PET or MRI) or amyloidosis by using cutpoints defined such that 90% of 75 clinically diagnosed AD dementia subjects were categorized as abnormal. APOE genotype was assessed using DNA extracted from blood. Every individual was assigned to one of four groups: A−N−, A+N−, A−N+, or A+N+. Age specific frequencies of the 4 A/N groups were determined cross-sectionally using multinomial regression models. Associations with APOE ε4 and sex effects were evaluated by including these covariates in the multinomial models.
The population frequency of A−N− was 100% (n=985) at age 50 and declined thereafter. The frequency of A+N− increased to a maximum of 28% (95% CI, 24%-32%) at age 74 then decreased to 17% (95% CI, 11%-25%) by age 89. A−N+ increased from age 60 onward reaching a frequency of 24% (95% CI, 16%-34%) by age 89. A+N+ increased from age 65 onward reaching a frequency of 42% (95% CI, 31%-52%) by age 89. A+N− and A+N+ were more frequent in APOE ε4 carriers. A+N+ was more, and A+N− less frequent in men.
Accumulation of A/N imaging abnormalities is nearly inevitable by old age yet people are able to remain cognitively normal despite these abnormalities. . The multinomial models suggest the A/N frequency trends by age are modified by APOE ε4 , which increases risk for amyloidosis, and male sex, which increases risk for neurodegeneration. Changing A/N frequencies with age suggest that individuals may follow different pathophysiological sequences.
National Institute on Aging; Alexander Family Professorship of Alzheimer's Disease Research.
PMCID: PMC4324499  PMID: 25201514
Cognitive aging; Brain aging; Amyloid imaging; Alzheimer disease; Brain atrophy and Alzheimer disease; FDG PET and Alzheimer disease
2.  Comparison of amyloid plaque contrast generated by T2-, T2*-, and susceptibility-weighted imaging methods in transgenic mouse models of Alzheimer’s disease 
One of the hallmark pathologies of Alzheimer’s disease (AD) is amyloid plaque deposition. Plaques appear hypointense on T2- and T2*-weighted MR images probably due to the presence of endogenous iron, but no quantitative comparison of various imaging techniques has been reported. We estimated the T1, T2, T2*, and proton density values of cortical plaques and normal cortical tissue and analyzed the plaque contrast generated by a collection of T2-, T2*-, and susceptibility-weighted imaging (SWI) methods in ex vivo transgenic mouse specimens. The proton density and T1 values were similar for both cortical plaques and normal cortical tissue. The T2 and T2* values were similar in cortical plaques, which indicates that the iron content of cortical plaques may not be as large as previously thought. Ex vivo plaque contrast was increased compared to a previously reported spin echo sequence by summing multiple echoes and by performing SWI; however, gradient echo and susceptibility weighted imaging was found to be impractical for in vivo imaging due to susceptibility interface-related signal loss in the cortex.
PMCID: PMC2743236  PMID: 19253386
MR microscopy; Alzheimer’s disease; magnetic resonance imaging; magnetic resonance micro imaging; transgenic mice; susceptibility weighted imaging
3.  Update on hypothetical model of Alzheimer’s disease biomarkers 
Lancet neurology  2013;12(2):207-216.
In 2010, the authors published a hypothetical model of the major biomarkers of Alzheimer’s disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. In the interim, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of the assumptions underlying our original model. Recent evidence has allowed us to modify our original model. Refinements include indexing subjects by time rather than clinical symptom severity; incorporating inter-subject variability in cognitive response to the progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and, recognition that the two major proteinopathies underlying AD biomarker changes, Aβ and tau, may be initiated independently in late onset AD where we hypothesize that an incident Aβopathy can accelerate an antecedent tauopathy.
PMCID: PMC3622225  PMID: 23332364
4.  Brain amyloidosis ascertainment from cognitive, imaging, and peripheral blood protein measures 
Neurology  2015;84(7):729-737.
The goal of this study was to identify a clinical biomarker signature of brain amyloidosis in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1) mild cognitive impairment (MCI) cohort.
We developed a multimodal biomarker classifier for predicting brain amyloidosis using cognitive, imaging, and peripheral blood protein ADNI1 MCI data. We used CSF β-amyloid 1–42 (Aβ42) ≤192 pg/mL as proxy measure for Pittsburgh compound B (PiB)-PET standard uptake value ratio ≥1.5. We trained our classifier in the subcohort with CSF Aβ42 but no PiB-PET data and tested its performance in the subcohort with PiB-PET but no CSF Aβ42 data. We also examined the utility of our biomarker signature for predicting disease progression from MCI to Alzheimer dementia.
The CSF training classifier selected Mini-Mental State Examination, Trails B, Auditory Verbal Learning Test delayed recall, education, APOE genotype, interleukin 6 receptor, clusterin, and ApoE protein, and achieved leave-one-out accuracy of 85% (area under the curve [AUC] = 0.8). The PiB testing classifier achieved an AUC of 0.72, and when classifier self-tuning was allowed, AUC = 0.74. The 36-month disease-progression classifier achieved AUC = 0.75 and accuracy = 71%.
Automated classifiers based on cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with a modest level of accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.
Classification of evidence:
This study provides Class II evidence that a classification algorithm based on cognitive, imaging, and peripheral blood protein measures identifies patients with brain amyloid on PiB-PET with moderate accuracy (sensitivity 68%, specificity 78%).
PMCID: PMC4336101  PMID: 25609767
5.  Effects of changing from non-accelerated to accelerated MRI for follow-up in brain atrophy measurement 
NeuroImage  2014;107:46-53.
Stable MR acquisition is essential for reliable measurement of brain atrophy in longitudinal studies. One attractive recent advance in MRI is to speed up acquisition using parallel imaging (e.g. reducing volumetric T1-weighted acquisition scan times from around 9 to 5 minutes). In some studies, a decision to change to an accelerated acquisition may have been deliberately taken, while in others repeat scans may occasionally be accidentally acquired with an accelerated acquisition. In ADNI, non-accelerated and accelerated scans were acquired in the same scanning session on each individual. We investigated the impact on brain atrophy as measured by k-means normalised boundary shift integral (KN-BSI) and deformation-based morphometry when changing from non-accelerated to accelerated MRI acquisitions over a 12-month interval using scans of 422 subjects from ADNI. KN-BSIs were calculated using both a non-accelerated baseline scan and non-accelerated 12-month scans (i.e. consistent acquisition), and a non-accelerated baseline scan and an accelerated 12-month scan (i.e. changed acquisition). Fluid-based non-rigid registration was also performed on those scans to estimate the brain atrophy rate. We found that the effect on KN-BSI and fluid-based non-rigid registration depended on the scanner manufacturer. For KN-BSI, in Philips and Siemens scanners, the change had very little impact on the measured atrophy rate (increase of 0.051% in Philips and -0.035% in Siemens from consistent acquisition to changed acquisition), whereas, in GE, the change caused a mean reduction of 0.65% in the brain atrophy rate. This is likely due to the difference in tissue contrast between grey matter and cerebrospinal fluid in the non-accelerated and accelerated scans in GE, which uses IR-FSPGR instead of MP-RAGE. For fluid-based non-rigid registration, the change caused a mean increase of 0.29% in the brain atrophy rate in the changed acquisition compared to consistent acquisition in Philips, whereas in GE and Siemens, the change had less impact on the mean atrophy rate (increase of 0.18% in GE and 0.049% in Siemens). Moving from non-accelerated baseline scans to accelerated scans for follow-up may have surprisingly little effect on computed atrophy rates depending on the exact sequence details and the scanner manufacturer; even accidentally inconsistent scans of this nature may still be useful.
PMCID: PMC4300278  PMID: 25481794
Boundary shift integral; accelerated acquisition; non-accelerated acquisition; brain atrophy; Alzheimer's disease
6.  Relationship between hippocampal atrophy and neuropathology markers: A 7T MRI validation study of the EADC-ADNI Harmonized Hippocampal Segmentation Protocol 
The pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Center Harmonized Hippocampal Segmentation Protocol (HarP).
Temporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aβ, and tau burden for each hippocampal subfield were obtained.
We found significant correlations between hippocampal volume and Braak and Braak staging (ρ = −0.75, P = .001), tau (ρ = −0.53, P = .034), Aβ burden (ρ = −0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield-wise significant associations were found for Aβ in CA1 (ρ = −0.58, P = .019) and subiculum (ρ = −0.75, P = .001), tau in CA2 (ρ = −0.59, P = .016), and CA3 (ρ = −0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001).
The observed associations provide the pathological confirmation of hippocampal morphometry as a valid biomarker for AD and the pathologic validation of HarP.
PMCID: PMC4348340  PMID: 25620800
Hippocampus; Atrophy; Hippocampal atrophy; Alzheimer; Dementia; Hippocampal segmentation; Hippocampal volumes; Subfields; Pathology; Braak; CERAD; Amyloid; Tau; Neuronal count
7.  Delphi definition of the EADC-ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance 
This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation.
The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher’s and binomial tests.
Agreement was significant on the inclusion of alveus/fimbria (P =.021), whole hippocampal tail (P =.013), medial border of the body according to visible morphology (P =.0006), and on this combined set of features (P =.001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer’s disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates.
Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.
PMCID: PMC4419736  PMID: 25130658
Hippocampus; Atrophy; Volumetry; Manual segmentation; Harmonization; Anatomical landmarks; Delphi procedure; Alzheimer’s disease; Medial temporal lobe; Hippocampal atrophy; Magnetic resonance; Neuroimaging; Standard operational procedures; Enrichment; MCI; Reliability
8.  The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity 
An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.
Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.
The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001).
The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.
PMCID: PMC4422168  PMID: 25267715
Hippocampal volumetry; Magnetic resonance; Alzheimer's disease; Biomarkers; Diagnostic criteria; Enrichment; Clinical trials; Validation; Harmonized protocol; Standard operating procedures; Manual segmentation
9.  Vascular imaging abnormalities and cognition: Mediation by Cortical Volume in non-demented persons: ARIC-NCS Study 
Background and Purpose
The relationships between cerebrovascular lesions visible on imaging and cognition are complex. We explored the possibility that cerebral cortical volume mediated the relationship.
1906 non-demented participants (59% women; 25% African-American; mean age 76.6 years) in the Atherosclerosis Risk in Communities (ARIC) study underwent cognitive assessments, risk factor assessments, and quantitative MR imaging for white matter hyperintensities (WMH) and infarcts. The Freesurfer imaging analysis pipeline was used to determine regional cerebral volumes. We examined associations of cognitive domain outcomes with cerebral volumes (hippocampus, and separate groups of posterior and frontal cortical regions of interest (ROI)) and cerebrovascular imaging features (presence of large or small cortical/subcortical infarcts and WMH volume). We performed mediation pathway analyses to assess the hypothesis that hippocampal and cortical volumes mediated associations between cerebrovascular imaging features and cognition.
In unmediated analyses, WMH and infarcts were both associated with worse psychomotor speed/executive function (PS/EF). In mediation analyses, WMH and infarcts associations on PS/EF were significantly attenuated, but not abolished, by the inclusion of the posterior cortical ROI volume in the models, and the infarcts on PS/EF association was attenuated, but not abolished, by inclusion of the frontal cortical ROI volume.
Both WMH and infarcts were associated with cortical volume, and both lesions were also associated with cognitive performance, implying shared pathophysiological mechanisms. Although cross-sectional, our findings suggest that WMH and infarcts could be proxies for clinically covert processes that directly damage cortical regions. Microinfarcts are one candidate for such a clinically covert process.
PMCID: PMC4308430  PMID: 25563642
Magnetic resonance imaging; cerebral small vessel disease; white matter hyperintensities; cerebral infarction; cognition
10.  Alliance for Aging Research AD Biomarkers Work Group: Structural MRI 
Neurobiology of aging  2011;32(0 1):S48-S57.
Biomarkers of Alzheimer's disease (AD) are increasingly important. All modern AD therapeutic trials employ AD biomarkers in some capacity. In addition, AD biomarkers are an essential component of recently updated diagnostic criteria for AD from the National Institute on Aging – Alzheimer's Association. Biomarkers serve as proxies for specific pathophysiological features of disease. The 5 most well established AD biomarkers include both brain imaging and cerebrospinal fluid (CSF) measures – CSF Abeta and tau, amyloid positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, and structural magnetic resonance imaging (MRI). This article reviews evidence supporting the position that MRI is a biomarker of neurodegenerative atrophy. Topics covered include methods of extracting quantitative and semi quantitative information from structural MRI; imaging-autopsy correlation; and evidence supporting diagnostic and prognostic value of MRI measures. Finally, the place of MRI in a hypothetical model of temporal ordering of AD biomarkers is reviewed.
PMCID: PMC3661287  PMID: 22078173
11.  Shapes of the Trajectories of Five Major Biomarkers of Alzheimer’s Disease 
Archives of neurology  2012;69(7):856-867.
To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.
Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.
Main Outcome Measures
The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).
Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.
Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.
PMCID: PMC3595157  PMID: 22409939
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; cerebro spinal fluid; amyloid PET imaging; FDG PET imaging
12.  An Operational Approach to NIA-AA Criteria for Preclinical Alzheimer’s Disease 
Annals of neurology  2012;71(6):765-775.
A workgroup commissioned by the Alzheimer’s Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer’s disease (AD). We performed a preliminary assessment of these guidelines.
We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cut-points. A group of 450 cognitively normal (CN) subjects from a population based sample was used to develop cognitive cut-points and to assess population frequencies of the different preclinical AD stages using different cut-point criteria.
The new criteria subdivide the preclinical phase of AD into stages 1–3. To classify our CN subjects, two additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected Non-AD Pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0; 16% stage 1; 12 % stage 2; 3% stage 3; and 23% SNAP.
This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving just 3% unclassified. Future longitudinal validation of the criteria will be important.
PMCID: PMC3586223  PMID: 22488240
13.  Mapping ventricular expansion onto cortical gray matter in older adults 
Neurobiology of aging  2014;36 Suppl 1:S32-S41.
Dynamic changes in the brain’s lateral ventricles on MRI are powerful biomarkers of disease progression in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Ventricular measures can represent accumulation of diffuse brain atrophy with very high effect sizes. Despite having no direct role in cognition, ventricular expansion co-occurs with volumetric loss in gray and white matter structures. To better understand relationships between ventricular and cortical changes over time, we related ventricular expansion to atrophy in cognitively-relevant cortical gray matter surfaces, which are more challenging to segment. In ADNI participants, percent change in ventricular volumes at one- (N=677) and two-year (N=536) intervals was significantly associated with baseline cortical thickness and volume in the full sample controlling for age, sex, and diagnosis, and in MCI separately. Ventricular expansion in MCI was associated with thinner GM in frontal, temporal, and parietal regions affected by AD. Ventricular expansion reflects cortical atrophy in early AD, offering a useful biomarker for clinical trials of interventions to slow AD progression.
PMCID: PMC4268107  PMID: 25311280
biomarkers; Alzheimer’s disease; mild cognitive impairment; brain imaging; magnetic resonance imaging (MRI); cortical; gray matter; atrophy; thickness; volume; surface area; brain structure; longitudinal
14.  Pattern of Brain Atrophy Rates in Autopsy-Confirmed Dementia with Lewy Bodies 
Neurobiology of aging  2014;36(1):452-461.
Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared to Alzheimer’s disease dementia (AD) on MRI. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from two serial MRIs in autopsy-confirmed DLB (n=20) and mixed DLB/AD patients (n=22), compared to AD (n=30) and elderly non-demented controls (n=15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to controls. The mixed DLB/AD patients displayed greater rates in the whole brain, temporo-parietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and can be used as biomarkers of AD progression in patients with LB pathology.
PMCID: PMC4268128  PMID: 25128280
autopsy-confirmed dementia with Lewy bodies; Alzheimer’s disease; serial MRI; atrophy rate; Braak neurofibrillary tangle stage; sample size estimate
15.  Empowering Imaging Biomarkers of Alzheimer’s Disease 
Neurobiology of aging  2014;36 Suppl 1:S69-S80.
In a previous report, we proposed a method for combining multiple markers of atrophy caused by Alzheimer’s Disease (AD) into a single atrophy score that is more powerful than any one feature. We applied the method to expansion rates of the lateral ventricles, achieving the most powerful ventricular atrophy measure to date. Here, we expand our method’s application to Tensor Based Morphometry (TBM) measures. We also combine the volumetric TBM measures with previously computed ventricular surface measures into a combined atrophy score. We further show that our atrophy scores are longitudinally unbiased, with the intercept bias estimated at two orders of magnitude below the mean atrophy of control subjects at one year. Both approaches yield the most powerful biomarker of atrophy not only for ventricular measures, but for all published unbiased imaging measures to date. A two-year trial using our measures requires only 31 [22 43] AD subjects, or 56 [44 64] subjects with Mild Cognitive Impairment (MCI) to detect 25% slowing in atrophy with 80% power and 95% confidence.
PMCID: PMC4268333  PMID: 25260848
Linear Discriminant Analysis; shape analysis; Tensor Based Morphometry; ADNI; lateral ventricles; Alzheimer’s Disease; mild cognitive impairment; biomarker; drug trial; machine learning
16.  Connectivity network measures predict volumetric atrophy in mild cognitive impairment 
Neurobiology of aging  2014;36(0 1):S113-S120.
Alzheimer’s disease (AD) is characterized by cortical atrophy and disrupted anatomical connectivity, and leads to abnormal interactions between neural systems. Diffusion weighted imaging (DWI) and graph theory can be used to evaluate major brain networks, and detect signs of a breakdown in network connectivity. In a longitudinal study using both DWI and standard MRI, we assessed baseline white matter connectivity patterns in 30 subjects with mild cognitive impairment (MCI; mean age: 71.8+/−7.5 yrs; 18M/12F) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using both standard MRI-based cortical parcellations and whole-brain tractography, we computed baseline connectivity maps from which we calculated global “small-world” architecture measures, including mean clustering coefficient (MCC) and characteristic path length (CPL). We evaluated whether these baseline network measures predicted future volumetric brain atrophy in MCI subjects, who are at risk for developing AD, as determined by 3D Jacobian “expansion factor maps” between baseline and 6-month follow-up anatomical scans. This study suggests that DWI-based network measures may be a novel predictor of AD progression.
PMCID: PMC4276308  PMID: 25444606
Graph theory; brain networks; white matter; DTI; tractography; ADNI; TBM; small worldness; connectivity
17.  Seemingly Unrelated Regression empowers detection of network failure in dementia 
Neurobiology of aging  2014;36(0 1):S103-S112.
Brain connectivity is progressively disrupted in Alzheimer’s disease (AD). Here we used a seemingly unrelated regression (SUR) model to enhance the power to identify structural connections related to cognitive scores. We simultaneously solved regression equations with different predictors and used correlated errors among the equations to boost power for associations with brain networks. Connectivity maps were computed to represent the brain’s fiber networks from diffusion-weighted MRI scans of 200 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We first identified a pattern of brain connections related to clinical decline using standard regressions powered by this large sample size. As AD studies with a large number of DTI scans are rare, it is important to detect effects in smaller samples using simultaneous regression modeling like SUR. Diagnosis of MCI or AD is well known to be associated with ApoE genotype and educational level. In a subsample with no apparent associations using the general linear model, power was boosted with our SUR model--combining genotype, educational level, and clinical diagnosis.
PMCID: PMC4276318  PMID: 25257986
Brain connectivity; neuroimaging genetics; HARDI tractography; seemingly unrelated regression (SUR); APOE4; multivariate analysis
18.  DTI-based maximum density path analysis and classification of Alzheimer’s disease 
Neurobiology of aging  2014;36(0 1):S132-S140.
Characterizing brain changes in Alzheimer’s disease (AD) is important for patient prognosis, and for assessing brain deterioration in clinical trials. In this diffusion tensor imaging study, we used a new fiber-tract modeling method to investigate white matter integrity in 50 elderly controls (CTL), 113 people with mild cognitive impairment (MCI), and 37 AD patients. After clustering tractography using an ROI atlas, we used a shortest path graph search through each bundle’s fiber density map to derive maximum density paths (MDPs), which we registered across subjects. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) along all MDPs and found significant MD and FA differences between AD patients and CTL subjects as well as MD differences between CTL and late MCI subjects. MD and FA were also associated with widely used clinical scores (MMSE). As an MDP is a compact, low-dimensional representation of white matter organization, we tested the utility of DTI measures along these MDPs as features for support vector machine (SVM) based classification of AD.
PMCID: PMC4283487  PMID: 25444597
ADNI; tractography; DTI; fiber tract modeling; white matter; connectivity; SVM; classification
20.  Algebraic connectivity of brain networks shows patterns of segregation leading to reduced network robustness in Alzheimer's disease 
Measures of network topology and connectivity aid the understanding of network breakdown as the brain degenerates in Alzheimer's disease (AD). We analyzed 3-Tesla diffusion-weighted images from 202 patients scanned by the Alzheimer's Disease Neuroimaging Initiative – 50 healthy controls, 72 with early- and 38 with late-stage mild cognitive impairment (eMCI/lMCI) and 42 with AD. Using whole-brain tractography, we reconstructed structural connectivity networks representing connections between pairs of cortical regions. We examined, for the first time in this context, the network's Laplacian matrix and its Fiedler value, describing the network's algebraic connectivity, and the Fiedler vector, used to partition a graph. We assessed algebraic connectivity and four additional supporting metrics, revealing a decrease in network robustness and increasing disarray among nodes as dementia progressed. Network components became more disconnected and segregated, and their modularity increased. These measures are sensitive to diagnostic group differences, and may help understand the complex changes in AD.
PMCID: PMC4669194  PMID: 26640830
brain network; algebraic connectivity; Fiedler value; modularity; Alzheimer's disease
21.  Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criteria for Alzheimer’s disease 
The promise of Alzheimer’s disease (AD) biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging (MRI) measure in AD and thus represents the most rational target for an initial effort at standardization.
Methods and Results
The authors of this position paper propose a path toward this goal. The steps include: 1) Establish and empower an oversight board to manage and assess the effort, 2) Adopt the standardized definition of anatomic hippocampal boundaries on MRI arising from the EADC-ADNI hippocampal harmonization effort as a Reference Standard, 3) Establish a scientifically appropriate, publicly available Reference Standard Dataset based on manual delineation of the hippocampus in an appropriate sample of subjects (ADNI), and 4) Define minimum technical and prognostic performance metrics for validation of new measurement techniques using the Reference Standard Dataset as a benchmark.
Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent is to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry is envisioned as a template that could be applied to other imaging biomarkers.
PMCID: PMC3396131  PMID: 21784356
Alzheimer’s disease; biomarkers; Magnetic resonance imaging; hippocampus; biomarker standards
22.  Evidence for Ordering of Alzheimer’s Disease Biomarkers 
Archives of Neurology  2011;68(12):1526-1535.
To empirically assess the concept that Alzheimer’s disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.
Validation sample
Multi-site, referral centers
We studied 401 elderly cognitively normal (CN), Mild Cognitive Impairment (MCI) and AD dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative. We compared the proportions of three AD biomarkers – CSF Aβ42, CSF total tau (t-tau), and hippocampal volume adjusted by intra-cranial volume (HVa) - that were abnormal as cognitive impairment worsened. Cut-points demarcating normal vs. abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples.
Main Outcome measures
AD biomarkers
Within each clinical group in the entire sample (n=401) CSF Aβ42 was abnormal more often than t-tau or HVa. Among the 298 subjects with both baseline and 12 month data, the proportion of subjects with abnormal Aβ42 did not change from baseline to 12 months in any group. The proportion of subjects with abnormal t-tau increased from baseline to 12 months in CN (p=0.05) but not in MCI or dementia. In 209 subjects with abnormal CSF AB42 at baseline, the percent abnormal HVa, but not t-tau, increased from baseline to 12 months in MCI.
Reduction in CSF Aβ42 denotes a pathophysiological process that significantly departs from normality (i.e., becomes dynamic) early, while t-tau and HVa are biomarkers of downstream pathophysiological processes. T-tau becomes dynamic before HVa, but HVa is more dynamic in the clinically symptomatic MCI and dementia phases of the disease than t-tau.
PMCID: PMC3387980  PMID: 21825215
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; CSF tau; CSF Abeta; Alzheimer’s disease staging
23.  Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge 
Neuroimage  2015;123:149-164.
Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated “direct” measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the distribution of atrophy rates in the Alzheimer's disease (AD) and control groups and of required sample sizes to detect a 25% treatment effect, in relation to healthy ageing, with 95% significance and 80% power over follow-up periods of 6, 12, and 24 months. Uncertainty in these estimates, and head-to-head comparisons between techniques, were carried out using the bootstrap. The lateral ventricles provided the most stable measurements, followed by the brain. The hippocampi had much more variability across participants, likely because of differences in segmentation protocol and less distinct boundaries. Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity. The resulting annualized rates of change derived from the model ranged from, for whole brain: − 1.4% to − 2.2% (AD) and − 0.35% to − 0.67% (control), for ventricles: 4.6% to 10.2% (AD) and 1.2% to 3.4% (control), and for hippocampi: − 1.5% to − 7.0% (AD) and − 0.4% to − 1.4% (control). There were large and statistically significant differences in the sample size requirements between many of the techniques. The lowest sample sizes for each of these structures, for a trial with a 12 month follow-up period, were 242 (95% CI: 154 to 422) for whole brain, 168 (95% CI: 112 to 282) for ventricles, 190 (95% CI: 146 to 268) for left hippocampi, and 158 (95% CI: 116 to 228) for right hippocampi. This analysis represents one of the most extensive statistical comparisons of a large number of different atrophy measurement techniques from around the globe. The challenge data will remain online and publicly available so that other groups can assess their methods.
•We compared numerous brain atrophy measurement techniques using multiple metrics.•Each participant produced measures on the exact same dataset, blinded to disease.•A central statistical analysis using linear mixed effect models was performed.•Head to head comparisons for each region were performed using sample size estimates.•Brain and ventricle measures were more consistent across groups than for hippocampi.
PMCID: PMC4634338  PMID: 26275383
24.  Transforming CSF Aβ42 measures into calculated Pittsburgh Compound B (PIBcalc) units of brain Aβ amyloid 
PIB PET and CSF Aβ42 demonstrate a highly significant inverse correlation. Both are presumed to measure brain Aβ amyloid load. Our objectives were to develop a method to transform CSF Aβ42 measures into calculated PIB measures (PIBcalc) of Aβ amyloid load, and to partially validate the method in an independent sample of subjects.
Forty-one ADNI subjects underwent PIB PET imaging and lumbar puncture (LP) at the same time. This sample, referred to as the “training” sample (9 cognitively normal (CN), 22 MCI, and 10 AD), was used to develop a regression model by which CSF Aβ42 (with APOE ε4 genotype as a covariate) was transformed into units of PIB PET (PIBcalc). An independent “supporting” sample of 362 (105 CN, 164 MCI, 93AD) ADNI subjects who underwent LP but not PIB PET imaging had their CSF Aβ42 values converted to PIBcalc. These values were compared to the overall PIB PET distribution found in the ADNI subjects (n = 102).
A linear regression model demonstrates good prediction of actual PIB PET from CSF Aβ42 measures obtained in the training sample (R2 = 0.77, P<0.001). PIBcalc data (derived from CSF Aβ42) in the supporting sample of 362 ADNI subjects who underwent LP but not PIB PET imaging demonstrates group-wise distributions that are highly consistent with the larger ADNI PIB PET distribution and with published PIB PET imaging studies.
Although the precise parameters of this model are specific for the ADNI sample, we conclude that CSF Aβ42 can be transformed into calculated PIB (PIBcalc) measures of Aβ amyloid load. Brain Aβ amyloid load can be ascertained at baseline in therapeutic or observational studies by either CSF or amyloid PET imaging and the data can be pooled using well-established multiple imputation techniques that account for the uncertainty in a CSF-based calculated PIB value.
PMCID: PMC3060961  PMID: 21282074
Alzheimer's disease; Pittsburgh Compound B; amyloid imaging; Aβ amyloid; cerebrospinal fluid; Alzheimer's disease biomarkers
25.  Time-to-event Voxel Based Techniques to Assess Regional Atrophy Associated with MCI Risk of Progression to AD 
NeuroImage  2010;54(2):985-991.
When using imaging to predict time to progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), time-to-event statistical methods account for varying lengths of follow-up times among subjects whereas two-sample t-tests in voxel-based morphometry (VBM) do not. Our objectives were to apply a time-to-event voxel-based analytic method to identify regions on MRI where atrophy is associated with significantly increased risk of future progression to AD in subjects with MCI and to compare it to traditional voxel-level patterns obtained by applying two-sample methods. We also compared the power required to detect an association using time-to-event methods versus two-sample approaches.
Subjects with MCI at baseline were followed prospectively. The event of interest was clinical diagnosis of AD. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on rank-transformed voxel-level gray matter density (GMD) estimates.
The greatest risk of progression to AD was associated with atrophy of the medial temporal lobes. Patients ranked at the 25th percentile of GMD in these regions had more than a doubling of risk of progression to AD at a given time-point compared to patients at the 75th percentile. Power calculations showed the time-to-event approach to be more efficient than the traditional two-sample approach.
We present a new voxel-based analytic method that incorporates time-to-event statistical methods. In the context of a progressive disease like AD, time-to-event VBM seems more appropriate and powerful than traditional two-sample methods.
PMCID: PMC2997139  PMID: 20832487
Alzheimer Disease; mild cognitive impairment; magnetic resonance imaging; Cox proportional hazards model

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