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issn:0003-99.2
1.  Shapes of the Trajectories of Five Major Biomarkers of Alzheimer’s Disease 
Archives of neurology  2012;69(7):856-867.
Objective
To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.
Design
Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Patients
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).
Results
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.
Conclusions
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.
doi:10.1001/archneurol.2011.3405
PMCID: PMC3595157  PMID: 22409939
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; cerebro spinal fluid; amyloid PET imaging; FDG PET imaging
2.  Evidence for Ordering of Alzheimer’s Disease Biomarkers 
Archives of Neurology  2011;68(12):1526-1535.
Objective
To empirically assess the concept that Alzheimer’s disease (AD) biomarkers significantly depart from normality in a temporally ordered manner.
Design
Validation sample
Setting
Multi-site, referral centers
Patients
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.
Interventions
None
Main Outcome measures
AD biomarkers
Results
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.
Conclusions
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.
doi:10.1001/archneurol.2011.183
PMCID: PMC3387980  PMID: 21825215
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; CSF tau; CSF Abeta; Alzheimer’s disease staging
3.  Treatment With Cholinesterase Inhibitors and Memantine of Patients in the Alzheimer’s Disease Neuroimaging Initiative 
Archives of Neurology  2011;68(1):58-66.
Objectives
To assess the clinical characteristics and course of patients with mild cognitive impairment (MCI) and mild Alzheimer disease (AD) treated with cholinesterase inhibitors (ChEIs) and memantine hydrochloride.
Design
Cohort study.
Setting
The 59 recruiting sites for the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Participants
Outpatients with MCI and AD in ADNI.
Main Outcome Measures
The AD Assessment Scale–cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR) scale, and Functional Activities Questionnaire (FAQ).
Results
A total of 177 (44.0%) of 402 MCI patients and 159 (84.6%) of 188 mild-AD patients were treated with ChEIs and 11.4% of MCI patients and 45.7% of AD patients with memantine at entry. Mild-cognitive-impairment patients who received ChEIs with or without memantine were more impaired, showed greater decline in scores, and progressed to dementia sooner than patients who did not receive ChEIs. Alzheimer-disease patients who received ChEIs and memantine took them longer, were more functionally impaired, and showed greater decline on the MMSE and CDR (but not on the ADAS-cog or FAQ) than those who received ChEIs only.
Conclusions
Academic physicians frequently prescribe ChEIs and memantine earlier than indicated in the US Food and Drug Administration–approved labeling to patients who are relatively more severely impaired or who are rapidly progressing toward cognitive impairment. The use of these medications in ADNI is associated with clinical decline and may affect the interpretation of clinical trial outcomes.
Study Registration
clinicalTrials.gov Identifier: NCT00106899
doi:10.1001/archneurol.2010.343
PMCID: PMC3259850  PMID: 21220675
4.  The Dynamics of Cortical and Hippocampal Atrophy in Alzheimer Disease 
Archives of neurology  2011;68(8):1040-1048.
Objective
To characterize rates of regional Alzheimer disease (AD)–specific brain atrophy across the presymptomatic, mild cognitive impairment, and dementia stages.
Design
Multicenter case-control study of neuroimaging, cerebrospinal fluid, and cognitive test score data from the Alzheimer’s Disease Neuroimaging Initiative.
Setting
Research centers across the United States and Canada.
Patients
We examined a total of 317 participants with base-line cerebrospinal fluid biomarker measurements and 3T1-weighted magnetic resonance images obtained within 1 year.
Main Outcome Measures
We used automated tools to compute annual longitudinal atrophy in the hippocampus and cortical regions targeted in AD. We used Mini-Mental State Examination scores as a measure of cognitive performance. We performed a cross-subject analysis of atrophy rates and acceleration on individuals with an AD-like cerebrospinal fluid molecular profile.
Results
In presymptomatic individuals harboring indicators of AD, baseline thickness in AD-vulnerable cortical regions was significantly reduced compared with that of healthy control individuals, but baseline hippocampal volume was not. Across the clinical spectrum, rates of AD-specific cortical thinning increased with decreasing cognitive performance before peaking at approximately the Mini-Mental State Examination score of 21, beyond which rates of thinning started to decline. Annual rates of hippocampal volume loss showed a continuously increasing pattern with decreasing cognitive performance as low as the Mini-Mental State Examination score of 15. Analysis of the second derivative of imaging measurements revealed that AD-specific cortical thinning exhibited early acceleration followed by deceleration. Conversely, hippocampal volume loss exhibited positive acceleration across all study participants.
Conclusions
Alzheimer disease–specific cortical thinning and hippocampal volume loss are consistent with a sigmoidal pattern, with an acceleration phase during the early stages of the disease. Clinical trials should carefully consider the nonlinear behavior of these AD biomarkers.
doi:10.1001/archneurol.2011.167
PMCID: PMC3248949  PMID: 21825241
5.  Effects of Subcortical Cerebral Infarction on Cortical Glucose Metabolism and Cognitive Function 
Archives of neurology  1999;56(7):809-814.
Background
The mechanism of dementia in subcortical cerebral infarction is incompletely understood.
Objective
To determine how cognitive function is related to cortical metabolism in patients with subcortical infarction and a continuum of cognitive impairment.
Methods
We used positron emission tomography (PET) and the glucose metabolic tracer fludeoxyglucose F 18 to study 8 patients with subcortical stroke and normal cognitive function (S-CN), 5 patients with subcortical stroke and cognitive impairment (S-CI) who did not have dementia, 8 patients with subcortical stroke and dementia (S-D), and 11 controls with no cognitive impairment or stroke. A subset of patients had absolute regional cerebral metabolic rate of glucose (CMRglc) determined, while in all subjects regional tracer uptake normalized to whole brain tracer uptake was calculated. PET data were analyzed by constructing volumes of interest using coregistered magnetic resonance imaging data and correcting the PET data for atrophy.
Results
Global CMRglc was significantly lower in the patients with S-D than in the control and S-CN groups, with S-CI rates intermediate to those of the S-D and S-CN groups. Absolute regional CMRs of glucose were similar in the S-D and S-CI groups and in the control and S-CN groups. The regional pattern, however, showed lower right frontal regional CMRglc ratios in all stroke groups compared with the controls. There were modest correlations between performance on the Mini-Mental State Examination and whole brain CMRglc when all 4 groups were included.
Conclusions
These results demonstrate that subcortical infarction produces global cerebral hypometabolism, which is related to the clinical status of the patients. In addition, specific frontal lobe hypometabolism also appears to be a feature of subcortical infarction. Taken together, both global and regional effects on cortical function mediate the production of clinical symptoms in patients with subcortical strokes.
PMCID: PMC2733358  PMID: 10404982
6.  Regional Gray and White Matter Metabolite Differences in Subjects With AD, With Subcortical Ischemic Vascular Dementia, and Elderly Controls With 1H Magnetic Resonance Spectroscopic Imaging 
Archives of neurology  1996;53(2):167-174.
Objective
To use 1H magnetic resonance spectroscopic imaging to study differences in neuron density (N-acetylaspartate [NAA]), membrane phospholipid metabolites (choline [Cho]), and creatine-containing metabolites (creatine plus phosphocreatine [Cr]) in subjects with Alzheimer’s disease (AD), with subcortical ischemic vascular dementia (SIVD), and elderly controls.
Design
Cross-sectional, between groups.
Setting
A Veterans Affairs medical center and university memory clinic.
Participants
Forty elderly subjects with AD (n=14), with SIVD (n=8), and elderly controls (n=18).
Main Outcome Measures
We used 1H magnetic resonance spectroscopic imaging to acquire spectra from a 80 × 100 × 17-mm volume superior to the lateral ventricles. Spectra were analyzed from voxels in anterior, medial, and posterior gray and white matter using nuclear magnetic resonance-1 and the results were compared between groups using repeated measures analysis of variance (ANOVA), Tukey’s test, and individual Student’s t tests.
Results
Using ANOVA, significantly lower levels of NAA/Cho and NAA/Cr and significantly higher levels of Cho/Cr were observed across both gray and white matter voxels in subjects with AD. Using individual Student’s t tests, a significantly lower level of NAA/Cho and a higher level of Cho/Cr were observed in the posterior gray matter in subjects with AD. Using ANOVA in subjects with SIVD, significantly lower gray and white matter NAA/Cr levels were observed. Using Tukey’s test, the NAA/Cr level was significantly lower in frontal white matter voxels in subjects with SIVD compared with controls.
Conclusions
Our findings in subjects with AD suggest neuron loss in gray matter, axon loss in white matter, and altered Cho metabolism in posterior brain regions. Our findings in subjects with SIVD are consistent with higher levels of creatine-containing metabolites and/or lower levels of NAA in frontal white matter.
PMCID: PMC2733342  PMID: 8639067
7.  Patterns of White Matter Atrophy in Frontotemporal Lobar Degeneration 
Archives of neurology  2007;64(11):1619-1624.
Background
Structural magnetic resonance imaging (MRI) has been used to investigate the in vivo pathology of frontotemporal lobar degeneration. However, few neuroimaging studies have focused on white matter (WM) alterations in this disease.
Objectives
To use volumetric MRI techniques to identify the patterns of WM atrophy in vivo in 2 clinical variants of frontotemporal lobar degeneration—fronto-temporal dementia (FTD) and semantic dementia—and to compare the patterns of WM atrophy with those of gray matter (GM) atrophy in these diseases.
Design
Structural MRIs were obtained from patients with FTD (n=12) and semantic dementia (n=13) and in cognitively healthy age-matched controls (n=24). Regional GM and WM were classified automatically from high-resolution T1-, T2-, and proton density-weighted MRIs with Expectation-Maximization Segmentation and compared between the groups using a multivariate analysis of covariance model that included age and WM lesion volumes as covariates.
Results
Patients with FTD had frontal WM atrophy and frontal, parietal, and temporal GM atrophy compared with controls, who had none. Patients with semantic dementia had temporal WM and GM atrophy and patients with FTD had frontal GM atrophy. Adding temporal WM volume to temporal GM volume significantly improved the discrimination between semantic dementia and FTD.
Conclusions
These results show that patients with frontotemporal lobar degeneration who are in relatively early stages of the disease (Clinical Dementia Rating score, 1.0-1.2) have WM atrophy that largely parallels the pattern of GM atrophy typically associated with these disorders.
doi:10.1001/archneur.64.11.1619
PMCID: PMC2443735  PMID: 17998444

Results 1-7 (7)