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Introduction: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease., Methods: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans., Results: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB., Discussion: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The timing of plasma biomarker changes is not well understood. The goal of this study was to evaluate the temporal co-evolution of plasma and positron emission tomography (PET) Alzheimer's disease (AD) biomarkers., Methods: We included 1408 Mayo Clinic Study of Aging and Alzheimer's Disease Research Center participants. An accelerated failure time (AFT) model was fit with amyloid beta (Aβ) PET, tau PET, plasma p-tau217, p-tau181, and glial fibrillary acidic protein (GFAP) as endpoints., Results: Individual timing of plasma p-tau progression was strongly associated with Aβ PET and GFAP progression. In the population, GFAP became abnormal first, then Aβ PET, plasma p-tau, and tau PET temporal meta-regions of interest when applying cut points based on young, cognitively unimpaired participants., Discussion: Plasma p-tau is a stronger indicator of a temporally linked response to elevated brain Aβ than of tau pathology. While Aβ deposition and a rise in GFAP are upstream events associated with tau phosphorylation, the temporal link between p-tau and Aβ PET was the strongest., Highlights: Plasma p-tau progression was more strongly associated with Aβ than tau PET. Progression on plasma p-tau was associated with Aβ PET and GFAP progression. P-tau181 and p-tau217 become abnormal after Aβ PET and before tau PET. GFAP became abnormal first, before plasma p-tau and Aβ PET., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background and Objectives: β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB., Methods: We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum., Results: Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB ( p < 0.001) and MCI-LB ( p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB ( p < 0.001) and DLB groups ( p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02)., Discussion: In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies., (© 2023 American Academy of Neurology.)

Whether a relationship exists between cerebrovascular disease and Alzheimer's disease has been a source of controversy. Evaluation of the temporal progression of imaging biomarkers of these disease processes may inform mechanistic associations. We investigate the relationship of disease trajectories of cerebrovascular disease (white matter hyperintensity, WMH, and fractional anisotropy, FA) and Alzheimer's disease (amyloid and tau PET) biomarkers in 2406 Mayo Clinic Study of Aging and Mayo Alzheimer's Disease Research Center participants using accelerated failure time models. The model assumes a common pattern of progression for each biomarker that is shifted earlier or later in time for each individual and represented by a per participant age adjustment. An individual's amyloid and tau PET adjustments show very weak temporal association with WMH and FA adjustments (R = -0.07 to 0.07); early/late amyloid or tau timing explains <1% of the variation in WMH and FA adjustment. Earlier onset of amyloid is associated with earlier onset of tau (R = 0.57, R 2  = 32%). These findings support a strong mechanistic relationship between amyloid and tau aggregation, but not between WMH or FA and amyloid or tau PET., (© 2023. The Author(s).)

Staging the severity of Alzheimer's disease pathology using biomarkers is useful for therapeutic trials and clinical prognosis. Disease staging with amyloid and tau PET has face validity; however, this would be more practical with plasma biomarkers. Our objectives were, first, to examine approaches for staging amyloid and tau PET and, second, to examine prediction of amyloid and tau PET stages using plasma biomarkers. Participants (n = 1136) were enrolled in either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center; had a concurrent amyloid PET, tau PET and blood draw; and met clinical criteria for cognitively unimpaired (n = 864), mild cognitive impairment (n = 148) or Alzheimer's clinical syndrome with dementia (n = 124). The latter two groups were combined into a cognitively impaired group (n = 272). We used multinomial regression models to estimate discrimination [concordance (C) statistics] among three amyloid PET stages (low, intermediate, high), four tau PET stages (Braak 0, 1-2, 3-4, 5-6) and a combined amyloid and tau PET stage (none/low versus intermediate/high severity) using plasma biomarkers as predictors separately within unimpaired and impaired individuals. Plasma analytes, p-tau181, Aβ1-42 and Aβ1-40 (analysed as the Aβ42/Aβ40 ratio), glial fibrillary acidic protein and neurofilament light chain were measured on the HD-X Simoa Quanterix platform. Plasma p-tau217 was also measured in a subset (n = 355) of cognitively unimpaired participants using the Lilly Meso Scale Discovery assay. Models with all Quanterix plasma analytes along with risk factors (age, sex and APOE) most often provided the best discrimination among amyloid PET stages (C = 0.78-0.82). Models with p-tau181 provided similar discrimination of tau PET stages to models with all four plasma analytes (C = 0.72-0.85 versus C = 0.73-0.86). Discriminating a PET proxy of intermediate/high from none/low Alzheimer's disease neuropathological change with all four Quanterix plasma analytes was excellent but not better than p-tau181 only (C = 0.88 versus 0.87 for unimpaired and C = 0.91 versus 0.90 for impaired). Lilly p-tau217 outperformed the Quanterix p-tau181 assay for discriminating high versus intermediate amyloid (C = 0.85 versus 0.74) but did not improve over a model with all Quanterix plasma analytes and risk factors (C = 0.85 versus 0.83). Plasma analytes along with risk factors can discriminate between amyloid and tau PET stages and between a PET surrogate for intermediate/high versus none/low neuropathological change with accuracy in the acceptable to excellent range. Combinations of plasma analytes are better than single analytes for many staging predictions with the exception that Quanterix p-tau181 alone usually performed equivalently to combinations of Quanterix analytes for tau PET discrimination., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Brain imaging research studies increasingly use "de-facing" software to remove or replace facial imagery before public data sharing. Several works have studied the effects of de-facing software on brain imaging biomarkers by directly comparing automated measurements from unmodified vs de-faced images, but most research brain images are used in analyses of correlations with cognitive measurements or clinical statuses, and the effects of de-facing on these types of imaging-to-cognition correlations has not been measured. In this work, we focused on brain imaging measures of amyloid (A), tau (T), neurodegeneration (N), and vascular (V) measures used in Alzheimer's Disease (AD) research. We created a retrospective sample of participants from three age- and sex-matched clinical groups (cognitively unimpaired, mild cognitive impairment, and AD dementia, and we performed region- and voxel-wise analyses of: hippocampal volume (N), white matter hyperintensity volume (V), amyloid PET (A), and tau PET (T) measures, each from multiple software pipelines, on their ability to separate cognitively defined groups and their degrees of correlation with age and Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB). We performed each of these analyses twice: once with unmodified images and once with images de-faced with leading de-facing software mri&#95;reface, and we directly compared the findings and their statistical strengths between the original vs. the de-faced images. Analyses with original and with de-faced images had very high agreement. There were no significant differences between any voxel-wise comparisons. Among region-wise comparisons, only three out of 55 correlations were significantly different between original and de-faced images, and these were not significant after correction for multiple comparisons. Overall, the statistical power of the imaging data for AD biomarkers was almost identical between unmodified and de-faced images, and their analyses results were extremely consistent., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

In tau PET, a reliable method to detect early tau accumulation in the brain is crucial. Noise, artifacts, and off-target uptake impede detection of subtle true-positive ligand binding. We hypothesize that identifying voxels with stable activity over time can enhance detection of true-positive tau. Methods: In total, 339 participants in the clinical spectrum ranging from clinically unimpaired to Alzheimer disease dementia underwent at least 2 serial tau PET scans with flortaucipir. The overlap index (OI) method was proposed to detect spatially identical, voxelwise SUV ratio (SUVR) elevation when seen sequentially in serial tau PET scans. The association of OI with tau accumulation, clinical diagnosis, and cognitive findings was evaluated. Results: OI showed good dynamic range in the low-SUVR window. Only OI was able to identify subgroups with increasing tau PET signal in low-SUVR meta-region-of-interest (ROI) groups. OI showed improved association with early clinical disease progression and cognitive scores versus meta-ROI SUVR measures. Conclusion: OI was more sensitive to tau signal elevation and longitudinal change than standard ROI measures, suggesting it is a more sensitive method for detecting early, subtle deposition of neurofibrillary tangles., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

We evaluated the relationship between baseline CSF p-tau181 and the rate of tau PET change in the temporal meta-ROI and entorhinal cortex (ERC) and how it varied by amyloid level (CSF Aβ42 or amyloid PET) among 143 individuals from the Mayo Clinic Study of Aging and Mayo Alzheimer Disease Research Center. Higher CSF p-tau181, lower CSF Aβ42, and higher amyloid PET levels were associated with faster rates of tau PET change in both the temporal meta-ROI and ERC. In the temporal meta-ROI, longitudinal tau PET accumulation occurred primarily in participants with abnormal biomarker levels and a diagnosis of dementia, which supports the hypothesis that tau aggregation begins later in the disease process. Compared to the temporal meta-ROI, the ERC showed greater change in tau PET in non-demented participants but less change in later disease stages, supporting ERC as a more sensitive marker of early tau PET changes but with less dynamic range over the disease spectrum. We found both amyloid and CSF p-tau181 were associated with rates of tau PET change but there were some differences in associations by region, amyloid biomarker, and disease stage., (Copyright © 2022. Published by Elsevier Inc.)

Background: Localized regions of left-right image intensity asymmetry (LRIA) were incidentally observed on T 2 -weighted (T 2 -w) and T 1 -weighted (T 1 -w) diagnostic magnetic resonance imaging (MRI) images. Suspicion of herpes encephalitis resulted in unnecessary follow-up imaging. A nonbiological imaging artifact that can lead to diagnostic uncertainty was identified., Purpose: To investigate whether systematic LRIA exist for a range of scanner models and to determine if LRIA can introduce diagnostic uncertainty., Study Type: A retrospective study using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data base., Subjects: One thousand seven hundred fifty-three (median age: 72, males/females: 878/875) unique participants with longitudinal data were included., Field Strength: 3T., Sequences: T 1 -w three-dimensional inversion-recovery spoiled gradient-echo (IR-SPGR) or magnetization-prepared rapid gradient-echo (MP-RAGE) and T 2 -w fluid-attenuated inversion recovery (FLAIR) long tau fast spin echo inversion recovery (LT-FSE-IR). Only General Electric, Philips, and Siemens' product sequences were used., Assessment: LRIA was calculated as the left-right percent difference with respect to the mean intensity from automated anatomical atlas segmented regions. Three neuroradiologists with 37 (**), 32 (**), and 3 (**) years of experience rated the clinical impact of 30 T 2 -w three-dimensional FLAIR exams with LRIA to determine the diagnostic uncertainty. Statistical comparisons between retrospective intensity normalized T 1 m and original T 1 -w images were made., Statistical Tests: For each image type, a linear mixed effects model was fit using LRIA scores from all scanners, regions, and participants as the outcome and age and sex as predictors. Statistical significance was defined as having a P-value <0.05., Results: LRIA scores were significantly different from zero on most scanners. All clinicians were uncertain or recommended definite diagnostic follow-up in 62.5% of cases with LRIA >10%. Individuals with acute brain pathology or focal neurologic deficits are not enrolled in ADNI; therefore, focal signal abnormalities were considered false positives., Data Conclusion: LRIA is system specific, systematic, creates diagnostic uncertainty, and impacts IR-SPGR, MP-RAGE, and LT-FSE-IR product sequences., Level of Evidence: 2 Technical Efficacy Stage: 3., (© 2022 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Brain aging is accompanied by patterns of functional and structural change. Alzheimer's disease (AD), a representative neurodegenerative disease, has been linked to accelerated brain aging. Here, we developed a deep learning-based brain age prediction model using a large collection of fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging and tested how the brain age gap relates to degenerative syndromes including mild cognitive impairment, AD, frontotemporal dementia and Lewy body dementia. Occlusion analysis, performed to facilitate the interpretation of the model, revealed that the model learns an age- and modality-specific pattern of brain aging. The elevated brain age gap was highly correlated with cognitive impairment and the AD biomarker. The higher gap also showed a longitudinal predictive nature across clinical categories, including cognitively unimpaired individuals who converted to a clinical stage. However, regions generating brain age gaps were different for each diagnostic group of which the AD continuum showed similar patterns to normal aging., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease pathology in the form of amyloid-β plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of Alzheimer's disease co-pathology on functional network changes within the default mode network (DMN) in DLB. Second, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 Alzheimer's disease and 99 cognitively unimpaired participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), amyloid-β-PET with Pittsburgh compound-B (PiB) and resting-state functional MRI scans. The resing-state functional MRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir PET and PiB PET standardized uptake value ratio (SUVr). The strength of interregional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and cold spots) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot and cold spots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r = -0.39, P = 0.04) and amyloid-PET uptake (r = -0.41, P = 0.03) in the DLB group, i.e. patients with DLB who have more concurrent Alzheimer's disease pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in cognitively unimpaired, Alzheimer's disease and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVrs in the target region, whereas higher functional connectivity to the tau cold spot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of Alzheimer's disease co-pathology in patients with DLB is associated with more Alzheimer's disease-like changes in functional connectivity. Furthermore, we found an association between the brain's functional network architecture and the distribution of tau pathology that has recently been described in Alzheimer's disease. We show that this relationship also exists in patients with DLB, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The mechanisms through which tau and amyloid-beta (Aβ) accumulate in the brain of Alzheimer's disease patients may differ but both are related to neuronal networks. We examined such mechanisms on neuroimaging in 58 participants with atypical Alzheimer's disease (posterior cortical atrophy or logopenic progressive aphasia). Participants underwent Aβ-PET, longitudinal tau-PET, structural MRI and resting-state functional MRI, which was analyzed with graph theory. Regions with high levels of Aβ were more likely to be functional hubs, with a high number of functional connections important for resilience to cascading network failures. Regions with high levels of tau were more likely to have low clustering coefficients and degrees, suggesting a lack of trophic support or vulnerability to local network failures. Regions strongly functionally connected to the disease epicenters were more likely to have higher levels of tau and, less strongly, of Aβ. The regional rate of tau accumulation was associated with tau levels in functionally connected regions, in support of tau accumulation in a functional network. This study elucidates the relations of tau and Aβ to functional connectivity metrics in atypical Alzheimer's disease, strengthening the hypothesis that the spread of the 2 proteins is driven by different biological mechanisms related to functional networks., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Altered iron metabolism has been hypothesized to be associated with Alzheimer's disease pathology, and prior work has shown associations between iron load and beta amyloid plaques. Quantitative susceptibility mapping (QSM) is a recently popularized MR technique to infer local tissue susceptibility secondary to the presence of iron as well as other minerals. Greater QSM values imply greater iron concentration in tissue. QSM has been used to study relationships between cerebral iron load and established markers of Alzheimer's disease, however relationships remain unclear. In this work we study QSM signal characteristics and associations between susceptibility measured on QSM and established clinical and imaging markers of Alzheimer's disease. The study included 421 participants (234 male, median age 70 years, range 34-97 years) from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center; 296 (70%) had a diagnosis of cognitively unimpaired, 69 (16%) mild cognitive impairment, and 56 (13%) amnestic dementia. All participants had multi-echo gradient recalled echo imaging, PiB amyloid PET, and Tauvid tau PET. Variance components analysis showed that variation in cortical susceptibility across participants was low. Linear regression models were fit to assess associations with regional susceptibility. Expected increases in susceptibility were found with older age and cognitive impairment in the deep and inferior gray nuclei (pallidum, putamen, substantia nigra, subthalamic nucleus) (betas: 0.0017 to 0.0053 ppm for a 10 year increase in age, p = 0.03 to <0.001; betas: 0.0021 to 0.0058 ppm for a 5 point decrease in Short Test of Mental Status, p = 0.003 to p<0.001). Effect sizes in cortical regions were smaller, and the age associations were generally negative. Higher susceptibility was significantly associated with higher amyloid PET SUVR in the pallidum and putamen (betas: 0.0029 and 0.0012 ppm for a 20% increase in amyloid PET, p = 0.05 and 0.02, respectively), higher tau PET in the basal ganglia with the largest effect size in the pallidum (0.0082 ppm for a 20% increase in tau PET, p<0.001), and with lower cortical gray matter volume in the medial temporal lobe (0.0006 ppm for a 20% decrease in volume, p = 0.03). Overall, these findings suggest that susceptibility in the deep and inferior gray nuclei, particularly the pallidum and putamen, may be a marker of cognitive decline, amyloid deposition, and off-target binding of the tau ligand. Although iron has been demonstrated in amyloid plaques and in association with neurodegeneration, it is of insufficient quantity to be reliably detected in the cortex using this implementation of QSM., Competing Interests: Declaration of Competing Interest B.B.B. has served as an investigator for a clinical trial sponsored for Biogen. He receives royalties from the publication of a book entitled Behavioral Neurology of Dementia (Cambridge Medicine 2009, 2017). He serves on the Scientific Advisory Board of the Tau Consortium. He receives research support from the NIH, the Mayo Clinic Dorothy and Harry T. Mangurian Jr Lewy Body Dementia Program, and the Little Family Foundation, C.R.J. serves on an independent data monitoring board for Roche and has consulted for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. D.T.J. receives funding from the NIH and the Minnesota Partnership for Biotechnology and Medical Genomics. K.K. serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc.; receives research support from Avid Radioparmaceuticals and Eli Lilly, and receives funding from NIH and Alzheimer's Drug Discovery Foundation. D.S.K. served on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety monitoring Board for a tau therapeutic for Biogen, but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock and Alzeca Biosciences but receives no personal compensation. He receives research support from the NIH. V.J.L. consults for Bayer Schering Pharma, Piramal Life Sciences, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the NIH (NIA, NCI). M.M.M. receives support from the NIH, unrestricted research grants from Biogen, and consults for Brain Protection Company. R.C.P. has consulted for Roche, Inc.; Merck, Inc.; Biogen, Inc.; Eisai, Inc. and is on a Data and Safety Monitoring Committee for Genentech, Inc. He receives research support from the National Institute on Aging, the GHR Foundation and the Alzheimer's Association. C.G.S. and J.G-R. receive research support from the NIH. M.L.S. has owned shares of the following medical related stocks, unrelated to the current work: Align Technology, Inc., LHC Group, Inc., Mesa Laboratories, Inc., Natus Medical Incorporated, Varex Imaging Corporation, CRISPR Therapeutics, Gilead Sciences, Inc., Globus Medical Inc., Inovio Biomedical Corp., Ionis Pharmaceuticals, Johnson & Johnson, Medtronic, Inc., Parexel International Corporation. P.M.C., H.J.W., S.D.W., H.B., T.M.T., J.L.G., report no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate β-amyloid and tau depositions using Pittsburgh compound B (PiB) positron emission tomography (PET) and AV1451 tau PET imaging in aging multiple sclerosis (MS) patients., Methods: Patients with MS (n = 16) and controls (n = 80) matched for age, sex, and APOE ε4 status from the population-based Mayo Clinic Study of Aging who underwent PiB PET imaging were studied. Of these individuals, 12 patients with MS and 60 matching controls also underwent AV1451 tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVrs) from the entire cortex and previously determined Alzheimer disease (AD) signature regions in the same population were calculated for group comparisons and testing for associations with age., Results: AD signature PiB SUVr (odds ratio [OR] [95% confidence interval (CI)] = 0.52 [0.27-0.98], p = 0.044), total cortical PiB SUVr (OR [95% CI] = 0.52 [0.28-0.99], p = 0.048), and the frequency of abnormal PiB SUVrs (OR [95% CI] = 0.10 [0.01-0.90], p = 0.040) were lower in MS than controls. Although AD-signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (OR [95% CI] = 10.65 [1.10-103.35], p = 0.041) in MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.14 [-0.023 to -0.006], p = 0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (estimate [95% CI] = -0.13 [-0.021 to -0.005], p = 0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls., Interpretation: Although both β-amyloid and tau are biomarkers of cognitive aging and AD, cortical β-amyloid deposition was lower in MS than age-matched controls, suggesting that some aspect of MS pathobiology retards the accumulation of β-amyloid but not the accumulation of tau. ANN NEUROL 2020;87:556-567., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

Objective: To determine the frequency of high-convexity tight sulci (HCTS) in a population-based sample and whether the presence of HCTS and related features influenced participants' cognitive status and classification within the new Alzheimer-biomarker framework., Methods: We analyzed 684 participants ≥50 years of age who were enrolled in the prospective population-based Mayo Clinic Study of Aging and underwent structural MRI, amyloid PET imaging, and tau PET imaging. A fully automated machine-learning algorithm that had been developed previously in house was used to detect neuroimaging features of HCTS. On the basis of PET and MRI measures, participants were classified as having normal (A - ) or abnormal (A + ) amyloid, normal (T - ) or abnormal (T + ) tau, and normal (N - ) or abnormal (N + ) neurodegeneration. The neuropsychological battery assessed domain-specific and global cognitive scores. Gait speed also was assessed. Analyses were adjusted for age and sex., Results: Of 684 participants, 45 (6.6%) were classified with HCTS according to the automated algorithm. Patients with HCTS were older than patients without HCTS (mean [SD] 78.0 [8.3] vs 71.9 [10.8] years; p < 0.001). More were cognitively impaired after age and sex adjustment (27% vs 9%; p = 0.005). Amyloid PET status was similar with and without HCTS, but tau PET standard uptake value ratio (SUVR) was lower for those with HCTS after age and sex adjustment ( p < 0.001). Despite a lower tau SUVR, patients with HCTS had lower Alzheimer disease (AD) signature cortical thickness. With the amyloid-tau-neurodegeneration framework, HCTS was overrepresented in the T - (N) + group, regardless of amyloid status., Conclusion: The HCTS pattern represents a definable subgroup of non-AD pathophysiology (i.e., T - [N] + ) that is associated with cognitive impairment. HCTS may confound clinical and biomarker interpretation in AD clinical trials., (© 2019 American Academy of Neurology.)

Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer's disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer's disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer's biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen's d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer's disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.

Functionally related brain regions are selectively vulnerable to Alzheimer's disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer's disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer's disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer's disease dementia, we found several distinct spatial patterns of tau deposition, including 'Braak-like' and 'non-Braak-like', across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with 'non-Braak-like' patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer's disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer's disease., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Understanding the variation in uptake between different amyloid PET tracers is important to appropriately interpret data using different amyloid tracers. Therefore, we compared the uptake differences in [ 18 F]Flutemetamol (FMT) and [ 11 C]PiB (PiB) PET in the same people., Methods: Structural MRI, FMT PET and PiB PET were each performed in 30 young cognitively normal (yCN), 31 elderly cognitively normal (eCN) and 21 Alzheimer's disease dementia (AD) participants. PiB and FMT images for each participant were compared quantitatively using voxel- and region-based analyses. Region of interest (ROI) analyses included comparisons of grey matter (GM) regions as well as white matter (WM) regions. Regional comparisons of each tracer between different groups and comparisons of the two modalities within the different groups were performed. To compare mean SUVr between modalities, and between diagnostic groups, we used paired t -tests and Student's t -test, respectively. We also compared the ability of the two tracers to discriminate between diagnostic groups using AUROC estimates. The effect of using different normalization regions on SUVr values was also evaluated., Results: Both FMT and PiB showed greater uptake throughout GM structures in AD vs. eCN or yCN. In all dual-modality group comparisons (FMT vs. PiB in yCN, eCN, and AD), greater WM uptake was seen with FMT vs. PiB. In yCN and eCN greater diffuse GM uptake was seen with FMT vs. PiB. When comparing yCN to eCN within each tracer, greater WM uptake was seen in eCN vs yCN., Conclusions: Flutemetamol and PiB show similar topographical GM uptake in AD and CN participants and the tracers show comparable group discrimination. Greater WM accumulation with FMT suggests that quantitative differences vs. PiB will be apparent when using WM or GM as a reference region. Both imaging tracers demonstrate increased WM uptake in older people. These findings suggest that using different amyloid tracers or different methods of analyses in serial brain imaging in an individual may result in artifactual amyloid change measurements. Clinical use of several amyloid tracers in the same patient will have challenges that need to be carefully considered.

Pattern of diffusion tensor MRI (DTI) alterations were investigated in pathologically-staged Alzheimer's disease (AD) patients (n = 46). Patients with antemortem DTI studies and a range of AD pathology at autopsy were included. Patients with a high neurofibrillary tangle (NFT) stage (Braak IV-VI) had significantly elevated mean diffusivity (MD) in the crus of fornix and ventral cingulum tracts, precuneus, and entorhinal white matter on voxel-based analysis after adjusting for age and time from MRI to death (p < 0.001). Higher MD and lower fractional anisotropy in the ventral cingulum tract, entorhinal, and precuneus white matter was associated with higher Braak NFT stage and clinical disease severity. There were no MD and fractional anisotropy differences among the low (none and sparse) and high (moderate and frequent) β-amyloid neuritic plaque groups. The NFT pathology of AD is associated with DTI alterations involving the medial temporal limbic connections and medial parietal white matter. This pattern of diffusion abnormalities is also associated with clinical disease severity., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Our goal was to develop cut points for amyloid positron emission tomography (PET), tau PET, flouro-deoxyglucose (FDG) PET, and MRI cortical thickness., Methods: We examined five methods for determining cut points., Results: The reliable worsening method produced a cut point only for amyloid PET. The specificity, sensitivity, and accuracy of cognitively impaired versus young clinically normal (CN) methods labeled the most people abnormal and all gave similar cut points for tau PET, FDG PET, and cortical thickness. Cut points defined using the accuracy of cognitively impaired versus age-matched CN method labeled fewer people abnormal., Discussion: In the future, we will use a single cut point for amyloid PET (standardized uptake value ratio, 1.42; centiloid, 19) based on the reliable worsening cut point method. We will base lenient cut points for tau PET, FDG PET, and cortical thickness on the accuracy of cognitively impaired versus young CN method and base conservative cut points on the accuracy of cognitively impaired versus age-matched CN method., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with probable dementia with Lewy bodies (DLB) often have Alzheimer's disease (AD)-related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV-1451 uptake in patients with probable DLB, compared to AD, and its relationship to β-amyloid deposition on PET., Methods: Consecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer's Disease Research Center underwent magnetic resonance imaging, AV-1451, and Pittsburgh compound-B (PiB) PET examinations. Age- and sex-matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas- and voxel-based analyses were performed., Results: The AD dementia group had significantly higher AV-1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV-1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006)., Interpretation: Medial temporal lobe AV-1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV-1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB. ANN NEUROL 2017;81:58-67., (© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

The availability of antemortem biomarkers for Alzheimer's disease (AD) enables monitoring the evolution of neurodegenerative processes in real time. Pittsburgh compound B (PIB) positron emission tomography (PET) was used to select participants in the Mayo Clinic Study of Aging and the Mayo Alzheimer's Disease Research Center with elevated β-amyloid, designated as "A+," and hippocampal volume and (18)fluorodeoxyglucose (FDG) positron emission tomography were used to characterize participants as having evidence of neurodegeneration ("N+") at the baseline evaluation. There were 145 clinically normal (CN) A+ individuals, 62 persons with mild cognitive impairment (MCI) who were A+ and 20 with A+ AD dementia. Over a period of 1-6 years, MCI A+N+ individuals showed declines in medial temporal, lateral temporal, lateral parietal, and to a lesser extent, medial parietal regions for both FDG standardized uptake value ratio and gray matter volume that exceeded declines seen in the CN A+N+ group. The AD dementia group showed declines in the same regions on FDG standardized uptake value ratio and gray matter volume with rates that exceeded that in MCI A+N+. Expansion of regional involvement and faster rate of neurodegeneration characterizes progression in the AD pathway., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To examine neurodegenerative imaging biomarkers in Alzheimer disease (AD) dementia from middle to old age., Methods: Persons with AD dementia and elevated brain β-amyloid with Pittsburgh compound B (PiB)-PET imaging underwent [(18)F]-fluorodeoxyglucose (FDG)-PET and structural MRI. We evaluated 3 AD-related neurodegeneration biomarkers: hippocampal volume adjusted for total intracranial volume (HVa), FDG standardized uptake value ratio (SUVR) in regions of interest linked to AD, and cortical thickness in AD-related regions of interest. We examined associations of each biomarker with age and evaluated age effects on cutpoints defined by the 90th percentile in AD dementia. We assembled an age-, sex-, and intracranial volume-matched group of 194 similarly imaged clinically normal (CN) persons., Results: The 97 participants with AD dementia (aged 49-93 years) had PiB SUVR ≥1.8. A nonlinear (inverted-U) relationship between FDG SUVR and age was seen in the AD group but an inverse linear relationship with age was seen in the CN group. Cortical thickness had an inverse linear relationship with age in AD but a nonlinear (flat, then inverse linear) relationship in the CN group. HVa showed an inverse linear relationship with age in both AD and CN groups. Age effects on 90th percentile cutpoints were small for FDG SUVR and cortical thickness, but larger for HVa., Conclusions: In persons with AD dementia with elevated PiB SUVR, values of each neurodegeneration biomarker were associated with age. Cortical thickness had the smallest differences in 90th percentile cutpoints from middle to old age, and HVa the largest differences., (© 2016 American Academy of Neurology.)

Alzheimer's disease (AD) researchers commonly use MRI as a quantitative measure of disease severity. Historically, hippocampal volume has been favored. Recently, "AD signature" measurements of gray matter (GM) volumes or cortical thicknesses have gained attention. Here, we systematically evaluate multiple thickness- and volume-based candidate-methods side-by-side, built using the popular FreeSurfer, SPM, and ANTs packages, according to the following criteria: (a) ability to separate clinically normal individuals from those with AD; (b) (extent of) correlation with head size, a nuisance covariatel (c) reliability on repeated scans; and (d) correlation with Braak neurofibrillary tangle stage in a group with autopsy. We show that volume- and thickness-based measures generally perform similarly for separating clinically normal from AD populations, and in correlation with Braak neurofibrillary tangle stage at autopsy. Volume-based measures are generally more reliable than thickness measures. As expected, volume measures are highly correlated with head size, while thickness measures are generally not. Because approaches to statistically correcting volumes for head size vary and may be inadequate to deal with this underlying confound, and because our goal is to determine a measure which can be used to examine age and sex effects in a cohort across a large age range, we thus recommend thickness-based measures. Ultimately, based on these criteria and additional practical considerations of run-time and failure rates, we recommend an AD signature measure formed from a composite of thickness measurements in the entorhinal, fusiform, parahippocampal, mid-temporal, inferior-temporal, and angular gyrus ROIs using ANTs with input segmentations from SPM12.

Objective: To investigate the effect of age, sex, APOE4 genotype, and lifestyle enrichment (education/occupation, midlife cognitive activity, and midlife physical activity) on Alzheimer disease (AD) biomarker trajectories using longitudinal imaging data (brain β-amyloid load via Pittsburgh compound B PET and neurodegeneration via (18)fluorodeoxyglucose (FDG) PET and structural MRI) in an elderly population without dementia., Methods: In the population-based longitudinal Mayo Clinic Study of Aging, we studied 393 participants without dementia (340 clinically normal, 53 mild cognitive impairment; 70 years and older) who had cognitive and physical activity measures and at least 2 visits with imaging biomarkers. We dichotomized participants into high (≥14 years) and low (<14 years) education levels using the median. For the entire cohort and the 2 education strata, we built linear mixed models to investigate the effect of the predictors on each of the biomarker outcomes., Results: Age was associated with amyloid and neurodegeneration trajectories; APOE4 status appears to influence only the amyloid and FDG trajectories but not hippocampal volume trajectory. In the high-education stratum, high midlife cognitive activity was associated with lower amyloid deposition in APOE4 carriers. APOE4 status was associated with lower FDG uptake in the entire cohort and in participants with lower education but not the high-education cohort., Conclusions: There were minimal effects of lifestyle enrichment on AD biomarker trajectories (specifically rates). Lifetime intellectual enrichment (high education, high midlife cognitive activity) is associated with lower amyloid in APOE4 carriers. High education is protective from the APOE4 effect on FDG metabolism. Differing education levels may explain the conflicting results seen in the literature., (© 2016 American Academy of Neurology.)

Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer's disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer's disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer's pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer's disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure--analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity 'overload' that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Different clinical syndromes can arise from Alzheimer's disease (AD) neuropathology, including dementia of the Alzheimer's type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA)., Objective: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD., Methods: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups., Results: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum., Conclusion: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.

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 24months. 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 12month 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., (Copyright © 2015. Published by Elsevier Inc.)

Importance: To understand how a model of Alzheimer disease pathophysiology based on β-amyloidosis and neurodegeneration predicts the regional anatomic expansion of hypometabolism and atrophy in persons with mild cognitive impairment (MCI)., Objective: To define the role of β-amyloidosis and neurodegeneration in the subsequent progression of topographic cortical structural and metabolic changes in MCI., Design, Setting, and Participants: Longitudinal, observational study with serial brain imaging conducted from March 28, 2006, to January 6, 2015, using a population-based cohort. A total of 96 participants with MCI (all aged >70 years) with serial imaging biomarkers from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center were included. Participants were characterized initially as having elevated or not elevated brain β-amyloidosis (A+ or A-) based on 11C-Pittsburgh compound B positron emission tomography. They were further characterized initially by the presence or absence of neurodegeneration (N+ or N-), where the presence of neurodegeneration was defined by abnormally low hippocampal volume or hypometabolism in an Alzheimer disease-like pattern on 18fluorodeoxyglucose (FDG)-positron emission tomography., Main Outcomes and Measures: Regional FDG standardized uptake value ratio (SUVR) and gray matter volumes in medial temporal, lateral temporal, lateral parietal, and medial parietal regions., Results: In the primary regions of interest (ROI), the A+N+ group (n = 45) had lower FDG SUVR at baseline compared with the A+N- group (n = 17) (all 4 ROIs; P < .001). The A+N+ group also had lower FDG SUVR at baseline (all 4 ROIs; P < .01) compared with the A-N- group (n = 12). The A+N+ group had lower medial temporal gray matter volume at baseline (P < .001) compared with either the A+N- group or A-N- group. The A+N+ group showed large longitudinal declines in FDG SUVR (P < .05 for medial temporal, lateral temporal, and medial parietal regions) and gray matter volumes (P < .05 for medial temporal and lateral temporal regions) compared with the A-N+ group (n = 22). The A+N+ group also showed large longitudinal declines compared with the A-N- group on FDG SUVR (P < .05 for medial temporal and lateral parietal regions) and gray matter volumes (all 4 ROIs; P < .05) compared with the A+N- group. The A-N+ group did not show declines in FDG SUVR or gray matter volume compared with the A+N- or A-N- groups., Conclusions and Relevance: Persons with MCI who were A+N+ demonstrated volumetric and metabolic worsening in temporal and parietal association areas, consistent with the expectation that the MCI stage in the Alzheimer pathway heralds incipient isocortical involvement. The A-N+ group, those with suspected non-Alzheimer pathophysiology, lacked a distinctive longitudinal volumetric or metabolic profile.

We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Our primary objective was to compare the performance of unaccelerated vs. accelerated structural MRI for measuring disease progression using serial scans in Alzheimer's disease (AD)., Methods: We identified cognitively normal (CN), early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI) and AD subjects from all available Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects with usable pairs of accelerated and unaccelerated scans. There were a total of 696 subjects with baseline and 3 month scans, 628 subjects with baseline and 6 month scans and 464 subjects with baseline and 12 month scans available. We employed the Symmetric Diffeomorphic Image Normalization method (SyN) for normalization of the serial scans to obtain tensor based morphometry (TBM) maps which indicate the structural changes between pairs of scans. We computed a TBM-SyN summary score of annualized structural changes over 31 regions of interest (ROIs) that are characteristically affected in AD. TBM-SyN scores were computed using accelerated and unaccelerated scan pairs and compared in terms of agreement, group-wise discrimination, and sample size estimates for a hypothetical therapeutic trial., Results: We observed a number of systematic differences between TBM-SyN scores computed from accelerated and unaccelerated pairs of scans. TBM-SyN scores computed from accelerated scans tended to have overall higher estimated values than those from unaccelerated scans. However, the performance of accelerated scans was comparable to unaccelerated scans in terms of discrimination between clinical groups and sample sizes required in each clinical group for a therapeutic trial. We also found that the quality of both accelerated vs. unaccelerated scans were similar., Conclusions: Accelerated scanning protocols reduce scan time considerably. Their group-wise discrimination and sample size estimates were comparable to those obtained with unaccelerated scans. The two protocols did not produce interchangeable TBM-SyN estimates, so it is arguably important to use either accelerated pairs of scans or unaccelerated pairs of scans throughout the study duration., (Copyright © 2015. Published by Elsevier Inc.)

We aimed to determine whether network-level functional connectivity differs in 2 clinical variants of Alzheimer's disease: logopenic primary progressive aphasia (lvPPA) and dementia of the Alzheimer's type (DAT). Twenty-four lvPPA subjects with amyloid deposition on positron emission tomography and task-free functional magnetic resonance imaging were matched to 24 amyloid-positive DAT subjects and 24 amyloid-negative controls. Independent-component analysis and spatial-temporal dual regression were used to assess functional connectivity within the language network, left and right working memory networks, and ventral default mode network. lvPPA showed reduced connectivity in left temporal language network and inferior parietal and prefrontal regions of the left working memory network compared with controls and DAT. Both groups showed reduced connectivity in the parietal regions of the right working memory network compared with controls. Only DAT showed reduced ventral default mode network connectivity compared with controls. Aphasia severity correlated with connectivity in the left working memory network within lvPPA. Patterns of network dysfunction differ across these 2 clinical variants of Alzheimer's disease, with lvPPA particularly associated with disruptions in the language and left working memory networks., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Microbleeds in the brain have been shown to occur in Alzheimer's disease (AD), affecting approximately a third of subjects that present with typical dementia of the Alzheimer's type (DAT). However, little is known about the frequency or distribution of microbleeds in subjects with AD that present with atypical clinical presentations., Objective: To determine whether the frequency and regional distribution of microbleeds in atypical AD differs from that observed in subjects with DAT, and to determine whether microbleeds in atypical AD are associated with age, demographics, or cognitive impairment., Methods: Fifty-five subjects with amyloid-β deposition on Pittsburgh compound B (PiB) PET who presented with predominant language (n = 37) or visuospatial/perceptual (n = 18) deficits underwent T2*weighted MRI. These subjects were compared to 41 PiB-positive subjects with DAT. Microbleeds were identified and assigned a lobar location., Results: The proportion of subjects with microbleeds did not differ between atypical AD (42%) and DAT (32%). However, atypical AD had larger numbers of microbleeds than DAT. In addition, the topographic distribution of microbleeds differed between atypical AD and DAT, with atypical AD showing the highest density of microbleeds in the frontal lobes. Among atypical AD, number of microbleeds was associated with age, but not gender or cognition. Microbleeds were more common in subjects with language (51%) versus visuospatial/perceptual deficits (22%)., Conclusions: Microbleeds are relatively common in both DAT and atypical AD, although atypical AD subjects appear to be at particular risk for developing large numbers of microbleeds and for developing microbleeds in the frontal lobe.

The Alzheimer's Disease Neuroimaging Initiative recently implemented accelerated T1-weighted structural imaging to reduce scan times. Faster scans may reduce study costs and patient attrition by accommodating people who cannot tolerate long scan sessions. However, little is known about how scan acceleration affects the power to detect longitudinal brain change. Using tensor-based morphometry, no significant difference was detected in numerical summaries of atrophy rates from accelerated and nonaccelerated scans in subgroups of patients with Alzheimer's disease, early or late mild cognitive impairment, or healthy controls over a 6- and 12-month scan interval. Whole-brain voxelwise mapping analyses revealed some apparent regional differences in 6-month atrophy rates when comparing all subjects irrespective of diagnosis (n = 345). No such whole-brain difference was detected for the 12-month scan interval (n = 156). Effect sizes for structural brain changes were not detectably different in accelerated versus nonaccelerated data. Scan acceleration may influence brain measures but has minimal effects on tensor-based morphometry-derived atrophy measures, at least over the 6- and 12-month intervals examined here., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Proton magnetic resonance spectroscopy ((1)H-MRS) is sensitive to early neurodegenerative processes associated with Alzheimer's disease (AD). Although (1)H-MRS metabolite ratios of N-acetyl aspartate (NAA)/creatine (Cr), NAA/myoinositol (mI), and mI/Cr measured in the posterior cingulate gyrus reveal evidence of disease progression in AD, pathologic underpinnings of the (1)H-MRS metabolite changes in AD are unknown. Pathologically diagnosed human cases ranging from no likelihood to high likelihood AD (n = 41, 16 females and 25 males) who underwent antemortem (1)H-MRS of the posterior cingulate gyrus at 3 tesla were included in this study. Immunohistochemical evaluation was performed on the posterior cingulate gyrus using antibodies to synaptic vesicles, hyperphosphorylated tau (pTau), neurofibrillary tangle conformational-epitope (cNFT), amyloid-β, astrocytes, and microglia. The slides were digitally analyzed using Aperio software, which allows neuropathologic quantification in the posterior cingulate gray matter. MRS and pathology associations were adjusted for time from scan to death. Significant associations across AD and control subjects were found between reduced synaptic immunoreactivity and both NAA/Cr and NAA/mI in the posterior cingulate gyrus. Higher pTau burden was associated with lower NAA/Cr and NAA/mI. Higher amyloid-β burden was associated with elevated mI/Cr and lower NAA/mI ratios, but not with NAA/Cr. (1)H-MRS metabolite levels reveal early neurodegenerative changes associated with AD pathology. Our findings support the hypothesis that a decrease in NAA/Cr is associated with loss of synapses and early pTau pathology, but not with amyloid-β or later accumulation of cNFT pathology in the posterior cingulate gyrus. In addition, elevation of mI/Cr is associated with the occurrence of amyloid-β plaques in AD., (Copyright © 2014 the authors 0270-6474/14/3416247-09$15.00/0.)

Tract-Based Spatial Statistics (TBSS) is a popular software pipeline to coregister sets of diffusion tensor Fractional Anisotropy (FA) images for performing voxel-wise comparisons. It is primarily defined by its skeleton projection step intended to reduce effects of local misregistration. A white matter "skeleton" is computed by morphological thinning of the inter-subject mean FA, and then all voxels are projected to the nearest location on this skeleton. Here we investigate several enhancements to the TBSS pipeline based on recent advances in registration for other modalities, principally based on groupwise registration with the ANTS-SyN algorithm. We validate these enhancements using simulation experiments with synthetically-modified images. When used with these enhancements, we discover that TBSS's skeleton projection step actually reduces algorithm accuracy, as the improved registration leaves fewer errors to warrant correction, and the effects of this projection's compromises become stronger than those of its benefits. In our experiments, our proposed pipeline without skeleton projection is more sensitive for detecting true changes and has greater specificity in resisting false positives from misregistration. We also present comparative results of the proposed and traditional methods, both with and without the skeleton projection step, on three real-life datasets: two comparing differing populations of Alzheimer's disease patients to matched controls, and one comparing progressive supranuclear palsy patients to matched controls. The proposed pipeline produces more plausible results according to each disease's pathophysiology., (Copyright © 2014. Published by Elsevier Inc.)

Objective: To determine antemortem MRI findings associated with microinfarcts at autopsy., Methods: Patients with microinfarcts (n = 22) and patients without microinfarcts (n = 44) who underwent antemortem MRI were identified from a dementia clinic-based, population-based, and community clinic-based autopsy cohort. The microinfarct and no-microinfarct groups were matched on age at MRI, age at death, sex, APOE status, Mini-Mental State Examination score, and pathologic diagnosis of Alzheimer disease. Brain infarcts were assessed on fluid-attenuated inversion recovery (FLAIR) MRI. White matter hyperintensities on FLAIR MRI and hippocampal volumes on T1-weighted MRI were quantified using automated methods. A subset of subjects with microinfarcts (n = 15) and a matched group of subjects without microinfarcts (n = 15) had serial T1-weighted MRIs and were included in an analysis of global and regional brain atrophy rates using automated methods., Results: The presence of cortical (p = 0.03) and subcortical (p = 0.02) infarcts on antemortem MRI was associated with presence of microinfarcts at autopsy. Higher numbers of cortical (p = 0.05) and subcortical (p = 0.03) infarcts on antemortem MRI were also associated with presence of microinfarcts. Presence of microinfarcts was not associated with white matter hyperintensities and cross-sectional hippocampal volume on antemortem MRI. Whole-brain and regional precuneus, motor, and somatosensory atrophy rates were higher in subjects with microinfarcts compared to subjects without microinfarcts., Conclusions: Microinfarcts increase brain atrophy rates independent of Alzheimer disease pathology. Association between microinfarct pathology and macroinfarcts on MRI suggests either common risk factors or a shared pathophysiology and potentially common preventive targets., (© 2014 American Academy of Neurology.)

Objective: To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample., Methods: A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A-) and baseline hippocampal volume (N+ or N-). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups., Results: At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A-N-), 29 (12%) amyloid negative and neurodegeneration positive (A-N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N-), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+., Conclusions: We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging-Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.

Background: Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid-modifying trials for treatment and prevention of Alzheimer's disease (AD)., Methods: Subjects were cognitively normal (n = 171), early-mild cognitive impairment (MCI) (n = 240), late-MCI (n = 111), and AD (n = 40) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6, and 12 months. β-amyloid load was assessed with (18)F-florbetapir positron emission tomography., Results: Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (P < .001) and β-amyloid load (P < .001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation = 0.49; P < .001)., Conclusions: Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with β-amyloid load., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T1-weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising screening visits, 1-year completers (subjects who all have screening, 6- and 12-month scans), 2-year annual completers (screening, 1-year and 2-year scans), 2-year completers (screening, 6-months, 1-year, 18-months [mild cognitive impaired (MCI) only], and 2-year scans), and complete visits (screening, 6-month, 1-year, 18-month [MCI only], 2-year, and 3-year [normal and MCI only] scans). As the ADNI-GO/ADNI-2 data become available, updated standard analysis sets will be posted regularly., (Copyright © 2013 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objectives: The logopenic variant of primary progressive aphasia is an atypical clinical variant of Alzheimer's disease which is typically characterized by left temporoparietal atrophy on magnetic resonance imaging and hypometabolism on F-18 fluorodeoxyglucose positron emission tomography. We aimed to characterize and compare patterns of atrophy and hypometabolism in logopenic primary progressive aphasia, and determine which brain regions and imaging modality best differentiates logopenic primary progressive aphasia from typical dementia of the Alzheimer's type., Methods: A total of 27 logopenic primary progressive aphasia subjects underwent fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging. These subjects were matched to 27 controls and 27 subjects with dementia of the Alzheimer's type. Patterns of atrophy and hypometabolism were assessed at the voxel and region-level using Statistical Parametric Mapping. Penalized logistic regression analysis was used to determine what combinations of regions best discriminate between groups., Results: Atrophy and hypometabolism was observed in lateral temporoparietal and medial parietal lobes, left greater than right, and left frontal lobe in the logopenic group. The logopenic group showed greater left inferior, middle and superior lateral temporal atrophy (inferior p = 0.02; middle p = 0.007, superior p = 0.002) and hypometabolism (inferior p = 0.006, middle p = 0.002, superior p = 0.001), and less right medial temporal atrophy (p = 0.02) and hypometabolism (p<0.001), and right posterior cingulate hypometabolism (p<0.001) than dementia of the Alzheimer's type. An age-adjusted penalized logistic model incorporating atrophy and hypometabolism achieved excellent discrimination (area under the receiver operator characteristic curve = 0.89) between logopenic and dementia of the Alzheimer's type subjects, with optimal discrimination achieved using right medial temporal and posterior cingulate hypometabolism, left inferior, middle and superior temporal hypometabolism, and left superior temporal volume., Conclusions: Patterns of atrophy and hypometabolism both differ between logopenic primary progressive aphasia and dementia of the Alzheimer's type and both modalities provide excellent discrimination between groups.

Objective: To model the temporal trajectory of β-amyloid accumulation using serial amyloid PET imaging., Methods: Participants, aged 70-92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimer's Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association., Results: Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined-reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5-2.5 is approximately 15 years., Conclusion: This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions.

Objective: A study was undertaken to investigate the association of intellectual and physical activity with biomarkers of Alzheimer disease (AD) pathophysiology and cognition in a nondemented elderly population. The biomarkers evaluated were brain Aβ load via Pittsburgh compound B (PiB)-positron emission tomography (PET), neuronal dysfunction via (18) F-fluorodeoxyglucose (FDG)-PET, and neurodegeneration via structural magnetic resonance imaging (MRI)., Methods: We studied 515 nondemented (428 cognitively normal and 87 mild cognitive impairment) participants in the population-based Mayo Clinic Study of Aging who completed a 3T MRI, PET scans, and APOE genotype, and had lifestyle activity measures and cognition data available. The imaging measures computed were global PiB-PET uptake, and global FDG-PET and MRI based hippocampal volume. We consolidated activity variables into lifetime intellectual, current intellectual, and current physical activities. We used a global cognitive z score as a measure of cognition. We applied 2 independent methods-partial correlation analysis adjusted for age and gender and path analysis using structural equations-to evaluate the associations between lifestyle activities, imaging biomarkers, and global cognition., Results: None of the lifestyle variables were correlated with the biomarkers, and the path associations between lifestyle variables and biomarkers were not significant (p > 0.05). Conversely, all the biomarkers were correlated with global cognitive z score (p < 0.05), and the path associations between (lifetime and current) intellectual activities and global z score were significant (p < 0.01)., Interpretation: Intellectual and physical activity lifestyle factors were not associated with AD biomarkers, but intellectual lifestyle factors explained variability in the cognitive performance in this nondemented population. This study provides evidence that lifestyle activities may delay the onset of dementia but do not significantly influence the expression of AD pathophysiology., (Copyright © 2012 American Neurological Association.)

Objective: To characterize the shape of the trajectories of Alzheimer disease biomarkers as a function of Mini-Mental State Examination (MMSE) score., Design and Setting: Longitudinal registries from the Mayo Clinic and the Alzheimer's Disease Neuroimaging Initiative., Patients: Two different samples (n = 343 and n = 598) were created that spanned the cognitive spectrum from normal to Alzheimer disease 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 score, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebrospinal fluid (CSF) Aβ42 and tau levels, amyloid and fluorodeoxyglucose positron emission tomography imaging, and structural magnetic resonance imaging., Results: Baseline biomarker values generally worsened (ie, nonzero slope) with lower baseline MMSE score. Baseline hippocampal volume, amyloid positron emission tomography, and fluorodeoxyglucose positron emission tomography values plateaued (ie, nonlinear slope) with lower MMSE score in 1 or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE score. Nonconstant within-subject rates (deceleration) of biomarker change were found in only 1 model., Conclusions: Biomarker trajectory shapes by MMSE score were complex and were affected by interactions with age and APOE status. Nonlinearity was found in several baseline effects models. Nonconstant within-subject rates of biomarker change were found in only 1 model, likely owing to limited within-subject longitudinal follow-up. Creating reliable models that describe the full trajectories of Alzheimer disease biomarkers will require significant additional longitudinal data in individual participants.

Objective: A workgroup commissioned by the Alzheimer's Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer disease (AD). We performed a preliminary assessment of these guidelines., Methods: We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis, and (18) fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cutpoints. A group of 450 cognitively normal (CN) subjects from a population-based sample was used to develop cognitive cutpoints and to assess population frequencies of the different preclinical AD stages using different cutpoint criteria., Results: The new criteria subdivide the preclinical phase of AD into stages 1 to 3. To classify our CN subjects, 2 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 cutpoints 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., Interpretation: 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 only 3% unclassified. Future longitudinal validation of the criteria will be important., (Copyright © 2012 American Neurological Association.)

The common neurodegenerative pathologies underlying dementia are Alzheimer's disease (AD), Lewy body disease (LBD) and frontotemporal lobar degeneration (FTLD). Our aim was to identify patterns of atrophy unique to each of these diseases using antemortem structural MRI scans of pathologically confirmed dementia cases and build an MRI-based differential diagnosis system. Our approach of creating atrophy maps using structural MRI and applying them for classification of new incoming patients is labeled Differential-STAND (Differential Diagnosis Based on Structural Abnormality in Neurodegeneration). Pathologically confirmed subjects with a single dementing pathologic diagnosis who had an MRI at the time of clinical diagnosis of dementia were identified: 48 AD, 20 LBD, 47 FTLD-TDP (pathology-confirmed FTLD with TDP-43). Gray matter density in 91 regions-of-interest was measured in each subject and adjusted for head size and age using a database of 120 cognitively normal elderly. The atrophy patterns in each dementia type when compared to pathologically confirmed controls mirrored known disease-specific anatomic patterns: AD-temporoparietal association cortices and medial temporal lobe; FTLD-TDP-frontal and temporal lobes and LBD-bilateral amygdalae, dorsal midbrain and inferior temporal lobes. Differential-STAND based classification of each case was done based on a mixture model generated using bisecting k-means clustering of the information from the MRI scans. Leave-one-out classification showed reasonable performance compared to the autopsy gold standard and clinical diagnosis: AD (sensitivity: 90.7%; specificity: 84%), LBD (sensitivity: 78.6%; specificity: 98.8%) and FTLD-TDP (sensitivity: 84.4%; specificity: 93.8%). The proposed approach establishes a direct a priori relationship between specific topographic patterns on MRI and "gold standard" of pathology which can then be used to predict underlying dementia pathology in new incoming patients., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer's dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were 'amyloid positive' (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were 'amyloid negative' (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan-Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer's disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer's disease co-existent with other pathologies.

Functions of the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) core fall into three categories: (1) those of the central MRI core laboratory at Mayo Clinic, Rochester, Minnesota, needed to generate high quality MRI data in all subjects at each time point; (2) those of the funded ADNI MRI core imaging analysis groups responsible for analyzing the MRI data; and (3) the joint function of the entire MRI core in designing and problem solving MR image acquisition, pre-processing, and analyses methods. The primary objective of ADNI was and continues to be improving methods for clinical trials in Alzheimer's disease. Our approach to the present ("ADNI-GO") and future ("ADNI-2," if funded) MRI protocol will be to maintain MRI methodological consistency in the previously enrolled "ADNI-1" subjects who are followed up longitudinally in ADNI-GO and ADNI-2. We will modernize and expand the MRI protocol for all newly enrolled ADNI-GO and ADNI-2 subjects. All newly enrolled subjects will be scanned at 3T with a core set of three sequence types: 3D T1-weighted volume, FLAIR, and a long TE gradient echo volumetric acquisition for micro hemorrhage detection. In addition to this core ADNI-GO and ADNI-2 protocol, we will perform vendor-specific pilot sub-studies of arterial spin-labeling perfusion, resting state functional connectivity, and diffusion tensor imaging. One of these sequences will be added to the core protocol on systems from each MRI vendor. These experimental sub-studies are designed to demonstrate the feasibility of acquiring useful data in a multicenter (but single vendor) setting for these three emerging MRI applications., (Copyright 2010 The Alzheimer)

Rates of brain atrophy derived from serial magnetic resonance (MR) studies may be used to assess therapies for Alzheimer's disease (AD). These measures may be confounded by changes in scanner voxel sizes. For this reason, the Alzheimer's Disease Neuroimaging Initiative (ADNI) included the imaging of a geometric phantom with every scan. This study compares voxel scaling correction using a phantom with correction using a 9 degrees of freedom (9DOF) registration algorithm. We took 129 pairs of baseline and 1-year repeat scans, and calculated the volume scaling correction, previously measured using the phantom. We used the registration algorithm to quantify any residual scaling errors, and found the algorithm to be unbiased, with no significant (p=0.97) difference between control (n=79) and AD subjects (n=50), but with a mean (SD) absolute volume change of 0.20 (0.20) % due to linear scalings. 9DOF registration was shown to be comparable to geometric phantom correction in terms of the effect on atrophy measurement and unbiased with respect to disease status. These results suggest that the additional expense and logistic effort of scanning a phantom with every patient scan can be avoided by registration-based scaling correction. Furthermore, based upon the atrophy rates in the AD subjects in this study, sample size requirements would be approximately 10-12% lower with (either) correction for voxel scaling than if no correction was used.