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Ann D. Cohen

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YNIMG Journal 2021 Journal Article

A multi-scanner neuroimaging data harmonization using RAVEL and ComBat

  • Mahbaneh Eshaghzadeh Torbati
  • Davneet S. Minhas
  • Ghasan Ahmad
  • Erin E. O’Connor
  • John Muschelli
  • Charles M. Laymon
  • Zixi Yang
  • Ann D. Cohen

Modern neuroimaging studies frequently combine data collected from multiple scanners and experimental conditions. Such data often contain substantial technical variability associated with image intensity scale (image intensity scales are not the same in different images) and scanner effects (images obtained from different scanners contain substantial technical biases). Here we evaluate and compare results of data analysis methods without any data transformation (RAW), with intensity normalization using RAVEL, with regional harmonization methods using ComBat, and a combination of RAVEL and ComBat. Methods are evaluated on a unique sample of 16 study participants who were scanned on both 1.5T and 3T scanners a few months apart. Neuroradiological evaluation was conducted for 7 different regions of interest (ROI's) pertinent to Alzheimer's disease (AD). Cortical measures and results indicate that: (1) RAVEL substantially improved the reproducibility of image intensities; (2) ComBat is preferred over RAVEL and the RAVEL-ComBat combination in terms of regional level harmonization due to more consistent harmonization across subjects and image-derived measures; (3) RAVEL and ComBat substantially reduced bias compared to analysis of RAW images, but RAVEL also resulted in larger variance; and (4) the larger root mean square deviation (RMSD) of RAVEL compared to ComBat is due mainly to its larger variance.

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YNICL Journal 2021 Journal Article

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome

  • Matthew D. Zammit
  • Dana L. Tudorascu
  • Charles M. Laymon
  • Sigan L. Hartley
  • Paul A. Ellison
  • Shahid H. Zaman
  • Beau M. Ances
  • Sterling C. Johnson

INTRODUCTION: Adults with Down syndrome are genetically predisposed to develop Alzheimer's disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. METHODS: ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aβ burden compared to the A- group, but not high enough to satisfy a conventional A + classification. RESULTS: and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). DISCUSSION: These results show that even the earliest detectable Aβ accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer's disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aβ accumulation begins to prevent the downstream cascade of events that leads to Alzheimer's disease.

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YNIMG Journal 2021 Journal Article

PET measurement of longitudinal amyloid load identifies the earliest stages of amyloid-beta accumulation during Alzheimer's disease progression in Down syndrome

  • Matthew D. Zammit
  • Dana L. Tudorascu
  • Charles M. Laymon
  • Sigan L. Hartley
  • Shahid H. Zaman
  • Beau M. Ances
  • Sterling C. Johnson
  • Charles K. Stone

INTRODUCTION: Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aβ) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aβ throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aβ to better characterize the natural history of Aβ accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. METHODS: ) which would have resulted in an Aβ-converter classification. With knowledge of trajectories of Aβ(-) accumulators, a new cutoff of Aβ(+) was derived to better identify subthreshold Aβ accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aβ change with 80% power (alpha 0.01) were determined for different groups of Aβ-status. RESULTS: . The estimated sample size necessary to detect a 25% reduction in Aβ was 79 for Aβ(-) accumulators and 59 for the Aβ-converter/Aβ(+) group in DS. CONCLUSION: changes were capable of distinguishing Aβ accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aβ accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aβ deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.

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YNICL Journal 2015 Journal Article

Comparison of qualitative and quantitative imaging characteristics of [11C]PiB and [18F]flutemetamol in normal control and Alzheimer's subjects

  • James M. Mountz
  • Charles M. Laymon
  • Ann D. Cohen
  • Zheng Zhang
  • Julie C. Price
  • Sanaa Boudhar
  • Eric McDade
  • Howard J. Aizenstein

INTRODUCTION: Neuritic amyloid plaques and neurofibrillary tangles, the hallmark pathologic lesions of Alzheimer's disease, are thought to develop before the symptoms of brain failure are clinically detectable. Imaging methods capable of detecting the presence of neuritic amyloid plaques should improve a clinician's ability to identify Alzheimer's disease during the earliest symptomatic phase and to identify at-risk individuals presymptomatically. Currently the best studied amyloid imaging ligand is [(11)C]Pittsburgh Compound B ([(11)C]PiB). However, the 20-minute half-life of this radiotracer limits its use. This study is designed to evaluate the performance characteristics of [(18)F]flutemetamol and to independently compare results to [(11)C]PiB in the same subjects. METHODS: Twenty-three subjects, 15 cognitively normal (NL) and 8 with a clinical diagnosis of Alzheimer's Dementia (AD), underwent [(11)C]PiB and [(18)F]flutemetamol PET scans within 28 days of study enrollment. We studied both normal and AD subjects to assess the uptake characteristics across a range of amyloid positivity. Blinded visual reads were conducted by five raters. Correlation analyses were performed between cortical SUVR for the two tracers and also between rater scores and SUVR for each tracer. Overall reader accuracy for classifying scans as amyloid positive or negative was determined for each tracer using SUVR classification as the standard. RESULTS: The linear correlation coefficient between global cortical SUVR for the two tracers was R(2) = 0.85, indicating that both tracers have similar retention characteristics. The two tracers were well correlated for rater-determined AD-like positivity (Cohen κ = 0.82). Averaged visual ratings and global cortical SUVR disagreed on their classification in 2/23 [(11)C]PiB scans and 4/23 [(18)F]flutemetamol scans. CONCLUSIONS: [(11)C]PiB and [(18)F]flutemetamol have similar retention characteristics across a range of amyloid negative to positive subjects. Both tracers performed similarly when a standardized visual read technique was used to classify scans as amyloid-positive or amyloid-negative and correlated well with SUVR classifications. However, care in visual interpretation of amyloid positive versus amyloid negative regions should be taken, particularly in the case of [(18)F]flutemetamol when considering cortical vs. white-matter retention.

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YNIMG Journal 2013 Journal Article

Classification of amyloid-positivity in controls: Comparison of visual read and quantitative approaches

  • Ann D. Cohen
  • Wenzhu Mowrey
  • Lisa A. Weissfeld
  • Howard J. Aizenstein
  • Eric McDade
  • James M. Mountz
  • Robert D. Nebes
  • Judith A. Saxton

An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aβ) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aβ deposition from those in which Aβ deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(−)] subjects. Methods We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(−) subjects was not so distinct. Results The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence. Conclusion The visual read and SKM methods, applied together, may optimize the identification of early Aβ deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.

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v2026.09.13