William E. Klunk

YNICL Journal 2022 Journal Article

White matter microstructure associations to amyloid burden in adults with Down syndrome

• Austin M. Bazydlo
• Matthew D. Zammit
• Minjie Wu
• Patrick J. Lao
• Douglas C. Dean
• Sterling C. Johnson
• Dana L. Tudorascu
• Ann Cohen

INTRODUCTION: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer's Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS. METHODS: and DTI measures were compared using tract-based spatial statistics (TBSS) and corrected for imaging site and chronological age. RESULTS: TBSS of the DTI maps showed widespread age-by-amyloid interaction with both fractional anisotropy (FA) and mean diffusivity (MD). Further, diffuse negative association of FA and positive association of MD with amyloid were observed. DISCUSSION: These findings are consistent with the white matter microstructural changes associated with AD disease progression in late onset AD in non-DS populations.

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.

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.

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.

YNICL Journal 2018 Journal Article

Impact of partial volume correction on the regional correspondence between in vivo [C-11]PiB PET and postmortem measures of Aβ load

• Davneet S. Minhas
• Julie C. Price
• Charles M. Laymon
• Carl R. Becker
• William E. Klunk
• Dana L. Tudorascu
• Eric E. Abrahamson
• Ronald L. Hamilton

The positron emission tomography (PET) radiotracer Pittsburgh Compound B ([C-11]PiB) demonstrates a high affinity for fibrillary amyloid-beta (Aβ) aggregates. However, [C-11]PiB's in vivo sensitivity and specificity is an ongoing area of investigation in correlation studies with postmortem measures of Aβ pathology. One potential confound in PET-to-postmortem correlation studies is the limited spatial resolution of PET and resulting partial volume effects (PVEs). In this work, we evaluated the impact of three partial volume correction (PVC) techniques – the Meltzer, the modified Müller-Gärtner, and the Region-Based Voxel-Wise – on correlations between region-matched in vivo [C-11]PiB standardized uptake value ratios (SUVRs) and postmortem measures of Aβ pathology in a unique cohort of nine subjects. Postmortem Aβ pathology was assessed histologically as percent area coverage of 6-CN-PiB positive and Aβ immunoreactive (4G8 antibody) deposits. The application of all three PVC techniques resulted in minimally reduced PET-to-postmortem correlations relative to no PVC. However, correlations to both 6-CN-PiB and 4G8 percent area across all PVC techniques and no PVC were statistically significant at p < 0. 01, suggesting that PVC is of minimal importance in understanding the relationship between Aβ PET and neuropathologically assessed Aβ. Thus, the utility of PVC in Aβ PET imaging should continue to be examined on an application-specific basis.

YNICL Journal 2018 Journal Article

Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies

• Yi Su
• Shaney Flores
• Russ C. Hornbeck
• Benjamin Speidel
• Andrei G. Vlassenko
• Brian A. Gordon
• Robert A. Koeppe
• William E. Klunk

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. Successful use of this tool is limited by the lack of a common standard in the quantification of amyloid imaging data. The Centiloid approach was recently proposed to address this problem and in this work, we report our implementation of this approach and evaluate the impact of differences in underlying image analysis methodologies using both cross-sectional and longitudinal datasets. The Centiloid approach successfully converts quantitative amyloid burden measurements into a common Centiloid scale (CL) and comparable dynamic range. As expected, the Centiloid values derived from different analytical approaches inherit some of the inherent benefits and drawbacks of the underlying approaches, and these differences result in statistically significant (p < 0. 05) differences in the variability and group mean values. Because of these differences, even after expression in CL, the 95% specificity amyloid positivity thresholds derived from different analytic approaches varied from 5. 7 CL to 11. 9 CL, and the reliable worsening threshold varied from −2. 0 CL to 11. 0 CL. Although this difference is in part due to the dependency of the threshold determination methodology on the statistical characteristics of the measurements. When amyloid measurements obtained from different centers are combined for analysis, one should not expect Centiloid conversion to eliminate all the differences in amyloid burden measurements due to variabilities in underlying acquisition protocols and analysis techniques.

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.

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.

YNIMG Journal 2011 Journal Article

Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET

• Bedda L. Rosario
• Lisa A. Weissfeld
• Charles M. Laymon
• Chester A. Mathis
• William E. Klunk
• Michael D. Berginc
• Jeffrey A. James
• Jessica A. Hoge

A major challenge in positron emission tomography (PET) amyloid imaging studies of Alzheimer's disease (AD) is the reliable detection of early amyloid deposition in human brain. Manual region-of-interest (ROI) delineation on structural magnetic resonance (MR) images is generally the reference standard for the extraction of count-rate data from PET images, as compared to automated MR-template(s) methods that utilize spatial normalization and a single set of ROIs. The goal of this work was to assess the inter-rater reliability of manual ROI delineation for PiB PET amyloid retention measures and the impact of CSF dilution correction (CSF) on this reliability for data acquired in elderly control (n=5) and AD (n=5) subjects. The intraclass correlation coefficient (ICC) was used to measure reliability. As a secondary goal, ICC scores were also computed for PiB outcome measures obtained by an automated MR-template ROI method and one manual rater; to assess the level of reliability that could be achieved using different processing methods. Fourteen ROIs were evaluated that included anterior cingulate (ACG), precuneus (PRC) and cerebellum (CER). The PiB outcome measures were the volume of distribution (VT), summed tissue uptake (SUV), and corresponding ratios that were computed using CER as reference (DVR and SUVR). Substantial reliability (ICC≥0. 932) was obtained across 3 manual raters for VT and SUV measures when CSF correction was applied across all outcomes and regions and was similar in the absence of CSF correction. The secondary analysis revealed substantial reliability in primary cortical areas between the automated and manual SUV [ICC≥0. 979 (ACG/PRC)] and SUVR [ICC≥0. 977/0. 952 (ACG/PRC)] outcomes. The current study indicates the following rank order among the various reliability results in primary cortical areas and cerebellum (high to low): 1) VT or SUV manual delineation, with or without CSF correction; 2) DVR or SUVR manual delineation, with or without CSF correction; 3) SUV automated delineation, with CSF correction; and 4) SUVR automated delineation, with or without CSF correction. The high inter-rater reliability of PiB outcome measures in primary cortical areas (ACG/PRC) is important as reliable methodology is needed for the detection of low levels of amyloid deposition on a cross-sectional basis and small changes in amyloid deposition on a longitudinal basis.

YNIMG Journal 2010 Journal Article

A multivariate approach for mapping longitudinal changes in amyloid deposition

• Bedda L. Rosario
• Lisa A. Weissfeld
• Charles M. Laymon
• Ann D. Cohen
• Jeffrey A. James
• William E. Klunk
• Chester A. Mathis
• Julie C. Price

YNIMG Journal 2010 Journal Article

Comparative evaluation of template-based region sampling for PiB PET data analysis

• Charles M. Laymon
• Bedda L. Rosario
• Andrew Redfield
• Michael Berginc
• William E. Klunk
• Chester A. Mathis
• Julie C. Price

YNIMG Journal 2010 Journal Article

Statistical modeling of longitudinal PiB retention

• Julie C. Price
• Lisa A. Weissfeld
• Chester A. Mathis
• Bedda L. Rosario
• Ann D. Cohen
• Judith A. Saxton
• Beth E. Snitz
• Michael Berginc

YNIMG Journal 2008 Journal Article

Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer’s disease

• Alexander Drzezga
• Timo Grimmer
• Gjermund Henriksen
• Isabelle Stangier
• Robert Perneczky
• Janine Diehl-Schmid
• Chester A. Mathis
• William E. Klunk

Semantic dementia (SD) is a rare clinical syndrome, assigned to the group of frontotemporal lobar degenerations (FTLD). Histopathological analysis has not revealed the deposition of amyloid plaques in the majority of SD cases, in contrast to dementia of the Alzheimer type (AD). However, based on clinical examination alone a reliable differentiation of the underlying pathology cannot be guaranteed, i. e. AD and SD may be confused in some cases. Our aim was to determine, whether AD and SD can be differentiated in vivo by means of amyloid plaque PET imaging. In groups of AD and SD patients, matched for gender, age and overall degree of cognitive impairment, cerebral glucose metabolism was examined with [18F]Fluorodeoxyglucose (FDG)-PET and cerebral amyloid plaque density was assessed using [11C]6-OH-BTA-1 (PIB)-PET. A volume-of-interest analysis (VOI), using the cerebellum as a reference region, and voxel-based statistical group comparisons (SPM2) were carried out between the patient groups and matched groups of healthy controls. To control for a potential influence of atrophy on the PET findings, a correction of partial volume effects was performed. Characteristic patterns of hypometabolism could be demonstrated in both clinically defined AD and SD with some regional overlap and subtle differences (AD: bilateral posterior cingulate, temporoparietal and frontal cortex; SD: left>right polar temporal, frontal mesial cortex). Compared with healthy controls, significant [11C]PIB amyloid plaque tracer binding was observed only in patients with AD (in bilateral temporoparietal, frontal and posterior cingulate cortex and the precuneus) but not in SD. This difference in amyloid plaque deposition could be reproduced in direct statistical comparison of AD and SD and clearly extended the metabolic differences between the patient groups. These findings support the notion that SD can be diagnosed in vivo as a separate entity from AD using amyloid plaque imaging. In general, amyloid plaque PET may complement neuropsychological assessment regarding reliable differential diagnosis of AD and FTLD dementias based on characterization of underlying pathology and may improve the definition of individual prognosis and the selection of patients for scientific trials.

YNIMG Journal 2007 Journal Article

Using a reference tissue model with spatial constraint to quantify [11C]Pittsburgh compound B PET for early diagnosis of Alzheimer's disease

• Yun Zhou
• Susan M. Resnick
• Weiguo Ye
• Hong Fan
• Daniel P. Holt
• William E. Klunk
• Chester A. Mathis
• Robert Dannals

Introduction: Reference tissue model (RTM) is a compartmental modeling approach that uses reference tissue time activity curve (TAC) as input for quantification of ligand–receptor dynamic PET without blood sampling. There are limitations in applying the RTM for kinetic analysis of PET studies using [11C]Pittsburgh compound B ([11C]PIB). For region of interest (ROI) based kinetic modeling, the low specific binding of [11C]PIB in a target ROI can result in a high linear relationship between the output and input. This condition may result in amplification of errors in estimates using RTM. For pixel-wise quantification, due to the high noise level of pixel kinetics, the parametric images generated by RTM with conventional linear or nonlinear regression may be too noisy for use in clinical studies. Methods: We applied RTM with parameter coupling and a simultaneous fitting method as a spatial constraint for ROI kinetic analysis. Three RTMs with parameter coupling were derived from a classical compartment model with plasma input: an RTM of 4 parameters (R 1, k′2R, k 4, BP) (RTM4P); an RTM of 5 parameters (R 1, k 2R, NS, k 6, BP) (RTM5P); and a simplified RTM (SRTM) of 3 parameters (R 1, k′2R, BP) (RTM3P). The parameter sets [k′2R, k 4], [k 2R, NS, k 6], and k′2R are coupled among ROIs for RTM4P, RTM5P, and RTM3P, respectively. A linear regression with spatial constraint (LRSC) algorithm was applied to the SRTM for parametric imaging. Logan plots were used to estimate the distribution volume ratio (DVR) (=1+BP (binding potential)) in ROI and pixel levels. Ninety-minute [11C]PIB dynamic PET was performed in 28 controls and 6 individuals with mild cognitive impairment (MCI) on a GE Advance scanner. ROIs of cerebellum (reference tissue) and 15 other regions were defined on coregistered MRIs. Results: The coefficients of variation of DVR estimates from RTM3P obtained by the simultaneous fitting method were lower by 77–89% (in striatum, frontal, occipital, parietal, and cingulate cortex) as compared to that by conventional single ROI TAC fitting method. There were no significant differences in both TAC fitting and DVR estimates between the RTM3P and the RTM4P or RTM5P. The DVR in striatum, lateral temporal, frontal and cingulate cortex for MCI group was 25% to 38% higher compared to the control group (p ≤0. 05), even in this group of individuals with generally low PIB retention. The DVR images generated by the SRTM with LRSC algorithm had high linear correlations with those from the Logan plot (R 2 =0. 99). Conclusion: In conclusion, the RTM3P with simultaneous fitting method is shown to be a robust compartmental modeling approach that may be useful in [11C]PIB PET studies to detect early markers of Alzheimer's disease where specific ROIs have been hypothesized. In addition, the SRTM with LRSC algorithm may be useful in generating R 1 and DVR images for pixel-wise quantification of [11C]PIB dynamic PET.

YNIMG Journal 2006 Journal Article

Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease

• Scott K. Ziolko
• Lisa A. Weissfeld
• William E. Klunk
• Chester A. Mathis
• Jessica A. Hoge
• Brian J. Lopresti
• Steven T. DeKosky
• Julie C. Price

Deposition of amyloid plaques is believed to be a central event in the development of Alzheimer's disease (AD). The present study was undertaken to evaluate statistical methods for the assessment of group differences in retention of an amyloid imaging agent, PIB, throughout the brain and to compare these results to FDG studies of glucose metabolism performed in the same subjects on the same day. PET studies were performed in 10 mild to moderate AD and 11 control subjects. Parametric images of PIB retention (over 90 min post-injection) were generated using the Logan graphical analysis with cerebellar (CER, reference region) data as input. FDG parametric images were created by summing the uptake over 40–60 min post-injection and normalizing that to the CER to give a standardized uptake value ratio. Data were compared using parametric (SPM) and non-parametric (SnPM) statistical methods with familywise error (FWE) and false discovery rate (FDR) corrections. PIB results were consistent with previous regional results as AD subjects showed highly significant retention in frontal, parietal, temporal, and posterior cingulate cortices (FDR-corrected p <1. 4e−10). FDG results showed regions of marginally significant decreases in uptake in AD subjects (frontal, parietal, temporal, posterior cingulate cortices: FDR-corrected p <0. 1) consistent with previous studies. Relative to FDG, the PIB analyses were of greater statistical significance and larger spatial extent. Additionally, the PIB analyses retained significance after both FWE and FDR corrections. These results indicate that voxel-based methods will be useful for future larger longitudinal studies of amyloid deposition that could improve AD diagnosis and anti-amyloid therapy assessment.