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1. Serotonin transporter density in isolated rapid eye movement sleep behavioral disorder

Author: Mark Garwood, Punithavathy Vijayakumar, Nicolaas I. Bohnen, Robert A. Koeppe, and Vikas Kotagal
Subjects: rapid eye movement sleep behavior disorder, serotonin, DASB, PET imaging, sleep, Medicine
Abstract: Background/objectiveThe serotoninergic nervous system is known to play a role in the maintenance of rapid eye movement (REM) sleep. Serotoninergic projections are known to be vulnerable in synucleinopathies. To date, positron emission tomography (PET) studies using serotonin-specific tracers have not been reported in isolated REM sleep behavior disorder (iRBD).MethodsWe conducted a cross-sectional imaging study using serotonin transporter (SERT) 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) PET to identify differences in serotonin system integrity between 11 participants with iRBD and 16 older healthy controls.ResultsParticipants with iRBD showed lower DASB distribution volume ratios (DVRs) in the total neocortical mantle [1.13 (SD: 0.07) vs. 1.19 (SD: 0.06); t = 2.33, p = 0.028)], putamen [2.07 (SD: 0.19) vs. 2.25 (SD: 0.18); t = 2.55, p = 0.017], and insula [1.26 (SD: 0.11) vs. 1.39 (SD: 0.09); t = 3.58, p = 0.001]. Paradoxical increases relative to controls were seen in cerebellar hemispheres [0.98 (SD: 0.04) vs. 0.95 (SD: 0.02); t = 2.93, p = 0.007)]. No intergroup differences were seen in caudate, substantia nigra, or other brainstem regions with the exception of the dorsal mesencephalic raphe [3.08 (SD: 0.53) vs. 3.47 (SD: 0.48); t = 2.00, p = 0.056] that showed a non-significant trend toward lower values in iRBD.ConclusionsInsular, neocortical, and striatal serotoninergic terminal loss may be common in prodromal synucleinopathies before the onset of parkinsonism or dementia. Given our small sample size, these results should be interpreted as hypothesis-generating/exploratory in nature.
Published: 2024
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2. Classifying migraine using PET compressive big data analytics of brain’s μ-opioid and D2/D3 dopamine neurotransmission

Author: Simeone Marino, Hassan Jassar, Dajung J. Kim, Manyoel Lim, Thiago D. Nascimento, Ivo D. Dinov, Robert A. Koeppe, and Alexandre F. DaSilva
Subjects: migraine disease, artificial intelligence, dopamine (raclopride), μ-opioid (carfentanil), computer-aided diagnosis, PET imaging data, Therapeutics. Pharmacology, RM1-950
Abstract: Introduction: Migraine is a common and debilitating pain disorder associated with dysfunction of the central nervous system. Advanced magnetic resonance imaging (MRI) studies have reported relevant pathophysiologic states in migraine. However, its molecular mechanistic processes are still poorly understood in vivo. This study examined migraine patients with a novel machine learning (ML) method based on their central μ-opioid and dopamine D2/D3 profiles, the most critical neurotransmitters in the brain for pain perception and its cognitive-motivational interface.Methods: We employed compressive Big Data Analytics (CBDA) to identify migraineurs and healthy controls (HC) in a large positron emission tomography (PET) dataset. 198 PET volumes were obtained from 38 migraineurs and 23 HC during rest and thermal pain challenge. 61 subjects were scanned with the selective μ-opioid receptor (μOR) radiotracer [11C]Carfentanil, and 22 with the selective dopamine D2/D3 receptor (DOR) radiotracer [11C]Raclopride. PET scans were recast into a 1D array of 510,340 voxels with spatial and intensity filtering of non-displaceable binding potential (BPND), representing the receptor availability level. We then performed data reduction and CBDA to power rank the predictive brain voxels.Results: CBDA classified migraineurs from HC with accuracy, sensitivity, and specificity above 90% for whole-brain and region-of-interest (ROI) analyses. The most predictive ROIs for μOR were the insula (anterior), thalamus (pulvinar, medial-dorsal, and ventral lateral/posterior nuclei), and the putamen. The latter, putamen (anterior), was also the most predictive for migraine regarding DOR D2/D3 BPND levels.Discussion: CBDA of endogenous μ-opioid and D2/D3 dopamine dysfunctions in the brain can accurately identify a migraine patient based on their receptor availability across key sensory, motor, and motivational processing regions. Our ML-based findings in the migraineur’s brain neurotransmission partly explain the severe impact of migraine suffering and associated neuropsychiatric comorbidities.
Published: 2023
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3. Regional serotonin terminal density in aging human brain: A [11C]DASB PET study

Author: Prabesh Kanel, Robert A. Koeppe, Vikas Kotagal, Stiven Roytman, Martijn L.T.M. Muller, Nicolaas I. Bohnen, and Roger L. Albin
Subjects: Serotonin, Serotonin transporter, Raphe, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: There are conflicting results regarding regional age-related changes in serotonin terminal density in human brain. Some imaging studies suggest age-related declines in serotoninergic terminals and perikarya. Other human imaging studies and post-mortem biochemical studies suggest stable brain regional serotoninergic terminal densities across the adult lifespan. In this cross-sectional study, we used [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile positron emission tomography to quantify brain regional serotonin transporter density in 46 normal subjects, ranging from 25 to 84 years of age. Both voxel-based analyses, using sex as a covariate, and volume-of-interest-based analyses were performed. Both analyses revealed age-related declines in [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile binding in numerous brain regions, including several neocortical regions, striatum, amygdala, thalamus, dorsal raphe, and other subcortical regions. Similar to some other neurotransmitter systems of subcortical origin, we found evidence of age-related declines in regional serotonin terminal density in both cortical and subcortical regions.
Published: 2023
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4. Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach

Author: Sarah K. Royse, Davneet S. Minhas, Brian J. Lopresti, Alice Murphy, Tyler Ward, Robert A. Koeppe, Santiago Bullich, Susan DeSanti, William J. Jagust, Susan M. Landau, and for the Alzheimer’s Disease Neuroimaging Initiative
Subjects: Centiloid, Florbetaben, Florbetapir, Amyloid imaging, Beta-amyloid, Standardization, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [18F]florbetaben (FBB) and [18F]florbetapir (FBP) data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples. Methods We analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer’s Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295). Results The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [18F]FBB: CLwhole cerebellum = 157.15 × SUVRFBB − 151.87; threshold=1.08, 18 CL [18F]FBP: CLwhole cerebellum = 188.22 × SUVRFBP − 189.16; threshold=1.11, 20 CL [18F]FBB: CLcomposite = 244.20 × SUVRFBB − 170.80 [18F]FBP: CLcomposite = 300.66 × SUVRFBP − 208.84 Conclusions FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.
Published: 2021
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5. Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment

Author: Zhengshi Yang, Jessica Z. K. Caldwell, Jeffrey L. Cummings, Aaron Ritter, Jefferson W. Kinney, Dietmar Cordes, The Alzheimer's Disease Neuroimaging Initiative (ADNI), Michael Weiner, Paul Aisen, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Enchi Liu, Tom Montine, Anthony Gamst, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Danielle Harvey, John Kornak, Anders Dale, Matthew Bernstein, Joel Felmlee, Nick Fox, Paul Thompson, Norbert Schuff, Gene Alexander, Charles DeCArli, Dan Bandy, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Nigel J. Cairns, Lisa Taylor-Reinwald, J. Q. Trojanowki, Les Shaw, Virginia M.Y. Lee, Magdalena Korecka, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Zaven Khachaturian, Richard Frank, Peter J. Snyder, Susan Molchan, Jeffrey Kaye, Joseph Quinn, Betty Lind, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Bryan M. Spann, James Brewer, Helen Vanderswag, Judith L. Heidebrink, Joanne L. Lord, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Munir Chowdhury, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, John C. Morris, Beau Ances, Maria Carroll, Sue Leon, Mark A. Mintun, Stacy Schneider, Daniel Marson, Randall Griffith, David Clark, Hillel Grossman, Effie Mitsis, Aliza Romirowsky, Leyla deToledo-Morrell, Raj C. Shah, Ranjan Duara, Daniel Varon, Peggy Roberts, Marilyn Albert, Chiadi Onyike, Stephanie Kielb, Henry Rusinek, Mony J de Leon, Lidia Glodzik, P. Murali Doraiswamy, Jeffrey R. Petrella, Edward R. Coleman, Steven E. Arnold, Jason H. Karlawish, David Wolk, Charles D. Smith, Greg Jicha, Peter Hardy, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Ruth A. Mulnard, Gaby Thai, Catherine Mc-Adams-Ortiz, Ramon Diaz-Arrastia, Kristen Martin-Cook, Michael DeVous, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Heather S Anderson, Russell H. Swerdlow, Liana Apostolova, Po H. Lu, George Bartzokis, Daniel H.S. Silverman, Neill R Graff-Radford, Francine Parfitt, Heather Johnson, Martin Farlow, Scott Herring, Ann M. Hake, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Howard Feldman, Michele Assaly, Andrew KertesZ, John Rogers, Dick Trost, Charles Bernick, Donna Munic, Diana Kerwin, Marek-Marsel Mesulam, Kristine Lipowski, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Walter Martinez, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Meghan Frey, Allyson Rosen, Jared Tinklenberg, Marwan Sabbagh, Christine Belden, Sandra Jacobson, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Salome K. Bwayo, Alan Lerner, Leon Hudson, Paula Ogrocki, Evan Fletcher, Owen Carmichael, John Olichney, Charles DeCarli, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Steven G. Potkin, Adrian Preda, Dana Nguyen, Pierre Tariot, Adam Fleisher, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Barry A. Hendin, Douglas W. Scharre, Maria Kataki, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Robert B. Santulli, Eben S. Schwartz, Kaycee M. Sink, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Henry Querfurth, Geoffrey Tremont, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, Jacobo Mintzer, Crystal Flynn Longmire, and Kenneth Spicer
Subjects: aging effect, caudate, mild cognitive impairment, functional connectivity, Alzheimer's Disease, sex difference, Psychiatry, RC435-571
Abstract: PurposeTo assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process.Materials and MethodsTwo hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI.ResultsThe MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10−7, right: P = 3.37 × 10−8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI.ConclusionSex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.
Published: 2022
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6. Use of 55 PET radiotracers under approval of a Radioactive Drug Research Committee (RDRC)

Author: Isaac M. Jackson, So Jeong Lee, Alexandra R. Sowa, Melissa E. Rodnick, Laura Bruton, Mara Clark, Sean Preshlock, Jill Rothley, Virginia E. Rogers, Leslie E. Botti, Bradford D. Henderson, Brian G. Hockley, Jovany Torres, David M. Raffel, Allen F. Brooks, Kirk A. Frey, Michael R. Kilbourn, Robert A. Koeppe, Xia Shao, and Peter J. H. Scott
Subjects: PET imaging, Regulatory oversight, Dosimetry, RDRC, IND, Radiopharmaceuticals, Medical physics. Medical radiology. Nuclear medicine, R895-920, Therapeutics. Pharmacology, RM1-950
Abstract: Abstract Background In the US, EU and elsewhere, basic clinical research studies with positron emission tomography (PET) radiotracers that are generally recognized as safe and effective (GRASE) can often be conducted under institutional approval. For example, in the United States, such research is conducted under the oversight of a Radioactive Drug Research Committee (RDRC) as long as certain requirements are met. Firstly, the research must be for basic science and cannot be intended for immediate therapeutic or diagnostic purposes, or to determine the safety and effectiveness of the PET radiotracer. Secondly, the PET radiotracer must be generally recognized as safe and effective. Specifically, the mass dose to be administered must not cause any clinically detectable pharmacological effect in humans, and the radiation dose to be administered must be the smallest dose practical to perform the study and not exceed regulatory dose limits within a 1-year period. In our experience, the main barrier to using a PET radiotracer under RDRC approval is accessing the required information about mass and radioactive dosing. Results The University of Michigan (UM) has a long history of using PET radiotracers in clinical research studies. Herein we provide dosing information for 55 radiotracers that will enable other PET Centers to use them under the approval of their own RDRC committees. Conclusions The data provided herein will streamline future RDRC approval, and facilitate further basic science investigation of 55 PET radiotracers that target functionally relevant biomarkers in high impact disease states.
Published: 2020
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7. Strategies for PET imaging of the receptor for advanced glycation endproducts (RAGE)

Author: Lindsey R. Drake, Allen F. Brooks, Jenelle Stauff, Phillip S. Sherman, Janna Arteaga, Robert A. Koeppe, Aimee Reed, Timothy J. Montavon, Marc B. Skaddan, and Peter J.H. Scott
Subjects: RAGE, Neuroimaging, Positron emission tomography, Radiochemistry, Neuroinflammation, Therapeutics. Pharmacology, RM1-950
Abstract: The implication of the receptor for advanced glycation end-products (RAGE) in numerous diseases and neurodegenerative disorders makes it interesting both as a therapeutic target and as an inflammatory biomarker. In the context of investigating RAGE as a biomarker, there is interest in developing radiotracers that will enable quantification of RAGE using positron emission tomography (PET) imaging. We have synthesized potential small molecule radiotracers for both the intracellular ([18F]InRAGER) and extracellular ([18F]RAGER) domains of RAGE. Herein we report preclinical evaluation of both using in vitro (lead panel screens) and in vivo (rodent and nonhuman primate PET imaging) methods. Both radiotracers have high affinity for RAGE and show good brain uptake, but suffer from off-target binding. The source of the off-target PET signal is not attributable to binding to melatonin receptors, but remains unexplained. We have also investigated use of lipopolysaccharide (LPS)-treated mice as a possible animal model with upregulated RAGE for evaluation of new imaging agents. Immunoreactivity of the mouse brain sections revealed increases in RAGE in the male cohorts, but no difference in the female groups. However, it proves challenging to quantify the changes in RAGE due to off-target binding of the radiotracers. Nevertheless, they are appropriate lead scaffolds for future development of 2nd generation RAGE PET radiotracers because of their high affinity for the receptor and good CNS penetration.
Published: 2020
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8. Cerebral topography of vesicular cholinergic transporter changes in neurologically intact adults: A [18F]FEOBV PET study

Author: Prabesh Kanel, Sygrid van der Zee, Carlos A. Sanchez-Catasus, Robert A. Koeppe, Peter J.H. Scott, Teus van Laar, Roger L. Albin, and Nicolaas I. Bohnen
Subjects: Acetylcholine transporter, Aging, Normal persons, VAChT PET, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Acetylcholine plays a major role in brain cognitive and motor functions with regional cholinergic terminal loss common in several neurodegenerative disorders. We describe age-related declines of regional cholinergic neuron terminal density in vivo using the positron emission tomography (PET) ligand [18F](–)5-Fluoroethoxybenzovesamicol ([18F]FEOBV), a vesamicol analogue selectively binding to the vesicular acetylcholine transporter (VAChT). A total of 42 subjects without clinical evidence of neurologic disease (mean 50.55 [range 20–80] years, 24 Male/18 Female) underwent [18F]FEOBV brain PET imaging. We used SPM based voxel-wise statistical analysis to perform whole brain voxel-based parametric analysis (family-wise error corrected, FWE) and to also extract the most significant clusters of regions correlating with aging with gender as nuisance variable. Age-related VAChT binding reductions were found in primary sensorimotor cortex, visual cortex, caudate nucleus, anterior to mid-cingulum, bilateral insula, para-hippocampus, hippocampus, anterior temporal lobes/amygdala, dorsomedial thalamus, metathalamus, and cerebellum (gender and FWE-corrected, P
Published: 2022
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9. Comparison of Pittsburgh compound B and florbetapir in cross‐sectional and longitudinal studies

Author: Yi Su, Shaney Flores, Guoqiao Wang, Russ C. Hornbeck, Benjamin Speidel, Nelly Joseph‐Mathurin, Andrei G. Vlassenko, Brian A. Gordon, Robert A. Koeppe, William E. Klunk, Clifford R. Jack Jr., Martin R. Farlow, Stephen Salloway, Barbara J. Snider, Sarah B. Berman, Erik D. Roberson, Jared Brosch, Ivonne Jimenez‐Velazques, Christopher H. vanDyck, Douglas Galasko, Shauna H. Yuan, Suman Jayadev, Lawrence S. Honig, Serge Gauthier, Ging‐Yuek R. Hsiung, Mario Masellis, William S. Brooks, Michael Fulham, Roger Clarnette, Colin L. Masters, David Wallon, Didier Hannequin, Bruno Dubois, Jeremie Pariente, Raquel Sanchez‐Valle, Catherine Mummery, John M. Ringman, Michel Bottlaender, Gregory Klein, Smiljana Milosavljevic‐Ristic, Eric McDade, Chengjie Xiong, John C. Morris, Randall J. Bateman, and Tammie L.S. Benzinger
Subjects: PiB, Florbetapir, Amyloid imaging, Centiloid, Positron emission tomography, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir‐based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter‐individual variability of the two tracers were compared using multivariate linear models both cross‐sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.
Published: 2019
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10. Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease

Author: Stephanie A. Schultz, Jeremy F. Strain, Adedamola Adedokun, Qing Wang, Oliver Preische, Jens Kuhle, Shaney Flores, Sarah Keefe, Aylin Dincer, Beau M. Ances, Sarah B. Berman, Adam M. Brickman, David M. Cash, Jasmeer Chhatwal, Carlos Cruchaga, Michael Ewers, Nick N. Fox, Bernardino Ghetti, Alison Goate, Neill R. Graff-Radford, Jason J. Hassenstab, Russ Hornbeck, Clifford Jack, Jr, Keith Johnson, Nelly Joseph-Mathurin, Celeste M. Karch, Robert A. Koeppe, Athene K.W. Lee, Johannes Levin, Colin Masters, Eric McDade, Richard J. Perrin, Christopher C. Rowe, Stephen Salloway, Andrew J. Saykin, Reisa Sperling, Yi Su, Victor L. Villemagne, Jonathan Vöglein, Michael Weiner, Chengjie Xiong, Anne M. Fagan, John C. Morris, Randall J. Bateman, Tammie L.S. Benzinger, Mathias Jucker, and Brian A. Gordon
Subjects: Neurofilament, Alzheimer's disease, Neurodegeneration, White matter, Blood-based biomarkers, Neuroimaging, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data.In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.
Published: 2020
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11. Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease

Author: Nelly Joseph‐Mathurin, Yi Su, Tyler M. Blazey, Mateusz Jasielec, Andrei Vlassenko, Karl Friedrichsen, Brian A. Gordon, Russ C. Hornbeck, Lisa Cash, Beau M. Ances, Thomas Veale, David M. Cash, Adam M. Brickman, Virginia Buckles, Nigel J. Cairns, Carlos Cruchaga, Alison Goate, Clifford R. Jack Jr., Celeste Karch, William Klunk, Robert A. Koeppe, Daniel S. Marcus, Richard Mayeux, Eric McDade, James M. Noble, John Ringman, Andrew J. Saykin, Paul M. Thompson, Chengjie Xiong, John C. Morris, Randall J. Bateman, Tammie L.S. Benzinger, and Dominantly Inherited Alzheimer Network
Subjects: Alzheimer's disease, Neuronal injury, Perfusion, FDG, PiB, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract Introduction 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C‐Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB‐R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross‐sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Results Metabolism and perfusion images were spatially correlated. Regional PiB‐R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. Discussion Hypometabolism estimated by PiB‐R1 may provide a measure of brain perfusion without increasing radiation exposure.
Published: 2018
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12. Utilizing the Centiloid scale in cross-sectional and longitudinal PiB PET studies

Author: Yi Su, Shaney Flores, Russ C. Hornbeck, Benjamin Speidel, Andrei G. Vlassenko, Brian A. Gordon, Robert A. Koeppe, William E. Klunk, Chengjie Xiong, John C. Morris, and Tammie L.S. Benzinger
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: 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
Published: 2018
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13. Prediction and Classification of Alzheimer’s Disease Based on Combined Features From Apolipoprotein-E Genotype, Cerebrospinal Fluid, MR, and FDG-PET Imaging Biomarkers

Author: Yubraj Gupta, Ramesh Kumar Lama, Goo-Rak Kwon, Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Steven Chao, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Gustavo Jimenez, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Lindsey Hergesheimer, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: Alzheimer's disease, MCIs (MCI stable), MCIc (MCI converted), sMRI, FDG-PET, CSF, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Alzheimer's disease (AD), including its mild cognitive impairment (MCI) phase that may or may not progress into the AD, is the most ordinary form of dementia. It is extremely important to correctly identify patients during the MCI stage because this is the phase where AD may or may not develop. Thus, it is crucial to predict outcomes during this phase. Thus far, many researchers have worked on only using a single modality of a biomarker for the diagnosis of AD or MCI. Although recent studies show that a combination of one or more different biomarkers may provide complementary information for the diagnosis, it also increases the classification accuracy distinguishing between different groups. In this paper, we propose a novel machine learning-based framework to discriminate subjects with AD or MCI utilizing a combination of four different biomarkers: fluorodeoxyglucose positron emission tomography (FDG-PET), structural magnetic resonance imaging (sMRI), cerebrospinal fluid (CSF) protein levels, and Apolipoprotein-E (APOE) genotype. The Alzheimer's Disease Neuroimaging Initiative (ADNI) baseline dataset was used in this study. In total, there were 158 subjects for whom all four modalities of biomarker were available. Of the 158 subjects, 38 subjects were in the AD group, 82 subjects were in MCI groups (including 46 in MCIc [MCI converted; conversion to AD within 24 months of time period], and 36 in MCIs [MCI stable; no conversion to AD within 24 months of time period]), and the remaining 38 subjects were in the healthy control (HC) group. For each image, we extracted 246 regions of interest (as features) using the Brainnetome template image and NiftyReg toolbox, and later we combined these features with three CSF and two APOE genotype features obtained from the ADNI website for each subject using early fusion technique. Here, a different kernel-based multiclass support vector machine (SVM) classifier with a grid-search method was applied. Before passing the obtained features to the classifier, we have used truncated singular value decomposition (Truncated SVD) dimensionality reduction technique to reduce high dimensional features into a lower-dimensional feature. As a result, our combined method achieved an area under the receiver operating characteristic (AU-ROC) curve of 98.33, 93.59, 96.83, 94.64, 96.43, and 95.24% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIs, AD vs. MCIc, HC vs. MCIc, and HC vs. MCIs subjects which are high relative to single modality results and other state-of-the-art approaches. Moreover, combined multimodal methods have improved the classification performance over the unimodal classification.
Published: 2019
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14. The Influence of Cerebrospinal Fluid Abnormalities and APOE 4 on PHF-Tau Protein: Evidence From Voxel Analysis and Graph Theory

Author: Yuan Li, Zhijun Yao, Yue Yu, Yu Fu, Ying Zou, Bin Hu, for the Alzheimer’s Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Tom Montine, Gustavo Jimenez, Michael Donohue, Devon Gessert, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Sarah Walter, Lindsey Hergesheimer, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Joseph Quinn, Lisa C. Silbert, Betty Lind, Jeffrey A. Kaye, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Jaimie Ziolkowski, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Javier Villanueva-Meyer, Valory Pavlik, Nathaniel Pacini, Ashley Lamb, Joseph S. Kass, Rachelle S. Doody, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Randy Yeh, Beau Ances, David Winkfield, Maria Carroll, Angela Oliver, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Hillel Grossman, Effie Mitsis, Raj C. Shah, Melissa Lamar, Patricia Samuels, Ranjan Duara, Maria T. Greig-Custo, Rosemarie Rodriguez, Chiadi Onyike, Daniel D’Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Jamika Singleton-Garvin, Anaztasia Ulysse, Mrunalini Gaikwad, P. Murali Doraiswamy, Jeffrey R. Petrella, Olga James, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Jason H. Karlawish, David A. Wolk, Sanjeev Vaishnavi, Christopher M. Clark, Steven E. Arnold, Charles D. Smith, Greg Jicha, Peter Hardy, Riham El Khouli, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Kim Martin, Nancy Kowalksi, Melanie Keltz, Bonnie S. Goldstein, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Gaby Thai, Aimee Pierce, Beatriz Yanez, Elizabeth Sosa, Megan Witbracht, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Ellen Woo, Daniel H.S. Silverman, Edmond Teng, Sarah Kremen, Liana Apostolova, Kathleen Tingus, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Chris (Chinthaka) Heyn, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, William Pavlosky, Irina Rachinsky, Dick Drost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, Jerome Yesavage, Joy L. Taylor, Steven Chao, Barton Lane, Allyson Rosen, Jared Tinklenberg, Edward Zamrini, Christine M. Belden, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Ntekim E. Oyonumo, Joanne Allard, Olu Ogunlana, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Joel Hetelle, Kathryn DeMarco, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Rawan Tarawneh, Earl A. Zimmerman, Dzintra Celmins, David Hart, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Mia Yang, Akiva Mintz, Rhode Island, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Courtney Bodge, Stephen Salloway, Paul Malloy, Stephen Correia, Athena Lee, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, John Rogers, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Delwyn D. Miller, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Susan K. Schultz, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Christi Leach, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Lindsey Hergesheimen, Jacqueline Hayes, Shannon Finley, Susan Landau, Erin Householder, Karl Friedl, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Bonnie Goldstein, Kimberly S. Martin, Steven G. Potkin, Adrian Preda, Dana Nguyen, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Gad Marshall, Marwan N. Sabbagh, Sandra A. Jacobson, Saba Wolday, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: PHF-Tau, graph theory, network properties, APOE 4, CSF-Tau, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Mild cognitive impairment (MCI) is a transitional state between the cognitive changes in normal aging and Alzheimer’s disease (AD), which induces abnormalities in specific brain regions. Previous studies showed that paired helical filaments Tau (PHF-Tau) protein is a potential pathogenic protein which may cause abnormal brain function and structure in MCI and AD patients. However, the understanding of the PHF-Tau protein network in MCI patients is limited. In this study, 225 subjects with PHF-Tau Positron Emission Tomography (PET) images were divided into four groups based on whether they carried Apolipoprotein E ε4 (APOE 4) or abnormal cerebrospinal fluid Total-Tau (CSF T-Tau). They are two important pathogenic factors that might cause cognitive function impairment. The four groups were: individuals harboring CSF T-Tau pathology but no APOE 4 (APOE 4−T+); APOE 4 carriers with normal CSF T-Tau (APOE 4+T−); APOE 4 carriers with abnormal CSF T-Tau (APOE 4+T+); and APOE 4 noncarriers with abnormal CSF T-Tau (APOE 4−T−). We explored the topological organization of PHF-Tau networks in these four groups and calculated five kinds of network properties: clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Our findings showed that compared with APOE 4−T− group, the other three groups showed different alterations in the clustering coefficient, shortest path length, Q value of modularity, nodal centrality and degree. Simultaneously, voxel-level analysis was conducted and the results showed that compared with APOE 4−T− group, the other three groups were found increased PHF-Tau distribution in some brain regions. For APOE 4+T+ group, positive correlation was found between the value of PHF-Tau distribution in altered regions and Functional Assessment Questionnaire (FAQ) score. Our results indicated that the effects of APOE 4 and abnormal CSF T-Tau may induce abnormalities of PHF-Tau protein and APOE 4 has a greater impact on PHF-Tau than abnormal CSF T-Tau. Our results may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI patients.
Published: 2019
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15. New Perspective for Non-invasive Brain Stimulation Site Selection in Mild Cognitive Impairment: Based on Meta- and Functional Connectivity Analyses

Author: Jiao Liu, Binlong Zhang, Georgia Wilson, Jian Kong, the Alzheimer’s Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, and Steven Chao
Subjects: mild cognitive impairment, non-invasive brain stimulation, stimulation site, meta-analysis, resting state functional connectivity, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: BackgroundNon-invasive brain stimulation (NIBS) has been widely used to treat mild cognitive impairment (MCI). However, there exists no consensus on the best stimulation sites.ObjectiveTo explore potential stimulation locations for NIBS treatment in patients with MCI, combining meta- and resting state functional connectivity (rsFC) analyses.MethodsThe meta-analysis was conducted to identify brain regions associated with MCI. Regions of interest (ROIs) were extracted based on this meta-analysis. The rsFC analysis was applied to 45 MCI patients to determine brain surface regions that are functionally connected with the above ROIs.ResultsWe found that the dorsolateral prefrontal cortex (DLPFC) and inferior frontal gyrus (IFG) were the overlapping brain regions between our results and those of previous studies. In addition, we recommend that the temporoparietal junction (including the angular gyrus), which was found in both the meta- and rsFC analysis, should be considered in NIBS treatment of MCI. Furthermore, the bilateral orbital prefrontal gyrus, inferior temporal gyrus, medial superior frontal gyrus, and right inferior occipital gyrus may be potential brain stimulation sites for NIBS treatment of MCI.ConclusionOur results provide several potential sites for NIBS, such as the DLFPC and IFG, and may shed light on the locations of NIBS sites in the treatment of patients with MCI.
Published: 2019
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16. Performing Sparse Regularization and Dimension Reduction Simultaneously in Multimodal Data Fusion

Author: Zhengshi Yang, Xiaowei Zhuang, Christopher Bird, Karthik Sreenivasan, Virendra Mishra, Sarah Banks, Dietmar Cordes, the Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Steven Chao, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Gustavo Jimenez, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Lindsey Hergesheimer, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: sparse principal component analysis, PCA, canonical correlation analysis, CCA, data fusion, mild cognitive impairment, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Collecting multiple modalities of neuroimaging data on the same subject is increasingly becoming the norm in clinical practice and research. Fusing multiple modalities to find related patterns is a challenge in neuroimaging analysis. Canonical correlation analysis (CCA) is commonly used as a symmetric data fusion technique to find related patterns among multiple modalities. In CCA-based data fusion, principal component analysis (PCA) is frequently applied as a preprocessing step to reduce data dimension followed by CCA on dimension-reduced data. PCA, however, does not differentiate between informative voxels from non-informative voxels in the dimension reduction step. Sparse PCA (sPCA) extends traditional PCA by adding sparse regularization that assigns zero weights to non-informative voxels. In this study, sPCA is incorporated into CCA-based fusion analysis and applied on neuroimaging data. A cross-validation method is developed and validated to optimize the parameters in sPCA. Different simulations are carried out to evaluate the improvement by introducing sparsity constraint to PCA. Four fusion methods including sPCA+CCA, PCA+CCA, parallel ICA and sparse CCA were applied on structural and functional magnetic resonance imaging data of mild cognitive impairment subjects and normal controls. Our results indicate that sPCA significantly can reduce the impact of non-informative voxels and lead to improved statistical power in uncovering disease-related patterns by a fusion analysis.
Published: 2019
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17. Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients

Author: Qian Zhao, Min Liu, Lingxia Ha, Yun Zhou, Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, Steven Chao, Scott Mackin, Rema Raman, Erin Drake, Mike Donohue, Gustavo Jimenez, Kelly Harless, Jennifer Salazar, Yuliana Cabrera, Lindsey Hergesheimer, Elizabeth Shaffer, Craig Nelson, David Bickford, Meryl Butters, Michelle Zmuda, Denise Reyes, Kelley M. Faber, Kelly N. Nudelman, Yiu Ho Au, Kelly Scherer, Daniel Catalinotto, Samuel Stark, Elise Ong, and Dariella Fernandez
Subjects: 18F-AV1451, Tau PET, cognitively normal, mild cognition impairment, Alzheimer's disease, Neurology. Diseases of the nervous system, RC346-429
Abstract: Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results:18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification.
Published: 2019
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18. Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder

Author: Scott A. Langenecker, Brian J. Mickey, Peter Eichhammer, Srijan Sen, Kathleen H. Elverman, Susan E. Kennedy, Mary M. Heitzeg, Saulo M. Ribeiro, Tiffany M. Love, David T. Hsu, Robert A. Koeppe, Stanley J. Watson, Huda Akil, David Goldman, Margit Burmeister, and Jon-Kar Zubieta
Subjects: positron emission tomography, intermediate cognitive phenotypes, major depressive disorder, serotonin, executive functioning, interference resolution, Psychology, BF1-990
Abstract: Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.
Published: 2019
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19. Impact of chronic migraine attacks and their severity on the endogenous μ-opioid neurotransmission in the limbic system

Author: Hassan Jassar, Thiago D. Nascimento, Niko Kaciroti, Marcos F. DosSantos, Theodora Danciu, Robert A. Koeppe, Yolanda R. Smith, Marcelo E. Bigal, Frank Porreca, Kenneth L. Casey, Jon-Kar Zubieta, and Alexandre F. DaSilva
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Objective: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous μ-opioid neurotransmission. Background: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids. Methods: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective μ-opioid receptor (μOR) radiotracer [11C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the μ-opioid receptor availability and the clinical data. Results: μOR availability, measured with [11C]carfentanil nondisplaceable binding potential (BPND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower μOR BPND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower μOR BPND values indicate either a decrease in μOR concentration or an increase in endogenous μ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in μOR BPND levels was explained by the type of migraine (CM vs. EM: partial-R2 = 0.47, P-value
Published: 2019
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20. The Effects of Intramuscular Naloxone Dose on Mu Receptor Displacement of Carfentanil in Rhesus Monkeys

Author: Peter J. H. Scott, Robert A. Koeppe, Xia Shao, Melissa E. Rodnick, Alexandra R. Sowa, Bradford D. Henderson, Jenelle Stauff, Phillip S. Sherman, Janna Arteaga, Dennis J. Carlo, and Ronald B. Moss
Subjects: opioid, naloxone, overdose, fentanyl, carfentanil, [11c]carfentanil, positron emission tomography, receptor occupancy, pharmacokinetics, Organic chemistry, QD241-441
Abstract: Naloxone (NLX) is a mu receptor antagonist used to treat acute opioid overdoses. Currently approved doses of naloxone to treat opioid overdoses are 4 mg intranasal (IN) and 2 mg intramuscular (IM). However, higher mu receptor occupancy (RO) may be required to treat overdoses due to more potent synthetic opioids such as fentanyl and carfentanil that have entered the illicit drug market recently. To address this need, a higher dose of NLX has been investigated in a 5 mg IM formulation called ZIMHI but, while the effects of intravenous (IV) and IN administration of NLX on the opioid mu receptor occupancy (RO) have been studied, comparatively little is known about RO for IM administration of NLX. The goal of this study was to examine the effect of IM dosing of NLX on mu RO in rhesus macaques using [11C]carfentanil positron emission tomography (PET) imaging. The lowest dose of NLX (0.06 mg/kg) approximated 51% RO. Higher doses of NLX (0.14 mg/kg, 0.28 mg/kg) resulted in higher mu RO of 70% and 75%, respectively. Plasma levels were 4.6 ng/mL, 16.8 ng/mL, and 43.4 ng/mL for the three IM doses, and a significant correlation between percent RO and plasma NLX level was observed (r = 0.80). These results suggest that higher doses of IM NLX result in higher mu RO and could be useful in combating overdoses resulting from potent synthetic opioids.
Published: 2020
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21. Corrigendum: Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Author: Shengwen Guo, Chunren Lai, Congling Wu, Guiyin Cen, The Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, and Steven Chao
Subjects: mild cognitive impairment, conversion, cortical feature, sparse-constrained regression, feature reduction, classification, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published: 2017
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22. Conversion Discriminative Analysis on Mild Cognitive Impairment Using Multiple Cortical Features from MR Images

Author: Shengwen Guo, Chunren Lai, Congling Wu, Guiyin Cen, The Alzheimer's Disease Neuroimaging Initiative, Michael W. Weiner, Paul Aisen, Michael Weiner, Ronald Petersen, Clifford R. Jack, William Jagust, John Q. Trojanowki, Arthur W. Toga, Laurel Beckett, Robert C. Green, Andrew J. Saykin, John Morris, Leslie M. Shaw, Zaven Khachaturian, Greg Sorensen, Maria Carrillo, Lew Kuller, Marc Raichle, Steven Paul, Peter Davies, Howard Fillit, Franz Hefti, David Holtzman, M. Marcel Mesulam, William Potter, Peter Snyder, Adam Schwartz, Tom Montine, Ronald G. Thomas, Michael Donohue, Sarah Walter, Devon Gessert, Tamie Sather, Gus Jiminez, Archana B. Balasubramanian, Jennifer Mason, Iris Sim, Danielle Harvey, Matthew Bernstein, Nick Fox, Paul Thompson, Norbert Schuff, Charles DeCArli, Bret Borowski, Jeff Gunter, Matt Senjem, Prashanthi Vemuri, David Jones, Kejal Kantarci, Chad Ward, Robert A. Koeppe, Norm Foster, Eric M. Reiman, Kewei Chen, Chet Mathis, Susan Landau, John C. Morris, Nigel J. Cairns, Erin Franklin, Lisa Taylor-Reinwald, Virginia Lee, Magdalena Korecka, Michal Figurski, Karen Crawford, Scott Neu, Tatiana M. Foroud, Steven Potkin, Li Shen, Kelley Faber, Sungeun Kim, Kwangsik Nho, Lean Thal, Leon Thal, Neil Buckholtz, Peter J. Snyder, Marilyn Albert, Richard Frank, John Hsiao, Jeffrey Kaye, Joseph Quinn, Lisa Silbert, Betty Lind, Raina Carter, Sara Dolen, Lon S. Schneider, Sonia Pawluczyk, Mauricio Becerra, Liberty Teodoro, Bryan M. Spann, James Brewer, Helen Vanderswag, Adam Fleisher, Judith L. Heidebrink, Joanne L. Lord, Sara S. Mason, Colleen S. Albers, David Knopman, Kris Johnson, Rachelle S. Doody, Javier Villanueva-Meyer, Valory Pavlik, Victoria Shibley, Munir Chowdhury, Susan Rountree, Mimi Dang, Yaakov Stern, Lawrence S. Honig, Karen L. Bell, Beau Ances, Maria Carroll, Mary L. Creech, Mark A. Mintun, Stacy Schneider, Angela Oliver, Daniel Marson, David Geldmacher, Marissa Natelson Love, Randall Griffith, David Clark, John Brockington, Erik Roberson, Hillel Grossman, Effie Mitsis, Raj C. Shah, Leyla deToledo-Morrell, Ranjan Duara, Maria T. Greig-Custo, Warren Barker, Chiadi Onyike, Daniel D'Agostino, Stephanie Kielb, Martin Sadowski, Mohammed O. Sheikh, Ulysse Anaztasia, Gaikwad Mrunalini, P. Murali Doraiswamy, Jeffrey R. Petrella, Salvador Borges-Neto, Terence Z. Wong, Edward Coleman, Steven E. Arnold, Jason H. Karlawish, David A. Wolk, Christopher M. Clark, Charles D. Smith, Greg Jicha, Peter Hardy, Partha Sinha, Elizabeth Oates, Gary Conrad, Oscar L. Lopez, MaryAnn Oakley, Donna M. Simpson, Anton P. Porsteinsson, Bonnie S. Goldstein, Kim Martin, Kelly M. Makino, M. Saleem Ismail, Connie Brand, Steven G. Potkin, Adrian Preda, Dana Nguyen, Kyle Womack, Dana Mathews, Mary Quiceno, Allan I. Levey, James J. Lah, Janet S. Cellar, Jeffrey M. Burns, Russell H. Swerdlow, William M. Brooks, Liana Apostolova, Kathleen Tingus, Ellen Woo, Daniel H.S. Silverman, Po H. Lu, George Bartzokis, Neill R Graff-Radford, Francine Parfitt, Kim Poki-Walker, Martin R. Farlow, Ann Marie Hake, Brandy R. Matthews, Jared R. Brosch, Scott Herring, Christopher H. van Dyck, Richard E. Carson, Martha G. MacAvoy, Pradeep Varma, Howard Chertkow, Howard Bergman, Chris Hosein, Sandra Black, Bojana Stefanovic, Curtis Caldwell, Ging-Yuek Robin Hsiung, Benita Mudge, Vesna Sossi, Howard Feldman, Michele Assaly, Elizabeth Finger, Stephen Pasternack, Irina Rachisky, Dick Trost, Andrew Kertesz, Charles Bernick, Donna Munic, Marek-Marsel Mesulam, Emily Rogalski, Kristine Lipowski, Sandra Weintraub, Borna Bonakdarpour, Diana Kerwin, Chuang-Kuo Wu, Nancy Johnson, Carl Sadowsky, Teresa Villena, Raymond Scott Turner, Kathleen Johnson, Brigid Reynolds, Reisa A. Sperling, Keith A. Johnson, Gad Marshall, Jerome Yesavage, Joy L. Taylor, Barton Lane, Allyson Rosen, Jared Tinklenberg, Marwan N. Sabbagh, Christine M. Belden, Sandra A. Jacobson, Sherye A. Sirrel, Neil Kowall, Ronald Killiany, Andrew E. Budson, Alexander Norbash, Patricia Lynn Johnson, Thomas O. Obisesan, Saba Wolday, Joanne Allard, Alan Lerner, Paula Ogrocki, Curtis Tatsuoka, Parianne Fatica, Evan Fletcher, Pauline Maillard, John Olichney, Charles DeCarli, Owen Carmichael, Smita Kittur, Michael Borrie, T-Y Lee, Rob Bartha, Sterling Johnson, Sanjay Asthana, Cynthia M. Carlsson, Pierre Tariot, Anna Burke, Ann Marie Milliken, Nadira Trncic, Stephanie Reeder, Vernice Bates, Horacio Capote, Michelle Rainka, Douglas W. Scharre, Maria Kataki, Brendan Kelley, Earl A. Zimmerman, Dzintra Celmins, Alice D. Brown, Godfrey D. Pearlson, Karen Blank, Karen Anderson, Laura A. Flashman, Marc Seltzer, Mary L. Hynes, Robert B. Santulli, Kaycee M. Sink, Gordineer Leslie, Jeff D. Williamson, Pradeep Garg, Franklin Watkins, Brian R. Ott, Geoffrey Tremont, Lori A. Daiello, Stephen Salloway, Paul Malloy, Stephen Correia, Howard J. Rosen, Bruce L. Miller, David Perry, Jacobo Mintzer, Kenneth Spicer, David Bachman, Stephen Pasternak, Irina Rachinsky, John Rogers, Dick Drost, Nunzio Pomara, Raymundo Hernando, Antero Sarrael, Susan K. Schultz, Karen Ekstam Smith, Hristina Koleva, Ki Won Nam, Hyungsub Shim, Norman Relkin, Gloria Chiang, Michael Lin, Lisa Ravdin, Amanda Smith, Balebail Ashok Raj, Kristin Fargher, Thomas Neylan, Jordan Grafman, Gessert Devon, Davis Melissa, Rosemary Morrison, Hayes Jacqueline, Finley Shannon, Kantarci Kejal, Ward Chad, Erin Householder, Crawford Karen, Neu Scott, Friedl Karl, Becerra Mauricio, Debra Fleischman, Konstantinos Arfanakis, Daniel Varon, Maria T Greig, Olga James, Bonnie Goldstein, Kimberly S. Martin, Dino Massoglia, Olga Brawman-Mintzer, Walter Martinez, Howard Rosen, Kelly Behan, Sterling C. Johnson, J. Jay Fruehling, Sandra Harding, Elaine R. Peskind, Eric C. Petrie, Gail Li, Jerome A. Yesavage, Ansgar J. Furst, and Steven Chao
Subjects: mild cognitive impairment, conversion, cortical feature, sparse-constrained regression, feature reduction, classification, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Neuroimaging measurements derived from magnetic resonance imaging provide important information required for detecting changes related to the progression of mild cognitive impairment (MCI). Cortical features and changes play a crucial role in revealing unique anatomical patterns of brain regions, and further differentiate MCI patients from normal states. Four cortical features, namely, gray matter volume, cortical thickness, surface area, and mean curvature, were explored for discriminative analysis among three groups including the stable MCI (sMCI), the converted MCI (cMCI), and the normal control (NC) groups. In this study, 158 subjects (72 NC, 46 sMCI, and 40 cMCI) were selected from the Alzheimer's Disease Neuroimaging Initiative. A sparse-constrained regression model based on the l2-1-norm was introduced to reduce the feature dimensionality and retrieve essential features for the discrimination of the three groups by using a support vector machine (SVM). An optimized strategy of feature addition based on the weight of each feature was adopted for the SVM classifier in order to achieve the best classification performance. The baseline cortical features combined with the longitudinal measurements for 2 years of follow-up data yielded prominent classification results. In particular, the cortical thickness produced a classification with 98.84% accuracy, 97.5% sensitivity, and 100% specificity for the sMCI–cMCI comparison; 92.37% accuracy, 84.78% sensitivity, and 97.22% specificity for the cMCI–NC comparison; and 93.75% accuracy, 92.5% sensitivity, and 94.44% specificity for the sMCI–NC comparison. The best performances obtained by the SVM classifier using the essential features were 5–40% more than those using all of the retained features. The feasibility of the cortical features for the recognition of anatomical patterns was certified; thus, the proposed method has the potential to improve the clinical diagnosis of sub-types of MCI and predict the risk of its conversion to Alzheimer's disease.
Published: 2017
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23. Strategies for the Production of [11C]LY2795050 for Clinical Use

Author: Tanpreet Kaur, Xia Shao, Mami Horikawa, Liam S. Sharninghausen, Sean Preshlock, Allen F. Brooks, Bradford D. Henderson, Robert A. Koeppe, Alexandre F. DaSilva, Melanie S. Sanford, and Peter J. H. Scott
Subjects: Organic Chemistry, Physical and Theoretical Chemistry
Published: 2023

24. Differential cholinergic systems’ changes in progressive supranuclear palsy versus Parkinson’s disease: an exploratory analysis

Author: Prabesh Kanel, C. Chauncey Spears, Stiven Roytman, Robert A. Koeppe, Kirk A. Frey, Peter J. H. Scott, Roger L. Albin, and Nicolaas I. Bohnen
Subjects: Psychiatry and Mental health, Neurology, Positron-Emission Tomography, Pedunculopontine Tegmental Nucleus, Cholinergic Agents, Humans, Parkinson Disease, Supranuclear Palsy, Progressive, Neurology (clinical), Article, Biological Psychiatry
Abstract: BACKGROUND: Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson’s disease (PD), but the extent and topography of subcortical deficits remains poorly understood. OBJECTIVE: To investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n=8) versus Parkinson’s disease (PD, n=107) and older controls (n=19) using vesicular acetylcholine transporter [(18)F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). METHODS: A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [(18)F]-FEOBV DVR images. RESULTS: Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p
Published: 2022

25. Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease

Author: Kelvin L. Chou, Praveen Dayalu, Robert A. Koeppe, Sid Gilman, C. Chauncey Spears, Roger L. Albin, and Vikas Kotagal
Subjects: Serotonin Plasma Membrane Transport Proteins, Serotonin, Neurology, Positron-Emission Tomography, Humans, Parkinson Disease, Neurology (clinical), Multiple System Atrophy
Abstract: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized.To use serotonin transporter [sup11/supC]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD.We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest.Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD.Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Published: 2022

26. Cholinergic brain network deficits associated with vestibular sensory conflict deficits in Parkinson’s disease: correlation with postural and gait deficits

Author: Nicolaas I. Bohnen, Prabesh Kanel, Stiven Roytman, Peter J. H. Scott, Robert A. Koeppe, Roger L. Albin, Kevin A. Kerber, and Martijn L. T. M. Müller
Subjects: Male, Vesicular Acetylcholine Transport Proteins, Cholinergic Agents, Brain, Parkinson Disease, Middle Aged, Psychiatry and Mental health, Neurology, Humans, Female, Neurology (clinical), Gait, Gait Disorders, Neurologic, Biological Psychiatry, Aged
Abstract: To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [
Published: 2022

27. No Dopamine Agonist Modulation of Brain [

Author: Roger L, Albin, Prabesh, Kanel, Teus, van Laar, Sygrid, van der Zee, Stiven, Roytman, Robert A, Koeppe, Peter J H, Scott, and Nicolaas I, Bohnen
Subjects: Male, Positron-Emission Tomography, Vesicular Acetylcholine Transport Proteins, Dopamine Agonists, Brain, Humans, Female, Parkinson Disease, Middle Aged, Aged
Abstract: The [
Published: 2023

28. Copper-Mediated Radiocyanation of Unprotected Amino Acids and Peptides

Author: Liam S. Sharninghausen, Sean Preshlock, Stephen T. Joy, Mami Horikawa, Xia Shao, Wade P. Winton, Jenelle Stauff, Tanpreet Kaur, Robert A. Koeppe, Anna K. Mapp, Peter J. H. Scott, and Melanie S. Sanford
Subjects: Colloid and Surface Chemistry, Positron-Emission Tomography, Animals, Tissue Distribution, General Chemistry, Amines, Amino Acids, Radiopharmaceuticals, Biochemistry, Article, Copper, Catalysis
Abstract: This report describes a copper-mediated radiocyanation of aryl halides that is applicable to complex molecules. This transformation tolerates an exceptionally wide range of functional groups, including unprotected amino acids. As such, it enables the site-specific introduction of (11)C[CN] into peptides at an iodophenylalanine residue. The use of a diamine-ligated copper(I) mediator is crucial for achieving high radiochemical yield under relatively mild conditions, thus limiting racemization and competing side reactions of other amino acid side chains. The reaction has been scaled and automated to deliver radiolabeled peptides, including analogues of adrenocorticotropic hormone 1–27 (ACTH) and nociceptin (NOP). For instance, this Cu-mediated radiocyanation was leveraged to prepare >40 mCi of [(11)C]cyano-NOP to evaluate biodistribution in a primate using positron emission tomography. This investigation provides preliminary evidence that nociceptin crosses the blood-brain barrier and shows uptake across all brain regions (SUV >1 at 60 min post-injection), consistent with the known distribution of NOP receptors in the rhesus brain.
Published: 2022

29. Automated production of [(11)C]butyrate for keto body PET imaging

Author: Ryan J. Pakula, David M. Raffel, Robert A. Koeppe, Wade P. Winton, Jenelle Stauff, Nicolaas I. Bohnen, Roger L. Albin, Peter J.H. Scott, and Xia Shao
Subjects: Cancer Research, Molecular Medicine, Radiology, Nuclear Medicine and imaging, Article
Abstract: The report describes an updated, fully automated method for the production of [(11)C]butyrate, validated for use in clinical studies. A commercially available GE Tracerlab FX(M) synthesis module was reconfigured to allow for air-free introduction of n-propyl magnesium chloride and to incorporate Sep-Pak cartridges to simplify and shorten the purification process, as compared to purifying the product using traditional HPLC. The method takes 20 min from end-of-bombardment and reliably produces injectable doses of [(11)C]butyrate (8029 ± 1628 MBq (217 ± 44 mCi), 14 % radiochemical yield based on [(11)C]CO(2,) non-decay corrected) in high radiochemical purity (>97 %), n = 3. With radiotracer in hand, PET scans of rats confirmed uptake of the radiopharmaceutical in the brain. Rat biodistribution data was obtained and used in conjunction with OLINDA software to determine an estimated human total body effective dose of 3.20 × 10(−3) mSv/MBq (1.19 × 10(−2) rem/mCi), along with preliminary rodent PET imaging that confirmed brain uptake. Lastly, our first human [(11)C]butyrate PET studies using a dynamic bolus injection technique (n = 5), with a graphical Logan analysis using a white matter reference region, confirmed good radiotracer uptake in the brain and with relatively more prominent uptake in the cerebellar hemispheres, vermis, cingulum cortex and the thalami.
Published: 2023

30. Whole brain MRI‐free tau and amyloid PET quantification

Author: Tyler J. Ward, Theresa M. Harrison, Alice Murphy, Suzanne L. Baker, Elizabeth C. Mormino, Robert A. Koeppe, William J. Jagust, and Susan M. Landau
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2022

31. Examining the effects of sex and age on tau PET binding in the absence of beta‐amyloid pathology

Author: Brian A. Gordon, Shaney Flores, Aylin Dincer, Sarah J. Keefe, Nicole S. McKay, Diana A. Hobbs, Julie K. Wisch, Russ C. Hornbeck, Erin E. Franklin, Clifford R. Jack, Robert A. Koeppe, Chengjie Xiong, Christopher H van Dyck, Eric McDade, Gregory Klein, Jeremie Pariente, Randall J. Bateman, John C. Morris, Beau M Ances, Tammie L.S. Benzinger, and Richard J. Perrin
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2022

32. Choice of Inversion Time for Arterial Spin Labeling MRI in the U.S. POINTER Lifestyle Intervention Trial

Author: Youngkyoo Jung, Sarah Y. Hong, Donghoon Kim, Prashanthi Vemuri, Bret J. Borowski, Clifford R. Jack, Robert A. Koeppe, Samuel N. Lockhart, Theresa M. Harrison, Leslie Gordineer, Nancy Woolard, Mark A. Espeland, Danielle J. Harvey, Laura Lovato, Arthur W. Toga, Joseph C. Masdeu, Hwamee Oh, Darren R. Gitelman, Neelum T. Aggarwal, Maria C. Carrillo, Heather M. Snyder, Rachel A. Whitmer, Laura D. Baker, Charles S. DeCarli, and Susan M. Landau
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2022

33. Progression of regional cortical cholinergic denervation in Parkinson’s disease

Author: Nicolaas I Bohnen, Stiven Roytman, Prabesh Kanel, Martijn L T M Müller, Peter J H Scott, Kirk A Frey, Roger L Albin, and Robert A Koeppe
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, Neurology, Biological Psychiatry
Abstract: Cortical cholinergic deficits contribute to cognitive decline and other deficits in Parkinson's disease. Cross-sectional imaging studies suggest a stereotyped pattern of posterior-to-anterior cortical cholinergic denervation accompanying disease progression in Parkinson's disease. We used serial acetylcholinesterase PET ligand imaging to characterize the trajectory of regional cholinergic synapse deficits in Parkinson's disease, testing the hypothesis of posterior-to-anterior progression of cortical cholinergic deficits. The 16 Parkinson's disease subjects (4 females/12 males; mean age: 64.4 ± 6.7 years; disease duration: 5.5 ± 4.2 years; Hoehn & Yahr stage: 2.3 ± 0.6 at entry) completed serial 11C-methyl-4-piperidinyl propionate acetylcholinesterase PET scans over a 4–8 year period (median 5 years). Three-dimensional stereotactic cortical surface projections and volume-of-interest analyses were performed. Cholinergic synapse integrity was assessed by the magnitude, k3, of acetylcholinesterase hydrolysis of 11C-methyl-4-piperidinyl propionate. Based on normative data, we generated Z-score maps for both the k3 and the k1 parameters, the latter as a proxy for regional cerebral blood flow. Compared with control subjects, baseline scans showed predominantly posterior cortical k3 deficits in Parkinson’s disease subjects. Interval change analyses showed evidence of posterior-to-anterior progression of cholinergic cortical deficits in the posterior cortices. In frontal cortices, an opposite gradient of anterior-to-posterior progression of cholinergic deficits was found. The topography of k3 changes exhibited regionally specific disconnection from k1 changes. Interval-change analysis based on k3/k1 ratio images (k3 adjustment for regional cerebral blood flow changes) showed interval reductions (up to 20%) in ventral frontal, anterior cingulate and Brodmann area 6 cortices. In contrast, interval k3 reductions in the posterior cortices, especially Brodmann areas 17–19, were largely proportional to k1 changes. Our results partially support the hypothesis of progressive posterior-to-cortical cholinergic denervation in Parkinson’s disease. This pattern appears characteristic of posterior cortices. In frontal cortices, an opposite pattern of anterior-to-posterior progression of cholinergic deficits was found. The progressive decline of posterior cortical acetylcholinesterase activity was largely proportional to declining regional cerebral blood flow, suggesting that posterior cortical cholinergic synapse deficits are part of a generalized loss of synapses. The disproportionate decline in regional frontal cortical acetylcholinesterase activity relative to regional cerebral blood flow suggests preferential loss or dysregulation of cholinergic synapses in these regions. Our observations suggest that cortical cholinergic synapse vulnerability in Parkinson's disease is mediated by both diffuse processes affecting cortical synapses and processes specific to subpopulations of cortical cholinergic afferents.
Published: 2022

34. Quantifying cardiac sympathetic denervation: first studies of 18F-fluorohydroxyphenethylguanidines in cardiomyopathy patients

Author: Kirk A. Frey, Jill Rothley, David M. Raffel, Guie Gu, Yong-Woon Jung, Robert A. Koeppe, and Thomas Crawford
Subjects: Denervation, medicine.medical_specialty, Sympathetic nervous system, business.industry, Cardiomyopathy, General Medicine, medicine.disease, Patlak plot, Sudden cardiac death, medicine.anatomical_structure, Text mining, Ventricle, Internal medicine, Cardiology, medicine, Radiology, Nuclear Medicine and imaging, business, Perfusion
Abstract: Purpose. The PET radiotracers 4-18F-fluoro-m-hydroxyphenethylguanidine (18F-4F-MHPG) and 3-18F-fluoro-p-hydroxyphenethylguanidine (18F-3F-PHPG) were developed for quantifying regional cardiac sympathetic nerve density using tracer kinetic analysis methods. The aim of this study was to evaluate their performance in cardiomyopathy patients.Methods: Eight cardiomyopathy patients selected for surgical placement of an implantable cardioverter defibrillator (ICD) were scanned with 18F-4F-MHPG and 18F-3F-PHPG on different days. In addition, an 13N-ammonia scan was performed to assess regional resting perfusion. The myocardial kinetics of 18F-4F-MHPG and 18F-3F-PHPG were analyzed using the Patlak graphical method to obtain Patlak slopes Kp (mL/min/g) as quantitative metrics of regional nerve density. Polar maps of the Patlak slopes were generated to map regional nerve density and to estimate the extent of cardiac denervation. For comparison purposes, regional tracer 'retention index' (RI) values (mL blood/min/mL tissue) were also calculated and used to estimate denervation extent metrics. Polar maps of resting perfusion estimates were used to estimate the pattern and extent of hypoperfusion.Results: Patlak analysis of 18F-4F-MHPG and 18F-3F-PHPG kinetics was successful in all subjects, demonstrating the robustness of this approach in cardiomyopathy patients. Substantial regional denervation was observed in all eight subjects, ranging from 25% to 74% of the left ventricle. Denervation zones were equal to or larger than the size of corresponding areas of hypoperfusion.Conclusion: 18F-4F-MHPG and 18F-3F-PHPG provide quantitative metrics of regional sympathetic nerve density and the extent of left ventricular denervation in patients with cardiomyopathy, supporting further clinical development of these agents.Trial registration: Registered at the ClinicalTrials.gov website (NCT02669563).URL: https://clinicaltrials.gov/ct2/show/NCT02669563
Published: 2021

35. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

Author: Christopher H. van Dyck, Roger Clarnette, Susan Mills, John C. Morris, Carlos Cruchaga, Anna Santacruz, Ging-Yuek Robin Hsiung, Roy Yaari, Suman Jayadev, Caroline Giacobino, William S. Brooks, Robert A. Koeppe, Raquel Sánchez-Valle, Anne M. Fagan, Eric McDade, Sarah B. Berman, Catherine J. Mummery, Florence Pasquier, Scott M. Berry, Randall J. Bateman, Brian A. Gordon, Jorge J. Llibre-Guerra, Maïté Formaglio, Paul S. Aisen, Paulo Fontoura, Mark A. Mintun, Bruno Dubois, Erik D. Roberson, Kelley Coalier, Ronald G. Thomas, Martin R. Farlow, John R. Sims, Serge Gauthier, Douglas Galasko, Mario Masellis, G. Mustafa Surti, Barbara A. Wendelberger, Guoqiao Wang, James J. Lah, Yan Li, David B. Clifford, David Wallon, Paul Delmar, Alison Goate, Rachelle S. Doody, Didier Hannequin, Stephen Salloway, Geoffrey A. Kerchner, Karen C. Holdridge, Ivonne Z. Jimenez-Velazquez, Janice M. Hitchcock, Monika Baudler, Lawrence S. Honig, Tammie L.S. Benzinger, Clifford R. Jack, Peter J. Snyder, Scott W. Andersen, J. Pariente, Andrew J. Aschenbrenner, Jason Hassenstab, Richard J. Perrin, Colin L. Masters, Chengjie Xiong, Jared R. Brosch, and B. Joy Snider
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Disease, Antibodies, Monoclonal, Humanized, Placebo, Asymptomatic, Article, General Biochemistry, Genetics and Molecular Biology, law.invention, Placebos, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Alzheimer Disease, law, Internal medicine, medicine, Humans, Solanezumab, Cognitive decline, Amyloid beta-Peptides, Dose-Response Relationship, Drug, business.industry, General Medicine, Middle Aged, 030104 developmental biology, 030220 oncology & carcinogenesis, Disease Progression, Biomarker (medicine), Female, medicine.symptom, Gantenerumab, business, Biomarkers, medicine.drug
Abstract: Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
Published: 2021

36. The Longitudinal Early‐onset Alzheimer's Disease Study (LEADS): Framework and methodology

Author: Steve Salloway, Anne M. Fagan, Neill R. Graff-Radford, Robert A. Koeppe, Ani Eloyan, Lea T. Grinberg, Bradford C. Dickerson, Constantine Gatsonis, Walter A. Kukull, Thomas S. Wingo, Amy Trullinger, Gregory S. Day, Emily Rogalski, David A. Wolk, Paul S. Aisen, Prashanthi Vemuri, Joel H. Kramer, Gil D. Rabinovici, Erik S. Musiek, Tatiana Foroud, Arthur W. Toga, Clifford R. Jack, Mario F. Mendez, Leonardo Iaccarino, Joseph C. Masdeu, Malia Rumbaugh, Keith N. Fargo, Liana G. Apostolova, Chiadi U. Onyike, Kelly N.H. Nudelman, Lawrence S. Honig, Maria C. Carrillo, Melissa E. Murray, and David T.W. Jones
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Disease, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Alzheimer Disease, Internal medicine, Stilbenes, National Institute on Aging (U.S.), medicine, Humans, Dementia, Cognitive Dysfunction, Early-onset Alzheimer's disease, Longitudinal Studies, Florbetaben, Aniline Compounds, medicine.diagnostic_test, business.industry, Health Policy, Brain, Magnetic resonance imaging, Cognition, Middle Aged, medicine.disease, Magnetic Resonance Imaging, United States, Clinical trial, Psychiatry and Mental health, Early Diagnosis, 030104 developmental biology, Positron-Emission Tomography, Biomarker (medicine), Female, Autopsy, Neurology (clinical), Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery
Abstract: Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18 F]Florbetaben and [18 F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.
Published: 2021

37. Covariance of Kinetic Parameter Estimators Based on Time Activity Curve Reconstructions: Preliminary Study on 1D Dynamic Imaging.

Author: Sangtae Ahn, Jeffrey A. Fessler, Thomas E. Nichols, and Robert A. Koeppe
Published: 2004
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38. Modeling autosomal dominant Alzheimer's disease with machine learning

Author: Hiroshi Mori, Laura Swisher, Sarah B. Berman, Yi Su, Aylin Dincer, Mathias Jucker, James M. Noble, Colin L. Masters, Jonathan Vöglein, Robert A. Koeppe, Bernardino Ghetti, Tammie L.S. Benzinger, DS Marcus, Jasmeer P. Chhatwal, Lisa Cash, Jason Hassenstab, Eric McDade, Randall J. Bateman, David M. Cash, Brian A. Gordon, Richard J. Perrin, Michael W. Weiner, Ari Stern, Nelly Joseph-Mathurin, Austin A. McCullough, Qing Wang, Johannes Levin, Karin L. Meeker, Deborah Koudelis, Michael J. Fulham, Jeremy F. Strain, Anne M. Fagan, Chengjie Xiong, Russ C. Hornbeck, Nick C. Fox, Adam M. Brickman, Stephen Salloway, Beau M. Ances, Clifford R. Jack, Celeste M. Karch, Carlos Cruchaga, William S. Brooks, Martin R. Farlow, Peter R. Schofield, Patrick Luckett, Hwamee Oh, John E. McCarthy, Todd A. Kuffner, William E. Klunk, John C. Morris, and Shaney Flores
Subjects: Male, magnetic resonance imaging (MRI), Epidemiology, Precuneus, genetics [Alzheimer Disease], Disease, computer.software_genre, 030218 nuclear medicine & medical imaging, Machine Learning, pathology [Alzheimer Disease], chemistry.chemical_compound, 0302 clinical medicine, autosomal dominant Alzheimer's disease (ADAD), pathology [Atrophy], Aniline Compounds, fluorodeoxyglucose (FDG), medicine.diagnostic_test, Health Policy, Magnetic Resonance Imaging, Pittsburgh compound B (PiB), Psychiatry and Mental health, medicine.anatomical_structure, Positron emission tomography, Mutation (genetic algorithm), Female, medicine.drug, Adult, Amyloid, genetics [Mutation], Machine learning, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Atrophy, Developmental Neuroscience, Alzheimer Disease, Fluorodeoxyglucose F18, metabolism [Fluorodeoxyglucose F18], medicine, Humans, ddc:610, metabolism [Amyloid], Fluorodeoxyglucose, business.industry, medicine.disease, Thiazoles, chemistry, Positron-Emission Tomography, Mutation, Neurology (clinical), Artificial intelligence, Geriatrics and Gerontology, Pittsburgh compound B, business, computer, 030217 neurology & neurosurgery
Abstract: INTRODUCTION: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease. METHODS: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein e4 (APOE e4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status. RESULTS: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R2 = 0.95), fluorodeoxyglucose (R2 = 0.93), and atrophy (R2 = 0.95) in mutation carriers compared to non-carriers. DISCUSSION: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.
Published: 2021

39. No Dopamine Agonist Modulation of Brain [18F]FEOBV Binding in Parkinson's Disease

Author: Roger L. Albin, Prabesh Kanel, Teus van Laar, Sygrid van der Zee, Stiven Roytman, Robert A. Koeppe, Peter J. H. Scott, Nicolaas I. Bohnen, University of Groningen, and Movement Disorder (MD)
Subjects: Male, Vesicular Acetylcholine Transport Proteins/metabolism, Parkinson Disease/diagnostic imaging, positron emission tomography, striatum, TRACER, Pharmaceutical Science, Dopamine Agonists/metabolism, fluoroethoxybenzovesamicol, POSITRON-EMISSION-TOMOGRAPHY, Drug Discovery, RISPERIDONE, ORAL HALOPERIDOL, Humans, Aged, RELEASE, vesicular acetylcholine transporter, NERVE GROWTH-FACTOR, Middle Aged, Brain/diagnostic imaging, Positron-Emission Tomography/methods, acetylcholine, D2 receptor, PET, Molecular Medicine, Female, RADIOTRACER, dopamine, CHOLINERGIC NEURONS
Abstract: The[F-18]fluoroethoxybenzovesamicol ([F-18]-FEOBV) positron emission tomography (PET) ligand targets the vesicular acetylcholine transporter. Recent [F-18]FEOBV PET rodent studies suggest that regional brain [F-18]FEOBV binding may be modulated by dopamine D2-like receptor agents. We examined associations of regional brain [F-18]FEOBV PET binding in Parkinson's disease (PD) subjects without versus with dopamine D2-like receptor agonist drug treatment. PD subjects (n = 108; 84 males, 24 females; mean age 68.0 +/- 7.6 [SD] years), mean disease duration of 6.0 +/- 4.0 years, and mean Movement Disorder Society-revised Unified PD Rating Scale III 35.5 +/- 14.2 completed [F-18]FEOBV brain PET imaging. Thirty-eight subjects were taking dopamine D2-like agonists. Vesicular monoamine transporter type 2 [C-11]dihydrotetrabenazine (DTBZ) PET was available in a subset of 54 patients. Subjects on dopamine D2-like agonists were younger, had a longer duration of disease, and were taking a higher levodopa equivalent dose (LED) compared to subjects not taking dopamine agonists. A group comparison between subjects with versus without dopamine D2-like agonist use did not yield significant differences in cortical, striatal, thalamic, or cerebellar gray matter [F-18]FEOBV binding. Confounder analysis using age, duration of disease, LED, and striatal [C-11]DTBZ binding also failed to show significant regional [F-18]FEOBV binding differences between these two groups. Chronic D2-like dopamine agonist use in PD subjects is not associated with significant alterations of regional brain [F-18]FEOBV binding.
Published: 2022

40. Evaluation of [18F]-N-Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies

Author: Waqas Rafique, Kirk A. Frey, Rodrigo O Kuljis, Vasko Kramer, Horacio Amaral, David M. Raffel, Patrick J. Riss, Robert A. Koeppe, Peter J. H. Scott, Arlette Haeger, and Allen F. Brooks
Subjects: 0303 health sciences, Biodistribution, medicine.diagnostic_test, Physiology, business.industry, Cognitive Neuroscience, Lansoprazole, Cell Biology, General Medicine, medicine.disease, Biochemistry, Imaging agent, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Positron emission tomography, In vivo, medicine, Nuclear medicine, business, Florbetaben, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract: Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/μmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 μg (range, 0.16-8.27 μg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.
Published: 2020

41. Topography of Cholinergic Changes in Dementia With Lewy Bodies and Key Neural Network Hubs

Author: Martijn L.T.M. Müller, Sygrid van der Zee, Kirk A. Frey, Carlos A. Sánchez-Catasús, Nicolaas I. Bohnen, Robert A. Koeppe, and Prabesh Kanel
Subjects: 0301 basic medicine, Lewy Body Disease, Male, medicine.medical_specialty, Neurology, Fornix, Brain, Article, 03 medical and health sciences, 0302 clinical medicine, Piperidines, Thalamus, PARKINSONS-DISEASE, mental disorders, Medicine, Dementia, Humans, In patient, Aged, Aged, 80 and over, Cerebral Cortex, medicine.diagnostic_test, Artificial neural network, business.industry, Dementia with Lewy bodies, ATTENTION, Cognition, medicine.disease, COGNITIVE IMPAIRMENT, Acetylcholine, Psychiatry and Mental health, 030104 developmental biology, Cross-Sectional Studies, Positron emission tomography, Positron-Emission Tomography, DENERVATION, Cholinergic, Female, Neurology (clinical), Nerve Net, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Objectives: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [F-18]- fluoroethoxybenzovesamicol ([F-18]- FEOBV) radioligand.Methods: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [F-18]-FEOBV PET.Results: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated non-diffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices.Conclusions: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.
Published: 2020

42. Quantification of amyloid beta and tau PET without a structural MRI

Author: Susan M, Landau, Tyler J, Ward, Alice, Murphy, Leonardo, Iaccarino, Theresa M, Harrison, Renaud, La Joie, Suzanne, Baker, Robert A, Koeppe, and William J, Jagust
Abstract: Relying on magnetic resonance imaging (MRI) for quantification of positron emission tomography (PET) images may limit generalizability of the results. We evaluated several MRI-free approaches for amyloid beta (Aβ) and tau PET quantification relative to MRI-dependent quantification cross-sectionally and longitudinally.We compared baseline MRI-free and MRI-dependent measurements of Aβ PET ([18F]florbetapir [FBP], N = 1290, [18F]florbetaben [FBB], N = 290) and tau PET ([18F]flortaucipir [FTP], N = 768) images with respect to continuous and dichotomous agreement, effect sizes of Aβ+ impaired versus Aβ- unimpaired groups, and longitudinal standardized uptake value ratio (SUVR) slopes in a subset of individuals.The best-performing MRI-free approaches had high continuous and dichotomous agreement with MRI-dependent SUVRs for Aβ PET and temporal flortaucipir (RThere is no consistent loss of baseline or longitudinal AD-related signal with MRI-free Aβ and tau PET image quantification.
Published: 2022

43. Regional Serotonin Terminal Density in Aging Human Brain: A [11C]DASB Pet Study

Author: Roger Albin, Prabesh Kanel, Vikas Kotagal, Martijn L.T.M. Muller, Nicolaas I. Bohnen, and Robert A. Koeppe
Subjects: History, Polymers and Plastics, Business and International Management, Industrial and Manufacturing Engineering
Published: 2022

44. AD‐causing variants that affect PSEN1 transmembrane domains are associated with faster neurodegeneration and cognitive decline compared to those affecting cytoplasmic domains

Author: Stephanie A. Schultz, Ricardo Francisco Allegri, Aaron P. Schultz, Alison Goate, Allan I. Levey, Anne M. Fagan, Bernard J Hanseeuw, Robert A. Koeppe, Brian A. Gordon, Carlos Cruchaga, Celeste M. Karch, Charles D. Chen, Chengjie Xiong, Clifford R. Jack, Colleen D Fitzpatrick, Eric McDade, Helena C Chui, Hiroshi Mori, Jae‐Hong Lee, James M Noble, Jason J. Hassenstab, Johannes Levin, John C. Morris, Keith A. Johnson, Lei Liu, Martin R. Farlow, Mathias Jucker, Michelle E. Farrell, Neill R. Graff‐Radford, Nelly Joseph‐Mathurin, Nick C Fox, Peter R Schofield, Ralph N Martins, Raquel Sanchez‐Valle, Richard J. Perrin, Sarah Berman, Stephen P. Salloway, Zahra Shirzadi, Pedro Rosa‐Neto, Tammie L.S. Benzinger, Randall J. Bateman, Reisa A. Sperling, and Jasmeer P. Chhatwal
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), ddc:610, Geriatrics and Gerontology
Abstract: Rates of cognitive and biomarker change in Autosomal Dominant Alzheimer disease (ADAD) vary substantially across individuals. Prior cross-sectional work suggests that the location of the pathogenic variant within PSEN1, specifically whether the underlying variant affects transmembrane (TM) or cytoplasmic (CY) domains in PSEN1, may be a key determinant in these differential rates of progression. Here we use longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN-Obs) to examine whether variants affecting TM versus CY domains in PSEN1 have differential rates of change in key cognitive and neurodegenerative markers, and whether these differences are relevant to ADAD clinical trials.MethodsUsing longitudinal clinical, cognitive, and MRI data from PSEN1 pathogenic variant carriers [TM group N=76 and CY group N=44; Table 1], we assessed rates of change in Mini-Mental State Exam (MMSE), Clinical Dementia Rating® Sum of Boxes (CDR®-SOB), and hippocampal volume (HV) using linear mixed effects models accounting for disease stage (estimated years to symptom onset [EYO]). We further assessed how PSEN1 mutation location (TM versus CY) impacts sample size and detectable effect size in a potential ADAD clinical trial (modeled as a 4-year trial with annual assessments; 80% power; α = 0.05).ResultsPSEN1 TM and PSEN1 CY groups did not differ on baseline age, EYO, or CDR®. The PSEN1 TM group had significantly greater rates of change on MMSE (B[SE] = -0.42[0.1], p=0.002), CDR®-SOB (B[SE] = 0.23[0.1], p=0.001), and HV atrophy (B[SE] = -58.93[14.3], p=0.0006 compared to the PSEN1 CY group (Fig.1). Consistent with these differential rates of change, power analyses indicated the required sample size to detect a 30% treatment effect on MMSE or HV would be reduced by 59.6% for MMSE and 91.0% for HV for a trial population comprised of PSEN1 TM versus CY carriers (Fig.2).ConclusionsIndividuals who had a variant affecting the transmembrane domains of PSEN1 had greater rates of cognitive decline and neurodegeneration compared to those with variants affecting cytoplasmic domains. In addition to having implications for ADAD pathophysiology, these results suggest that incorporating information regarding the location of PSEN1 variants may be beneficial in analyzing and designing stratification approaches for ADAD trials.
Published: 2022

45. Cognitive, neuropsychiatric and imaging comparisons between early‐onset and late‐onset Alzheimer’s disease participants from LEADS and ADNI3

Author: Liana G. Apostolova, Ani Eloyan, Sujuan Gao, Leonardo Iaccarino, Alexandra Touroutoglou, Paul S Aisen, Laurel Beckett, Bret J Borowski, Michael C Donohue, Anne M Fagan, Tatiana M. Foroud, Constantine Gatsonis, Clifford R. Jack, Joel H Kramer, Robert A. Koeppe, Andrew J. Saykin, Arthur W. Toga, Prashanthi Vemuri, Gregory S Day, Neill R. Graff‐Radford, Lawrence S Honig, David T. Jones, Joseph C Masdeu, Mario Mendez, Chiadi U Onyike, Emily J Rogalski, Stephen P. Salloway, David A. Wolk, Thomas S. Wingo, Maria C. Carrillo, Gil D. Rabinovici, and Brad C. Dickerson
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2021

46. Exploring Multimodal Ocular Imaging for Retinal Biomarkers of Alzheimer’s Disease, Frontotemporal Dementia, and Cognitively Normal Subjects

Author: Kelly Z. Young, Omar Moinuddin, Cagri G. Besirli, Benjamin K. Young, Sami J. Barmada, Nikhila S. Khandwala, Kerby Shedden, Yunshu Zhou, Sanjana K. Sathrasala, Robert A. Koeppe, Roger L. Albin, and Warren Pan
Subjects: medicine.medical_specialty, genetic structures, business.industry, Retinal, Ocular imaging, Disease, medicine.disease, eye diseases, chemistry.chemical_compound, chemistry, Ophthalmology, mental disorders, medicine, sense organs, business, Frontotemporal dementia
Abstract: Background and ObjectivesAlzheimer’s disease (AD) and frontotemporal dementia (FTD) are difficult to reliably differentiate clinically. While their distinct pathologies may be captured by existing diagnostic modalities, these are expensive, time-consuming, and often inaccessible. Dementias are associated with visual dysfunctions, perhaps due to changes in the retina, a developmental outgrowth of the central nervous system. We explore the role of multimodal ocular imaging in the diagnosis of two dementias, AD and FTD.MethodsWe recruited 5 AD participants, 2 FTD participants, and 9 age-matched controls. Each participant underwent comprehensive ophthalmologic examination and imaging (optical coherence tomography (OCT), OCT-angiography (OCTA), wide-field fundus photography, near-infrared imaging, and fundus autofluorescence). Ocular findings were correlated with cerebral amyloid burden, as measured by [11C]PiB PET.ResultsOCT analysis identified a trend toward differences in retinal nerve fiber layer (RNFL) thicknesses among dementia subtypes (p = 0.064). AD eyes had increased RNFL thicknesses compared to FTD (p = 0.046) and control eyes (p = 0.046), and AD RNFL thickness was positively associated with amyloid burden (p = 0.037). OCTA fractal analysis revealed decreased vascular complexity within the retinal superficial vascular complex in AD compared to FTD eyes (p = 0.035). Lastly, fundus autofluorescence demonstrated increased signal intensity in AD eyes compared to control eyes (p = 0.046). However, these findings were not statistically significant following correction for multiple comparisons.DiscussionDespite identifying trends toward differences in retinal layer thicknesses unique to individuals with AD and FTD, our study suggests that changes in retinal thicknesses alone may not serve as reliable biomarkers for distinguishing between dementia subtypes. However, multiple ocular imaging modalities may be considered in conjunction with clinical presentation to aid in diagnosing and monitoring AD and FTD.Trial registrationThe study was prospectively registered on clinicaltrials.gov (NCT03699644) on October 9, 2018.
Published: 2021

47. Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease

Author: Catriona McLean, Randall J. Bateman, Aihong Zhou, Carlos Cruchaga, Nigel J. Cairns, John M. Ringman, Robert A. Koeppe, Colin L. Masters, Bernardino Ghetti, Erin E. Franklin, Yi Su, Celeste M. Karch, Namita Sinha, Austin A. McCullough, Yan Li, Vijay Sharma, Eric McDade, Clifford R. Jack, Charles D. Chen, Russ C. Hornbeck, William E. Klunk, Karl A. Friedrichsen, John C. Morris, Tammie L.S. Benzinger, Chengjie Xiong, Tammaryn Lashley, Richard J. Perrin, Jasmeer P. Chhatwal, Brian A. Gordon, Nelly Joseph-Mathurin, and Alison Goate
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Plaque, Amyloid, Article, Pathology and Forensic Medicine, Temporal lobe, Cohort Studies, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Alzheimer Disease, medicine, Middle frontal gyrus, Humans, Aged, Amyloid beta-Peptides, Aniline Compounds, business.industry, Parietal lobe, Middle Aged, medicine.disease, Thiazoles, chemistry, Frontal lobe, Positron-Emission Tomography, Female, Neurology (clinical), Cerebral amyloid angiopathy, Alzheimer's disease, Occipital lobe, Pittsburgh compound B, business
Abstract: Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem-commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.
Published: 2021

48. µ-Opioid Activity in Chronic TMD Pain Is Associated with COMT Polymorphism

Author: Robert A. Koeppe, Vicki L. Ellingrod, Alexandre F. DaSilva, Hassan Jassar, Jon Kar Zubieta, Theodora E. Danciu, Thiago D. Nascimento, Emily Bellile, D. Salman, Niko Kaciroti, N. Yang, and Christian S. Stohler
Subjects: Adult, Male, Pain Threshold, Genotype, Receptors, Opioid, mu, Catechol O-Methyltransferase, Bioinformatics, Polymorphism, Single Nucleotide, Genetic profile, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Facial pain, General Dentistry, business.industry, Chronic pain, Research Reports, 030206 dentistry, Temporomandibular Joint Disorders, medicine.disease, Analgesics, Opioid, Opioid, Case-Control Studies, Positron-Emission Tomography, Comt polymorphism, Female, Chronic Pain, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Clinicians have the dilemma of prescribing opioid or nonopioid analgesics to chronic pain patients; however, the impact of pain on our endogenous µ-opioid system and how our genetic profile (specifically catechol-O-methyltransferase [ COMT] polymorphisms) impacts its activation are currently unknown. Twelve chronic temporomandibular disorder (TMD) patients and 12 healthy controls (HCs) were scanned using positron emission tomography (PET) with [11C]carfentanil, a selective radioligand for µ-opioid receptors (µORs). The first 45 min of each PET measured the µOR nondisplaceable binding potential (BPND) at resting state, and the last 45 min consisted of a 20-min masseteric pain challenge with an injection of 5% hypertonic saline. Participants were also genotyped for different COMT alleles. There were no group differences in µOR BPND at resting state (early phase). However, during the masseteric pain challenge (late phase), TMD patients exhibited significant reductions in µOR BPND (decreased [11C]carfentanil binding) in the contralateral parahippocampus ( P = 0.002) compared to HCs. The µOR BPND was also significantly lower in TMD patients with longer pain chronicity ( P < 0.001). When considering COMT genotype and chronic pain suffering, TMD patients with the COMT 158Met substitution had higher pain sensitivity and longer pain chronicity with a 5-y threshold for µOR BPND changes to occur in the parahippocampus. Together, the TMD diagnosis, COMT 158Met substitution, and pain chronicity explained 52% of µOR BPND variance in the parahippocampus (cumulative R2 = 52%, P < 0.003, and HC vs. TMD Cohen’s effect size d = 1.33 SD). There is strong evidence of dysregulation of our main analgesic and limbic systems in chronic TMD pain. The data also support precision medicine by helping identify TMD patients who may be more susceptible to chronic pain sensitivity and opioid dysfunction based on their genetic profile.
Published: 2019

49. Cholinergic system changes of falls and freezing of gait in Parkinson's disease

Author: Nicolaas I. Bohnen, Martijn L.T.M. Müller, William T. Dauer, Kirk A. Frey, Prabesh Kanel, Zhi Zhou, Roger L. Albin, and Robert A. Koeppe
Subjects: 0301 basic medicine, Male, Parkinson's disease, genetic structures, Vesicular Acetylcholine Transport Proteins, Thalamus, Striatum, Lateral geniculate nucleus, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Vesicular acetylcholine transporter, medicine, Humans, Cholinergic synapse, Research Articles, Gait Disorders, Neurologic, Aged, Aged, 80 and over, business.industry, Parkinson Disease, Middle Aged, medicine.disease, Acetylcholinesterase, Cholinergic Neurons, Corpus Striatum, 030104 developmental biology, Neurology, chemistry, Positron-Emission Tomography, Cholinergic, Accidental Falls, Female, Neurology (clinical), business, Neuroscience, 030217 neurology & neurosurgery, Biomarkers, Research Article
Abstract: Objective Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. Methods Ninety-four PD subjects underwent clinical assessment and VAChT ([18 F]FEOBV) PET. Results Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. Interpretation Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538-549.
Published: 2019

50. Comparison of Pittsburgh compound B and florbetapir in cross‐sectional and longitudinal studies

Author: William S. Brooks, Ivonne Jimenez-Velazques, Jérémie Pariente, Andrei G. Vlassenko, William E. Klunk, Robert A. Koeppe, Serge Gauthier, Smiljana Milosavljevic-Ristic, Guoqiao Wang, Michel Bottlaender, Roger Clarnette, Shauna H. Yuan, Raquel Sánchez-Valle, Russ C. Hornbeck, Ging-Yuek Robin Hsiung, Gregory Klein, Clifford R. Jack, Colin L. Masters, Nelly Joseph-Mathurin, Bruno Dubois, Barbara J. Snider, Shaney Flores, Douglas Galasko, David Wallon, Chengjie Xiong, Tammie L.S. Benzinger, Stephen Salloway, Christopher H. van Dyck, Sarah B. Berman, Brian A. Gordon, Catherine J. Mummery, Michael J. Fulham, John C. Morris, Yi Su, John M. Ringman, Randall J. Bateman, Jared R. Brosch, Martin R. Farlow, Benjamin Speidel, Suman Jayadev, Erik D. Roberson, Didier Hannequin, Lawrence S. Honig, Eric McDade, and Mario Masellis
Subjects: Positron emission tomography, Multivariate statistics, Amyloid, PiB, Amyloid pet, Neuroimaging, lcsh:Geriatrics, Imaging data, lcsh:RC346-429, Amyloid imaging, White matter, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Nuclear magnetic resonance, Genetics, medicine, Centiloid, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, Significant difference, Neurosciences, Florbetapir, lcsh:RC952-954.6, Psychiatry and Mental health, medicine.anatomical_structure, chemistry, Neurology (clinical), business, Pittsburgh compound B, 030217 neurology & neurosurgery
Abstract: Introduction Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B–based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. Methods Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. Results Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. Discussion Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.
Published: 2019

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