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1. Associations among amyloid status, age, and longitudinal regional brain atrophy in cognitively unimpaired older adults

Author

Nosheny, Rachel L, Insel, Philip S, Mattsson, Niklas, Tosun, Duygu, Buckley, Shannon, Truran, Diana, Schuff, N, Aisen, Paul S, Weiner, Michael W, and Initiative, Alzheimer's Disease Neuroimaging

Subjects
Biological Psychology, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Aging, Dementia, Behavioral and Social Science, Alzheimer's Disease, Neurodegenerative, Acquired Cognitive Impairment, Neurosciences, Brain Disorders, Basic Behavioral and Social Science, Clinical Research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Mental health, Aged, Aged, 80 and over, Amyloid beta-Peptides, Atrophy, Brain, Cognition, Cognitive Dysfunction, Databases, Factual, Female, Humans, Longitudinal Studies, Male, Middle Aged, Amyloid-beta, Brain atrophy, Alzheimer's disease, Alzheimer's Disease Neuroimaging Initiative, Amyloid-β, Clinical Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ and age on longitudinal, regional atrophy rates, while accounting for confounding variables including sex, APOE ε4 genotype, white matter lesions, and cerebrospinal fluid total and phosphorylated tau levels. We not only found overlapping patterns of atrophy in Aβ+ versus Aβ- participants but also identified regions where atrophy pattern differed between the 2 groups. Higher Aβ load was associated with increased longitudinal atrophy in the entorhinal cortex, amygdala, and hippocampus, even when accounting for age and other variables. Age was associated with atrophy in insula, fusiform gyrus, and isthmus cingulate, even when accounting for Aβ. We found age by Aβ interactions in the postcentral gyrus and lateral orbitofrontal cortex. These results elucidate the separate and related effects of age, Aβ, and other important variables on longitudinal brain atrophy rates in CU older adults.

Published
2019

2. Amyloid in dementia associated with familial FTLD: not an innocent bystander

Author

Naasan, G, Rabinovici, GD, Ghosh, P, Elofson, JD, Miller, BL, Coppola, G, Karydas, A, Fong, J, Perry, D, Lee, SE, Yokoyama, JS, Seeley, WW, Kramer, JH, Weiner, MW, Schuff, N, Jagust, WJ, Grinberg, LT, Pribadi, M, Yang, Z, Sears, R, Klein, E, Wojta, K, and Rosen, HJ

Subjects
Clinical Sciences, Psychology, Cognitive Sciences, Experimental Psychology, Neurosciences, Biological psychology, Clinical and health psychology
Abstract

Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case–control study compared clinical features, fluorodeoxyglucose-positron emission tomography metabolism and gray matter volume loss in 30 patients with familial FTLD in whom amyloid status was confirmed with autopsy or Pittsburgh compound B-PET. Compared to the amyloid-negative patients, the amyloid-positive patients performed significantly worse on several cognitive tests and showed hypometabolism and volume loss in more temporoparietal regions. Our results suggest that in FTLD amyloid positivity is associated with a more Alzheimer’s disease-like pattern of neurodegeneration.

Published
2016

4. Voxel-based T2 relaxation rate measurements in temporal lobe epilepsy (TLE) with and without mesial temporal sclerosis

Author

Mueller, S G, Laxer, K D, Schuff, N, and Weiner, Michael W

Subjects
TLE, extratemporal, voxel-based, mesiotemporal sclerosis, normal MRI, relaxation rate
Abstract

Introduction: Quantitative measurements of T-2 relaxation in the hippocampus for focus lateralization in mesial temporal lobe epilepsy (mTLE) are well established. Less is known to what degree such relaxation abnormalities also affect regions beyond the ipsilateral hippocampus. Therefore, the aim of this study was to characterize extent and distribution pattern of extrahippocampal relaxation abnormalities in TLE with (TLE-MTS) and without MRI evidence of mesial-temporal sclerosis (TLE-no). Methods: Double spin echo images (TE1/2: 20/80 ms) acquired in 24 TLE-MTS and 18 TLE-no were used to calculate relaxation rate maps. These maps were analyzed by SPM2 and by selecting regions of interest (ROI) in the hippocampus and several extrahippocampal brain regions. Results: In TLE-MTS, the results of the SPM and ROI analysis were in good agreement and showed the most severe relaxation rate decreases in the ipsilateral hippocampus but also in other ipsilateral temporal regions, orbitofrontal, and parietal regions and to a lesser degree in contralateral frontal regions. The relaxation rate decreases in TLE-no were confined to small regions in the ipsilateral anterior inferior and medial temporal lobe in the SPM analysis while ROI analysis showed additional regions in the ipsilateral hippocampus, amygdala, and anterior cingulate. Conclusion: TLE-MTS showed extensive, widespread but predominantly ipsilateral temporal and also extratemporal T-2 relaxation rate decreases. In contrast, the findings of the SPM and ROI analyses in TLE-no suggested that if relaxation rate decreases are present, they are less uniform and generally milder than in TLE-MTS. This further supports the hypothesis that TLE-no is a distinct clinicopathological entity from TLE-MTS and probably heterogeneous in itself.

Published
2007

5. Bayesian parallel Imaging with edge-preserving priors

Author

Raj, Ashish, Singh, Gurmeet, Zabih, R, Kressler, B, Wang, Y, Schuff, N, and Weiner, M

Subjects
parallel imaging, edge-preserving priors, Bayesian reconstruction, SENSE, graph cuts, regularization
Abstract

Existing parallel MRI methods are limited by a fundamental trade-off in that suppressing noise introduces aliasing artifacts. Bayesian methods with an appropriately chosen image prior offer a promising alternative; however, previous methods with spatial priors assume that intensities vary smoothly over the entire image, resulting in blurred edges. Here we introduce an edge-preserving prior (EPP) that instead assumes that intensities are piecewise smooth, and propose a new approach to efficiently compute its Bayesian estimate. The estimation task is formulated as an optimization problem that requires a non-convex objective function to be minimized in a space with thousands of dimensions. As a result, traditional continuous minimization methods cannot be applied. This optimization task is closely related to some problems in the field of computer vision for which discrete optimization methods have been developed in the last few years. We adapt these algorithms, which are based on graph cuts, to address our optimization problem. The results of several parallel imaging experiments on brain and torso regions performed under challenging conditions with high acceleration factors are shown and compared with the results of conventional sensitivity encoding (SENSE) methods. An empirical analysis indicates that the proposed method visually improves overall quality compared to conventional methods.

Published
2007

6. Comparison of methods for measuring longitudinal brain change in cognitive impairment and dementia

Author

Cardenas, V A, Du, A T, Hardin, D, Ezekiel, F, Weber, P, Jagust, W J, Chui, H C, Schuff, N, and Weiner, M W

Subjects
cognitive disorders/dementia, neuroradiology, image processing, longitudinal
Abstract

Purpose: The goal of this project was to compare MRI measures of hippocampal, entorhinal cortex (ERC), and whole brain longitudinal change in cognitively normal elderly controls (C), non-demented subjects with cognitive impairment (CI), and demented (D) subjects. Methods: 16 C, 6 CI, and 7 D subjects of comparable age were studied with MRI twice, at least 1 year apart. Longitudinal change in total brain size was measured by several methods, including computerized segmentation, non-linear warping, and change in the fluid/tissue boundaries between cerebrospinal fluid (CSF) and brain. Change in hippocampal volume was measured by semi-automated methods, and ERC volumes were manually measured. Results: The annual rate of atrophy was greater in D versus C and D versus CI for cortical gray matter (cGM) (P = 0.009 and 0.002), hippocampus (P = 0.0001 and 0.002), and for the change in the fluid/tissue boundary (P = 0.03 and 0.03). The annual rate of atrophy of ERC was greater in both CI and D versus C (P = 0.01 and 0.0002). No significant differences between groups were found using non-linear warping. Conclusions: In CI, the greatest annual rates of atrophy were in ERC, while in D the greatest annual rates of atrophy were in hippocampus and cortex. Progressive ERC atrophy was observed with a greater degree of cognitive impairment, while hippocampal and cortical atrophy were only observed in demented subjects. (C) 2002 Elsevier Science Inc. All rights reserved.

Published
2003

21. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Author

Young, A. L., Marinescu, R. V., Oxtoby, N. P., Bocchetta, M., Yong, K., Firth, N. C., Cash, D. M., Thomas, D. L., Dick, K. M., Cardoso, J., van Swieten, J., Borroni, B., Galimberti, D., Masellis, M., Tartaglia, M. C., Rowe, J. B., Graff, C., Tagliavini, F., Frisoni, G. B., Laforce, R., Finger, E., de Mendonca, A., Sorbi, S., Warren, J. D., Crutch, S., Fox, N. C., Ourselin, S., Schott, J. M., Rohrer, J. D., Alexander, D. C., Andersson, C., Archetti, S., Arighi, A., Benussi, L., Binetti, G., Black, S., Cosseddu, M., Fallstrom, M., Ferreira, C., Fenoglio, C., Freedman, M., Fumagalli, G. G., Gazzina, S., Ghidoni, R., Grisoli, M., Jelic, V., Jiskoot, L., Keren, R., Lombardi, G., Maruta, C., Meeter, L., Mead, S., van Minkelen, R., Nacmias, B., Oijerstedt, L., Padovani, A., Panman, J., Pievani, M., Polito, C., Premi, E., Prioni, S., Rademakers, R., Redaelli, V., Rogaeva, E., Rossi, G., Rossor, M., Scarpini, E., Tang-Wai, D., Thonberg, H., Tiraboschi, P., Verdelho, A., Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J., Shaw, L. M., Khachaturian, Z., Sorensen, G., Kuller, L., Raichle, M., Paul, S., Davies, P., Fillit, H., Hefti, F., Holtzman, D., Mesulam, M. M., Potter, W., Snyder, P., Schwartz, A., Montine, T., Thomas, R. G., Donohue, M., Walter, S., Gessert, D., Sather, T., Jiminez, G., Harvey, D., Bernstein, M., Thompson, P., Schuff, N., Borowski, B., Gunter, J., Senjem, M., Vemuri, P., Jones, D., Kantarci, K., Ward, C., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Taylor-Reinwald, L., Lee, V., Korecka, M., Figurski, M., Crawford, K., Neu, S., Foroud, T. M., Potkin, S., Shen, L., Faber, K., Kim, S., Nho, K., Thal, L., Buckholtz, N., Albert, M., Frank, R., Hsiao, J., Kaye, J., Quinn, J., Lind, B., Carter, R., Dolen, S., Schneider, L. S., Pawluczyk, S., Beccera, M., Teodoro, L., Spann, B. M., Brewer, J., Vanderswag, H., Fleisher, A., Heidebrink, J. L., Lord, J. L., Mason, S. S., Albers, C. S., Knopman, D., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Rountree, S., Dang, M., Stern, Y., Honig, L. S., Bell, K. L., Ances, B., Carroll, M., Leon, S., Mintun, M. A., Schneider, S., Oliver, A., Marson, D., Griffith, R., Clark, D., Geldmacher, D., Brockington, J., Roberson, E., Grossman, H., Mitsis, E., de Toledo-Morrell, L., Shah, R. C., Duara, R., Varon, D., Greig, M. T., Roberts, P., Onyike, C., D'Agostino, D., Kielb, S., Galvin, J. E., Cerbone, B., Michel, C. A., Rusinek, H., de Leon, M. J., Glodzik, L., De Santi, S., Doraiswamy, P. M., Petrella, J. R., Wong, T. Z., Arnold, S. E., Karlawish, J. H., Wolk, D., Smith, C. D., Jicha, G., Hardy, P., Sinha, P., Oates, E., Conrad, G., Lopez, O. L., Oakley, M. A., Simpson, D. M., Porsteinsson, A. P., Goldstein, B. S., Martin, K., Makino, K. M., Ismail, M. S., Brand, C., Mulnard, R. A., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Weiner, M., Martin-Cook, K., Devous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Swerdlow, R. H., Apostolova, L., Tingus, K., Woo, E., Silverman, D. H., P. H., Lu, Bartzokis, G., Graff-Radford, N. R., Parfitt, F., Kendall, T., Johnson, H., Farlow, M. R., Hake, A. M., Matthews, B. R., Herring, S., Hunt, C., van Dyck, C. H., Carson, R. E., Macavoy, M. G., Chertkow, H., Bergman, H., Hosein, C., Stefanovic, B., Caldwell, C., Hsiung, G. -Y. R., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Bernick, C., Munic, D., Kerwin, D., Mesulam, M. -M., Lipowski, K., C. -K., Wu, Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, R. S., Reynolds, B., Sperling, R. A., Johnson, K. A., Marshall, G., Frey, M., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M. N., Belden, C. M., Jacobson, S. A., Sirrel, S. A., Kowall, N., Killiany, R., Budson, A. E., Norbash, A., Johnson, P. L., Allard, J., Lerner, A., Ogrocki, P., Hudson, L., Fletcher, E., Carmichael, O., Olichney, J., Decarli, C., Kittur, S., Borrie, M., Lee, T. -Y., Bartha, R., Johnson, S., Asthana, S., Carlsson, C. M., Potkin, S. G., Preda, A., Nguyen, D., Tariot, P., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D. W., Kataki, M., Adeli, A., Zimmerman, E. A., Celmins, D., Brown, A. D., Pearlson, G. D., Blank, K., Anderson, K., Santulli, R. B., Kitzmiller, T. J., Schwartz, E. S., Sink, K. M., Williamson, J. D., Garg, P., Watkins, F., Ott, B. R., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, H. J., Miller, B. L., Mintzer, J., Spicer, K., Bachman, D., Pasternak, S., Rachinsky, I., Drost, D., Pomara, N., Hernando, R., Sarrael, A., Schultz, S. K., Ponto, L. L. B., Shim, H., Smith, K. E., Relkin, N., Chaing, G., Raudin, L., Smith, A., Fargher, K., Raj, B. A., Neylan, T., Grafman, J., Davis, M., Morrison, R., Hayes, J., Finley, S., Friedl, K., Fleischman, D., Arfanakis, K., James, O., Massoglia, D., Fruehling, J. J., Harding, S., Peskind, E. R., Petrie, E. C., Li, G., Yesavage, J. A., Taylor, J. L., and Furst, A. J.

Published
2018

22. Calbindin and parvalbumin are early markers of non-mitotically regenerating hair cells in the bullfrog vestibular otolith organs

Author

Steyger, P. S, Burton, M, Hawkins, J. R, Schuff, N. R, and Baird, R. A

Subjects
Life Sciences (General)
Abstract

Earlier studies have demonstrated hair cell regeneration in the absence of cell proliferation, and suggested that supporting cells could phenotypically convert into hair cells following hair cell loss. Because calcium-binding proteins are involved in gene up-regulation, cell growth, and cell differentiation, we wished to determine if these proteins were up-regulated in scar formations and regenerating hair cells following gentamicin treatment. Calbindin and parvalbumin immunolabeling was examined in control or gentamicin-treated (GT) bullfrog saccular and utricular explants cultured for 3 days in amphibian culture medium or amphibian culture medium supplemented with aphidicolin, a blocker of nuclear DNA replication in eukaryotic cells. In control cultures, calbindin and parvalbumin immunolabeled the hair bundles and, less intensely, the cell bodies of mature hair cells. In GT or mitotically-blocked GT (MBGT) cultures, calbindin and parvalbumin immunolabeling was also seen in the hair bundles, cuticular plates, and cell bodies of hair cells with immature hair bundles. Thus, these antigens were useful markers for both normal and regenerating hair cells. Supporting cell immunolabeling was not seen in control cultures nor in the majority of supporting cells in GT cultures. In MBGT cultures, calbindin and parvalbumin immunolabeling was up-regulated in the cytosol of single supporting cells participating in scar formations and in supporting cells with hair cell-like characteristics. These data provide further evidence that non-mitotic hair cell regeneration in cultures can be accomplished by the conversion of supporting cells into hair cells.

Published
1997
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23. Intracellular distributions and putative functions of calcium-binding proteins in the bullfrog vestibular otolith organs

Author

Baird, R. A, Steyger, P. S, and Schuff, N. R

Subjects
Life Sciences (General)
Abstract

Hair cells in the bullfrog vestibular otolith organs were immunolabeled by monoclonal and polyclonal antisera against calbindin (CaB), calmodulin (CaM), calretinin (CaR), and parvalbumin (PA). S-100, previously shown to immunolabel striolar hair cells in fish vestibular organs, only weakly immunolabeled hair cells in the bullfrog vestibular otolith organs. Immunolabeling was not detected in supporting cells. With the exception of CaR, myelinated axons and unmyelinated nerve terminals were immunolabeled by all of the above antisera. Immunolabeling was seen in all saccular hair cells, although hair cells at the macular margins were immunolabeled more intensely for CaB, CaM, and PA than more centrally located hair cells. As the macula margins are known to be a growth zone, this labeling pattern suggests that marginal hair cells up-regulate their calcium-binding proteins during hair cell development. In the utriculus, immunolabeling for CaM and PA was generally restricted to striolar hair cells. CaR immunolabeling was restricted to the stereociliary array. Immunolabeling for other calcium-binding proteins was generally seen in both the cell body and hair bundles of hair cells, although this labeling was often localized to the stereociliary array and the apical portion of the cell body. CaM and PA immunolabeling in the stereociliary array in saccular and utricular striolar cells suggests a functional role for these proteins in mechanoelectric transduction and adaptation.

Published
1997
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25. Regional differences in lectin binding patterns of vestibular hair cells

Author

Baird, Richard A, Schuff, N. R, and Bancroft, J

Subjects
Life Sciences (General)
Abstract

Surface glycoconjugates of hair cells and supporting cells in the vestibular endorgans of the bullfrog were identified using biotinylated lectins with different carbohydrate specificities. Lectin binding in hair cells was consistent with the presence of glucose and mannose (CON A), galactose (RCA-I), N-acetylgalactosamine (VVA), but not fucose (UEA-I) residues. Hair cells in the bullfrog sacculus, unlike those in the utriculus and semicircular canals, did not stain for N-acetylglucosamine (WGA) or N-acetylgalactosamine (VVA). By contrast, WGA and, to a lesser extent, VVA, differentially stained utricular and semicircular canal hair cells, labeling hair cells located in peripheral, but not central, regions. In mammals, WGA uniformly labeled Type 1 hair cells while labeling, as in the bullfrog, Type 2 hair cells only in peripheral regions. These regional variations were retained after enzymatic digestion. We conclude that vestibular hair cells differ in their surface glycoconjugates and that differences in lectin binding patterns can be used to identify hair cell types and to infer the epithelial origin of isolated vestibular hair cells.

Published
1994

26. Peripheral innervation patterns of vestibular nerve afferents in the bullfrog utriculus

Author

Baird, Richard A and Schuff, N. R

Subjects
Life Sciences (General)
Abstract

Vestibular nerve afferents innervating the bullfrog utriculus differ in their response dynamics and sensitivity to natural stimulation. They also supply hair cells that differ markedly in hair bundle morphology. To examine the peripheral innervation patterns of individual utricular afferents more closely, afferent fibers were labeled by the extracellular injection of horseradish peroxidase (HRP) into the vestibular nerve after sectioning the vestibular nerve medial to Scarpa's ganglion to allow the degeneration of sympathetic and efferent fibers. The peripheral arborizations of individual afferents were then correlated with the diameters of their parent axons, the regions of the macula they innervate, and the number and type of hair cells they supply. The utriculus is divided by the striola, a narrow zone of distinctive morphology, into media and lateral parts. Utiricular afferents were classified as striolar or extrastriolar according to the epithelial entrance of their parent axons and the location of their terminal fields. In general, striolar afferents had thicker parent axons, fewer subepithelial bifurcations, larger terminal fields, and more synaptic endings than afferents in extrstriolar regions. Afferents in a juxtastriolar zone, immediately adjacent to the medial striola, had innervation patterns transitional between those in the striola and more peripheral parts of the medial extrastriola. moast afferents innervated only a single macular zone. The terminal fields of striolar afferents, with the notable exception of a few afferents with thin parent axons, were generally confined to one side of the striola. Hair cells in the bullfrog utriculus have perviously been classified into four types based on hair bundle morphology. Afferents in the extrastriolar and juxtastriolar zones largely or exclusively innervated Type B hair cells, the predominant hair cell type in the utricular macula. Striolar afferents supplied a mixture of four hair cell types, but largely contacted Type B and Type C hair cells, particularly on the outer rows of the medial striola. Afferents supplying more central striolar regions innervated fewer Type B and larger numbers of Type E and Type F hair cells. Striolar afferents with thin parent axons largely supplied Type E hair cells with bulbed kniocilia in the innermost striolar rows.

Published
1994

27. Hair cell regeneration in the bullfrog vestibular otolith organs following aminoglycoside toxicity

Author

Baird, Richard A, Torres, M. A, and Schuff, N. R

Subjects
Life Sciences (General)
Abstract

Adult bullfrogs were given single intraotic injections of the aminoglycoside antibiotic gentamicin sulfate and sacrificed at postinjection times ranging from 0.5 to 9 days. The saccular and utricular maculae of normal and injected animals were examined in wholemount and cross-section. Intraotic 200 (mu) M gentamicin concentrations resulted in the uniform destruction of the hair bundles and, at later times, the cell bodies of saccular hair cells. In the utriculus, striolar hair cells were selectively damaged while extrastriolar hair cells were relatively unaffected. Regenerating hair cells, identified in sectioned material by their small cell bodies and short, well-formed hair bundles, were seen in the saccular and utricular maculae as early as 24-48 h postinjection. Immature versions of mature hair cell types in both otolith organs were recognized by the presence of absence of a bulbed kinocilia and the relative lengths of their kinocilia and longest sterocilia. Utricular hair cell types with kinocilia longer than their longest stereocilia were observed at earlier times than hair cell types with shorter kinocilia. In the same sacculus, the hair bundles of gentamicin-treated animals, even at 9 days postinjection, were significantly smaller than those of normal animals. The hair bundles of utricular hair cells, on the other hand, reached full maturity within the same time period.

Published
1994

28. Regional differences in lectin binding patterns of vestibular hair cells

Author

Baird, R. A, Schuff, N. R, and Bancroft, J

Subjects
Life Sciences (General)
Abstract

Surface glycoconjugates of hair cells and supporting cells in the vestibular endorgans of the bullfrog were identified using biotinylated lectins with different carbohydrate specificities. Lectin binding in hair cells was consistent with the presence of glucose and mannose (CON A), galactose (RCA-I), N-acetylglucosamine (WGA), N-acetylgalactosamine (VVA), but not fucose (UEA-I) residues. Hair cells in the bullfrog sacculus, unlike those in the utriculus and semicircular canals, did not strain for N-acetylglucosamine (WGA) or N-acetylgalactosamine (VVA). By contrast, WGA and, to a lesser extent, VVA, differentially stained utricular and semicircular canal hair cells, labeling hair cells located in peripheral, but not central, regions. In mammals, WGA uniformly labeled Type I hair cells while labeling, as in the bullfrog, Type II hair cells only in peripheral regions. These regional variations were retained after enzymatic digestion. We conclude that vestibular hair cells differ in their surface glycoconjugates and that differences in lectin binding patterns can be used to identify hair cell types and to infer the epithelial origin of isolated vestibular hair cells.

Published
1993
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29. Hair cell regeneration in the bullfrog vestibular otolith organs following aminoglycoside toxicity

Author

Baird, R. A, Torres, M. A, and Schuff, N. R

Subjects
Life Sciences (General)
Abstract

Adult bullfrog were given single intraotic injections of the aminoglycoside antibiotic gentamicin sulfate and sacrificed at postinjection times ranging from 0.5 to 9 days. The saccular and utricular maculae of normal and injected animals were examined in wholemount and cross-section. Intraotic 200 microM gentamicin concentrations resulted in the uniform destruction of the hair bundles and, at later times, the cell bodies of saccular hair cells. In the utriculus, striolar hair cells were selectively damaged while extrastriolar hair cells were relatively unaffected. Regenerating hair cells, identified in sectioned material by their small cell bodies and short, well-formed hair bundles, were seen in the saccular and utricular maculae as early as 24-48 h postinjection. Immature versions of mature hair cell types in both otolith organs were recognized by the presence or absence of a bulbed kinocilia and the relative lengths of their kinocilia and longest stereocilia. Utricular hair cell types with kinocilia longer than their longest stereocilia were observed at earlier than hair cell types with shorter kinocilia. In the sacculus, the hair bundles of gentamicin-treated animals, even at 9 days postinjection, were significantly smaller than those of normal animals. The hair bundles of utricular hair cells, on the other hand, reached full maturity within the same time period.

Published
1993
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30. Association between anticholinergic medication use and cognition, brain metabolism, and brain atrophy in cognitively normal older adults

Author

Risacher, SL, McDonald, BC, Tallman, EF, West, JD, Farlow, MR, Unverzagt, FW, Gao, S, Boustani, M, Crane, PK, Petersen, RC, Jack, CR, Jagust, WJ, Aisen, PS, Weiner, MW, Saykin, AJ, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Morris, J, Shaw, LM, Khachaturian, Z, Sorensen, G, Carrillo, M, Kuller, L, Raichle, M, Paul, S, Davies, P, Fillit, H, Hefti, F, Holtzman, D, Mesulam, MM, Potter, W, Snyder, PJ, Schwartz, A, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Balasubramanian, AB, Mason, J, Sim, I, Harvey, D, Bernstein, M, Fox, N, Thompson, P, Schuff, N, DeCarli, C, Borowski, B, Gunter, J, Senjem, M, Vemuri, P, Jones, D, Kantarci, K, Ward, C, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Landau, S, Cairns, NJ, Householder, E, Taylor-Reinwald, L, Lee, V, Korecka, M, Figurski, M, Crawford, K, and Neu, S

Abstract

Copyright 2016 American Medical Association. All rights reserved. IMPORTANCE The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications. OBJECTIVE To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS). DESIGN, SETTING, AND PARTICIPANTS The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC- participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015. MAIN OUTCOMES AND MEASURES Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC- participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression. RESULTS The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores onWeschler Memory Scale-Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC- participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC- participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC- participants; P = .04) than the 350 AC- participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC- participants. CONCLUSIONS AND RELEVANCE The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.

Published
2016

32. Sex-dependent association of common variants of microcephaly genes with brain structure

Author

Rimol, L. M., Agartz, I., Djurovic, S., Brown, A. A., Roddey, J. C., Kahler, A. K., Mattingsdal, M., Athanasiu, L., Joyner, A. H., Schork, N. J., Halgren, E., Sundet, K., Melle, I., Dale, A. M., Andreassen, O. A., Weiner, M., Thal, L., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J., Toga, A. W., Beckett, L., Green, R. C., Gamst, A., Potter, W. Z., Montine, T., Anders, D., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., Bandy, D., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Shaw, L., Lee, V. M.- Y., Korecka, M., Crawford, K., Neu, S., Harvey, D., Kornak, J., Kachaturian, Z., Frank, R., Snyder, P. J., Molchan, S., Kaye, J., Vorobik, R., Quinn, J., Schneider, L., Pawluczyk, S., Spann, B., Fleisher, A. S., Vanderswag, H., Heidebrink, J. L., Lord, J. L., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Stern, Yaakov, Honig, L. S., Bell, K. L., Morris, J. C., Mintun, M. A., Schneider, S., Marson, D., Griffith, R., Badger, B., Grossman, H., Tang, C., Stern, J., deToledo-Morrell, L., Shah, R. C., Bach, J., Duara, R., Isaacson, R., Strauman, S., Albert, M. S., Pedroso, J., Toroney, J., Rusinek, H., de Leon, M. J., De Santi, S. M., Doraiswamy, P. M., Petrella, J. R., Aiello, M., Clark, C. M., Pham, C., Nunez, J., Smith, C. D., Given II, C. A., Hardy, P., DeKosky, S. T., Oakley, M., Simpson, D. M., Ismail, M. S., Porsteinsson, A., McCallum, C., Cramer, S. C., Mulnard, R. A., McAdams-Ortiz, C., Diaz-Arrastia, R., Martin-Cook, K., DeVous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Laubinger, M. M., Bartzokis, G., Silverman, D. H. S., Lu, P. H., Fletcher, R., Parfitt, F., Johnson, H., Farlow, M., Herring, S., Hake, A. M., van Dyck, C. H., MacAvoy, M. G., Bifano, L. A., Chertkow, H., Bergman, H., Hosein, C., Black, S., Graham, S., Caldwell, C., Feldman, H., Assaly, M., Hsiung, G.-Y. R., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Gitelman, D., Johnson, N., Mesulam, M., Sadowsky, C., Villena, T., Mesner, S., Aisen, P. S., Johnson, K. B., Behan, K. E., Sperling, R. A., Rentz, D. M., Johnson, K. A., Rosen, A., Tinklenberg, J., Ashford, W., Sabbagh, M., Connor, D., Obradov, S., Killiany, R., Norbash, A., Obisesan, T. O., Jayam-Trouth, A., Wang, P., Auchus, A. P., Huang, J., Friedland, R. P., DeCarli, C., Fletcher, E., Carmichael, O., Kittur, S., Mirje, S., Johnson, S. C., Borrie, M., Lee, T.-Y., Asthana, S., Carlsson, C. M., Potkin, S. G., Highum, D., Preda, A., Nguyen, D., Tariot, P. N., Hendin, B. A., Scharre, D. W., Kataki, M., Beversdorf, D. Q., Zimmerman, E. A., Celmins, D., Brown, A. D., Gandy, S., Marenberg, M. E., Rovner, B. W., Pearlson, G., Blank, K., Anderson, K., Saykin, A. J., Santulli, R. B., Pare, N., Williamson, J. D., Sink, K. M., Potter, H., Ashok Raj, B., Giordano, A., Ott, B. R., Wu, C.-K., Cohen, R., Wilks, K. L., and Alzheimer's Disease Neuroimaging Initiative

Subjects
Adult, Male, Microcephaly, Molecular Sequence Data, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Brain mapping, ASPM, Sex Factors, medicine, Animals, Humans, SNP, Genetic Predisposition to Disease, Genetics, Brain Mapping, Multidisciplinary, CDK5RAP2, Brain morphometry, Brain, Middle Aged, Biological Sciences, medicine.disease, Magnetic Resonance Imaging, Phenotype, Brain size, Female
Abstract

Loss-of-function mutations in the genes associated with primary microcephaly (MCPH) reduce human brain size by about two-thirds, without producing gross abnormalities in brain organization or physiology and leaving other organs largely unaffected [Woods CG, et al. (2005) Am J Hum Genet 76:717–728]. There is also evidence suggesting that MCPH genes have evolved rapidly in primates and humans and have been subjected to selection in recent human evolution [Vallender EJ, et al. (2008) Trends Neurosci 31:637–644]. Here, we show that common variants of MCPH genes account for some of the common variation in brain structure in humans, independently of disease status. We investigated the correlations of SNPs from four MCPH genes with brain morphometry phenotypes obtained with MRI. We found significant, sex-specific associations between common, nonexonic, SNPs of the genes CDK5RAP2 , MCPH1 , and ASPM , with brain volume or cortical surface area in an ethnically homogenous Norwegian discovery sample ( n = 287), including patients with mental illness. The most strongly associated SNP findings were replicated in an independent North American sample ( n = 656), which included patients with dementia. These results are consistent with the view that common variation in brain structure is associated with genetic variants located in nonexonic, presumably regulatory, regions.

Published
2009

33. MR Vascular Fingerprinting in Stroke and Brain Tumors Models

Author

Lemasson, B., primary, Pannetier, N., additional, Coquery, N., additional, Boisserand, Ligia S. B., additional, Collomb, Nora, additional, Schuff, N., additional, Moseley, M., additional, Zaharchuk, G., additional, Barbier, E. L., additional, and Christen, T., additional

Published
2016
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34. Large-scale genomics unveil polygenic architecture of human cortical surface area

Author

Chen, CH, Peng, Q, Schork, AJ, Lo, MT, Fan, CC, Wang, Y, Desikan, RS, Bettella, F, Hagler, DJ, Westlye, LT, Kremen, WS, Jernigan, TL, Le Hellard, S, Steen, VM, Espeseth, T, Huentelman, M, Håberg, AK, Agartz, I, Djurovic, S, Andreassen, OA, Schork, N, Dale, AM, McCabe, C, Chang, L, Akshoomoff, N, Newman, E, Ernst, T, Van Zijl, P, Kuperman, J, Murray, S, Bloss, C, Appelbaum, M, Gamst, A, Thompson, W, Bartsch, H, Weiner, M, Aisen, P, Petersen, R, Jack, CR, Jagust, W, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Saykin, AJ, Morris, J, Shaw, LM, Khachaturian, Z, Sorensen, G, Carrillo, M, Kuller, L, Raichle, M, Paul, S, Davies, P, Fillit, H, Hefti, F, Holtzman, D, Mesulman, MM, Potter, W, Snyder, PJ, Schwartz, A, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Harvey, D, Bernstein, M, Fox, N, Thompson, P, Schuff, N, DeCarli, C, Borowski, B, Gunter, J, Senjem, M, Vemuri, P, Jones, D, Kantarci, K, Ward, C, Koeppe, RA, Foster, N, and Reiman, EM

Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from ∼ 2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a larger heritable effect for visual and auditory sensory and insular cortices (h2 ∼ 0.45). Genome-wide SNPs collectively account for, on average, about half of twin heritability across cortical regions (N = 466 twins). We find enriched genetic effects in or near genes. We also observe that SNPs in evolutionarily more conserved regions contributed significantly to the heritability of cortical surface area, particularly, for medial and temporal cortical regions. SNPs in less conserved regions contributed more to occipital and dorsolateral prefrontal cortices.

Published
2015

35. Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2

Author

Jack, CR, Barnes, J, Bernstein, MA, Borowski, BJ, Brewer, J, Clegg, S, Dale, AM, Carmichael, O, Ching, C, DeCarli, C, Desikan, RS, Fennema-Notestine, C, Fjell, AM, Fletcher, E, Fox, NC, Gunter, J, Gutman, BA, Holland, D, Hua, X, Insel, P, Kantarci, K, Killiany, RJ, Krueger, G, Leung, KK, Mackin, S, Maillard, P, Malone, IB, Mattsson, N, McEvoy, L, Modat, M, Mueller, S, Nosheny, R, Ourselin, S, Schuff, N, Senjem, ML, Simonson, A, Thompson, PM, Rettmann, D, Vemuri, P, Walhovd, K, Zhao, Y, Zuk, S, and Weiner, M

Subjects
mental disorders
Abstract

© 2015 The Authors. Published by Elsevier Inc. Introduction Alzheimer's Disease Neuroimaging Initiative (ADNI) is now in its 10th year. The primary objective of the magnetic resonance imaging (MRI) core of ADNI has been to improve methods for clinical trials in Alzheimer's disease (AD) and related disorders. Methods We review the contributions of the MRI core from present and past cycles of ADNI (ADNI-1, -Grand Opportunity and -2). We also review plans for the future-ADNI-3. Results Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. Discussion Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in AD and will continue to do so in the future.

Published
2015

36. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE

Author

Ayton, S, Faux, NG, Bush, AI, Weiner, MW, Aisen, P, Petersen, R, Jack, CR, Jagust, W, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Saykin, AJ, Morris, J, Shaw, LM, Khachaturian, Z, Sorensen, G, Kuller, L, Raichle, M, Paul, S, Davies, P, Fillit, H, Hefti, F, Holtzman, D, Mesulam, MM, Potter, W, Snyder, P, Schwartz, A, Montine, T, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Jiminez, G, Harvey, D, Bernstein, M, Fox, N, Thompson, P, Schuff, N, Borowski, B, Gunter, J, Senjem, M, Vemuri, P, Jones, D, Kantarci, K, Ward, C, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Landau, S, Cairns, NJ, Householder, E, Taylor-Reinwald, L, Lee, V, Korecka, M, Figurski, M, Crawford, K, Neu, S, Foroud, TM, Potkin, S, Shen, L, Faber, K, Kim, S, Nho, K, Thal, L, Buckholtz, N, Albert, M, Frank, R, Hsiao, J, Kaye, J, Quinn, J, Lind, B, Carter, R, Dolen, S, Schneider, LS, Pawluczyk, S, Beccera, M, Teodoro, L, Spann, BM, Brewer, J, Vanderswag, H, Fleisher, A, Heidebrink, JL, Lord, JL, Mason, SS, Albers, CS, Knopman, D, Johnson, K, Doody, RS, Villanueva-Meyer, J, Chowdhury, M, and Rountree, S

Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ε4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ε4 being the major genetic risk factor for AD.

Published
2015

37. Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

Author

Jahanshad, N., Rajagopalan, P., Hua, X., Hibar, D. P., Nir, T. M., Toga, A. W., Jack, C. R., Saykin, A. J., Green, R. C., Weiner, M. W., Medland, S. E., Montgomery, G. W., Hansell, N. K., McMahon, K. L., de Zubicaray, G. I., Martin, N. G., Wright, M. J., Thompson, P. M., the Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aisen, P., Petersen, R., Jagust, W., Trojanowski, J. Q., Beckett, L., Morris, J., Liu, E., Montine, T., Gamst, A., Thomas, R. G., Donohue, M., Walter, S., Gessert, D., Sather, T., Harvey, D., Kornak, J., Dale, A., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., DeCarli, C., Bandy, D., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Mathis, C., Cairns, N. J., Taylor-Reinwald, L., Trojanowki, J. Q., Shaw, L., Lee, V. M. Y., Korecka, M., Crawford, K., Neu, S., Foroud, T. M., Potkin, S., Shen, L., Khachaturian, Z., Frank, R., Snyder, P. J., Molchan, S., Kaye, J., Quinn, J., Lind, B., Dolen, S., Schneider, L. S., Pawluczyk, S., Spann, B. M., Brewer, J., Vanderswag, H., Heidebrink, J. L., Lord, J. L., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Stern, Yaakov, Honig, L. S., Bell, K. L., Morris, J. C., Ances, B., Carroll, M., Leon, S., Mintun, M. A., Schneider, S., Marson, D., Griffith, R., Clark, D., Grossman, H., Mitsis, E., Romirowsky, A., deToledo-Morrell, L., Shah, R. C., Duara, R., Varon, D., Roberts, P., Albert, M., Onyike, C., Kielb, S., Rusinek, H., de Leon, M. J., Glodzik, L., De Santi, S., Doraiswamy, P. M., Petrella, J. R., Coleman, R. E., Arnold, S. E., Karlawish, J. H., Wolk, D., Smith, C. D., Jicha, G., Hardy, P., Lopez, O. L., Oakley, M., Simpson, D. M., Porsteinsson, A. P., Goldstein, B. S., Martin, K., Makino, K. M., Ismail, M. S., Brand, C., Mulnard, R. A., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Martin-Cook, K., DeVous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Swerdlow, R. H., Apostolova, L., Lu, P. H., Bartzokis, G., Silverman, D. H. S., Graff-Radford, N. R., Parfitt, F., Johnson, H., Farlow, M. R., Hake, A. M., Matthews, B. R., Herring, S., van Dyck, C. H., Carson, R. E., MacAvoy, M. G., Chertkow, H., Bergman, H., Hosein, C., Black, S., Stefanovic, B., Caldwell, C., Hsiung, G.-Y. R., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Munic, D., Kerwin, D., Mesulam, M.-M., Lipowski, K., Wu, C.-K., Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, R. S., Reynolds, B., Sperling, R. A., Johnson, K. A., Marshall, G., Frey, M., Yesavage, J., Taylor, J. L., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M., Belden, C., Jacobson, S., Kowall, N., Killiany, R., Budson, A. E., Norbash, A., Johnson, P. L., Obisesan, T. O., Wolday, S., Bwayo, S. K., Lerner, A., Hudson, L., Ogrocki, P., Fletcher, E., Carmichael, O., Olichney, J., Kittur, S., Borrie, M., Lee, T.- Y., Bartha, R., Johnson, S., Asthana, S., Carlsson, C. M., Potkin, S. G., Preda, A., Nguyen, D., Tariot, P., Fleisher, A., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, D. W., Kataki, M., Zimmerman, E. A., Celmins, D., Brown, A. D., Pearlson, G. D., Blank, K., Anderson, K., Santulli, R. B., Schwartz, E. S., Sink, K. M., Williamson, J. D., Garg, P., Watkins, F., Ott, B. R., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, H. J., Miller, B. L., Mintzer, J., Longmire, C. F., Spicer, K., Finger, E., Rachinsky, I., and Drost, D.

Published
2013
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38. T2-based arterial spin labeling measurements of blood to tissue water transfer in human brain

Author

Gregori, J., Schuff, N., Kern, R., Günther, M., and Publica

Abstract

Purpose: To investigate blood to tissue water transfer in human brain, in vivo and spatially resolved using a T2-based arterial spin labeling (ASL) method with 3D readout. Materials and Methods: A T2-ASL method is introduced to measure the water transfer processes between arterial blood and brain tissue based on a 3D-GRASE (gradient and spin echo) pulsed ASL sequence with multiecho readout. An analytical mathematical model is derived based on the General Kinetic Model, including blood and tissue compartment, T1 and T2 relaxation, and a blood-to-tissue transfer term. Data were collected from healthy volunteers on a 3 T system. The mean transfer time parameter T(ind bl --> ex) (blood to extravascular compartment transfer time) was derived voxelwise by nonlinear least-squares fitting. Results: Whole-brain maps of T(ind bl --> ex) show stable results in cortical regions, yielding different values depending on the brain region. The mean value across subjects and regions of interest (ROIs) in gray matter was 440 ± 30 msec. Conclusion: A novel method to derive whole-brain maps of blood to tissue water transfer dynamics is demonstrated. It is promising for the investigation of underlying physiological mechanisms and development of diagnostic applications in cerebrovascular diseases.

Published
2013

39. Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans

Author

Bakken, TE, Roddey, JC, Djurovic, S, Akshoomoff, N, Amaral, DG, Bloss, CS, Casey, BJ, Chang, L, Ernst, TM, Gruen, JR, Jernigan, TL, Kaufmann, WE, Kenet, T, Kennedy, DN, Kuperman, JM, Murray, SS, Sowell, ER, Rimol, LM, Mattingsdal, M, Melle, I, Agartz, I, Andreassen, OA, Schork, NJ, Dale, AM, Alzheimer’s Disease Neuroimaging Initiative, Pediatric Imaging, Neurocognition, Genetics Study, Weiner, M, Aisen, P, Petersen, R, Jack, CR, Jr, Jagust, W, Trojanowki, JQ, Toga, AW, Beckett, L, Green, RC, Saykin, AJ, Morris, J, Liu, E, Montine, T, Gamst, A, Thomas, RG, Donohue, M, Walter, S, Gessert, D, Sather, T, Harvey, D, Kornak, J, Dale, A, Bernstein, M, Felmlee, J, Fox, N, Thompson, P, Schuff, N, Alexander, G, DeCarli, C, Bandy, D, Koeppe, RA, Foster, N, Reiman, EM, Chen, K, Mathis, C, Cairns, NJ, Taylor-Reinwald, L, Shaw, L, Lee, VM, Korecka, M, Crawford, K, Neu, S, Foroud, TM, Potkin, S, Shen, L, Kachaturian, Z, Frank, R, Snyder, PJ, Molchan, S, Kaye, J, Quinn, J, Lind, B, Dolen, S, Schneider, LS, Pawluczyk, S, Spann, BM, Brewer, J, Vanderswag, H, Heidebrink, JL, Lord, JL, Johnson, K, Doody, RS, Villanueva-Meyer, J, Chowdhury, M, Stern, Yaakov, Honig, LS, Bell, KL, Morris, JC, Ances, B, Carroll, M, Leon, S, Mintun, MA, Schneider, S, Marson, D, Griffith, R, Clark, D, Grossman, H, Mitsis, E, Romirowsky, A, deToledo-Morrell, L, Shah, RC, Duara, R, Varon, D, Roberts, P, Albert, M, Onyike, C, Kielb, S, Rusinek, H, de, Leon, MJ, Glodzik, L, De, Santi, S, Doraiswamy, PM, Petrella, JR, Coleman, RE, Arnold, SE, Karlawish, JH, Wolk, D, Smith, CD, Jicha, G, Hardy, P, Lopez, OL, Oakley, M, Simpson, DM, Porsteinsson, AP, Goldstein, BS, Martin, K, Makino, KM, Ismail, MS, Brand, C, Mulnard, RA, Thai, G, Mc-Adams-Ortiz, C, Womack, K, Mathews, D, Quiceno, M, Diaz-Arrastia, R, King, R, Martin-Cook, K, DeVous, M, Levey, AI, Lah, JJ, Cellar, JS, Burns, JM, Anderson, HS, Swerdlow, RH, Apostolova, L, Lu, PH, Bartzokis, G, Silverman, DH, Graff-Radford, NR, Parfitt, F, Johnson, H, Farlow, MR, Hake, AM, Matthews, BR, Herring, S, van, Dyck, CH, Carson, RE, MacAvoy, MG, Chertkow, H, Bergman, H, Hosein, C, Black, S, Stefanovic, B, Caldwell, C, Ging-Yuek, Hsiung, R, Feldman, H, Mudge, B, Assaly, M, Kertesz, A, Rogers, J, Trost, D, Bernick, C, Munic, D, Kerwin, D, Mesulam, MM, Lipowski, K, Wu, CK, Johnson, N, Sadowsky, C, Martinez, W, Villena, T, Turner, RS, Reynolds, B, Sperling, RA, Johnson, KA, Marshall, G, Frey, M, Yesavage, J, Taylor, JL, Lane, B, Rosen, A, Tinklenberg, J, Sabbagh, M, Belden, C, Jacobson, S, Kowall, N, Killiany, R, Budson, AE, Norbash, A, Johnson, PL, Obisesan, TO, Wolday, S, Bwayo, SK, Lerner, A, Hudson, L, Ogrocki, P, Fletcher, E, Carmichael, O, Olichney, J, Kittur, S, Borrie, M, Lee, TY, Bartha, R, Johnson, S, Asthana, S, Carlsson, CM, Potkin, SG, Preda, A, Nguyen, D, Tariot, P, Fleisher, A, Reeder, S, Bates, V, Capote, H, Rainka, M, Scharre, DW, Kataki, M, Zimmerman, EA, Celmins, D, Brown, AD, Pearlson, GD, Blank, K, Anderson, K, Santulli, RB, Schwartz, ES, Sink, KM, Williamson, JD, Garg, P, Watkins, F, Ott, BR, Querfurth, H, Tremont, G, Salloway, S, Malloy, P, Correia, S, Rosen, HJ, Miller, BL, Mintzer, J, Longmire, CF, Spicer, K, Finger, E, Rachinsky, I, Drost, D, Jernigan, T, McCabe, C, Grant, E, Ernst, T, Kuperman, J, Chung, Y, Murray, S, Bloss, C, Darst, B, Pritchett, L, Saito, A, Amaral, D, DiNino, M, Eyngorina, B, Sowell, E, Houston, S, Soderberg, L, Kaufmann, W, van, Zijl, P, Rizzo-Busack, H, Javid, M, Mehta, N, Ruberry, E, Powers, A, Rosen, B, Gebhard, N, Manigan, H, Frazier, J, Kennedy, D, Yakutis, L, Hill, M, Gruen, J, Bosson-Heenan, J, and Carlson, H

Subjects
anatomy & histology, pathology [Visual Cortex], Adult, Diagnostic Imaging, Male, Linkage disequilibrium, Visual perception, genetic structures, Adolescent, Genotype, Imaging genetics, methods [Diagnostic Imaging], Single-nucleotide polymorphism, Genome-wide association study, Saccharomyces cerevisiae, Biology, Polymorphism, Single Nucleotide, Cohort Studies, methods [Brain Mapping], pathology [Brain], Cortex (anatomy), Genetic variation, Medicine and Health Sciences, medicine, Humans, genetics [Phosphoric Diester Hydrolases], Aged, Visual Cortex, Genetics, Brain Mapping, Multidisciplinary, Models, Genetic, Phosphoric Diester Hydrolases, metabolism [Saccharomyces cerevisiae], Brain, Genetic Variation, Genomics, Middle Aged, Biological Sciences, Visual cortex, medicine.anatomical_structure, Female, Genome-Wide Association Study
Abstract

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association ( P combined = 3.2 × 10 −8 ). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10 −9 ) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5′ UTR of GPCPD1 , glycerophosphocholine phosphodiesterase GDE1 homolog ( Saccharomyces cerevisiae ), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

Published
2012

40. Arterial spin labeling MRI study of age and gender effects on brain perfusion hemodynamics

Author

Liu, Y., Zhu, X., Feinberg, D., Guenther, M., Gregori, J., Weiner, M.W., Schuff, N., and Publica

Abstract

Normal aging is associated with diminished brain perfusion measured as cerebral blood flow (CBF), but previously it is difficult to accurately measure various aspects of perfusion hemodynamics including: bolus arrival times and delays through small arterioles, expressed as arterial-arteriole transit time. To study hemodynamics in greater detail, volumetric arterial spin labeling MRI with variable postlabeling delays was used together with a distributed, dual-compartment tracer model. The main goal was to determine how CBF and other perfusion hemodynamics vary with aging. Twenty cognitive normal female and 15 male subjects (age: 23-84 years old) were studied at 4 T. Arterial spin labeling measurements were performed in the posterior cingulate cortex, precuneus, and whole brain gray matter. CBF declined with advancing age (P < 0.001). Separately from variations in bolus arrival times, arterial-arteriole transit time increased with advancing age (P < 0.01). Finally, women had overall higher CBF values (P < 0.01) and shorter arterial-arteriole transit time (P < 0.01) than men, regardless of age. The findings imply that CBF and blood transit times are compromised in aging, and these changes together with differences between genders should be taken into account when studying brain perfusion.

Published
2012

41. Multivariate Statistical Mapping of Spectroscopic Imaging Data

Author

Young, K., Govind, V., Sharma, K., Studholme, C., Maudsley, A.A, and Schuff, N.

Subjects
Adult, Male, Aspartic Acid, Magnetic Resonance Spectroscopy, Amyotrophic Lateral Sclerosis, Brain, Reproducibility of Results, Middle Aged, Sensitivity and Specificity, Article, Choline, Creatinine, Multivariate Analysis, Humans, Algorithms, Biomarkers
Abstract

For magnetic resonance spectroscopic imaging studies of the brain, it is important to measure the distribution of metabolites in a regionally unbiased way; that is, without restrictions to a priori defined regions of interest. Since magnetic resonance spectroscopic imaging provides measures of multiple metabolites simultaneously at each voxel, there is furthermore great interest in utilizing the multidimensional nature of magnetic resonance spectroscopic imaging for gains in statistical power. Voxelwise multivariate statistical mapping is expected to address both of these issues, but it has not been previously employed for spectroscopic imaging (SI) studies of brain. The aims of this study were to (1) develop and validate multivariate voxel-based statistical mapping for magnetic resonance spectroscopic imaging and (2) demonstrate that multivariate tests can be more powerful than univariate tests in identifying patterns of altered brain metabolism. Specifically, we compared multivariate to univariate tests in identifying known regional patterns in simulated data and regional patterns of metabolite alterations due to amyotrophic lateral sclerosis, a devastating brain disease of the motor neurons.

Published
2010

42. Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer's disease

Author

Wolk, D. A., Dickerson, B. C., the Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aiello, M., Aisen, P., Albert, M. S., Alexander, G., Anderson, H. S., Anderson, K., Apostolova, L., Arnold, S., Ashford, W., Assaly, M., Asthana, S., Bandy, D., Bartha, R., Bates, V., Beckett, L., Bell, K. L., Benincasa, A. L., Bergman, H., Bernick, C., Bernstein, M., Black, S., Blank, K., Borrie, M., Brand, C., Brewer, J., Brown, A. D., Burns, J. M., Cairns, N. J., Caldwell, C., Capote, H., Carlsson, C. M., Carmichael, O., Cellar, J. S., Celmins, D., Chen, K., Chertkow, H., Chowdhury, M., Clark, D., Connor, D., Correia, S., Crawford, K., Dale, A., de Leon, M. J., De Santi, S. M., DeCarli, C., deToledo-Morrell, L., DeVous, M., Diaz-Arrastia, R., Dolen, S., Donohue, M., Doody, R. S., Doraiswamy, P. M., Duara, R., Englert, J., Farlow, M., Feldman, H., Felmlee, J., Fleisher, A., Fletcher, E., Foroud, T. M., Foster, N., Fox, N., Frank, R., Gamst, A., Given, C. A., Graff-Radford, N. R., Green, R. C., Griffith, R., Grossman, H., Hake, A. M., Hardy, P., Harvey, D., Heidebrink, J. L., Hendin, B. A., Herring, S., Honig, L. S., Hosein, C., Robin Hsiung, G.-Y., Hudson, L., Ismail, M. S., Jack, C. R., Jacobson, S., Jagust, W., Jayam-Trouth, A., Johnson, K., Johnson, H., Johnson, N., Johnson, K. A., Johnson, S., Kachaturian, Z., Karlawish, J. H., Kataki, M., Kaye, J., Kertesz, A., Killiany, R., Kittur, S., Koeppe, R. A., Korecka, M., Kornak, J., Kozauer, N., Lah, J. J., Laubinger, M. M., Lee, V. M.- Y., Lee, T.- Y., Lerner, A., Levey, A. I., Longmire, C. F., Lopez, O. L., Lord, J. L., Lu, P. H., MacAvoy, M. G., Malloy, P., Marson, D., Martin-Cook, K., Martinez, W., Marzloff, G., Mathis, C., Mc-Adams-Ortiz, C., Mesulam, M., Miller, B. L., Mintun, M. A., Mintzer, J., Molchan, S., Montine, T., Morris, J., Mulnard, R. A., Munic, D., Nair, A., Neu, S., Nguyen, D., Norbash, A., Oakley, M., Obisesan, T. O., Ogrocki, P., Ott, B. R., Parfitt, F., Pawluczyk, S., Pearlson, G., Petersen, R., Petrella, J. R., Potkin, S., Potter, W. Z., Preda, A., Quinn, J., Rainka, M., Reeder, S., Reiman, E. M., Rentz, D. M., Reynolds, B., Richard, J., Roberts, P., Rogers, J., Rosen, A., Rosen, H. J., Rusinek, H., Sabbagh, M., Sadowsky, C., Salloway, S., Santulli, R. B., Saykin, A. J., Scharre, D. W., Schneider, L., Schneider, S., Schuff, N., Shah, R. C., Shaw, L., Shen, L., Silverman, D. H. S., Simpson, D. M., Sink, K. M., Smith, C. D., Snyder, P. J., Spann, B. M., Sperling, R. A., Spicer, K., Stefanovic, B., Stern, Yaakov, Stopa, E., Tang, C., Tariot, P., Taylor-Reinwald, L., Thai, G., Thomas, R. G., Thompson, P., Tinklenberg, J., Toga, A. W., Tremont, G., Trojanowki, J. Q., Trost, D., Turner, R. S., van Dyck, C. H., Vanderswag, H., Varon, D., Villanueva-Meyer, J., Villena, T., Walter, S., Wang, P., Watkins, F., Williamson, J. D., Wolk, D., Wu, C.-K., Zerrate, M., and Zimmerman., E. A.

Published
2010
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43. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly

Author

Ho, A. J., Stein, J. L., Hua, X., Lee, S., Hibar, D. P., Leow, A. D., Dinov, I. D., Toga, A. W., Saykin, A. J., Shen, L., Foroud, T., Pankratz, N., Huentelman, M. J., Craig, D. W., Gerber, J. D., Allen, A. N., Corneveaux, J. J., Stephan, D. A., DeCarli, C. S., DeChairo, B. M., Potkin, S. G., Jack, C. R., Weiner, M. W., Raji, C. A., Lopez, O. L., Becker, J. T., Carmichael, O. T., Thompson, P. M., the Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Thal, L., Petersen, R., Jagust, W., Trojanowki, J., Beckett, L., Green, R. C., Gamst, A., Potter, W. Z., Montine, T., Anders, D., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., Alexander, G., Bandy, D., Koeppe, R. A., Foster, N., Reiman, E. M., Chen, K., Shaw, L., Lee, V. M.- Y., Korecka, M., Crawford, K., Neu, S., Harvey, D., Kornak, J., Kachaturian, Z., Frank, R., Snyder, P. J., Molchan, S., Kaye, J., Vorobik, R., Quinn, J., Schneider, L., Pawluczyk, S., Spann, B., Fleisher, A. S., Vanderswag, H., Heidebrink, J. L., Lord, J. L., Johnson, K., Doody, R. S., Villanueva-Meyer, J., Chowdhury, M., Stern, Yaakov, Honig, L. S., Bell, K. L., Morris, J. C., Mintun, M. A., Schneider, S., Marson, D., Griffith, R., Badger, B., Grossman, H., Tang, C., Stern, J., deToledo-Morrell, L., Shah, R. C., Bach, J., Duara, R., Isaacson, R., Strauman, S., Albert, M. S., Pedroso, J., Toroney, J., Rusinek, H., de Leon, M. J., De Santi, S. M., Doraiswamy, P. M., Petrella, J. R., Aiello, M., Clark, C. M., Pham, C., Nunez, J., Smith, C. D., Given II, C. A., Hardy, P., DeKosky, S. T., Oakley, M., Simpson, D. M., Ismail, M. S., Porsteinsson, A., McCallum, C., Cramer, S. C., Mulnard, R. A., McAdams-Ortiz, C., Diaz-Arrastia, R., Martin-Cook, K., DeVous, M., Levey, A. I., Lah, J. J., Cellar, J. S., Burns, J. M., Anderson, H. S., Laubinger, M. M., Bartzokis, G., Silverman, D. H. S., Lu, P. H., Fletcher, R., Parfitt, F., Johnson, H., Farlow, M., Herring, S., Hake, A. M., van Dyck, C. H., MacAvoy, M. G., Bifano, L. A., Chertkow, H., Bergman, H., Hosein, C., Black, S., Graham, S., Caldwell, C., Feldman, H., Assaly, M., Hsiung, G.-Y. R., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Gitelman, D., Johnson, N., Mesulam, M., Sadowsky, C., Villena, T., Mesner, S., Aisen, P. S., Johnson, K. B., Behan, K. E., Sperling, R. A., Rentz, D. M., Johnson, K. A., Rosen, A., Tinklenberg, J., Ashford, W., Sabbagh, M., Connor, D., Obradov, S., Killiany, R., Norbash, A., Obisesan, T. O., Jayam-Trouth, A., Wang, P., Auchus, A. P., Huang, J., Friedland, R. P., DeCarli, C., Fletcher, E., Carmichael, O., Kittur, S., Mirje, S., Johnson, S. C., Borrie, M., Lee, T.-Y., Asthana, S., Carlsson, C. M., Highum, D., Preda, A., Nguyen, D., Tariot, P. N., Hendin, B. A., Scharre, D. W., Kataki, M., Beversdorf, D. Q., Zimmerman, E. A., Celmins, D., Brown, A. D., Gandy, S., Marenberg, M. E., Rovner, B. W., Pearlson, G., Blank, K., Anderson, K., Santulli, R. B., Pare, N., Williamson, J. D., Sink, K. M., Potter, H., Ashok Raj, B., Giordano, A., Ott, B. R., Wu, C.-K., Cohen, R., and Wilks, K. L.

Published
2010
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44. Voxelwise multivariate analysis of multimodality magnetic resonance imaging

Author

Naylor, MG, Naylor, MG, Cardenas, VA, Tosun, D, Schuff, N, Weiner, M, Schwartzman, A, Naylor, MG, Naylor, MG, Cardenas, VA, Tosun, D, Schuff, N, Weiner, M, and Schwartzman, A

Abstract

Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remain a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer's disease, in which data from three MRI modalities are available. © 2013 Wiley Periodicals, Inc.

Published
2014

48. Generative FDG-PET and MRI model of aging and disease progression in Alzheimer's disease.

Author

Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aisen, P., Petersen, R., Jack CR.<Suffix>Jr</Suffix>, Jagust, W., Trojanowki, JQ., Toga, AW., Beckett, L., Green, RC., Saykin, AJ., Morris, J., Liu, E., Montine, T., Gamst, A., Thomas, RG., Donohue, M., Walter, S., Gessert, D., Sather, T., Harvey, D., Kornak, J., Dale, A., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., DeCarli, C., Bandy, D., Koeppe, RA., Foster, N., Reiman, EM., Chen, K., Mathis, C., Cairns, NJ., Taylor-Reinwald, L., Shaw, L., Lee, VM., Korecka, M., Crawford, K., Neu, S., Foroud, TM., Potkin, S., Shen, L., Kachaturian, Z., Frank, R., Snyder, PJ., Molchan, S., Kaye, J., Quinn, J., Lind, B., Dolen, S., Schneider, LS., Pawluczyk, S., Spann, BM., Brewer, J., Vanderswag, H., Heidebrink, JL., Lord, JL., Johnson, K., Doody, RS., Villanueva-Meyer, J., Chowdhury, M., Stern, Y., Honig, LS., Bell, KL., Morris, JC., Ances, B., Carroll, M., Leon, S., Mintun, MA., Schneider, S., Marson, D., Griffith, R., Clark, D., Grossman, H., Mitsis, E., Romirowsky, A., deToledo-Morrell, L., Shah, RC., Duara, R., Varon, D., Roberts, P., Albert, M., Onyike, C., Kielb, S., Rusinek, H., de Leon MJ., Glodzik, L., De Santi, S., Doraiswamy, P., Petrella, JR., Coleman, R., Arnold, SE., Karlawish, JH., Wolk, D., Smith, CD., Jicha, G., Hardy, P., Lopez, OL., Oakley, M., Simpson, DM., Porsteinsson, AP., Goldstein, BS., Martin, K., Makino, KM., Ismail, M., Brand, C., Mulnard, RA., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Martin-Cook, K., DeVous, M., Levey, AI., Lah, JJ., Cellar, JS., Burns, JM., Anderson, HS., Swerdlow, RH., Apostolova, L., Lu, PH., Bartzokis, G., Silverman, DH., Graff-Radford, NR., Parfitt, F., Johnson, H., Farlow, MR., Hake, AM., Matthews, BR., Herring, S., van Dyck CH., Carson, RE., MacAvoy, MG., Chertkow, H., Bergman, H., Hosein, C., Black, S., Stefanovic, B., Caldwell, C., Hsiung, GY., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Munic, D., Kerwin, D., Mesulam, MM., Lipowski, K., Wu, CK., Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, RS., Reynolds, B., Sperling, RA., Johnson, KA., Marshall, G., Frey, M., Yesavage, J., Taylor, JL., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M., Belden, C., Jacobson, S., Kowall, N., Killiany, R., Budson, AE., Norbash, A., Johnson, PL., Obisesan, TO., Wolday, S., Bwayo, SK., Lerner, A., Hudson, L., Ogrocki, P., Fletcher, E., Carmichael, O., Olichney, J., Kittur, S., Borrie, M., Lee, TY., Bartha, R., Johnson, S., Asthana, S., Carlsson, CM., Potkin, SG., Preda, A., Nguyen, D., Tariot, P., Fleisher, A., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, DW., Kataki, M., Zimmerman, EA., Celmins, D., Brown, AD., Pearlson, GD., Blank, K., Anderson, K., Santulli, RB., Schwartz, ES., Sink, KM., Williamson, JD., Garg, P., Watkins, F., Ott, BR., Querfurth, H., Tremont, G., Salloway, S., Malloy, P., Correia, S., Rosen, HJ., Miller, BL., Mintzer, J., Longmire, CF., Spicer, K., Finger, E., Rachinsky, I., Drost, D., Dukart, J., Kherif, F., Mueller, K., Adaszewski, S., Schroeter, M.L., Frackowiak, R.S., Draganski, B., Alzheimer's Disease Neuroimaging Initiative, Weiner, M., Aisen, P., Petersen, R., Jack CR.<Suffix>Jr</Suffix>, Jagust, W., Trojanowki, JQ., Toga, AW., Beckett, L., Green, RC., Saykin, AJ., Morris, J., Liu, E., Montine, T., Gamst, A., Thomas, RG., Donohue, M., Walter, S., Gessert, D., Sather, T., Harvey, D., Kornak, J., Dale, A., Bernstein, M., Felmlee, J., Fox, N., Thompson, P., Schuff, N., DeCarli, C., Bandy, D., Koeppe, RA., Foster, N., Reiman, EM., Chen, K., Mathis, C., Cairns, NJ., Taylor-Reinwald, L., Shaw, L., Lee, VM., Korecka, M., Crawford, K., Neu, S., Foroud, TM., Potkin, S., Shen, L., Kachaturian, Z., Frank, R., Snyder, PJ., Molchan, S., Kaye, J., Quinn, J., Lind, B., Dolen, S., Schneider, LS., Pawluczyk, S., Spann, BM., Brewer, J., Vanderswag, H., Heidebrink, JL., Lord, JL., Johnson, K., Doody, RS., Villanueva-Meyer, J., Chowdhury, M., Stern, Y., Honig, LS., Bell, KL., Morris, JC., Ances, B., Carroll, M., Leon, S., Mintun, MA., Schneider, S., Marson, D., Griffith, R., Clark, D., Grossman, H., Mitsis, E., Romirowsky, A., deToledo-Morrell, L., Shah, RC., Duara, R., Varon, D., Roberts, P., Albert, M., Onyike, C., Kielb, S., Rusinek, H., de Leon MJ., Glodzik, L., De Santi, S., Doraiswamy, P., Petrella, JR., Coleman, R., Arnold, SE., Karlawish, JH., Wolk, D., Smith, CD., Jicha, G., Hardy, P., Lopez, OL., Oakley, M., Simpson, DM., Porsteinsson, AP., Goldstein, BS., Martin, K., Makino, KM., Ismail, M., Brand, C., Mulnard, RA., Thai, G., Mc-Adams-Ortiz, C., Womack, K., Mathews, D., Quiceno, M., Diaz-Arrastia, R., King, R., Martin-Cook, K., DeVous, M., Levey, AI., Lah, JJ., Cellar, JS., Burns, JM., Anderson, HS., Swerdlow, RH., Apostolova, L., Lu, PH., Bartzokis, G., Silverman, DH., Graff-Radford, NR., Parfitt, F., Johnson, H., Farlow, MR., Hake, AM., Matthews, BR., Herring, S., van Dyck CH., Carson, RE., MacAvoy, MG., Chertkow, H., Bergman, H., Hosein, C., Black, S., Stefanovic, B., Caldwell, C., Hsiung, GY., Feldman, H., Mudge, B., Assaly, M., Kertesz, A., Rogers, J., Trost, D., Bernick, C., Munic, D., Kerwin, D., Mesulam, MM., Lipowski, K., Wu, CK., Johnson, N., Sadowsky, C., Martinez, W., Villena, T., Turner, RS., Reynolds, B., Sperling, RA., Johnson, KA., Marshall, G., Frey, M., Yesavage, J., Taylor, JL., Lane, B., Rosen, A., Tinklenberg, J., Sabbagh, M., Belden, C., Jacobson, S., Kowall, N., Killiany, R., Budson, AE., Norbash, A., Johnson, PL., Obisesan, TO., Wolday, S., Bwayo, SK., Lerner, A., Hudson, L., Ogrocki, P., Fletcher, E., Carmichael, O., Olichney, J., Kittur, S., Borrie, M., Lee, TY., Bartha, R., Johnson, S., Asthana, S., Carlsson, CM., Potkin, SG., Preda, A., Nguyen, D., Tariot, P., Fleisher, A., Reeder, S., Bates, V., Capote, H., Rainka, M., Scharre, DW., Kataki, M., Zimmerman, EA., Celmins, D., Brown, AD., Pearlson, GD., Blank, K., 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Abstract

The failure of current strategies to provide an explanation for controversial findings on the pattern of pathophysiological changes in Alzheimer's Disease (AD) motivates the necessity to develop new integrative approaches based on multi-modal neuroimaging data that captures various aspects of disease pathology. Previous studies using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) and structural magnetic resonance imaging (sMRI) report controversial results about time-line, spatial extent and magnitude of glucose hypometabolism and atrophy in AD that depend on clinical and demographic characteristics of the studied populations. Here, we provide and validate at a group level a generative anatomical model of glucose hypo-metabolism and atrophy progression in AD based on FDG-PET and sMRI data of 80 patients and 79 healthy controls to describe expected age and symptom severity related changes in AD relative to a baseline provided by healthy aging. We demonstrate a high level of anatomical accuracy for both modalities yielding strongly age- and symptom-severity- dependant glucose hypometabolism in temporal, parietal and precuneal regions and a more extensive network of atrophy in hippocampal, temporal, parietal, occipital and posterior caudate regions. The model suggests greater and more consistent changes in FDG-PET compared to sMRI at earlier and the inversion of this pattern at more advanced AD stages. Our model describes, integrates and predicts characteristic patterns of AD related pathology, uncontaminated by normal age effects, derived from multi-modal data. It further provides an integrative explanation for findings suggesting a dissociation between early- and late-onset AD. The generative model offers a basis for further development of individualized biomarkers allowing accurate early diagnosis and treatment evaluation.

Published
2013

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