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1. Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN).

Author

McKay, NS, Gordon, BA, Hornbeck, RC, Dincer, A, Flores, S, Keefe, SJ, Joseph-Mathurin, N, Jack, CR, Koeppe, R, Millar, PR, Ances, BM, Chen, CD, Daniels, A, Hobbs, DA, Jackson, K, Koudelis, D, Massoumzadeh, P, McCullough, A, Nickels, ML, Rahmani, F, Swisher, L, Wang, Q, Allegri, RF, Berman, SB, Brickman, AM, Brooks, WS, Cash, DM, Chhatwal, JP, Day, GS, Farlow, MR, la Fougère, C, Fox, NC, Fulham, M, Ghetti, B, Graff-Radford, N, Ikeuchi, T, Klunk, W, Lee, J-H, Levin, J, Martins, R, Masters, CL, McConathy, J, Mori, H, Noble, JM, Reischl, G, Rowe, C, Salloway, S, Sanchez-Valle, R, Schofield, PR, Shimada, H, Shoji, M, Su, Y, Suzuki, K, Vöglein, J, Yakushev, I, Cruchaga, C, Hassenstab, J, Karch, C, McDade, E, Perrin, RJ, Xiong, C, Morris, JC, Bateman, RJ, Benzinger, TLS, Dominantly Inherited Alzheimer Network, McKay, NS, Gordon, BA, Hornbeck, RC, Dincer, A, Flores, S, Keefe, SJ, Joseph-Mathurin, N, Jack, CR, Koeppe, R, Millar, PR, Ances, BM, Chen, CD, Daniels, A, Hobbs, DA, Jackson, K, Koudelis, D, Massoumzadeh, P, McCullough, A, Nickels, ML, Rahmani, F, Swisher, L, Wang, Q, Allegri, RF, Berman, SB, Brickman, AM, Brooks, WS, Cash, DM, Chhatwal, JP, Day, GS, Farlow, MR, la Fougère, C, Fox, NC, Fulham, M, Ghetti, B, Graff-Radford, N, Ikeuchi, T, Klunk, W, Lee, J-H, Levin, J, Martins, R, Masters, CL, McConathy, J, Mori, H, Noble, JM, Reischl, G, Rowe, C, Salloway, S, Sanchez-Valle, R, Schofield, PR, Shimada, H, Shoji, M, Su, Y, Suzuki, K, Vöglein, J, Yakushev, I, Cruchaga, C, Hassenstab, J, Karch, C, McDade, E, Perrin, RJ, Xiong, C, Morris, JC, Bateman, RJ, Benzinger, TLS, and Dominantly Inherited Alzheimer Network

Abstract

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.

Published
2023

4. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease

Author

Lopez, O.L., Becker, J.T., Wahed, A.S., Saxton, J., Sweet, R.A., Wolk, D.A., Klunk, W., and DeKosky, S.T.

Subjects
Cholinesterase inhibitors -- Usage, Cholinesterase inhibitors -- Health aspects, Alzheimer's disease -- Care and treatment, Alzheimer's disease -- Patient outcomes, Drug therapy -- Usage, Drug therapy -- Patient outcomes, Health, Psychology and mental health
Published
2009

5. CLINICAL AND BIOMARKER CHANGES IN DOMINANTLY INHERITED ALZHEIMERʼS DISEASE: P01-04

Author

Schofield, P R, Bateman, R J, Xiong, C, Benzinger, T LS, Fagan, A M, Goate, A, Fox, N C, Marcus, D S, Cairns, N J, Xie, X, Blazey, T M, Holtzman, D M, Santacruz, A, Buckles, V, Oliver, A, Moulder, K, Aisen, P S, Ghetti, B, Klunk, W E, McDade, E, Martins, R N, Masters, C L, Mayeux, R, Ringman, J M, Rossor, M N, Sperling, R A, Salloway, S, and Morris, J C

Published
2013

12. Amyloid and tau pathology associations with personality traits, neuropsychiatric symptoms, and cognitive lifestyle in the preclinical phases of sporadic and autosomal dominant Alzheimer’s disease

Author

Pichet Binette, A., Vachon-Presseau, É., Morris, J., Bateman, R., Benzinger, T., Collins, D.L., Poirier, J., Breitner, J.C.S., Villeneuve, S., Allegri, R., Amtashar, F., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, Jill, Buckles, V., Chea, S., Chhatwal, J., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D‘Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., DiBari, S.H., Ikeuchi, T., Ikonomovic, S., Jerome, G., Jucker, M., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Levin, J., Marcus, D., Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J.H., Salloway, S., Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Tam, A., Labonté, A., Faubert, A-M, Mathieu, A., Madjar, C., Carrier, C.E., Dansereau, C., Kazazian, C., Lepage, C., Picard, C., Maillet, D., Michaud, D., Couture, D., Dea, D., Cuello, C., Barkun, A., Evans, A., Courcot, B., Tardif, C., Debacker, C., Jack, C.R., Fontaine, D., Knopman, D.S., Maultaup, G., Near, J., Leoutsakos, J-M, Maltais, J-R, Brandt, J., Pruessner, J., Morris, J.C., Cheewakriengkrai, L., Münter, L-M, Collins, L., Chakravarty, M., Sager, M.A., Dauar-Tedeschi, M., Eisenberg, M., Rajah, N., Aisen, P., Toussaint, J., Rosa-Neto, P., Bellec, P., Kostopoulos, P., Etienne, P., Tariot, P.N., Orban, P., Sperling, R.A., Hoge, R., Thomas, R.G., Gauthier, S., Craft, S., Montine, T.J., Nair, V., Bohbot, V., Venugopalan, V., Fonov, V., Ituria-Medina, Y., Khachaturian, Z.S., Teigner, E., Anthal, E., Yu, E., Ferdinand, F., Pogossova, G., Mayrand, G., Duclair, G., Gagné, G., Newbold-Fox, H., Leppert, I., Vallée, I., Vogel, J.W., Tremblay-Mercier, J., Frenette, J., Frappier, J., Kat, J., Miron, J., Wan, K., Mahar, L., Carmo, L., Théroux, L., Dadar, M., Dufour, M., Lafaille-Magnan, M-E, Appleby, M., Savard, M., Tuwaig, M., Petkova, M., Rioux, P., Meyer, P-F, El-Khoury, R., Gordon, R., Giles, R., Das, S., Wang, S., Tabrizi, S., Mathotaarachchi, S., Dubuc, S., Lee, T., Beaudry, T., Gervais, V., Pagé, V., Gonneaud, J., Ayranci, G., Pascoal, T.A., Desautels, R., Benbouhoud, F., Saint-Fort, E.F., Verfaillie, S.C.J., Farzin, S., Salaciak, A., Tullo, S., Vachon-Presseau, E., Daoust, L-A, Köbe, T., Spreng, N., McSweeney, M., Nilsson, N., Pishnamazi, M., Bedetti, C., Pichet Binette, A., Vachon-Presseau, É., Morris, J., Bateman, R., Benzinger, T., Collins, D.L., Poirier, J., Breitner, J.C.S., Villeneuve, S., Allegri, R., Amtashar, F., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, Jill, Buckles, V., Chea, S., Chhatwal, J., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D‘Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., DiBari, S.H., Ikeuchi, T., Ikonomovic, S., Jerome, G., Jucker, M., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Levin, J., Marcus, D., Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J.H., Salloway, S., Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Tam, A., Labonté, A., Faubert, A-M, Mathieu, A., Madjar, C., Carrier, C.E., Dansereau, C., Kazazian, C., Lepage, C., Picard, C., Maillet, D., Michaud, D., Couture, D., Dea, D., Cuello, C., Barkun, A., Evans, A., Courcot, B., Tardif, C., Debacker, C., Jack, C.R., Fontaine, D., Knopman, D.S., Maultaup, G., Near, J., Leoutsakos, J-M, Maltais, J-R, Brandt, J., Pruessner, J., Morris, J.C., Cheewakriengkrai, L., Münter, L-M, Collins, L., Chakravarty, M., Sager, M.A., Dauar-Tedeschi, M., Eisenberg, M., Rajah, N., Aisen, P., Toussaint, J., Rosa-Neto, P., Bellec, P., Kostopoulos, P., Etienne, P., Tariot, P.N., Orban, P., Sperling, R.A., Hoge, R., Thomas, R.G., Gauthier, S., Craft, S., Montine, T.J., Nair, V., Bohbot, V., Venugopalan, V., Fonov, V., Ituria-Medina, Y., Khachaturian, Z.S., Teigner, E., Anthal, E., Yu, E., Ferdinand, F., Pogossova, G., Mayrand, G., Duclair, G., Gagné, G., Newbold-Fox, H., Leppert, I., Vallée, I., Vogel, J.W., Tremblay-Mercier, J., Frenette, J., Frappier, J., Kat, J., Miron, J., Wan, K., Mahar, L., Carmo, L., Théroux, L., Dadar, M., Dufour, M., Lafaille-Magnan, M-E, Appleby, M., Savard, M., Tuwaig, M., Petkova, M., Rioux, P., Meyer, P-F, El-Khoury, R., Gordon, R., Giles, R., Das, S., Wang, S., Tabrizi, S., Mathotaarachchi, S., Dubuc, S., Lee, T., Beaudry, T., Gervais, V., Pagé, V., Gonneaud, J., Ayranci, G., Pascoal, T.A., Desautels, R., Benbouhoud, F., Saint-Fort, E.F., Verfaillie, S.C.J., Farzin, S., Salaciak, A., Tullo, S., Vachon-Presseau, E., Daoust, L-A, Köbe, T., Spreng, N., McSweeney, M., Nilsson, N., Pishnamazi, M., and Bedetti, C.

Abstract

Background Major prevention trials for Alzheimer’s disease (AD) are now focusing on multidomain lifestyle interventions. However, the exact combination of behavioral factors related to AD pathology remains unclear. In 2 cohorts of cognitively unimpaired individuals at risk of AD, we examined which combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle (years of education or lifetime cognitive activity) related to the pathological hallmarks of AD, amyloid-β, and tau deposits. Methods A total of 115 older adults with a parental or multiple-sibling family history of sporadic AD (PREVENT-AD [PRe-symptomatic EValuation of Experimental or Novel Treatments for AD] cohort) underwent amyloid and tau positron emission tomography and answered several questionnaires related to behavioral attributes. Separately, we studied 117 mutation carriers from the DIAN (Dominant Inherited Alzheimer Network) study group cohort with amyloid positron emission tomography and behavioral data. Using partial least squares analysis, we identified latent variables relating amyloid or tau pathology with combinations of personality traits, neuropsychiatric symptoms, and cognitive lifestyle. Results In PREVENT-AD, lower neuroticism, neuropsychiatric burden, and higher education were associated with less amyloid deposition (p = .014). Lower neuroticism and neuropsychiatric features, along with higher measures of openness and extraversion, were related to less tau deposition (p = .006). In DIAN, lower neuropsychiatric burden and higher education were also associated with less amyloid (p = .005). The combination of these factors accounted for up to 14% of AD pathology. Conclusions In the preclinical phase of both sporadic and autosomal dominant AD, multiple behavioral features were associated with AD pathology. These results may suggest potential pathways by which multidomain interventions might help delay AD onset or progression.

Published
2020

13. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease

Author

Barthélemy, N.R., Li, Y., Joseph-Mathurin, N., Gordon, B.A., Hassenstab, J., Benzinger, T.L.S., Buckles, V., Fagan, A.M., Perrin, R.J., Goate, A.M., Morris, J.C., Karch, C.M., Xiong, C., Allegri, R., Mendez, P.C., Berman, S.B., Ikeuchi, T., Mori, H., Shimada, H., Shoji, M., Suzuki, K., Noble, J., Farlow, M., Chhatwal, J., Graff-Radford, N.R., Salloway, S., Schofield, P.R., Masters, C.L., Martins, R.N., O’Connor, A., Fox, N.C., Levin, J., Jucker, M., Gabelle, A., Lehmann, S., Sato, C., Bateman, R.J., McDade, E., Bateman, R., Bechara, J., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Chea, S., Chrem Mendez, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Fitzpatrick, C., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Groves, A., Hoechst-Swisher, L., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., Morris, J., Nagamatsu, A., Neimeyer, K., Norton, J., Perrin, R., Raichle, M., Renton, A., Ringman, J., Roh, J.H., Schofield, P., Sigurdson, W., Sohrabi, H., Sparks, P., Taddei, K., Wang, P., Xu, X., Barthélemy, N.R., Li, Y., Joseph-Mathurin, N., Gordon, B.A., Hassenstab, J., Benzinger, T.L.S., Buckles, V., Fagan, A.M., Perrin, R.J., Goate, A.M., Morris, J.C., Karch, C.M., Xiong, C., Allegri, R., Mendez, P.C., Berman, S.B., Ikeuchi, T., Mori, H., Shimada, H., Shoji, M., Suzuki, K., Noble, J., Farlow, M., Chhatwal, J., Graff-Radford, N.R., Salloway, S., Schofield, P.R., Masters, C.L., Martins, R.N., O’Connor, A., Fox, N.C., Levin, J., Jucker, M., Gabelle, A., Lehmann, S., Sato, C., Bateman, R.J., McDade, E., Bateman, R., Bechara, J., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Chea, S., Chrem Mendez, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Fitzpatrick, C., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Groves, A., Hoechst-Swisher, L., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Kuder-Buletta, E., Laske, C., Lee, J-H, Martins, R., Mason, N.S., Masters, C., Maue-Dreyfus, D., Morris, J., Nagamatsu, A., Neimeyer, K., Norton, J., Perrin, R., Raichle, M., Renton, A., Ringman, J., Roh, J.H., Schofield, P., Sigurdson, W., Sohrabi, H., Sparks, P., Taddei, K., Wang, P., and Xu, X.

Abstract

Development of tau-based therapies for Alzheimer’s disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer’s disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.

Published
2020

14. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease

Author

Preische, O., Schultz, S.A., Apel, A., Kuhle, J., Kaeser, S.A., Barro, C., Gräber, S., Kuder-Buletta, E., LaFougere, C., Laske, C., Vöglein, J., Levin, J., Masters, C.L., Martins, R., Schofield, P.R., Rossor, M.N., Graff-Radford, N.R., Salloway, S., Ghetti, B., Ringman, J.M., Noble, J.M., Chhatwal, J., Goate, A.M., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Wang, G., Fagan, A.M., McDade, E.M., Gordon, B.A., Jucker, M., Allegri, R., Amtashar, F., Bateman, R., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Buckles, V., Chea, S., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D’Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikeuchi, T., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Lee, J-H, Marcus, D., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Morris, J., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J-H, Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Preische, O., Schultz, S.A., Apel, A., Kuhle, J., Kaeser, S.A., Barro, C., Gräber, S., Kuder-Buletta, E., LaFougere, C., Laske, C., Vöglein, J., Levin, J., Masters, C.L., Martins, R., Schofield, P.R., Rossor, M.N., Graff-Radford, N.R., Salloway, S., Ghetti, B., Ringman, J.M., Noble, J.M., Chhatwal, J., Goate, A.M., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Wang, G., Fagan, A.M., McDade, E.M., Gordon, B.A., Jucker, M., Allegri, R., Amtashar, F., Bateman, R., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Buckles, V., Chea, S., Chrem, P., Chui, H., Cinco, J., Clifford, J., Cruchaga, C., D’Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Goate, A., Goldman, J., Gordon, B., Graff-Radford, N., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikeuchi, T., Ikonomovic, S., Jerome, G., Karch, C., Kasuga, K., Kawarabayashi, T., Klunk, W., Koeppe, R., Lee, J-H, Marcus, D., Mason, N.S., Masters, C., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Morris, J., Nagamatsu, A., Neimeyer, K., Noble, J., Norton, J., Perrin, R., Raichle, M., Ringman, J., Roh, J-H, Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., and Xu, X.

Abstract

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker.

Published
2019

15. An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations

Author

Dube, U., Del-Aguila, J.L., Li, Z., Budde, J.P., Jiang, S., Hsu, S., Ibanez, L., Fernandez, M.V., Farias, F., Norton, J., Gentsch, J., Wang, F., Allegri, R., Amtashar, F., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Buckles, V., Chea, S., Chrem, P., Chui, H., Cinco, J., Clifford, J., D'Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikeuchi, T., Ikonomovic, S., Jerome, G., Jucker, M., Kasuga, K., Kawarabayashi, T., Klunk, W., koeppe, R., Kuder-Buletta, E., Laske, C., Levin, J., Marcus, D., Martins, R., Mason, N.S., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Nagamatsu, A., Neimeyer, K., Noble, J., Perrin, R., Raichle, M., Ringman, J., Roh, J-H, Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., Xu, X., Dube, U., Del-Aguila, J.L., Li, Z., Budde, J.P., Jiang, S., Hsu, S., Ibanez, L., Fernandez, M.V., Farias, F., Norton, J., Gentsch, J., Wang, F., Allegri, R., Amtashar, F., Benzinger, T., Berman, S., Bodge, C., Brandon, S., Brooks, W., Buck, J., Buckles, V., Chea, S., Chrem, P., Chui, H., Cinco, J., Clifford, J., D'Mello, M., Donahue, T., Douglas, J., Edigo, N., Erekin-Taner, N., Fagan, A., Farlow, M., Farrar, A., Feldman, H., Flynn, G., Fox, N., Franklin, E., Fujii, H., Gant, C., Gardener, S., Ghetti, B., Goate, A., Goldman, J., Gordon, B., Gray, J., Gurney, J., Hassenstab, J., Hirohara, M., Holtzman, D., Hornbeck, R., Houeland DiBari, S., Ikeuchi, T., Ikonomovic, S., Jerome, G., Jucker, M., Kasuga, K., Kawarabayashi, T., Klunk, W., koeppe, R., Kuder-Buletta, E., Laske, C., Levin, J., Marcus, D., Martins, R., Mason, N.S., Maue-Dreyfus, D., McDade, E., Montoya, L., Mori, H., Nagamatsu, A., Neimeyer, K., Noble, J., Perrin, R., Raichle, M., Ringman, J., Roh, J-H, Schofield, P., Shimada, H., Shiroto, T., Shoji, M., Sigurdson, W., Sohrabi, H., Sparks, P., Suzuki, K., Swisher, L., Taddei, K., Wang, J., Wang, P., Weiner, M., Wolfsberger, M., Xiong, C., and Xu, X.

Abstract

Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA–AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis.

Published
2019

18. Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old

Author

Lopez, O. L., primary, Klunk, W. E., additional, Mathis, C., additional, Coleman, R. L., additional, Price, J., additional, Becker, J. T., additional, Aizenstein, H. J., additional, Snitz, B., additional, Cohen, A., additional, Ikonomovic, M., additional, McDade, E., additional, DeKosky, S. T., additional, Weissfeld, L., additional, and Kuller, L. H., additional

Published
2014
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21. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease

Author

Benzinger, TLS, Blazey, T, Jack, CR, Koeppe, RA, Su, Y, Xiong, C, Raichle, ME, Snyder, AZ, Ances, BM, Bateman, RJ, Cairns, NJ, Fagan, AM, Goate, A, Marcus, DS, Aisen, PS, Christensen, JJ, Ercole, L, Hornbeck, RC, Farrar, AM, Aldea, P, Jasielec, MS, Owen, CJ, Xie, X, Mayeux, R, Brickman, A, McDade, E, Klunk, W, Mathis, CA, Ringman, J, Thompson, PM, Ghetti, B, Saykin, AJ, Sperling, RA, Johnson, KA, Salloway, S, Correia, S, Schofield, PR, Masters, CL, Rowe, C, Villemagne, VL, Martins, R, Ourselin, S, Rossor, MN, Fox, NC, Cash, DM, Weiner, MW, Holtzman, DM, Buckles, VD, Moulder, K, Morris, JC, Benzinger, TLS, Blazey, T, Jack, CR, Koeppe, RA, Su, Y, Xiong, C, Raichle, ME, Snyder, AZ, Ances, BM, Bateman, RJ, Cairns, NJ, Fagan, AM, Goate, A, Marcus, DS, Aisen, PS, Christensen, JJ, Ercole, L, Hornbeck, RC, Farrar, AM, Aldea, P, Jasielec, MS, Owen, CJ, Xie, X, Mayeux, R, Brickman, A, McDade, E, Klunk, W, Mathis, CA, Ringman, J, Thompson, PM, Ghetti, B, Saykin, AJ, Sperling, RA, Johnson, KA, Salloway, S, Correia, S, Schofield, PR, Masters, CL, Rowe, C, Villemagne, VL, Martins, R, Ourselin, S, Rossor, MN, Fox, NC, Cash, DM, Weiner, MW, Holtzman, DM, Buckles, VD, Moulder, K, and Morris, JC

Abstract

Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

Published
2013

22. THE ROAD AHEAD TO CURE ALZHEIMER\'S DISEASE: DEVELOPMENT OF BIOLOGICAL MARKERS AND NEUROIMAGING METHODS FOR PREVENTION TRIALS ACROSS ALL STAGES AND TARGET POPULATIONS

Author

Cavedo, E., primary, Lista, S., additional, Khachaturian, Z., additional, Aisen, P., additional, Amouyel, P., additional, Herholz, K., additional, Jack Jr, C.R., additional, Sperling, R., additional, Cummings, J., additional, Blennow, K., additional, O’Bryant, S., additional, Frisoni, G.B., additional, Khachaturian, A., additional, Kivipelto, M., additional, Klunk, W., additional, Broich, K., additional, Andrieu, S., additional, Thiebaut de Schotten, M., additional, Mangin, J.-F., additional, Lammertsma, A.A., additional, Johnson, K., additional, Teipel, S., additional, Drzezga, A., additional, Bokde, A., additional, Colliot, O., additional, Bakardjian, H., additional, Zetterberg, H., additional, Dubois, B., additional, Vellas, B., additional, Schneider, L.S., additional, and Hampel, H., additional

Published
2014
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31. Imaging amyloid deposition in Lewy body diseases

Author

Gomperts, S. N., primary, Rentz, D. M., additional, Moran, E., additional, Becker, J. A., additional, Locascio, J. J., additional, Klunk, W. E., additional, Mathis, C. A., additional, Elmaleh, D. R., additional, Shoup, T., additional, Fischman, A. J., additional, Hyman, B. T., additional, Growdon, J. H., additional, and Johnson, K. A., additional

Published
2008
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33. Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

Author

Klunk, W. E., primary, Price, J. C., additional, Mathis, C. A., additional, Tsopelas, N. D., additional, Lopresti, B. J., additional, Ziolko, S. K., additional, Bi, W., additional, Hoge, J. A., additional, Cohen, A. D., additional, Ikonomovic, M. D., additional, Saxton, J. A., additional, Snitz, B. E., additional, Pollen, D. A., additional, Moonis, M., additional, Lippa, C. F., additional, Swearer, J. M., additional, Johnson, K. A., additional, Rentz, D. M., additional, Fischman, A. J., additional, Aizenstein, H. J., additional, and DeKosky, S. T., additional

Published
2007
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34. Imaging -amyloid burden in aging and dementia

Author

Rowe, C. C., primary, Ng, S., additional, Ackermann, U., additional, Gong, S. J., additional, Pike, K., additional, Savage, G., additional, Cowie, T. F., additional, Dickinson, K. L., additional, Maruff, P., additional, Darby, D., additional, Smith, C., additional, Woodward, M., additional, Merory, J., additional, Tochon-Danguy, H., additional, O'Keefe, G., additional, Klunk, W. E., additional, Mathis, C. A., additional, Price, J. C., additional, Masters, C. L., additional, and Villemagne, V. L., additional

Published
2007
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35. 11 C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration

Author

Rabinovici, G. D., primary, Furst, A. J., additional, O'Neil, J. P., additional, Racine, C. A., additional, Mormino, E. C., additional, Baker, S. L., additional, Chetty, S., additional, Patel, P., additional, Pagliaro, T. A., additional, Klunk, W. E., additional, Mathis, C. A., additional, Rosen, H. J., additional, Miller, B. L., additional, and Jagust, W. J., additional

Published
2007
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49. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2.

Author

Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, Bird TD, Jayadev, Suman, Leverenz, James B, Steinbart, Ellen, Stahl, Justin, Klunk, William, Yu, Cheng-En, and Bird, Thomas D

Abstract

Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel 2 base pair deletion in presenilin 2 at nucleotide 342/343, predicted to produce a frame-shift and premature termination. We conclude that mutations in presenilin 2 are rare with only seven being well documented in the literature. The best studied N141I mutation produces an Alzheimer's disease phenotype with a wide range of onset ages overlapping both early and late onset Alzheimer's disease, often associated with seizures, high penetrance and typical Alzheimer's disease neuropathology. A novel premature termination mutation supports loss of function or haploinsufficiency as pathogenic mechanisms in presenilin 2 associated Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Published
2010
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