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6. Changes in hepatitis C burden and treatment trends in Europe during the era of direct-acting antivirals: a modelling study

Author

Chen, Q, Ayer, T, Bethea, E, Kanwal, F, Wang, X, Roberts, M, Zhuo, Y, Fagiuoli, S, Petersen, J, Chhatwal, J, Chen Q, Ayer T, Bethea E, Kanwal F, Wang X, Roberts M, Zhuo Y, Fagiuoli S, Petersen J, Chhatwal J., Chen, Q, Ayer, T, Bethea, E, Kanwal, F, Wang, X, Roberts, M, Zhuo, Y, Fagiuoli, S, Petersen, J, Chhatwal, J, Chen Q, Ayer T, Bethea E, Kanwal F, Wang X, Roberts M, Zhuo Y, Fagiuoli S, Petersen J, and Chhatwal J.

Abstract

Objectives Oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have dramatically changed the treatment paradigm. Our aim was to project temporal trends in HCV diagnosis, treatment and disease burden in France, Germany, Italy, Spain and the UK. Design A mathematical simulation model of natural history of HCV infection. Participants HCV-infected patients defined based on country-specific age, fibrosis and genotype distributions. Interventions HCV screening practice and availability of different waves of DAA treatment in each country. Outcome measures Temporal trends in the number of patients who achieve sustained virological response (SVR), fail treatment (by drug regimen) and develop advanced sequelae from 2014 to 2030 in each country. Results We projected that 1 324 000 individuals would receive treatment from 2014 to 2030 in the five European countries and 12 000-37 000 of them would fail to achieve SVR. By 2021, the number of individuals cured of HCV would supersede the number of actively infected individuals in France, Germany, Spain and the UK. Under status quo, the diagnosis rate would reach between 65% and 75% and treatment coverage between 65% and 74% by 2030 in these countries. The number of patients who fail treatment would decrease over time, with the majority of those who fail treatment having been exposed to non-structural protein 5A inhibitors. Conclusions In the era of DAAs, the number of people with HCV who achieved a cure will exceed the number of viraemic patients, but many patients will remain undiagnosed, untreated, fail multiple treatments and develop advanced sequelae. Scaling-up screening and treatment capacity, and timely and effective retreatment are needed to avail the full benefits of DAAs and to meet HCV elimination targets set by WHO.

Published
2019

7. The BDNFVal66Met SNP modulates the association between beta-amyloid and hippocampal disconnection in Alzheimer’s disease

Author

Franzmeier, N, Ren, J, Damm, A, Monté-Rubio, G, Boada, M, Ruiz, A, Ramirez, A, Jessen, F, Düzel, E, Rodríguez Gómez, O, Benzinger, T, Goate, A, Karch, CM, Fagan, AM, McDade, E, Buerger, K, Levin, J, Duering, M, Dichgans, M, Suárez-Calvet, M, Haass, C, Gordon, BA, Lim, YY, Masters, CL, Janowitz, D, Catak, C, Wolfsgruber, S, Wagner, M, Milz, E, Moreno-Grau, S, Teipel, S, Grothe, MJ, Kilimann, I, Rossor, M, Fox, N, Laske, C, Chhatwal, J, Falkai, P, Perneczky, R, Lee, JH, Spottke, A, Boecker, H, Brosseron, F, Fliessbach, K, Heneka, MT, Nestor, P, Peters, O, Fuentes, M, Menne, F, Priller, J, Spruth, EJ, Franke, C, Schneider, A, Westerteicher, C, Speck, O, Wiltfang, J, Bartels, C, Araque Caballero, MÁ, Metzger, C, Bittner, D, Salloway, S, Danek, A, Hassenstab, J, Yakushev, I, Schofield, PR, Morris, JC, Bateman, RJ, Ewers, M, Franzmeier, N, Ren, J, Damm, A, Monté-Rubio, G, Boada, M, Ruiz, A, Ramirez, A, Jessen, F, Düzel, E, Rodríguez Gómez, O, Benzinger, T, Goate, A, Karch, CM, Fagan, AM, McDade, E, Buerger, K, Levin, J, Duering, M, Dichgans, M, Suárez-Calvet, M, Haass, C, Gordon, BA, Lim, YY, Masters, CL, Janowitz, D, Catak, C, Wolfsgruber, S, Wagner, M, Milz, E, Moreno-Grau, S, Teipel, S, Grothe, MJ, Kilimann, I, Rossor, M, Fox, N, Laske, C, Chhatwal, J, Falkai, P, Perneczky, R, Lee, JH, Spottke, A, Boecker, H, Brosseron, F, Fliessbach, K, Heneka, MT, Nestor, P, Peters, O, Fuentes, M, Menne, F, Priller, J, Spruth, EJ, Franke, C, Schneider, A, Westerteicher, C, Speck, O, Wiltfang, J, Bartels, C, Araque Caballero, MÁ, Metzger, C, Bittner, D, Salloway, S, Danek, A, Hassenstab, J, Yakushev, I, Schofield, PR, Morris, JC, Bateman, RJ, and Ewers, M

Abstract

In Alzheimer’s disease (AD), a single-nucleotide polymorphism in the gene encoding brain-derived neurotrophic factor (BDNFVal66Met) is associated with worse impact of primary AD pathology (beta-amyloid, Aβ) on neurodegeneration and cognitive decline, rendering BDNFVal66Met an important modulating factor of cognitive impairment in AD. However, the effect of BDNFVal66Met on functional networks that may underlie cognitive impairment in AD is poorly understood. Using a cross-validation approach, we first explored in subjects with autosomal dominant AD (ADAD) from the Dominantly Inherited Alzheimer Network (DIAN) the effect of BDNFVal66Met on resting-state fMRI assessed functional networks. In seed-based connectivity analysis of six major large-scale networks, we found a stronger decrease of hippocampus (seed) to medial-frontal connectivity in the BDNFVal66Met carriers compared to BDNFVal homozogytes. BDNFVal66Met was not associated with connectivity in any other networks. Next, we tested whether the finding of more pronounced decrease in hippocampal-medial-frontal connectivity in BDNFVal66Met could be also found in elderly subjects with sporadically occurring Aβ, including a group with subjective cognitive decline (N = 149, FACEHBI study) and a group ranging from preclinical to AD dementia (N = 114, DELCODE study). In both of these independently recruited groups, BDNFVal66Met was associated with a stronger effect of more abnormal Aβ-levels (assessed by biofluid-assay or amyloid-PET) on hippocampal-medial-frontal connectivity decreases, controlled for hippocampus volume and other confounds. Lower hippocampal-medial-frontal connectivity was associated with lower global cognitive performance in the DIAN and DELCODE studies. Together these results suggest that BDNFVal66Met is selectively associated with a higher vulnerability of hippocampus-frontal connectivity to primary AD pathology, resulting in greater AD-related cognitive impairment.

Published
2021

8. Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease

Author

Keret, O, Staffaroni, AM, Ringman, JM, Cobigo, Y, Goh, S-YM, Wolf, A, Allen, IE, Salloway, S, Chhatwal, J, Brickman, AM, Reyes-Dumeyer, D, Bateman, RJ, Benzinger, TLS, Morris, JC, Ances, BM, Joseph-Mathurin, N, Perrin, RJ, Gordon, BA, Levin, J, Voeglein, J, Jucker, M, Fougere, C, Martins, RN, Sohrabi, HR, Taddei, K, Villemagne, VL, Schofield, PR, Brooks, WS, Fulham, M, Masters, CL, Ghetti, B, Saykin, AJ, Jack, CR, Graff-Radford, NR, Weiner, M, Cash, DM, Allegri, RF, Chrem, P, Yi, S, Miller, BL, Rabinovici, GD, Rosen, HJ, Keret, O, Staffaroni, AM, Ringman, JM, Cobigo, Y, Goh, S-YM, Wolf, A, Allen, IE, Salloway, S, Chhatwal, J, Brickman, AM, Reyes-Dumeyer, D, Bateman, RJ, Benzinger, TLS, Morris, JC, Ances, BM, Joseph-Mathurin, N, Perrin, RJ, Gordon, BA, Levin, J, Voeglein, J, Jucker, M, Fougere, C, Martins, RN, Sohrabi, HR, Taddei, K, Villemagne, VL, Schofield, PR, Brooks, WS, Fulham, M, Masters, CL, Ghetti, B, Saykin, AJ, Jack, CR, Graff-Radford, NR, Weiner, M, Cash, DM, Allegri, RF, Chrem, P, Yi, S, Miller, BL, Rabinovici, GD, and Rosen, HJ

Abstract

INTRODUCTION: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. METHODS: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. RESULTS: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset. DISCUSSION: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.

Published
2021

11. Securing sustainable funding for viral hepatitis elimination plans

Author

Hatzakis, A. Lazarus, J.V. Cholongitas, E. Baptista-Leite, R. Boucher, C. Busoi, C.-S. Deuffic-Burban, S. Chhatwal, J. Esmat, G. Hutchinson, S. Malliori, M.-M. Maticic, M. Mozalevskis, A. Negro, F. Papandreou, G.A. Papatheodoridis, G.V. Peck-Radosavljevic, M. Razavi, H. Reic, T. Schatz, E. Tozun, N. Younossi, Z. Manns, M.P.

Abstract

The majority of people infected with chronic hepatitis C virus (HCV) in the European Union (EU) remain undiagnosed and untreated. During recent years, immigration to EU has further increased HCV prevalence. It has been estimated that, out of the 4.2 million adults affected by HCV infection in the 31 EU/ European Economic Area (EEA) countries, as many as 580 000 are migrants. Additionally, HCV is highly prevalent and under addressed in Eastern Europe. In 2013, the introduction of highly effective treatments for HCV with direct-acting antivirals created an unprecedented opportunity to cure almost all patients, reduce HCV transmission and eliminate the disease. However, in many settings, HCV elimination poses a serious challenge for countries’ health spending. On 6 June 2018, the Hepatitis B and C Public Policy Association held the 2nd EU HCV Policy summit. It was emphasized that key stakeholders should work collaboratively since only a few countries in the EU are on track to achieve HCV elimination by 2030. In particular, more effort is needed for universal screening. The micro-elimination approach in specific populations is less complex and less costly than country-wide elimination programmes and is an important first step in many settings. Preliminary data suggest that implementation of the World Health Organization (WHO) Global Health Sector Strategy on Viral Hepatitis can be cost saving. However, innovative financing mechanisms are needed to raise funds upfront for scaling up screening, treatment and harm reduction interventions that can lead to HCV elimination by 2030, the stated goal of the WHO. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Published
2020

14. 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

15. 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

16. Predicting sporadic Alzheimer's disease progression via inherited Alzheimer's disease-informed machine-learning

Author

Franzmeier, N, Koutsouleris, N, Benzinger, T, Goate, A, Karch, CM, Fagan, AM, McDade, E, Duering, M, Dichgans, M, Levin, J, Gordon, BA, Lim, YY, Masters, CL, Rossor, M, Fox, NC, O'Connor, A, Chhatwal, J, Salloway, S, Danek, A, Hassenstab, J, Schofield, PR, Morris, JC, Bateman, RJ, Ewers, M, Franzmeier, N, Koutsouleris, N, Benzinger, T, Goate, A, Karch, CM, Fagan, AM, McDade, E, Duering, M, Dichgans, M, Levin, J, Gordon, BA, Lim, YY, Masters, CL, Rossor, M, Fox, NC, O'Connor, A, Chhatwal, J, Salloway, S, Danek, A, Hassenstab, J, Schofield, PR, Morris, JC, Bateman, RJ, and Ewers, M

Abstract

INTRODUCTION: Developing cross-validated multi-biomarker models for the prediction of the rate of cognitive decline in Alzheimer's disease (AD) is a critical yet unmet clinical challenge. METHODS: We applied support vector regression to AD biomarkers derived from cerebrospinal fluid, structural magnetic resonance imaging (MRI), amyloid-PET and fluorodeoxyglucose positron-emission tomography (FDG-PET) to predict rates of cognitive decline. Prediction models were trained in autosomal-dominant Alzheimer's disease (ADAD, n = 121) and subsequently cross-validated in sporadic prodromal AD (n = 216). The sample size needed to detect treatment effects when using model-based risk enrichment was estimated. RESULTS: A model combining all biomarker modalities and established in ADAD predicted the 4-year rate of decline in global cognition (R2 = 24%) and memory (R2 = 25%) in sporadic AD. Model-based risk-enrichment reduced the sample size required for detecting simulated intervention effects by 50%-75%. DISCUSSION: Our independently validated machine-learning model predicted cognitive decline in sporadic prodromal AD and may substantially reduce sample size needed in clinical trials in AD.

Published
2020

17. Peripheral Oxidative Stress Markers Are Related To Vascular Risk Factors And Subcortical Small Vessel Disease

Author

Warrick, N., Seitz, D., Prorok, J., Shawcross, D., Mahootchi, T., Esensoy, A., Yu, D., Danieli, E., Pushpakumar, D., Tony, J., Jacob, K., Dong, J., Javed, F., D’Souza, A., Mollayeva, T., Colantonio, A., Schulz, M., Burhan, A., Naidu, A. Srinivasan, Sarquis-Adamson, Y., Montero-Odasso, M., Cooper, N., Sekhon, H., Launay, C., Allali, G., Chabot, J., Beauchet, O., Watson, B., Lin, T., Korczak, A., Bartha, C., Best, S., Truemner, J., Borrie, M., Cammer, A., Whiting, S., Morgan, D., Newman, K., Duong, J. A., Mok, A., Wang, A. H., Lavoie, M., Bier, N., Macoir, J., Adlimoghaddam, A., Turner, R. S., Cadonic, C., Albensi, B. C., Davis, J., Lewis, V.-L., Pacione, J., Skanes, C., Feltz, N., Loncar, A., Naglie, G., Sanford, S., Stasiulis, E., Rapoport, M., Vrkljan, B., Tuokko, H., Porter, M., Polgar, J., Moorhouse, P., Mazer, B., Marshall, S., Gelinas, I, Crizzle, A, Belchior, P., Bedard, M, Kokorelias, K., Cameron, J., Gignac, M., Bechard, L., Beaton, D., McGilton, K.A., Tartaglia, M. C., Black, S., Mirza, S., Mutsaerts, H.-J., Cash, D., Bocchetta, M., Thomas, D., Dick, K., van Swieten, J., Borroni, B., Galimberti, D., Rowe, J., Bethell, J., Pringle, D., Commisso, E., Chambers, L., Cohen, C., Cowan, K., Fehr, P., Szeto, P., McGilton, K., Shaw, C., Okamura, H., Otani, M., Shimoyama, N., Fujii, T., Lusk, J., Punzalan, M., Dove, E., Cotnam, K., Astell, A., Chow, A. Froehlich, Bayly, M., Kosteniuk, J., Elliot, V., O’Connell, M. E., Kirk, A., Stewart, N., Holroyd-Leduc, J., Daku, J., Kennett-Russill, D., Hack, T., Dilara, A., Astell, A. J., Hernandez, A., Divine, A., Hunter, S., Jacova, C., Alexander, C., Joseph, J. T., Alvarez, A., Smith, E., Woo, S. M. S., Chan, P., Wilkins-Ho, M., Blackburn, P., Fernando, N., Mehra, A., Vasser, E., Musacchio, M., Waxman, R., Fischler, I., Ghaffar, O., DeBay, D. R., Macdonald, I. R., Reid, G. A., Pottie, I. R., Maxwell, S. P., Cash, M. K., Martin, E., Bowen, C. V., Darvesh, S., MacPhee, J., Jorgensen, M., Fogarty, J., Phillips, N., Diprospero, C., Parent, A., Whitehead, V., Campbell, T., Mohades, Z., Chertkow, H., Wong, S., Wilchesky, M., McCusker, J., Champoux, N., Vu, T.T. M., Ciampi, A., Monette, J., Lungu, O., Ballard, S. A., Belzile, E., Carmichael, P.-H., Voyer, P., Cetin-Sahin, D., Gore, B., Peretti, M., Gore, G., Landry, V., Yetman, L., MacDonald, E., McGibbon, C., MacNeil, D., Jarrett, P., Iaboni, A., Andrews, J., Hafezi, S., Marshall, C., Tsokas, M., Martin, L. Schindel, Van Ooteghem, K., Mansfield, A., Marcil, M., Gold, D., Musselman, K., Flint, A., Finger, E., Feldman, H., Cummings, J., Coleman, K., Boxer, A., Berry, S., Hsiung, R., Curtis, A., Zhang, K., Davidson, H. R., Boccone, G., Camicioli, R., Masellis, M., Tierney, M., Dolatabadi, E., Taati, B., Jonas-Simpson, C., Donovan, L., Cross, N., Keren, R., Shan, R., Holley, J., Waisman, Z., Katchaluba, J., Wimhurst, C., Steele, M., Loganathan, P., Gural, P., Shearer, T., Reardon, J., Pilgrim, J., Pitawanakwat, K., Jones, L., Piriano, E., Blind, M., Otowadjiwan, J., Makela, R., Spicer, B., Bretzlaff, M., Jacklin, K., McKay, Kristy, Graham, N., Tang-Wai, D., Leonard, C., Mitchell, S., Laird, L., Rochon, E., Maclagan, L., Maxwell, C., Guan, J., Campitelli, M., Herrmann, N., Lapane, K., Hogan, D., Amuah, J., Gill, S., Bronskill, S., Ebert, P., Kwok, J., Watt, A., Garrett, S., Hoefling, L., Ellery, C., Leggieri, M., Fornazzari, L., Thaut, M., Munoz, D., Barfett, J., Fischer, C., Schweizer, T., Yogaparan, T., Dallaire-Théroux, C., Potvin, O., Dieumegarde, L., Duchesne, Simon, Amini, A.E. Ebrahim, Amini, A.Z. Ebrahim, Dao, E., Barha, C. K., Best, J. R., Hsiung, G.-Y. R., Tam, R., Liu-Ambrose, T., Sztramko, R., Wurster, A., Papaiouannou, A., Cowan, D., St. Onge, J., Allaby, C., Harrison, L., Cimino, C., Marr, S., Patterson, C., Woo, T., Levinson, A., Fisher, S., Mojaverian, N., Hsu, A., Taljaard, M., Manuel, D., Tanuseputro, P., Park, E., Liu, L., VanderPloeg, K., Black, A., Bartha, R., Rabin, J., Yang, H.-S., Schultz, A., Hanseeuw, B., Marshall, G., Hedden, T., Rentz, D., Johnson, K., Sperling, R., Chhatwal, J., Desmarais, P., Miville, C., Keith, J., Lanctôt, K., Thomas, N., Mattek, N., Riley, T., Witter, P., Reynolds, C., Austin, J., Sharma, N., Kaye, J., Bechard, L. E., Mitchell, C. M., Regan, K., Bergelt, M. D., Middleton, L.E., Hewston, P., Kennedy, C., Merom, D., Trainor, L., Grenier, A., Ioannidis, G., Lee, J., Papaioannou, A., Qian, W., Churchill, N., Kumar, S., Rajji, T., Ojeda-López, C., Milán-Tomás, Á., Lam, B., Gao, F. Q., Cumberbatch, S., Gies, S., Tomas, A. Milan, Ojeda-Lopez, C., Lim, A. S., Black, S. E., Sharma, M. J., Ramirez, J., Holmes, M. F., Gao, F., Varatharajah, B., Yhap, V., Appel, L., Bogler, O., Appel, E., Wiseman, M., Cohen, L., Hill, D., Abrams, H., Campos, J., Sapkota, S., Adamo, S., Stuss, D. T., Martinez, M., Multani, N., Anor, C. J., Fox, S., Lang, A. E., Marras, C., Compagnone, J., Li, J., Freedman, M., Kleiner-Fisman, G., Kennedy, J., Chen, R., Lang, A., Sévigny-Dupont, P., Bocti, C., Joannette, M., Lavallée, M. M., Joubert, S., Knoefel, F., Goubran, R., Baker, A., Fraser, S., Allard, B., Wallace, B., Stroulia, E., Guana, V., Masson, P., Alli, S., Kolla, N., De Luca, V., Bouvier, L., Monetta, L., Vitali, P., Laforce, R., Martel-Sauvageau, V., Talebzadeh, A., Ashourinia, K., Moy, S., Lake, A., Cockburn, A., Krisman, D., Sadasivan, B., Sit, W., Stoops, S., McCurbin, S., Cullen, S., Carroll, S., Tasmim, S., Kapoor, E., Callahan, B., Sharma, M., Bierstone, D., Stuss, D., Kapadia, M., Mian, F., Ma, D., Rosa, E., Michalski, B., Zovkic, I., Forsythe, P., Sakic, B., Fahnestock, M., Baxter, J., Peloso, S., Tung, J., Cox, L., Benjamin, S., An, H., Ho, J., Turcotte, V., Parent, C., Gauthier-Beaupré, A., Biss, R., Sultana, A., Chu, C. H., Sun, W., Bartfay, E., Smye, V., Newton, D., Pepin, M., Biswas, S., Madahey, H., Crawford, S. J., Gutmanis, I., Blake, C., Duchesne, S., Hudon, C., Mah, L., Ali, A., Shorey, C., Szabuniewicz, C. M., Anderson, N. D., Verhoeff, N. P. L. G., Cheers, S., Penko, M., Gevaert, V., Yang, Y., Law, J., Modarresi, S., Grahn, J., Overend, T., Amini, D., Thiruparanathan, T., Cheung, T., Iskandar, S., Arone, Y., Young, C., Berezuk, C., and Zakzanis, K.

Subjects
Abstracts
Published
2018

25. Developing a competency-based undergraduate logbook for pediatrics: Process and lessons.

Author

Singh, T, Aulakh, R, Gupta, P, and Chhatwal, J

Subjects
AFFECT (Psychology), PEDIATRICS, CURRICULUM, HUMAN services programs, EDUCATIONAL tests & measurements, UNDERGRADUATES, LEARNING strategies, OUTCOME-based education
Abstract

With the first MBBS batch admitted under the new National Medical Commission (NMC) undergraduate curriculum entering pediatric clinical posting soon, creation of a Pediatric logbook in consonance with this competency-based curriculum was felt to be a need of the hour. No such document is yet available in the public domain. The logbook template, created after enormous brainstorming amongst authors, includes 176 Shows (S), Shows How (SH) and Perform (P) level competencies. These were further segregated into certifiable (23), affective domain (25) and clinic/field visits (9) leaving 51 as documentable competencies. The institutions may use this template to build their own institute-specific logbook based on the infrastructure, faculty strength, clinical patient load, student intake and preferred assessment method(s). It would also be worthwhile to integrate this with the internship logbook (and later the postgraduate one for students opting for post-graduation in pediatrics) to provide a longitudinal record of each student's trajectory of learning. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
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26. 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

27. Seizures as an early symptom of autosomal dominant Alzheimer's disease

Author

Vöglein, J, Noachtar, S, McDade, E, Quaid, KA, Salloway, S, Ghetti, B, Noble, J, Berman, S, Chhatwal, J, Mori, H, Fox, N, Allegri, R, Masters, CL, Buckles, V, Ringman, JM, Rossor, M, Schofield, PR, Sperling, R, Jucker, M, Laske, C, Paumier, K, Morris, JC, Bateman, RJ, Levin, J, Danek, A, Vöglein, J, Noachtar, S, McDade, E, Quaid, KA, Salloway, S, Ghetti, B, Noble, J, Berman, S, Chhatwal, J, Mori, H, Fox, N, Allegri, R, Masters, CL, Buckles, V, Ringman, JM, Rossor, M, Schofield, PR, Sperling, R, Jucker, M, Laske, C, Paumier, K, Morris, JC, Bateman, RJ, Levin, J, and Danek, A

Abstract

Our objective was to assess the reported history of seizures in cognitively asymptomatic mutation carriers for autosomal dominant Alzheimer's disease (ADAD) and the predictive value of seizures for mutation carrier status in cognitively asymptomatic first-degree relatives of ADAD patients. Seizure occurrence in the Dominantly Inherited Alzheimer Network observational study was correlated with mutation carrier status in cognitively asymptomatic subjects. Of 276 cognitively asymptomatic individuals, 11 (4%) had experienced seizures, and nine of these carried an ADAD mutation. Thus, in the Dominantly Inherited Alzheimer Network population, seizure frequency in mutation carriers was significantly higher than in noncarriers (p = 0.04), and the positive predictive value of seizures for the presence of a pathogenic mutation was 81.8%. Among cognitively asymptomatic ADAD family members, the occurrence of seizures increases the a priori risk of 50% mutation-positive status to about 80%. This finding suggests that ADAD mutations increase the risk of seizures.

Published
2019

28. Hepatitis C: The beginning of the end—key elements for successful European and national strategies to eliminate HCV in Europe

Author

Papatheodoridis, G.V. Hatzakis, A. Cholongitas, E. Baptista-Leite, R. Baskozos, I. Chhatwal, J. Colombo, M. Cortez-Pinto, H. Craxi, A. Goldberg, D. Gore, C. Kautz, A. Lazarus, J.V. Mendão, L. Peck-Radosavljevic, M. Razavi, H. Schatz, E. Tözün, N. van Damme, P. Wedemeyer, H. Yazdanpanah, Y. Zuure, F. Manns, M.P.

Abstract

Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely “silent pandemic,” its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week. © 2018 John Wiley & Sons Ltd

Published
2018

30. Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer's disease

Author

Lim, YY, Hassenstab, J, Goate, A, Fagan, AM, Benzinger, TLS, Cruchaga, C, McDade, E, Chhatwal, J, Levin, J, Farlow, MR, Graff-Radford, NR, Laske, C, Masters, CL, Salloway, S, Schofield, P, Morris, JC, Maruff, P, Bateman, RJ, Lim, YY, Hassenstab, J, Goate, A, Fagan, AM, Benzinger, TLS, Cruchaga, C, McDade, E, Chhatwal, J, Levin, J, Farlow, MR, Graff-Radford, NR, Laske, C, Masters, CL, Salloway, S, Schofield, P, Morris, JC, Maruff, P, and Bateman, RJ

Abstract

© 2018 American Neurological Association Objective: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline. Methods: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. Results: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42. Interpretation: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424–435.

Published
2018

31. Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

Author

Karch, CM, Hernández, D, Wang, JC, Marsh, J, Hewitt, AW, Hsu, S, Norton, J, Levitch, D, Donahue, T, Sigurdson, W, Ghetti, B, Farlow, M, Chhatwal, J, Berman, S, Cruchaga, C, Morris, JC, Bateman, RJ, Pébay, A, Goate, AM, Karch, CM, Hernández, D, Wang, JC, Marsh, J, Hewitt, AW, Hsu, S, Norton, J, Levitch, D, Donahue, T, Sigurdson, W, Ghetti, B, Farlow, M, Chhatwal, J, Berman, S, Cruchaga, C, Morris, JC, Bateman, RJ, Pébay, A, and Goate, AM

Abstract

Background: Mutations in amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) cause autosomal dominant forms of Alzheimer disease (ADAD). More than 280 pathogenic mutations have been reported in APP, PSEN1, and PSEN2. However, understanding of the basic biological mechanisms that drive the disease are limited. The Dominantly Inherited Alzheimer Network (DIAN) is an international observational study of APP, PSEN1, and PSEN2 mutation carriers with the goal of determining the sequence of changes in presymptomatic mutation carriers who are destined to develop Alzheimer disease. Results: We generated a library of 98 dermal fibroblast lines from 42 ADAD families enrolled in DIAN. We have reprogrammed a subset of the DIAN fibroblast lines into patient-specific induced pluripotent stem cell (iPSC) lines. These cells were thoroughly characterized for pluripotency markers. Conclusions: This library represents a comprehensive resource that can be used for disease modeling and the development of novel therapeutics.

Published
2018

32. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer's disease

Author

Franzmeier, N, Duezel, E, Jessen, F, Buerger, K, Levin, J, Duering, M, Dichgans, M, Haass, C, Suarez-Calvet, M, Fagan, AM, Paumier, K, Benzinger, T, Masters, CL, Morris, JC, Perneczky, R, Janowitz, D, Catak, C, Wolfsgruber, S, Wagner, M, Teipel, S, Kilimann, I, Ramirez, A, Rossor, M, Jucker, M, Chhatwal, J, Spottke, A, Boecker, H, Brosseron, F, Falkai, P, Fliessbach, K, Heneka, MT, Laske, C, Nestor, P, Peters, O, Fuentes, M, Menne, F, Priller, J, Spruth, EJ, Franke, C, Schneider, A, Kofler, B, Westerteicher, C, Speck, O, Wiltfang, J, Bartels, C, Caballero, MAA, Metzger, C, Bittner, D, Weiner, M, Lee, J-H, Salloway, S, Danek, A, Goate, A, Schofield, PR, Bateman, RJ, Ewers, M, Franzmeier, N, Duezel, E, Jessen, F, Buerger, K, Levin, J, Duering, M, Dichgans, M, Haass, C, Suarez-Calvet, M, Fagan, AM, Paumier, K, Benzinger, T, Masters, CL, Morris, JC, Perneczky, R, Janowitz, D, Catak, C, Wolfsgruber, S, Wagner, M, Teipel, S, Kilimann, I, Ramirez, A, Rossor, M, Jucker, M, Chhatwal, J, Spottke, A, Boecker, H, Brosseron, F, Falkai, P, Fliessbach, K, Heneka, MT, Laske, C, Nestor, P, Peters, O, Fuentes, M, Menne, F, Priller, J, Spruth, EJ, Franke, C, Schneider, A, Kofler, B, Westerteicher, C, Speck, O, Wiltfang, J, Bartels, C, Caballero, MAA, Metzger, C, Bittner, D, Weiner, M, Lee, J-H, Salloway, S, Danek, A, Goate, A, Schofield, PR, Bateman, RJ, and Ewers, M

Abstract

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset intera

Published
2018

35. Further Research Needed for Chronic Myeloid Leukemia? A Value-of-Information Analysis

Author

Rochau, U, Kühne, F, Jahn, B, Kurzthaler, C, Corro-Ramos, I, Chhatwal, J, Stollenwerk, B, Goldhaber-Fiebert, J, and Siebert, U

Subjects
Value-of-Information Analysis, Decision Analysis, ddc: 610, Chronic Myeloid Leukemia, 610 Medical sciences, Medicine, Cost-effectiveness Analysis
Abstract

Introduction: Value-of-Information analysis extends traditional decision analysis and can help to guide decisions about future research priorities: If and what further research is needed? Our aim was to guide decisions regarding prioritization of future outcomes research on parameters related to[for full text, please go to the a.m. URL], GMDS 2015; 60. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V. (GMDS)

Published
2015
Full Text
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37. Amyloid, Tau, and Functional connectivity

Author

UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Schultz, A, Chhatwal, J, Hedden, T, Sepulcre, J, Mormino, E, Huijbers, W, Hanseeuw, Bernard, Sperling, R, Johnson, K, Human Amyloid Imaging 2016, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Schultz, A, Chhatwal, J, Hedden, T, Sepulcre, J, Mormino, E, Huijbers, W, Hanseeuw, Bernard, Sperling, R, Johnson, K, and Human Amyloid Imaging 2016

Published
2016

38. Evidence that striatal amyloidosis is a marker of disease progression across the spectrum of Alzheimer's disease

Author

UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Hanseeuw, Bernard, Bark, J, Chhatwal, J, Jacobs, H, Marshall, G, Mormino, E, Papp, K, Amariglio, R, Schultz, A, Sepulcre, J, Vannini, P, Rentz, D, Sperling, R, Johnson, K, Human Amyloid Imaging 2016, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Hanseeuw, Bernard, Bark, J, Chhatwal, J, Jacobs, H, Marshall, G, Mormino, E, Papp, K, Amariglio, R, Schultz, A, Sepulcre, J, Vannini, P, Rentz, D, Sperling, R, Johnson, K, and Human Amyloid Imaging 2016

Published
2016

45. Functional connectivity in autosomal dominant and late-onset Alzheimer disease

Author

Thomas, JB, Brier, MR, Bateman, RJ, Snyder, AZ, Benzinger, TL, Xiong, C, Raichle, M, Holtzman, DM, Sperling, RA, Mayeux, R, Ghetti, B, Ringman, JM, Salloway, S, McDade, E, Rossor, MN, Ourselin, S, Schofield, PR, Masters, CL, Martins, RN, Weiner, MW, Thompson, PM, Fox, NC, Koeppe, RA, Jack, CR, Mathis, CA, Oliver, A, Blazey, TM, Moulder, K, Buckles, V, Hornbeck, R, Chhatwal, J, Schultz, AP, Goate, AM, Fagan, AM, Cairns, NJ, Marcus, DS, Morris, JC, Ances, BM, Thomas, JB, Brier, MR, Bateman, RJ, Snyder, AZ, Benzinger, TL, Xiong, C, Raichle, M, Holtzman, DM, Sperling, RA, Mayeux, R, Ghetti, B, Ringman, JM, Salloway, S, McDade, E, Rossor, MN, Ourselin, S, Schofield, PR, Masters, CL, Martins, RN, Weiner, MW, Thompson, PM, Fox, NC, Koeppe, RA, Jack, CR, Mathis, CA, Oliver, A, Blazey, TM, Moulder, K, Buckles, V, Hornbeck, R, Chhatwal, J, Schultz, AP, Goate, AM, Fagan, AM, Cairns, NJ, Marcus, DS, Morris, JC, and Ances, BM

Abstract

IMPORTANCE: Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile. OBJECTIVE: To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD. DESIGN, SETTING, AND PARTICIPANTS: We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivitymagnetic resonance imaging at multiple international academic sites. MAIN OUTCOMES AND MEASURES: For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs. RESULTS: A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers. CONCLUSIONS AND RELEVANCE: Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivitymagnetic resonance imagingmay be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

Published
2014

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