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1. Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial

Author: Mills, S.M., Mallmann, J., Santacruz, A.M., Fuqua, A., Carril, M., Aisen, P.S., Althage, M.C., Belyew, S., Benzinger, T.L., Brooks, W.S., Buckles, V.D., Cairns, N.J., Clifford, D., Danek, A., Fagan, A.M., Farlow, M., Fox, N., Ghetti, B., Goate, A.M., Heinrichs, D., Hornbeck, R., Jack, C., Jucker, M., Klunk, W.E., Marcus, D.S., Martins, R.N., Masters, C.M., Mayeux, R., McDade, E., Morris, J.C., Oliver, A., Ringman, J.M., Rossor, M.N., Salloway, S., Schofield, P.R., Snider, J., Snyder, P., Sperling, R.A., Stewart, C., Thomas, R.G., Xiong, C., and Bateman, R.J.
Published: 2013
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2. Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum

Author: Jansen, W.J., Janssen, O., Tijms, B.M., Vos, S.J.B., Ossenkoppele, R., Visser, P.J., Group, A.B.S., Aarsland, D., Alcolea, D., Altomare, D., Arnim, C. von, Baiardi, S., Baldeiras, I., Barthel, H., Bateman, R.J., Berckel, B. Van, Binette, A.P., Blennow, K., Boada, M., Boecker, H., Bottlaender, M., Braber, A., Brooks, D.J., Buchem, M.A. van, Camus, V., Carill, J.M., Cerman, J., Chen, K., Chételat, G., Chipi, E., Cohen, A.D., Daniels, A., Delarue, M., Didic, M., Drzezga, A., Dubois, B., Eckerström, M., Ekblad, L.L., Engelborghs, S., Epelbaum, S., Fagan, A.M., Fan, Y., Fladby, T., Fleisher, A.S., Flier, W.M. van der, Förster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Frings, L., Frisoni, G.B., Fröhlich, L., Gabryelewicz, T., Gertz, H.J., Gill, K.D., Gkatzima, O., Gómez-Tortosa, E., Grimmer, T., Guedj, E., Habeck, C.G., Hampel, H., Handels, R., Hansson, O., Hausner, L., Hellwig, S., Heneka, M.T., Herukka, S.K., Hildebrandt, H., Hodges, J., Hort, J., Huang, C.C., Iriondo, A.J., Itoh, Y., Ivanoiu, A., Jagust, W.J., Jessen, F., Johannsen, P., Johnson, K.A., Kandimalla, R., Kapaki, E.N., Kern, S., Kilander, L., Klimkowicz-Mrowiec, A., Klunk, W.E., Koglin, N., Kornhuber, J., Kramberger, M.G., Kuo, H.C., Laere, K. Van, Landau, S.M., Landeau, B., Lee, Dyantha I. van der, Leon, M., Leyton, C.E., Lin, K.J., Lleó, A., Löwenmark, M., Madsen, K., Maier, W., Marcusson, J., Olde Rikkert, M.G.M., Verbeek, M.M., Zboch, M., Zetterberg, H., Jansen, W.J., Janssen, O., Tijms, B.M., Vos, S.J.B., Ossenkoppele, R., Visser, P.J., Group, A.B.S., Aarsland, D., Alcolea, D., Altomare, D., Arnim, C. von, Baiardi, S., Baldeiras, I., Barthel, H., Bateman, R.J., Berckel, B. Van, Binette, A.P., Blennow, K., Boada, M., Boecker, H., Bottlaender, M., Braber, A., Brooks, D.J., Buchem, M.A. van, Camus, V., Carill, J.M., Cerman, J., Chen, K., Chételat, G., Chipi, E., Cohen, A.D., Daniels, A., Delarue, M., Didic, M., Drzezga, A., Dubois, B., Eckerström, M., Ekblad, L.L., Engelborghs, S., Epelbaum, S., Fagan, A.M., Fan, Y., Fladby, T., Fleisher, A.S., Flier, W.M. van der, Förster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Frings, L., Frisoni, G.B., Fröhlich, L., Gabryelewicz, T., Gertz, H.J., Gill, K.D., Gkatzima, O., Gómez-Tortosa, E., Grimmer, T., Guedj, E., Habeck, C.G., Hampel, H., Handels, R., Hansson, O., Hausner, L., Hellwig, S., Heneka, M.T., Herukka, S.K., Hildebrandt, H., Hodges, J., Hort, J., Huang, C.C., Iriondo, A.J., Itoh, Y., Ivanoiu, A., Jagust, W.J., Jessen, F., Johannsen, P., Johnson, K.A., Kandimalla, R., Kapaki, E.N., Kern, S., Kilander, L., Klimkowicz-Mrowiec, A., Klunk, W.E., Koglin, N., Kornhuber, J., Kramberger, M.G., Kuo, H.C., Laere, K. Van, Landau, S.M., Landeau, B., Lee, Dyantha I. van der, Leon, M., Leyton, C.E., Lin, K.J., Lleó, A., Löwenmark, M., Madsen, K., Maier, W., Marcusson, J., Olde Rikkert, M.G.M., Verbeek, M.M., Zboch, M., and Zetterberg, H.
Abstract: Contains fulltext : 248802.pdf (Publisher’s version ) (Closed access)
Published: 2022

3. Presymptomatic Dutch-Type hereditary cerebral amyloid Angiopathy-Related blood metabolite alterations

Author: Chatterjee, P., Fagan, A.M., Xiong, C., McKay, M., Bhatnagar, A., Wu, Y., Singh, A.K., Taddei, K., Martins, I., Gardener, S.L., Molloy, M.P., Multhaup, G., Masters, C.L., Schofield, P.R., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Greenberg, S.M., Wermer, M.J.H., van Buchem, M.A., Sohrabi, H.R., Martins, R.N., Chatterjee, P., Fagan, A.M., Xiong, C., McKay, M., Bhatnagar, A., Wu, Y., Singh, A.K., Taddei, K., Martins, I., Gardener, S.L., Molloy, M.P., Multhaup, G., Masters, C.L., Schofield, P.R., Benzinger, T.L.S., Morris, J.C., Bateman, R.J., Greenberg, S.M., Wermer, M.J.H., van Buchem, M.A., Sohrabi, H.R., and Martins, R.N.
Abstract: Background:Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective:Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods:Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results:275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 0.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = –0.527, p = 0.030). Conclusion:The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.
Published: 2021

4. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

Author: Britschgi, M., Olin, C.E., Johns, H.T., Takeda-Uchimura, Y., LeMieux, M.C., Rufibach, K., Rajadas, K., Zhang, H., Tomooka, B., Robinson, W.H., Clark, C.M., Fagan, A.M., Galasko, D.R., Holtzman, D.M., Jutel, M., Kaye, J.A., Lemere, C.A., Leszek, J., Li, G., Peskind, E.R., Quinn, J.F., Yesavage, J.A., Ghiso, J.A., and Wyss-Coray, T.
Subjects: Alzheimer's disease -- Development and progression, Antigen-antibody reactions -- Research, Peptides -- Health aspects, Aging -- Research, Science and technology
Abstract: A number of distinct [beta]-amyloid (A[beta]) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural A[beta]-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic A[beta] and amyloidogenic non-A[beta] species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of A[beta] and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of A[beta]1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant A[beta], ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from A[beta] toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with A[beta] the monkeys developed high titers not only against A[beta] peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of A[beta] antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.
Published: 2009

5. 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

6. Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR

Author: Fundin, B.T., Silos-Santiago, I., Ernfors, P., Fagan, A.M., Aldskogius, H., DeChiara, T.M., Phillips, H.S., Barbacid, M., Yancopoulos, G.D., and Rice, F.L.
Subjects: Mechanoreceptors -- Research, Gene mutations -- Research, Mice -- Genetic aspects, Biological sciences
Abstract: The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and p75. NT-4 has no obvious detrimental impact on the mechanoreceptor development in the presence of BDNF. Fourth, NT-4 and BDNF signaling through trkB may suppress Merkel innerration and NT3 signaling through trkC may suppress Ruffini innervation. Finally, regardless of the neurotrophin/receptor dependency for afferent survival and neurite outgrowth, NT-3 has an impact on the formation of all the sensory endings. In the context of these findings, indications of competitive and suppressive interactions that appear to regulate the balance of innervation density among the various sets of innervation were evident.
Published: 1997

7. 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

8. Amyloid imaging of dutch‐type hereditary cerebral amyloid angiopathy carriers

Author: Schultz, A.P., Kloet, R.W., Sohrabi, H.R., Weerd, L., Rooden, S., Wermer, M.J.H., Moursel, L.G., Yaqub, M., Berckel, B.N.M., Chatterjee, P., Gardener, S.L., Taddei, K., Fagan, A.M., Benzinger, T.L., Morris, J.C., Sperling, R., Johnson, K., Bateman, R.J., Gurol, M.E., Buchem, M.A., Martins, R., Chhatwal, J.P., Greenberg, S.M., Schultz, A.P., Kloet, R.W., Sohrabi, H.R., Weerd, L., Rooden, S., Wermer, M.J.H., Moursel, L.G., Yaqub, M., Berckel, B.N.M., Chatterjee, P., Gardener, S.L., Taddei, K., Fagan, A.M., Benzinger, T.L., Morris, J.C., Sperling, R., Johnson, K., Bateman, R.J., Gurol, M.E., Buchem, M.A., Martins, R., Chhatwal, J.P., and Greenberg, S.M.
Abstract: Objective To determine whether amyloid imaging with the positron emission tomography (PET) agent Pittsburgh compound B (PiB) can detect vascular β‐amyloid (Aβ) in the essentially pure form of cerebral amyloid angiopathy associated with the Dutch‐type hereditary cerebral amyloid angiopathy (D‐CAA) mutation. Methods PiB retention in a cortical composite of frontal, lateral, and retrosplenial regions (FLR) was measured by PiB‐PET in 19 D‐CAA mutation carriers (M+; 13 without neurologic symptoms, 6 with prior lobar intracerebral hemorrhage) and 17 mutation noncarriers (M−). Progression of PiB retention was analyzed in a subset of 18 serially imaged individuals (10 asymptomatic M+, 8 M−). We also analyzed associations between PiB retention and cerebrospinal fluid (CSF) Aβ concentrations in 17 M+ and 11 M− participants who underwent lumbar puncture and compared the findings to PiB‐PET and CSF Aβ in 37 autosomal dominant Alzheimer disease (ADAD) mutation carriers. Results D‐CAA M+ showed greater age‐dependent FLR PiB retention (p < 0.001) than M−, and serially imaged asymptomatic M+ demonstrated greater longitudinal increases (p = 0.004). Among M+, greater FLR PiB retention associated with reduced CSF concentrations of Aβ40 (r = −0.55, p = 0.021) but not Aβ42 (r = 0.01, p = 0.991). Despite comparably low CSF Aβ40 and Aβ42, PiB retention was substantially less in D‐CAA than ADAD (p < 0.001). Interpretation Increased PiB retention in D‐CAA and correlation with reduced CSF Aβ40 suggest this compound labels vascular amyloid, although to a lesser degree than amyloid deposits in ADAD. Progression in PiB signal over time suggests amyloid PET as a potential biomarker in trials of candidate agents for this untreatable cause of hemorrhagic stroke. ANN NEUROL 2019;86:616–625
Published: 2019

9. Association of cerebral amyloid-β Aggregation with cognitive functioning in persons without dementia

Author: Jansen, W.J. Ossenkoppele, R. Tijms, B.M. Fagan, A.M. Hansson, O. Klunk, W.E. Van Der Flier, W.M. Villemagne, V.L. Frisoni, G.B. Fleisher, A.S. Lleó, A. Mintun, M.A. Wallin, A. Engelborghs, S. Na, D.L. Chételat, G. Molinuevo, J.L. Landau, S.M. Mattsson, N. Kornhuber, J. Sabri, O. Rowe, C.C. Parnetti, L. Popp, J. Fladby, T. Jagust, W.J. Aalten, P. Lee, D.Y. Vandenberghe, R. De Oliveira, C.R. Kapaki, E. Froelich, L. Ivanoiu, A. Gabryelewicz, T. Verbeek, M.M. Sanchez-Juan, P. Hildebrandt, H. Camus, V. Zboch, M. Brooks, D.J. Drzezga, A. Rinne, J.O. Newberg, A. De Mendonça, A. Sarazin, M. Rabinovici, G.D. Madsen, K. Kramberger, M.G. Nordberg, A. Mok, V. Mroczko, B. Wolk, D.A. Meyer, P.T. Tsolaki, M. Scheltens, P. Verhey, F.R.J. Visser, P.J. Aarsland, D. Alcolea, D. Alexander, M. Almdahl, I.S. Arnold, S.E. Baldeiras, I. Barthel, H. Van Berckel, B.N.M. Blennow, K. Van Buchem, M.A. Cavedo, E. Chen, K. Chipi, E. Cohen, A.D. Förster, S. Fortea, J. Frederiksen, K.S. Freund-Levi, Y. Gkatzima, O. Gordon, M.F. Grimmer, T. Hampel, H. Hausner, L. Hellwig, S. Herukka, S.-K. Johannsen, P. Klimkowicz-Mrowiec, A. Köhler, S. Koglin, N. Van Laere, K. De Leon, M. Lisetti, V. Maier, W. Marcusson, J. Meulenbroek, O. Møllergård, H.M. Morris, J.C. Nordlund, A. Novak, G.P. Paraskevas, G.P. Perera, G. Peters, O. Ramakers, I.H.G.B. Rami, L. Rodríguez-Rodríguez, E. Roe, C.M. Rot, U. Rüther, E. Santana, I. Schröder, J. Seo, S.W. Sorininen, H. Spiru, L. Stomrud, E. Struyfs, H. Teunissen, C.E. Vos, S.J.B. Van Waalwijk Van Doorn, L.J.C. Waldemar, G. Wallin, Å.K. Wiltfang, J. Zetterberg, H. Amyloid Biomarker Study Group
Subjects: mental disorders
Abstract: IMPORTANCE Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4%[95%CI, 0%-7%] at 72 years and 21% [95%CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3%[95%CI, -1%to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16%[95%CI, 12%-20%], P < .001) and low MMSE (mean difference, 14%[95%CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
Published: 2018

10. Prevalence of the apolipoprotein E epsilon4 allele in amyloid beta positive subjects across the spectrum of Alzheimer's disease

Author: Mattsson, N., Groot, C. de, Jansen, W.J., Landau, S.M., Villemagne, V.L., Engelborghs, S., Mintun, M.M., Lleo, A., Molinuevo, J.L., Jagust, W.J., Frisoni, G.B., Ivanoiu, A., Chetelat, G., Oliveira, C. de, Rodrigue, K.M., Kornhuber, J., Wallin, A., Klimkowicz-Mrowiec, A., Kandimalla, R., Popp, J., Aalten, P.P., Aarsland, D., Alcolea, D., Almdahl, I.S., Baldeiras, I., Buchem, M.A. van, Cavedo, E., Chen, K., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gill, K.D., Gkatzima, O., Grimmer, T., Hampel, H., Herukka, S.K., Johannsen, P., Laere, K. Van, Leon, M.J. de, Maier, W., Marcusson, J., Meulenbroek, O.V., Mollergard, H.M., Morris, J.C., Mroczko, B., Nordlund, A., Prabhakar, S., Peters, O., Rami, L., Rodriguez-Rodriguez, E., Roe, C.M., Ruther, E., Santana, I., Schroder, J., Seo, S.W., Soininen, H., Spiru, L., Stomrud, E., Struyfs, H., Teunissen, C.E., Verhey, F.R.J., Vos, S.J.B., Waalwijk van Doorn, L.L.C. van, Waldemar, G., Wallin, A.K., Wiltfang, J., Vandenberghe, R., Brooks, D.J., Fladby, T., Rowe, C.C., Drzezga, A., Verbeek, M.M., Sarazin, M., Wolk, D.A., Fleisher, A.S., Klunk, W.E., Na, D.L., Sanchez-Juan, P., Lee, D.Y., Nordberg, A., Tsolaki, M., Camus, V., Rinne, J.O., Fagan, A.M., Zetterberg, H., Blennow, K., Rabinovici, G.D., Hansson, O., Berckel, B.N. van, Flier, W.M. van der, Scheltens, P., Visser, P.J., Ossenkoppele, R., Mattsson, N., Groot, C. de, Jansen, W.J., Landau, S.M., Villemagne, V.L., Engelborghs, S., Mintun, M.M., Lleo, A., Molinuevo, J.L., Jagust, W.J., Frisoni, G.B., Ivanoiu, A., Chetelat, G., Oliveira, C. de, Rodrigue, K.M., Kornhuber, J., Wallin, A., Klimkowicz-Mrowiec, A., Kandimalla, R., Popp, J., Aalten, P.P., Aarsland, D., Alcolea, D., Almdahl, I.S., Baldeiras, I., Buchem, M.A. van, Cavedo, E., Chen, K., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gill, K.D., Gkatzima, O., Grimmer, T., Hampel, H., Herukka, S.K., Johannsen, P., Laere, K. Van, Leon, M.J. de, Maier, W., Marcusson, J., Meulenbroek, O.V., Mollergard, H.M., Morris, J.C., Mroczko, B., Nordlund, A., Prabhakar, S., Peters, O., Rami, L., Rodriguez-Rodriguez, E., Roe, C.M., Ruther, E., Santana, I., Schroder, J., Seo, S.W., Soininen, H., Spiru, L., Stomrud, E., Struyfs, H., Teunissen, C.E., Verhey, F.R.J., Vos, S.J.B., Waalwijk van Doorn, L.L.C. van, Waldemar, G., Wallin, A.K., Wiltfang, J., Vandenberghe, R., Brooks, D.J., Fladby, T., Rowe, C.C., Drzezga, A., Verbeek, M.M., Sarazin, M., Wolk, D.A., Fleisher, A.S., Klunk, W.E., Na, D.L., Sanchez-Juan, P., Lee, D.Y., Nordberg, A., Tsolaki, M., Camus, V., Rinne, J.O., Fagan, A.M., Zetterberg, H., Blennow, K., Rabinovici, G.D., Hansson, O., Berckel, B.N. van, Flier, W.M. van der, Scheltens, P., Visser, P.J., and Ossenkoppele, R.
Abstract: Item does not contain fulltext, INTRODUCTION: Apolipoprotein E (APOE) epsilon4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta (Abeta) pathology. METHODS: We included 3451 Abeta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon4 prevalence in relation to age, sex, education, and geographical location. RESULTS: The APOE epsilon4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Abeta+ cognitively normal and Abeta+ mild cognitive impairment (P < .05) but not in Abeta+ AD dementia (P = .66). The prevalence was highest in Northern Europe but did not vary by sex or education. DISCUSSION: The APOE epsilon4 prevalence in AD was higher than that in previous studies, which did not require presence of Abeta pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
Published: 2018

11. The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review

Author: Hansson, O., Mikulskis, A., Fagan, A.M., Teunissen, C., Zetterberg, H., Vanderstichele, H., Molinuevo, J.L., Shaw, L.M., Vandijck, M., Verbeek, M.M., Savage, M., Mattsson, N., Lewczuk, P., Batrla, R., Rutz, S., Dean, R.A., Blennow, K., Hansson, O., Mikulskis, A., Fagan, A.M., Teunissen, C., Zetterberg, H., Vanderstichele, H., Molinuevo, J.L., Shaw, L.M., Vandijck, M., Verbeek, M.M., Savage, M., Mattsson, N., Lewczuk, P., Batrla, R., Rutz, S., Dean, R.A., and Blennow, K.
Abstract: Item does not contain fulltext, INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers have the potential to improve the diagnostic accuracy of Alzheimer's disease, yet there is a lack of harmonized preanalytical CSF handling protocols. METHODS: This systematic review summarizes the current literature on the influence of preanalytical variables on CSF biomarker concentration. We evaluated the evidence for three core CSF biomarkers: beta-amyloid 42, total tau, and phosphorylated tau. RESULTS: The clinically important variables with the largest amount of conflicting data included the temperature at which samples are stored, the time nonfrozen samples can be stored, and possible effects of additives such as detergents, blood contamination, and centrifugation. Conversely, we discovered that there is consensus that tube material has a significant effect. DISCUSSION: A unified CSF handling protocol is recommended to reduce preanalytical variability and facilitate comparison of CSF biomarkers across studies and laboratories. In future, experiments should use a gold standard with fresh CSF collected in low binding tubes.
Published: 2018

12. Association of Cerebral Amyloid-beta Aggregation With Cognitive Functioning in Persons Without Dementia

Author: Jansen, W.J., Ossenkoppele, R., Tijms, B.M., Fagan, A.M., Hansson, O., Klunk, W.E., Flier, W.M. van der, Villemagne, V.L., Frisoni, G.B., Fleisher, A.S., Lleo, A., Mintun, M.A., Wallin, A., Engelborghs, S., Na, D.L., Chetelat, G., Molinuevo, J.L., Landau, S.M., Mattsson, N., Kornhuber, J., Sabri, O., Rowe, C.C., Parnetti, L., Popp, J., Fladby, T., Jagust, W.J., Aalten, P., Lee, D.Y., Vandenberghe, R., Oliveira, C. de, Kapaki, E., Froelich, L., Ivanoiu, A., Gabryelewicz, T., Verbeek, M.M., Sanchez-Juan, P., Hildebrandt, H., Camus, V., Zboch, M., Brooks, D.J., Drzezga, A., Rinne, J.O., Newberg, A., Mendonca, A. de, Sarazin, M., Rabinovici, G.D., Madsen, K., Kramberger, M.G., Nordberg, A., Mok, V., Mroczko, B., Wolk, D.A., Meyer, P.T., Tsolaki, M., Scheltens, P., Verhey, F.R.J., Visser, P.J., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., Berckel, B.N. van, Blennow, K., Buchem, M.A. van, Cavedo, E., Chen, K., Chipi, E., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gkatzima, O., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Johannsen, P., Klimkowicz-Mrowiec, A., Kohler, S., Koglin, N., Laere, K. Van, Leon, M., Lisetti, V., Maier, W., Marcusson, J., Meulenbroek, O., Mollergard, H.M., Morris, J.C., Nordlund, A., Novak, G.P., Paraskevas, G.P., Perera, G., Peters, O., Ramakers, I., et al., Jansen, W.J., Ossenkoppele, R., Tijms, B.M., Fagan, A.M., Hansson, O., Klunk, W.E., Flier, W.M. van der, Villemagne, V.L., Frisoni, G.B., Fleisher, A.S., Lleo, A., Mintun, M.A., Wallin, A., Engelborghs, S., Na, D.L., Chetelat, G., Molinuevo, J.L., Landau, S.M., Mattsson, N., Kornhuber, J., Sabri, O., Rowe, C.C., Parnetti, L., Popp, J., Fladby, T., Jagust, W.J., Aalten, P., Lee, D.Y., Vandenberghe, R., Oliveira, C. de, Kapaki, E., Froelich, L., Ivanoiu, A., Gabryelewicz, T., Verbeek, M.M., Sanchez-Juan, P., Hildebrandt, H., Camus, V., Zboch, M., Brooks, D.J., Drzezga, A., Rinne, J.O., Newberg, A., Mendonca, A. de, Sarazin, M., Rabinovici, G.D., Madsen, K., Kramberger, M.G., Nordberg, A., Mok, V., Mroczko, B., Wolk, D.A., Meyer, P.T., Tsolaki, M., Scheltens, P., Verhey, F.R.J., Visser, P.J., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., Berckel, B.N. van, Blennow, K., Buchem, M.A. van, Cavedo, E., Chen, K., Chipi, E., Cohen, A.D., Forster, S., Fortea, J., Frederiksen, K.S., Freund-Levi, Y., Gkatzima, O., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Johannsen, P., Klimkowicz-Mrowiec, A., Kohler, S., Koglin, N., Laere, K. Van, Leon, M., Lisetti, V., Maier, W., Marcusson, J., Meulenbroek, O., Mollergard, H.M., Morris, J.C., Nordlund, A., Novak, G.P., Paraskevas, G.P., Perera, G., Peters, O., and Ramakers, I., et al.
Abstract: Contains fulltext : 190311.pdf (Publisher’s version ) (Closed access), Importance: Cerebral amyloid-beta aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-beta aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score
Published: 2018

13. Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease

Author: Brown, B.M., Sohrabi, H.R., Taddei, K., Gardener, S.L., Rainey-Smith, S.R., Peiffer, J.J., Xiong, C., Fagan, A.M., Benzinger, T., Buckles, V., Erickson, K.I., Clarnette, R., Shah, T., Masters, C.L., Weiner, M., Cairns, N., Rossor, M., Graff-Radford, N.R., Salloway, S., Vöglein, J., Laske, C., Noble, J., Schofield, P.R., Bateman, R.J., Morris, J.C., Martins, R.N., Brown, B.M., Sohrabi, H.R., Taddei, K., Gardener, S.L., Rainey-Smith, S.R., Peiffer, J.J., Xiong, C., Fagan, A.M., Benzinger, T., Buckles, V., Erickson, K.I., Clarnette, R., Shah, T., Masters, C.L., Weiner, M., Cairns, N., Rossor, M., Graff-Radford, N.R., Salloway, S., Vöglein, J., Laske, C., Noble, J., Schofield, P.R., Bateman, R.J., Morris, J.C., and Martins, R.N.
Abstract: Introduction: The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers. Methods: In 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression. Results: No differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels. Discussion: Our findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.
Published: 2017

14. Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels

Author: Ju, Y.S., Ooms, S.J., Sutphen, C., Macauley, S.L., Zangrilli, M.A., Jerome, G., Fagan, A.M., Mignot, E., Zempel, J.M., Claassen, J.A., Holtzman, D.M., Ju, Y.S., Ooms, S.J., Sutphen, C., Macauley, S.L., Zangrilli, M.A., Jerome, G., Fagan, A.M., Mignot, E., Zempel, J.M., Claassen, J.A., and Holtzman, D.M.
Abstract: Item does not contain fulltext, See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-beta, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimer's disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-beta or other Alzheimer's disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-beta, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-beta40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-beta, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-beta levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep.
Published: 2017

15. Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis

Author: Jansen, W.J. Ossenkoppele, R. Knol, D.L. Tijms, B.M. Scheltens, P. Verhey, F.R.J. Visser, P.J. Aalten, P. Aarsland, D. Alcolea, D. Alexander, M. Almdahl, I.S. Arnold, S.E. Baldeiras, I. Barthel, H. Van Berckel, B.N.M. Bibeau, K. Blennow, K. Brooks, D.J. Van Buchem, M.A. Camus, V. Cavedo, E. Chen, K. Chetelat, G. Cohen, A.D. Drzezga, A. Engelborghs, S. Fagan, A.M. Fladby, T. Fleisher, A.S. Van Der Flier, W.M. Ford, L. Forster, S. Fortea, J. Foskett, N. Frederiksen, K.S. Freund-Levi, Y. Frisoni, G.B. Froelich, L. Gabryelewicz, T. Gill, K.D. Gkatzima, O. Gomez-Tortosa, E. Gordon, M.F. Grimmer, T. Hampel, H. Hausner, L. Hellwig, S. Herukka, S.-K. Hildebrandt, H. Ishihara, L. Ivanoiu, A. Jagust, W.J. Johannsen, P. Kandimalla, R. Kapaki, E. Klimkowicz-Mrowiec, A. Klunk, W.E. Kohler, S. Koglin, N. Kornhuber, J. Kramberger, M.G. Van Laere, K. Landau, S.M. Lee, D.Y. De Leon, M. Lisetti, V. Lleo, A. Madsen, K. Maier, W. Marcusson, J. Mattsson, N. De Mendonca, A. Meulenbroek, O. Meyer, P.T. Mintun, M.A. Mok, V. Molinuevo, J.L. Mollergard, H.M. Morris, J.C. Mroczko, B. Van Der Mussele, S. Na, D.L. Newberg, A. Nordberg, A. Nordlund, A. Novak, G.P. Paraskevas, G.P. Parnetti, L. Perera, G. Peters, O. Popp, J. Prabhakar, S. Rabinovici, G.D. Ramakers, I.H.G.B. Rami, L. De Oliveira, C.R. Rinne, J.O. Rodrigue, K.M. Rodriguez-Rodriguez, E. Roe, C.M. Rot, U. Rowe, C.C. Ruther, E. Sabri, O. Sanchez-Juan, P. Santana, I. Sarazin, M. Schroder, J. Schutte, C. Seo, S.W. Soetewey, F. Soininen, H. Spiru, L. Struyfs, H. Teunissen, C.E. Tsolaki, M. Vandenberghe, R. Verbeek, M.M. Villemagne, V.L. Vos, S.J.B. Van Waalwijk Van Doorn, L.J.C. Waldemar, G. Wallin, A. Wallin, A.K. Wiltfang, J. Wolk, D.A. Zboch, M. Zetterberg, H. the Amyloid Biomarker Study Group
Subjects: mental disorders
Abstract: IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE andWeb of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION: AND SYNTHESIS: Individual recordswere provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95%CI, 8%-13%) to 44%(95%CI, 37%-51%) among participants with normal cognition; from 12%(95%CI, 8%-18%) to 43%(95%CI, 32%-55%) among patients with SCI; and from 27%(95%CI, 23%-32%) to 71%(95%CI, 66%-76%) among patients with MCI. APOE-ϵ4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ϵ4ϵ4 carriers, 50 years for ϵ2ϵ4 carriers, 55 years for ϵ3ϵ4 carriers, 65 years for ϵ3ϵ3 carriers, and 95 years for ϵ2ϵ3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia. Copyright 2015 American Medical Association. All rights reserved.
Published: 2015

16. Plasma phospholipid and sphingolipid alterations in presenilin1 mutation carriers: A pilot study

Author: Chatterjee, P., Lim, W.L.F., Shui, G., Gupta, V.B., James, I., Fagan, A.M., Xiong, C., Sohrabi, H.R., Taddei, K., Brown, B.M., Benzinger, T., Masters, C., Snowden, S.G., Wenk, M.R., Bateman, R.J., Morris, J.C., Martins, R.N., Chatterjee, P., Lim, W.L.F., Shui, G., Gupta, V.B., James, I., Fagan, A.M., Xiong, C., Sohrabi, H.R., Taddei, K., Brown, B.M., Benzinger, T., Masters, C., Snowden, S.G., Wenk, M.R., Bateman, R.J., Morris, J.C., and Martins, R.N.
Abstract: Background and Objective: Aberrant lipid metabolism has been implicated in sporadic Alzheimer’s disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD). Methods: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman’s correlation coefficient. Results: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p < 0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p < 0.05). Conclusion: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort.
Published: 2016

17. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis

Author: Jansen, W.J., Ossenkoppele, R., Knol, D.L., Tijms, B.M., Scheltens, P.J., Verhey, F.R.J., Visser, P.J., Aalten, P., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., Berckel, B.N. van, Bibeau, K., Blennow, K., Brooks, D.J., Buchem, M.A. van, Camus, V., Cavedo, E., Chen, K., Chetelat, G., Cohen, A.D., Drzezga, A., Engelborghs, S., Fagan, A.M., Fladby, T., Fleisher, A.S., Flier, W.M. van der, Ford, L., Forster, S., Fortea, J., Foskett, N., Frederiksen, K.S., Freund-Levi, Y., Frisoni, G.B., Froelich, L., Gabryelewicz, T., Gill, K.D., Gkatzima, O., Gomez-Tortosa, E., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Hildebrandt, H., Ishihara, L., Ivanoiu, A., Jagust, W.J., Johannsen, P., Kandimalla, R., Kapaki, E., Klimkowicz-Mrowiec, A., Klunk, W.E., Kohler, S., Koglin, N., Kornhuber, J., Kramberger, M.G., Laere, K. Van, Landau, S.M., Lee, D.Y., Leon, M., Lisetti, V., Lleo, A., Madsen, K., Maier, W., Marcusson, J., Mattsson, N., Mendonca, A. de, Meulenbroek, O.V., Meyer, P.T., Mintun, M.A., Mok, V., Molinuevo, J.L., Mollergard, H.M., Morris, J.C., Mroczko, B., Mussele, S. Van der, Na, D.L., Newberg, A., Nordberg, A., Nordlund, A., Novak, G.P., Paraskevas, G.P., Parnetti, L., Perera, G., Peters, O., Popp, J., Prabhakar, S., Rabinovici, G.D., Ramakers, I.H., Rami, L., Oliveira, C.R., Rinne, J.O., Rodrigue, K.M., Rodriguez-Rodriguez, E., Verbeek, M.M., et al., Jansen, W.J., Ossenkoppele, R., Knol, D.L., Tijms, B.M., Scheltens, P.J., Verhey, F.R.J., Visser, P.J., Aalten, P., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., Berckel, B.N. van, Bibeau, K., Blennow, K., Brooks, D.J., Buchem, M.A. van, Camus, V., Cavedo, E., Chen, K., Chetelat, G., Cohen, A.D., Drzezga, A., Engelborghs, S., Fagan, A.M., Fladby, T., Fleisher, A.S., Flier, W.M. van der, Ford, L., Forster, S., Fortea, J., Foskett, N., Frederiksen, K.S., Freund-Levi, Y., Frisoni, G.B., Froelich, L., Gabryelewicz, T., Gill, K.D., Gkatzima, O., Gomez-Tortosa, E., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Hildebrandt, H., Ishihara, L., Ivanoiu, A., Jagust, W.J., Johannsen, P., Kandimalla, R., Kapaki, E., Klimkowicz-Mrowiec, A., Klunk, W.E., Kohler, S., Koglin, N., Kornhuber, J., Kramberger, M.G., Laere, K. Van, Landau, S.M., Lee, D.Y., Leon, M., Lisetti, V., Lleo, A., Madsen, K., Maier, W., Marcusson, J., Mattsson, N., Mendonca, A. de, Meulenbroek, O.V., Meyer, P.T., Mintun, M.A., Mok, V., Molinuevo, J.L., Mollergard, H.M., Morris, J.C., Mroczko, B., Mussele, S. Van der, Na, D.L., Newberg, A., Nordberg, A., Nordlund, A., Novak, G.P., Paraskevas, G.P., Parnetti, L., Perera, G., Peters, O., Popp, J., Prabhakar, S., Rabinovici, G.D., Ramakers, I.H., Rami, L., Oliveira, C.R., Rinne, J.O., Rodrigue, K.M., Rodriguez-Rodriguez, E., Verbeek, M.M., and et al.
Abstract: Item does not contain fulltext, IMPORTANCE: Cerebral amyloid-beta aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-epsilon4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE epsilon4epsilon4 carriers, 50 years for epsilon2epsilon4 carriers, 55 years for epsilon3epsilon4 c
Published: 2015

18. Decreased platelet APP isoform ratios in autosomal dominant Alzheimer's disease: Baseline data from a DIAN cohort subset

Author: Chatterjee, P., Gupta, V.B., Fagan, A.M., Jasielec, M.S., Xiong, C., Sohrabi, H.R., Dhaliwal, S., Taddei, K., Bourgeat, P., Brown, B.M., Benzinger, T., Bateman, R.J., Morris, J.C., Martins, R.N., Chatterjee, P., Gupta, V.B., Fagan, A.M., Jasielec, M.S., Xiong, C., Sohrabi, H.R., Dhaliwal, S., Taddei, K., Bourgeat, P., Brown, B.M., Benzinger, T., Bateman, R.J., Morris, J.C., and Martins, R.N.
Abstract: Introduction: This study examines platelet amyloid precursor protein (APP) isoform ratios of 120KDa to 110KDa (APPr) between mutation carriers (MC) carrying a mutation for autosomal dominant Alzheimer's disease (ADAD) and non-carriers (NC). Two previous studies reported no significant difference in APPr between ADAD MC and NC, which may have been due to the small sample size in both studies. The current study examines APPr in MC versus NC in a larger sample. In addition, it investigated whether APPr correlate with neuroimaging data, neuropsychological data and cerebrospinal fluid biomarkers in a cohort subset derived from the Dominantly Inherited Alzheimer Network (DIAN) study. Methods: APPr were quantified by western blotting. Fifteen MC (symptomatic and asymptomatic) were compared against twelve NC using univariate general linear model. All participants underwent neuroimaging and neuropsychological testing which were correlated with APPr using Pearson's correlation coefficient (r). Results: APPr were lower in MC compared to NC (p=0.003) while Mini-Mental State Examination (MMSE) scores were not significantly different (p>0.1). Furthermore, APPr inversely correlated with amyloid imaging in the Caudate Nucleus (r=-0.505; p<0.05) and Precuneus (r=-0.510; p<0.05). Conclusion: APPr are lower in ADAD MC compared to NC, and inversely correlated with brain amyloid load prior to significant differences in cognitive health. However, the use of APPr as a biomarker needs to be explored further.
Published: 2015

19. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

Author: Amyloid Biomarker Study Group, Jansen, W.J., Ossenkoppele, R., Knol, D.L., Tijms, B.M., Scheltens, P., Verhey, F.R., Visser, P.J., Aalten, P., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., van Berckel, B.N., Bibeau, K., Blennow, K., Brooks, D.J., van Buchem, M.A., Camus, V., Cavedo, E., Chen, K., Chetelat, G., Cohen, A.D., Drzezga, A., Engelborghs, S., Fagan, A.M., Fladby, T., Fleisher, A.S., van der Flier, W.M., Ford, L., Förster, S., Fortea, J., Foskett, N., Frederiksen, K.S., Freund-Levi, Y., Frisoni, G.B., Froelich, L., Gabryelewicz, T., Gill, K.D., Gkatzima, O., Gómez-Tortosa, E., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Hildebrandt, H., Ishihara, L., Ivanoiu, A., Jagust, W.J., Johannsen, P., Kandimalla, R., Kapaki, E., Klimkowicz-Mrowiec, A., Klunk, W.E., Köhler, S., Koglin, N., Kornhuber, J., Kramberger, M.G., Van Laere, K., Landau, S.M., Lee, D.Y., de Leon, M., Lisetti, V., Lleó, A., Madsen, K., Maier, W., Marcusson, J., Mattsson, N., de Mendonça, A., Meulenbroek, O., Meyer, P.T., Mintun, M.A., Mok, V., Molinuevo, J.L., Møllergård, H.M., Morris, J.C., Mroczko, B., Van der Mussele, S., Na, D.L., Newberg, A., Nordberg, A., Nordlund, A., Novak, G.P., Paraskevas, G.P., Parnetti, L., Perera, G., Peters, O., Popp, J., Prabhakar, S., Rabinovici, G.D., Ramakers, I.H., Rami, L., Resende de Oliveira, C., Rinne, J.O., Rodrigue, K.M., Rodríguez-Rodríguez, E., Roe, C.M., Rot, U., Rowe, C.C., Rüther, E., Sabri, O., Sanchez-Juan, P., Santana, I., Sarazin, M., Schröder, J., Schütte, C., Seo, S.W., Soetewey, F., Soininen, H., Spiru, L., Struyfs, H., Teunissen, C.E., Tsolaki, M., Vandenberghe, R., Verbeek, M.M., Villemagne, V.L., Vos, S.J., van Waalwijk van Doorn, L.J., Waldemar, G., Wallin, A., Wallin, Å.K., Wiltfang, J., Wolk, D.A., Zboch, M., Zetterberg, H., Amyloid Biomarker Study Group, Jansen, W.J., Ossenkoppele, R., Knol, D.L., Tijms, B.M., Scheltens, P., Verhey, F.R., Visser, P.J., Aalten, P., Aarsland, D., Alcolea, D., Alexander, M., Almdahl, I.S., Arnold, S.E., Baldeiras, I., Barthel, H., van Berckel, B.N., Bibeau, K., Blennow, K., Brooks, D.J., van Buchem, M.A., Camus, V., Cavedo, E., Chen, K., Chetelat, G., Cohen, A.D., Drzezga, A., Engelborghs, S., Fagan, A.M., Fladby, T., Fleisher, A.S., van der Flier, W.M., Ford, L., Förster, S., Fortea, J., Foskett, N., Frederiksen, K.S., Freund-Levi, Y., Frisoni, G.B., Froelich, L., Gabryelewicz, T., Gill, K.D., Gkatzima, O., Gómez-Tortosa, E., Gordon, M.F., Grimmer, T., Hampel, H., Hausner, L., Hellwig, S., Herukka, S.K., Hildebrandt, H., Ishihara, L., Ivanoiu, A., Jagust, W.J., Johannsen, P., Kandimalla, R., Kapaki, E., Klimkowicz-Mrowiec, A., Klunk, W.E., Köhler, S., Koglin, N., Kornhuber, J., Kramberger, M.G., Van Laere, K., Landau, S.M., Lee, D.Y., de Leon, M., Lisetti, V., Lleó, A., Madsen, K., Maier, W., Marcusson, J., Mattsson, N., de Mendonça, A., Meulenbroek, O., Meyer, P.T., Mintun, M.A., Mok, V., Molinuevo, J.L., Møllergård, H.M., Morris, J.C., Mroczko, B., Van der Mussele, S., Na, D.L., Newberg, A., Nordberg, A., Nordlund, A., Novak, G.P., Paraskevas, G.P., Parnetti, L., Perera, G., Peters, O., Popp, J., Prabhakar, S., Rabinovici, G.D., Ramakers, I.H., Rami, L., Resende de Oliveira, C., Rinne, J.O., Rodrigue, K.M., Rodríguez-Rodríguez, E., Roe, C.M., Rot, U., Rowe, C.C., Rüther, E., Sabri, O., Sanchez-Juan, P., Santana, I., Sarazin, M., Schröder, J., Schütte, C., Seo, S.W., Soetewey, F., Soininen, H., Spiru, L., Struyfs, H., Teunissen, C.E., Tsolaki, M., Vandenberghe, R., Verbeek, M.M., Villemagne, V.L., Vos, S.J., van Waalwijk van Doorn, L.J., Waldemar, G., Wallin, A., Wallin, Å.K., Wiltfang, J., Wolk, D.A., Zboch, M., and Zetterberg, H.
Abstract: IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 y
Published: 2015

20. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

Author: Mattsson, N. Andreasson, U. Persson, S. Arai, H. Batish, S.D. Bernardini, S. Bocchio-Chiavetto, L. Blankenstein, M.A. Carrillo, M.C. Chalbot, S. Coart, E. Chiasserini, D. Cutler, N. Dahlfors, G. Duller, S. Fagan, A.M. Forlenza, O. Frisoni, G.B. Galasko, D. Galimberti, D. Hampel, H. Handberg, A. Heneka, M.T. Herskovits, A.Z. Herukka, S.-K. Holtzman, D.M. Humpel, C. Hyman, B.T. Iqbal, K. Jucker, M. Kaeser, S.A. Kaiser, E. Kapaki, E. Kidd, D. Klivenyi, P. Knudsen, C.S. Kummer, M.P. Lui, J. Lladó, A. Lewczuk, P. Li, Q.-X. Martins, R. Masters, C. McAuliffe, J. Mercken, M. Moghekar, A. Molinuevo, J.L. Montine, T.J. Nowatzke, W. O'Brien, R. Otto, M. Paraskevas, G.P. Parnetti, L. Petersen, R.C. Prvulovic, D. De Reus, H.P.M. Rissman, R.A. Scarpini, E. Stefani, A. Soininen, H. Schröder, J. Shaw, L.M. Skinningsrud, A. Skrogstad, B. Spreer, A. Talib, L. Teunissen, C. Trojanowski, J.Q. Tumani, H. Umek, R.M. Van Broeck, B. Vanderstichele, H. Vecsei, L. Verbeek, M.M. Windisch, M. Zhang, J. Zetterberg, H. Blennow, K.
Abstract: Background: The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. Methods: The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. Results: Forty laboratories participated. Twenty-six used INNOTEST enzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. Conclusions: Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers. © 2011 The Alzheimer's Association. All rights reserved.
Published: 2011

21. CSF biomarker variability in the Alzheimer's Association quality control program

Author: Mattsson, N., Andreasson, U., Persson, S., Carrillo, M.C., Collins, S., Chalbot, S., Cutler, N., Dufour-Rainfray, D., Fagan, A.M., Heegaard, N.H.H., Robin Hsiung, G.Y., Hyman, B., Iqbal, K., Lachno, D.R., Lleo, A., Lewczuk, P., Molinuevo, J.L., Parchi, P., Regeniter, A., Rissman, R., Rosenmann, H., Sancesario, G., Schroder, J., Shaw, L.M., Teunissen, C.E., Trojanowski, J.Q., Vanderstichele, H., Vandijck, M., Verbeek, M.M., Zetterberg, H., Blennow, K., Kaser, S.A., et al., Mattsson, N., Andreasson, U., Persson, S., Carrillo, M.C., Collins, S., Chalbot, S., Cutler, N., Dufour-Rainfray, D., Fagan, A.M., Heegaard, N.H.H., Robin Hsiung, G.Y., Hyman, B., Iqbal, K., Lachno, D.R., Lleo, A., Lewczuk, P., Molinuevo, J.L., Parchi, P., Regeniter, A., Rissman, R., Rosenmann, H., Sancesario, G., Schroder, J., Shaw, L.M., Teunissen, C.E., Trojanowski, J.Q., Vanderstichele, H., Vandijck, M., Verbeek, M.M., Zetterberg, H., Blennow, K., Kaser, S.A., and et al.
Abstract: Item does not contain fulltext, BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories. METHODS: Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Molndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection. RESULTS: A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20% to 30%; within-run CVs, less than 5% to 10%; and longitudinal within-laboratory CVs, 5% to 19%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP). CONCLUSIONS: The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.
Published: 2013

22. Erratum to “Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial” [Rev. Neurol. 169 (10) (2013) 737–743]

Author: Mills, S.M., primary, Mallmann, J., additional, Santacruz, A.M., additional, Fuqua, A., additional, Carril, M., additional, Aisen, P.S., additional, Althage, M.C., additional, Belyew, S., additional, Benzinger, T.L., additional, Brooks, W.S., additional, Buckles, V.D., additional, Cairns, N.J., additional, Clifford, D., additional, Danek, A., additional, Fagan, A.M., additional, Farlow, M., additional, Fox, N., additional, Ghetti, B., additional, Goate, A.M., additional, Heinrichs, D., additional, Hornbeck, R., additional, Jack, C., additional, Jucker, M., additional, Klunk, W.E., additional, Marcus, D.S., additional, Martins, R.N., additional, Masters, C.M., additional, Mayeux, R., additional, McDade, E., additional, Morris, J.C., additional, Oliver, A., additional, Ringman, J.M., additional, Rossor, M.N., additional, Salloway, S., additional, Schofield, P.R., additional, Snider, J., additional, Snyder, P., additional, Sperling, R.A., additional, Stewart, C., additional, Thomas, R.G., additional, Xiong, C., additional, and Bateman, R.J., additional
Published: 2013
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23. Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer’s disease subjects

Author: Hata, S., Taniguchi, M., Piao, Y., Ikeuchi, T., Fagan, A.M., Holtzman, D.M., Bateman, R., Sohrabi, H.R., Martins, R.N., Gandy, S., Urakami, K., Suzuki, T., Hata, S., Taniguchi, M., Piao, Y., Ikeuchi, T., Fagan, A.M., Holtzman, D.M., Bateman, R., Sohrabi, H.R., Martins, R.N., Gandy, S., Urakami, K., and Suzuki, T.
Abstract: Background Alcadeinα (Alcα) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-β precursor protein (APP). Successive cleavage of APP by β- and γ-secretases generates the aggregatable amyloid-β peptide (Aβ), while cleavage of APP or Alcα by α- and γ-secretases generates non-aggregatable p3 or p3-Alcα peptides. Aβ and p3-Alcα can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alcα in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD). Results Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alcα, we determined levels of total p3-Alcα in CSF from subjects in one of four diagnostic categories (elderly controls, MCI, SAD, or other neurological disease) derived from three independent cohorts. Levels of Aβ40 correlated with levels of total p3-Alcα in all cohorts. Conclusions We confirm that Aβ40 is the most abundant Aβ species, and we propose a model in which CSF p3-Alcα can serve as a either (1) a nonaggregatable surrogate marker for γ-secretase activity; (2) as a marker for clearance of transmembrane domain peptides derived from integral protein catabolism; or (3) both. We propose the specification of an MCI/SAD endophenotype characterized by co-elevation of levels of both CSF p3-Alcα and Aβ40, and we propose that subjects in this category might be especially responsive to therapeutics aimed at modulation of γ-secretase function and/or transmembrane domain peptide clearance. These peptides may also be used to monitor the efficacy of therapeutics that target these steps in Aβ metabolis
Published: 2012

24. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

Author: Mattsson, N., Andreasson, U., Persson, S., Arai, H., Batish, S.D., Bernardini, S., Bocchio-Chiavetto, L., Blankenstein, M.A., Carrillo, M.C., Chalbot, S., Coart, E., Chiasserini, D., Cutler, N., Dahlfors, G., Duller, S., Fagan, A.M., Forlenza, O., Frisoni, G.B., Galasko, D., Galimberti, D., Hampel, H., Handberg, A., Heneka, M.T., Herskovits, A.Z., Herukka, S.K., Holtzman, D.M., Humpel, C., Hyman, B.T., Iqbal, K., Jucker, M., Kaeser, S.A., Kaiser, E., Kapaki, E., Kidd, D., Klivenyi, P., Knudsen, C.S., Kummer, M.P., Lui, J., Llado, A., Lewczuk, P., Li, Q.X., Martins, R., Masters, C., McAuliffe, J., Mercken, M., Moghekar, A., Molinuevo, J.L., Montine, T.J., Nowatzke, W., O'Brien, R., Otto, M., Paraskevas, G.P., Parnetti, L., Petersen, R.C., Prvulovic, D., Reus, H.P.M. de, Rissman, R.A., Scarpini, E., Stefani, A., Soininen, H., Schroder, J., Shaw, L.M., Skinningsrud, A., Skrogstad, B., Spreer, A., Talib, L., Teunissen, C., Trojanowski, J.Q., Tumani, H., Umek, R.M., Broeck, B. Van, Vanderstichele, H., Vecsei, L., Verbeek, M.M., Windisch, M., Zhang, J., Zetterberg, H., Blennow, K., Mattsson, N., Andreasson, U., Persson, S., Arai, H., Batish, S.D., Bernardini, S., Bocchio-Chiavetto, L., Blankenstein, M.A., Carrillo, M.C., Chalbot, S., Coart, E., Chiasserini, D., Cutler, N., Dahlfors, G., Duller, S., Fagan, A.M., Forlenza, O., Frisoni, G.B., Galasko, D., Galimberti, D., Hampel, H., Handberg, A., Heneka, M.T., Herskovits, A.Z., Herukka, S.K., Holtzman, D.M., Humpel, C., Hyman, B.T., Iqbal, K., Jucker, M., Kaeser, S.A., Kaiser, E., Kapaki, E., Kidd, D., Klivenyi, P., Knudsen, C.S., Kummer, M.P., Lui, J., Llado, A., Lewczuk, P., Li, Q.X., Martins, R., Masters, C., McAuliffe, J., Mercken, M., Moghekar, A., Molinuevo, J.L., Montine, T.J., Nowatzke, W., O'Brien, R., Otto, M., Paraskevas, G.P., Parnetti, L., Petersen, R.C., Prvulovic, D., Reus, H.P.M. de, Rissman, R.A., Scarpini, E., Stefani, A., Soininen, H., Schroder, J., Shaw, L.M., Skinningsrud, A., Skrogstad, B., Spreer, A., Talib, L., Teunissen, C., Trojanowski, J.Q., Tumani, H., Umek, R.M., Broeck, B. Van, Vanderstichele, H., Vecsei, L., Verbeek, M.M., Windisch, M., Zhang, J., Zetterberg, H., and Blennow, K.
Abstract: Contains fulltext : 98400.pdf (publisher's version ) (Closed access), BACKGROUND: The cerebrospinal fluid (CSF) biomarkers amyloid beta (Abeta)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. METHODS: The program is open for laboratories using commercially available kits for Abeta, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Molndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. RESULTS: Forty laboratories participated. Twenty-six used INNOTEST enzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Abeta-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Abeta triplex (AbetaN-42, AbetaN-40, and AbetaN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories. CONCLUSIONS: Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.
Published: 2011

25. Cognitively unimpaired HIV-positive subjects do not have increased 11 C-PiB

Author: Ances, B.M., primary, Christensen, J.J., additional, Teshome, M., additional, Taylor, J., additional, Xiong, C., additional, Aldea, P., additional, Fagan, A.M., additional, Holtzman, D.M., additional, Morris, J.C., additional, Mintun, M.A., additional, and Clifford, D.B., additional
Published: 2010
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26. Biological effects of astrocyte-secreted apoE/lipoproteins: Role of LRP

Author: Holtzman, David M., LaDu, M.J., Van Eldik, L., Bu, Guojun, Wu, S., Patel, S., Fagan, A.M., Sun, Y.L., Holtzman, David M., LaDu, M.J., Van Eldik, L., Bu, Guojun, Wu, S., Patel, S., Fagan, A.M., and Sun, Y.L.
Published: 1999

27. Differential dependency of developing mechanoreceptors on neurotrophins, trk receptors, and p75LNGFR

Author: Fundin, Bengt, Silos-Santiago, I, Ernfors, Patrik, Fagan, A.M., Aldskogius, Håkan, DeChiara, T.M., Phillips, H, Barbacid, M, Yancopoulos, G.D., Rice, Frank L., Fundin, Bengt, Silos-Santiago, I, Ernfors, Patrik, Fagan, A.M., Aldskogius, Håkan, DeChiara, T.M., Phillips, H, Barbacid, M, Yancopoulos, G.D., and Rice, Frank L.
Abstract: The impact of null mutations of the genes for the NGF family of neurotrophins and their receptors was examined among the wide variety of medium to large caliber myelinated mechanoreceptors which have a highly specific predictable organization in the mystacial pad of mice. Immunofluorescence with anti-protein gene product 9.5, anti-200-kDa neurofilament protein (RT97), and anti-calcitonin gene-related product was used to label innervation in mystacial pads from mice with homozygous null mutations for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), the three tyrosine kinase receptors (trkA, trkB, trkC), and the low-affinity nerve growth factor receptor p75. Specimens were sacrificed at birth and at 1, 2, and 4 weeks for each type of mutation as well as at 11 weeks and 1 year for p75 and trkC mutations, respectively. Our results demonstrate several major concepts about the role of neurotrophins in the development of cutaneous mechanoreceptors that are supplied by medium to large caliber myelinated afferents. First, each of the high-affinity tyrosine kinase receptors, trkA, trkB, and trkC, as well as the low-affinity p75 receptor has an impact on at least one type of mechanoreceptor. Second, consistent with the various affinities for particular trk receptors, the elimination of NGF, BDNF, and NT-3 has an impact comparable to or more complex than the absence of their most specific high-affinity receptors: trkA, trkB, and trkC, respectively. These complexities include potential NT-3 signaling through trkA and trkB to support some neuronal survival. Third, most types of afferents are dependent on a different combination of neurotrophins and receptors for their survival: reticular and transverse lanceolate afferents are dependent upon NT-3, NGF, and trkA; Ruffini afferents upon BDNF and trkB; longitudinal lanceolate afferents upon NGF, trkA, BDNF, and trkB; and Merkel afferents on NGF, trkA, NT-3, trkC, and
Published: 1997
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28. Tracheal rupture after tracheal intubation

Author: REGRAGUI, I.A., primary, FAGAN, A.M., additional, and NATRAJAN, K.M., additional
Published: 1994
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29. Mechanisms of sprouting in the adult central nervous system: Cellular responses in areas of terminal degeneration and reinnervation in the rat hippocampus

Author: Fagan, A.M., primary and Gage, F.H., additional
Published: 1994
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30. Intrathoracic meningocele in a patient with neurofibromatosis

Author: Sarkar, P.K., primary and Fagan, A.M., additional
Published: 1991
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31. Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease(e–Pub ahead of print)

Author: Roe, C.M., Fagan, A.M., Williams, M.M., Ghoshal, N., Aeschleman, M., Grant, E.A., Marcus, D.S., Mintun, M.A., Holtzman, D.M., and Morris, J.C.
Abstract: To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers A42, tau, ptau181, tau/A42, and ptau181/A42.
Published: 2011
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32. Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB

Author: Ances, B.M., Christensen, J.J., Teshome, M., Taylor, J., Xiong, C., Aldea, P., Fagan, A.M., Holtzman, D.M., Morris, J.C., Mintun, M.A., and Clifford, D.B.
Abstract: Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV) individuals. Similar abnormalities in brain amyloid-42 (42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB), a biomarker for 42 deposition, in cognitively unimpaired HIV (n 10) participants and matched community controls without dementia (n 20).
Published: 2010
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33. Grafting genetically modified cells into the rat brain: characteristics of E. coli β-galactosidase as a reporter gene

Author: Shimohama, S., primary, Rosenberg, M.B., additional, Fagan, A.M., additional, Wolff, J.A., additional, Short, M.P., additional, Breakefield, X.O., additional, Friedmann, T., additional, and Gage, F.H., additional
Published: 1989
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34. The role of nerve growth factor family receptors in the development of the mammalian nervous system

Author: Fagan, A.M., Barbacid, M., and Smeyne, R.J.
Published: 1994
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34 results on '"Fagan, A.M."'

1. Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial

2. Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum

3. Presymptomatic Dutch-Type hereditary cerebral amyloid Angiopathy-Related blood metabolite alterations

4. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease

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

6. Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR

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

8. Amyloid imaging of dutch‐type hereditary cerebral amyloid angiopathy carriers

9. Association of cerebral amyloid-β Aggregation with cognitive functioning in persons without dementia

10. Prevalence of the apolipoprotein E epsilon4 allele in amyloid beta positive subjects across the spectrum of Alzheimer's disease

11. The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review

12. Association of Cerebral Amyloid-beta Aggregation With Cognitive Functioning in Persons Without Dementia

13. Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease

14. Slow wave sleep disruption increases cerebrospinal fluid amyloid-beta levels

15. Prevalence of cerebral amyloid pathology in persons without dementia: A meta-analysis

16. Plasma phospholipid and sphingolipid alterations in presenilin1 mutation carriers: A pilot study

17. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis

18. Decreased platelet APP isoform ratios in autosomal dominant Alzheimer's disease: Baseline data from a DIAN cohort subset

19. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.

20. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

21. CSF biomarker variability in the Alzheimer's Association quality control program

22. Erratum to “Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial” [Rev. Neurol. 169 (10) (2013) 737–743]

23. Multiple γ-secretase product peptides are coordinately increased in concentration in the cerebrospinal fluid of a subpopulation of sporadic Alzheimer’s disease subjects

24. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers

25. Cognitively unimpaired HIV-positive subjects do not have increased 11 C-PiB

26. Biological effects of astrocyte-secreted apoE/lipoproteins: Role of LRP

27. Differential dependency of developing mechanoreceptors on neurotrophins, trk receptors, and p75LNGFR

28. Tracheal rupture after tracheal intubation

29. Mechanisms of sprouting in the adult central nervous system: Cellular responses in areas of terminal degeneration and reinnervation in the rat hippocampus

30. Intrathoracic meningocele in a patient with neurofibromatosis

31. Improving CSF biomarker accuracy in predicting prevalent and incident Alzheimer disease(e–Pub ahead of print)

32. Cognitively unimpaired HIV-positive subjects do not have increased 11C-PiB

33. Grafting genetically modified cells into the rat brain: characteristics of E. coli β-galactosidase as a reporter gene

34. The role of nerve growth factor family receptors in the development of the mammalian nervous system

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34 results on '"Fagan, A.M."'

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