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Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

Abstract

Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-β plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-β plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-β plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-β plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-β plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.

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    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden Agneta.K.Nordberg@ki.se.

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    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.

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    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.

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    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden 2 Department of Psychology, Stockholm University, 106 91 Stockholm, Sweden 3 Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.

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    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.

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    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.

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    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.

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    3 Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden 4 Department NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.

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    3 Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden 4 Department NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.

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    5 Department of Surgical Sciences, Section of Nuclear Medicine & PET, Uppsala University, 751 85 Uppsala, Sweden.

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    6 Department of Chemistry, Uppsala University, 701 05 Uppsala, Sweden.

    1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden 3 Department of Geriatric Medicine, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.

    Source

    Brain : a journal of neurology 139:Pt 3 2016 Mar pg 922-36

    MeSH

    Adult
    Aged
    Alzheimer Disease
    Amyloid beta-Peptides
    Cross-Sectional Studies
    Female
    Follow-Up Studies
    Gliosis
    Humans
    Longitudinal Studies
    Male
    Middle Aged
    Plaque, Amyloid
    Positron-Emission Tomography

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    26813969

    Citation

    Rodriguez-Vieitez, Elena, et al. "Diverging Longitudinal Changes in Astrocytosis and Amyloid PET in Autosomal Dominant Alzheimer's Disease." Brain : a Journal of Neurology, vol. 139, no. Pt 3, 2016, pp. 922-36.
    Rodriguez-Vieitez E, Saint-Aubert L, Carter SF, et al. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease. Brain. 2016;139(Pt 3):922-36.
    Rodriguez-Vieitez, E., Saint-Aubert, L., Carter, S. F., Almkvist, O., Farid, K., Schöll, M., ... Nordberg, A. (2016). Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease. Brain : a Journal of Neurology, 139(Pt 3), pp. 922-36. doi:10.1093/brain/awv404.
    Rodriguez-Vieitez E, et al. Diverging Longitudinal Changes in Astrocytosis and Amyloid PET in Autosomal Dominant Alzheimer's Disease. Brain. 2016;139(Pt 3):922-36. PubMed PMID: 26813969.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease. AU - Rodriguez-Vieitez,Elena, AU - Saint-Aubert,Laure, AU - Carter,Stephen F, AU - Almkvist,Ove, AU - Farid,Karim, AU - Schöll,Michael, AU - Chiotis,Konstantinos, AU - Thordardottir,Steinunn, AU - Graff,Caroline, AU - Wall,Anders, AU - Långström,Bengt, AU - Nordberg,Agneta, Y1 - 2016/01/26/ PY - 2015/07/29/received PY - 2015/11/20/accepted PY - 2016/1/28/entrez PY - 2016/1/28/pubmed PY - 2016/7/19/medline KW - 11C-Pittsburgh compound B KW - 11C-deuterium-L-deprenyl KW - 18F-fluorodeoxyglucose KW - astrocytosis KW - autosomal dominant Alzheimer’s disease SP - 922 EP - 36 JF - Brain : a journal of neurology JO - Brain VL - 139 IS - Pt 3 N2 - Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-β plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-β plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-β plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-β plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-β plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology. SN - 1460-2156 UR - https://www.unboundmedicine.com/medline/citation/26813969/Diverging_longitudinal_changes_in_astrocytosis_and_amyloid_PET_in_autosomal_dominant_Alzheimer's_disease_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awv404 DB - PRIME DP - Unbound Medicine ER -