Format

Send to

Choose Destination
Brain. 2016 Mar;139(Pt 3):922-36. doi: 10.1093/brain/awv404. Epub 2016 Jan 26.

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

Author information

1
1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden Agneta.K.Nordberg@ki.se.
2
1 Department NVS, Centre for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden.
3
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.
4
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.
5
5 Department of Surgical Sciences, Section of Nuclear Medicine & PET, Uppsala University, 751 85 Uppsala, Sweden.
6
6 Department of Chemistry, Uppsala University, 701 05 Uppsala, Sweden.
7
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.

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.

KEYWORDS:

11C-Pittsburgh compound B; 11C-deuterium-L-deprenyl; 18F-fluorodeoxyglucose; astrocytosis; autosomal dominant Alzheimer’s disease

PMID:
26813969
PMCID:
PMC4766380
DOI:
10.1093/brain/awv404
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central Icon for Karolinska Institutet, Link to Full Text
Loading ...
Support Center