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

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          Abstract

          See Schott and Fox (doi: [Related article:]10.1093/brain/awv405) for a scientific commentary on this article.

          The relationships between pathophysiological processes in Alzheimer’s disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer’s disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.

          Abstract

          See Schott and Fox (doi: [Related article:]10.1093/brain/awv405) for a scientific commentary on this article.

          The relationships between pathophysiological processes in Alzheimer’s disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer’s disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.

          Abstract

          See Schott and Fox (doi: [Related article:]10.1093/brain/awv405) for a scientific commentary on this article.

          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 11C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ( 11C-Pittsburgh compound B), and glucose metabolism ( 18F-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 11C-Pittsburgh compound B-positive ( n = 13; 62.0 ± 6.4; seven male) and 11C-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 11C-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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          Most cited references 82

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          Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.

          Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
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            Mild cognitive impairment as a diagnostic entity.

            The concept of cognitive impairment intervening between normal ageing and very early dementia has been in the literature for many years. Recently, the construct of mild cognitive impairment (MCI) has been proposed to designate an early, but abnormal, state of cognitive impairment. MCI has generated a great deal of research from both clinical and research perspectives. Numerous epidemiological studies have documented the accelerated rate of progression to dementia and Alzheimer's disease (AD) in MCI subjects and certain predictor variables appear valid. However, there has been controversy regarding the precise definition of the concept and its implementation in various clinical settings. Clinical subtypes of MCI have been proposed to broaden the concept and include prodromal forms of a variety of dementias. It is suggested that the diagnosis of MCI can be made in a fashion similar to the clinical diagnoses of dementia and AD. An algorithm is presented to assist the clinician in identifying subjects and subclassifying them into the various types of MCI. By refining the criteria for MCI, clinical trials can be designed with appropriate inclusion and exclusion restrictions to allow for the investigation of therapeutics tailored for specific targets and populations.
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              Neuropathological stageing of Alzheimer-related changes

               H Braak,  E Braak (1991)
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                Author and article information

                Journal
                Brain
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                March 2016
                26 January 2016
                26 January 2016
                : 139
                : 3
                : 922-936
                Affiliations
                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 Department NVS, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, 141 57 Huddinge, Stockholm, Sweden
                5 Department of Surgical Sciences, Section of Nuclear Medicine & PET, Uppsala University, 751 85 Uppsala, Sweden
                6 Department of Chemistry, Uppsala University, 701 05 Uppsala, Sweden
                Author notes
                Correspondence to: Agneta Nordberg, MD, PhD, Professor, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Translational Alzheimer Neurobiology, Novum 5th Floor, Blickagången 6, SE-141 57 Huddinge, Sweden E-mail: Agneta.K.Nordberg@ 123456ki.se

                *Present address: Wolfson Molecular Imaging Centre, University of Manchester, Manchester, M20 3LJ, UK

                Present address: MedTech West and the Department of Clinical Neuroscience and Rehabilitation, University of Gothenburg, 413 45 Gothenburg, Sweden

                See Schott and Fox (doi: [Related article:]10.1093/brain/awv405) for a scientific commentary on this article.

                Article
                awv404
                10.1093/brain/awv404
                4766380
                26813969
                © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                Page count
                Pages: 15
                Categories
                Original Articles
                1010

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