DOI: 10.7272/q6154f00
title: CSF Biomarker and PIB-PET Derived Beta-Amyloid Signature Predicts Metabolic, Grey Matter and Cognitive Changes in Non-Demented Subjects

description: Beta-amyloid (Aß is a histopathological hallmark of Alzheimer's
 disease dementia, but high levels of Aß in the brain can also be found in
 a substantial proportion of nondemented subjects. Here we investigated
 which 2-year rate of brain and cognitive changes are present in
 nondemented subjects with high and low Aß levels, as assessed with
 cerebrospinal fluid and molecular positron emission tomography (PET)-based
 biomarkers of Aß. In subjects with mild cognitive impairment, increased
 brain Aß levels were associated with significantly faster cognitive
 decline, progression of gray matter atrophy within temporal and parietal
 brain regions, and a trend for a faster decline in parietal
 Fludeoxyglucose (FDG)-PET metabolism. Changes in gray matter and FDG-PET
 mediated the association between Aß and cognitive decline. In contrast,
 elderly cognitively healthy controls (HC) with high Aß levels showed only
 a faster medial temporal lobe and precuneus volume decline compared with
 HC with low Aß. In conclusion, the current results suggest not only that
 both functional and volumetric brain changes are associated with high Aß
 years before the onset of dementia but also that HC with substantial Aß
 levels show higher Aß pathology resistance, lack other pathologies that
 condition neurotoxic effects of Aß, or accumulated Aß for a shorter time
 period.
description: Subjects: The study included 465 subjects of which 124 were elderly
 cognitively HC subjects, 229 subjects were diagnosed with amnestic MCI and
 112 subjects had probable AD, recruited within the North American
 multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI, for
 database, see www.loni.ucla.edu/ADNI). ADNI was launched in 2003 by the
 National Institute on Aging, the National Institute of Biomedical Imaging
 and Bioengineering (NIBIB), the Food and Drug Administration, private
 pharmaceutical companies, and nonprofit organizations, as a $60 million,
 5-year public-private partnership. The primary goal of ADNI has been to
 test whether serial magnetic resonance imaging (MRI), PET, other
 biological markers, and clinical and neuropsychological assessment can be
 combined to measure the progression of MCI and early Alzheimer's
 disease (AD). The initial goal of ADNI was to recruit 800 adults, ages 55
 to 90, to participate in the research—approximately 200 cognitively normal
 older individuals to be followed for 3 years, 400 people with MCI to be
 followed for 3 years, and 200 people with early AD to be followed for 2
 years. For up-to-date information, see www.adni-info.org. The current
 sample was restricted to those subjects who had either a PIB-PET
 assessment or a CSF-Aß-1-42 measurement. Within this subset, PIB-PET was
 available in 103 subjects including 19 HC, 65 MCI, and 19 AD subjects. The
 CSF-Aß-1-42 concentration was assessed in a total of 116 HC, 199 MCI, and
 102 AD subjects (see Fig. 1 for further information on subjects and data
 inclusion). Within 55 subjects, both CSF Ab1--42 and PIB-PET were
 assessed. The observation interval covered 2 years, where
 neuropsychological assessment, FDG-PET scanning, and MRI acquisition was
 conducted at baseline, 6, 12, and 24 month. All collected data are freely
 accessible online to researchers (http://www.loni.ucla.edu/ADNI). General
 inclusion criteria included an age between 55 and 90 years, a modified
 Hachinski score =4, education of at least 6 grade level, and stable
 treatment of at least 4 weeks in case of treatment with permitted
 medication (for full list, see http://www.adni-info.org, Procedures
 Manual). The diagnosis of AD was made according to the NINCDS-ADRDA
 criteria (McKhann et al. 1984). Inclusion criteria for AD encompassed
 subjective memory complaint, memory impairment as assessed by an education
 adjusted score on delayed recall of a single paragraph recall from the
 Wechsler Logical Memory II Subscale as follows: 0–7 years of education,
 =2; for 8–15 years, =4; for 16 years or more, =8, a Mini Mental State Exam
 (MMSE) score between 20 and 26, and a clinical dementia rating (CDR) score
 of 0.5 or 1. For the diagnosis of amnestic MCI, the subjects had to show
 subjective memory impairment and objective memory impairment identical to
 that for AD, a CDR of 0.5 including the memory box score of 0.5 or
 greater, and a MMSE score between 24 and 30, with unimpaired general
 cognitive ability and functional performance such that they did not meet
 criteria for dementia. HC had to show normal performance on the Logical
 Memory II Subscale adjusted for education as follows: 0–7 years, =3, 8–15
 years, =5; 16 or more years, =9, and absence of significant impairment on
 cognitive function or activities of daily living (Ewers et al. 2010). CSF
 Measurement: All CSF samples collected at the different centers were
 shipped on dry ice to the Penn ADNI Biomarker Core Laboratory at the
 University of Pennsylvania, Philadelphia, for storage at -80°C until
 further analysis at the laboratory. More details on data collection of the
 CSF samples can be found at http://www.adni-info.org, under "ADNI
 study procedures." The CSF concentration of Aß-1-42, t-tau, and
 p-tau181 were measured in the baseline CSF samples using the multiplex
 xMAP Luminex platform (Lumnix Corp, Austin, TX) at the Penn ADNI Biomarker
 Core Laboratory. For detailed description, see Shaw et al. (2009).
 PIB-PET, FDG-PET, MRI Acquisition, and ROI Measurement: All MRI data were
 acquired on 1.5-T MRI scanners using a volumetric T1-weighted sequences to
 map brain structures, optimized for the different scanners as indicated at
 http://www.loni.ucla.edu/ADNI/Research/Cores/index (Jack, Bernstein, et
 al. 2008). Freesurfer software version 4.5 (Dale et al. 1999; Fischl et
 al. 1999) was employed to measure longitudinal changes in regional brain
 volumes. Briefly, the image-processing pipeline using FreeSurfer consisted
 of five stages: an affine registration with Talairach space, an initial
 volumetric labeling, bias field correction, nonlinear alignment to the
 Talairach space, and a final labeling of the volume. The fully automated
 labeling of volumes is achieved by warping a population based brain atlas
 to the target brain and by maximizing an a posteriori probability of the
 labels given specific constraints. A full description of the FreeSurfer
 processing steps can be found in (Fischl et al. 2002). The procedures have
 been extensively validated. MRI-volume ROIs were selected based on the
 previous meta-analyses on MRI gray matter volume measures that were most
 predictive of AD, including the hippocampus, middle temporal gyrus,
 superior temporal gyrus, amygdala, parahippocampus, entorhinal cortex,
 inferior parietal lobe, precuneus, and thalamus (Schroeter et al. 2009).
 PET data were acquired on multiple instruments of varying resolution. PIB
 scans were collected as 4 × 5 min frames beginning 50 min after injection
 of tracer. FDG scans were collected as 6 × 5 min frames beginning 30 min
 after injection of approximately 5 mCi of tracer. Attenuation correction
 was performed either via transmission scan or computer tomography. Images
 were uploaded to the Laboratory of Neuroimaging where they were processed
 to provide standard orientation, voxel size, and resolution. FDG-PET ROIs
 were constructed based on a meta-analysis of the location of FDG-PET
 changes in the brain that are typically affected in AD as described
 previously (Jagust et al. 2009; Landau et al. 2009). FDG uptake was
 normalized to a reference region composed of the pons and cerebellum and
 measured in the target ROIs that included bilateral angular gyrus,
 posterior cingulate/precuneus, and inferior temporal cortex as described
 previously (Jagust et al. 2009). PIB-PET uptake was normalized to the
 cerebellum to generate maps of the PIB-PET score used for further
 statistical analysis. Target ROIs were drawn on a structural MRI template
 from a single 79-year-old MCI subject scanned at the University of
 Pittsburgh. This image was deemed an "average" older subject
 with typical atrophy and ventricular size. Each subject's PIB-PET
 score map was coregistered to the individual MRI with SPM5 that was
 normalized to the MCI template with SPM5 and permitted the transformation
 of the subject's PIB-PET to the template space. ROIs in which PIB
 uptake is known to predominate were averaged in left and right hemispheres
 and comprised of prefrontal, lateral temporal, anterior cingulate gyrus,
 parietal and posterior cingulate/precuneus. Further information is
 available at the ADNI webpage (http://www.loni.ucla.edu/ADNI/).
 Neuropsychological Tests: Global cognitive ability was assessed with the
 neuropsychological test battery Alzheimer's Disease Assessment
 Scale–cognitive section (ADAS-cog) (Rosen et al. 1984). The ADAS-cog score
 is the total score on a number of tests on learning and memory, language
 production, language comprehension, constructional praxis, ideational
 praxis, and orientation (see ADNI procedures manual for details at
 http://www.adni-info.org/Scientists/ProceduresManuals.aspx). A higher
 score on ADAS-cog scores indicates lower cognitive performance. Episodic
 memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT),
 using the score on the 30-min delayed recall of a list of 15 words that
 had been repeatedly presented and recalled during the learning phase of 5
 verbal presentations of the list (Rey 1964). The test score corresponds to
 the number of words recalled on the 30-min delayed test. For details on
 the administration and scoring, see the "Procedures Manual"
 (http://www.adni-info.org/Scientists/ProceduresManuals.aspx).