Mean regional volumes in the Pittsburgh compound B (PiB)–positive and PiB-negative groups. A, Hippocampal volume; B, temporal neocortex volume; C, anterior cingulate volume; and D, posterior cingulate volume. Error bars are SEM.
Longitudinal course of participants with high amyloid values (mean cortical binding potential, ≥0.20) and at least 4 cognitive assessments. Zero on the time axis is time of positron emission tomography (PET).
Storandt M, Mintun MA, Head D, Morris JC. Cognitive Decline and Brain Volume Loss as Signatures of Cerebral Amyloid-β Peptide Deposition Identified With Pittsburgh Compound BCognitive Decline Associated With Aβ Deposition. Arch Neurol. 2009;66(12):1476–1481. doi:10.1001/archneurol.2009.272
Copyright 2009 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2009
To examine the relation of amyloid-β peptide (Aβ) levels in the cerebral cortex with structural brain integrity and cognitive performance in cognitively healthy older people.
Longitudinal study from May 22, 1985, through October 15, 2008.
Washington University Alzheimer Disease Research Center.
A total of 135 individuals aged 65 to 88 years with a Clinical Dementia Rating of 0.
Main Outcome Measures
The relations between mean cortical carbon 11 (11C)–labeled Pittsburgh compound B (PiB) binding potential values, proportional to the density of fibrillar Aβ binding sites in the brain, concurrent regional brain volumes as assessed by magnetic resonance imaging, and both concurrent and longitudinal cognitive performance in multiple domains.
Elevated cerebral Aβ levels, in some cases comparable to those seen in individuals with Alzheimer disease, were observed in 29 participants, who also had smaller regional volumes in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate. Concurrent cognitive performance was unrelated to Aβ levels but was related to regional brain volumes with the exception of the caudate. Longitudinal cognitive decline in episodic and working memory and visuospatial ability was associated with elevated Aβ levels and decreased hippocampal volume.
The in vivo measure of cerebral amyloidosis known as [11C]PiB is associated with cross-sectional regionally specific brain atrophy and longitudinal cognitive decline in multiple cognitive domains that occur before the clinical diagnosis of Alzheimer disease. These findings contribute to the understanding of the cognitive and structural consequences of Aβ levels in cognitively healthy older adults.
Amyloid imaging with positron emission tomography (PET) and the benzothiazole tracer labeled with carbon 11 (11C), Pittsburgh compound B (PiB), is a noninvasive method to assess cerebral amyloid-β peptide (Aβ) levels in the brains of living people1 and serves as an important new tool in the study of Alzheimer disease (AD). The compound binds to fibrillar amyloid plaques and to amyloid angiopathy in human postmortem specimens,2 and PiB uptake corresponds to postmortem assessment of parenchymal Aβ plaques.3,4 Previous reports5- 7 indicate that some older adults without cognitive impairment at death have brain amyloid plaque levels, 1 of the histopathologic hallmarks of AD, comparable to those measured in individuals with AD. Similarly, some older people without cognitive impairment have elevated Aβ levels as assessed in vivo with [11C]PiB.8,9
Although abnormal amyloid plaque levels can occur in people without dementia, the extent to which those levels are associated with behavioral deficit or brain atrophy is unclear. Four studies addressed the relation between brain Aβ levels and concurrent objective cognitive performance in people without clinical impairment; the results of those studies conflict. One study10 of 32 individuals reported that higher plaque levels were correlated (−0.38) with poorer episodic memory but not other types of cognitive ability. This might be expected if, as is usually thought, the earliest detectable deficit in AD is in episodic memory. Individuals with very early symptomatic AD may not satisfy the current criteria for clinical diagnosis of AD, which require another cognitive deficit and interference with function. Three other studies, of 20,11 43,12 and 3713 cognitively healthy individuals, respectively, failed to find any consistent relation between [11C]PiB level and any cognitive domain. In terms of brain atrophy, 1 of these studies observed correlations between [11C]PiB levels and hippocampal volume in clinically healthy individuals.13 Differences between clinically healthy individuals with or without elevated [11C]PiB levels have been observed in the temporal pole but not other cortical regions or the hippocampus.11,14
In this report we evaluate the relation between brain Aβ levels and concurrent cognitive performance and structural brain integrity in 135 people without clinically detectable cognitive impairment. Longitudinal cognitive performance was also examined to determine whether the course varied with plaque burden or regional brain volume.
The 135 control individuals were recruited from the community and enrolled in longitudinal studies at the Washington University Alzheimer Disease Research Center beginning May 22, 1985. All were clinically evaluated to be cognitively healthy (with a Clinical Dementia Rating15 [CDR] of 0) at entry and continued to have a CDR of 0 through amyloid and structural imaging beginning April 21, 2004. The CDR designation of 0 excludes even minimal cognitive deficit. Table 1 gives the sample characteristics. All procedures were approved by the Institutional Review Board of Washington University; written informed consent was obtained from participants and their collateral sources. Data from many of these participants have appeared in previous reports from the Alzheimer Disease Research Center.
At entry and annual follow-up, experienced clinicians determined whether each participant had impairment (CDR>0) or not (CDR=0), on the sole basis of semistructured interviews with participants and their knowledgeable collateral sources (usually a spouse or adult child) followed by a neurologic examination of the participant. The clinician determined whether any cognitive problems represented decline from the former level of function for that individual and whether those problems interfered to some degree with the ability of the person to perform accustomed activities. The assessment included a health history, medication inventory, assessment of depression and aphasia, and the Mini-Mental State Examination.16 Clinicians varied from year to year; they were unaware of the results of previous clinical evaluations and previous and current psychometric tests. The CDR staging and diagnostic protocol is sensitive to clinical progression and highly predictive (93%) of autopsy-confirmed AD.17,18
A few weeks after the annual clinical assessment, a 1.5-hour psychometric battery19 was administered. Examination of the factor structure of the battery revealed a stable 4-factor structure of 1 global and 3 specific factors (all at the same level) in samples with autopsy-confirmed AD and no dementia.19 Four measures formed each of 3 specific factors; all 12 measures contributed to the global factor. The verbal memory factor included the Wechsler Memory Scale20 Logical Memory (immediate recall) and Associate Learning, the Wechsler Adult Intelligence Scale21 Information, and the Boston Naming Test.22 The visuospatial factor included the Benton Visual Retention Test: Form D-Copy,23 the Wechsler Adult Intelligence Scale Digit Symbol and Block Design, and Trail Making Test A.24 The working memory factor included Letter Fluency (S, P)25 and the Wechsler Memory Scale Mental Control and Digit Span (forward and backward). We stopped using the Benton measure after 2003. Therefore, unweighted mean z scores on the remaining tests for each factor were averaged to form the 4 composites analyzed herein. The reference group for the z scores was 310 participants (initial assessment) from the data archives of the center. Participants were chosen because they continued to have a CDR of 0 as long as they were followed up; these participants included many individuals from the current sample.
Median time between PET and concurrent clinical assessment was 3.9 months (range, same day to 1.4 years); median time to concurrent psychometric assessment was 4.1 months (range, same day to 1.5 years). Initial cognitive assessment occurred up to 19 years before imaging. Detailed information on the imaging procedures was reported previously.8 Imaging was conducted via a commercial scanner (961 HR ECAT PET scanner or 962 HR+ ECAT PET scanner; Siemens Corporation, New York, New York) in a darkened, quiet room. A thermoplastic mask minimized head motion, and participants kept their eyes closed during the scan. Radiochemical synthesis of [11C]PiB was conducted according to published literature.26 After a transmission scan to measure attenuation, [11C]PiB (5.3 to 20.1 mCi; mean, 12.1 mCi) was administered intravenously simultaneously with initiation of a 60-minute dynamic PET scan in 3-dimensional mode (septa retracted; 24 × 5-second frames, 9 × 20-second frames, 10 × 1-minute frames, and 9 × 5-minute frames). The measured attenuation factors and a ramp filter were used to reconstruct the dynamic PET images. A fully 3-dimensional, single-scatter simulation algorithm was used to correct scatter.27 Participants also underwent anatomic magnetic resonance imaging (MRI) by means of medium resolution (1 × 1 × 1.25 mm) MPRAGE T1-weighted volume acquisitions. A high-resolution, low-noise anatomical image data set for region-of-interest (ROI) determination was created for each participant by aligning and averaging two 133 magnetization-prepared rapid acquisition gradient-echo (MPRAGE) sequences.8,28 The structural MRI of each participant was registered to a standard atlas target29 that minimizes bias owing to atrophy. Alignment of each PET scan to the MRI from that same participant was accomplished with an in-house cross-modal registration algorithm.8 We then used a comprehensive biomedical imaging software suite (Analyze 8.0; Mayo Clinic, Rochester, Minnesota) to create 3-dimensional ROIs for each participant on the basis of his or her MRI. Detailed information on the boundaries of specific regions is available.8 Regions of interest were then applied to unblurred images of the PET dynamic data, which yielded high-resolution regional time-activity curves. Each time-activity curve was analyzed for PiB-specific binding via the Logan graphical analysis,30 with cerebellum data as a reference tissue input function.31 The cerebellum served as the reference because there is little specific binding of PiB in postmortem samples of cerebellar cortex even among those with AD at autopsy.26 The slope produced by Logan graphical analysis is equal to the tracer distribution volume in the tissue of interest when compared with the input function. A binding potential32 for each ROI was calculated by subtracting 1 from the distribution volume to express the regional binding values in a manner proportional to the number of binding sites. The binding potential values from the prefrontal cortex, gyrus rectus, lateral temporal, and precuneus ROIs were averaged to calculate a mean cortical binding potential (MCBP) value based on brain regions known to have high PiB uptake among participants with AD.8 Two measures were used in analyses, the quantitative MCBP and MCBP dichotomized at 0.20,33 so that annual rates of cognitive change could be estimated for those with (positive) and without (negative) substantial brain amyloid plaque burden.
The interval between structural imaging ranged from 0 days to 1.6 years (median, 3.4 months) for PET, 0 days to 1.25 years (median, 3.1 months) for clinical assessment, and 0 days to 1.5 years (median, 2.9 months) for psychometrics. One to four T1-weighted images were acquired in 1 scanning session in 118 participants on either a Sonata 1.5T (n = 4), Vision 1.5T (n = 34), or Trio 3.0T scanner (n = 80) (Siemens Corporation). No difference was found in the proportion of individuals with an MCBP greater than 0.20 across scanners. Image processing steps are described in detail in previous publications28,34,35 and include motion correction, averaging across scans, atlas transformation, and inhomogeneity correction. Processing resulted in registered structural data resampled to 1-mm3 voxels in the atlas space described by Talairach and Tournoux.29
Regional volume estimates were obtained via the Freesurfer image analysis suite (Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, Massachusetts), which implements an automated probabilistic labeling procedure.35,36 Each voxel in an image is assigned a neuroanatomical label on the basis of probabilistic information from a manually labeled training set that included healthy adults and patients with AD. This technique generates volumes with a high correspondence to manually generated volumes.36 The ROIs included the caudate nucleus, prefrontal cortex (combined superior, middle, and inferior frontal gyri), orbital frontal, lateral parietal (combined inferior parietal, superior parietal, and supramarginal regions), temporal neocortical (combined superior, middle, and inferior temporal gyri), anterior cingulate, posterior cingulate, precuneus, hippocampal, and parahippocampal regions (including entorhinal cortex) regions. Intracranial volume (ICV) was used to adjust ROIs for head size variation based on a covariance approach: adjusted volume in cubic millimeters was determined as
Raw Volume − (b × [ICV − Mean ICV]),
where b is the slope of the regression of an ROI volume on ICV and mean ICV. Although there are concerns with regard to biases across scanner and field strength aggregation, there is also evidence of reliability of some Freesurfer-derived quantitative estimates.37,38 A comparison between the Vision 1.5T and Trio 3T scanners (Siemens Corporation) of Freesurfer-derived volumes for regions examined herein yielded an average intraclass correlation of 0.81.
Variables were assessed for normality with 1-sample Kolmogorov-Smirnov tests. Pearson correlations were computed for quantitative variables; φ was used for 2 dichotomous variables; t and χ2 tests were used for cross-sectional group comparisons. Statistical significance was defined as P < .05.
The longitudinally measured cognitive composites (gathered at the times when individuals had CDRs of 0) were examined by means of PROC MIXED (SAS statistical software, version 9.1; SAS Institute Inc, Cary, North Carolina). In the analysis that examined amyloid burden, the model included the fixed-effect quantitative MCBP and the random variable time from date of imaging (negative values before imaging, positive values after). A significant interaction between MCBP and time indicated that the rate of longitudinal change varied with the level of brain Aβ. Analogous analyses were conducted by the use of regional brain volume instead of MCBP. To reduce capitalization on chance, only 3 regions (hippocampus, posterior cingulate, and precuneus) known to be affected early in AD39 or to have high Aβ deposition1,8 were examined. The longitudinal analyses were repeated by the use of MCBP dichotomized at 0.2033 and hippocampal volume dichotomized at the 25th percentile to estimate rates of annual cognitive change (ie, slopes in z score units) for those with high vs low amyloid burden or volume loss.
The cognitive composites and all measures of regional volume were normally distributed, but the MCBP was skewed. As indicated in Table 1, 29 people with a CDR of 0 at the time of imaging had values greater than 0.20. The MCBP was uncorrelated with age, education level, sex, or Mini-Mental State Examination score (r <.14), but 65.4% of the PiB-positive group had 1 or 2 APOE ε4 alleles compared with 24.0% in the PiB-negative group (Φ = 0.29). The MCBP was also uncorrelated with any of the cognitive composites (global, −0.05; verbal memory, −0.09; spatial, 0.02; working memory, 0.03) or individual cognitive measures (r = −0.14 to 0.06) assessed concurrently with PET. As depicted in Figure 1, significant differences in volumes between the PiB-positive (n = 26) and PiB-negative (n = 92) groups were observed in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate with trends in the precuneus (P = .08) and parahippocampal regions (P = .07). No differences were found in the remaining regions. Controlling for APOE status did not change the results. Similar results were obtained with the data from the scanner with the largest sample (Trio 3T, Siemens Corporation; 63 PiB negative, 17 PiB positive).
A significant interaction was found between time and MCBP in the longitudinal analyses for 2 specific composites: visuospatial and working memory. As indicated in Table 2, slopes for the PiB-negative group were not significantly different from 0, whereas slopes for the PiB-positive group were significantly different from 0 and downward for the visuospatial and working memory composites. Figure 2 illustrates the actual longitudinal course on the visuospatial composite of participants from the PiB-positive group who had at least 4 cognitive assessments; those with fewer assessments were not included in Figure 2 to reduce overlap.
The nonsignificant group × time interaction for verbal memory was unexpected, given the common belief that memory deficits mark early stages of symptomatic AD. Because the verbal memory factor included both episodic and semantic memory measures, the 4 individual tests were examined separately. The interaction was significant for the Associate Learning standard test of episodic memory. The slope for the PiB-negative group was upward (0.03), whereas it was downward (−0.05) for the PiB-positive group. The interaction was not significant for any of the other verbal memory measures. The lack of significance on the Logical Memory test may be related to substantial missing data on this measure near the time of PET; the funding agency required substitution of a different version of the test on September 1, 2005.
In terms of the relation between regional volume and cognition measured concurrently, the global composite was moderately correlated with all regions except the caudate (r = 0.19 to 0.41). The strongest regional correlations were seen with the spatial composite (r = 0.29 to 0.54). The verbal composite was modestly correlated with volume in all regions (r = 0.21 to 0.28) except the caudate and parahippocampus. Working memory was correlated only with volume in the lateral temporal (r = 0.27) and anterior cingulate (r = 0.19) regions. In longitudinal analyses that related regional volume to cognitive course, a significant interaction was found for hippocampus volume and time for the global, verbal, and spatial composites and a trend for working memory. Dichotomization of the hippocampal volume at the 25th percentile produced the slopes indicated in Table 3. Those with less volume had negative slopes. The interaction between time and volume in either the posterior cingulate or the precuneus was not significant for any of the composites.
The longitudinal cognitive decline in older adults with PiB-positive test results and volumetric reductions in multiple brain regions suggests that cerebral amyloidosis in aging without dementia is not a benign process. More than one-fifth (22.0%) of individuals with a CDR of 0 had substantial cerebral amyloidosis. The reported prevalence of symptomatic AD at the age of 75 years in population studies40,41 is consistent with this frequency of cognitively healthy individuals with PiB-positive results, and provides inferential support for the notion of preclinical AD. Estimates of preclinical AD on the basis of neuropathologic studies5- 7 are somewhat higher (30.0%-40.0%), but those samples were older than this sample examined in vivo (eg, 85 vs 75 years). Because AD is age associated, a higher prevalence rate is expected in older samples. Elevated [11C]PiB levels in individuals with a CDR of 0 was accompanied by smaller hippocampal and temporal neocortical volumes (these brain regions are known to be affected early in the disease).39 Because the hippocampus has only mild levels of Aβ binding,8 these volumetric reductions may indicate pathologic processes (eg, neurofibrillary degeneration) in addition to amyloid deposition. In either case, the existence of atrophy further substantiates the concept of preclinical AD. Structural imaging work has focused on the medial temporal lobe, but atrophy was also observed in the cingulate cortex, which is consistent with the topographical distribution of gray matter loss observed in voxel-wise analyses in AD.42 Smaller hippocampal volume13 and thinning of the temporal pole14 have been observed in individuals without dementia and with amyloid deposition. Reduced cerebrospinal fluid levels of Aβ42, another marker of cerebral amyloidosis in preclinical AD, also is associated with whole brain atrophy in cognitively healthy individuals.43
The longitudinal cognitive course for people with low levels of Aβ in the brain and greater volume in the hippocampus indicates that most older adults maintained an essentially flat cognitive trajectory in contrast with the slightly downward cognitive course for those with either elevated Aβ levels or reduced hippocampal volume. Annual estimated slopes for the group with PiB-positive results were not large, but they included the entire course while they maintained a CDR of 0. More notable decline in performance would be expected if it were possible to identify the time when a person changes from a flat course to a downward one and to determine if more sensitive measures were available, especially of memory. Because PiB and volume values were available from only one time, it is unknown if the cognitive decline began before, concurrently with, or after increased cerebral Aβ burden or hippocampal atrophy. Clearly, however, amyloidosis, atrophy, and deterioration in cognitive test performance occur before clinical diagnosis of dementia, even at a center that successfully diagnoses dementia much earlier than is typical.18
The factors examined herein are not process-pure measures, but decline occurred in visuospatial ability and working memory and a measure of episodic memory. This widespread effect on cognition is consistent with the widespread distribution of cerebral amyloid burden observed herein and reported previously.8,9,11 Continued focus solely on episodic memory in the diagnosis of dementia means that other types of cognitive deficits that may even precede memory difficulties are not evaluated, which makes it difficult to assess their influence. In addition, dependence on cognitive test performance at a single point is ineffectual for detection of dementia in its earliest stage. Although correlated with regional brain volume, concurrent cognitive measures were unrelated to Aβ; time between cognitive and amyloid assessment was occasionally lengthy, but 85% of assessments were within 6 months. It appears that individual differences in cognitive ability, such as memory, are too large to allow effective assessment of very early symptomatic AD through comparison with normative values.18 The current performance of the individual must be compared with previous levels by either serial testing or informant-based clinical assessment that compares current functioning with previously attained levels.
Correspondence: John C. Morris, MD, Alzheimer’s Disease Research Center, Department of Neurology, School of Medicine, Washington University, 4488 Forest Park Ave, Ste 160, St Louis, MO 63108 (email@example.com).
Accepted for Publication: May 29, 2009.
Author Contributions:Study concept and design: Storandt. Acquisition of data: Storandt, Mintun, Head, and Morris. Analysis and interpretation of data: Storandt, Mintun, and Head. Drafting of the manuscript: Storandt. Critical revision of the manuscript for important intellectual content: Mintun, Head, and Morris. Statistical analysis: Storandt. Obtained funding: Storandt, Mintun, and Morris. Administrative, technical, and material support: Mintun and Morris. Study supervision: Mintun and Head.
Financial Disclosure: None reported.
Funding/Support: This study was supported by National Institute on Aging grants P30 NS048056 (Dr Mintun) and P50 AG05861, P01 AG03991, and P01 AG026276 (Dr Morris), and by the Charles and Joanne Knight Alzheimer Research Initiative of the Washington University Alzheimer Disease Research Center (Dr Morris).
Additional Contributions: We thank the Alzheimer Disease Research Center's Clinical Core for the clinical and psychometric assessments; the Imaging Core, particularly Tessa Mazzocco, MS, Marlisa Isom, BS, and Lindsay Casmaer, BS, who gathered the structural MRI data; and the Genetics Core, who gathered the APOE data.