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CROSS-SECTIONAL AND LONGITUDINAL BRAIN-VOLUME DECLINE IN AGING AND AD

A.F. FOTENOS, R.L. BUCKNER

From the Division of Biology and Biomedical Sciences (A.F. Fotenos and Dr. Buckner), Washington University Medical School, St. Louis MO, and Department of Psychology, Center for Brain Science, Howard Hughes Medical Institute, Harvard University, Cambridge MA, Martinos Center, Massachusetts General Hospital, Department of Radiology, Harvard Medical School, Boston, MA (Dr. Buckner). Supported by grants AG 05681 and AG 03991 from the National Institute on Aging, Bethesda, MD; IIRG-00-1944 from the Alzheimer's Association; the James S McDonnell Foundation; and the Howard Hughes Medical Institute. Address correspondence to Anthony Fotenos, Psychology Department Campus Box 1125, One Brookings Drive, St. Louis, MO 63108; phone: (314) 566-0842; fax: (314) 935-4711; email: Anthony.Fotenos@wustl.edu.

Abstract: Structural MRI was used to estimate rates of gray matter, white matter, and whole-brain volume decline in normal aging and Alzheimer’s Disease (AD), based on a combination of cross-sectional and longitudinal sampling of 370 individuals age 18 to 97. Hierarchical regression of whole-brain volume estimates normalized for head-size from nondemented individuals across the adult lifespan revealed a strong linear, moderate quadratic pattern of decline beginning in early adulthood, with later onset of white-matter than gray-matter loss. Whole-brain volume differences were detected by age 30. Estimates of volume decline predicted from the cross-sectional sample overlapped with the rates measured longitudinally in older, nondemented individuals (mean decline of -0.45% per year). In serially scanned individuals with very mild to mild dementia of the Alzheimer type, atrophy rate more than doubled (-0.98% per year). These and related findings are discussed in terms of a multiple factor framework of aging and AD.

A persistent challenge in Alzheimer’s Disease (AD) research has been to distinguish disease-specific pathology from normal aging. For example, structural brain-change is a hallmark of AD, but also manifests in nondemented adults followed longitudinally [1]. The goal of this study [2] was to characterize normal aging in terms of whole-brain volume development across the adult lifespan, and to determine to what degree early-stage AD causes departure from this normal trajectory. Important features of the study design included a relatively large sample of 370 adults

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(age 18 to 97), longitudinal clinical characterization of older adult participants (> 65) using the Clinical Dementia Rating (CDR) scale [3], and longitudinal imaging of a subset of the older adult participants for comparison of cross-sectional and longitudinal estimates of brain-volume change. At least three specific questions could be addressed by this design. First, how early in normal adult aging do whole-brain volume differences appear? There has been some disagreement in prior volumetric research regarding whether younger adults (< 50) exhibit age-associated brain- volume differences. Second, do the cross-sectional estimates of brain- volume decline in nondemented older adults match longitudinal estimates? Secular cohort effects, such as baseline differences in whole-brain volume between older versus younger adults, would be expected to selectively confound cross-sectional estimates, leading to cross-sectional/longitudinal differences. Finally, to what extent does longitudinal whole-brain atrophy accelerate in early-stage DAT? Prior research has found significantly more rapid rates of decline, but differs as to its magnitude. This last question is of particular clinical relevance because longitudinal whole-brain atrophy represents a promising surrogate marker for trials of AD therapy [4]. A total of 370 adults (age 18 to 97 at baseline) participated in a structural MR imaging session. Of these individuals, 79 participated on two separate occasions separated by an extended interval to allow for longitudinal data analysis (1.0 to 3.9 year interval; mean = 1.8 years). Young and middle-aged adults were recruited from the Washington University community. Nondemented and demented older adults were recruited exclusively from the ongoing longitudinal sample of the Washington University AD Research Center (ADRC). Dementia severity was quantified using the CDR, with 0, 0.5, and 1 corresponding to nondemented (n = 94), very mild (n = 69), and mild DAT (n = 29). Although several DAT participants had cognitive test scores that might qualify for classification as mild cognitive impairment, a CDR score of 0.5 or greater in this sample is highly predictive of AD, both in clinical progression and neuropathologic diagnosis at autopsy. Volumetric estimates were based on the average of multiple, high- resolution, structural T1-weighted MRIs acquired at each image session on a 1.5-T scanner. The volumetric estimates consisted of head-size normalized gray-matter (nGM), white-matter (nWM), and whole-brain volume (nWBV). They were derived from a validated, automated segmentation procedure described in [2] and [5]. The unit of normalized volume is percent, representing the proportion of estimated total intracranial volume occupied by gray and white matter. For the full cross-sectional sample of nondemented adults, nWBV

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declined from 85% at age 20 to 74% at age 80, a mean rate of -0.23% per year with acceleration into advanced aging. Hierarchical polynomial regression showed that the relationship between nGM and age was predominantly linear, with decline significant even in the young-adult range of 18 to 30. In contrast, the relationship between nWM and age was quadratic, with minimal decline in early adulthood. Considering only the nondemented older adults, the cross-sectional volume loss ranged from -0.31% to -0.46% per year, similar to the longitudinal estimate of -0.45% per year. The longitudinal atrophy rate in the individuals with very mild to mild DAT was -0.98% per year, approximately doubling the rate for the age- matched, nondemented sample. Of the 43 nondemented (CDR 0) individuals followed longitudinally from their first scan, six declined to a CDR of 0.5 at the time of their last scan. The longitudinal atrophy rate of those who started with a CDR of 0 and declined (-0.88%) matched the rate of those who started with a CDR of 0.5 (-0.90% per year). Post hoc testing revealed a trend toward a difference between the nondemented group (CDR 0 to 0) and the decliner group (CDR 0 to 0.5), though the small sample size limited statistical power.

Figure 1

Summary plot of cross-sectional and longitudinal whole-brain volume decline in normal aging and AD. The “normal aging cross-sectional” curve represents the best- fit polynomial regression of all nondemented individuals (n = 272, age 18 to 95). The “normal aging longitudinal” line represents the mean slope and intercept of all nondemented older adults scanned longitudinally (n = 38, age 65 to 95). The “Alzheimer’s longitudinal” line represents the mean slope and intercept for all longitudinally scanned individuals with AD (n = 33 CDR 0.5, age 65 to 93; n = 8 CDR 1, age 69 to 97). Note the overlap between cross-sectional and longitudinal estimates of normal brain-volume decline, and the markedly accelerated atrophy rate in AD.

and longitudinal estimates of normal brain-volume decline, and the markedly accelerated atrophy rate in AD. 236

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COMMENT

In a large, cross-sectional sample of nondemented adults, significant decline in whole-brain volume was detected in early adulthood and continued into old age, with distinct patterns for gray- and white-matter loss. The cross-sectional rate of decline overlapped the longitudinal rate in the older, nondemented adults. This observed agreement indicates that secular or other cohort differences minimally influenced cross-sectional, whole-brain volume estimates in this sample. For the longitudinal subset of older adults in the earliest stages of DAT, the rate of whole-brain atrophy (-0.98% per year) was more than twice the nondemented rate (-0.45 per year), indicating marked acceleration. The sensitivity to clinical progression of automated whole-brain measures such as nWBV, combined with their reliability and cross-sectional validity, highlights the promise of global volumetric biomarkers. Taken together, this and related research support a multiple factor framework of aging and AD [6]. For example, in the context of brain morphometry, a plausible three-factor framework distinguishes between early-, middle-, and late-onset patterns of volume decline. The early-onset pattern evident by age 30 may represent lifelong developmental processes that preferentially affect gray matter, particularly association cortical areas [1]. The middle-onset pattern begins around age 50 and continues (perhaps even accelerates) into advanced aging, includes white matter, particularly in anterior regions sensitive to common cardiovascular risk factors [1]. Finally, a late-onset pattern associates with AD, presumably follows the exponential increase in AD prevalence in advanced aging, and prominently includes medial temporal and posterior cortex [7]. Lifelong brain development thus represents a complex landscape of change with disease-related processes causing departure from trajectories of normal aging. Future research to determine whether these structural patterns relate to independent mechanisms, and the elucidation of these mechanisms, will ultimately clarify the distinction between normal aging and AD.

REFERENCES

1. Raz, N., Lindenberger, U., Rodrigue, K.M., Kennedy, K.M., Head, D., Williamson, A., Dahle, C., Gerstorf, D. and Acker, J.D. (2005). Regional Brain Changes in Aging Healthy Adults: General Trends, Individual Differences and Modifiers. Cereb Cortex.

2. Fotenos, A.F., Snyder, A.Z., Girton, L.E., Morris, J.C. and Buckner, R.L. (2005). Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD. Neurology 64, 1032-1039.

3. Morris, J.C. (1993). The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 43, 2412-2414.

4. Fox, N.C., Black, R.S., Gilman, S., Rossor, M.N., Griffith, S.G., Jenkins, L., Koller, M. (2005). Effects of ABeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology

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64, 1563-1572.

5. Buckner, R.L., Head, D., Parker, J., Fotenos, A.F., Marcus, D., Morris, J.C. and Snyder, A.Z. (2004). A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage 23, 724-738.

6. Buckner, R.L. (2004). Memory and executive function in aging and AD: Multiple factors that cause decline and reserve factors that compensate. Neuron 44, 195-208.

7. Buckner, R.L., Snyder, A.Z., Shannon, B.J., LaRossa, G., Sachs, R., Fotenos, A.F., Sheline, Y.I., Klunk, W., Mathis, C., Morris, J.C., and Mintun, M.A. (2005) Molecular, structural, and functional characterization of Alzheimer's disease: Evidence for a relation between default activity, pathology, and memory. J Neurosci 25, 7709 – 7717.

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