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CROSS-SECTIONAL & LONGITUDINAL BRAIN

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.

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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

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