Normative estimates of cross-sectional

and longitudinal brain volume decline

in aging and AD
A.F. Fotenos, ScB; A.Z. Snyder, PhD, MD; L.E. Girton, BA; J.C. Morris, MD; and R.L. Buckner, PhD

Abstract—Objective: To test the hypotheses 1) that whole-brain volume decline begins in early adulthood, 2) that
cross-sectional and longitudinal atrophy estimates agree in older, nondemented individuals, and 3) that longitudinal
atrophy accelerates in the earliest stages of Alzheimer disease (AD). Methods: High-resolution, high-contrast structural
MRIs were obtained from 370 adults (age 18 to 97). Participants over 65 (n ⫽ 192) were characterized using the Clinical
Dementia Rating (CDR) as either nondemented (CDR 0, n ⫽ 94) or with very mild to mild dementia of the Alzheimer type
(DAT, CDR 0.5 and 1, n ⫽ 98). Of these older participants, 79 belonged to a longitudinal cohort and were imaged again a
mean 1.8 years after baseline. Estimates of gray matter (nGM), white matter (nWM), and whole-brain volume (nWBV)
normalized for head sizes were generated based on atlas registration and image segmentation. Results: Hierarchical
regression of nWBV estimates from nondemented individuals across the adult lifespan revealed a strong linear, moderate
quadratic pattern of decline beginning in early adulthood, with later onset of nWM than nGM loss. Whole-brain volume
differences were detected by age 30. The cross-sectional atrophy model overlapped with the rates measured longitudinally
in older, nondemented individuals (mean decline of ⫺0.45% per year). In those individuals with very mild DAT, atrophy
rate more than doubled (⫺0.98% per year). Conclusions: Nondemented individuals exhibit a slow rate of whole-brain
atrophy from early in adulthood with white-matter loss beginning in middle age; in older adults, the onset of dementia of
the Alzheimer type is associated with a markedly accelerated atrophy rate.
NEUROLOGY 2005;64:1032–1039

Pathologic brain processes that lead to dementia co-
exist with normal aging processes that also influence
the brain but do not manifest as disease. To better
understand the nature of normal brain development
in advanced aging and how the earliest stages of
dementia of the Alzheimer type (DAT) cause depar-
ture from that trajectory, we report here a large-
sample study of 370 adults age 18 to 97. We sought
to characterize the normal development of whole-
brain volumes in the absence of dementia and deter-
mine, through a combination of cross-sectional and
longitudinal estimates, to what degree the presence
of early-stage DAT causes departure from normal
development.
An important feature of the study design is the
direct contrast of cross-sectional and longitudinal es-
timates of brain change. Cross-sectional estimates
are efficient in that a single measure can be used as
the dependent measure. To the degree that different
normal individuals have predictable brain sizes and
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Con-
tents for the March 22 issue to find the title link for this article.
changes in brain size, a single point estimate may be
informative regarding their likely future course and
risk of disease. However, reviews of the structural
aging literature highlight the need for longitudinal
data because of between-subject variance.1–3 Longitu-
dinal data reduce between-subject variance by using
an individual as his or her own baseline and also
control for differences that potentially complicate
cross-sectional samples. For example, cross-sectional
samples may include hidden group heterogeneity (co-
hort effects), such as environmental differences be-
tween when people were born (secular effects). MRI
is readily able to obtain longitudinal data through
repeated imaging of the same person over time.4
The present design, which combines cross-
sectional and longitudinal approaches,5 allows three
basic questions to be addressed. First, to what extent
and at what age does nondemented aging associate
with cross-sectional brain-volume reduction? Some
volumetric reports suggest that whole-brain volume
is stable in nondemented adults under 50,6 –10
whereas others find volume loss in this age
range,5,11–15 a difference possibly related to differen-
tial contributions of gray- and white-matter loss to

From the Division of Biology and Biomedical Sciences (A.F. Fotenos and Dr. Buckner), Mallinckrodt Institute of Radiology (Drs. Snyder and Buckner),
Department of Neurology (Drs. Snyder and Morris), Howard Hughes Medical Institute (L.E. Girton and Dr. Buckner), and Department of Psychology (Dr.
Buckner), Washington University, St. Louis, MO.
Supported by grants P50 AG 05681 and P01 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.
Received May 24, 2004. Accepted in final form November 30, 2004.
Address correspondence and reprint requests to Dr. Anthony Fotenos, HHMI at Washington University, Psychology Department Campus Box 1125, One
Brookings Drive, St. Louis, MO 63108; e-mail: Anthony.Fotenos@wustl.edu

1032 Copyright © 2005 by AAN Enterprises, Inc.

Table Sample characteristics

Old

Young Middle-aged CDR 0 DAT (CDR 0.5) DAT (CDR 1)

No. (cross-sectional) 127 51 94 69 29

Female/male 64/63 29/22 67/27 32/37 21/8
Age ⫾ SD, y 23 ⫾ 3 50 ⫾ 8 78 ⫾ 8 78 ⫾ 6 79 ⫾ 6
(18–34) (35–64) (65–95) (65–93) (69–97)
Education ⫾ SD, y 15 ⫾ 3 14 ⫾ 3 13 ⫾ 3
(8–23) (7–20) (7–20)
MMSE ⫾ SD 29 ⫾ 1 26 ⫾ 3 22 ⫾ 4
(25–30) (18–30) (13–28)
Prescriptions, n 2.9 ⫾ 2.1 2.4 ⫾ 1.9 2.7 ⫾ 2.3
(0–9) (0–8) (0–8)
Systolic BP, mm Hg 136 ⫾ 18 143 ⫾ 21 146 ⫾ 26
(102–192) (104–188) (90–192)
Diastolic BP, mm Hg 73 ⫾ 10 73 ⫾ 10 77 ⫾ 11
(40–96) (50–98) (60–100)
Reported HBP, % 43.0 41.8 48.3
Diabetes, % 10.8 11.8 10.7
No. with follow-up (longitudinal) 38 33 8
Female/male 30/8 10/23 5/3
Scan interval ⫾ SD, y 1.8 ⫾ 0.5 1.8 ⫾ 0.5 1.8 ⫾ 0.4
(1.1–3.9) (1.3–3.5) (1.0–2.4)

The sample consisted of 370 individuals (272 nondemented and 98 with DAT). Mean values given ⫾ SD. Values in parentheses repre-
sent the range. Education (n ⫽ 7), MMSE (n ⫽ 11), and clinical data (n ⫽ 16) were not available for some participants. Compared to
the older nondemented adults, the older adults with dementia had lower scores on the MMSE (t[179] ⫽ 10.02, p ⬍ 0.001) and slightly
fewer years of education (t[183] ⫽ 2.55, p ⬍ 0.05).

CDR ⫽ Clinical Dementia Rating, with 0, 0.5, and 1 corresponding to nondemented, very mild, and mild DAT; DAT ⫽ dementia of the
Alzheimer type; MMSE ⫽ Mini-Mental State Examination where scores range from 30 (best) to 0 (worst); HBP ⫽ high blood pressure.

brain aging.4 Second, does the cross-sectional rate of
atrophy in nondemented older adults match the lon-
gitudinal rate? As noted above, a number of potential
confounds could lead to a mismatch between cross-
sectional and longitudinal findings. If the cross-
sectional observations accurately predict the
longitudinal atrophy rate, it is reasonable to assume
that cohort and secular effects are minimal and vol-
ume loss progresses in a predictable manner in the
absence of dementia. Finally, to what extent does the
rate of whole-brain atrophy accelerate in early-stage
DAT? The available reports addressing this question
have found significant acceleration, but differ as to
its magnitude.16-18
Methods. Participants. 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 sepa-
rated by an extended interval to allow for longitudinal data anal-
ysis (1.0 to 3.9 year interval; mean ⫽ 1.8 years). Twenty
additional individuals were scanned twice at a short interval
(mean ⫽ 21 days, range 1 to 64) to allow estimation of measure-
ment reliability. Participants were paid for their participation and
gave written informed consent in accordance with guidelines of
the Washington University Human Studies Committee. Data from
subsets of the participants have been used in previous studies.15,19
Young and middle-aged adults were recruited from the Wash-
ington University community. Nondemented and demented older
adults were recruited exclusively from the ongoing longitudinal
sample of the Washington University AD Research Center
(ADRC). ADRC volunteers are more likely than the population of
the St. Louis metropolitan area to have a high school education,
and volunteers with severe comorbidities such as major depres-
sion or disabling stroke are excluded.20 Approximately 40% of
ADRC participants who met the study’s clinical criteria (nonde-
mented or dementia restricted to DAT) declined to participate in
an MRI; 7% were ineligible based on MRI contraindications. There
was no statistically significant difference in age, years of educa-
tion, or scores on the Mini-Mental State Examination (MMSE21)
between ADRC participants who did and did not undergo MRI.
Dementia severity was quantified using the Clinical Dementia
Rating (CDR22) scale for all ADRC volunteers, and recruitment for
MRI was independent of longitudinal clinical progression. The
average duration between clinical assessment and participation in
the MRI session was 101 days (range ⫽ 3 to 332 days). The 98
participants with DAT exhibited very mild (CDR 0.5, n ⫽ 69) to
mild (CDR ⫽ 1, n ⫽ 29) dementia severity. Of the 205 older adults
who underwent MRI, 13 (6%; 7 CDR ⫽ 1, 3 CDR ⫽ 0.5, 3 CDR ⫽
0) did not complete the imaging protocol; one dropped out on
repeat imaging. Although several DAT participants had cognitive
test scores (e.g., MMSE) 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.23,24 Demographic and clini-
cal data for participants are presented in the table.
March (2 of 2) 2005 NEUROLOGY 64 1033
Figure 1. Whole-brain volume measurement and normalization procedure. (A) Single magnetization-prepared rapid gra-
dient echo (MP-RAGE) image as acquired in native space. (B) Within-participant averaged MP-RAGE image (n ⫽ 4); note
the increased contrast-to-noise. (C) Averaged image after registration to a target atlas composed of representative young
and old individuals in Talairach and Tournoux29 space. (D) Averaged, atlas-registered image after masking and field-
inhomogeneity correction. (E) Final segmented image; normalized whole-brain volume (nWBV) is defined as the percent-
age of the brain mask (non-black background) occupied by voxels classified as gray and white matter.
Image acquisition. Multiple (three or four) high-resolution
structural T1-weighted magnetization-prepared rapid gradient
echo (MP-RAGE) images were acquired on a 1.5-T Vision scanner
(Siemens, Erlangen, Germany). MP-RAGE parameters were em-
pirically optimized for gray-white contrast (repetition time [TR] ⫽
9.7 msec, echo time [TE] ⫽ 4 msec, flip angle [FA] ⫽ 10, inversion
time [TI] ⫽ 20 msec, delay time [TD] ⫽ 200 msec, 256 ⫻ 256 [1
mm ⫻ 1 mm] in-plane resolution, 128 sagittal 1.25 mm slices
without gaps, time per acquisition ⫽ 6.6 minutes). Participants
were provided cushioning, headphones, and a thermoplastic face
mask for communication and to minimize head movements. Posi-
tioning was low in the head coil (toward the feet) to center the
field of view on the cerebral hemispheres. The MP-RAGE images
were acquired as the second part of a 70-minute protocol that also
included fast low angle shot (FLASH) gradient echo, turbo spin
echo (TSE), and diffusion tensor imaging (DTI) acquisitions. The
DTI data have been reported elsewhere.25
Image analysis. Normalized gray matter (nGM; gray paren-
chyma within the entire intracranial volume down to approximately
the superior arch of C1), white matter (nWM), and whole-brain
volume (nWBV; gray plus white parenchyma) were computed for
each image session. The procedure was based on a validated,
open-source segmentation tool.26,27 Prior to image segmentation,
the images were preprocessed to normalize for head size and in-
tensity variation that might affect image segmentation.
Preprocessing included multiple steps. Head-size normaliza-
tion used a validated method based on atlas registration.28 The
normalization is proportional to manually measured total intra-
cranial volume (TIV, r ⫽ 0.93) and minimally biased by atrophy.
Images were corrected for interscan head movement and spatially
warped into the atlas space of Talairach and Tournoux.29 The
template atlas consisted of a combined young-and-old target pre-
viously generated from a representative sample of young (n ⫽ 12)
and nondemented old (n ⫽ 12) adults. The use of a combined
template has been shown to minimize the potential bias of an
atlas normalization procedure to overexpand atrophied brains.28
For registration, a 12-parameter affine transformation was com-
puted to minimize the variance between the first MP-RAGE image
and the atlas target.30 The remaining MP-RAGE images were
registered to the first (in-plane stretch allowed) and resampled via
transform composition into a 1-mm isotropic image in atlas space.
All images were visually inspected to verify appropriate atlas
transformation. The result was a single, high-contrast, averaged
MP-RAGE image in atlas space (figure 1). Subsequent preprocess-
ing steps included skull removal by application of a loose-fitting
atlas mask and correction for intensity inhomogeneity due to non-
uniformity in the magnetic field. Intensity variation was corrected
across contiguous regions, based on a quadratic inhomogeneity
model.
Following preprocessing, the segmentation algorithm classified
each voxel of the average image as CSF, gray, or white matter.26,27
This segmentation starts with an initial estimation step to obtain
and classify tissue parameters. An expectation-maximization algo-
rithm then updates class labels and tissue parameters in order to
1034 NEUROLOGY 64 March (2 of 2) 2005
iterate toward the maximum likelihood estimates of a hidden
Markov, random field model. The model uses spatial proximity to
constrain the probability with which voxels of a given intensity
are estimated to belong to each tissue class.
Normalized volumes were computed as the proportion of all
voxels within the brain mask occupied by gray (nGM), white
(nWM), or gray plus white (nWBV, equivalent to 100 ⫺ %CSF)
voxels. The unit of normalized volume is percent, which repre-
sents the percentage of estimated TIV.
Test-retest measurement reliability. In order to estimate mea-
surement reliability, normalized volumes for the same person
were compared over two imaging sessions separated by a brief
interval, during which it is reasonable to assume minimal true
change. Twenty individuals contributed to the test-retest group
(young, n ⫽ 16; middle-aged, n ⫽ 1; older, n ⫽ 3), with a mean
delay of 21 days between test and retest (range 1 to 64 days). The
mean absolute percentage differences (MAPD, the absolute differ-
ence between test and retest volumes divided by the overall mean,
expressed in percent) were 0.92% for nGM (CI 0.53 to 1.30), 0.80%
for nWM (CI 0.5 to 1.1), and 0.49% for nWBV (CI 0.28 to 0.71).
The coefficients of variation (CV, the SD of the difference between
test and retest volumes divided by the overall mean, expressed in
percent) were 1.24% (nGM), 1.04% (nWM), and 0.68% (nWBV).
The interclass correlations between values paired by participant,
but randomly assigned to test or retest, were high (r[nGM] ⫽ 0.99,
r[nWM] ⫽ 0.98, and r[nWBV] ⫽ 0.99).
Cross-sectional analysis. Normalized volumes were plotted
against age for the 370 unique participants. Statistical analysis
was conducted with the JMP software package (SAS Institute,
Cary, NC). Hierarchical polynomial regression was used to test
between linear and curvilinear models of cross-sectional volume
as a function of age. With the sample restricted to one volume
measurement per nondemented individual, higher order terms of
the subject’s age at scan were tested until they no longer contrib-
uted significantly to the model; the resulting models are referred
to as the cross-sectional, nondemented aging curves. Normalized
volumes in the older DAT and older nondemented samples were
then compared using analysis of covariance with nGM, nWM, or
nWBV as the dependent measure and age, sex, and dementia
status as cofactors.
Longitudinal analysis. The longitudinal analysis was re-
stricted to the most reliable whole-brain data and sought to quan-
tify the whole-brain atrophy rate within older nondemented and
DAT individuals. Atrophy rate was computed as the slope of the
line connecting nWBV measurements within each individual, di-
vided by baseline nWBV, expressed as percent change per year.
For example, in a participant with two scans, atrophy rate was
computed as nWBV at scan 2 minus nWBV at scan 1, divided by
the interval between measurements, divided by nWBV at scan 1,
times 100. Analysis of covariance was again used to test for differ-
ences in atrophy rate based on age, sex, and dementia status.
Comparison of cross-sectional and longitudinal data. To com-
pare cross-sectional and longitudinal data, atrophy rate was esti-
mated from the cross-sectional, nondemented aging curve and

compared with the longitudinal, nondemented atrophy rate. Atro-
phy rate was estimated from the cross-sectional curve by express-
ing its slope as a percentage of nWBV at the mean age of the
older, nondemented sample (age ⫽ 78, nWBV ⫽ 74.8%). For
graphical comparison, trendlines were plotted for nondemented
and demented aging. The slope of the nondemented trendline, for
example, was determined by the mean atrophy rate of the nonde-
mented, longitudinal sample; the y-intercept was determined by
interpolating nWBV from the nondemented, cross-sectional sam-
ple (mean age ⫽ 81, nWBV ⫽ 74.1%; DAT trendline drawn equiv-
alently, mean age 78, nWBV ⫽ 72.0%; see figure 3).
Results. Cross-sectional. The cross-sectional dataset is
plotted in figures 2 and 3A and summarized in absolute
volumes without head-size normalization in table E-1 (on
the Neurology Web site at www.neurology.org). Nonde-
mented individuals between 18 and 95 years old exhibited
an age-associated decline in normalized gray matter (nGM;
r ⫽ ⫺0.91, F[1,270] ⫽ 1311.00, p ⬍ 0.001), white matter
(nWM; r ⫽ ⫺0.25, F[1,270] ⫽ 17.71, p ⬍ 0.001), and whole-
brain volume (nWBV; r ⫽ ⫺0.88, F[1,270] ⫽ 939.59, p ⬍
0.001). The age-by-volume correlation remained significant
when considering the age range of 18 to 30 for nGM (r ⫽
Figure 2. Cross-sectional plots of gray
and white matter, normalized for head
size. (A) Cross-sectional plot of normal-
ized gray matter (nGM) across the adult
lifespan; each data point represents a
unique participant from a single scan-
ning session. For participants with
follow-up data, the session with nearest-
in-time clinical data is used (see the ta-
ble). The best-fit polynomial regression is
drawn only for the nondemented individ-
uals (blue) and is represented by the
dashed line for women (55.1 ⫺
0.065[AGE] ⫺ 0.001[AGE2]) and the solid
line for men (54.4 ⫺ 0.076[AGE] ⫺
0.001[AGE2]). (B) Cross-sectional plot of
normalized white matter (nWM) across
the adult lifespan. The dashed line repre-
sents the nondemented, female regression
(30.4 ⫹ 0.089[AGE] ⫺ 0.001[AGE2]); the
solid line represents the nondemented,
male regression (30.3 ⫹ 0.100[AGE] ⫺
0.001[AGE2]). Note the inflection in the
nWM curves (around age 42 for men and
45 for women) and the greater separation
between nondemented and DAT individu-
als (red vs blue) in the nGM plot. DAT ⫽
dementia of the Alzheimer type.
⫺0.20, F[1,121] ⫽ 4.91, p ⬍ 0.05) and nWBV (r ⫽ ⫺0.19,
F[1,121] ⫽ 4.58, p ⬍ 0.05), but not for nWM (F ⬍ 1). Consid-
ering the full age range, adding a quadratic term improved
the models of nGM (F[2,269] ⫽ 681.24, p ⬍ 0.001, R2 ⫽ 0.84),
nWM (F[2,269] ⫽ 18.96, p ⬍ 0.001, ⫽ R2 ⫽ 0.12), and
nWBV (F[2,269] ⫽ 533.32, p ⬍ 0.001, R2 ⫽ 0.80). The
addition of a cubic term failed to add a significant effect for
any model (F ⬍ 1).
In addition to the cross-sectional, nondemented aging
curves, figures 2 and 3A illustrate that individuals with
DAT (CDR ⫽ 0.5 and 1) exhibited volume reduction dispro-
portionate to age. A full-factorial analysis of covariance on
the older sample with age, sex, and dementia status as
covariates was significant for nGM (F[7,184] ⫽ 20.79, p ⬍
0.001), nWM (F[7.184] ⫽ 3.14, p ⬍ 0.01), and nWBV
(F[7,184] ⫽ 19.80, p ⬍ 0.001), with main effects for all
three covariates. Post hoc testing indicated women had
more nGM (43.0% vs 42.2%, p ⫽ 0.051), nWM (30.9% vs
30.1%, p ⬍ 0.05), and nWBV (73.9% vs 72.3%, p ⬍ 0.01)
than men. The presence of DAT was associated with a
decrease in nGM (43.7% vs 41.7%, p ⬍ 0.001), nWM (31.1%
March (2 of 2) 2005 NEUROLOGY 64 1035

vs 30.2%, p ⬍ 0.05), and nWBV (74.7% vs 71.9%, p ⬍
0.001; figure 4A).
Longitudinal. The longitudinal dataset, obtained in
older adults, is plotted in figure 3B. The whole-brain atro-
phy rate in nondemented older adults was ⫺0.45% (SD ⫽
0.53) per year. The atrophy rate in age-matched individu-
als with DAT was ⫺0.98% (SD ⫽ 1.0) per year. A full-
factorial analysis of covariance with age, sex, and
dementia status at last scan as covariates, and atrophy
rate as the dependent measure, was significant (F[7,71] ⫽
2.16, p ⬍ 0.05), with a main effect for dementia status and
a significant interaction between age and dementia status.
The longitudinal, nondemented atrophy rate of ⫺0.45% per
year showed no correlation with age within the older sam-
ple (r ⫽ ⫺0.17, p ⫽ 0.30; see figure 4C) and closely
matched the atrophy rate estimated from the cross-
sectional, nondemented aging curve, which varied from
⫺0.31% to ⫺0.46% per year over the same age range.
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. Figure 4B compares
1036 NEUROLOGY 64 March (2 of 2) 2005
Figure 3. Cross-sectional and longitudi-
nal plots of whole-brain volume, normal-
ized for head size. (A) Cross-sectional plot
of normalized whole-brain volume
(nWBV) across the adult lifespan. The
line represents the best-fit polynomial re-
gression of all nondemented individuals
and is referred to as the cross-sectional,
nondemented aging curve (85.3 ⫹
0.013[AGE] ⫺ 0.002[AGE2]). (B) Longitu-
dinal plot of nWBV in older adults (note
scale change); lines connect nWBV at
baseline and follow-up scans (or the best
fit, for participants with multiple follow-
ups), such that the slope of each line as a
proportion of baseline nWBV represents
an individual’s atrophy rate. The slope of
the thick blue line represents the esti-
mated longitudinal rate of change for all
of the nondemented individuals and over-
laps with the slope of the cross-sectional,
nondemented aging curve (shown in
black). The slope of the thick red line rep-
resents the longitudinal rate of change
for all of the individuals with dementia
of the Alzheimer type (DAT) and suggests
accelerated volume loss in DAT. Lines
connected by blue triangles and red
squares represent individuals who con-
verted from a Clinical Dementia Rating
of 0 to 0.5 during the interscan interval;
they are included in the DAT mean.
the rate of atrophy in individuals based on their CDR
scores at first and last scan. The rate of those who started
with a CDR of 0 and declined (⫺0.88% per year, SD ⫽
0.60) matched the rate of those who started with CDR of
0.5 (⫺0.90% per year, SD ⫽ 0.74). Post hoc testing re-
vealed a trend toward a difference (t[41] ⫽ 3.03, p ⫽ 0.09)
between the nondemented group (CDR 0 3 0) and the
decliner group (CDR 0 3 0.5), although the small sample
size limited statistical power.
Discussion. 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. For the longitudinal sub-
set 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

Figure 4. Summary data. (A) Mean cross-sectional nor-
malized whole-brain volume (nWBV) for individuals 65
and over separated by Clinical Dementia Rating (CDR) (0,
0.5, and 1). All differences are significant. (B) Longitudi-
nal atrophy rates, expressed in nWBV loss per year rela-
tive to baseline, are separated by CDR status at first and
last session. Atrophy rate was significantly greater for the
group entering the experiment with very mild dementia
(CDR 0.5 3 0.5/1) than the group entering without de-
mentia that remained stable (CDR 0 3 0) and resembles
the rate for the group that manifested the earliest signs of
dementia of the Alzheimer type (DAT) during the experi-
ment (CDR 0 3 0.5), though we await confirmation in a
larger sample. (C) Individual atrophy rates are plotted vs
age, with the trendline drawn through the CDR 0 3 0.
year), indicating marked acceleration. These main
results are elaborated in terms of the three questions
posed in the introduction.
The cross-sectional, nondemented aging curve (see
quadratic regression, figure 3A) shows that nWBV
declined from 85% at age 20 to 74% at age 80, a
lifespan atrophy rate of 0.23% per year, in general
agreement with prior studies. Table E-2 (on the Neu-
rology Web site at www.neurology.org) summarizes
the results from 12 cross-sectional MR reports on
healthy aging that cover the adult lifespan and re-
port whole-brain or gray/white-matter estimates as a
percentage of head size. A number of other reports
are qualitatively similar, but employ quantitatively
distinct units that cannot be directly compared to the
present results.11,13,31–38 As the median of all esti-
mates shown in table E-2, nWBV declines from 89%
at age 20 to 78% at age 80 (median 0.23% per year
atrophy). Strong agreement with a recent
population-based, volumetric survey of 2,081 individ-
uals, age 34 to 97, argues in favor of the generaliz-
ability of this sample and these findings.39
Comparable pathologic estimates fall below the
range in table E-2; a quadratic regression of volu-
metric data from one such study suggests that across
the reference age range (20 to 80), brain volume as a
percentage of cranial cavity volume decreased from
92% to 85% (0.14% per year atrophy).6 This early
study employed a volumetric method involving fluid
displacement that did not account for ventricular
volume and likely overestimated brain volume and
underestimated atrophy.
In addition to quantifying the magnitude of vol-
ume decline, the present results converge with oth-
ers on a temporal sequence placing brain volume
reduction at or before the start of early adult-
hood.5,11–15 Whole-brain volume decline was signifi-
cant within the adult sample when it was restricted
to age 18 to 30, although greater volume reductions
were noted in the older adults as compared to the
young adults. The significant age correlation in this
youngest subset argues against a sample contami-
nated with preclinical AD (i.e., individuals with the
pathologic substrate of AD who are not yet suffi-
ciently impaired to be recognized clinically as de-
mented) as the only explanation for atrophy in
nondemented older populations.
A moderate acceleration of volume loss in nonde-
mented aging occurred in middle age, around the
inflection point of the nWM curve at age 44 (see
figure 2B). Similar downward inflections7,31 after a
period of white volume stability9,11,40,41 or possibly
growth10,12,14,42,43 during the third and fourth decades
have been attributed to the prolonged and heterochro-
nologic development of brain myelination.44 – 46 This de-
layed pattern of nWM loss (however, see references 37,
38, and 47) contrasts with the more linear course of
nGM decline throughout adulthood, potentially sug-
gesting separate age-related mechanisms for each.4
Sex effects were minimal in our results. For the
overall cross-sectional sample, which was not sex
balanced across age, men had approximately 12%
more brain volume than women prior to head-size
correction and 0.3% less after head-size correction.
March (2 of 2) 2005 NEUROLOGY 64 1037
The slightly more downward age-course in men than
women did not reach significance for nWBV, nGM, or
nWM, but tended in the same direction as reported
age-by-sex interactions.8,32,33,37,39 Main sex effects
from studies that report no age-by-sex interactions
can be compared with the present 0.3% normalized
volume difference: four12,40,47,48 report similar sex ef-
fects (female ⬎ male), three9,10,42 report no sex effect,
and three34,38,41 report sex effects in the opposite di-
rection (male ⬎ female). The small magnitude of any
true difference after head-size normalization, the
possibility of differential healthfulness between sex
cohorts, and methodologic differences likely contrib-
ute to inconsistent sex findings.
The longitudinal rate of whole-brain atrophy aver-
aged ⫺0.45% per year in the older, nondemented
sample. At least seven prior studies have quantified
longitudinal, whole-brain volume change in nonde-
mented individuals over a comparable age range.
Six18,42,48 –51 have documented annualized rates of
about ⫺0.5% (⫺0.37 to ⫺0.88), comparable to the
present finding, whereas one52 reported a rate of
⫺2.1%.4 Differences in inclusion/exclusion criteria,
scan resolution, and MRI maintenance may explain
the divergence of the latter study.
Returning to the present findings, the overlap be-
tween the longitudinal atrophy rate in nondemented
individuals (⫺0.45%) and the cross-sectional esti-
mate (⫺0.31 to ⫺0.46%) for the 65 through 95 age
range demonstrates excellent agreement. In addi-
tion, longitudinal reports covering the young adult
age range5,42 find slower atrophy rates than in this
older, longitudinal sample, suggesting that the trend
toward accelerated atrophy with age in figure 4C
might reach significance with wider longitudinal sam-
pling or increased sample size. Together, our results
indicate that secular effects and other confounds mini-
mally influence cross-sectional, whole-brain volume es-
timates. For instance, if developmental conditions
varied among sampled age cohorts, such that people
born in more recent years tended to have increased
brain volume in proportion to head size than people
born in earlier years, we would expect the slope of
the cross-sectional aging curve to exceed the longitu-
dinal slope. A difference might similarly result if
aging mechanisms were idiosyncratic and either the
longitudinal rates formed a multimodal distribution
or sampling characteristics differed among the longi-
tudinal and cross-sectional cohorts. Instead, the ob-
served agreement suggests that the brain loses
volume with age according to uniform and predict-
able, though largely unknown, mechanisms.48
It is established that individuals with DAT exhibit
decreased brain volume relative to their nondemented
peers, with the underlying pathology prominent in re-
gions within the medial temporal lobe.53–55 MRI studies
have detected accelerated global and regional volume
change in DAT.3,56 In addition, comparing nonde-
mented aging with DAT in figure 2 tentatively sug-
gests that gray matter is more vulnerable than white
matter to very mild to mild AD pathology.51
1038 NEUROLOGY 64 March (2 of 2) 2005
Our longitudinal data indicate a ⫺0.98% per year
whole-brain atrophy rate in the earliest stages of
DAT (CDR 0.5). This rate can be directly compared
to recent estimates for nondemented individuals who
converted to DAT during follow-up (⫺0.8%) and
those with slow-progressing (⫺0.6%) and fast-
progressing (⫺1.4%) DAT at baseline.18 Faster
whole-brain atrophy rates (⫺5.2%51 and ⫺2.4%57)
have been reported in smaller cohorts with more ad-
vanced AD (baseline MMSEs ⬍ 20). Other estimates
of longitudinal whole-brain change in DAT derive
from the brain-boundary shift integral (BBSI), which
models boundary changes in serially registered
scans.58 With at least one exception,16 atrophy rate
estimates based on the BBSI have exceeded ⫺2% per
year,17,58 for example, a ⫺2.37% BBSI atrophy rate in
54 DAT patients.49 Divergence in longitudinal atro-
phy rates may reflect differences in atrophy mea-
surements and DAT cohorts; the DAT sample
yielding the ⫺2.37% estimate had a lower age (61 vs
79) and MMSE (20 vs 26) than in the present study
and included early onset and familial cases.
Providing evidence that the specific DAT sample
represents an important factor, in a sample of 5 “pre-
clinical” familial cases followed during their conver-
sion to DAT, the atrophy rate was found to be
⫺1.23% per year using the BBSI and ⫺1.08% per
year using TIV correction, very similar to the rates
reported here.59 The estimates here and in the liter-
ature suggest that nonfamilial, late-onset DAT is
characterized by at least a 1% per year volume loss
in its earliest clinical presentation with acceleration
as the disease progresses.17 This initial rate of brain
volume loss represents a doubling from that of non-
demented individuals.
Our results tentatively suggest that accelerated
loss in whole-brain volume may begin in the preclin-
ical phase of AD.60 In particular, the small sample of
nondemented individuals who declined over the
course of our observation period showed accelerated
atrophy rates similar to the individuals with very
mild DAT at baseline. The reliability, cross-sectional
validity, and sensitivity to clinical progression of au-
tomated whole-brain measures such as nWBV, com-
bined with their potential to detect preclinical AD,
highlights the promise of global volumetric
biomarkers.18
Acknowledgment
The authors thank the Washington University ADRC and the
Conte Center for clinical assistance and participant recruitment,
Elizabeth Grant for database assistance, Chengjie Xiong for dis-
cussion of statistical procedures, Daniel Marcus for database de-
velopment and support, and Susan Larson, Amy Sanders, and
Glenn Foster for assistance with MRI data collection.
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