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Age-Related Changes in Frontal and Temporal Lobe Volumes in Men
A Magnetic Resonance Imaging Study
George Bartzokis, MD;
Mace Beckson, MD;
Po H. Lu, MA;
Keith H. Nuechterlein, PhD;
Nancy Edwards, MA;
Jim Mintz, PhD
Arch Gen Psychiatry. 2001;58:461-465.
ABSTRACT
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Background Imaging and postmortem studies provide converging evidence that, beginning
in adolescence, gray matter volume declines linearly until old age, while
cerebrospinal fluid volumes are stable in adulthood (age 20-50 years). Given
the fixed volume of the cranium in adulthood, it is surprising that most studies
observe no white matter volume expansion after approximately age 20 years.
We examined the effects of the aging process on the frontal and temporal lobes.
Methods Seventy healthy adult men aged 19 to 76 years underwent magnetic resonance
imaging. Coronal images focused on the frontal and temporal lobes were acquired
using pulse sequences that maximized gray vs white matter contrast. The volumes
of total frontal and temporal lobes as well as the gray and white matter subcomponents
were evaluated.
Results Age-related linear loss in gray matter volume in both frontal (r = -0.62, P<.001) and
temporal (r = -0.48, P<.001)
lobes was confirmed. However, the quadratic function best represented the
relationship between age and white matter volume in the frontal (P<.001) and temporal (P<.001) lobes.
Secondary analyses indicated that white matter volume increased until age
44 years for the frontal lobes and age 47 years for the temporal lobes and
then declined.
Conclusions The changes in white matter suggest that the adult brain is in a constant
state of change roughly defined as periods of maturation continuing into the
fifth decade of life followed by degeneration. Pathological states that interfere
with such maturational processes could result in neurodevelopmental arrests
in adulthood.
INTRODUCTION
BRAIN MORPHOMETRY undergoes profound changes throughout the life span.
Cross-sectional studies examining brain development in children and adolescents
demonstrate increasing white matter volume and decreasing gray matter volume
in later childhood and early adolescence.1, 2, 3, 4
These findings were recently confirmed in a prospective magnetic resonance
imaging (MRI) study of brain development that demonstrated that white matter
volume increases linearly between ages 4 to 20 years,4
a period characterized by increased myelination and axonal growth.5 Unlike the white matter changes, cortical gray matter
changes were quadratic rather than linear and exhibited region-specific patterns
of change within this age span. Gray matter reached maximum volume at approximately
age 12 years in the frontal lobes but not until age 16 years in the temporal
lobes; after these ages, gray matter volumes decreased.4
Postmortem data indicate that the pattern exhibited by gray matter is
representative of brain maturation. This process initially involves cell growth,
arborization, synaptogenesis, and cell proliferation, followed by neuronal
pruning, resulting in an elimination of 40% of cortical synapses from the
maximum childhood level to adult level and further decline in old age.6, 7 Imaging studies confirm that after
adolescence, cortical gray matter volume continues to decrease linearly throughout
the life span.3, 8, 9, 10, 11, 12, 13
Postmortem data suggest that this decrease is primarily a result of large
neuron shrinkage with minimal if any neuronal cell loss before age 55 years.14, 15, 16
Imaging studies of normal adult aging (aged  18 years) consistently
show age-related enlargement of cerebrospinal fluid (CSF) spaces and the reciprocal
reduction of total cerebral brain volume.3, 11, 12, 17, 18
These age-related changes are curvilinear, with cortical and ventricular CSF
compartments remaining relatively stable up to age 40 to 50 years and subsequently
undergoing steep volume expansion.3, 11
Even though gray matter volume loss begins in mid adolescence, CSF and
total cerebral brain volume remain stable until age 40 to 50 years.3, 11, 13 It is therefore logical
to postulate that other tissues, namely the white matter, should undergo concomitant
expansion, similar in proportion to the gray matter loss, to maintain stable
total cerebral and CSF volumes throughout early and middle adulthood. This
white matter volume increase has yet to be demonstrated at the whole brain
or lobar anatomic level. In fact, existing imaging studies consistently report
that white matter volume remains constant into the seventh decade, unaffected
by the aging process.3, 8, 9, 10, 11, 12, 13
The failure of imaging studies to detect age-related white matter volume
increase in adulthood may be accounted for by methodological issues. These
include the use of axial images aimed at studying the brain in its entirety3, 8, 9, 10, 13, 17, 18, 19
rather than focusing on frontal and temporal lobes, which complete maturational
changes later than the occipital lobe5, 6, 7
and are involved in behavioral plasticity and continued brain development.14, 15, 16, 20, 21, 22
In addition, the use of automated procedures for gray and white matter segmentation
and suboptimal contrast can contribute to misclassification of tissues,3, 8, 9, 10, 11, 13, 23
and slice thickness greater than 3 mm can increase partial volume effects.3, 8, 9, 10, 13, 17
The current study addresses these methodological concerns and focuses
on examining the effects of the aging process on the frontal and temporal
lobes. These structures continue maturing and developing (as defined by continued
myelination) into the fourth and fifth decade5
and are clearly implicated in many age-related neuropsychiatric diseases such
as schizophrenia and Alzheimer disease.
SUBJECTS AND METHODS
SUBJECTS
Seventy healthy men aged 19 to 76 years were recruited from community
volunteers. Each subject completed a clinical interview based on written standardized
questions and administered by an experienced clinician-investigator (G.B.)
to assess the history of medical, psychiatric, and substance dependence disorders.
Selection criteria were as follows: no evidence of meaningful current or past
psychiatric diagnosis or substance dependence based on DSM-IV criteria; no meaningful use of drugs or alcohol in the past
year (amount of use did not meet DSM-IV criteria
for substance dependence or abuse); no history or gross evidence of central
nervous system impairment or any history of neurologic disorder (head trauma
with loss of consciousness for >15 minutes); no history of chronic medical
conditions likely to result in structural brain abnormalities (ie, stroke,
transient ischemic attack, seizures, hypertension, diabetes); and self-report
that no first-degree relatives have been treated for a major psychiatric disorder.
These criteria excluded 3 subjects with a history of head trauma. One additional
subject was excluded from analysis because he was a statistical outlier on
the temporal lobe volume measure (>4 SDs greater than the mean of the other
subjects). The remaining 70 participants averaged 38.6 years in age (SD, 15.6
years), 16.8 years of education (SD, 2.5 years; range, 12-22 years), and the
ethnic composition comprised 44 white men, 15 African American men, 2 Hispanic
men, and 9 Asian men. All subjects provided written informed consent approved
by the local institutional review board prior to study participation.
MAGNETIC RESONANCE IMAGING PROTOCOL
The MRI examination used a 1.5-T instrument using previously published
methods.24 In brief, a coronal pilot sequence
was used to align a sagittal MRI pilot sequence. The sagittal pilot sequence
was then used to specify the position of the coronal image acquisition grid.
The sagittal image containing the left hippocampus was used to define an oblique
coronal acquisition plane perpendicular to the hippocampus. Two coronal sequences
of the same brain slices were acquired: a transverse asymmetric dual spin
echo Carr-Purcell-Meiboom-Gill sequence (repetition time, 2500 milliseconds;
echo times, 30 and 90 milliseconds) and an inversion recovery (IR) sequence
(repetition time, 2500 milliseconds; inversion time, 600 milliseconds; echo
time, 30 milliseconds). Both sequences had 2 repetitions, 256 x 192
view matrix, 25-cm field of view, and produced coregistered 3-mm thick contiguous
slices. These images provide excellent multiparameter visualization of the
frontal and temporal lobes. The IR sequences provide the maximum gray vs white
matter contrast available with MRI, improving the identification and quantification
of these tissues.
IMAGE ANALYSIS
Imaging measures were obtained using an image workstation that read
compact disks containing the original MRI data stored in digital format. Two
raters who were blind to the clinical data quantified the frontal and temporal
lobe regions of interest (ROI) using previously published methods.24
The raters, using a calculated T2 image derived from the spin echo sequence,
manually traced a rough contour surrounding the brain by maintaining the cursor
on the bright CSF pixels and cutting through the brain to exclude subcortical
gray and white matter and insular cortex (Figure 1). All pixels with T2 values in the CSF range (T2 >130 milliseconds)
were then eliminated from the image using the "shrink image" function of the
software. Thus, the resulting ROI contained only brain pixels. Once the brain
ROI was quantified, it was pasted onto the IR image (depicted as the outside
[brain/CSF] border in Figure 1).
Then, the pixel intensities of the IR image were displayed in histogram form,
and the gray matter histogram peak was eliminated. The resulting measure was
the white matter area (depicted as the inside [gray/white] border in Figure 1). The gray matter area was obtained
by subtracting the white matter area of each lobe from the total lobe area.
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Figure 1. Oblique coronal inversion recovery
image with drawings of frontal and temporal lobe gray matter and white matter
regions of interest (ROI). The frontal and temporal lobe ROI are separated
from the rest of the brain by linear cuts through the brain matter: medially,
bisecting the corpus callosum; and laterally, from the superior fundus of
the circular sulcus of the insula to the most superior and lateral point of
the lateral ventricles, and from the inferior fundus of the circular sulcus
of the insula through the temporal lobe stalk to the cerebrospinal fluid of
the temporal horn.
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A contiguous 7-slice volume centered on the anterior commissure was
used for data quantification. Volumes were computed by summing the products
of each cross-sectional area with the slice thickness. Test-retest reliabilities
for the ROI were good; the intraclass reliability coefficients (rxx) were 0.85 and 0.86 for total temporal and frontal lobe
volumes, respectively, and 0.82 and 0.90 for the temporal and frontal white
matter, respectively.24 Interrater reliabilities
between the 2 raters were also high with intraclass reliability coefficients
(rxx) of 0.99 and 0.98 for total temporal
and frontal lobe volumes, respectively, and 0.84 and 0.92 for frontal and
temporal white matter volumes, respectively. Because gray matter volume is
a calculated value based on total and white matter volume, reliability coefficients
were not calculated for this brain variable.
STATISTICAL ANALYSIS
Linear and nonlinear relationships between age and brain structural
volumes were examined with Pearson product moment correlation analyses and
hierarchical polynomial regression analyses. Height was statistically controlled
as a partial variable and introduced into all the analyses to adjust for variations
in body size on the brain and its regions and control for the "secular effect"
(the progressive trend toward increased body height and brain weight in the
20th century). To compare whether the peak of the quadratic age regression
curves differed between 2 regions, a bootstrap replication analysis was employed.25 One thousand bootstrap replication samples were created
to serve as a sampling reference, and each replication was an individual random
draw of 70 cases from the sample. All tests were 2-tailed, and the 
level of significance was .05.
RESULTS
Examination of brain structural changes in men aged 19 to 76 years revealed
significant linear age-related decreases in both frontal and temporal lobe
volumes (r = -0.43, P<.001
and r = -0.35, P =
.003, respectively). Segmenting the frontal and temporal lobes into cortical
gray and white matter tissues revealed a significant linear decline in gray
matter with age in both frontal (r = -0.62, P<.001) and temporal (r = -0.48, P<.001) lobes. These results are consistent with prior
reports on brain volume changes with normal aging.3, 8, 9, 10, 11, 12
White matter volume did not exhibit a linear association with age in
either region (P>.48). In fact, the quadratic function
of the polynomial regression approach emerged as the best representation of
the relationship between age and white matter volume changes in both frontal
(P<.001) and temporal (P<.001)
lobes (Figure 2). All the analyses
were repeated, controlling for education and ethnicity to ensure that the
observed changes in brain tissue matter were not better accounted for by other
demographic characteristics, but adjusting for these 2 potential confounding
variables did not meaningfully alter any of the results.
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Figure 2. Regression of frontal (A) and
temporal (B) lobe white matter volume on age in a sample of 70 normal adult
men.
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The age at which the white matter tissue reaches maximum volume, derived
from the quadratic curves, was calculated to be 44.6 years for the frontal
lobes and 47.5 years for the temporal lobes. A bootstrap replication analysis25 confirmed that maximum white matter volume is reached
at a later age in the temporal lobe vs the frontal (P
= .01).
Since this is the first report, to our knowledge, to demonstrate gross
increases in white matter volume after age 20 years, secondary follow-up analyses
were conducted to investigate the age-related brain tissue changes in younger
adults. This sample consisted of the youngest 52 subjects younger than the
age at which maximum white matter volumes are reached. In the frontal lobes,
significant age-associated loss in gray matter was observed (r = -0.34, P = .01) with concurrent
significant increase in white matter tissue (r =
0.52, P<.001), while total frontal lobe volume
remained unchanged (r = 0.20, P = .16). Temporal lobe gray matter volume demonstrated a negative
trend with age (r = -0.23, P = .10) and temporal white matter volume increased significantly with
age (r = 0.53, P<.001).
As with the frontal lobes, the opposing gray and white matter volume changes
canceled each other, resulting in no age-related change in total temporal
lobe volume (r = 0.09, P
= .52).
COMMENT
The most striking observation of the current study is the quadratic
age-related pattern of white matter volume changes (Figure 2). Contrary to previously published imaging studies reporting
static white matter volume after adolescence,3, 8, 9, 10, 11, 12, 13
the data suggest that white matter volumes of frontal and temporal lobes continue
to increase into the fifth decade and decline thereafter. The rate and pattern
of white matter change seems to be regionally specific as it reaches peak
volume at about age 44 years in the frontal lobes and age 47 years in the
temporal lobes. The regionally specific pattern of white matter development
in adulthood is similar in temporal order and magnitude to the regionally
specific pattern of gray matter volume expansion and contraction occurring
in childhood and adolescence.4 This temporally
parallel pattern observed in the 2 lobes suggests a maturational continuum
between the gray matter volume peaks occurring in adolescence and the white
matter peaks occurring in midlife.
Several limitations of our study must be acknowledged prior to further
interpretation. First, only data from men were presented, and the educational
attainment of the participants exceeds usual norms; therefore, the results
cannot be generalized to women or less-educated groups. Second, the sample
of this cross-sectional study was not derived using random selection from
the normative population; therefore, interpretation of the observed age-related
differences between age group means as "changes" or "increases" must be made
with caution.26 For simplicity and ease of
conceptualization, the results are discussed as changes or increases over
time; however, conclusions regarding the developmental course of the changes
and their application to individuals will need further definition through
longitudinal studies. Third, the brain variables were analyzed without examining
for left-right asymmetry. Finally, the volume measures were obtained on only
a sample of the total frontal and temporal lobes and cannot be generalized
to the entire brain. However, the specificity of the regions quantified maximizes
the inclusion of the frontal and temporal neurocortical zones (regions Yakovlev
and Lecours5[p49] referred to as the supralimbic
and paralimbic zones) involved in continued maturation into middle age and
excludes areas (internal capsule and subcortical gray matter) that are postulated
to complete the myelination cycle by the third decade.5
The cortex undergoes profound changes with aging, consisting primarily
of shrinkage of large neurons and increase in the proportion of small neurons,14, 15, 16 visualized in this
and other studies3, 8, 9, 10, 11, 12, 13
as a reduction in the volume of cortical gray matter (Figure 3). Frontal and temporal lobe white matter volume expansion
into the fifth decade suggests an increase of myelination and/or interconnectivity
of these lobes. Postmortem studies have shown that associative neocortex of
the human frontal and temporal cortices continues to develop (as judged by
continued myelination of the white matter of these regions) up to the fifth
decade and beyond,5, 27, 28
suggesting that after this age, degenerative processes may cancel out any
myelination-related white matter volume increase on MRI. An increase in myelination
and/or interconnectivity could facilitate the synchronous integration of information
across the many spatially segregated associative neocortex regions involved
in higher cognitive functions.21, 22
The speed of neural transmission depends on the structural properties of the
connecting fibers, including axon diameter and the thickness of the insulating
myelin sheath.29
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Figure 3. Regression of frontal (A) and
temporal (B) lobe gray matter volume on age in a sample of 70 normal adult
men.
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The present in vivo evidence of increasing white matter volume with
age in the frontal and temporal lobes supports the concept of continued brain
maturation into the fifth decade. The results could be analogized to the Internet
phenomenon in which increasing computer interconnectivity and/or accelerated
speed of connections facilitate an increase in capacity and utility. The development
of better emotional regulation, response inhibition, and possibly the concept
of wisdom commonly associated with the mid- and late-life periods30, 31 may be manifestations of this quantifiable
brain maturation process. This interpretation suggests that the brain could
experience neurodevelopmental arrest, even in adulthood, if pathological states
(eg, brain trauma, schizophrenia, severe stress, substance abuse) alter the
normal age-related pattern of structural changes. Finally, the data suggest
that during the life span, the brain is in a constant state of change roughly
defined as periods of development and maturation followed by degeneration
and that, biologically speaking, the societal concept of a stable or unchanging
adult brain may not be valid.
AUTHOR INFORMATION
Accepted for publication December 21, 2000.
This work was supported by the Research and Psychiatry Services of the
Department of Veterans Affairs, the National Alliance for Research on Schizophrenia
and Depression (Dr Bartzokis), National Institutes of Mental Health grants
MH-51928 (Dr Bartzokis) and MH-37705 (Dr Nuechterlein), the Medication Development
Division of the National Institute on Drug Abuse (1YO1 DA 50038), and the
Marie Wilson Howells Endowment, University of Arkansas for Medical Sciences,
Little Rock (Dr Bartzokis).
The authors thank Sun Sook Hwang, MS, for statistical support and Yolanda
Yamat, BA, for technical assistance.
From the Department of Psychiatry, University of Arkansas for Medical
Sciences (Dr Bartzokis and Mr Lu), and the Mental Health Service Line, Central
Arkansas Veterans Healthcare System (Dr Bartzokis), Little Rock; the Greater
Los Angeles VA Healthcare System, West Los Angeles, Calif (Drs Bartzokis,
Beckson, and Mintz, Mr Lu, and Ms Edwards); and the Department of Psychiatry,
University of California, Los Angeles (Drs Bartzokis, Beckson, Nuechterlein,
and Mintz and Ms Edwards).
Corresponding author and reprints: George Bartzokis, MD, Central
Arkansas Veterans Healthcare System, 2200 Fort Roots Dr, Bldg 170, (116A/NLR),
North Little Rock, AR 72114 (e-mail: gbar{at}ucla.edu).
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Br. J. Psychiatry 2004;184:468-469.
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From the Cover: Dynamic mapping of human cortical development during childhood through early adulthood
Gogtay et al.
Proc. Natl. Acad. Sci. USA 2004;101:8174-8179.
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Cognitive Correlates of White Matter Growth and Stress Hormones in Female Squirrel Monkey Adults
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J. Neurosci. 2004;24:3655-3662.
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Progressive Structural Brain Abnormalities and Their Relationship to Clinical Outcome: A Longitudinal Magnetic Resonance Imaging Study Early in Schizophrenia
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Arch Gen Psychiatry 2003;60:585-594.
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White Matter Changes in Schizophrenia: Evidence for Myelin-Related Dysfunction
Davis et al.
Arch Gen Psychiatry 2003;60:443-456.
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White Matter Structural Integrity in Healthy Aging Adults and Patients With Alzheimer Disease: A Magnetic Resonance Imaging Study
Bartzokis et al.
Arch Neurol 2003;60:393-398.
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Brain Volume Changes in First-Episode Schizophrenia: A 1-Year Follow-up Study
Cahn et al.
Arch Gen Psychiatry 2002;59:1002-1010.
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Age-Related Total Gray Matter and White Matter Changes in Normal Adult Brain. Part I: Volumetric MR Imaging Analysis
Ge et al.
Am. J. Neuroradiol. 2002;23:1327-1333.
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Temporal lobe volume changes in people at high risk of schizophrenia with psychotic symptoms
LAWRIE et al.
Br. J. Psychiatry 2002;181:138-143.
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Brain Volumes and Surface Morphology in Monozygotic Twins
White et al.
Cereb Cortex 2002;12:486-493.
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Temporal Lobe Morphology in Normal Aging and Traumatic Brain Injury
Bigler et al.
Am. J. Neuroradiol. 2002;23:255-266.
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