volume decline associated with aging, alzheimer’s disease, and socioeconomic status: structural...

WASHINGTON UNIVERSITY

Division of Biology and Biomedical Sciences

Program in Neurosciences

Dissertation Examination Committee: Randy Buckner, Chair

Denise Head John Morris Joseph Price

Bradley Schlaggar David Van Essen

VOLUME DECLINE ASSOCIATED WITH AGING, ALZHEIMER’S DISEASE, AND SOCIOECONOMIC STATUS:

STRUCTURAL NEUROIMAGING ACROSS THE ADULT LIFE-SPAN

by

Anthony Frank Fotenos

A dissertation presented to the Graduate School of Arts and Sciences

of Washington University in partial fulfillment of the

requirements for the degree of Doctor of Philosophy

May 2008

Saint Louis, Missouri

ACKNOWLEDGEMENTS

Washington University has built its reputation on a foundation I have come to

learn is rock solid: a community of inspiring people. I am fortunate to be surrounded by

such people, both at the University and at home, and many have contributed to this thesis.

Starting with the older adult volunteers in our neuroimaging experiments, their wisdom

and service have led me to wonder about all the positive aspects of lifelong development

and not just to fear growing old. From the staff of the Alzheimer Disease Research Center

(ADRC) responsible for pooling so many of these generous participants, I want to thank

Amy Buckley, Virginia Buckles, and Mary Coats for clinical assistance and participant

recruitment; Elizabeth Grant for database assistance; and Chengjie Xiong, David

Johnson, and Cathy Roe for discussion of statistical procedures. I am grateful to Bruce

Fischl, Anders Dale, Xiao Han, Rudolph Pienaar, Brian Quinn, and Andre van der

Kouwe from the Martinos Center for Biomedical Imaging in Boston for collaborating on

the application of their innovative magnetic resonance sequence. Within the Cognitive

Neuroscience and Neuroimaging Labs, I thank Daniel Marcus, Mohana Ramaratnam, and

Tim Olsen for database development and support; Dana Sacco, Erin Laciny, Jamie

Parker, Susan Larson, Kate O'Brien, Laura Williams, Amy Sanders, and Glenn Foster for

assistance with MRI and PET data collection; and my labmates, Luigi Maccotta, Ted

Satterthwaite, and Ben Shannon, for serving as friendly and stimulating neighbors. Based

on my invariably positive interactions with the staff of the University’s graduate

programs, I appreciate how Brian Sullivan, Andrew Richards, Christy Durbin, Sally

ii

Vogt, and Anna Cook-Linsenman (formerly of the Buckner lab) keep everyone

humming.

I am especially grateful that Washington University provides faculty leaders

whom I have learned from, emulate, and can look up towards with admiration and

gratitude. Denise Head, Daniel Goldberg, Martha Storandt, Mark Mintun, John Morris,

Joel Price, Brad Schlaggar, Martha Storandt, Avi Snyder, and David Van Essen are all

exemplary scientists, who have shared their expertise generously with me as mentors. No

one sets a higher standard than my advisor, Randy Buckner, who has given selflessly of

his resources and shown by example how to think and work productively to advance our

understanding of the brain. “What would Randy do?” has already become and I am sure

will continue to serve as a refrain helping to guide me throughout my career.

Finally, I acknowledge my grandparents, Kal, Frank, Max, and Miriam; my

parents, Jim and Carol; my beloved wife, Saori; and my children, Naomi and Noah. The

love and joy we share brings life to my life.

iii

TABLE OF CONTENTS

Acknowledgements………………………………………………………………….. ii

Table of Contents……………………………………………………………………. iv

List of Figures……………………………………………………………………….. v

List of Tables………………………………………………………………………… vi

Abstract…………………………………………………………………………........ vii

Chapter 1: Introduction, Background, and Significance…………………………. 1

Chapter 2: Normative Estimates of Cross-Sectional And Longitudinal Brain

Volume Decline In Aging and AD…………………………………… 15

Chapter 3: Summary Of Three-Month Study to Discriminate Atrophy In AD

from Nondemented Aging……………………………………………. 42

Chapter 4: Brain Volume Decline In Aging: Evidence For A Relationship

Between SES, Preclinical AD, And Reserve…………………………. 52

Chapter 5: General Discussion…………………………………………………… 82

iv

LIST OF FIGURES

Figure 1.1 Age extrapolation issues and synapse estimates…...………………… 4

Figure 1.2 Longitudinal time-courses of normal brain volume decline………….. 7

Figure 2.1 Whole-brain volume measurement and normalization procedure……. 23

Figure 2.2 Cross-sectional plots of gray and white matter, normalized for head

size …………………………………………………………………… 27

Figure 2.3 Cross-sectional and longitudinal plots of whole-brain volume,

normalized for head size……………………………………………… 30

Figure 2.4 Summary data………………………………………………………… 32

Figure 3.1 Multi-echo FLASH (MEF) imaging from one older adult participant.. 44

Figure 3.2 Post-processing and null results for three-month discrimination with

multi-echo FLASH (MEF)…………………………………………… 48

Figure 4.1 Cross-sectional plot of brain volume in nondemented adults over the

adult life-span………………………………………………………… 69

Figure 4.2 Cross-sectional and longitudinal plots of brain volume as a function

of socioeconomic status………………………………………………. 71

Figure 4.3 Adjusted whole brain volume by PIB status…………………………. 75

Figure 4.4 The relationship between adjusted whole brain volume and SES is

stronger in nondemented participants who subsequently develop

dementia……………………………………………………………… 76

Figure 5.1 Thesis results within a multiple factor framework of brain aging…… 83

v

LIST OF TABLES

Table 2.1 Sample characteristics………………………………………………... 20

Table 2.2 Estimated gray, white, and whole-brain volume (WBV) by age

decade in nondemented individuals…………………………………... 29

Table 2.3 Comparative whole-brain estimates from cross-sectional, MR studies 36

Table 3.1 Longitudinal sample with complete baseline and follow-up MEF

images………………………………………………………………… 43

Table 4.1 MRI sample…………………………………………………………... 61

Table 4.2 PIB amyloid imaging sample………………………………………… 66

vi

ABSTRACT OF THE DISSERTATION

Volume Decline Associated with Aging, Alzheimer’s Disease, and Socioeconomic Status: Structural Neuroimaging across the Adult Life-span

by

Anthony Frank Fotenos

Doctor of Philosophy in Biology and Biomedical Sciences (Neurosciences)

Washington University in St. Louis, 2006

Professor Randy Buckner, Chair

This thesis concerns the neurodegeneration in the most burdensome

neurodegenerative disease, Alzheimer’s (AD). A unifying aim is to clarify how

neurodegeneration in AD relates to aging (a risk factor for AD) and socioeconomic status

(SES, a protective factor for AD). Three quantitative structural magnetic resonance

imaging (MRI) studies toward this goal are described. The first study characterized cross-

sectional and longitudinal rates of whole brain volume decline in nondemented adults and

compared these normal rates to atrophy measured early in symptomatic AD. The results

based on cross-sectional and longitudinal measures overlapped and showed that

nondemented aging is accompanied by steady volume decline even in the youngest

adults, with marked acceleration in the earliest stages of dementia.

Standard imaging methods used in this initial study required almost two years of

follow-up to discriminate between longitudinal change in demented and nondemented

samples. The second study aimed to reduce this follow-up interval to a more clinically

vii

practical three months, principally through the implementation of recently developed

multi-echo fast low-angle shot (MEF) MR sequences. Null results for this three-month

study are summarized.

The third study derived from the initial finding of brain aging in the absence of

dementia. SES is one factor known to protect against dementia incidence. We found that

older adults with high SES have reduced brain volume (cross-sectional result) and more

rapid volume loss (longitudinal result) than less privileged peers. Additional findings

based on amyloid imaging with positron emission tomography (PET) and clinical follow-

up suggest that the capacity of individuals with high SES to cope longer with preclinical

AD pathology, consistent with the reserve hypothesis, may help to explain these

counterintuitive main results. Implications of this thesis research and possible future

directions are discussed within the context of a multiple factor framework of brain aging.

viii

CHAPTER 1

INTRODUCTION, BACKGROUND, AND SIGNIFICANCE

Life-span brain morphometry. In 1907, Alois Alzheimer linked brain atrophy with a new

disease that would come to bear his name (AD). He wrote in his case report on Auguste

D., “The post-mortem showed an evenly atrophic brain without macroscopic focal

degeneration…Only a tangle of fibrils indicates the place where a neuron was previously

located…Many neurons, especially the ones in the upper layer, have completely

disappeared” (Alzheimer et al., 1995). In the same report, Alzheimer also identified

widespread “miliary foci,” since recognized as β-amyloid (Aβ) plaques (Glenner and

Wong 1984, Masters et al., 1985). Today, an emerging hypothesis regarding AD

pathogenesis arranges Aβ and neurofibrillary tangles (NFTs) in a cascade leading to

neuronal degeneration, atrophy, and dementia (Hardy and Selkoe 2002, Walsh and

Selkoe 2004). Other models start differently (for example, Lee et al., 2004, de la Torre

2004), but they end the same, with at least three related implications for structural

neuroimaging, the method on which this thesis is based. First, given the link between AD

pathogenesis and atrophy, neuroimaging offers a noninvasive opportunity to measure AD

damage at the macroscopic structural level (Jack et al., 2002, Silbert et al., 2003,

Csernansky et al., 2004). Second, curing AD pathogenesis in advanced dementia might

arrest patients in a state of neurodegeneration and permanent dysfunction. Structural

neuroimaging is thus increasingly oriented toward early disease detection (DeKosky and

Marek 2003, Glodzik-Sobanska et al., 2005). Third, early detection of AD-dependent

1

structural change requires careful comparison to normal brain morphometry (Giedd 2004,

Raz 2004). I will accordingly begin with an overview of normal brain aging, and then

turn to a discussion of AD, morphometric methods, and possible modifiers as background

and motivation for the thesis research discussed in Chapters 2-5.

This thesis samples over an extended period of human adulthood from 18 to 97.

Within this age range, older adults (≥ 65) account for a growing proportion of the

developed world’s population and carry the heaviest burden of chronic disease (Goulding

et al., 2003). Aging research thus tends to focus on older adults. Does the structure of

their brains normally differ from that of younger adults (~18-44)? Starting at the cellular

level, in terms of neuron number, the emerging consensus favors overall stability (<10%

decline between age 20 and 90; Haug et al., 1984, Pakkenberg et al., 2003), with limited

areas of age-related loss (for example, in the substantia nigra; reviewed in Morrison and

Hof 1997, Turlejski and Djavadian 2002). Preliminary data also suggest minimal loss

with age in the number of glia (Pakkenberg et al., 2003). In contrast to the numerical size

stability of neurons, dendritic spine counts and spine density estimates are markedly

reduced in the old (for example, over 40% less in apical dendrites of layer III pyramidal

neurons around the superior temporal sulcus; Duan et al., 2003; reviewed in Uylings and

de Brabander 2002). Consistent with cortical spine loss, synapse (specifically, input)

elimination has been demonstrated in the parasympathetic ganglion of the aged mouse

(Coggan et al., 2004). Subcortically, in white matter, autopsy studies have increasingly

focused on extensive fiber loss, especially of small myelinated fibers; neuropathological

estimates of adult-span white volume decline run as high as 25% (Pakkenberg et al.,

2

2003, Svennerholm et al., 1997), and these may underestimate fiber loss, which appears

to decline exponentially with age (Marner et al., 2003). This pattern of late acceleration,

associated ultrastructural abnormalities, and the unique ischemic vulnerability of

oligodendrocytes all point to the possibility that microscopic white matter lesions

represent a distinct senescent process common after middle age (Peters and Rosene 2003,

Bartzokis 2004a).

Microscopic autopsy research faces the difficulty of collecting representative

human samples and the time demands of characterizing neurons and glia (for discussion

of sampling problems, see Svennerholm et al., 1997). As a consequence, many aging

studies employ the efficient extreme group design, comparing oldest to youngest adults

and precluding time-course analysis (Salthouse 2000). A particularly clear example of

this sampling limitation comes from the following plots of synapse density in 21 brains, 8

from adults over age 60 and 7 from infants under one (Huttenlocher 1979).

3

FIGURE 1.1

Syna

pses

/Neu

ron

x 10

4

Syna

pses

/mm

3x

108

FIGURE 1.1

Syna

pses

/Neu

ron

x 10

4

Syna

pses

/mm

3x

108

Figure 1.1. Age extrapolation issues and synapse estimates from layer III of human middle frontal gyrus from Huttenlocher (1979). (A) Raw synapse numbers from electron photomicrographs. Note non-uniform x-axis and skewed age distribution. (B) Synapse numbers accounting for changes in neuron number; note changed x-axis scaling.

The often cited plot is on the left (Figure 1.1A); it shows that electron

microscopic counts of phosphotungstic acid-stained synaptic profiles increase in the first

year of life and are generally higher in early childhood than in old age. The plot on the

right (Figure 1.1B) provides a moderated view by accounting for differences in neuron

number with age. Subsequent investigations of pediatric samples have replicated the

essential finding that synaptic density peaks within the first few years of life; they also

provide evidence that a decline in synapse number begins in childhood (reviewed in

Feinberg et al., 1990, Huttenlocher 2002). However critical evaluation of the age

distribution in Figure 1.1, particularly accounting for the non-uniform age-axis (often a

4

sign of biased sampling), shows the 21-brain sample “ranging from newborn to 90 years”

has a gaping hole through 80% of that range. The same can thus be said about the fit line

through so little data. This example prompts two related observations. First,

understanding of human aging tends to be weakest in the working adult range (~25-60),

perhaps because this group works to survive into old age prior to autopsy. Second, it may

be helpful to distinguish between aging in the familiar sense of growing old and less fit

(senescent aging) versus aging in the constitutive sense of courses of change that extend

over the lifetime (physiological aging, a gap in the understanding of which Figure 1.1

highlights).

Estimating time-courses, even limited to adulthood, requires large sample sizes,

generally favoring macroscopic measures, such as brain weight and volume. How does

normal aging appear with more data at the macroscopic level? Early autopsy reports did

not account for the weight (Dekaban 1978) or volume (Davis and Wright 1977) of

ventricular CSF; they modeled changes with age as flat prior to around age 50, and

declining thereafter (~10% total; though see Pakkenberg and Voigt 1964, Miller et al.,

1980). However, more recent autopsy (Svennerholm et al., 1997) and cross-sectional

MRI studies almost universally converge on a linear time-course of volume decline in

young adulthood, with the largest samples showing mild acceleration after middle age

(Good et al., 2001, DeCarli et al., 2004). In contrast to the whole brain pattern of early

decline, white volume estimates remain stable (Pfefferbaum et al., 1994, Blatter et al.,

1995, Guttmann et al., 1998) or increase slightly (Courchesne et al., 2000, Ge et al., 2002,

Sowell et al., 2003, Jernigan and Fennema-Notestine 2004, Walhovd et al., 2005,

5

Kruggel 2006) until middle-age (age 40 to 60). White volume decline follows and

accelerates in old age, in agreement with the recent autopsy findings on fiber loss

discussed above. MRI studies that report minimal white volume decline (Van Laere and

Dierckx 2001) tend to have fewer or healthier older participants, reinforcing the

importance of sample health and age distribution when comparing studies.

To attribute effects to age, designers of cross-sectional MRI and autopsy studies

must assume that older and younger individuals differ only with respect to their ages and

not their birth cohorts or other variables. Longitudinal studies are now possible to test

these assumptions using in vivo neuroimaging. In the study described in Chapter 2, we

directly compared longitudinal decline estimates from a subset of nondemented adults to

cross-sectional estimates from the larger sample. At least seven prior studies have

quantified longitudinal, whole brain decline in nondemented adults over 60. Six (Chan et

al., 2001, Wang and Doddrell 2002, Liu et al., 2003, Resnick et al., 2003, Thompson et

al., 2003, Jack et al., 2004) documented annualized loss of about 0.5% (0.37 to 0.88),

whereas one (Tang et al., 2001) reported a rate of 2.1%. Longitudinal studies sampling

from younger adults have found slower, not non-zero, rates of decline (0.2-0.3%/yr;

Giedd et al., 1999, Liu et al., 2003), again consistent with an acceleration of white

volume decline in older age.

Figure 1.2 shows data from two independent longitudinal studies designed to

provide insight on physiological aging (Liu et al., 2003, Raz et al., 2005). The left graph

(Figure 1.2A) plots whole brain volume adjusted for intracranial volume, derived using

automated segmentation (see legend). The right graph (Figure 1.2B) plots the volume of

6

the lateral prefrontal cortex, also adjusted for intracranial volume, but derived from

manual measurements. Each line represents an individual study participant. Brain volume

appears to decline continuously throughout adolescence and adulthood.

FIGURE 1.2

A B

Age (Years) Age (Years)

Adj

uste

d Vo

lum

e (c

m3 )

FIGURE 1.2

A B

Age (Years) Age (Years)

Adj

uste

d Vo

lum

e (c

m3 )

A

c

p

A

s

h

n

Figure 1.2. Longitudinal time-courses of normal brain volume decline. (A) Whole brainvolume covariance adjusted (statistically matched) for intracranial volume from 90 healthy volunteers, concentrated at baseline in the 14 to 55 age range (mean 37), with repeat imaging after 3.5 years. Volume was measured via automated gray/white/csf segmentation of longitudinally registered scan pairs from each study participant (from Figure 2 in Liu et al., 2003). (B) Manually segmented lateral prefrontal cortical volume from 72 healthy volunteers, 20 to 77 at baseline (mean 52), with repeat imaging after 5 years (from Figure 6 in Raz et al., 2005).

lzheimer’s Disease. The definitive diagnosis of AD requires histopathologic

onfirmation (Ball et al., 1997, McKeel et al., 2004); it is uncertain when the disease

rocess starts in any given individual (Borenstein et al., 2006). Cross-sectional study of

D progression would call for individuals to be matched on all variables other than time

ince disease onset. Given the uncertainty surrounding onset, longitudinal neuroimaging

as a key role to play in characterizing the progression of AD, since age of onset is

aturally matched within subject (Kantarci and Jack 2003, Glodzik-Sobanska et al.,

7

2005). A handful of reports on serial MRI have found whole brain atrophy accelerates in

AD, but differ as to the magnitude. The difference in annualized atrophy rates between

nondemented individuals who converted to dementia of the Alzheimer type (DAT)

during follow-up (0.8%) and those with slow-progressing (0.6%) and fast-progressing

(1.4%) DAT at baseline suggests that dementia severity and atrophy rate are associated

(Jack et al., 2004). Accordingly, most reports on more severely demented samples

estimate whole brain atrophy rates more rapid than 2% per year (Chan et al., 2001, Wang

et al., 2002, Thompson et al., 2003, Schott et al., 2005), consistent with a nonlinear

(accelerating) atrophy model of DAT (Chan et al., 2003, Rusinek et al., 2004).

Regarding the anatomy of atrophy in AD, a recent report from our laboratory

(Buckner et al., 2005) compared the spatial distribution of maps from five different

neuroimaging methods, based on different samples, and proposes a provocative

hypothesis regarding the natural history of AD. Nonlinear registration (see below) was

used to estimate atrophy at the voxel level in participants with DAT. Compared to

nondemented participants, in which declines have been found steepest in lateral

prefrontal, orbitofrontal, and inferior parietal regions (Jernigan et al., 2001, Ohnishi et al.,

2001, Sowell et al., 2003, Salat et al., 2004, Raz et al., 2005), atrophy in DAT was most

prominently accelerated in medial temporal regions and a distributed network of parietal

cortex, including the precuneus, posterior cingulate, retrosplenium, and lateral posterior

parietal regions, consistent with prior studies (Brun and Gustafson 1976, Callen et al.,

2001, Ohnishi et al., 2001, Scahill et al., 2002, Yoshiura et al., 2002, Boxer et al., 2003,

Miller et al., 2003, Thompson et al., 2003, Karas et al., 2004, Chetelat et al., 2005,

8

Pennanen et al., 2005). Positron emission tomography (PET) maps of default activity

(areas receiving more blood flow when young healthy participants were not engaging in

goal-directed tasks across a variety of experiments; reviewed in Gusnard and Raichle

2001) and MRI maps of memory retrieval (areas with increased signal when young,

healthy participants correctly recognize old versus new items; reviewed in Wagner et al.,

2005) showed surprising anatomical convergence, particularly in parietal cortex. This

convergence between maps of functional and metabolic activity in young adults and

pathology in late-onset DAT suggests functional or metabolic activity early in life may

contribute to AD in older age (Borenstein et al., 2006, Selkoe 2006).

Morphometric methods. How is brain structure measured to generate the findings and

hypotheses surveyed above? My interest is with individual brain change over time, but a

historical review (Rushton and Ankney 1996) of controversial, between-group brain

differences serves as a reminder that Morton (1849), Broca (1861), and Galton (1888),

among other nineteenth-century scientists, pioneered the field of head and brain

morphometry. More recent morphometric developments in the field of neuropathology

include the invention of a pneumatic device for assessing intracranial volume (Davis and

Wright 1977) and the random sampling, 3-D dissector method of counting neurons

without bias (reviewed in Morrison and Hof 1997).

In the 1970s, the developers of modern MRI variously solved the problem of 3-D

NMR (Damadian 1971, Lauterbur 1973, Mansfield and Maudsley 1977). The conceptual

basis for all spatial encoding schemes is the linear equation relating magnetic field

9

strength to the resonance (Larmor) frequency of the hydrogen proton. Magnetic field

strength can be regularly varied using gradient coils, such that for a given gradient and

radio frequency (RF) bandwidth, protons at a known fixed interval (spatial frequency)

along a known slice thickness can all be made to precess at multiples of the same known

Larmor frequency. Intrinsic tissue properties (T1, T2, and proton density, PD) and

magnetic field susceptibility differences determine the re-transmitted radio signal

received from these spatially selected protons during the readout interval. Spin-lattice

relaxation time (T1) or spin-spin relaxation time (T2) can be emphasized, depending on

the time between excitations (repetition time, TR) and the time between gradient switches

(echo time, TE). As described in Chapter 3, we have collected longitudinal MR data

using a new multi-echo fast low-angle shot (MEF) sequence, from which intrinsic tissue

property estimates (T1, T2*, and PD) can be derived (Fischl et al., 2004).

Several strategies exist for next transforming a high resolution (~cubic mm) brain

image into morphometric data. Manual methods based on tracing the outline of known

anatomical boundaries are considered the gold standard (for example, Jernigan et al.,

2001, Raz et al., 2004, Head et al., 2005). However, automated methods offer the

potential for greater throughput and extensibility. Within the category of automated

volumetric methods, linear (Woods et al., 1992, Snyder 1996, Smith et al., 2002, Buckner

et al., 2004) and nonlinear (Christensen et al., 1996, Miller 2004) registration is used in

this research. In general, the goal of registration is to match for and thereby eliminate

uninteresting sources of structural variance such as scanner drift, head positioning, and

head size. Registration to stereotaxic atlases also enables discussion of space to occur in

10

the same language. The highest parameter linear registration is a 12-parameter affine; it

represents a procedure for minimizing the difference (registration error) between a source

and target image by translating, rotating, stretching, and skewing the source image. An

important methodological question for measuring brain change, addressed by an earlier

study from our lab (Buckner et al., 2004), is whether head size accounts for the scaling

properties of linear registration. We found a very high (r = 0.93) correlation between

manual (total intracranial volume, TIV) and registration-based (estimated TIV, eTIV)

head size estimates, and both were independent of brain atrophy in demented samples.

These findings indicate that differences in head size drive image scaling when the

difference between a source MRI and sample-representative target atlas are minimized by

linear registration. Head-size corrected estimates are reported either as ratios or residuals

of eTIV (Mathalon et al., 1993, Sanfilipo et al., 2004, Van Petten 2004). Residual

correction is more robust against group differences in head size; however, for

comparisons in which these have been explicitly studied and ruled out (Buckner et al.,

2004), we have used ratio correction as the more conventional (for example, (Pantel et

al., 2004, DeCarli et al., 2004, Kruggel 2006) and transparent alternative (see Chapters 2

and 3).

Starting where linear registration leaves off, high dimensional nonlinear

registration computes transformations at the voxel level in order to reduce registration

error to zero, under assumptions that brain images behave according to known material

properties (for example, like a viscoelastic fluid; for a review of how fluid warping is

being applied, see May et al., 2006). The extent of voxel-wise contraction or expansion

11

embedded within the nonlinear transformation provides an estimate of regional volume

change, though the precise relationship between the magnitude and spatial distribution of

such estimates and underlying anatomy remains to be validated. We have implemented a

fluid warping algorithm in order to compare longitudinal, voxel-wise atrophy estimates in

normal old aging and DAT (Buckner et al., 2005, discussed above).

The widely used voxel-based morphometric (VBM) method is based on

registration that ranges from linear to “global nonlinear,” the latter involving some

nonlinear warping but with final registration error greater than zero (Ashburner and

Friston 2000, Ashburner and Friston 2001). As a result of what is essentially a

compromise between precision and computational speed, significant structural

differences reported using VBM should probably be interpreted as gross regional

estimates and viewed in the context of metric whole brain gray and white differences that

drive them (Bookstein 2001, Tisserand et al., 2002, Mehta et al., 2003, Davatzikos 2004).

Unfortunately, these metric estimates often go unreported in VBM papers and negative

findings tend to be overemphasized, leading to difficulty interpreting some papers that

rely exclusively on this method (for example, Maguire et al., 2000, Colcombe et al.,

2003, Mechelli et al., 2004).

Modifiers. Relevant to understanding brain aging in nondemented samples (our aim in

Chapter 4), there are few studies that demonstrate modification of the downward slopes

illustrated in Figure 1.2. Sluming and colleagues (2002) reported that whole brain volume

was less correlated with age in a group of professional musicians than matched

12

nonmusicians controls. VBM analysis with a lower statistical threshold in an a priori

region of left frontal cortex confirmed that gray volume was significantly increased there

in musicians. A more recent VBM study of older adults found a significant interaction

between age and estimates of maximal oxygen uptake, such that higher fitness was

associated with greater than age-predicted gray volume throughout association cortex and

greater than age-predicted white volume, particularly in the frontal lobes (Colcombe et

al., 2003). Both these studies suggest long-term motor-related activity moderates age-

associated volume decline.

Five other reports on normal structural modifiers fail to find such moderation for

estimates of long-term cognitive activity; if anything, the reports suggest an amplifying

role. Coffey and colleagues (1999) report a very weak but significant correlation between

education and cerebral spinal fluid (CSF) volume in 320 normal older adults (such that

the most educated had more sulcal CSF). A meta-analysis of 33 published papers on

volume decline in the hippocampus also failed to find moderation by fitness of memory,

as assessed by cognitive testing (Van Petten 2004). Again, the trend pointed in the

amplifying direction, especially with younger samples (such that those remembering

most had the smallest hippocampi). More recently in children, vocabulary gains (Sowell

et al., 2004) and superior IQ (Shaw et al., 2006) have been linked to distributed regions of

increased cortical thinning.

In contrast to this mixed picture of non-pathological brain aging modification,

considerable evidence suggests a variety of long-term environmental or experiential

factors moderate the risk of dementia. In particular, education, occupation, literacy, IQ,

13

and active lifestyle all have experimental support as protective factors against DAT

(Gurland 1981, Zhang et al., 1990, Whalley et al., 2000, Fratiglioni et al., 2004, Manly et

al., 2005, Valenzuela and Sachdev 2006). The evidence for modification generally falls

into two categories: a negative correlation with indices of disease expression and a

positive correlation with indices of pathological severity. For example, more educated

individuals have been linked to a lower incidence (reduced risk) of dementia diagnosis

(Launer et al., 1999, Valenzuela and Sachdev 2006). In contrast, at the cusp of dementia

or in patients otherwise matched for clinical severity, cognitive performance and glucose

metabolism have been found to decline more rapidly in the more educated (Stern et al.,

1992, Amieva et al., 2005, Scarmeas et al., 2006). A combination of direct relationships

between education and pathology and between education and physiological brain aging

might conceivably contribute to these findings (Snowdon 2003, Shaw et al., 2006).

However, the reserve hypothesis offers the most parsimonious explanation. The

hypothesis is that education and related variables moderate the relationship between

pathology and disease expression (Katzman 1993, Satz 1993, Stern 2002, Bennett et al.,

2005, Scarmeas and Stern 2004, Bennett et al., 2005, Stern 2006, Roe et al., 2006). We

will return to the reserve hypothesis as a potential explanation for our finding that brain

volume decline is associated with educational and occupational attainment

(socioeconomic status or SES) in nondemented older adults in Chapter 4.

14

CHAPTER 2

NORMATIVE ESTIMATES OF CROSS-SECTIONAL AND LONGITUDINAL

BRAIN VOLUME DECLINE IN AGING AND AD

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’s disease (AD). Methods: High-resolution, high-contrast structural

magnetic resonance images (MRIs) were obtained from 370 adults (age 18 to 95).

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 life-span 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

15

(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 DAT is associated with a markedly

accelerated atrophy rate.

INTRODUCTION

Pathological brain processes that lead to dementia coexist 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 departure from that

trajectory, we report here a large-sample study of 370 adults age 18 to 95. The goals of

this study were to characterize the normal development of whole-brain volumes in the

absence of dementia and determine, 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 estimates 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 changes in brain size, a single point

estimate may be informative regarding their likely future course and risk of disease.

16

However, reviews of the structural aging literature highlight the need for longitudinal

data because of between-subject variance (Raz 2000, Uylings and de Brabander 2002,

Kantarci and Jack 2003). Longitudinal 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 (cohort effects), such as environmental differences between

when people were born (secular effects). MRI is readily able to obtain longitudinal data

through repeated imaging of the same person over time (reviewed in Raz 2004).

The present design, which combines cross-sectional and longitudinal approaches

(Giedd et al., 1999), 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 (Davis and Wright 1977, Miller et al., 1980, Matsumae et

al., 1996, Guttmann et al., 1998, Ge et al., 2002), whereas others find volume loss in this

age range (Pfefferbaum et al., 1994, Giedd et al., 1999, Courchesne et al., 2000, Rovaris

et al., 2003, Sowell et al., 2003, Salat et al., 2004), a difference possibly related to

differential contributions of gray- and white-matter loss to brain aging (Raz 2004).

Second, does the cross-sectional rate of atrophy in nondemented older adults match the

longitudinal 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 volume loss progresses in a predictable

17

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 (Cardenas et al., 2003,

Chan et al., 2003, Jack et al., 2004).

METHOD

Participants. Three hundred and seventy adults (age 18 to 95 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). Twenty additional individuals were scanned twice at

a short interval (mean = 21 days, range 1 to 64) to allow estimation of measurement

reliability. Participants were paid for their participation and gave 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 (Salat et al.,

2004, Head et al., 2005).

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 ADRC. The 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 depression or disabling stroke are

excluded (Villareal et al., 2003). Approximately 40% of ADRC participants who met the

18

study’s clinical criteria (nondemented 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 education, or scores on the mini-mental

state exam (MMSE; Folstein et al., 1975) between ADRC participants who did and did

not undergo MRI. Dementia severity was quantified using the Clinical Dementia Rating

(CDR; Morris 1993) 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 Alzheimer’s disease, both in

clinical progression and neuropathological diagnosis at autopsy (Berg et al., 1998, Morris

et al., 2001, Galvin et al., 2005). Demographic and clinical data for participants are

presented in Table 2.1.

19

TABLE 2.1. Sample Characteristics

Young Middle-aged Old

CDR 0 DAT (CDR 0.5) DAT (CDR 1)

N (cross-sectional) 127 51 94 69 29

Female/Male 64/63 29/22 67/27 32/37 21/8

Age ± SD, yrs 23±3 (18-34)

50±8 (35-64)

78±8 (65-95)

78±6 (65-93)

79±6 (69-97)

Education ± SD, yrs 15±3 (8-23)

14±3 (7-20)

13±3 (7-20)

MMSE ± SD 29±1 (25-30)

26±3 (18-30)

22±4 (13-28)

Prescriptions, n 2.9±2.1 (0-9)

2.4±1.9 (0-8)

2.7±2.3 (0-8)

Systolic BP, mmHg 136±18 (102-192)

143±21 (104-188)

146±26 (90-192)

Diastolic BP, mmHg 73±10 (40-96)

73±10 (50-98)

77±11 (60-100)

Reported HBP, % 43.0 41.8 48.3

Diabetes, % 10.8 11.8 10.7

N with follow-up (longitudinal) 38 33 8

Female/Male 30/8 10/23 5/3

Scan interval ± SD, yrs 1.8±0.5 (1.1-3.9)

1.8±0.5 (1.3-3.5)

1.8±0.4 (1.0-2.4)

Notes: The sample consisted of 370 individuals (272 nondemented and 98 with DAT). DAT = dementia of the Alzheimer type; MMSE = mini-mental state examination where scores range from 30 (“best”) to 0 (“worst”); CDR = Clinical Dementia Rating, with 0, 0.5, and 1 corresponding to nondemented, very mild, and mild DAT; HBP = high blood pressure; TIA = transient ischemic attack. Mean values given ± standard deviation (SD).

20

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

empirically optimized for gray-white contrast (repetition time (TR) = 9.7 ms, echo time

(TE) = 4 ms, flip angle (FA) = 10, inversion time (TI) = 20 ms, delay time (TD) = 200

ms, 256 x 256 (1 mm x 1 mm) in-plane resolution, 128 sagittal 1.25 mm slices without

gaps, time per acquisition = 6.6 min). Participants were provided cushioning, head

phones, and a thermoplastic face mask for communication and to minimize head

movements. Positioning 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 CAP 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 (Head et al., 2004).

Image analysis. Normalized gray-matter (nGM; gray parenchyma 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 (Zhang et al., 2001, Smith 2002). Prior to image segmentation, the

images were pre-processed to normalize for head-size and intensity variation that might

affect image segmentation.

21

Pre-processing included multiple steps. Head-size normalization used a validated

method based on atlas registration (Buckner et al., 2004). The normalization is

proportional to manually measured total intracranial volume (TIV, r = 0.93) and

minimally biased by atrophy. Images were corrected for inter-scan head movement and

spatially warped into the atlas space of Talairach and Tournoux (1988). The template

atlas consisted of a combined young-and-old target previously generated from a

representative sample of the 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 over-expand atrophied brains (Buckner et al., 2004). For

registration, a 12-parameter affine transformation was computed to minimize the variance

between the first MP-RAGE image and the atlas target (Snyder 1996). 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 (see Figure 2.1). Subsequent pre-

processing 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 pre-processing, the segmentation algorithm classified each voxel of the

average image as cerebral spinal fluid (CSF), gray, or white matter (Zhang et al., 2001,

Smith 2002). This segmentation starts with an initial estimation step to obtain and

22

classify tissue parameters. An expectation-maximization algorithm then updates class

labels and tissue parameters in order to 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.

FIGURE 2.1FIGURE 2.1

N

o

%

p

Figure 2.1. Whole-brain volume measurement and normalization procedure. (A) Single MP-RAGE image as acquired in native space. (B) Within-participant averagedMP-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 Tournoux (1988) 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 percentage of the brain mask (non-black background) occupied by voxels classified as gray and white matter.

ormalized volumes were computed as the proportion of all voxels within the brain mask

ccupied by gray (nGM), white (nWM), or gray plus white (nWBV, equivalent to 100 –

CSF) voxels. The unit of normalized volume is percent, which represents the

ercentage of estimated TIV.

23

Test-retest measurement reliability. In order to estimate measurement 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 difference (MAPD, the absolute difference

between test and retest volumes divided by the overall mean, expressed in percent) was

0.92% for nGM (CI 0.53-1.30), 0.80% for nWM (CI 0.5-1.1), and 0.49% for nWBV (CI

0.28-0.71). The coefficients of variation (CV, the standard deviation 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, North Carolina). 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

contributed significantly to the model; the resulting models are referred to as cross-

sectional, nondemented aging curves. Normalized volumes in the older DAT and older

24

nondemented samples were then compared using analysis of covariance with nGM,

nWM, or nWBV as the dependent measure and age, gender, and dementia status as

cofactors.

Longitudinal analysis. The longitudinal analysis was restricted to the most reliable

whole-brain data and sought to quantify 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, divided 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 differences in atrophy rate based on age, gender,

and dementia status.

Comparison of cross-sectional and longitudinal data. To compare cross-sectional and

longitudinal data, atrophy rate was estimated from the cross-sectional, nondemented

aging curve and compared with the longitudinal, nondemented atrophy rate. Atrophy rate

was estimated from the cross-sectional curve by expressing 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 nondemented, longitudinal sample; the y-intercept was determined by

25

interpolating nWBV from the nondemented, cross-sectional sample (mean age = 81,

nWBV = 74.1%; DAT trendline drawn equivalently, mean age 78, nWBV = 72.0%; see

Figure 2.3B).

RESULTS

Cross-sectional. The cross-sectional dataset is plotted in Figures 2.2 and 2.3A and

summarized in absolute volumes without head-size normalization in Table 2.2.

Nondemented 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 = -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). Considering the full age range, adding a quadratic term significantly 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 2.2 and

2.3A illustrate that individuals with DAT (CDR = 0.5 and 1) exhibited volume reduction

disproportionate to age. A full-factorial analysis of covariance on the older sample with

age, gender, and dementia status as covariates was significant for nGM (F[7, 184] =

26

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

significant decrease in nGM (43.7% vs. 41.7%, p < 0.001), nWM (31.1% vs 30.2%, p <

0.05), and nWBV (74.7% vs. 71.9%, p < 0.001; see Figure 2.4A).

Figure 2.2 (next page). Cross-sectional plots of gray and white matter, normalized for head size. (A) Cross-sectional plot of nGM across the adult life-span; each data point represents a unique participant from a single scanning session. For participants with follow-up data, the session with nearest-in-time clinical data is used (see Table 1). The best-fit polynomial regression is drawn only for the nondemented individuals (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 nWM across the adult life-span. The dashed line represents 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 inflectionin the nWM curves (around age 42 for men and 45 for women) and the greater separation between nondemented and DAT individuals (red versus blue) in the nGM plot. DAT = dementia of the Alzheimer type; nGM = normalized gray matter; nWM = normalized white matter.

27

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(%)

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nWM

(%)

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B

DAT, maleNondemented, maleDAT, femaleNondemented, femaleDAT, maleNondemented, maleDAT, femaleNondemented, femaleDAT, maleNondemented, maleDAT, femaleNondemented, female


FIGURE 2.2

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FIGURE 2.2

28

TABLE 2.2. Estimated gray, white, and whole-brain volume (WBV) by age decade in nondemented individuals

Age decade n Age ± SD,

yrs Gray ± SD,

cm3White ± SD,

cm3WBV ± SD,

cm3

Female

18-25 55 21.3 ± 2.0 739 ± 67 442 ± 37 1180 ± 101

26-35 9 28.2 ± 2.8 690 ± 73 420 ± 40 1110 ± 113

36-45 12 40.7 ± 3.0 684 ± 76 427 ± 45 1111 ± 117

46-55 12 50.6 ± 2.6 637 ± 51 426 ± 31 1063 ± 75

56-65 8 62.4 ± 3.0 591 ± 31 409 ± 21 1000 ± 36

66-75 26 70.8 ± 2.5 594 ± 55 416 ± 39 1010 ± 88

76-85 23 81.1 ± 2.5 581 ± 53 409 ± 41 990 ± 86

86-95 15 89.7 ± 2.2 548 ± 63 404 ± 56 952 ± 110

Male

18-25 48 21.9 ± 1.9 794 ± 57 486 ± 34 1280 ± 85

26-35 16 29.2 ± 2.7 756 ± 49 471 ± 34 1226 ± 79

36-45 4 43.8 ± 0.5 729 ± 132 481 ± 81 1209 ± 212

46-55 9 48.8 ± 2.7 740 ± 58 485 ± 42 1224 ± 85

56-65 9 60.7 ± 3.1 706 ± 56 497 ± 53 1203 ± 102

66-75 13 72.5 ± 2.8 670 ± 55 465 ± 45 1135 ± 88

76-85 9 82.2 ± 3.4 647 ± 76 486 ± 91 1133 ± 153

86-95 4 88.7 ± 1.6 594 ± 115 420 ± 63 1015 ± 168

Notes: Cross-sectional, nondemented sample (n = 272). Gray, white, and WBV represent native volumes (without correction for head size). Men have more gray (708.4 cm3 vs. 629.5 cm3, p < 0.001) and white (470.1 cm3 vs. 420.7 cm3, p < 0.001) volume than women.

29

Longitudinal. The longitudinal dataset, obtained in older adults, is plotted in Figure 2.3B.

The whole-brain atrophy rate in nondemented older adults was -0.45% (SD = 0.53) per

year. The atrophy rate in age-matched individuals with DAT was -0.98% (SD = 1.0) per

year. A full-factorial analysis of covariance with age, gender, 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 significant correlation with age within the older sample (r = -0.17, p

= 0.30; see Figure 2.4C) 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.

Figure 2.3 (next page). Cross-sectional and longitudinal plots of whole-brain volume, normalized for head size. (A) Cross-sectional plot of nWBV across the adult life-span. The line represents the best-fit polynomial regression of all nondemented individuals and is referred to as the cross-sectional, nondemented aging curve (85.3 + 0.013[AGE] – 0.002[AGE2]). (B) Longitudinal 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 estimated longitudinal rate of change for all of the nondemented individuals and overlaps with the slope of the cross-sectional, nondemented aging curve (shown in black). The slope of the thick red line represents the longitudinal rate of change for all of the DAT individuals and suggests accelerated volume loss in DAT. Lines connected by blue triangles and red squares represent individuals who converted from a CDR of 0 to 0.5 during the inter-scan interval; they are included in the DAT mean. CDR = clinical dementia rating; DAT = dementia of the Alzheimer type; nWBV = normalized whole-brain volume.

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FIGURE 2.3

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FIGURE 2.3


B

31

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 2.4B compares 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 revealed a trend toward a difference (t[41] = 3.03, p = 0.09) between the

nondemented group (CDR 0 → 0) and the decliner group (CDR 0 → 0.5), though the

small sample size limited statistical power.

Figure 2.4 (next page). Summary data. (A) Mean cross-sectional nWBV for individuals 65 and over separated by CDR (0, 0.5, and 1). All differences are significant. (B) Longitudinal atrophy rates, expressed in nWBV loss per year relative 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 → 0.5/1) than the group entering without dementia that remained stable (CDR 0 → 0) and resembles the rate for the group that manifested the earliest signs of DAT during the experiment (CDR 0 → 0.5), though we await confirmation in a larger sample. (C) Individual atrophy rates are plotted versus age, with the trendline drawn through the CDR 0 → 0 group showing minimal acceleration with age. DAT = dementia of the Alzheimer type; CDR = clinical dementia rating.

32

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phy

(%/y

r)

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N=37

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FIGURE 2.4

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phy

(%/y

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0 → 0 0 → 0.5 0.5 → 0.5/1

FIGURE 2.4

33

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

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. 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

2.3A) shows that normalized, whole-brain volume (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 2.3 summarizes the results from twelve cross-sectional MR reports on

healthy aging that cover the adult lifespan and report whole-brain or gray/white-matter

estimates as a percentage of head size. A number other reports are qualitatively similar,

but employ quantitatively distinct units that cannot be directly compared to the present

results (Pfefferbaum et al., 1994, Harris et al., 1994, Christiansen et al., 1994, Murphy et

al., 1996, Raz et al., 1997, Passe et al., 1997, Jernigan et al., 2001, Rovaris et al., 2003,

Sullivan et al., 2004, Raz et al., 2004). As the median of all estimates shown in Table 2.3,

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 2081 individuals,

34

age 34 to 97, argues in favor of the generaralizablilty of this sample and these findings

(DeCarli et al., 2004). Comparable pathologic estimates fall below the range in Table 2.3;

a quadratic regression of volumetric data from one such study suggests that across the

reference age range (20-80), brain volume as a percentage of cranial cavity volume

decreased from 92% to 85% (0.14% per year atrophy; Davis and Wright 1977). 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.

35

TABLE 2.3. Comparative whole brain estimates from cross-sectional, MR studies

Reference Sample

size Mean age

Predicted nWBV at age 20, %

Predicted nWBV at age 80, %

Vol decline, %/yr

Age correlation,

r Best-fit

regression

Jernigan 90 58 45 93 82 -0.21 -0.62 linear

Gur 91 69 43 93 85 -0.15 -0.56 linear

Coffey 92 76 62 -0.27 exponential

Blatter 95 194 39 94 86 -0.15 -0.68 linear

Matsumae 96 49 56 96 84 -0.23 linear

Guttmann 98 72 59 88 80 -0.17 linear

Courchesne 00 116 21 89 74 -0.28 -0.57 quadratic

Good 01 465 30 77 65 -0.27

Van Laere 01 81 44 85 77 -0.16 linear

Ge 02 54 47 90 78 -0.24

Sowell 03 176 32 89 81 -0.16 linear

DeCarli 04 2081 62 86 74 -0.27 -0.63 quadratic

Mean 89 79 -0.23

Present study 272 47

85 74 -0.23 -0.88 quadratic

Notes: nWBV = normalized whole-brain volume, employing head-size correction. Predicted nWBV at ages 20 and 80 was interpolated from regression formulas or plots of whole-brain or gray plus white volume relative to head size as a function of age. Rate of volume decline was estimated by dividing the change in nWBV per year by linearly interpolated nWBV at study age.

36

In addition to quantifying the magnitude of volume decline, the present results

converge with others on a temporal sequence placing brain volume reduction at or before

the start of early adulthood (Pfefferbaum et al., 1994, Giedd et al., 1999, Courchesne et

al., 2000, Rovaris et al., 2003, Sowell et al., 2003, Salat et al., 2004). Whole-brain

volume decline was significant 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 contaminated with preclinical AD (i.e., individuals with the pathologic substrate

of AD who are not yet sufficiently impaired to be recognized clinically as demented) as

the only explanation for atrophy in nondemented older populations.

A moderate acceleration of volume loss in nondemented aging occurred in middle

age, around the inflection point of the normalized white-matter (nWM) curve at age 44

(see Figure 2.2B). Similar downward inflections (Miller et al., 1980, Harris et al., 1994)

after a period of white volume stability (Pfefferbaum et al., 1994, Blatter et al., 1995,

Guttmann et al., 1998, Good et al., 2001) or possibly growth (Courchesne et al., 2000, Ge

et al., 2002, Liu et al., 2003, Sowell et al., 2003, Jernigan and Fennema-Notestine 2004)

during the third and fourth decades have been attributed to the prolonged and

heterochronologic development of brain myelination (for review and discussion, see

Bartzokis 2004a, Bartzokis 2004b, Sowell et al., 2004). This delayed pattern of nWM

loss (though see Van Laere and Dierckx 2001, Sullivan et al., 2004, Raz et al., 2004)

contrasts with the more linear course of normalized gray-matter (nGM) decline

37

throughout adulthood, potentially suggesting separate age-related mechanisms for each

(Raz 2004).

Gender effects were minimal in our results. For the overall cross-sectional

sample, which was not gender 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. 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-gender interactions (Christiansen et al., 1994, Murphy et al., 1996, Matsumae et al.,

1996, DeCarli et al., 2004, Sullivan et al., 2004). Main gender effects from studies that

report no age-by-gender interactions can be compared with the present 0.3% normalized

volume difference: four (Blatter et al., 1995, Courchesne et al., 2000, Van Laere and

Dierckx 2001, Resnick et al., 2003) report similar gender effects (female > male), three

(Guttmann et al., 1998, Ge et al., 2002, Liu et al., 2003) report no gender effect, and three

(Raz et al., 1997, Good et al., 2001, Raz et al., 2004) report gender effects in the opposite

direction (male > female). The small magnitude of any true difference after head-size

normalization, the possibility of differential healthfulness between gender cohorts, and

methodological differences likely contribute to inconsistent gender findings.

The longitudinal rate of whole-brain atrophy averaged -0.45% per year in the

older, nondemented sample. At least seven prior studies have quantified longitudinal,

whole-brain volume change in nondemented individuals over a comparable age range.

Six (Chan et al., 2001, Wang and Doddrell 2002, Liu et al., 2003, Resnick et al., 2003,

Thompson et al., 2003, Jack et al., 2004) have documented annualized rates of about -

38

0.5% (-0.37 to -0.88) , comparable to the present finding, whereas one (Tang et al., 2001)

reported a rate of -2.1% (reviewed in Raz 2004). 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 between the longitudinal atrophy

rate in nondemented individuals (-0.45%) and the cross-sectional estimate (-0.31 to -

0.46%) for the 65 through 95 age-range demonstrates excellent agreement. In addition,

longitudinal reports covering the young adult age-range (Giedd et al., 1999, Liu et al.,

2003) find slower atrophy rates than in this older, longitudinal sample, suggesting that the

trend toward accelerated atrophy with age in Figure 2.4C might reach significance with

wider longitudinal sampling or increased sample size. Together, our results indicate that

secular effects and other confounds minimally influence cross-sectional, whole-brain

volume estimates. 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 longitudinal 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

longitudinal and cross-sectional cohorts. Instead, the observed agreement suggests that

the brain loses volume with age according to uniform and predictable, though largely

unknown, mechanisms (Resnick et al., 2003).

39

It is well established that individuals with DAT exhibit decreased brain volume

relative to their nondemented peers, with the underlying pathology prominent in regions

within the medial temporal lobe (Hubbard and Anderson 1981, Braak and Braak 1997,

Price et al., 2001). MRI studies have detected accelerated global and regional volume

change in DAT (Jernigan et al., 1991, Kantarci and Jack 2003). In addition, comparing

nondemented aging with DAT in Figure 2.2 tentatively suggests that gray matter is more

vulnerable than white matter to very mild to mild AD pathology (Thompson et al., 2003).

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 (Jack et al.,

2004). Faster whole-brain atrophy rates (-5.2%; Thompson et al., 2003) and (-2.4%;

Wang et al., 2002) have been reported in smaller cohorts with more advanced 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 (Fox and Freeborough 1997). With at least one exception

(Cardenas et al., 2003), atrophy rate estimates based on the BBSI have exceeded -2% per

year (Fox and Freeborough 1997, Chan et al., 2003), for example, a -2.37% BBSI atrophy

rate in 54 DAT patients (Chan et al., 2001). Divergence in longitudinal atrophy rates may

reflect differences in atrophy measurements and DAT cohorts; the DAT sample yielding

the -2.37% estimate had a lower age (61 versus 79) and MMSE (20 versus 26) than in the

present study and included early-onset and familial cases.

40

Providing evidence that the specific DAT sample represents an important factor,

in a sample of 5 “preclinical” familial cases followed during their conversion 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 (Schott et al., 2003). The estimates

here and in the literature suggest that non-familial, 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 (Chan et al., 2003). This initial rate of brain volume loss represents

a doubling from that of nondemented individuals.

Our results tentatively suggest that accelerated loss in whole-brain volume may

begin in the preclinical phase of AD (DeKosky and Marek 2003). 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

automated whole-brain measures such as nWBV, combined with their potential to detect

preclinical AD, highlights the promise of global volumetric biomarkers (Jack et al.,

2004).

41

CHAPTER 3

SUMMARY OF THREE-MONTH STUDY

TO DISCRIMINATE ATROPHY IN AD FROM NONDEMENTED AGING

Fischl and colleagues (2004) recently reported a model for magnetic resonance

(MR) image analysis that relates the probability of misclassifying a voxel in a

segmentation procedure (Fischl et al., 2002) to the acquisition parameters (repetition time

[TR], echo time [TE], and flip angle) used to sequence acquisition of fast low-angle shot

(FLASH) MR images. This theoretical advance of embedding MR physics into

morphometric algorithms enabled the development of a new multiecho FLASH (MEF)

sequence optimized for segmentation. The motivation for developing MEF was that it

might lead to practical advances in the structural characterization of neurodegenerative

disorders. We tested whether MEF could advance the efficiency of longitudinal studies in

Alzheimer’s disease (AD) in our three-month study, summarized in this chapter. A

follow-up period of three months represents the shortest interval reported to date relative

to comparables studies that have aimed to discriminate atrophy in AD from normal aging

(Bradley et al., 2002, Schott et al., 2005).

Baseline MR images were obtained from 30 participants enrolled in the ongoing

studies of the Washington University AD Research Center (ADRC). These participants

were evenly divided among a nondemented (CDR 0) group and a dementia of the

Alzheimer’s type (DAT, CDR 0.5/1) group, based on their Clinical Dementia Rating

(CDR, Morris 1993), as previously described (Fotenos et al., 2005). Follow-up images

42

were acquired a mean 95 (SD = 11) days after baseline. Ten additional young adults were

scanned twice within a short interval (mean 11 days) to allow estimation of measurement

reliability. Sample characteristics are summarized in Table 3.1.

TABLE 3.1. Longitudinal sample with complete baseline and follow-up MEF images

Test-retest CDR 0 DAT (CDR 0.5) DAT (CDR 1)

Number 10 15 9 6

Female/male 6/4 10/5 4/5 3/3

Age ± SD, y 27 ± 10 (19-54)

80 ± 10 (63-95)

78 ± 5 (72-85)

75 ± 4 (70-79)

Education ± SD, y 16 ± 3 (12-23)

15 ± 2 (12-18)

15 ± 2 (12-16)

MMSE ± SD

29 ± 1 (26-30)

26 ± 3 (21-30)

19 ± 4 (15-23)

Retest interval ± SD, d 12 ± 11 (3-29)

96 ± 13 (84-129)

92 ± 10 (83-115)

96 ± 7 (91-109)

The imaging protocol ran approximately 40 minutes on a 1.5 T Siemens Sonata

(van der Kouwe 2005). The protocol consisted of an initial fast FLASH sequence (TR =

2.4 ms, TE = 1.13 ms, resolution = 3.3 x 2.5 x 2.5 mm, time = 0:48 min) for online rigid-

body registration to a template, thus ensuring uniform head positioning during all

subsequent scans. Standard FLAIR (TR = 1000, TE = 1.13, 3.3 x 2.5 x 2.5, 3:42) and

MPRAGE (TR = 2730,TE=3.41, 1.3 x 1.0 x 1.3, 8:46) runs followed. Next came the two

main MEF sequences (TR = 20; TE = 1.8, 3.62, 5.44, 7.26, 9.08, 10.9, 12.72, 14.54, 1.3 x

1.0 x 1.3, 8:12), the first T1-weighted at a flip angle of 30 (MEF30) and the second

proton-density weighted at a flip angle of 5 (MEF5). Finally, a magnetization transfer

43

corrected MEF5 and two more fast FLASH sequences were acquired, one with the head

coil and the other with the body coil, for use in correcting B1 inhomogeneity. The multi-

gigabyte MEF k-space data was reconstructed off-line, and the resulting 16 images from

the main MEF30 and MEF5 runs, along with pre-processing output, are shown in Figure

3.1.

B

C

D

E

F

A

FIGURE 3.1

B

C

D

E

F

A

FIGURE 3.1

Figure 3.1. Multi-echo FLASH (MEF) imaging from one older adult participant. (A) The eight echoes from the T1-weighted MEF30 sequence (top row) and proton-density (PD) weighted MEF5 sequence (bottom row) show intensity decay as echo-time increases to the right, reflecting dephasing of transverse magnetization (T2*). (B)Weighted average of the MEF scans. (C) Synthesized T1, (D) T2*, and (E) PD maps. (F) Standard, 8-minute structural image (MPRAGE), acquired as a control in the imaging protocol.

44

Preprocessing of the MEF images acquired at each imaging session consisted of

four main steps: 3-D gradient unwarping; rigid registration of MEF5 to MEF30 images;

weighted averaging; and voxel-wise T1, T2*, and PD parameter estimation. Gradient

unwarping corrected for geometric distortion caused by nonlinearities in the gradient coil;

the 3-D implementation improved on the 2-D algorithm installed on the Siemens Sonata.

Head movement between acquisition of the MEF30 and MEF5 scans was corrected by 6-

paramater affine transformation (Smith et al., 2004). The transformed images were then

averaged based on weightings derived from a linear discrimination analysis that

maximized contrast-to-noise between manually segmented gray and white voxels (Han

2005). As an alternative method of dimensionality reduction, maps of relaxometry

parameter estimates were synthesized based on the Bloch equation and changes in TE

and flip angle (α) in the MEF sequence. The Bloch equation specifies the relationship

between image intensity and relaxometry parameters as follows:

/ 1

/ 2*/ 1

1( , ) sin1 cos

TR TTE T

TR T

eS PD ee

αα

−−

−

−=

−m β , (0.1)

where S = image intensity, β = [T1, T2*, PD], and [ , ,TR TE ]α=m .

Morphometric analysis started with the resulting MEF images (see Figure 3.1B-

E). Figure 3.2 summarizes the main analytical strategies and results. Three-month change

in CDR 0 and DAT groups was compared in terms of whole brain and regional atrophy

and relaxometry parameters. In preparation for these analyses, the three-month data was

45

registered to the baseline using a nine-parameter affine transform (translation plus

rotation plus stretch), and this transform was algebraically composed with the baseline-

to-atlas transform (12-parameter affine) so that each participant’s structural data was

corrected in atlas space for serial differences in head position and scanner drift

(Freeborough et al., 1996, Snyder 1996). The atlas template was composed of a

subsample of combined young-and-old data in the atlas space of Talairach and Tournoux

(1988), with construction as described previously (Buckner et al., 2004). Normalized

whole brain volume (nWBV) at baseline and follow-up was computed using the

segmentation workflow described in Figure 2.1. In addition, perpendicular displacement

between sessions at the edge of the segmented brain image was integrated for a direct

measure of global atrophy (Smith et al., 2002, Smith et al., 2004).

Maps of regional atrophy were derived from adding a nonlinear registration (fluid

warping) step after the rigid body registration, as previously described (Buckner et al.,

2005). Fluid warping aims to transform the follow-up image so that the difference

between follow-up and baseline is minimized (Christensen et al., 1996, Miller 2004). The

divergence of the intersession deformation at each voxel represents local contraction or

expansion, and, when divided by the intersession interval, has units of fractional loss or

gain per year. Divergence maps were compared between CDR 0 and DAT groups using

voxel-wise t-tests. The maps of relaxometry estimates, and relaxometry change maps,

were also compared using t-tests, as well as by visual inspection of individual intensity

distributions.

46

The global atrophy (Figure 3.2A, right), regional atrophy (Figure 3.2B, right), and

relaxometry analyses (Figure 3.2C) all showed no significant difference for three-month

change between CDR 0 and DAT groups. Test-retest error (Figure 3.2A, left), computed

as the mean absolute volume change (as a percentage of whole brain volume) between

scan pairs just days apart, was 0.24% for MPRAGE pairs acquired as described in

Chapter 2 (n = 23), 0.27% for MPRAGE pairs acquired as part of the present MEF

protocol, and 0.25% for the MEF-average pairs (p = 0.93). Analysis of baseline whole

brain volume (not shown) indicated that DAT was associated with a marginal decrease

(nWBV 69% vs. 67%, p = 0.06). In contrast, change estimates over the three-month

interval substantially overlapped between groups, with global atrophy rates of 1.2%/yr in

the CDR 0 group and 1.4%/yr in the DAT group (p = 0.77). Similarly, three-month

regional (voxel-wise) atrophy (see Figure 3.2B, right) did not show the pattern of parietal

and medial temporal discrimination over years-long intervals reported elsewhere for DAT

(Scahill et al., 2002, Toga and Thompson 2003). This convergent pattern is reprinted for

reference from our lab (Buckner et al., 2005) along with unpublished t-maps for standard

MPRAGE images acquired in 44 CDR 0 and 40 DAT participants over a mean two-year

interval (Figure 3.2B, left). Finally, the distribution of T1, T2*, and PD estimates in

participant’s relaxometry maps also substantially overlapped (see Figure 3.2C), and these

estimates had low reliability (for example, > 2% mean absolute percentage difference for

whole brain T1; see also DeMyer et al., 1988, Wang et al., 2004).

47

Figure 3.2 (next page). Post-processing and null results for three-month discrimination with multi-echo FLASH (MEF). (A) Whole brain atrophy in terms of mean absolute estimates of error from test-retest sampling (left) and annualized change from three-month sampling (right). (B) Regional discrimination of DAT and CDR 0 groups over two years of follow-up from Buckner and colleagues (left; Buckner et al., 2005) with no discrimination over three months (right). (C) Overlapping distributions of T1, T2*, and PD estimates from baseline relaxometry maps.

48

-2.5

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0

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0.2

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Multi-echoFLASH

Erro

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)

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Young

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2.0 5.0t-stat

DATStandard MPRAGE

CDR 0 Difference

Z=38

Z=-2

2

0.3 1.0Atrophy (%/Yr)

DAT CDR 0 DifferenceMulti-echo FLASH

Z=38

Z=-2

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A

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FIGURE 3.2

-2.5

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Z=38

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DAT CDR 0 DifferenceMulti-echo FLASH

Z=38

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A

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FIGURE 3.2

49

Results from this study suggest that structural MRI based on the newly developed

MEF sequence does not lead to ready improvement in standard volumetric estimates,

such that three-month change in nondemented vs. demented samples overlapped. This

null result converges with limitations encountered in related work on the application of

the MEF sequence within the laboratory responsible for its innovation (Xiao Han,

personal communication, July 11, 2005). In contrast, a recent report based on standard

structural imaging in more advanced dementia (corresponding to DAT with a CDR of 1

to 2, n = 38) found that interval change over 6-12 months, particularly in the volume of

the lateral ventricles, was sufficient for discrimination from nondemented aging (Schott

et al., 2005; see also, Gunter et al., 2003). This finding suggests that sampling and

processing methods, as much as or more than image acquisition, may be key to

improving the efficiency of structural imaging studies. We have noted the possibility, for

example, that unreliability in the processing steps prior to segmentation (such as in

masking, registration, resampling, or corrections for field distortions) may be a main

contributor to test-retest error, since the mean absolute percentage difference for

estimated total intracranial volume (eTIV), computed prior to segmentation, and for

normalized whole brain volume (nWBV), computed after, are both around 0.5%

(Buckner et al., 2004, Fotenos et al., 2005). Simply put, the complexity of volumetric

estimation is likely an important factor in measurement error. Based on the result with

ventricular change noted above, we suggest that a promising direction for future research

is to develop a method for the single-step measurement of ventricular volume from

unprocessed MRIs. Such a specialized tool could take advantage of the high contrast and

50

stereotypy of ventricular CSF, and possibly also multi-spectral information, such as

offered by the MEF.

51

CHAPTER 4

BRAIN VOLUME DECLINE IN AGING:

EVIDENCE FOR A RELATIONSHIP BETWEEN

SES, PRECLINICAL AD, AND RESERVE

ABSTRACT

Objective: To explore the influence of socioeconomic status (SES) on structural brain

aging in nondemented older adults, including the role of preclinical Alzheimer’s disease

(AD). Methods: Head-size adjusted whole brain volume (aWBV) was estimated from

MRI in 362 individuals age 18 to 93. Of these, SES was assessed in a main cohort of 100

nondemented older adults age 65 to 93 (Clinical Dementia Rating [CDR] 0 at initial

MRI) using the Hollingshead two-factor index of social position. 83 of these participants

received follow-up clinical assessment subsequent to MRI, and 33 were imaged

longitudinally. To test whether preclinical AD can influence brain volume, MRI data

were analyzed from a sample of 58 CDR 0 participants (age 47 to 86) who had

participated in amyloid imaging with [11C]Pittsburgh Compound-B (PIB). Results:

aWBV was estimated to decline by 0.22%/yr between the ages of 20 and 80, with

accelerated decline in advanced aging. In older adults > 65, increasing SES was

associated with smaller aWBV (3.8% difference spanning the sample range from middle

to high privilege) and more rapid volume loss (0.39%/yr to 0.68%/yr from middle to high

privilege). Supporting an influence of preclinical AD, aWBV was reduced by 2.5% in

52

individuals positive for PIB binding (n = 9) as compared to individuals negative for PIB

binding (n = 49). Follow-up clinical data revealed the volume reduction associated with

SES was greater in those who developed signs of very mild dementia subsequent to MRI

(preclinical dementia group, n = 19) compared to those who remained nondemented

(stable CDR 0 group, n = 64). Conclusions: Brain volume loss is accelerated in privileged

nondemented older adults relative to less privileged peers. The capacity of more

privileged individuals to cope longer with preclinical pathology prior to disease

expression, as predicted by the cognitive reserve hypothesis, may contribute to this effect.

53

INTRODUCTION

Brain volume decline is characteristic of life-long processes that begin in

adolescence, or earlier, and continue into advanced aging (Giedd et al., 1999, Courchesne

et al., 2000, Raz et al., 2005). Relevant to Alzheimer’s disease (AD), volume loss

accelerates markedly in the earliest stages of the disease (Fox and Schott 2004, Jack et

al., 2004, Fotenos et al., 2005). These and related observations lead to the conclusion that

whole brain volume is determined by a constellation of factors that include normal

developmental change as well as pathological processes (Buckner 2004, Raz 2004,

Hedden and Gabrieli 2005). Measurement of whole brain volume differences between

individuals and change within individuals provides an opportunity to better understand

modifiers of normal and pathological aging.

Here we sought to explore the influence of socioeconomic status (SES) on brain

volume in a large cohort of nondemented older adults and to supplement this analysis

with subject stratification based on amyloid binding measured with [11C]Pittsburgh

Compound-B (PIB) and longitudinal clinical assessment. The primary motivation is the

observation that high SES, representing both educational and occupational attainment, is

a protective factor for AD (Zhang et al., 1990, Stern et al., 1995, Bennett et al., 2003,

Amieva et al., 2005; reviewed in Scarmeas and Stern 2004, Valenzuela and Sachdev

2006). It is unknown to what degree the influence of SES reflects modification of

disease-associated processes (Snowdon et al., 2000), antecedent capacity to buffer

pathology (Katzman 1993, Satz 1993), active capability to compensate for the disease

54

(Stern 2002, Stern 2006), ascertainment bias (Tuokko et al., 2003) or any combination of

these possibilities. Analysis of whole brain volume including its relation to amyloid

binding (as a proxy measure for AD pathology) and longitudinal clinical evaluation (as a

measure of dementia onset) may provide insight.

Direct precedent for this research comes from Coffey and colleagues (Coffey et

al., 1999), who observed that years of formal education may amplify volume decline in

nondemented older adults. Specifically, the more educated individuals showed

indications of reduced brain volume, based on a measure of peripheral cerebrospinal fluid

(CSF) adjusted for age and head size. An intriguing possibility is that socioeconomically

privileged individuals are better able to respond to the initial stages of neurodegenerative

disease and their impairment does not reach a level that is clinically apparent. This notion

of neuropsychological mediation between brain pathology and disease expression is

referred to as cognitive reserve (Stern 2002, Stern 2006).

Relevant to the possibility of clinically silent disease, we previously found that in

vivo measurement of amyloid via PIB binding reached levels suggestive of AD pathology

in some nondemented participants (Clinical Dementia Rating [CDR] 0; Buckner et al.,

2005, Fagan et al., 2006, Mintun et al., 2006). Post-mortem, 34% (14/41) of participants

from our center who were nondemented at expiration nevertheless met established

histologic criteria for AD (Galvin et al., 2005). The discrepancy between post-mortem

AD pathology and symptomatic disease expression is well replicated (Rothschild 1937,

Katzman et al., 1988, Price and Morris 1999, Esiri et al., 2001, Bennett et al., 2006, Lippa

55

and Morris 2006; reviewed in Mortimer et al., 2005), and the term “preclinical AD”

describes the initial period of disjunction.

The preclinical period may relate to cognitive reserve, with longer preclinical

periods expected to track putative markers of reserve, such as educational and

occupational attainment, literacy, IQ, and active lifestyle. The literature on incident

dementia offers indirect evidence for this reserve hypothesis, finding that higher reserve

variables predict less frequent disease expression (reviewed in Fratiglioni et al., 2004,

Valenzuela and Sachdev 2006). More direct evidence has come from recent studies that

collected pathological measures at autopsy together with premorbid variables on reserve

and disease expression; the reserve hypothesis predicts that increasing reserve raises the

pathological threshold for impairment, and the results of these clinicopathologic studies

support this (Bennett et al., 2003, Bennett et al., 2005).

In the present study, we sought to address three questions concerning the

possibility of SES influences on brain volume. First, in nondemented older adults

carefully screened for dementia, is brain volume associated with SES? We used the

Hollingshead two-factor index of social position, which includes years of formal

education, but also weights for occupational attainment over the extended period between

schooling and retirement (Hollingshead 1957). The dependent measure was a reliable,

validated metric of whole brain volume (Buckner et al., 2004, Fotenos et al., 2005), and

the sample was screened for dementia based on the sensitive, informant-based CDR scale

(Morris 1993, Carr et al., 2000, Storandt et al., 2006). Extrapolating from the reported

result on education (Coffey et al., 1999), we hypothesized that individuals with a life

56

experience of higher SES (more combined educational and occupational attainment)

would correspond to those with less brain volume.

Second, do brain volume differences related to SES reflect different rates of

longitudinal brain volume change? Cross-sectional volume differences may represent

baseline differences, independent of aging. Here, based on the subgroup of our

nondemented sample with follow-up MRI over an extended interval, we explored the

association between longitudinal brain aging and SES. Extending our cross-sectional

prediction, we hypothesized that brain volume loss within individuals over time would be

more rapid in the more privileged.

Third, does cognitive reserve explain the hypothesized structure-privilege

relationships? An explanation for smaller brain volume in privileged individuals may be

that they are more likely to experience atrophy associated with preclinical AD (Coffey et

al., 1999). A group with preclinical AD and other brain pathologies may be contained

within the nondemented sample; in this subgroup, atrophy is expected to advance longer

prior to disease progression in individuals with more reserve. We explored this possibility

by examining whether a substantial number of individuals with presumptive evidence of

AD pathology (PIB+ binding) were contained within our nondemented population and

further whether brain volume differs in these individuals compared to PIB- peers. Based

on the hypothesis that preclinical AD is a cause of reduced brain volume in the most

privileged individuals, we further analyzed longitudinally measured clinical conversion

(from no dementia to very mild dementia) to explore whether the interaction of SES with

clinical conversion accounts for the brain volume reduction. Support for the reserve

57

hypothesis would come from finding that brain volume loss was accounted for by

privileged individuals on the verge of clinically detectable dementia.

METHODS

Participants. MRI images from 362 individuals (age 18 to 93) were obtained from

participants in the ongoing longitudinal studies of the Washington University Alzheimer

Disease Research Center (ADRC) and our ongoing studies of normal aging and

development (Berg et al., 1998, Galvin et al., 2005). More detailed attrition and selection

characteristics of this population have been described previously (Fotenos et al., 2005).

All participants were scanned with identical procedures. A subset of 100 nondemented

older adults (age 65 to 93) comprised the main cohort of clinically screened individuals

for which extensive data analysis was performed. Of these 100, 33 were followed by MRI

for an extended interval to allow for longitudinal data analysis (mean = 3.1 times over a

3.1 to 6.5 year interval; mean = 4.3 years).

MR participants were classified as nondemented if their CDR nearest the time of

baseline MRI was 0. Clinicians determined the CDR, blind to the results of

neuropsychological testing and prior clinical assessment, through examination of the

participant and interview with an informant (usually a family member) who knew the

participant well and could provide information regarding decline from the participant’s

normal cognitive and functional abilities (Morris 1993). Designation of CDR 0.5 (very

mild dementia) thus indicates early clinical impairment relative to an individual’s

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baseline, in contrast to impaired test performance relative to group norms in mild

cognitive impairment (Morris et al., 2001, Storandt et al., 2006). The orientation of the

CDR to intraindividual change helps to avoid mistaking low baseline functioning for

dementia or, conversely, mistaking no dementia for high baseline functioning in the

presence of AD (ascertainment bias; Tuokko et al., 2003). As an example of the CDR’s

sensitivity to early symptomatic AD, a recent report from our center found that over one

third (276 of 728) of a CDR 0.5 sample had neuropsychological test scores that did not

fall below the required cutoffs for MCI (pre-MCI group), despite the presence of

individual decline and neuropathological AD (43 of 47 in the autopsied pre-MCI group;

Storandt et al., 2006).

In the present study, the mean duration between clinical assessment and baseline

MRI was 116 days (range = 0 to 314 days). Participants were paid for their participation

and gave informed consent in accordance with guidelines of the Washington University

Human Studies Committee. Data from some of these participants have been reported in

previous studies (Salat et al., 2004, Head et al., 2005, Fotenos et al., 2005, Buckner et al.,

2005, Burns et al., 2005).

SES was assessed for all older adults at a participant’s initial clinical evaluation,

using the Hollingshead two-factor index of social position (Hollingshead 1957). The

Hollingshead index represents a linear combination of educational and household

occupational attainment, with occupation almost doubly weighted. The index ranges from

11 to 77 and can be grouped into five SES categories (I-V). In order to control for

potential health confounds related to deprivation in the underprivileged (House et al.,

59

1994; reviewed in House and Williams 2000) and because the cohort from which data

were drawn contains too few low-SES individuals to disentangle these effects, this study

focused on variation of the Hollingshead index within the range of the high-privilege,

high-middle, and middle SES groups (I-III; Fratiglioni et al., 1999). None of the health

variables presented in the table of sample characteristics (Table 4.1) differed between

these groups.

60

TABLE 4.1. MRI sample

Young Middle Aged Nondemented Old (CDR 0)

Middle SES

High-Middle SES

High SES

N (cross-sectional) 127 135 31 40 29

Female/Male 67/60 91/44 21/10 30/10 16/13

Sum Box Score 0/0.5 26/5 35/5 28/1

Age ± SD, yrs 23±3 (18-34)

52±7 (35-64)

77±8 (65-90)

77±7 (65-93)

78±7 (65-92)

Hollingshead ± SD 35±4 (29-43)

22±3 (18-27)

13±2 (11-15)

MMSE ± SD 29±1 (25-30)

29±1 (26-30)

29±1 (26-30)

Prescriptions, n 2.8±1.8 (0-8)

2.6±2.1 (0-7)

2.7±1.8 (0-6)

Systolic BP, mmHg 134±17 (110-192)

139±18 (110-190)

131±15 (102-158)

Diastolic BP, mmHg 73±12 (50-94)

75±9 (56-96)

69±10 (40-90)

Weight (sex-adjusted), lbs 159±36 (100-245)

159±27 (112-220)

158±26 (121-206)

N with follow-up (longitudinal) 11 15 7

Female/Male 6/5 9/6 5/2

Duration of MRI follow-up ± SD, yrs 4.4±1.1 (3.3-6.3)

4.3±0.7 (3.1-5.8)

4.4±1.0 (3.1-6.5)

MRIs per participant ± SD, n 3.1±0.7 (2-4)

3.0±0.7 (2-4)

3.1±0.8 (2-5)

Notes: Data are shown corresponding to the earliest imaging session (baseline). SES is grouped in order of increasing privilege based on published cutoffs for the Hollingshead two-factor index of social position. The Sum Box Score represents a more quantitative form of the global CDR based on the sum of ratings in

61

each of six domains assessed by the CDR. A Sum Box Score of 0.5 indicates very mild impairment in one domain other than memory; all participants had a global CDR of 0, indicating no dementia. Mean values are given ± the standard deviation. Values in parenthesis represent the range. MMSE = Mini-Mental State Examination where scores range from 30 (best) to 0 (worst); BP = blood pressure; CDR = Clinical Dementia Rating; SES = socioeconomic status.

Estimation of whole brain volume. Our method of image acquisition and brain volume

estimation has been described previously (Buckner et al., 2004, Fotenos et al., 2005).

Briefly, 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). Repetition time was 9.7 ms, echo time was 4 ms,

flip angle was 10°, inversion time was 20 ms, and resolution was 1 × 1 × 1.25.

Image processing involved the following fully automated steps: within-participant

averaging, atlas registration, resampling to isotropic voxels (1 mm cubic), correction for

intensity inhomogeneity (B1 bias-field), skull masking, and segmentation into gray,

white, and CSF compartments. The registration was based on computation of a 12-

paramater affine transformation aimed at minimizing variance between the first MP-

RAGE and a combined young-and-old template in the atlas space of Talairach and

Tournoux (Talairach and Tournoux 1988, Snyder 1996, Buckner et al., 2004). Estimated

total intracranial volume (eTIV) was computed based on the atlas transformation.

Specifically, the atlas scaling factor (ASF), which represents the determinant of the

transformation matrix, is highly correlated with manually measured total intracranial

volume (TIV, r = 0.93) and minimally biased by atrophy (Buckner et al., 2004). The

inverse of the ASF was used as the eTIV, as in our earlier report (Fotenos et al., 2005).

The segmentation used a validated algorithm for computing the maximum likelihood

62

estimates of a hidden Markov, random field model, constrained by both intensity and

spatial proximity parameters (Zhang et al., 2001, Smith et al., 2004).

Whole brain volume (WBV) was computed as the sum of gray and white

compartments. Head size differences were corrected using a covariance procedure (as

opposed to ratio normalization) in order to eliminate the possibility of shared

denominator variance introducing spurious associations between corrected volume

estimates and covariates of interest (Mathalon et al., 1993, Buckner et al., 2004). The

term adjusted whole brain volume (aWBV) is used to denote covariance-adjusted

volumes, as distinct from proportionally normalized whole brain volume (nWBV). The

formula for aWBV, adjusted for head size, follows:

aWBV = WBV – b(eTIV – mean eTIV)

where WBV is the uncorrected (native) whole brain volume, b is the slope of the volume

regression on eTIV, eTIV is the ASF-derived head size estimate, and mean eTIV is the

sample mean. In instances where the influences of multiple variables on WBV were

being explored simultaneously, eTIV was always entered as a covariate and the

dependent variable is denoted as aWBV to reflect this adjustment.

Cross-sectional analysis. To explore differences in brain volume across the full life-span,

aWBV was plotted cross-sectionally versus age for the entire sample of 362 individuals,

including the cohort of 100 clinically screened nondemented older participants (age 65 to

63

93) and the young and middle-aged volunteers from the community (age 18 to 64), who

participated in MRI under identical conditions. Statistical analysis was conducted with

both JMP and SAS software packages (SAS Institute, Cary, NC). Analysis of covariance

and hierarchical polynomial regression were used to model aWBV as a function of age

and sex.

To test for a cross-sectional relationship between SES and brain volume, analysis

was restricted to the main carefully screened older adult sample of 100, and SES was

entered as the predictor variable, with age and sex as covariates. We limited the analysis

to whole brain estimates because they are almost twice as reliable as separated gray and

white estimates and avoid potential confounds involving white-matter intensity changes

(Jernigan et al., 2001, Fotenos et al., 2005).

Longitudinal analysis. To test for a longitudinal relationship between SES and brain

volume, we used multilevel modeling (SAS PROC MIXED, full maximum likelihood

estimation) with aWBV as the dependent measure and the time-by-SES term as the

predictor; covariates were baseline age, time (expressed as years from baseline), SES,

and sex. Multilevel modeling handles intrinsically correlated within-individual data of

uneven number and spacing more sensitively than ordinary-least-squared (OLS) slope

analysis (Singer and Willett 2003). For visualization, however, the most precise OLS

regressions of aWBV against time were plotted per individual, with individuals ranked by

SES (via the Hollingshead index).

64

Preclinical Alzheimer’s disease. As will be shown, SES exerts an influence on brain

volume with the most privileged individuals showing reduced brain volume (cross-

sectional data) and accelerated volume loss (longitudinal data). The reserve hypothesis to

explain this counterintuitive pattern is that preclinical AD exerts an influence on brain

volume with the more privileged individuals harboring preclinical AD longer or more

frequently than in the less privileged. To explore the role of preclinical AD on brain

volume and its relation to SES, two sets of additional data were analyzed. The first

analysis, based on amyloid plaque imaging, explored whether preclinical AD could exert

an influence on brain volume. The second analysis, based on follow-up clinical data,

explored whether an interaction between SES and preclinical dementia status influenced

brain volume.

Visualization of amyloid was enabled by PIB, a radiotracer with high affinity for

amyloid in Aβ plaques (Klunk et al., 2004). As part of the larger research program at

Washington University, PIB was imaged with PET in a sample of 58 nondemented

ADRC participants that partially overlapped with the main sample. Characteristics of the

PIB sample are described in Table 4.2; 28 of those with PIB imaging overlapped the main

cohort described in Table 4.1. The rest were either younger, less privileged, or missing

SES data. Those not within the main cohort nonetheless received identical MRI. The

combination of PIB-PET and structural MRI allowed us to estimate the percentage of our

nondemented sample that harbored a putative sign of AD pathology and to test whether

CDR 0 individuals with high PIB uptake (PIB+) exhibit brain volume reduction relative

65

to peers with minimal PIB uptake (PIB-). This analysis establishes whether AD in its

preclinical phase is capable of exerting an influence on brain volume.

TABLE 4.2. PIB amyloid imaging sample

CDR 0 PIB- CDR 0 PIB+

N (cross-sectional) 49 9

Female/Male 39/10 7/2

Box score 0/0.5 46/3 9/0

Age ± SD, yrs 69±11 (47-86)

72±7 (61-81)

Education ± SD, yrs 16±3 (11-20)

14±3 (11-18)

MMSE ± SD 29±1 (26-30)

29±1 (26-30)

Weight (sex-adjusted), lbs 159±26 (114-237)

134±26 (118-176)

Notes: Preclinical AD, as suggested by imaging of [11C]Pittsburgh Compound-B (PIB) in a separate sample, was explored for potential contributions to structural MRI findings. Positive/negative groupings (PIB-/+) were based on mean regional PIB uptake, as described in the text. Abbreviations and format are the same as Table 4.1. The PIB+ group weighed less than the PIB- group after adjusting for sex (t[53] = 2.63, p < 0.05). There were no other significant group differences, including for additional clinical variables in Table 4.1 (not shown).

PIB-PET image acquisition and analysis are detailed elsewhere (Buckner et al.,

2005, Fagan et al., 2006, Mintun et al., 2006). Briefly, 10 mCi PIB, synthesized

according to published methods (Mathis et al., 2003), was injected into the antecubital

vein of participants resting eyes-closed in a 961 HR ECAT PET scanner (CTI, Knoxville,

TN). Images were acquired in 3-D and reconstructed into 5-min frames (septa withdrawn;

66

with scatter correction and a ramp filter; ~5.5-6 mm full width half maximum) over a 60-

min scanning interval. Frames were motion corrected and atlas registered via composition

of affine transforms of PET to MRI to atlas (Snyder 1996). PIB uptake in four brain

regions (prefrontal, lateral temporal, precuneus, and gyrus rectus) was obtained by

manual drawing of ROIs on the coregistered MRI and application to the dynamic PET

data. Binding potential (BP) was calculated using Logan graphical analysis with a

cerebellar reference ROI (Logan et al., 1996; for ROI descriptions, see Fagan et al.,

2006). A mean BP for these four regions greater than 0.2 was used to classify individuals

with higher relative cortical binding as PIB+, based on the demonstrated association

between CDR, CSF amyloid-β42, and quantitative PIB uptake (Fagan et al., 2006).

Baseline MRIs from individuals classified as PIB+ were then compared against PIB-

MRIs, in a separate analysis of the PIB sample using aWBV as the dependent measure.

Age and sex were covariates.

For the second analysis, preclinical dementia was assessed by examining the

longitudinal history of clinical examinations. A large overlapping clinical sample (in

contrast to the limited overlapping PIB sample) allowed us to explore interactions with

SES. Specifically, 83 of the 100 participants characterized in Table 4.1 as CDR 0 around

the time of baseline MRI received at least one subsequent clinical evaluation (mean 2.9,

range 1 to 6; mean follow-up interval of 3.0 years, range 0.5 to 6.4 years). Participants

were grouped relative to their initial MRI as preclinically demented if they received a

CDR of 0.5 at any subsequent clinical examination. Group status (preclinical versus

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stable CDR 0) was added as an additional term in the cross-sectional analysis of SES

described above.

RESULTS

Brain volume is reduced in nondemented aging. Cross-sectional brain volumes in

nondemented individuals, age 18 to 93, are illustrated in Figure 4.1 (using covariance-

adjusted whole brain volume; aWBV). Parameter estimates for age, age2, sex, and age-

by-sex were all significant in the model (F[5,356] = 1394.14, p < 0.001, R2 = 0.95). For a

sense of effect size, aWBV can be compared at age 20 and age 80, with estimated

declines from 1199 cm3 to 1025 cm3 in men and from 1195 cm3 to 1050 cm3 in women

(decline in annualized percentage terms, 0.24%/yr and 0.20%/yr respectively). Note that

initial aWBV is almost identical between men and women, reflecting the adjustment’s

ability to accommodate head size differences (Buckner et al., 2004). The significance of

the quadratic age term reflects the acceleration of volume decline in advanced aging.

Considering the age range between 65 and 80, the estimated declines were 0.40%/yr for

men and 0.35%/yr for women.

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Figure 4.1. Cross-sectional plot of brain volume in nondemented adults over the adult life-span. Adjusted whole brain volume (aWBV, shown adjusted for head size) declines 13% (0.22%/year) between age 20 and age 80; deviation from a linear time-course is mild, though significant.

Privileged older adults have reduced brain volume. Figure 4.2A focuses on the role of

SES as a potential modifier of whole brain volume among nondemented older adults (age

> 65 yr). After accounting for effects of age, sex, and age-by-sex on aWBV (model

F[5,94] = 218.74, p < 0.001, R2 = 0.92), more privileged individuals were associated with

lower volume estimates (β = 1.3 cm3 per Hollingshead unit, p < 0.01). For example,

spanning the sample range from middle privilege (Hollingshead = 43) to highest privilege

69

(Hollingshead = 11), aWBV was estimated to decrease from 1066 to 1026 cm3 (3.8%

difference).

Privileged older adults show accelerated longitudinal volume loss. To determine whether

cross-sectional differences associated with SES relate to aging, volume change was

estimated within participants using longitudinal MRI (Figure 4.2B). Consistent with the

cross-sectional analysis, more privileged individuals exhibited accelerated loss of aWBV

(time-by-SES β = 0.11 cm3 per year per Hollingshead, p < 0.05), controlling for sex-by-

time and main effects of SES and time within the multilevel model (χ2 = 191.96, d.f. = 3,

p < 0.001; adding baseline age did not contribute). For example, spanning the

longitudinal sample range from middle privilege (Hollingshead = 40) to highest privilege

(Hollingshead = 11), model estimates of aWBV loss nearly doubled from 4.3 cm3/yr to

7.4 cm3/yr (0.39%/yr to 0.68%/yr, relative to model intercept). Similar parameter

estimates for the time-by-SES interaction (β = 0.11 cm3 per year per Hollingshead unit, p

< 0.05) were obtained with a model of aWBV controlling for baseline aWBV (χ2 =

20.48, d.f. = 2, p < 0.001).

70

Figure 4.2 (next page). Cross-sectional and longitudinal plots of brain volume as a function of socioeconomic status. (A) Cross-sectional adjusted whole brain volume (aWBV, shown adjusted for effects of head size, age, and sex) is reduced in more privileged individuals (1.3 cm3 per Hollingshead unit). Each data point represents a nondemented older adult from the main sample of 100. (B) Longitudinal aWBV from 33 of the above 100 who participated in follow-up MRI; here each data point represents an MRI, with best-fit lines connecting each participants’s data. Lines are positioned according to participants’ Hollingshead, and time is nested with 5 years scaled as shown (Hollingshead does not vary per individual). Baseline reduction in aWBV with privilege is readily apparent in the longitudinal subgroup. The downward tilting in slope with privilege (time-by-SES interaction) is more subtle, though visible, and of primary interest. Modeling predicts an increase in volume loss from 4.3 cm3/yr to 7.4 cm3/yr across the sample range, after accounting for effects of baseline age, SES, and sex (aWBV is shown adjusted for head size). SES = socioeconomic status, with privilege shown increasing from left to right, based on the Hollingshead two-factor index of social position

71

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72

TABLE 4.3. Summary Data

Adjusted Whole Brain Volume ± SD (n), cm3 Change ± SD (n), cm3/y

SES All (100) Stable CDR 0 (64) Preclinical CDR 0 (19) Longitudinal (33)

Middle 1058 ± 59 (31) 1057 ± 54 (20) 1095 ± 20 (5) -4.8 ± 3.2 (7)

High-Middle 1038 ± 42 (40) 1041 ± 44 (26) 1022 ± 35 (8) -6.6 ± 3.3 (15)

High 1029 ± 40 (29) 1025 ± 42 (18) 1017 ± 37 (6) -6.8 ± 2.5 (11)

Notes: Mean values ± standard deviation for cross-sectional volume and longitudinal change estimates. Adjusted whole brain volume (aWBV) is shown for the main nondemented sample of 100, as well by group for the sub-sample with clinical follow-up. For summary, WBV was adjusted only for eTIV on the n = 100 sample (see text for estimates after correcting for additional covariates). Summary change estimates were based on the slopes of ordinary-least-square regressions through each participant’s sample of aWBV measurements over time. SES = socioeconomic status.

Evidence that reserve may be an important factor in AD. Figures 4.3 and 4.4 display

results that explore aWBV in relation to amyloid imaging with PIB and follow-up clinical

assessments. The results, in composite, suggest brain volume differences linked to SES

are associated with preclinical dementia. First, 9 of 58 individuals (16%) within the

separate CDR 0 PIB sample (ages 47 to 86) summarized in Table 4.2 were positive for

PIB binding, suggesting many may harbor preclinical AD. Second, Figure 4.3 shows that

there was a main effect (p < 0.05) of positive PIB binding on brain volume: aWBV was

estimated to decline 27 cm3 (2.5%, from 1066 to 1039 cm3) in the CDR 0 PIB+ group,

after adjusting for effects of age (model F[3,54] = 151.62, p < 0.001, R2 = 0.89). This

result indicates that a marker of AD pathology (PIB binding to amyloid) is associated

with brain volume differences in a nondemented sample.

73

Third, Figure 4.4 offers tentative support for a contribution of preclinical

dementia to the effect of SES depicted in Figure 4.2A. Participants were grouped as

preclinical if subsequent clinical evaluation using the CDR indicated the onset of very

mild dementia (CDR 0.5). Adding group status to the cross-sectional model (F[7,92] =

164.10.02, p < 0.001, R2 = 0.93) revealed a trend for a group-by-privilege interaction (β =

1.9 cm3 per Hollinshead per clinical conversion, p = 0.08; the interaction term became

significant [β = 2.4, p < 0.05] when the model was run on the full nondemented sample,

which assumes those CDR 0 individuals with no clinical follow-up remain

nondemented.) The magnitude of the interaction predicts that the cross-sectional decline

in aWBV with privilege (β = 1.3 cm3 less aWBV per Hollingshead unit overall) will

increase by 1.9 cm3 per Hollingshead unit in individuals with preclinical dementia.

74

1020

1030

1040

1050

1060

1070

1080

CDR 0 PIB-

Adju

sted

Who

le B

rain

Vol

ume

(cm

3 )

CDR 0 PIB+

n = 49

n = 9

0

*

FIGURE 4.3

1020

1030

1040

1050

1060

1070

1080

CDR 0 PIB-

Adju

sted

Who

le B

rain

Vol

ume

(cm

3 )

CDR 0 PIB+

n = 49

n = 9

0

*

FIGURE 4.3

Figure 4.3. Adjusted whole brain volume (aWBV, shown adjusted for effects of head size and age) is 27 cm3 (2.5%) lower in nondemented participants with high uptake of PIB, which binds to amyloid-β in plaques. PIB = [11C]Pittsburgh Compound-B (PIB); CDR = Clinical Dementia Rating, with 0 indicating no dementia.

75

900

950

1000

1050

1100

1150

-47 -43 -39 -35 -31 -27 -23 -19 -15 -11 -70

CDR 0.5

Stable CDR 0 (n = 64)Preclinical CDR 0 (n = 19)

SES (Hollingshead)

Adju

sted

Who

le B

rain

Vol

ume

(cm

3 )5 yrs


CDR 0.5


SES (Hollingshead)

Adju

sted

Who

le B

rain

Vol

ume

(cm

3 )5 yrs


FIGURE 4.4

900

950

1000

1050

1100

1150

-47 -43 -39 -35 -31 -27 -23 -19 -15 -11 -70

CDR 0.5


SES (Hollingshead)

Adju

sted

Who

le B

rain

Vol

ume

(cm

3 )5 yrs


CDR 0.5


SES (Hollingshead)

Adju

sted

Who

le B

rain

Vol

ume

(cm

3 )5 yrs


FIGURE 4.4

Figure 4.4. The relationship between adjusted whole brain volume (aWBV, as shown in Figure 2A) and SES is stronger in nondemented participants who subsequently develop dementia. Each data point represents the same nondemented older adult as shown in Figure 2A for the 83 participants who received clinical follow-up subsequent to MRI. Lines extending from each point represent the duration of clinical follow-up, with 5 years nested and scaled as shown. A vertical tick marks when certain participants received a CDR of 0.5, indicating very mild dementia. These participants are classified as preclinically demented with respect to MRI, acquired when all were nondemented (CDR 0). The magnitude of the decline in aWBV with privilege is tentatively greater in the preclinical group. As shown, the best-fit regressions decline by 1.4 cm3 per Hollingshead in the stable CDR group and 3.4 cm3 per Hollingshead in the preclinical group. CDR = Clinical Dementia Rating; SES = socioeconomic status, with privilege shown increasing from left to right, based on the Hollingshead two-factor index of social position.

76

DISCUSSION

Nondemented participants with high SES (the most privileged individuals) were

found to have reduced whole brain volume (cross-sectional analysis) and accelerated

volume loss (longitudinal analysis). The capacity for more privileged individuals to cope

longer with brain pathology before manifesting signs of dementia, consistent with the

reserve hypothesis, may explain this counterintuitive association as elaborated below.

SES associated with brain volume reduction in nondemented aging. The main result in

the present paper is the strong evidence that high SES is associated with lower adjusted

whole brain volume in nondemented older adults (see Figure 4.2). It is worth

emphasizing that, by design, this study concerns individual differences in long-term

structural change (illustrated in Figure 4.1), not early-established differences such as in

head size (reviewed in Rushton and Ankney 1996, Wickett et al., 2000). This focus on

change is clear in the longitudinal result, which shows accelerated volume loss in more

privileged individuals, but even the cross-sectional analysis indirectly uses individuals as

their own control, primarily in the adjustment for head size. Thus, baseline differences in

head size across SES levels do not account for the present results. Moreover, in the

present sample, we did not find significant head size differences attributable to SES.

Our main cross-sectional finding (Figure 4.2A) replicates and strengthens the

most comparable study from Coffey and colleagues (Coffey et al., 1999). Spanning a

representative range of their sample from 8 to 17 years of education, peripheral CSF was

77

reported to increase by 15.9 cm3 (1.7% of whole brain mean; for a similar result with

analysis restricted to patients with probable AD, see Kidron et al., 1997). Peripheral CSF

was defined from traced structures as cranial minus brain minus ventricular volume, and

its increase was interpreted as indirect evidence of greater age-related brain volume

decline in the more educated. The negative finding for the direct measure of whole brain

volume was attributed to measurement error. Here, we restricted our cross-sectional

analysis to a direct measure of whole brain volume using estimates from multiple high

contrast MRI images and the effect was found to be robust.

The longitudinal finding illustrated in Figure 4.2B confirms the direction of the

association between volume and privilege and provides novel evidence that this

association is related to aging and present in older age. The overall rate of decline with

age (6.36 cm3/yr or 0.58%/yr) is within the range (0.37%/yr to 0.88%/yr) reported by

comparable studies with longitudinal MRI of the whole brain in nondemented older

adults (reviewed in Fotenos et al., 2005). Considering the accelerated atrophy rate

associated with SES in this study (ranging from of 0.39%/yr to 0.68%/yr between middle

and high privilege), it is possible that some of the variance between prior studies arose

due to sample differences in SES.

The role of preclinical AD and cognitive reserve. What explains these results? Based on

similar cross-sectional findings in advanced aging (Coffey et al., 1999) and AD (Kidron

et al., 1997), others have offered theoretical accounts invoking the cognitive reserve

hypothesis (see also Kramer et al., 2004, Scarmeas and Stern 2004). In addition to clear

78

documentation of the influence of SES on brain volume, we present here three novel

observations to support the possibility that cognitive reserve contributes to these

observations. First, 16% of our nondemented PIB sample showed high levels of binding

indicative of amyloid plaque presence, suggesting a number of individuals harbor

preclinical AD. Second, high PIB binding was associated with reduced aWBV (Figure

4.3). Third, in the larger sample with follow-up clinical data, a trend for a group-by-

privilege interaction was observed with reduced aWBV associated with more privileged

individuals who soon showed signs of very mild dementia (Figure 4.4). This interaction

was significant when considering all nondemented individuals, including those without

follow-up clinical assessment. Together, these results suggest that AD-dependent atrophy

is detectable prior to the earliest currently recognizable clinical expression of dementia

(Gosche et al., 2002, den Heijer et al., 2006, Jagust et al., 2006). The interaction clarifies

the association with SES and suggests that the most privileged individuals are able to

harbor neurodegenerative disease further into its course without clinical detection. While

indirect, evidence for accelerated atrophy linked to disease also suggests that preclinical

pathology may have advanced to the point of influencing cellular integrity or cell loss

(Terry et al., 1991, Price et al., 2001), and this underscores the potential of volumetric

biomarkers in the assessment and tracking of early AD (Mortimer et al., 2005).

A reserve explanation for our results is consistent with recent evidence that more

educated individuals declined more rapidly on neuropsychological tests several years

prior to AD diagnosis (Amieva et al., 2005, Scarmeas et al., 2006). Other studies have

controlled for AD pathology and shown that the same plaque burden lead to less global

79

cognitive decline in more educated groups (Bennett et al., 2003, Bennett et al., 2005).

Comparable education-related differences in dementia expression have been

demonstrated in a large, multi-center sample restricted to individuals meeting

neuropathologic criteria for AD (Roe et al., submitted). Preclinical individuals with

greater reserve would be expected to have more advanced pathology in order to explain

why they show more severe structural or functional decline. In this study, assuming

pathology develops independent of reserve variables (Del Ser et al., 1999, Bennett et al.,

2003, Mortimer et al., 2005; though see Jankowsky et al., 2005, Lazarov et al., 2005),

such explanatory differences in pathology might arise from within-individual differences

in preclinical duration or between-individual differences in the frequency of clinical

exclusion related to SES. The present data thus are consistent with SES influencing the

ability to detect cognitive impairment in the presence of pathology and possibly cell loss.

It is unclear whether there is any modification of the underlying disease process by life

experiences associated with SES. Education and occupational attainment may protect

against AD through a “use it and hide it” mechanism in comparison to the more

traditionally assumed “use it or lose it” explanation (Swaab et al., 2002).

Limitations and caveats. Limitations of this study highlight open questions and may help

to guide future research. The present study explored SES between the middle and high

range. Thus, our results cannot speak to how low SES affects brain aging and AD, and

future structural research in the underprivileged is needed (Del Ser et al., 1999, Mortimer

et al., 2003).

80

Not all reports exploring reserve and brain volume measures find an association in

nondemented older adults (Coffey et al., 1992, Passe et al., 1997, Raz et al., 2005). The

convergence of cross-sectional and longitudinal evidence here strengthens our confidence

that the association holds for this sample. Sample and measurement differences may

account for null findings, and we are aware of no contradictory studies that suggest a

moderating role (opposite to the amplifying role reported here) of educational or

occupational attainment on brain aging (for review of modifiers, see Kramer et al., 2004,

Van Petten 2004). Replication in additional large-sample studies will be important for

generalizing these results.

A final point to raise is that, while the present results support a cognitive reserve

model, further data will be required to test the model and to explore whether it can fully

account for all of the data or whether additional factors are at work. Specifically, it

remains difficult to account fully for the magnitude of the SES-related volume difference

unless the reserve differential is longer and/or CDR 0 pathology more burdensome than

recent research suggests (Amieva et al., 2005, Bennett et al., 2005, Galvin et al., 2005).

We thus conclude that cognitive reserve likely explains some, but perhaps not all, of the

relationship between SES and structural brain aging.

81

CHAPTER 5

GENERAL DISCUSSION

Centenarians are the most rapidly growing age group in the United States (Wan et

al., 2005). One centenarian who serves as an example of successful aging is Sister

Marcella. When Sister Marcella died, age 101, at the Counsel Hill convent of the School

Sisters of Notre Dame, she had been followed as part of the Nun Study for four years

(Snowdon 2003). Up until her death, she rated her ability to care for herself as

“excellent.” She was known for her remarkable memory and storytelling, and cognitive

testing confirmed a high and maintained level of function. At autopsy, her brain was

largely free of pathology: it weighed 1280 grams, was rated Braak stage 0 (Braak and

Braak 1991), and showed no evidence of stroke.

As Sister Marcella’s example makes clear, advanced age is not synonymous with

AD and dementia. This thesis has compared structural brain change between demented

and nondemented adults. Underlying our experimental strategy has been the hypothesis

that multiple factors may contribute independently to demented and nondemented brain

aging (Berg 1985, Morris 1999, Della-Maggiore et al., 2002, Buckner 2004, Hedden and

Gabrieli 2005). This multiple factor framework compares to a unitary framework that

places AD and dementia at the tail-end of a single aging continuum (Brayne and

Calloway 1988, Whalley 2002, Bartzokis 2004, de la Torre 2004a). Taken together, the

results of this thesis strengthen the multiple factor framework. We thus review our results

82

in terms of AD and non-AD factors that may separately contribute to age-related

structural change (see Figure 5.1).

Figure 5.1 (next page). Thesis results within a multiple factor framework of brain aging. This figure summarizes the main results in the left column, with the middle and right columns showing which parts on the left are hypothesized to reflect AD (middle column) and non-AD (right column) factors. Possible pathophysiological processes underlying such factors are discussed within the text. (A) From Figure 2.3; note the possibility that that separate non-AD processes (right column) may contribute to early-onset (black) and older-onset (blue) components of the adult-span curve; (B) from Figure 3.2; and (C) from Figure 4.3. See individual figure legends for details.

83

Age

Brai

n Vo

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Age

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Brai

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e

Z=38

Z=-2

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0.3 1.0Atrophy

Z=-7

DAT CDR 0

SES

Brai

n Vo

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Brai

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Result AD Factors Non-AD Factors

FIGURE 5.1

B

C

A

Z=38

Z=-2

2

0.3 1.0Atrophy

Z=-7

DAT CDR 0

Z=38

Z=-2

2

0.3 1.0Atrophy

Z=-7

DAT CDR 0

Age

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n Vo

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Age

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Age

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Z=38

Z=-2

2

0.3 1.0Atrophy

Z=-7

DAT CDR 0

Z=38

Z=-2

2

0.3 1.0Atrophy

Z=-7

DAT CDR 0

SES

Brai

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Brai

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SES

Brai

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SES

Brai

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Result AD Factors Non-AD Factors

FIGURE 5.1

B

C

A

Z=38

Z=-2

2

0.3 1.0Atrophy

Z=-7

DAT CDR 0

Z=38

Z=-2

2

0.3 1.0Atrophy

Z=-7

DAT CDR 0

84

Before elaborating on this decomposition, what might AD and non-AD factors

represent? At least two increasingly well characterized pathophysiological cascades

emerge as leading candidates from the literature: AD as a process of amyloid-beta (Aβ)

misfolding and toxicity (Selkoe 2004, Walsh and Selkoe 2004) and sporadic small vessel

disease (SVD) as a process of microvasculature fibrosis and ischemia (Pugh and Lipsitz

2002, Ringelstein and Nabavi 2005, Farkas et al., 2006). We begin with a brief overview

of this pathophysiology. In the case of AD, alterations in four genes have been identified

that cause early-onset or accelerated late-onset familial disease; strikingly, all have been

linked to the metabolism of Aβ (Tanzi and Bertram 2005). Extracellular soluble Aβ

oligomers (Dodart et al., 2002) and diffuse and fibrillar plaques (Urbanc et al., 2002)

have been found to interfere with synaptic function and associate with the activation of

microglia and astrocytes, though gaps remain in the mechanism linking Aβ to tauopathy.

In DAT, loss of synapses strongly correlates with cognitive decline (Terry et al., 1991,

Coleman and Yao 2003), prominently involving impairment in declarative memory

(Spaan et al., 2003, Galvin et al., 2005). Tauopathy and atrophy progress sequentially

(Braak et al., 1999, Delacourte et al., 1999), with early involvement of medial temporal

regions and associated neocortex (see Figure 3.2B; also Buckner et al., 2005); Aβ

aggregation is spatiotemporally heterogeneous, but correlated with disease staging

(Delacourte et al., 2002, Klunk et al., 2004).

Turning to sporadic SVD, an accelerated form (analogous to early-onset familial

AD) may be represented by cerebtal autosomal dominant arteriopathy with subcortical

infarcts and leukoencephalopathy (CADASIL; reviewed in Kalimo et al., 2002,

85

Ringelstein and Nabavi 2005). The implicated mutation weakens the contact between

vascular smooth muscle cells (Shawber and Kitajewski 2004), a possible model for how

risk factors, including hypertension, hyperinsulinism, hyperhomocysteinemia, and

hyperlipidemia (Longstreth et al., 1996, Laloux et al., 2004, Ringelstein and Nabavi

2005), may function in sporadic (wild-type) SVD. MRI findings in SVD include lacunar

infarcts, T2-weighted hyperintensities, perivascular (Virchow-Robin) spaces, and

atrophy, most prominently in frontal white matter (Weis et al., 1991, Double et al., 1996,

Head et al., 2004). Though sporadic SVD may rarely progress to frank vascular dementia

in isolation (Nolan et al., 1998), it is associated with the exaggeration of age-related

declines on measures of executive function, cognitive speed, affect, gait, and bladder

control (Sakakibara et al., 1999, de Groot et al., 2000, Schmidtke and Hull 2002, Wolfson

et al., 2005, Charlton et al., 2006). In summary, sporadic AD and SVD are both widely

prevalent, adverse, age-related processes, but SVD has a distinct pathological signature,

spatiotemporal distribution, genetic risk profile, and neuropsychological sequela. Thus

SVD represents a plausible non-AD factor in the cause of common and consequential

age-related brain change, providing context for the following decomposition of these

thesis results into AD and non-AD factors of structural brain change.

For whole brain volume, we found that nondemented aging is accompanied by

steady volume decline even in the youngest adults, with atrophy rate more than doubling

in the earliest stages of DAT. By itself, the acceleration of structural loss in DAT does

not distinguish between unitary or multiple factor interpretations; however, closer

inspection raises at least three problems for the unitary account. First, as Figure 2.3A

86

makes clear, whole brain volume in the oldest old nondemented individuals falls below

the range for the younger old with dementia. This deviation from a directly proportional

relationship between volume decline and DAT suggests that certain factors that do not

cause DAT nevertheless contribute to volume decline. Second, it is difficult to account

for age-related volume decline in young adults (<30) in terms of known pathological

cascades, particularly as studies of childhood development show that a downward linear

trajectory may start in adolescence (Buckner et al., 2005, Courchesne et al., 2000, Liu et

al., 2003). Third, the decomposition of whole brain volume into gray and white

compartments in Figure 2.2 shows a mostly linear course for gray decline and nonlinear

course for white matter, again consistent with potentially independent factors.

In addition to these whole brain findings, regional analysis provides evidence of

an anatomical dissociation. Although the statistical maps in Figure 3.2B showed minimal

difference between DAT and CDR 0 groups for three-month change, there were

significant differences in the reference study with longer (mean two-year) follow-up

(from Buckner et al., 2005). Atrophy in DAT was most prominently accelerated in medial

temporal regions and a distributed network of parietal cortex, including the precuneus,

posterior cingulate, retrosplenium, and lateral posterior parietal regions. The basis for a

relationship between medial temporal atrophy and parietal atrophy in the natural history

of AD is a target of active investigation (for example, Vincent et al., 2006). Relevant to

the anatomical dissociation of AD and non-AD factors, prefrontal atrophy was prominent

in the nondemented sample, but there was no acceleration in these prefrontal regions in

DAT. This observation of differential vulnerability suggests that contributions to age-

87

related prefrontal atrophy may be independent of AD (Hubbard and Anderson 1981,

Double et al., 1996, Ohnishi et al., 2001, Head et al., 2005).

Future research should continue toward understanding these non-AD factors. A

key unresolved question is how non-AD factors contribute to age-related change in white

matter versus gray matter (Raz 2004). Neuroimaging methods for measuring white matter

aging focus on change in relaxometry (white matter hyperintensities and infarcts), water

diffusion along and dependent on the integrity of fiber tracts (diffusion tensor

anisotropy), and structure (white matter volume loss). It remains unclear whether

vascular disease linked to these white matter changes, another pathological process, or a

normal physiological process contributes to age-related, AD-independent gray matter

loss. Modifier studies will be key to resolving questions of cause and effect in brain aging

and motivated our interest in a candidate modifier, socioeconomic status (SES), in our

final study.

Our SES results draw attention to uncertainties and interactions within the

multiple factor framework. We found a positive association between SES and age-related

volume loss in nondemented older adults. Yet we also found evidence that preclinical AD

may account for this association. Preclinical AD represents a source of uncertainty in the

multiple factor framework because it complicates experimental isolation of non-AD

factors. Relating preclinical AD to brain structure, preliminary results from amyloid

imaging (see Figure 4.3) suggest that atrophy may accelerate in association with high

plaque binding prior to the onset of dementia (see also Kaye et al., 1997, Fox et al., 1999,

Gosche et al., 2002, Marquis et al., 2002, Archer et al., 2006, den Heijer et al., 2006,

88

Jagust et al., 2006). A methodological implication is that observational studies may be

insufficient to isolate factor-pure experimental variables for studies of physiological

aging. For example, to determine whether SES associates with accelerated brain aging,

not just in the absence of dementia, but in the absence of potential pathological factors,

interventional designs would offer the best control. Neuroimaging studies along these

lines might assign participants to high- and low-intensity education courses, or (a quasi

intervention) track students during the school-year versus summer months (see also

Draganski et al., 2004, May et al., 2006).

Lastly, we have argued that the reserve hypothesis may explain why SES relates

most strongly to brain volume in nondemented participants on the cusp of dementia (see

Figure 4.4). Reserve represents the accumulated capacity to buffer and compensate for

pathology; as a reserve variable, SES is a putative proxy for this lifetime process of

accumulation (Stern 2006). The simplifying assumption has generally been that

accumulation of reserve has no effect on AD or brain aging. However, our results leave

open this possibility. Further challenging an isolated reserve model, evidence is

beginning to build for a direct connection between cognitive stimulation and AD

pathology (Jankowsky et al., 2003, Kamenetz et al., 2003, Cirrito et al., 2005, Lazarov et

al., 2005; reviewed in Selkoe 2006). As more preclinical candidates are identified with

PIB, it will be interesting to test whether amyloid pathology, and not just dementia risk,

varies as a function of reserve variables, such as SES, in support of a more direct

interaction (Snowdon et al., 1996, Snowdon et al., 2000). For in the final analysis, the

decomposition of aging into multiple factors as discussed above is just a first step toward

89

understanding how AD, vascular disease, reserve, and other physiological and

pathophysiological processes interact to create the constellation of changes observed in

the brain throughout the life-span.

90

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