Diagnosis

The traditional diagnostic role of cross-sectional imaging

in dementia has been to identify treatable causes of dementia, such as
hydrocephalus, brain tumor, and subdural hematoma. While the search
for additional positive imaging diagnostic criteria that are specific for
different dementing illnesses continues, several of the imaging findings
discussed in this chapter seem to be sensitive enough to serve as
useful ancillary diagnostic criteria in the appropriate clinical setting.
These are: (i) atrophy of the medial temporal lobes, for the diagnosis of
AD, (ii) focal frontal-temporal atrophy, for the diagnosis of frontaltemporal
dementia
(FTD),
(iii)
cortical
and
subcortical
infarction/ischemic changes, for the diagnosis of cerebral-vascular
disease, and (iv) elevated signal on T2-weighted images in the striatum
bilaterally, for the diagnosis of sporadic Creutzfeldt-Jakob (CJD) disease
(104,105), or the pulvinar bilaterally for the diagnosis of variant CJD
(vCJD) (106).
Staging of Disease Severity in Alzheimer's Disease
A number of anatomic imaging studies have documented a
close correlation between the severity of the cognitive deficit in AD
patients and the severity of cerebral atrophy as measured with in vivo
MR (107-111). More recently, Bobinski et al. (112) have undertaken a
formal correlation between measurements of hippocampal volume
from MR exams done on postmortem brains, and histologic measures
of AD pathology. They found a highly significant correlation between
postmortem
MR-defined hippocampal volume and histologically
defined hippocampal area. They also found a significant correlation
between the MR measures of hippocampal atrophy and histologic
measures of cell loss.
Research at Mayo Clinic in this area has consisted of
correlation between premortem MR and postmortem staging of AD
pathology using the method of Braak and Braak (113). We found a
significant inverse correlation between hippocampal volume and Braak
pathologic stage.
These data combined with those of Bobinski indicate that
MR-defined hippocampal volume measurements represent a valid in
vivo surrogate for the pathologic staging of AD.
Monitoring Disease Progression

MR also may be used to monitor progression of the

disease. In this setting, MR studies typically are performed serially, and
longitudinal measurements are made of the rate of change. This type
of information is useful in two different contexts. First, the rate of
change, for example, of brain volume may be a useful adjunct for
monitoring progression of the disease in individual patients either for
purposes of clinical
prognostication or to gauge the impact of
therapeutic intervention. Longitudinal measurements also may be
useful as a means of comparing rates of change among different
groups of subjects. The use of serial imaging measurements as a
surrogate marker of drug efficacy in therapeutic trials is a major new
development in structural MR (114-116).
Clinical Features
AD is the most common cause of dementia in the elderly.
The disease is characterized clinically by a progressive dementia that
typically begins with an isolated memory impairment. Declarative
memory (i.e., memory for explicit factual material) is the most
profoundly affected cognitive domain early in the disease course. No
absolute diagnostic test exists for AD. The diagnosis is based on clinical
criteria and requires demonstration of a progressive deficit in more
than one cognitive domain, usually memory plus another, after other
possible causes of dementia have been excluded (117). The definitive
diagnosis of AD can be made only on examination of tissue and
therefore requires either autopsy, or biopsy. The clinical diagnosis of
AD typically is rendered in the terms "possible" or "probable" AD.

The fact that a declarative memory impairment typically

is first symptom observable in an individual who later develops AD has
led to codifying a clinical syndrome of "mild cognitive impairment"
(MCI) (118-122). MCI is defined clinically as an isolated memory
impairment with other cognitive domains and activities of daily living
intact. MCI is viewed by many as a transition state between normal
cognition and AD. Longitudinal studies have demonstrated that a
clinical diagnosis of MCI is a significant risk factor for the subsequent
development of probable AD. The rate of conversion from MCI to AD is
approximately 12% per year vs. 1% to 2% per year for cognitively
normal elderly persons (123). Within 6 years, approximately 80% of
individuals diagnosed with MCI will have converted to AD.

Four genes have been implicated in the pathogenesis of

AD (124-129). The majority of individuals with autosomal-dominant

transmitted AD have mutations in one of three genes; the amyloid

precursor protein gene on chromosome 21, the presenilin-1 gene on
chromosome 14, and the presenilin-2 gene on chromosome 1. These
early onset familial forms of AD typically present in individuals under
the age of 60, some as young as the 30s. These three known
autosomal-dominant mutations account for only a small fraction (5% to
10%) of all cases of AD in the general population, however.
The majority of prevalent AD cases, >90%, are sporadic
with onset after age 65. While a positive family history is a clear risk
factor for late-onset AD, specific causative genetic mutations have not
been identified. Much attention has recently focused on the
relationship between apolipoprotein E (APOE) and AD. APOE is a
component of lipoproteins and has been studied extensively in the
fields of lipid metabolism and atherosclerosis. Three normally occurring
alleles of APOE have been identified, e2, e3, e4. All individuals carry
two copies of the APOE gene and with 3 different alleles, six genotypes
are possible. APOE e3 is the most prevalent allele in the general
population with a frequency of roughly 80%. APOE e4 is associated
with elevated serum cholesterol levels, while APOE e2 is associated
with an increased risk for type III hyperlipoproteinemia. APOE e4 also is
associated with an elevated risk of developing AD (130-133). The APOE
e3/4 genotype confers a roughly three-fold increase in risk of
developing AD, while e4/4 confers an eight-folding increased risk of
developing AD when compared to the risk associated with the e3/3
genotype. The risk of developing AD associated with e4 however
appears to diminish after age 75 (134).
The e2 allele decreases the risk of developing AD,
however this protective effect is not as strong as the risk conferred to
carriers of e4 allele. In addition to elevating the risk of developing AD,
the mean age at onset of the disease in e4 carriers is earlier than e3/3
individuals.
When duration of illness is controlled, the number of
senile plaques observed at autopsy is increased in e4 carriers
compared to e3/3 individuals (135,136). However, neither the number
of neurofibrillary tangles nor the estimated neuron loss is associated
with genotype (135,136). This latter neuropathologic observation
matches the clinical observation that e4 carriers do not have an
accelerated rate of clinical disease progression when compared to e3/3
individuals (137).
The use of APOE as a diagnostic marker of AD has been
debated intensely. Recent recommendations argue against the use of
APOE genotyping as a method of determining whether currently
asymptomatic individuals will develop AD in the future. One half of all

AD patients are not e4 carriers. In one study (138), one half of e4/4
homozygotes in their 80s were noted to be cognitively intact. One
recommended clinical use for APOE genotyping is in the differential
diagnosis of a patient with dementia, because individuals who are
demented and who are found to be e4/4 homozygotes are very likely to
have AD as the causative pathology (139).
Pathology and Etiology
The major pathologic features that characterize AD are
senile plaques, neurofibrillary tangles, decreased synaptic density,
neuron loss, and cerebral atrophy (Fig. 22.11) (140-145). Intense
debate has centered on which of two primary neuropathologic deposits
in AD, plaques vs tangles, are causative. The anatomic distribution of
neurofibrillary tangles is much more closely associated with the pattern
of neuron loss and with the clinical symptoms in AD (146-148).
Conversely, the available genetic evidence strongly implicates a
derangement in amyloid metabolism as the primary etiologic factor in
AD.

A
B

C
D

Figure 22-11. A: Gross pathology of a fresh, whole brain

with Alzheimer's Disease (AD). Note pronounced diffuse atrophy with
marked sulcal enlargement. B: Gross pathology, coronal section, fresh,
from a subject with AD. Atrophy of
amygdala, hippocampus, and
entorhinal cortex, with consequent enlargement of temporal horns. C:
Neurofibrillary tangles (elongated brown staining structures) and senile
plaques (irregular brown staining structures) in the subiculum
(retrocommissural hippocampus) in AD subject, labeled with tau
antibody. D: Low-power micrograph of a section of AD cortex was
probed with antibodies to A$ by immunohistochemistry. Numerous
diffuse and neuritic amyloid plaques are labeled with the antibody

throughout the cortex but not in the subjacent white matter. E: Hirano
bodies in the hippocampus.
The right half of the section is stained with a standard H
& E preparation. The left half is the same section, which was
immunostained following removal of H & E dyes. These intraneuronal
rod-shaped inclusions are easily seen on the immunostained section
(left) as brown, rodlike structures. The same section was stained by
routine H & E technique; Hirano bodies are eosinophilic and more
subtle. Hirano bodies arise as a consequence of perturbations of the
microfilament system (i.e., actin, tropomyosin, vinculin, and alpha
actinin).

It is well established that the neurofibrillary pathology of

AD begins in the transentorhinal area and then progresses in a
stereotypical fashion next to the hippocampus, to adjacent medial
temporal lobe limbic areas, to neocortical association areas, and lastly
to primary sensory and motors areas (113,149). Neurofilaments and
microtubules are the two major components of the neuronal
cytoskeleton. Neurofilament provide structural support and promote
axonal and dendritic growth. Microtubules facilitate the transport of
materials between the cell body and its processes. Neurofibrillary
tangles are the end result of the breakdown of the microtubule
component of the neuro cytoskeleton. A component of the microtubule
system is tau protein. Neurofibrillary tangles consist of pathologic
aggregates of tau protein (148,150). These pathologic aggregates form
in the presence of hyperphosphoralation of the tau protein (Fig. 22.12).
In the hyperphosphoralated state, the tau protein is no longer able to
promote
assembly
and
stability
of
microtubules.
The
hyperphosphoralated tau disassociates from the microtubule, assumes
a paired helical filament configuration, and forms insoluble
neurofibrillary tangles inside neurons. The end result is collapse of the
microtubule system and the formation of dystrophic neuritis, which
contain abundant tau neurofibrillary tangles.

Figure 22-12. Neurofibrillary Tangles. Tau-stained

neurofibrillary tangles inside dystrophic neurites.
The second pathologic lesion associated with AD is the
senile (neuritic) plaque. A neuritic plaque consists of a dense central
beta amyloid core with inflammatory cells and dystrophic neurites in its
periphery. The beta amyloid core is made up of fragments of the
amyloid precursor protein, which have aggregated in the extracellular

space (151) (Fig. 22.13). Amyloid precursor protein (APP) is a single

transmembrane protein found normally in membranes of intracellular
organelles and cell membranes. Normal metabolism of APP includes
cleavage by alpha, beta, and gamma secretase, which results in
several fragments (152). The most important of these with respect to
AD pathology are the A1-40 and A1-42 fragments (153). These two
fragments aggregate into dense pleated sheets that form the central
core of amyloid plaques. Of the two, A1-40 is more abundant, while
A1-42 is more prone to coalesce into insoluble, extracellular -pleated
fibrils. A widely held view is that abnormal amyloid metabolism is the
causative or etiologic agent in AD (152,154). Abnormal extracellular
accumulation of insoluble amyloid A1-42 and A1-40 fibrils are felt
by many to represent the first step in the disease. The known genetic
mutations that result in the inevitable development of AD pathology
all appear to be related to abnormal amyloid metabolism. Individuals
with familial early onset AD as a result of AAP mutations as well as
individuals with Down syndrome (trisomy 21) "over produce" APP and
therefore A fragments as well. The presenilin-1 and presenilin-2
mutations associated with early onset familial disease are thought to
be related to impairments in
APP metabolism. With progressive accumulation of A1-40
and A1-42, extracellular amyloid plaques increase in size and attract
other proteins as well as an inflammatory response. Microglial are
found at the periphery of the amyloid core and astrocytes surround the
microglial. Injury and death of neurons may be from a direct cytotoxic
effect of amyloid, an inflammatory response to the developing plaques,
or both. Clinical symptoms result from cell death and injury.

Figure 22-13. Senile Plaque. Thioflavin staining of the

amyloid core of a senile plaque.
Structural MR Imaging in Alzheimer's Disease
Assessment of Cerebral Atrophy in Alzheimer's Disease by MR Imaging

Different approaches have been employed to assess brain

size with anatomic MR. Measures of atrophy can be divided into those
that assess hemispheric atrophy, and those that assess atrophy in
specific anatomic areas of the brain. Methods for assessing atrophy can

be divided into two general categories, visual ranking of scans, and

formal quantitative measures of particular anatomic features. Visual
ranking of cerebral atrophy represents an extension of the clinical
practice of neuroradiology in which the severity of cerebral atrophy is
commonly graded as mild, moderate, or severe.

The second approach to evaluating cerebral atrophy is

quantitative. Quantitative measures can be characterized as linear,
area, or volumetric (155). Because the brain and CSF spaces are
morphologically complicated three-dimensional structures, one might
assume that greater accuracy would be obtained with a volume
measurement than with a more simple linear or area measurement.
Cerebral atrophy is a negative phenomenon that does not
lend itself to traditional positive counting methods (for example
counting the number of the senile plaques or neurofibrillary tangles).
Therefore, cerebral atrophy must be characterized as a loss of brain
volume (or enlargement of the CSF spaces) relative to what should
have been present (156). At least three important variables affect brain
volume measurements in any individual, age, gender, and head size
(head size being a surrogate for height or body habitus). To evaluate
brain volume measurements in individual, elderly subjects, these
measurements must be adjusted for age, gender, and head size and
then referenced to an appropriate control population (157).
Diagnosis of Alzheimer's Disease: Clinical Studies
Different types of clinical studies have been performed in an
attempt to validate the utility of MR-based imaging measurements for
the diagnosis of AD. The published literature on this subject can be
divided into four categories depending on the study design employed.
These categories are: (a) Cross-sectional, case-control comparisons in
which the cases are patients with clinically well established AD; (b)
cross-sectional, case-control comparisons in which the cases are
patients with very mild AD; (c) Cross-sectional, case-control
comparisons in which the "cases" represent individuals who are at
elevated risk for developing AD, but who at the time of the study do
not meet established criteria for the diagnosis of AD; (d) Longitudinal
cohort studies.

The four types of clinical studies are listed above in

ascending hierarchical rank order in terms of their significance in
validating an imaging test as an early diagnostic marker of AD. Crosssectional, case-control comparisons in patients with clinically well

established AD constitute the least convincing evidence of the ability of

an imaging test to make an early diagnosis of AD, whereas prediction
of the subsequent risk of developing AD in clinically presymptomatic
patients constitutes the most convincing demonstration of the utility of
an imaging test for early diagnosis.
Cross-sectional Case-Control Studies of Clinically Well
Established Alzheimer's Disease
The initial step in identifying imaging markers that might
be useful for the early diagnosis of AD is to establish that a significant
difference in
an imaging measure exists between patients with
clinically well-established AD and age-matched elderly controls. An
imaging test that is significantly different between controls and
patients with established AD may not necessarily be very useful for the
early diagnosis of AD,
however, imaging markers that are not different between
controls and established AD patients are very unlikely to be useful for
early diagnosis. Much of the published literature to date on the use of
imaging for the diagnosis of AD has been based on this study
design(158-164).
While a number of different radiographic features have
been assessed, recent interest has focused on the hippocampus or
other medial temporal lobe structures with the intention of identifying
markers of early disease (Fig. 22.14). The rationale for the focus on the
medial temporal lobe has been (a) medial-temporal lobe limbic
structures, particularly the hippocampus, play a central role in memory
function, (b) memory impairment is the clinical hallmark of AD, (c)
modern MR can precisely depict medial-temporal lobe neuroanatomy.
Approaches include, visual ranking of the size of the hippocampus or
peri-hippocampal CSF spaces, linear measurements of the inter-uncal
distance, linear measurements of the medium thickness of the medial
temporal lobe, area measurements of the hippocampus, and volume
measurements of
the hippocampus or other named medial temporal lobe
limbic structures (156,165-175). The optimal approach is controversial,
and generally each research group advocates their own approach. The
sensitivity and specificity with which controls can be separated from
patients with well-established clinical AD has varied among different
published studies. The ability of an imaging measurement to separate
controls from AD patients clearly depends on the inclusion criteria used
for selecting both the control subjects and the AD patients. In any
particular study, the younger and healthier the control subjects and

the more severely impaired the AD group, the better the diagnostic
separation between controls and the AD patients.

A
B

Figure 22-14. (A) Cognitively Normal Elderly Control. 87year-old cognitively normal man. Autopsy confirmed the absence of
significant Alzheimer's Disease (AD) pathology. Note that while the
brain displays mild generalized atrophy in comparison to a young
individual, atrophy in the medial temporal lobes/hippocampi is not
pronounced. (B) AD. 88-year-old woman with a clinical diagnosis of
probable AD, which was confirmed at autopsy. Note the selective,
severe atrophy of the medial temporal lobes/hippocampi bilaterally.
Cross-Sectional, Case-Control Studies of Early Alzheimer's Disease
The clinical studies described in this section consist of a
comparison of controls to patients with clinically diagnosed AD whose
mean Mini-Mental State Examination (MMSE) score was e22. Although
this represents an arbitrary cutoff, the MMSE score is a universally used
instrument and therefore defining "early" AD by MMSE e22 is at least
operationally feasible. In most published anatomic MR studies of early
AD, some assessment of medial-temporal lobe atrophy has been
employed as the imaging metric. This includes visual ranking (mild,
moderate, severe) of medial-temporal lobe atrophy (176) formal
measures of hippocampal volume (177-179) combinations of medialtemporal and extra-temporal measures (161,180) or combinations of
different named medial-temporal lobe structures (171).
In our own study of anatomic MR measurements in early AD, we
performed MR-based volumetric measurements of the hippocampus,
parahippocampal gyrus, and amygdala in 126 cognitively normal
elderly control subjects and 94 patients probably with AD (181). AD
disease severity was staged by the clinical dementia (CDR) score.
Patients with CDR 0.5 were classified as very mild disease; those with a
CDR score of 1, mild disease; and those with a CDR score of 2,
moderate disease. Of the different medial-temporal lobe measures, the
hippocampal volume was best at discriminating control subjects from
AD patients. The mean hippocampal volumes for AD patients relative
to control subjects by severity of disease were as follows: CDR 0.5 AD,
-1.75 SD below the control mean; CDR 1 AD, -1.99 SD below the control
mean; and CDR 2 AD, -2.22 SD below the control mean. We therefore

observed an increase in the difference between controls and AD

patients as the severity of the impairment increased. The most
significant finding, however, was the ability of hippocampal volume
measurements to discriminate between control subjects and AD
patients with very mild disease. 97.2% of all CDR 0.5 AD patients had
hippocampal volumes below the 50th percentile of normal. These data
demonstrated that MR volume measurements of hippocampal atrophy
are a sensitive marker of the pathology of AD early in the disease.
Cross-Sectional, Case-Control Studies of Premorbid, At-Risk Patients

Several groups have performed cross-sectional studies

comparing anatomic MR measurements in controls to those in at-risk
subjects. "At risk" is defined as individuals who at the time of the study
do not meet clinical criteria for AD, but are at increased risk for
developing AD in the future. For example, individuals who carry the
e4 allele of apolipoprotein E, patients with a MCI, or patients with an
age-associated memory impairment (AAMI) (182-184).

We tested the hypothesis that MR-based measurements

of the entorhinal cortex are more sensitive than measurements of
hippocampal
volume in discriminating among three clinical groups;
controls, patients with MCI, and patients with clinically diagnosed
probable AD (185).
The motivation for this study was the following. Although
MR-based measurements of hippocampal atrophy have been shown to
be a
sensitive indicator of the early pathologic degeneration of
the medial temporal lobe in AD, AD pathology first appears in the
transentorhinal
cortex not the hippocampus. Entorhinal measurements
theoretically should, therefore, be more sensitive to the very earliest
structural
manifestations of AD, which might be present in at-risk
patients who were destined to convert to AD. We studied 30 controls,
30 MCI

patients, and 30 AD patients who were matched between

clinical groups on age, gender, and education (185). All underwent a
standardized
MR imaging protocol from which we made measurements
of hippocampal volume, entorhinal cortex, and the cumulative length
of the medial
border of the entorhinal cortex. Pairwise intergroup
differences (p <0.01) were found for all MR measurements and
between all groups with
the exception of the cumulative length of the entorhinal
cortex, which did not differentiate controls from MCI patients. While the
hippocampal
and entorhinal cortex volume measurements provide
slightly better intergroup discrimination than the entorhinal distance
measurement, overall
differences in discriminating ability among the three MR
measurements were minor. The data illustrate that despite the
theoretical rationale
for the superiority of entorhinal measurements in early AD
and presymptomatic at-risk patients (i.e., MCIs), we found MR
measurements of
the hippocampus and entorhinal cortex were
approximately equivalent at intergroup
discrimination. More
importantly, however, the data
demonstrate that clear differences between controls and
premorbid at-risk patients (i.e., MCIs) can be detected with MR.

Longitudinal Cohort Studies

The final category of clinical studies to consider are

longitudinal in design. Two different types of studies have been
performed. In the first,
patients are imaged only at the time of enrollment. A
group of patients who are elevated risk for developing AD (for example,
on the basis of

extreme old age, having MCI, or being an APOE e4 carrier)

but who, at the time of enrollment, do not meet criteria for AD, are
followed
longitudinally. In this type of study, the ability of an
imaging measurement to predict the future development of AD is
assessed. In the second
type of longitudinal study, patients are imaged at the
time of clinical enrollment and then later at the time(s) of repeat
clinical assessment(s).
This permits correlation between changes in imaging and
changes in clinical status.

Prediction of Alzheimer's Disease by a Single Imaging

Study

Several published studies fall under the category of using

a single baseline anatomic MR measurement at the time of enrollment
to predict
subsequent conversion to AD. Our own work in 0this area
employed MR-based hippocampal volume in patients with MCI to
predict future
conversion to AD (186). Eighty consecutive patients who
met criteria for the diagnosis of MCI were recruited from the Mayo
Clinic
Alzheimer's Disease Center/Alzheimer's Disease Patient
Registry. At entry into the study, each patient received an MR
examination of the
head from which the volumes of both hippocampi were
measured (Fig. 22.15). Patients were followed longitudinally with
approximately
annual clinical/cognitive assessments. The primary
endpoint was the crossover of individual MCI patients to the clinical
diagnosis of AD
during longitudinal clinical followup. During the period of
longitudinal observation, which averaged 32.6 months, 27 of the 80
MCI patients

became demented. Hippocampal atrophy at baseline was

significantly associated with crossover from MCI to AD (relative risk
0.69, p =
0.015) (Fig. 22.16).

Figure 22-15. Stable vs. cross-over mild cognitive

impairment (MCI). The column of images on the left are cropped
oblique
coronal magnetic resonance (MR) images through the
temporal lobes of a 75-year-old woman with MCI. The upper image
is through the body of the hippocampus and lower image
is through the head of the hippocampus. This MCI patient remained
stable over 49 months of clinical followup. At baseline her
hippocampal volume was slightly above average for controls. On
the right are matched imaging sections of a 70-year-old
woman, who was initially categorized as MCI, but become demented
after 43.5 months of follow-up. Her hippocampal volume
was highly atrophic with respect to controls. The hippocampi of the
patient who became demented (right) are visibly atrophic
relative to the stable patient (left) despite the fact that the
crossover patient was 5 years younger. The anatomic
outlines of the left hippocampus are indicated.

Figure 22-16. Hippocampal volume and crossover from

mild cognitive impairment (MCI) to Alzheimer's Disease.
Kaplan-Meyer curves of patients whose hippocampal W
score at baseline was W < 0 (i.e., > the expected mean for

controls), -2.5 <W <0 (i.e., between the control mean

and 1st percentile of controls), and W<-2.5 (i.e., < the 1st percentile
for controls).

When hippocampal volume was entered into bivariate

models using age, post-menopausal estrogen replacement, standard
neuropsychological
tests, apolipoprotein E, genotype, history of ischemic
heart disease and hypertension, the relative risks were not
substantially different from
that found univariately, and the associations between
hippocampal volume and crossover remained significant. We conclude
that in older
patients with MCI, hippocampal atrophy determined by
premorbid MR-based volume measurements is predictive of
subsequent conversion to
AD.

Vissur et al. (187) and Killiany et al. (188) have published

studies documenting the association between baseline MR volume
measurements
and subsequent conversion to AD in at-risk individuals.
deLeon et al. (189) employed visual rating of hippocampal atrophy at
baseline to
predict subsequent conversion.

Prediction and Clinical Characterization by Serial Imaging

Studies

We also have assessed the correlation between the rate

of hippocampal atrophy and the change in cognitive status of controls,
MCIs, and

AD patients over time (116). We identified 129 subjects

from the Mayo Clinic Alzheimer's Disease Research Center/Alzheimer's
Disease
Patient Registry who met established criteria for normal
controls, MCI or probable AD both at entry and at the time of a
subsequent clinical
followup evaluation three 1 year later. Each subject
underwent an MR examination of the head at the time of the initial
assessment and at
the time of the followup clinical assessment. The
annualized percentage change in hippocampal volume was computed.
Controls and MC
patients could either remain cognitively stable or could
decline to a lower functioning group over the period of observation.
This study allowed
us to test the hypothesis that the annualized rates of
hippocampal atrophy differ as a function of both baseline and change
in clinical group
membership (control, MCI, or AD). This also is equivalent
to testing the hypothesis that the rates of hippocampal atrophy were
significantly
associated with conversion to AD in individuals who were
either controls or MCI at baseline. The mean annualized rates of
hippocampal
atrophy by followup clinical group were: control-stable
1.73%, control-decliner 2.81%, MCI-stable 2.55%, MCI-decliner 3.69%,
and AD
3.5%. Within the control and MCI groups, those who
declined to a lower functioning clinical group over the course of
followup had a
significantly greater rate of volume loss than those who
remained clinically stable.

Kaye et al. (190) measured serial hippocampal and

parahippocampal volumes in 30 individuals who at baseline were
cognitively normal but

were at risk for developing AD on the basis of extreme old

age. Twelve of the 30 experienced significantly cognitive decline over
the period
of observation. They found more rapid volume loss in the
parahippocampal gyrus in decliners compared with stable elderly
individuals.

Fox et al. (114,191,192) have pioneered the

measurement of change in global cerebral volume from serial MR
studies. They studied 28
individuals who at baseline were asymptomatic, but who
were at risk for future development of AD because of a family history of
autosomal-dominant, early-onset (less than 65 years)
Alzheimer's disease (193). Five at-risk patients developed symptoms of
cognitive decline
during followup and subsequently progressed to fulfill
established criteria for probable AD. The median rate of atrophy of
1.5% per year in
these 5 individuals was significantly greater (p < 0.0005)
than the median rate of 0.2% in a comparable control group and also
significantly
greater than the median rate of 0.1% per year in the 23
at-risk individuals who remained asymptomatic. While minor overlap in
the annualized
rates of whole brain atrophy was present between the
members of the decliner group and the at-risk unaffected group, there
was no overlap
between the decliner group and the normal controls.
Other MR Techniques in Alzheimer's Disease

MR Spectroscopy

The primary 1HMRS abnormalities that have been

associated with AD are a decrease in N-acetyl aspartate (NAA) and an
elevation in

myoinositol (MI) (194,195). NAA is found in neurons and a

decrease in NAA follows logically from the neuron loss associated with
AD.
NAA also has been proposed as a marker of neuron
viability, as declines in NAA are reversible in some situations, for
example, reversible
ischemia, or epilepsy (196). This has lead some
investigators to advocate that a decline in NAA may precede cell loss in
AD, and thus
1HMRS may be a more sensitive marker of early disease
than anatomic MR. Myoinositol is located primarily in astrocytes. It is
elevated in
AD and Down syndrome, however the reason for this
elevation is not entirely clear. One intriguing possibility is that the
observed elevation in
myoinositol is a function of the glial activation associated
with neuritic plaques (197,198).

While the number of 1HMRS publications is far smaller

than the number of anatomic MR studies, a convincing body of
literature exists
documenting significant differences in certain 1HMRS
metabolites between controls and patients with established AD. As is
the case with
anatomic MR studies, for the most part the published
1HMRS literature has employed a cross-sectional case vs. control
comparison design
(183,194,195,199-203).

Fewer spectroscopic studies have been performed

comparing control subjects to at-risk subjects. We compared 1HMRS
findings in the
superior temporal lobe, posterior cingulate gyri, and
medial occipital lobe among 21 patients with MCI, 21 patients with
probable AD, and 63

elderly controls (197). These areas are known to be

involved at different neurofibrillary pathologic stages of AD. The
NAA/Cr ratios were
significantly lower in AD patients compared to both MCI
and normal control subjects in the left superior temporal and posterior
cingulate
volumes of interest. Myo-inositol (MI)/creatine (Cr) ratios
measured from the posterior cingulate VOI (volume of interest) were
significantly
higher in both MCI and AD patients than controls. These
findings suggest that the initial 1HRMS change in the pathologic
progression of AD
is an increase in MI/Cr. A decrease in N-acetylaspartate
(NAA)/Cr develops later in the disease.

Diffusion-Weighted Imaging

Diffusion-weighted MR (DWI) is an imaging technique that

is sensitive to the microscopic movement of water molecules in
biologic tissue
(204,205). Several cross-sectional case-control studies
have been published assessing the ability of DWI to differentiate
between controls and
clinically established AD patients (206-208). While
published results are not entirely consistent, in general, an increase in
diffusion values has
been seen in selected regions of interest (ROIs) in AD
patients compared to controls. Results on diffusion asymmetry are less
consistent,
with some studies reporting increased diffusion
asymmetry in AD, while in other studies diffusion asymmetry has not
been a prominent
feature of AD.

The Mayo Clinic group recently compared the ADC and

the anisotropy indices (AI) obtained from frontal, parietal, temporal,
occipital,
anterior, and posterior cingulate white matter, thalamic
and hippocampal regions of interest (ROI) in 21 probable AD, 19 MCI
patients, and 55
normal aging elderly controls without evidence of
cognitive impairment (209). The major finding of this study was a
bilateral elevation in
hippocampal ADC in both MCI and AD patients compared
to controls. Most importantly, hippocampal ADC were significantly
different
between controls and MCI patients, indicating that an
elevation in hippocampal ADC may reflect early microstructural
changes in the
progression of Alzheimer's pathology.

Sanson et al. (208) found an elevation in the ADC of the

parietal white matter in patients with established AD compared to
controls. Hanyu
et al. (207) found an elevation in ADC in the temporal
stem in patients with established AD compared to controls.

MR Perfusion

A characteristic bilateral temporal-parietal decrease in

cerebral blood flow has been well documented using nuclear medicine
techniques in
AD (210,211). Gonzales et al. (212) studied clinically
established AD patients with dynamic bolus tracking MR. The technique
provides
images of dynamic contrast susceptibility weighting that
mirror regional blood volume distribution. These dynamic contrast
susceptibility

images were compared to 18FDG PET studies in the same

patients and a high degree of concordance was found. Gonzales et al.
(212)
concluded that the characteristic bilateral temporal
parietal perfusion/metabolism defects seen with PET/SPECT in AD can
be identified with
dynamic contrast susceptibility MR techniques. Harris et
al. (213) used a similar MR technique and compared the results to
SPECT
measures of cerebral perfusion. The dynamic
susceptibility contrast MR approach compared favorably to SPECT in
distinguishing controls
from patients with established AD. More recently, Alsop et
al. (214) employed an MR measurement of cerebral perfusion using an
arterial
spin-labeling technique. They found significant perfusion
differences between controls and patients with established AD in the
temporal,
parietal, frontal, and posterior cingulate cortices (Fig.
22.17).

A
B

Figure 22-17. Perfusion MR in Alzheimer's Disease (AD)

compared with FT dementia. In AD, significant hypoperfusion is
seen predominantly in posterior parieto-occipital and to a
lesser extent frontotemporal regions (A). This is in distinction from
the hypoperfusion in frontotemporal dementia (B), where
the hypoperfusion is mainly in the frontal regions, and to a lesser
extent the parietal regions. (Courtesy of D. Alsop, Beth
Israel Medical Center, Boston, from Alsop DC, Detre JA,
Grossman M. Assessment of cerebral blood flow in
Alzheimer's disease by spin-labeled magnetic resonance imaging.

Annals of Neurology 2000;47:93-100, with permission)

Functional Activation

Medial temporal lobe functional activation in response to

declarative memory paradigms has been demonstrated in normal
young volunteers
by several investigators using functional MR (fMR) (215221). An fMR examination of declarative memory should serve as a
functional
medial-temporal lobe "stress test." This approach has
significant theoretical appeal because functional changes in response
to early AD
pathology should precede the gross anatomic changes
measured by structural MR (222). Functional MR activation studies in
aging and
dementia have been performed in small numbers of AD
patients at a few research sites (223,224). Investigators have been
able to
demonstrate decreased functional activation in the
medial-temporal region in patients with AD when compared to agematched controls. This
is an area of research that is just beginning to unfold and
it is being pursued at a number of research sites. Significant technical
problems
remain to be solved, however, including: fMR artifacts
from head motion, artifacts from magnetic susceptibility effects in the
medial-basal
temporal lobe, potential decreased vascular
responsiveness in elderly persons, and design of appropriate
paradigms for medial-temporal fMR
activation, which can be performed reliably by elderly and
impaired subjects.