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Overview

Current diagnosis of Alzheimer disease (Alzheimer's disease) is made by clinical, neuropsychological,


and neuroimaging assessments. Routine structural neuroimaging evaluation is based on nonspecific
features such as atrophy, which is a late feature in the progression of the disease. Therefore,
developing new approaches for early and specific recognition of Alzheimer disease at the prodromal
stages is of crucial importance.
Alzheimer disease was first described in 1907 by Alois Alzheimer. From its original status as a rare
disease, Alzheimer disease has become one of the most common diseases in the aging population,
ranking as the fourth most common cause of death. Alzheimer disease is a progressive
neurodegenerative disorder characterized by the gradual onset of dementia. The pathologic hallmarks
of the disease are beta-amyloid (A) plaques, neurofibrillary tangles (NFTs), and reactive gliosis.
(See the images and slideshows below.)
Coronal, T1-weighted magnetic resonance imaging (MRI) scan in a patient with
moderate Alzheimer disease. Brain image reveals hippocampal atrophy, especially on the right side.
Axial, T2-weighted magnetic resonance imaging (MRI) scan of the brain reveals
atrophic changes in the temporal lobes.
Click here to view a slideshow presentation on Alzheimer Disease. Click here to view the Alzheimer
Disease Radiograph slideshow.
Effective therapies to cure Alzheimer disease, or to simply halt or slow its progression, are still
lacking. A number of in vivo neuroimaging techniques that can be used to reliably and noninvasively
assess aspects of neuroanatomy, chemistry, physiology, and pathology hold promise. With time and
improvements in technology, these imaging techniques may yield acceptable neuroimaging
biomarkers for Alzheimer disease.
Although present therapy for Alzheimer disease involves enhancers of cholinergic function, disease-
modifying agents may be available in the future. Emphasis is being placed on detecting the
presymptomatic phase of the disease, which can be termed mild cognitive impairment (MCI).
Neuroimaging is also used to exclude other causes of dementia, such as normal-pressure
hydrocephalus, brain tumors, subdural hematoma, and multiple infarctions.
Preferred examination
Magnetic resonance imaging (MRI) can be considered the preferred neuroimaging examination for
Alzheimer disease because it allows for accurate measurement of the 3-dimensional (3D) volume of
brain structures, especially the size of the hippocampus and related regions.
Neuroimaging is widely believed to be generally useful for excluding reversible causes of dementia
syndrome, such as normal-pressure hydrocephalus, brain tumors, and subdural hematoma, and for
excluding other likely causes of dementia, such as cerebrovascular disease.
The practice parameters for the diagnosis and evaluation of dementia, as published by the American
Academy of Neurology (AAN), consider structural brain imaging optimal.
[1]
Nonenhanced computed
tomography (CT) scanning and MRI are the appropriate imaging methods.
[2]
The AAN suggests that
neuroimaging may be most useful in patients with dementia characterized by an early onset or an
unusual course.
There have been several studies of neuroimaging findings in Alzheimer disease. Van de Pol et al
found that medial temporal lobe atrophy seems to be a more important predictor of cognition than
small-vessel disease in MCI. Lacunes were associated with performance on the Digit Symbol
Substitution Test, especially in subjects with milder median temporal lobe atrophy (MTA). There was
no discernible association between white matter hyperintensities (WMHs) and the cognitive measures
in this study after adjustment for age.
[3]

Study of the dopamine transporter (DaTScan) is used to distinguish Lewy body dementia from
Alzheimer disease. Numerous studies are under way to identify specific imaging markers for different
types of dementia, including cerebral volumetric measurements, diffusion imaging, spectroscopy,
very-high-field MRI scans of senile plaques, and positron emission tomography (PET) scan markers
of senile plaques.
[4]

Blood-brain barrier (BBB) impairment is a stable characteristic over 1 year and is present in an
important subgroup of patients with Alzheimer disease. Age, gender,ApoE status, vascular risk
factors, and baseline Mini-Mental State Examination score did not explain the variability in BBB
integrity. BBB impairment as a possible modifier of disease progression is suggested by correlations
between the CSF-albumin index and measures of disease progression over 1 year.
[5]
The BBB is
dysfunctional in a portion of all patients with Alzheimer disease, primarily in men. BBB dysfunction
may influence the clearance of both harmful and beneficial substances across the barrier. Renal
function may have an impact on the BBB.
[6]

Pittsburgh Compound-B PET scan findings match histopathologic reports of A distribution in aging
and dementia. Noninvasive longitudinal studies to better understand the role of amyloid deposition in
the course of neurodegeneration and to determine if A deposition in nondemented subjects is
preclinical Alzheimer disease are now feasible. Our findings also suggest that A may influence the
development of dementia with Lewy bodies, and therefore, strategies to reduce A may benefit this
condition.
[7, 8, 9, 10]

De Leon et al concluded that the combined use of conventional imaging, such as MRI or
fluorodeoxyglucose PET (FDG-PET) scanning, with selected CSF biomarkers can incrementally
contribute to the early and specific diagnosis of Alzheimer disease. Moreover, selected combinations
of imaging and CSF biomarker measures are of importance in monitoring the course of Alzheimer
disease and, therefore, are relevant to evaluating clinical trials.
[11]

CT Scan
The initial criteria for CT scan diagnosis of Alzheimer disease includes diffuse cerebral atrophy with
enlargement of the cortical sulci and increased size of the ventricles. A multitude of studies indicated
that cerebral atrophy is significantly greater in patients with Alzheimer disease than in patients who
are aging without Alzheimer disease.
This concept was soon challenged, however, because cerebral atrophy can be present in elderly and
healthy persons, and some patients with dementia may have no cerebral atrophy, at least in the early
stages. The extent of cerebral atrophy was determined by using linear measurements; in particular,
bifrontal and bicaudate diameters and the diameters of the third and lateral ventricles. Various
measurements were adjusted according to the diameter of the skull to account for normal variation.
To complement this modification, volumetric studies of the ventricles were done. Despite these
efforts, it is still difficult to distinguish between findings in a healthy elderly patient and those in a
patient with dementia.
In addition, a review of serial CT scans obtained over several months was not clinically useful in the
primary diagnosis of the disease.
Rate of change of brain atrophy
Changes in the rate of atrophy progression can be useful in diagnosing Alzheimer
disease.
[12]
Longitudinal changes in brain size are associated with longitudinal progression of cognitive
loss,
[13]
and enlargement of the third and lateral ventricles is greater in patients with Alzheimer disease
than in control subjects.
[14]

Changes in brain structure
Diffuse cerebral atrophy with widened sulci and dilatation of the lateral ventricles can be observed.
Disproportionate atrophy of the medial temporal lobe, particularly of the volume of the hippocampal
formations (< 50%), can be seen.
Dilatation of the perihippocampal fissure is a useful radiologic marker for the initial diagnosis of
Alzheimer disease, with a predictive accuracy of 91%.
[15]
The hippocampal fissure is surrounded
laterally by the hippocampus, superiorly by the dentate gyrus, and inferiorly by the subiculum. These
structures are all involved in the early development of Alzheimer disease and explain the enlargement
in the early stages. At the medial aspect, the fissure communicates with the ambient cistern, and its
enlargement on CT scans is often seen as hippocampal lucency or hypoattenuation in the temporal
area medial to the temporal horn.
The temporal horns of the lateral ventricles may be enlarged. Prominence of the choroid and
hippocampal fissures and enlargement of the sylvian fissure may be noted. White matter attenuation
is not a feature of Alzheimer disease.
Degree of confidence
CT scan indices of hippocampal atrophy are highly associated with Alzheimer disease, but the
specificity is not well established. Use of a nonquantitative rating scale showed a sensitivity of 81%
and a specificity of 67% in differentiating 21 patients with Alzheimer disease with moderate dementia
from 21 age-matched control subjects.
[16]
Hippocampal volumes in a sample of similar size permitted
correct classification of 85% of control subjects.
[17]

MRI
Many studies have shown that cerebral atrophy is significantly greater in patients with Alzheimer
disease (Alzheimer's disease) than in persons without it. However, the variability of atrophy in the
normal aging process makes it difficult to use MRI as a definitive diagnostic technique. (See the
images below.)
Coronal, T1-weighted magnetic resonance imaging (MRI) scan in a patient with
moderate Alzheimer disease. Brain image reveals hippocampal atrophy, especially on the right side.
Axial, T2-weighted magnetic resonance imaging (MRI) scan of the brain reveals
atrophic changes in the temporal lobes. Axial, T2-weighted magnetic resonance imaging
(MRI) scan shows dilated sylvian fissure resulting from adjacent cortical atrophy, especially on the right side.
Axial, T1-weighted magnetic resonance imaging (MRI) scan shows a dilated sylvian
fissure caused by adjacent cortical atrophy. Axial, T1-weighted magnetic resonance
imaging (MRI) scan shows bilateral cortical atrophy with accentuated cortical sulci; there is decreased involvement in
the posterior aspect. Axial, T1-weighted magnetic resonance imaging (MRI) scan
shows bilateral cortical atrophy with accentuated cortical sulci; there is decreased involvement in the posterior aspect.
Fox et al used an automated technique that is potentially applicable in the clinical setting to subtract
MRI scans obtained an average of 1 year apart. They observed that there was a significant difference
between the rate of change in patients with Alzheimer disease and the rate in control subjects. With
MRI, sensitivity and specificity were approximately 90% for predicting the decline in dementia.
[18]

Early MRI studies to evaluate the size of the hippocampus in patients with Alzheimer disease relative
to control subjects showed large reductions in hippocampal volumes (approximately 50%) and high
sensitivity and specificity for classification.
[19]
Over time, enlargement of the temporal horns, as well as
of the third and lateral ventricles, was noted in patients with Alzheimer disease compared with control
subjects.
On structural MRI, atrophy of the entorhinal cortex is already present in MCI. In the autosomal-
dominant forms of Alzheimer disease, the rate of atrophy of the medial temporal structures
differentiates affected individuals from control subjects as early as 3 years before the clinical onset of
cognitive impairment. The accelerated annual rate of brain atrophy is a surrogate tool for evaluating
new therapies in small samples that saves time and resources.
MRI measurements of the hippocampus, amygdala, cingulate gyrus, head of the caudate nucleus,
temporal horn, lateral ventricles, third ventricle, and basal forebrain yield a prediction rate of 77% for
conversion to Alzheimer disease from questionable Alzheimer disease.
[20, 21]

Functional MRI (fMRI) techniques can be used to measure cerebral perfusion. Dynamic susceptibility
contrast (DSC) MRI consists of the passage of a concentrated bolus of a paramagnetic contrast agent
that sufficiently distorts the local magnetic field to cause a transient loss of signal with pulse
sequences, especially T2-weighted sequences. The passage of contrast material is imaged over time
by sequential rapid imaging of the same section. In animal studies, the rate of change of signal
intensity over time gives a measure directly proportional to cerebral blood volume. Studies in humans
have shown a correlation between PET and DSC MRI scan results, as well as between cerebral blood
volumes measured with DSC MRI and perfusion on single-photon emission computed tomography
(SPECT) scanning.
Studies have been performed using MRI with echo-planar imaging and signal targeting with
attenuation radiofrequency (EPISTAR) in patients with Alzheimer disease. Focal areas of
hypoperfusion were in the posterior temporoparietooccipital regions. Ratios of signal intensity in the
parieto-occipital and temporo-occipital areas to signal intensity on whole section signal intensity were
significantly lower in the patients with Alzheimer disease than in those without it. The parieto-occipital
ratios were not correlated with the severity of dementia, as measured by using the Blessed Dementia
Scale Information Memory Concentration subset.
With fMRI, structural imaging can be done by using the same imaging plane, field of view, and section
thickness. Activational fMRI studies have included blood oxygenation leveldependent (BOLD)
imaging, which uses changes in the level of oxygenated hemoglobin in capillary beds to depict areas
of regional brain activation. In Alzheimer disease, fMRI activation in the hippocampal and prefrontal
regions is decreased.
On fMRI, paradigms activate a larger area of parietotemporal association cortex in persons at high
risk for Alzheimer disease than in others, whereas the entorhinal cortex activation is relatively low in
MCI.
[22]

The techniques are reasonably sensitive and specific in differentiating Alzheimer disease from
changes resulting from normal aging, and studies with pathologic confirmation show good sensitivity
and specificity in differentiating Alzheimer disease from other dementias. These techniques can also
be used to detect abnormalities in asymptomatic or presymptomatic individuals, and they may help in
predicting the decline to dementia.
Degree of confidence
MRI findings of hippocampal atrophy are highly associated with Alzheimer disease (Alzheimer's
disease), but the specificity is not well established.
[23]
Studies have shown that in patients with
Alzheimer disease and moderate dementia, hippocampal volumes permitted correct classification in
85% of patients.
[24]
In patients with Alzheimer disease and mild dementia, sensitivity was 77%, and
specificity, 80%.
[25]
Hippocampal volume was the best discriminator, although a number of medical
temporal-lobe structures were studied, including the amygdala and the parahippocampal gyrus.
False positives/negatives
Hippocampal atrophy appears to be a feature of vascular disease (multi-infarct dementia)
and Parkinson disease, even in patients with Parkinson disease without dementia. Hippocampal and
entorhinal cortical atrophy are features offrontotemporal dementia, but they do not appear to be as
profound as atrophy is in Alzheimer disease (Alzheimer's disease).
[26]

SPECT Scanning
Single-photon emission computed tomography (SPECT) scanning uses direct photon-emitting
isotopes rather than radioisotopes. SPECT isotopes have an average half-life of 6-12 hours.
SPECT instrumentation is highly variable; therefore, use of a SPECT scanner with poor resolution can
result in poor clinical performance. Positron-emission tomography (PET) scanning uses tracers that
measure regional glucose metabolism (rCMRGlc). SPECT imaging is most commonly used for blood-
flow measurement.
Early SPECT studies of blood flow replicated findings of functional reductions in the posterior
temporal and parietal cortex. The severity of temporoparietal hypofunction has been correlated with
the severity of dementia in a number of studies.
[12, 27, 28]

Reductions of blood flow and oxygen use can be found in the temporal and parietal neocortex in
patients with Alzheimer disease and moderate to severe symptoms.
[16]
Early reductions of glucose
metabolism are seen in the posterior cingulate cortex.
SPECT scanning is not commonly used to assess Alzheimer disease. SPECT scanning is useful in
the diagnostic assessment of Alzheimer disease if standardized and semiquantitative techniques are
used.
Trollor et al examined 18 patients with early Alzheimer disease and 10 healthy, elderly control
subjects with high-resolution SPECT scanning during their performance of a simple word-
discrimination task and observed a gradation of regional cerebral blood flow (rCBF) values in both
groups. The lowest values were in the hippocampus and the highest in the striatum, thalamus, and
cerebellum. In the study, SPECT images were coregistered with individual MRI scans, allowing for the
delineation of predetermined neuroanatomic regions of interest (ROI).
[17]

Compared with healthy control subjects, patients with Alzheimer disease had low relative rCBF in the
parietal and prefrontal cortices. Analysis of individual the ROI demonstrated bilateral reduction of
rCBF in the prefrontal poles and posterior temporal and anterior parietal cortex, with unilateral
reduction of rCBF in the left dorsolateral prefrontal cortex, right posterior parietal cortex, and left
cingulate body. No significant differences in hippocampal, occipital, or basal ganglia rCBF were found.
Discriminant function analysis indicated that rCBF in the prefrontal polar regions permitted the best
classification.
[17]

In class II studies, the sensitivity of SPECT scanning was lower than that of the clinical
diagnosis.
[29]
Sensitivity increased as the severity of dementia worsened, but the pretest probability of
Alzheimer disease increased as well.
[30]

The added value of SPECT scanning was greatest for a positive test among patients with mild
dementia in whom the diagnosis of Alzheimer disease was substantially doubted.
[31]
In this situation, a
positive SPECT scan result would have increased the posttest probability of Alzheimer disease by
30%, whereas a negative test result would have increased the likelihood of the absence of Alzheimer
disease by only 10%.
[32]

Degree of confidence
Without surprise, clinically validated SPECT scan studies showing differences between patients with
Alzheimer disease (Alzheimer's disease) and control subjects reveal high sensitivities and specificities
of 80-90%.
[32]

In one study, investigators compared patients from a dementia clinic with a community sample of
control subjects using quantitative SPECT scanning and reported a 63% sensitivity and an 87%
specificity. Alzheimer disease was defined in the study as temporal-lobe perfusion more than 2
standard deviations below control values.
Holman et al found that bilateral temporoparietal hypoperfusion had a positive predictive value of 82%
for Alzheimer disease.
[33]
Using inhaled xenon-133 (
133
Xe) and injected technetium-99m
[
99m
Tc]hexamethylpropyleneamine oxime, researchers reported a sensitivity of 76% and a specificity
of 73%, with a positive predictive value of 92% and a negative predictive value of 57%.
[34]
These
studies may assist in the early and late diagnosis of Alzheimer disease and with the differential
diagnosis of dementias.
PET Scanning
PET scanning is a powerful imaging technique that enables in vivo examination of brain functions. It
allows for noninvasive quantification of cerebral blood flow, metabolism, and receptor binding. PET
scanning helps in understanding the disease's pathogenesis, making the correct diagnosis, and
monitoring the disease's progression and response to treatment.
[35]

PET scanning involves the introduction of a radioactive tracer into the human body, usually with an
intravenous injection. A tracer is essentially a biologic compound of interest that is labeled with a
positron-emitting isotope, such as carbon-11 (
11
C), fluorine-18 (
18
F), or oxygen-15 (
15
O). These
isotopes are used because they have relatively short half-lives (from minutes to < 2h), allowing the
tracers to reach equilibrium in the body without exposing the subjects to prolonged radiation.
The 2 most common physiologic process measurements performed using PET scanning are glucose
with [
18
F]FDG and cerebral blood flow using water.
[23]

FDG-PET has been used extensively to study Alzheimer disease, and it is evolving into an effective
tool for early diagnosis and for differentiation of Alzheimer disease from other types of dementia.
FDG-PET has been used to detect persons at risk for Alzheimer disease even before the onset of
symptoms.
[36]

Patients with Alzheimer disease have characteristic temporoparietal glucose hypometabolism, the
degree of which is correlated with the severity of dementia.
[37]
(Temporal and parietal glucose
hypometabolism is widely seen on PET images in patients with Alzheimer disease.) With disease
progression, frontal involvement may be evident. Glucose hypometabolism in Alzheimer disease is
likely to be caused by a combination of neuronal cell loss and decreased synaptic activity.
[38]

In control subjects, entorhinal cortex hypometabolism on FDG-PET has predictive value in the
progression of dementia to MCI or, even, to Alzheimer disease.
[39, 40]
The identification of asymptomatic
individuals at risk will have an enormous role in the treatment strategy for Alzheimer
disease.
[41]
Individuals at high risk for Alzheimer disease (asymptomatic carriers of the APOE*E4
allele) exhibit a pattern of glucose hypometabolism similar to that of patients with Alzheimer disease.
After a mean follow-up of 2 years, the cortical metabolic abnormality continues to decline despite
preservation of cognitive performance.
[42, 40]

In patients with Alzheimer disease, PET performed with ligand PK11195 labeled with
11
C, or (R)-[
11
C]
PK11195, showed increased binding in the entorhinal, temporoparietal, and cingulate cortices. This
finding corresponded to the postmortem distribution of Alzheimer disease pathology.
[43]

Degree of confidence
Despite the technical differences, results from PET and SPECT scanning are comparable, although
data suggest that PET scanning is more sensitive than SPECT scanning.
[44]
On PET or SPECT
scanning, mild Alzheimer disease may be more difficult to detect than moderate or severe disease. In
Alzheimer disease, FDG-PET has a sensitivity of 94% and a specificity of 73%. It can also be used to
correctly predict a progressive course of dementia with a 91% sensitivity and a nonprogressive course
with a 75% specificity.
[45]
Efforts to develop a specific ligand for A plaques may further enhance the
sensitivity of PET scanning for early diagnosis of Alzheimer disease and may provide a biologic
marker of disease progression.
[43]

In their study, Boxer et al reported that different amyloid-binding PET scan agentsPittsburgh
Compound-B and FDDNPmay have differential sensitivity to prion-related brain pathology and that
a combination of amyloid imaging agents may be useful in the diagnosis of early onset dementia.
[46]

Florbetapir F 18 (AMYViD) was approved by the FDA in April 2012 as a diagnostic imaging agent. It is
indicated for PET brain imaging of beta-amyloid neuritic plagues in adults being evaluated for
Alzheimer disease or other cognitive decline.
Approval for florbetapir F 18 was based on 3 clinical studies that examined images from healthy adult
patients as well as patients with a range of cognitive disorders, including some terminally ill patients
who had agreed to participate in a postmortem brain donation program. Measurements from
postmortem cortical amyloid burden correlated with median florbetapir F 18 scores (r=0.78; P<
0.0001).
[47]

In a study by Clark et al, the presence and density of beta amyloid correlated closely in individuals
who had florbetapir-PET imaging within 99 days before death and then upon autopsy.
[48]
Patients with
probably Alzheimer disease, mild cognitive impairment, or older healthy controls showed significantly
different mean cortical florbetapir uptake value ratios in a study by Fleisher et al.
[49]

In October 2013, the FDA approved the a second 18F-labeled Pittsburgh compound B (PIB)
derivative, flutemetamol F18 injection (Vizamyl), for use with PET brain imaging in adults undergoing
evaluation for Alzheimer disease and dementia. Like florbetapir F18, flutemetamol F18 attaches to
beta-amyloid in the brain and produces a PET image that can be used to assess its presence. A
positive scan indicates there is likely a moderate or greater amount of amyloid in the brain, but it does
not establish a diagnosis of Alzheimer disease or other dementia. The effectiveness of flutemetamol
F18 was established in 2 clinical studies with 384 participants who had a range of cognitive
function.
[50]












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