Dr. Mehta is an Associate Professor of Radiology, and Dr. Thomas is a Radiology Fellow, at the University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH.
Dementia is an acquired, progressive, global impairment of
intellectual functioning involving memory, language, thinking, and
perception. This disorder can be caused by more than 80 diseases, a few
of which can be reversible. Dementia can present a diagnostic challenge
to clinicians as there can be much overlap between the various causes
(Table 1). In addition, several of the diseases share common
histopathologic and clinical features, and rather than reflecting
discrete entities, are felt to be part of a spectrum of
neurodegenerative syndromes.1,2 Currently, 35 million people
worldwide are affected by dementia, with 5 million new cases added every
year. In the absence of new treatment breakthroughs, 80 million cases
are predicted by 2040,3 with the rising prevalence due mainly to increasing life expectancy.
Criteria for dementia
The clinical diagnosis of dementia is based mainly on clinical criteria, such as those delineated in the DSM-IV and DSM-TR.4
The criteria will be revised this year, but currently they consist of
the development of multiple cognitive deficits, including impairments in
memory andin at least one of the following: language, motor activity,
recognition, and executive function. In addition, the cognitive deficits
must be severe enough to interfere with social/professional function,
and they must represent a decrease from baseline.
A diagnosis of
dementia should not be made if the cognitive deficits occur exclusively
during the course of a delirium. However, dementia may be related
etiologically to a general medical condition, cerebrovascular disease,
persisting effects of substance abuse (including toxin exposure),
infections like HIV, or multiple other etiologies. Alzheimer’s disease
(AD) is usually diagnosed by excluding the above etiologies; each of
these is classified as a separate category in DSM-TR.
Neuronuclear imaging applications in dementia
undergoing a dementia work-up must have a comprehensive clinical exam
that includes a medical history obtained from both the patient and a
well-acquainted informant, cognitive scales or neuropsychological
testing, laboratory tests, and structural imaging, such as magnetic
resonance imaging (MRI) and computed tomography (CT). Single photon
emission computed tomography (SPECT) has historically been the modality
of choice for functional neuroimaging in the dementia work up, but is
being replaced by positron emission tomography (PET). SPECT mainly
assesses perfusion, while PET focuses primarily on metabolism, with both
presenting similar diagnostic information. The advantages of PET over
SPECT include better spatial resolution and the ability to quantify
changes. In addition, the magnitude of hypometabolism seen with 18FDG-PET is frequently greater than that seen with SPECT.5
Common tracers for SPECT imaging include the cerebral blood flow agents
99m-Tc hexamethylpropyleneamineoxime (HM-PAO) and technetium Tc-99m
bicisate. F-18 fluorodeoxyglucose (FDG) is the most commonly used agent
in PET imaging. As a glucose analogue, FDG reflects cerebral glucose
metabolism(Figure 1). Other PET agents are being developed to assess
more specific cellular and neurotransmitter activities; several are
discussed later in this article.
Protocol standardization is
important for consistent FDG brain-PET imaging. The brain-PET protocol
in our department includes securing intravenous (IV) access 15 minutes
prior to injection, which minimizes stress. In addition, to minimize
activation of the visual cortex and other brain centers, patients are
provided with a comfortable resting place in a stress-free, quiet,
semi-dark environment during the radiopharmaceutical uptake phase.
Sedation, if necessary, should be performed after radiopharmaceutical
dosing. The scan itself is performed in a comfortable but standardized
position with contemporaneous acquisition of low-dose CT images for
attenuation correction. Postprocessed images are digitally coregistered
and reconstructed in the orthogonal planes for interpretation. The
software used in our department also allows for digital coregistration
Alzheimer’s disease (AD)
AD, the most
common form of dementia, was originally described in 1907 by the German
psychiatrist and neuropathologist, Alois Alzheimer, who presented
clinical and neuropathological features of a demented woman who died at
age 51. Alzheimer noted postmortem pathology findings of thinned
cerebral cortex, senile plaques, and neurofibrillary tangles (Figure 2),
which are still considered to be pathologic hallmarks of the disease.
AD is estimated to cause approximately 70% of all dementias. The age of
onset is typically between 40 and 90 years,with greater incidence in
those ≥65 years of age. The prevalence of the disease rises
exponentially with age, increasing from 3% in those aged50-75 years to
50% among those ≥80 years old.6 The risk factors for AD are summarized in Table 2.
is a major health problem, bringing enormous economic, social, and
personal costs. Data from the National Institute of Aging, a division of
the U.S. National Institutes of Health, indicate that 5.1 million
Americans currently have AD and the cost of care approaches $148 billion
per year. Based on its current incidence, the aging of baby boomers,
and the absence of effective prevention, an estimated 72 million people
will be affected with AD in 2030.7
is a progressive neurodegenerative disease that results in irreversible
loss of brain cells. The disease usually begins with mild memory
problems and ends with severe brain damage, severe memory loss,
confusion, depression, hallucinations, delusions, restlessness,
sleeplessness,and loss of appetite. The most common and distinctive
hallmark histologic brain lesions are senile plaques and neurofibrillary
tangles (NFTs).The disease is felt to represent a spectrum that extends
from mild cognitive impairment (MCI) to severe AD. In MCI, patients
demonstrate decreased memory or language that is severe enough to be
noticeable but not severe enough to interfere with daily life; it is
seen in up to 20% ofAmericans and has 2 subtypes — nonamnesiac and
amnesiac. Patients in the nonamnesiac category present with behavioral
changes, including alterations in language, judgment, and attention.
Patients with the amnesiac variety are often aware of memory issues and
are still able to function effectively. Not all patients with MCI will
progress to AD; annually, 10% to 15% of patients with amnesiac MCI will
progress, while others may improve with time. PET imaging can help with
early identification and interventions in those who may progress.8 Standardized
primary cognitive assessments, such as the mini-mental state
examination (MMSE), provide a brief, focused survey of cognitive domains
most often affected in AD and allow for objective documentation of
Role of PET in the diagnosis of AD
imaging with MRI, SPECT, and PET can improve diagnostic accuracy in
differentiating AD from potentially treatable causes of dementia such as
toxic metabolic states, depression, and normal pressure hydrocephalus.
When PET results are combined with clinical criteria, the false positive
rate in AD can be reduced from 23% to 11%.9 The classic
pattern of AD on PET imaging is bilateral temporoparietal and posterior
cingulate cortex hypometabolism (Figures 3 and 4); abnormal metabolism
can also be seen asymmetrically, particularl yearly in the disease.
Frontal lobe involvement may also be seen in later stages (Figure 5).
The exact cause for the decline in brain glucose metabolism in AD
remains unclear. Hippocampal atrophy may be seen on conventional
cross-sectional imaging.10,11 Hoffman et al showed that
FDG-PET demonstration of the classic metabolic abnormality in patients
with pathologically verified AD has a sensitivity of 93%, a specificity
of 63%, and an accuracy of 82%.10 Sparing of primary
neocortical areas, including the sensorimotor cortex, visual cortex,
subcortical gray matter, basal ganglia, thalami, and cerebellum could
help differentiate AD from subcortical causes of dementia like
Parkinson’s dementia, vascular dementia, etc. FDG-PET imaging can also
help evaluate MCI. A large multicenter study showed that MCI patients
demonstrated primarily posterior cingulate cortex and hippocampal
hypometabolism (81%); neocortical abnormalities varied according to
neuropsychological profiles.A classical AD metabolic pattern was
observed in 79% of MCI patients who presented with deficits in multiple
cognitive domains and in 31% of patients with amnesic MCI. FDG-PET
abnormalities in nonamnesiac MCI ranged from normal metabolism to
patterns resembling frontotemporal dementia and diffuse Lewy body
disease, suggesting another dimension to the spectrum of AD.12 Preliminary
PET data show a promising ability to predict progression from MCI to
AD. Landau et al evaluated multiple markers for disease progression and,
among their findings, noted that patients with abnormal results on
FDG-PET and with abnormal episodic memory were 11.7 times more likely to
convert from MCI to AD.13
A meta-analysis of 15
articles published between 1989 and 2003 demonstrated a sensitivity of
86% (95% confidence interval [CI]:76%, 93%) and a specificity of 86%
(95% CI: 72%, 93%) for FDG PET14 in the diagnosis of AD.
However, recent studies on larger patient populations demonstrate
sensitivities approaching 93% to 95% in AD12,15 (Table 3).
Early and accurate AD diagnosis is important for patients to derive the
maximum benefit from available pharmacologic and cognitive therapies.
Although no definitive treatment orcure is available for AD at this
time, different pharmacologic agents are being actively investigated;
several are available to treat symptoms of the disease. Cholinesterase
inhibitors like Aricept, the most widely used and only FDA-approved drug
for all stages of AD, improves acetylcholine levels, which are
deficient in all stages of the disease. Available data suggest that
approximately 15% to 40% of AD patients treated with the drug show
varying degrees of cognitive improvement. Another drug, Namenda,
approved for moderate-to-severe AD, is thought to regulate glutamate, a
neuroprotective agent, which can reduce oxidative stress. Early
diagnosis of AD also allows for contemporaneous initiation of
palliative, psychosocial, and cognitive therapies, as well as initiation
of support systems. It also provides the patient adequate time to
address personal, financial, and legal ramifications of the disease.
et al performed a decision analysis to compare the relative value of a
conventional approach (based on clinical criteria for the presence of
dementia and excluding nonAD etiologies that could contribute to
patients’ symptoms) versus an FDG-PET-based strategy.16 The
PET algorithm reduced false-negative and false-positive findings
compared to the conventional clinical approach (3.1% vs. 82%, and12% vs.
23%, respectively, at a prevalence rate of 51.6% in the group). A cost
saving of $1,138 per correct diagnosis and a lower cost-per-unit benefit
were maintained over a wide range of tested values for sensitivity,
specificity, cost of PET, and long-term care. Silverman concluded that
using PET in the work-up of early dementia in elderly patients can
contribute significantly and economically to the evaluation and
treatment of these patients. The Center for Medicare and Medicaid
Services (CMS), in a decision memorandum on Sept.15, 2004, ruledthat FDG
brain-PET scans are reasonable and necessary in patients with a
recently established diagnosis of dementia with cognitive decline
documented for at least 6 months. Eligible patients are to have met the
criteria for both AD and/or frontotemporal dementia (FTD) and to have
already been evaluated for specific alternative degenerative diseases or
causative factors. Medicare also covers FDG-PET in CMS approved
practical clinical trials that focus on the utility of FDG-PET in the
diagnosis or treatment of mild cognitive impairment or early dementia.17
has been shown to provide important prognostic information in dementia.
A negative PET scan is indicative of unlikely progression of cognitive
impairment for a mean follow-up of 3 years in those patients who
initially present with cognitive symptoms of dementia.18
Diffuse Lewy body disease (DLB)
is the second most common cause of dementia, accounting for 15% to 20%
of all cases. Fluctuating cognition, visual hallucinations, and lowered
attention span often precede memory loss; this contrasts with AD, in
which prominent and progressive memory loss often precedes
neuropsychiatric features. Patients with DLB may also demonstrate
Parkinsonian-like symptoms. The specificity for diagnosis based on
clinical criteria is variable (30% to 100%); sensitivity is low (22% to
75%).19 The pattern of FDG metabolism in DLB differs fromAD;
in contrast to the classic appearance of bilateral temporal-parietal
reductions in FDG metabolism with AD, DLB commonly appears as globally
reduced cortical metabolism, most notably in the visual association
cortex of the occipital lobe (Figure 6). The reduction in occipital
glucose metabolism in DLB can differentiate DLB from AD with a
sensitivity of 86% to 90% and a specificity of 80% to 91%.19,20
The reason for the selective involvement of the occipital region is
unclear and has been attributed to the degeneration of dopaminergic
neurons or cholinergic neurons from the basal nucleus of Meynert;
imaging with dopaminergic ligands has been suggested to increase
specificity for diagnosis of the disease. In addition, the relative
preservation of the mid- or posterior-cingulate gyrus metabolism
(cingulate island sign) may enhance PET specificity in differentiating
DLB from AD.
movement disorder originally described in 1817 by James Parkinson,
Parkinson’s disease (PD) is characterized by the deterioration of
neurons in the substantia nigra, resulting in decreased dopamine levels.
Cognitive deficits appear in the late stage of the disease in about 41%
of the patients with PD; these may range from isolated cognitive
impairment to severe dementia. Imaging features of the disease often
correlate with an AD-type pattern on functional FDG-PET imaging,
although more occipital involvement and more sparing of the
mesiotemporal area may be seen with PD. A recent study suggests that
more extensive changes may actually be seen in PD patients with
dementia;21 this study compared 18-FDG and 11-C PIB metabolic
patterns along with structural changes on MRI in nondemented
Parkinson’s (PD) and demented Parkinson’s (PDD) patients, with healthy
patients serving as controls. Their data suggest that the development of
dementia in PD may also be associated with frontal lobe atrophy on MRI,
with extension of hypometabolism on FDG-PET beyond the occipital lobe
into the frontal lobe, and even through more diffuse brain areas, such
as the deep brain structures. The degree of glucose hypometabolism was
associated with the degree of cognitive impairment. Beta amyloid
deposition is not believed to be a hallmark of PD dementia; if seen
postmortem, its presence is thought to reflect the coincidental
development of Alzheimer’s disease.
Frontotemporal lobar dementia (FTD)
is a general term for a diverse group of disorders associated with
selective degeneration of the prefrontal and anterior temporal cortex.
Given the distribution of the cortical abnormalities, salient clinical
characteristics of these disorders include profound alterations in
personality and social conduct, agnosia, and impulsivity. These symptoms
occur in the context of relative preservation of the instrumental
functions of perception,spatial skills, praxis, and memory.22
disease accounts for the largest proportion (at least 70%) of patients
with frontotemporal lobar degeneration; the disease is characterized by
the presence of Pick bodies, protein tangles in neuronal tissues.
Disease onset tends to occur at a younger age than that of AD,with the
most common incidence occurring between ages 45 and 65; the disorder can
also present before age 30, as well as in the elderly.The cause of
Pick’s disease is unknown; some forms of inherited frontal lobe dementia
can be indistinguishable, clinically and histologically, from Pick’s
Differentiating between FTD and AD is currently based on
clinical data and examination, but the distinct metabolic patterns of
both diseases as seen on PET can significantly improve diagnostic
accuracy. A prospective FDG-PET study evaluated 22 patients with FTD who
underwent both baseline and follow-up scans during an average duration
of 19.5 months. PET demonstrated symmetrical hypometabolism of the
frontal lobes with relative sparing of the motor cortex, caudate nuclei,
insula, and thalami at baseline.23 At follow-up, further
significant reductions in glucose metabolism were observed in the
parietal and temporal cortices. The use of FDG-PET stereotactic surface
projection (SSP) metabolic and statistical maps have been shown to
improve sensitivity of PET in early diagnosis of FTD.20
Preliminary data from neurochemical studies of FTD patients, as well as
functional PET imaging using serotonin receptors, have indicated
abnormalities in serotonin metabolism, which has led to clinical trials
of drugs with serotoninergic effects.
the past few years, much attention has focused on the development of
radiotracers for PET imaging of more specific pathologic processes,
including agents that detect the beta-amyloid deposits, the
neurofibrillary tangles, and other processes in AD. The deposition of
beta-amyloid (Aβ) is thought by many to be an early event in the
pathogenesis of AD. Pittsburgh Compound B (C11PIB), a thioflavine analogue, was the first tracer used to selectively label Aβ in vivo. A relatively simple and practical way to quantify Aβ uptake in vivo in a clinical setting is by quantifying C11PIB
binding. In AD, marked PIB retention occurs in areas of ß-amyloid
deposition, such as in the temporoparietal cortex. Recent studies
indicate a future potential use for C11PIB in predicting time of progression of MCI to AD.24
Cholinergic agents are also being developed for PET imaging and may
provide additional evidence for the cholinergic hypothesis of AD, as
well as provide insight into the functional mechanisms of novel drug
therapies directed to the cholinergic system.
The evaluation of
dopamine receptor integrity with carbon-11 dihydrotetrabenazine (DTBZ)
has also been extensively researched in patients with diffuse Lewy body
disease and Parkinson’s disease. Early studies suggest that the
distribution volume of DTBZ is significantly decreased in the caudate
nuclei and putamen in DLB and PD patients compared to patients with AD.25 Several other agents are in the pipeline for targeted receptor imaging, several of which are mentioned in Table 4.
role of PET in the clinical workup and management of dementia is
expected to increase in the near future, not only for preclinical and
differential diagnoses but also for the evaluation of response to novel
therapies that are currently in development. The widespread availability
ofPET scanners, along with new and improved quantitative analysis
methods, has improved scan quality and diagnostic information provided
by these studies. Data suggest that including PET in the diagnostic
algorithm of patients with dementia can result in more cost-effective
and accurate diagnoses, particularly in differentiating DD from FTD.
Kertesz A. Pick Complex: An integrative approach to frontotemporal
dementia: Primary progressive aphasia, corticobasal degeneration, and
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- Kertesz A, Hudson L, Mackenzie IR, Munoz DG. The pathology and nosology of primary progressive aphasia. Neurology. 1994;44:2065-2072.
- Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: A Delphi consensus study. Lancet. 2005;366:2112-2117.
- DSM-IV-TR: The Current Manual. http://www.psych.org/MainMenu/Research/DSMIV/DSMIVTR.aspx. Accessed January 13, 2011.
DH. Brain 18F-FDG PET in the diagnosis of neurodegenerative dementias:
Comparison with perfusion SPECT and with clinical evaluations lacking
nuclear imaging. J Nucl Med. 2004;45:594-607.
- Zhu CW, Sano M. Economic considerations in the management of Alzheimer’s disease. Clin Interv Aging. 2006;1:143-154.
- General Information. http://www.nia.nih.gov/Alzheimers/AlzheimersInformation/GeneralInfo/. Accessed January 13, 2011.
- Schuff N, Zhu XP. Imaging of mild cognitive impairment and early dementia. Br J Radiol. 2007;80 Spec No 2:S109-14.
DH, Cummings JL, Small GW, et al. Added clinical benefit of
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- Hoffman JM, Welsh-Bohmer KA, Hanson M, et al. FDG PET imaging in patients with pathologically verified dementia. J Nucl Med. 2000;41: 1920-1928.
Yamaguchi S, Meguro K, Itoh M, et al. Decreased cortical glucose
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L, Tsui WH, Herholz K, et al. Multicenter standardized 18F-FDG PET
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- Landau SM, Harvey D, Madison CM, et al. Comparing predictors of conversion and decline in mild cognitive impairment. Neurology. 2010;75:230-238.
- Patwardhan MB, McCrory DC, Matchar DB, et al. Alzheimer disease: Operating characteristics of PET--a meta-analysis. Radiology. 2004;231:73-80.
A, Ono K, Ikeda T, et al. A comparison of the diagnostic sensitivity of
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- Silverman DH, Gambhir SS, Huang HW, et al. Evaluating early
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- Silverman DH, Small GW, Chang CY, et al. Positron emission
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- Lim SM,
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- Minoshima S,
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P, Scheinin N, Aalto S, et al. [(11)C]PIB-, [(18)F]FDG-PET and MRI
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- Neary D, Snowden J, Mann D. Frontotemporal dementia. Lancet Neurol. 2005;4:771-780.
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Jack CR,Jr, Wiste HJ, Vemuri P, et al. Brain beta-amyloid measures and
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