SPECT Predict the Future for Mild Cognitive Impairment?
clinical role of Single Photon Emission Computed Tomography
(SPECT) in the diagnosis and prognostication of dementing illnesses
remains controversial. Numerous studies have compared SPECT
in patients with Alzheimer's Disease (AD) and other dementias,
and age-matched controls. The typical abnormality in AD is bilateral
posterior temporal/parietal hypoperfusion, which often correlates
with mental status, and can be asymmetrical. This pattern is
found in approximately 60-90% of Alzheimer's patients,1-3
but other patterns have been identified including frontal involvement
with or without parietal-temporal deficits and unilateral parietal/temporal
hypoperfusion.4 Some studies have shown good correlation
between such SPECT patterns and autopsy diagnosis.5,6
Generally speaking, however, the sensitivity and specificity
of these patterns have varied in different series depending
on the severity of the patient sample and the comparison group,
which usually includes normal age-matched controls or patients
with other types of dementia. The situation is further complicated
by the confounding effects of factors, such as age of onset,
years of education, duration of illness, severity of disease,
etc., on perfusion ratios.7 The effect of disease
severity on sensitivity and specificity was well-illustrated
in a sample of 48 AD patients classified as mild, moderate or
severe and 60 normal controls drawn from a population-based
study by Claus et al. (1994). ROC curve analysis was used to
determine the value added by semiquantitative SPECT in clinical
diagnosis of AD.8 With specificity set at 90%, sensitivity was
42% in mild, 50% in moderate and 79% in severe AD. In mild dementia
where diagnosis may be in doubt (i.e. a priori probability of
50%), the diagnostic gain was substantial (34%) for an abnormal
scan, but poor when the scan was negative. Thus, depending on
the results of the particular series, some authors continue
to advocate the use of SPECT in the differential diagnosis of
dementia,1,2,9 while others reject it as not cost-effective.8,10,11
clinical application of SPECT has also been further hampered
by lack of standardization.12 Acquisition parameters
including the camera used, reconstruction algorithms and image
display can all influence interpretation. Brain-dedicated triple-head
cameras have better spatial resolution than single-head cameras;
this can affect sensitivity in small regions targeted in AD
such as the hippocampus. Whether visual or semiquantitative
analysis is used can also affect results. With semiquantitative
analysis, group differences can often be discerned, but the
problem for the clinician is the application of such results
to the individual case. Visual analysis is still the primary
mode of interpretation in the clinical setting, even though
automatic, semiquantitative methods could be applied quickly
and efficiently by properly developed computerized algorithms.
Semiquantitative methods usually increase sensitivity but may
decrease specificity. Furthermore, lack of agreement on how
best to measure regions of interest, what reference regions
to use and software discrepancies between different camera system
manufacturers continue to retard optimal application of the
these difficulties, the question has arisen whether SPECT would
also be useful in subjects with mild cognitive impairment (MCI)
to predict who will progress to dementia. MCI, a term derived
from the DSM-III-R and ICD-10, refers to mild memory or other
cognitive impairments in the absence of functional disabilities.13
Similar terms, all with slightly differing criteria, have included
age-associated memory impairment (AAMI), age-associated cognitive
decline (AACD), and cognitive impairment not demented (CIND)
but MCI is emerging as the preferred designation and so will
be used in this. According to the recent Canadian study of Health
and Aging, 30% of Canadians over 65 have MCI, including 8% who
had no obvious systemic or psychiatric illnesses contributing.13
This MCI population appears to be bimodal; approximately 50%
will decline to dementia within three years and the remainder
have stable, mild cognitive impairments that do not appear to
progress.14-16 It may be that if such individuals
are observed long enough they will decline, but few studies
have gone beyond two or three years of follow-up. In one study
where participants were followed for seven years, the conversion
rate to dementia was 69%, with decline occurring in all subjects
within four years of observation.15 Clearly, as therapies
that may delay progression in AD become available, MCI will
be an important target group for intervention since a successful
delaying strategy could postpone clinically significant disease
for some years or at least until the person dies of other causes.
SPECT can contribute to this predictive exercise was addressed
in the study reported in this issue by McKelvey et al.17
A well-documented group of subjects with MCI, were followed
over a mean period of three years. The authors used the term
AACD for this group, who were defined as having a history of
mild memory decline, evidence of mild memory impairment on standardized
neuropsychological testing and an assigned rating of 0.5 (questionable
dementia) on the Clinical Dementia Rating (CDR) scale.18
SPECT scans were analyzed visually, with good inter-rater agreement,
using a dichotomous classification of the abnormalities seen
typically in AD. The results showed that 64% of these subjects
had abnormal scans and that there were no differences in demographic
or neuropsychological factors at study initiation between those
with or without abnormalities on their scans. The exception
was clinical depression, which was more highly represented in
the subjects with normal scans (62%) compared to those with
abnormal scans (20%). If the subjects with depression were eliminated,
the frequency of abnormal scans (78%) was virtually identical
to a study published by the same group in subjects with probable
AD, in whom 76% were found to have abnormal scans.10 The
high incidence of abnormal scans in this patient population,
with a distribution of abnormality quite typical for AD, is
noteworthy; it may be that a CDR of 0.5 based on a structured
interview actually selecting a higher proportion of patients
with pre-clinical AD than other criteria that have been used
for MCI. Of the 34 survivors available for follow-up, 27 were
followed for more than two years and seven for less than two
years. Fifty-three percent of the subjects showed decline to
dementia. There were no differences in age, education, and duration
of follow-up or performance on initial neuropsychological tests
in those who did or did not decline. The presence of an abnormal
SPECT initially did not accurately predict decrease on the Mini
Mental State score or who would decline to dementia. Specifically,
67% (12/18) of those who progressed had an abnormal scan initially,
but 31% (5/16) with normal scans also progressed. Overall, the
positive and negative predictive values were approximately 50%.
It is not clear from the data provided if elimination of the
depressed patients would have improved these odds.
this clinician-friendly, well-conducted study, visual SPECT
interpretation was applied in a standardized fashion to a clearly
defined cohort of individuals at potential risk for developing
dementia. The authors conclude quite definitively that visual
analysis of SPECT in this population is not at all useful in
predicting who will progress to dementia. There are some limitations
to this study, however, which must be taken into account when
assessing the generalizability of these results. The sample
size, although respectable, was still relatively small, with
too few subjects to allow for epidemiological and other factors
that may influence SPECT patterns and rate of decline to be
taken into account. Unlike other studies, performance on delayed
recall did not apparently have any predictive value. The role
played by depression in this particular sample is also unclear.
The authors do not indicate how depressive symptoms were assessed,
but depressive symptoms were apparently not an exclusion criterion
for participation in the study. Since depression can be a reversible
cause of cognitive impairment, this is of some note, particularly
since 62% of the patients with clinical depression (8/13) had
normal SPECT scans. In this context it is notable that in a
longitudinal SPECT study of cognitively impaired subjects, reversible
deficits on SPECT in patients followed over one year were associated
with resolving clinical depression while persisting deficits
were more likely to be seen in patients with true dementia.19
In the current study,17 the length of follow-up was
limited, and while the majority were followed for at least two
years, it is still possible that some patients would have converted
to dementia with longer follow-up. Another limitation is that
visual interpretation of scans was used with a dichotomous classification
as normal or abnormal. While this has the advantage of easy
applicability, semiquantitative measures may have been more
does this study based on visual inspection of SPECT scans compare
to other series that have examined the predictive value of SPECT
in patients with MCI? In a longitudinal study of 18 subjects
with MCI studied by quantitative Xenon SPECT and followed over
two years, Celsis et al. (1997) reported that reduced parietal-temporal
perfusion and the degree of right-left parietal-temporal asymmetry
were intermediate in the MCI group compared to normal controls
and patients with probable AD.20 Although initial
mean parietal-temporal flow differed significantly in patients
with MCI compared to the other two groups, it did not distinguish
between the five subjects who did and the 13 who did not become
demented over two years. The degree of parietal-temporal asymmetry,
however, did predict conversion to dementia.20 In
a larger sample, using HMPAO as tracer in a brain-dedicated,
high resolution SPECT camera, Johnson et al. (1998) were able
to distinguish four groups of subjects based on regional SPECT
perfusion ratios, including normal controls (N = 34), subjects
with AD (N = 56) and subjects with questionable AD (CDR 0.5)
at baseline, 18 of whom progressed and 27 of whom did not progress
to AD over two years of follow-up.21 Using a sophisticated
statistical technique, singular value decomposition, these authors
were able to identify regional decreases in perfusion that were
most predictive of conversion to AD. The four main regions were
the hippocampal-amygdaloid complex, the anterior and posterior
cingulate, and the anterior thalamus. Such studies demonstrate
that with semiquantitative analysis and a spatial resolution
adequate to detect perfusion in limbic structures, areas known
to be targeted early in AD, differences can be detected between
MCI patients who will and will not progress to dementia. To
apply such findings to individual cases in the clinical context,
however, simple, automated algorithms to quantify perfusion
in these regions and larger samples to determine normal cut-offs
and confidence intervals would be needed.
applied, SPECT can also be useful in detecting heterogeneity
in AD subjects and potentially provide an individualized profile
of perfusion changes over time which may be helpful in documenting
progression rates and evaluating response to new therapies.
It is unlikely that SPECT alone, however, will be adequate to
diagnose and track progression of AD pre-clinically or clinically.
This is partly because of factors we do not yet understand which
determine blood flow ratios in relation to pathological changes
in different brain regions. Work in progress in our laboratory,
mapping limbic system atrophy and perfusion changes using co-registered
SPECT and MRI, has shown that regional structural atrophy is
actually more discriminatory between AD and normal control subjects
than perfusion ratios.22 Also many series have reported
a small incidence of normal SPECT scans in clinically diagnosed
probable AD patients (for example, in 11% of the Black et al.
series7). It may be that individuals vary in their
capacity to compensate for pathological change and can maintain
regional perfusion, at least in early stages of disease.
utility of SPECT in predicting development of dementia in MCI
needs to be considered in the context of other modalities as
well. Certain biological markers such as the presence of APO
E421,23 or a positive tropicamide eye-drop test24,25
have not proved to be helpful. The most cost-effective measure
may be simple neuropsychological tests. Several studies have
indicated that impairments in delayed recall and mental control
are good predictors of later development of disease.14,16,26,27
Atrophy of the medial temporal structures, as quantitatively
measured on MRI, may also be predictive. Even though there is
considerable cross-sectional overlap between normal aged controls
and AD subjects, smaller volumes of temporal lobe structures
are also associated with a higher risk of conversion to dementia.28,29
of the considerable disease heterogeneity in AD, it is likely
that more than one modality may be needed to differentiate AD
from normal aging and other dementias. For example, performance
on selected neuropsychological tasks used in conjunction with
brain measures on MRI and SPECT may improve predictive accuracy.
This has yet to be determined, however. In cross-sectional diagnosis
of AD, a combination of SPECT perfusion and medial temporal
lobe measures appears to be more powerful than either method
alone.22,30,31 Serum or CSF markers may also eventually
contribute to this differentiation,32 but it is likely
that some type of brain imaging will still need to be used in
conjunction with daily function, cognitive and behavioural assessment
to provide information for individual staging and to monitor
progression of disease. More research is required to determine
the optimal combination of these biomarkers. Clearly for the
imaging tools to become clinically relevant and cost-effective,
reliable, automatic or semi-automatic analysis procedures must
be developed so they can be applied in a time-efficient manner.
The potential is certainly there to do this already, but more
effort to achieve consensus on the best measures to use will
be necessary if progress is to be achieved in applying these
powerful image techniques successfully to daily practice.
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