of Prognostic Significance of SPECT Abnormalities in Non-demented
Elderly Subjects with Memory Loss
McKelvey, H. Bergman, J. Stern, C. Rush, G. Zahirney and H.
Objective: To determine if hypoperfusion abnormalities
on single photon emission computed tomography (SPECT) are
associated with poorer cognitive function at baseline or increased
risk of decline in cognitive function and progression to dementia
in memory-impaired but non-demented elderly subjects meeting
the criteria for aging associated cognitive decline (AACD).
Design: Cross sectional study of 36 AACD subjects
comparing hexamethyl propylene-amine oxime (HMPAO) SPECT results
rated by visual inspection with base line cognitive functioning.
Prospective study of these AACD subjects with clinical and
neuropsychological follow-up over 35 months. Setting:
The memory clinic and nuclear medicine unit of a university
teaching hospital. Subjects: Thirty-six subjects
meeting the criteria for AACD recruited from patients seen
on a physician referral basis. Main outcome measures:
1) Baseline cognitive function as measured by the
Mini Mental State Examination (MMSE), Boston naming, Logical
Memory I subtest of the WAIS-R, and verbal fluency, correlated
with SPECT status. 2) Decline in cognitive function as measured
by clinical exam and the MMSE, with progression to dementia
on follow-up being correlated with SPECT status at baseline.
Results: 18 of the 36 subjects progressed to
dementia (probable Alzheimer's Disease) over follow-up. No
correlation was found between the presence or absence of SPECT
abnormality and MMSE or other cognitive measures. There was
no correlation between the presence or absence of SPECT abnormality
at initial examination, and cognitive decline according to
the MMSE, or with the occurrence of clinical dementia on follow-up.
Conclusions: We conclude that SPECT abnormalities
assessed by visual inspection do not correlate with severity
of impairment in AACD individuals, and are not useful in predicting
progression to dementia in AACD subjects.
Anomalies tomodensitométriques chez les vieillards
non déments. But: Notre objectif
était de déterminer si des anomalies d'hypoperfusion,
à la tomographie à émetteur gamma (SPECT),
sont associées à une fonction cognitive altérée
à l'évaluation initiale ou à un risque
accru de déclin des fonctions cognitives et à
une progression vers la démence chez des sujets âgés
non déments mais ayant des troubles de mémoire
et qui satisfont aux critères de l'échelle du
Déclin cognitif associé au vieillissement (DCAV).
Plan de l'étude: Il s'agit d'une étude
transversale chez 36 sujets comparant les résultats
de HMPAO SPECT, évalués par inspection, avec
la fonction cognitive initiale. Nous avons étudié
de façon prospective ces sujets avec DCAV au moyen
d'un suivi clinique et neuropsychologique de plus de 35 mois.
Cadre de l'étude: Cette étude
a été réalisée dans une clinique
de la mémoire et une unité de médecine
nucléaire d'un hôpital universitaire. Sujets:
Trente-six sujets qui rencontraient les critères
de DCAV ont été recrutés parmi les patients
référés à la clinique par un médecin.
Mesure principale des résultats: 1. La
fonction cognitive initiale, telle que mesurée par
le "Mini Mental state examination" (MMSE), l'Épreuve
de dénomination sous confrontation de Boston, le Sous-test
de mémoire logique de l'Échelle clinique de
mémoire du Weschler I, l'Épreuve de fluidité
verbale, a été corrélée avec les
résultats du SPECT. 2. Le déclin de la fonction
cognitive mesuré par un examen clinique et le MMSE,
avec progression vers la démence au cours du suivi,
a été corrélé aux résultats
du SPECT initial. Résultats: 18 des 36
sujets ont progressé vers la démence (maladie
d'Alzheimer probable) au cours du suivi. Nous n'avons trouvé
aucune corrélation entre la présence ou l'absence
d'anomalies au SPECT et le MMSE ou les autres mesures cognitives.
Il n'y avait pas de corrélation entre la présence
ou l'absence d'anomalies au SPECT à l'examen initial
et le déclin cognitif selon le MMSE ou le développement
d'une démence au cours du suivi clinique. Conclusions:
Nous concluons qu'il n'y a pas de corrélation entre
les anomalies au SPECT, qui sont notées par inspection
visuelle, et la sévérité de l'atteinte
chez les sujets avec DCAV et que ces anomalies ne sont pas
utiles pour prédire la progression de la démence
chez ces sujets.
J. Neurol. Sci. 1999; 26:23-28
studies have demonstrated a high incidence of parietal and/or
temporal hypoperfusion in subjects with probable Alzheimer's
disease (AD) using single photon emission computed tomography
(SPECT).1-3 Estimates vary between 51 and 96 percent
for parieto-temporal defects, and between 81 and 100 percent
for any abnormality in probable AD subjects. Many authors
have suggested that SPECT may be useful in the diagnosis of
AD and in the differentiation of AD from other forms of dementia.4-10
Furthermore, the degree of temporal lobe decreased regional
cerebral blood flow in AD subjects may even predict their
rate of decline over follow-up.9 On the other hand
some authors have questioned the utility of SPECT for routine
diagnostic purposes in mildly impaired AD patients.11-16
recent SPECT study (Celsis, et al.)17 evaluated
elderly subjects with cognitive decline who did not meet the
criteria for probable AD. These subjects have been demonstrated
to be at high risk for progression to dementia.18,19
This group, recently referred to as aging-associated cognitive
decline (AACD) by a committee of World Health Organization20
consists of individuals who have had a gradual decline in
memory and/or other cognitive functions for at least six months,
corroborated by neuropsychological testing. Individuals must
score at least one standard deviation below age-adjusted norms
on relevant neuropsychological tests, but the level of impairment
must be insufficient to make a diagnosis of dementia by commonly
used criteria such as the NINCDS-ADRDA criteria.21
The AACD criteria also specify that other neurologic or systemic
disease likely to cause impairment in cognitive functioning
be excluded by clinical examination and appropriate laboratory
investigations, as with the NINCDS-ADRDA criteria for AD.
et al.18 studied a similar group which they refer
to as "questionable dementia". These subjects all scored 0.5
on the Washington University clinical dementia rating scale.22
This level of function implies mild consistent forgetfulness,
but no impairment of orientation, and slight or no functional
impairment in judgment, community affairs, hobbies and personal
care. They found that of 16 members in this group, 11 progressed
to dementia in a follow-up of 84 months. Similarly, Tuokko
et al.19 studied a group of subjects referred for
a change in memory functioning who did not meet the NINCDS-ADRDA
criteria for dementia. They found that 18 of 45 of their subjects
in this group progressed to dementia on follow-up 12-18 months
later. In contrast, studies of elderly subjects with only
subjective memory loss without clear objective evidence of
impairment, have shown them to be much less likely to progress
to dementia over the short term.23
investigators have attempted to derive neuropsychological
instruments to predict progression to dementia in subjects
with mild memory decline.24-27 While several tests
have been reported to correlate with progression to dementia,
none have been shown to reliably predict such progression
in individual subjects. Imaging studies such as SPECT would
therefore be diagnostically useful if abnormal patterns were
found to predict progression in these subjects. Celsis et
al.17 studied 18 such individuals who were followed
over a two-year period, during which five progressed to dementia.
Several of these five were distinguished by the presence of
a temporoparietal asymmetry of cerebral blood flow on initial
SPECT, providing intriguing evidence that SPECT patterns might
be prognostically useful in this group of individuals.
this paper we report a group of non-demented elderly subjects
with mild memory impairment who met the criteria for AACD.
These subjects have undergone SPECT as part of their initial
workup, and have been followed long enough that a significant
proportion have progressed to dementia. In this study we report
the results of their SPECT examinations and correlate them
with the subsequent clinical course, in particular, progression
subjects meeting the above criteria for AACD were recruited
from patients seen on a physician referral basis in the Jewish
General Hospital/ McGill University Memory Clinic. All had
a history of memory decline in the last 1-4 years reported
by the patient, caregiver (usually the spouse), or both. The
mean duration of reported memory loss prior to presentation
was 1.6 years. All subjects were documented to have mild memory
impairment on neuropsychological testing, which included the
Logical Memory I and II components of the Weschler Memory
Scale,28 the Knopman and Ryberg test of verbal
memory,29 and the Mini-mental status exam (MMSE),30
along with other standardized neuropsychological measures
(Table 1). Deficits in
other cognitive areas were minimal or, more commonly, non-existent.
They did not meet the NINCDS-ADRDA criteria for the diagnosis
of probable AD or dementia due to the lack of other associated
cognitive deficits or to the lack of impairment of daily functioning.
All were classified according to the Washington University
clinical dementia rating scale (CDR),22 and met
the criteria for "0.5" on that scale as described above. There
was no evidence on clinical evaluation of systemic or other
neurological disease sufficient to interfere with cognitive
function. Structural brain disease was excluded by CT and/or
MRI, and blood work was done including CBC, routine chemistry,
thyroid function, serum B12, folate, and VDRL. All subjects
scored less than 4 on the Hachinski ischemic scale.31
subjects underwent neuropsychological evaluation which included,
in addition to the tests noted above, a shortened version
of the Boston naming test,32 letter and category
fluency,33 tests of block design34 and
clock drawing,35 a word to picture matching task
(with perceptual distractors) as a screening test for visual
perceptual ability,40 as well as the digit symbol
and digit span sub-tests of the WAIS-R verbal intelligence
was carried out using 20 mCi of technetium 99mTc-hexamethyl
propylene-amine oxide (HMPAO). To optimize soft tissue clearance,
there was a 90-120 minute delay from the time of injection
to the commencement of imaging. Imaging was performed with
a single head rotating gamma camera (Elscint 409) equipped
with a high resolution low energy collimator. Data were obtained
from the 140 KEV photo peak (20% window) over a 360 degree
rotation and a 64 X 64 matrix. A step and shoot format was
utilized with an aquisition time of 30 sec/frame and a zoom
factor of 1.33.
non-uniformity correction, transaxial views were generated
via a filtered back projection algorithm utilizing a METZ
filter with a power of 3 and a system resolution of 14 mm
full width, half maximum. The resulting images were re-oriented
to the orbito-meatal line, and orthogonal, coronal, and sagittal
projections were then generated. Each set of images was then
normalized to the maximum pixel count before viewing. Images
were read blindly by two nuclear medicine specialists, and
were subsequently rated according to the classification scheme
of Holman et al.36 shown in Table
subjects were followed at 9-12 month intervals with both clinical
assessment and repeat neuropsychological examination.
sectional data on SPECT images of 58 subjects from the same
clinic population who met the NINCDS-ADRDA criteria for probable
AD, as well as 20 normal controls, have been reported separately.11
between subjects who declined and those who did not were assessed
by t-test. Outcome data were analyzed by analysis of variance,
using both outcomes of decline documented on MMSE, and clinical
diagnosis of dementia, as outcome variables. Correlation of
the presence of clinical and SPECT features with outcome were
assessed using Chi-square analyses.
the time of initial evaluation, the 36 AACD subjects had an
average age of 71 +/- 7 years (range 58 to 84) and an average
MMSE of 26.9 (range 21-30, s.d. = 3.0). There were 19 males
and 18 females and they had 10.8 +/- 3 years of education.
A summary of their neuropsychological results is given in
Table 1. Thirty-four
of the subjects scored at least 1 s.d. below the age-adjusted
mean on one or more memory test administered (Logical Memory
1 and 2 of the Wechsler memory scale,34 and the
delayed verbal memory test of Knopman and Ryberg29),
while two subjects were impaired only on non-memory cognitive
tasks. In addition, there were mild cognitive deficits (on
picture naming, digit span, verbal fluency, and block design)
seen in 23 of the 36 subjects, not sufficient in any case
to warrant a diagnosis of dementia (see
SPECT scans were read blindly by two nuclear medicine specialists.
The classification of Holman was applied as in Table
2.. It should be noted that there was no disagreement
between the 2 raters as to the appropriate SPECT pattern assignment
of any patient. We thus had excellent inter-rater reliability.
number of AACD subjects with each SPECT pattern is given in
Table 3, along
with the average MMSE, Boston naming, logical memory I, and
verbal fluency scores at the time of SPECT acquisition for
subjects in each category. Thirteen subjects had normal SPECT
scans, and 23 had "abnormal" patterns. At initial evaluation,
these latter subjects with SPECT abnormalities (patterns B-G)
had an average MMSE score of 27.6, while those with normal
SPECT studies actually had a slightly worse average score
of 27.0. These differences were not significant on t-test.
Similarly, the average scores on the Boston naming and verbal
fluency tests were slightly worse in those subjects with normal
SPECT scans, while the logical memory I average score was
minimally better. None of these differences reached significance
(p < .05) on t-test. Nor was there any group difference
between subjects with normal and abnormal SPECT results when
analyzed in terms of age, education, duration of symptoms,
or any other neuropsychological variable. The only variable
showing an asymmetric distribution was the presence of clinical
depression; 8 of the subjects with normal scans were rated
as clinically depressed, compared with only 4 subjects showing
abnormal scan patterns (three being SPECT patterns typical
for AD, and one being a non-typical pattern). This was significant
by chi-square (df = 2, chi-square = 7.1, p < .05).
clinical evaluation including neuropsychological testing was
carried out on the cohort of subjects. Two subjects died prior
to their first annual follow-up, and were reportedly not deteriorated
compared to their baseline evaluation. Another two subjects
died following one year follow-up (at which time they were
considered cognitively intact). The other 32 subjects have
had ongoing clinical assessment to the present time. Excluding
the two who died prior to follow-up (who have not been entered
into follow-up analysis), there have been thirty-four AACD
subjects followed for an average of 35 +/- 13 months (range
13-56). Over that time, the MMSE of the entire group has declined
by an average of 3.5 points (range -2 to 13 points decline).
Longer follow-up led to a greater degree of deterioration
documented; for the 7 subjects with two years or less follow-up,
the decline averaged 1.0 on the MMSE, while for the other
27 subjects (mean follow-up of 37 months), the decline averaged
4.5 on the MMSE.
of the subjects have shown progressive deterioration, and
are now classified clinically as showing dementia (probable
Alzheimer's Disease in all cases). In one of these subjects,
the MMSE was originally taken as 21 (out of 30), although
she appeared functionally intact, and was therefore diagnosed
as AACD. On follow-up, the MMSE was still 21/30, but there
had been clear cognitive and functional deterioration extending
beyond memory, warranting the label of dementia. In the other
17 cases showing deterioration to dementia, the MMSE had fallen
by 2 or more points over follow-up. Of the remaining subjects,
still considered as AACD on follow-up, one subject had a decline
on MMSE of 3 points (from 28 to 25) after 30 months follow-up,
but the other 17 had MMSE declines of less than 2 with no
clinical or neuropsychological progression. Analysis by t-test
was carried out between initial variables for subjects who
eventually progressed to dementia, vs. those individuals who
did not progress to dementia over follow-up. There was no
significant difference between the two groups in terms of
initial age, education, or duration of follow-up (p = .16,
.06, and .08 respectively). Neither was there any difference
between those subjects in terms of any of the neuropsychological
variables listed in Table
1. Progression to dementia was analyzed in terms of the
initial clinical profile (no cognitive deficit, memory impairment
only, memory plus other cognitive deficit, non-memory deficits
only). Analysis by chi-square revealed no pattern or relationship
between the clinical profile and progression (df = 3, chi-square
= 6.63). Thus, progression to dementia at time of follow-up
did not appear to be correlated with any clear aspects of
the initial clinical profile, or the presence of any initial
neuropsychological abnormality in our group of subjects.
average initial and follow-up MMSE scores grouped according
to SPECT pattern are presented in Table
4. Those with abnormal SPECT examinations declined by
an average of 3.7 points on the MMSE while those with normal
SPECT's declined by 3.5 points. The initial and follow-up
MMSE scores were subjected to a repeated measures 2 X 2 ANOVA
with SPECT status (normal, abnormal) as the between groups
measure and the MMSE (time 1, time 2) as the within subjects
measure. This demonstrated a main effect of time of testing
[F (1,32) = 17.9, p < .001], indicating that collapsed
across groups there was a significant decline in MMSE. There
was no main effect of SPECT status [F (1,32) = 0.26, p
= .6], implying that there was no overall relation between
SPECT status and MMSE. In particular, there was no repeated
measures by SPECT status interaction [F (1,32), p = .99].
This demonstrates that the presence of SPECT abnormality was
not associated with any worse decline in the MMSE. Similar
results were obtained when only those subjects with SPECT
patterns considered more "typical" for AD (patterns B, C,
D) were considered, and those subjects with a more atypical
SPECT pattern (patterns E-G) for AD were excluded from analysis.
was no correlation between initial SPECT pattern, and subsequent
progression to dementia in the 34 subjects over a follow-up
period. This was the case whether SPECT patterns were analyzed
as normal vs. abnormal (chi-square = .52, df = 1, NS) or normal
vs. "typical for AD" (patterns B, C, D) vs. "patterns more
atypical for AD "(patterns E-G) (chi-square = 1.16, df = 2,
NS). The same finding held when each SPECT pattern was evaluated
separately compared with progression to dementia (chi-square
= 5.6, df = 6, NS). Twelve of 23 subjects with an abnormal
SPECT progressed to dementia, while six of eleven subjects
with a normal SPECT progressed to dementia. All those subjects
who did not progress remained in the AACD category. (Table
using as a cut-off score a decline by two or more points on
the MMSE (which was characteristic of most subjects eventually
receiving a diagnosis of dementia), eleven of 23 subjects
with an abnormal SPECT declined significantly, while seven
of eleven with a normal SPECT had a similar decline (Chi square
= .15, df = 1, NS). We were therefore unable to find any correlation
between the presence or absence of SPECT abnormality and progression
as measured by either clinical diagnosis or change in the
studies have shown an incidence of SPECT abnormality in AD
subjects of 68 to 100 percent based on either visual inspection
or significant differences from controls using semi-quantitative
methods.1-10,36 In the AD subjects reported by
our group,11 76 percent had some SPECT abnormality.
The AD subjects in these studies have all been defined by
the NINCDS-ADRDA criteria, thereby implying an 85-90% chance
of having pathology consistent with AD prior to having the
test.37-39 The possible additional diagnostic precision
achieved with the use of SPECT in this group of patients is
therefore very limited. Where SPECT is potentially of more
value in increasing diagnostic precision is in those subjects
with memory impairment not meeting the criteria for dementia,
who have been demonstrated to have a high risk of progression
to dementia.18,19 It is these subjects who are
still very functional who have the most potential for therapeutic
benefit from future therapies designed to arrest the progression
of the disease, but who are currently excluded from most drug
trials. However, the point in the course of the disease process
at which perfusion abnormalities can be demonstrated with
SPECT has not been clearly elucidated.
have found a high rate of SPECT abnormality in this AACD group,
64% of cases, which is close to the rate of abnormal SPECT
findings found in the probable AD subjects by our group and
others.1-11 We therefore doubt that semi-quantitative
analysis would have yielded different results compared to
our visual inspection of images, and this has been the general
result in other centres that have applied both approaches
(Claus, personal communication). In spite of this high rate
of abnormality, we found no correlation between the presence
or absence of SPECT abnormality and progression as measured
by change in MMSE or by frank progression to dementia. On
examination of Table
4, it is also clear that decline is similar for subjects
with each specific type of SPECT abnormality as well. The
35 month follow-up, while shorter than that of Morris et al.,26
was sufficient to allow progression to dementia in 50% of
our cohort. Given the high rate of SPECT abnormalities encountered
in the AACD group, it is doubtful that the lower sensitivity
of visual inspection of SPECT images (as opposed to quantitative
analysis) is the cause of its lack of prognostic usefulness
in our group of subjects. Rather, there appears to be a high
rate of SPECT abnormality in subjects with AACD, irrespective
of whether they went on to progress to AD over the subsequent
year or not.
is possible that with further follow-up more subjects with
SPECT abnormalities will progress to dementia. It may also
be, however, that many AACD subjects have SPECT abnormalities
for reasons other than underlying preclinical Alzheimer's
disease, and that such abnormalities therefore do not imply
an increased risk of progression to dementia.
our study, we sought to utilize conventional visual SPECT
analysis as it is carried out in most clinical centres; we
did not apply more specialized data analysis tools such as
semi-quantitative analysis, and cannot address their usefulness
in predicting progression in these subjects. However semi-quantitative
analysis remains of limited availability for routine clinical
use at present. We are therefore led to conclude that SPECT,
when analysed by conventional means, is not useful in predicting
decline to dementia in AACD subjects.
work was supported by a fellowship grant from the Fonds de
la Recherche en Santé du Quebec (F.R.S.Q.) to R. McKelvey,
a scholarship from the Medical Research Council of Canada
to H. Chertkow, a team grant from the F.R.S.Q. to H. Chertkow
and H. Bergman and a grant from the Alzheimer's Society of
Canada. We thank the clinical staff of the Jewish General
Hospital Memory Clinic for their cooperation and Shelley Solomon
for outstanding administrative assistance.
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Chertkow H, Bub D. Semantic memory loss in dementia of Alzheimer's
type: What do various measures measure? Brain 1990; 113: 397-417.
the Bloomfield Centre for Aging, Sir Mortimer B. Davis
- Jewish General Hospital, McGill University, Montreal
(R.M., G.Z., H.C.); Division of Geriatric Medicine,
Department of Medicine, Sir Mortimer B. Davis - Jewish
General Hospital, McGill University (R.M., H.B., H.C.);
Department of Nuclear Medicine, Sir Mortimer B. Davis
- Jewish General Hospital, McGill University (J.S.,
C.R.); Research Centre, Centre Hospitalier Côte-des-Neiges,
Montreal (H.C.); Dalhousie University, Halifax, N.S.,
Dr. Everett Chalmers Hospital, Fredericton, N.B. (R.M.).
May 28, 1998. Accepted in final form August 31, 1998.
requests to: Dr H. Chertkow, Lady Davis Institute
and Sir Mortimer B. Davis -Jewish General Hospital,
3755 Chemin de la Cote Ste. Catherine, Montreal, Quebec,
Canada H3T 1E2
J. Neurol. Sci. 1999; 26:23-28