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Early and Widespread Cholinergic Losses Differentiate Dementia With Lewy Bodies From Alzheimer Disease
Pietro Tiraboschi, MD;
Larry A. Hansen, MD;
Michael Alford, BA;
Annette Merdes, MD;
Eliezer Masliah, MD;
Leon J. Thal, MD;
Jody Corey-Bloom, MD, PhD
Arch Gen Psychiatry. 2002;59:946-951.
ABSTRACT
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Background Reductions in cholinergic function occur in Alzheimer disease (AD) and
dementia with Lewy bodies and correlate with cognitive decline. However, whether
such alterations appear in early-stage disease is unclear.
Objective To examine the timing of cholinergic deficits in AD and dementia with
Lewy bodies.
Methods Autopsy series of 89 patients with AD and 50 patients with the Lewy
body variant of AD (LBV). Stage of disease was stratified according to results
of the last Mini-Mental State Examination (MMSE) before death as mild, moderate,
severe, or very severe. We analyzed choline acetyltransferase (ChAT) activity
in the midfrontal, superior temporal, and inferior parietal cortices.
Results Although compared with a normal control group ChAT activity was decreased
in the AD and LBV cohorts, ChAT activity reduction for the LBV cohort was
much greater. Moreover, although the decline in ChAT activity in the AD cohort
compared with the normal control group was significant only for patients in
later stages of the illness, the decline in the LBV cohort was significant
for those who died with mild-stage disease. When less impaired patients in
each cohort (MMSE,  10) underwent separate analysis, the relationship of
ChAT activity with the MMSE score was strong and significant for the LBV cohort
alone.
Conclusions Although cholinergic deficits are seen in both AD and LBV, loss of ChAT
activity is less severe and occurs later in the clinical course of AD. Conversely,
in LBV, loss of ChAT activity is already prominent in the earliest stages
of the illness, suggesting that cholinergic replacement therapy may be more
effective in LBV than in AD, especially in mild-stage disease.
INTRODUCTION
ALZHEIMER DISEASE (AD) is the most common form of primary degenerative
dementia in the elderly, characterized by gradually worsening memory in association
with aphasia, apraxia, agnosia, and disturbances of visuospatial perception.
Although research in AD has focused on the functional role of multiple neurotransmitter
systems, the cholinergic basal forebrain has been the most thoroughly studied.
In AD, in which memory impairment is prominent, cholinergic function has been
found to be markedly decreased, mainly as a result of neuronal loss in the
basal forebrain, especially in the nucleus basalis of Meynert.1
The activity of choline acetyltransferase (ChAT), the presynaptic synthetic
enzyme for acetylcholine, has been shown to be reduced by 50% to 90% in patients
with AD compared with age-matched normal control (NC) subjects.2-3
Changes in other cholinergic markers have also been reported, including a
decline in high-affinity nicotinic receptors4
and a reduction in presynaptic muscarinic receptor activity.5
Several studies have correlated decrements in ChAT activity with clinical
indices of dementia severity.2, 6-7
However, recent studies have reported that cholinergic enzyme activity is
significantly reduced only in brains of severely demented patients with AD,
suggesting that cholinergic dysfunction is not present until relatively late
in the course of the illness.8-9
Dementia with Lewy bodies (DLB) has been recognized as another common
cause of cognitive deterioration in the elderly. Much attention has focused
on identifying reliable criteria that allow discrimination between DLB and
AD.10-12 In addition
to cognitive impairment, the core clinical features of DLB are visual hallucinations,
fluctuating attention, and parkinsonism.11-12
Neuropsychologically, patients with DLB may display a different pattern of
cognitive decline, with worse performance on tests of visuospatial activity,
initiation, and perseveration.13 Furthermore,
the progression of their deterioration on global measures of dementia (eg,
the Mini-Mental State Examination [MMSE]14
and the Mattis Dementia Rating Scale)15 may
be faster than that observed in patients with AD.16
Neuropathologically, in most brains of patients with DLB, accompanying AD
pathologic changes in the form of neocortical diffuse plaques, neuritic plaques,
and modest numbers of neurofibrillary tangles are found in the medial temporal
lobe (ie, the Lewy body variant of AD [LBV]).10
A few brains, however, have no more AD pathologic changes than do age-matched
controls. Neurochemically, although the decline of ChAT activity has been
shown to be much greater in patients with DLB than in those with AD,17 the strength of its association with cognitive decline
has been more controversial.18-20
Apart from a small number of autopsy studies that included cases with
mild impairment,8, 21-22
descriptions of neurochemical changes in AD and DLB have been generally based
on findings in patients with late-stage disease. Moreover, few studies have
been performed using biopsy specimens of living patients with mild to moderate
dementia.22-23 Finally, most of
these studies considered mixed populations of patients with AD and DLB, since
they were performed before DLB had been well defined. Consequently, how early
in the course of each of these diseases neurochemical alterations occur remains
relatively unclear.
In the present study, we sought to determine whether cholinergic dysfunction
was an early event in AD and LBV by examining the activity of ChAT in autopsy
specimens of these prospectively observed cohorts who died at different stages
of their illness (classified clinically as mild, moderate, severe, and very
severe). In addition, we investigated the relationship between the decline
in ChAT activity and dementia severity in AD and LBV.
PATIENTS AND METHODS
PATIENTS
The patients included in the present study were observed clinically
at the University of California–San Diego Alzheimer's Disease Research
Center, Seniors Only Care, San Diego, or in the private practices of its senior
clinicians. They represent all patients who underwent autopsy between 1985
and the present with a clinical diagnosis of AD or LBV or normal control (NC)
for whom ChAT activity was available, and where cognitive testing was administered
within 24 months prior to death.
Eighty-nine patients with AD and 50 with LBV met the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised
Third Edition for a clinical diagnosis of dementia24
or of the National Institute of Neurological and Communicative Disorders and
Stroke–Alzheimer's Disease and Related Disorders Association for probable
or possible AD.25 In addition, they met the
criteria of the National Institute on Aging for a pathological diagnosis of
AD26 and of the Consortium to Establish a Registry
for Alzheimer's Disease for a diagnosis of probable or definite AD.27 Patients with LBV also met the criteria of the Consortium
on DLB for a pathological diagnosis of DLB.11-12
All patients with AD and LBV were stratified according to their last MMSE
score before death as having mild (MMSE score, 20; n = 14 for the AD cohort
and n = 7 for the LBV cohort), moderate (MMSE score, 10-19; n = 20 for the
AD cohort and n = 10 for the LBV cohort), severe (MMSE score, 1-9; n = 29
for the AD cohort and n = 11 for the LBV cohort), and very severe disease
(MMSE score, 0; n = 26 for the AD cohort and n = 22 for the LBV cohort).
The NC group consisted of 18 patients with no evidence of cognitive
impairment or any other neurologic or psychiatric disorder. Twelve of these
patients were also considered neuropathologically normal. The remaining 6
patients had only sufficient senile plaques to meet the National Institute
on Aging criteria for AD or neuritic plaques to meet the criteria of the Consortium
to Establish a Registry for Alzheimer's Disease for possible AD, but did not
display any cognitive impairment on results of extensive neuropsychological
testing administered in these cases less than 1 year before death.
NEUROPSYCHOLOGICAL EXAMINATION
Mean scores are reported for the following 3 commonly used measures
of global cognitive status: the MMSE, the Blessed Information-Memory-Concentration
test,28 and the Mattis Dementia Rating Scale.
Most of the patients had also received the comprehensive neuropsychological
battery administered through the Alzheimer's Disease Research Center as part
of their annual evaluation.29
NEUROPATHOLOGICAL EXAMINATION
Pathological assessment was performed by one of us (L.A.H.). Autopsy
was performed within 12 hours of death using a protocol described by Terry
et al.30 The left half of the brain was fixed
by means of immersion in 10% formalin for 5 to 7 days, at which time blocks
were taken for paraffin embedding from the midfrontal (MF), rostral superior
temporal (ST), and inferior parietal (IP) areas of the neocortex, hippocampus,
entorhinal cortex, basal ganglia/substantia innominata, mesencephalon, and
pons. The neocortical areas correspond to Brodmann areas 46, 38, and 39. The
paraffin blocks of neocortex were cut at 7-µm thickness for hematoxylin-eosin
and thioflavine S staining. Total plaque, neuritic plaque, and neurofibrillary
tangle counts were determined by the same examiner (L.A.H.) using the same
criteria consistently. Lewy bodies were detected using hematoxylin-eosin and/or
anti-ubiquitin immunostaining, as recommended by the Consortium on Dementia
with Lewy Bodies.11-12 Specifically,
to receive a pathological diagnosis of LBV, 1 or more Lewy bodies had to be
present in both the neocortex and brainstem in addition to significant AD
pathologic changes.
NEUROCHEMISTRY
Samples were taken from the MF, ST, and IP areas of frozen, unfixed
cortex from the right half of the brain and homogenized in 1mM EDTA (pH, 7.0)
containing 0.1% Triton X-100 (Sigma-Aldrich Corp, St Louis, Mo). Analysis
of ChAT activity was performed by means of the modified Fonnum technique.31-32 The coefficient of variation was
3%, with an intra-assay variability of 7.9%.
STATISTICAL ANALYSIS
Mean values among groups (AD vs NC and LBV vs NC) were compared using
1-way analysis of variance (ANOVA). In case of unequality of group variances
(P<.05, Bartlett test), the ANOVA was preceded
by logarithmic transformation of raw data. When a significant global result
(overall P<.05) was obtained, the ANOVA was followed
by the Tukey-Kramer multiple comparisons test to compare each pair of means.
Correlation analyses were performed by means of Pearson product moment correlations.
RESULTS
The mean values for the demographics, clinical indices, and biochemical
results are summarized in Table 1
and Table 2. As expected, disease duration increased and cognitive performance worsened
with disease stage in both cohorts. Compared with the NC group, ChAT activity
was significantly decreased in the AD and LBV groups. However, loss of ChAT
activity for the LBV cohort was much greater than that for the AD cohort,
despite comparable mean ages at death, test-death intervals, and disease severity.
Although decline of ChAT activity in AD compared with the NC group was statistically
significant only for patients who died in the later stages of the disease,
decline of ChAT activity in the LBV cohort was statistically significant in
the earliest stages of the illness.
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Table 1. Demographic, Neuropsychological, and Neurochemical Variables
in AD*
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Table 2. Demographic, Neuropsychological, and Neurochemical Variables
in LBV*
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Unlike the LBV group, for whom ChAT activity was significantly reduced
(almost maximally) in all brain areas beginning in the mildest stages of the
disease (MMSE, 20), the AD cohort displayed region-specific differences,
with decrements of ChAT activity occurring relatively earlier in the ST cortex
(moderate AD) than in the MF and IP cortices (severe AD). Specifically, compared
with the NC group, ST ChAT activity was significantly decreased in patients
with moderate AD at death (MMSE, 10-19), whereas MF and IP ChAT activities
were significantly reduced only in the AD cohort with more severe impairment
(MMSE, <10). This pattern of ChAT activity decline in LBV and AD did not
change, even when the NC group was limited to the patients with neuropathologically
normal findings (n = 12).
The correlations of ChAT activity with the MMSE are shown in Table 3. Correlations between the last
MMSE score before death and ChAT activity were most robust for AD when the
entire AD cohort (including many patients with severe and very severe AD)
was considered. However, when only less impaired patients (with mild and/or
moderate AD) in each cohort were included in the analyses, the relationship
between the last MMSE before death and ChAT activity was considerably stronger
for the LBV cohort in all neocortical regions examined.
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Table 3. Correlations Between MMSE Scores and ChAT Activity in AD and
LBV*
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COMMENT
The present study investigated the timing and distribution of ChAT activity
decline during the course of AD and LBV and the relationship between reduction
of ChAT activity and dementia severity in these illnesses. To explore this,
we used (1) large and well-characterized cohorts of patients with AD and LBV
with the last neuropsychological assessment reasonably close to death, and
(2) tissue samples from multiple neocortical areas of the patients.
Although definite conclusions about longitudinal changes occurring in
individual patients can hardly be drawn from a cross-sectional study, our
data strongly support the view that the integrity of cholinergic neurotransmission
is affected at different points in the course of these diseases. Cholinergic
dysfunction appears to occur early in LBV, whereas in AD, it is seemingly
severely reduced only in the later stages of the illness. Furthermore, although
this neurochemical deficit may be fairly generalized beginning with early-stage
disease in LBV, there may be region-specific differences, with the temporal
cortex more susceptible to the loss of ChAT activity than the frontal and
parietal cortices, in AD. In fact, ST ChAT activity was significantly decreased
in patients with moderate AD at death, whereas MF and IP ChAT activities were
significantly reduced only in the AD cohort with more severe impairment. This
is in contrast to a recent study by Davis et al,8
in which no regional differences in ChAT activity decline were observed, and
suggests that the progression of deterioration in AD may depend on the involvement
of an increasing number of specific neocortical regions as the disease advances.
In contrast to AD, the pattern of ChAT activity decline in LBV—early
and more extensive, involving all neocortical regions—may contribute
to its characteristic clinical profile. In particular, the higher prevalence
of psychotic symptoms (visual hallucinations and delusions), severe visuospatial
dysfunction, and prominent deficits in executive function, attention, and
literal fluency reported for patients with mild- to moderate-stage LBV11-13 may be related to
earlier and greater reductions of ChAT activity in the temporal, parietal,
and frontal cortices, respectively.
Loss of ChAT activity has been shown to correlate with cognitive decline
in patients with AD by several investigators,2, 6-8
who reported correlation coefficients ranging from 0.467
to 0.82.2 Although these discrepancies across
studies may have several explanations, such as heterogeneity of populations
(demented patients alone vs mixtures of patients with and without cognitive
impairment), tissue samples (biopsy vs autopsy specimens), and brain regions
considered for biochemical assay (eg, allocortical vs neocortical areas),
different disease severity of the cohorts examined was likely the most important
reason. In our AD sample, the strength of correlation between ChAT activity
decline and cognitive impairment increased with increasing severity of dementia
of the patients included in the analyses. When the whole AD cohort and the
NC group were considered, our results (r = 0.52 [MF
and IP cortices]; r = 0.59 [ST cortex]) were quite
consistent with those found by other investigators.7-8
The relationship between ChAT activity and cognitive performance has
been more controversial in DLB, in which reported correlation coefficients
range from 0.2520 to 0.90.18
The same reasons raised for discrepancies in studies of AD and, in particular,
the different disease severity of the patients examined, might have contributed
to this great variability, since the magnitudes of correlation coefficients
in previous studies were considerably reduced when more deteriorated patients
were included.20 Moreover, the present study
clearly shows that in LBV, unlike AD, the relationship between ChAT activity
decline and cognitive impairment weakens as the severity of dementia of the
patients included in the analyses increases.
Our findings may have several therapeutic implications. First, our data
may provide a rationale for the greater responses reported for patients with
more advanced AD in experimental trials of cholinesterase inhibitors, implying
that even patients with severe AD retain the capacity to respond to cholinergic
treatment. Second, and more important, these results suggest that cholinergic
replacement therapy may be particularly effective in LBV, beginning with the
earliest stages. Cholinergic replacement therapy has been postulated to play
an important role in the treatment of LBV after 3 patients with combined LB-AD
pathology and very low neocortical ChAT activity were reported to show a substantial
response to tacrine hydrochloride treatment.33
Evidence has also shown that cholinesterase inhibitors may have neuropsychiatric
benefits,34 including reduction of agitation,
delusions, and hallucinations, which are highly prevalent in LBV.11-12 Although a recent pharmacological
trial35 has only partially supported these
findings, the present study strongly suggests that cholinergic replacement
therapy may have greater benefits, especially early, for patients with LBV
than for those with AD. This observation should be further assessed in well-designed,
randomized clinical trials.
AUTHOR INFORMATION
Submitted for publication May 31, 2001; final revision received December
11, 2001; accepted December 17, 2001.
This study was supported by grant AG05131 from the National Institutes
of Health, Bethesda, Md.
We thank Katherine Foster and Barbara Reader for the technical assistance
they provided in this study.
Corresponding author and reprints: Jody Corey-Bloom, MD, PhD, Neurology
Service (Mail Code 9127), San Diego Veterans Affairs Medical Center, 3350
La Jolla Village Dr, San Diego, CA 92161-3064 (e-mail: jcoreybl{at}vapop.ucsd.edu).
From Neurologia, Ospedale San Paolo, Milano, Italy (Dr Tiraboschi);
the Department of Neurosciences, University of California– San Diego,
La Jolla (Drs Hansen, Merdes, Masliah, Thal, and Corey-Bloom and Mr Alford);
and the Neurology Service, San Diego Veterans Affairs Medical Center, San
Diego, Calif (Drs Thal and Corey-Bloom).
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