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Cortical biopsy in Alzheimer's disease Diagnostic accuracy and neurochemical neuropathological and cognitive correlations.

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Cortical Biopsy in Alzheimer's Disease:
Diagnostic Accuracy and Neurochernical,
Neuropathological, and Cognitive
Steven T. DeKosky, MD,' Robert E. Harbaugh, MD,t Frederick A. Schmitt, PhD,S Roy A. E. Bakay, MD,§
Helena Chang Chui, MDJI David S. Knopman, MD,'l Teddi M. Reeder, BS, RN,? Andrew G. Shetter, MD,'
Howard J. Senter, MD,#* William R. Markesbery, MD,S and the Intraventricular Bethanecol Study Group??
Neurochemical assessments were performed on biopsy samples taken from the right frontal lobe of patients diagnosed
with Alzheimer's disease (AD), before the implantation of a ventricular catheter and pump assembly for the infusion
of bethanechol chloride as an experimental therapy. The pathologically diagnosed patients with AD (n = 35; mean
age, 67 k 1.5 yr) were compared with a group of samples from normal age-equivalent autopsied controls (n = 22;
mean age, 68 2 2 yr) and autopsied AD brains (n = 11; mean age, 73 & 2 yr). Samples were assayed for choline
acetyltransferase(ChAT), acetylcholinesterase,binding to C3H}quinuclidinylbenzilate as an index of total muscarinic
cholinergic binding, and I3H)pirenzepine binding as an index of M l cholinergic receptor subtype binding. Mean
levels of ChAT activity were decreased in the biopsied patients to 36% of age-matched autopsied controls. The loss
of ChAT activity correlated significantly with the Mini-Mental State Examination, an index of global cognitive
function. Mean ChAT activity in autopsied AD cortex was further decreased compared with controls, indicating
continuous decline through the course of the disease. Acetylcholinesterase followed a similar, less dramatic decline.
N o differences were found in {3H3quinuclidinyl benzilate binding or E3Hlpirenzepine binding between biopsied
and autopsied controls. Neuritic plaque counts did not correlate with either the Mini-Mental State Examination or
ChAT activity in the biopsy specimens. The correlation of cortical ChAT activity with degree of dementia, although
considerably weaker than those of cortical synaptic density with dementia, is the first demonstration of such a relationship in biopsied patients, and suggests another reason why the AD brain may be unresponsive to presynaptic cholinergic manipulations or attempts at enhancement.
DeKosky ST, Harbaugh RE, Schmitt FA, Bakay RAE, Chui HC, Knopman DS, Reeder TM,
Shetter AG, Senter HJ, Markesbery WR, IntraventricularBethanecol Study Group.
Cortical biopsy in Alzheimer's disease: diagnostic accuracy and neurochemical,
neuropathological, and cognitive correlations. Ann Neurol 1992;32:625-632
From the 'Departments of Psychiatry and Neurology and Alzheimer's Disease Research Center, Western Psychiatric Institute and
University of Pittsburgh Medical Center, Pittsburgh, PA; ?Dartmouth Hitchcock Medical Center, Hanover, NH; $University of
Kentucky Medical Center, Lexington, KY; §Emory Clinic, Atlanta,
GA; ''University of Southern California, Downey, CA; 'University
of Minnesota, #Barrow Neurological Institute, Phoenix, AZ; and
**Western Pennsylvania Hospital, Pittsburgh, PA.
ttThe following institutions, personnel, and funding agencies were
involved in this study: Barrow Neurological Institute, Phoenix, AZ:
Philip Carter, MD, James L. Frey, MD, Arthur Schwam, PhD, and
Andrew G. Shetter, MD (funding from the Arizona Disease Control
Commission). Dartmouth-Hitchcock Medical Center, Hanover,
N H Colin D. Allen, MD, Lynette Bob, BA, Rita Casey, PhD,
Charles M. Culver, MD, Robert E. Harbaugh, MD, and Teddi M.
Reeder, BS, RN (funding from the American Health Assistance
Foundation and National Institute of Mental Health Grant lROl
MH40505-01). The Emory Clinic, Atlanta, GA: Roy A. E. Bakay,
MD, David Freides, PhD, Herbert R. Karp, MD, and Suzanne S .
Mirra, MD (funding from the Veterans Administration Hospital,
Decatur, GA). University of Kentucky, Lexington, Ky: Steven T.
DeKosky, MD, William R. Markesbery, MD, and Frederick A.
Schmitt, PhD (funding from NIA AGO5 144 and AGO5 119 and the
VA Research Service). University of Minnesota, Minneapolis, MN:
Susan Deinard, RN, Donald Erickson, MD, Michael Fuhrman, BS,
and David S . Knopman, MD (funding from the Twin Cities Chapter
of the Alzheimer's Disease and Related Disorders Association and
the University of Minnesota Hospitals). University of Pittsburgh:
Steven T. DeKosky, MD (support from NIA AG05133). University
of Southern California, Downey, CA: Eileen Bardolph, MD, Helena
Chang Chui, MD, Steven Giannotta, MD, Barbara Smith, RNC,
Evelyn Teng, PhD, and Bradley Williams, PharmD (funding from
the Estelle Doheny Foundation). Western Pennsylvania Hospital,
Pittsburgh, PA: Lorraine Klauscher, RN, Rick Kortyna, PAC, Howard J. Senter, MD, and Arthur Vega, PhD (funding from the Western Pennsylvania Guild, The Western Pennsylvania Foundation, and
the Western Pennsylvania Hospital).
Received Nov 14, 1991, and in revised form Apr 16, 1992. Accepted for publication Apr 16, 1992.
Address correspondence to Dr DeKosky, University of Pittsburgh,
Alzheimer's Disease Research Center, 3600 Forbes Avenue, Suite
400, Pittsburgh, PA 15213.
Copyright 0 1992 by the American Neurological Association 625
Rarely does the opportunity present itself to obtain
biopsy tissue from living patients with Alzheimer’s disease (AD). In 1984, Harbaugh and associates [ l ]
published a preliminary report of a beneficial effect
of intraventricular bethanecol chloride, a cholinergic
receptor agonist, o n the cognitive symptoms of AD.
That study led to a larger multicenter study to evaluate
the suitability of this medication for therapeutic use
[2]. T h e protocol for the multicenter study required a
biopsy of the right frontal cortex of all patients at the
time of catheter placement. This enabled separation of
true patients with AD from patients with dementia but
without AD (who, for the most part, d o not have cholinergic deficits 131). It also provided a unique opportunity to assess markers of cholinergic neurotransmission
and their relationship to cognitive and neuropathological findings, and allow assessment of diagnostic accuracy of the clinical criteria used to select patients with
probable AD. The current study summarizes the diagnostic findings in the intraventricular bethanecol study.
It compares cholinergic enzyme activity and cholinergic receptor content to mental status assessments and
cortical neuritic plaque (NP) counts from the same biopsy samples. Levels of cholinergic enzymes from ageequivalent autopsy cases of normal control subjects and
patients with AD were evaluated to compare loss of
these markers at a relatively early stage of the disease.
Patient Selection
Biopsy patients were selected according to Alzheimer’s Disease and Related Disorders Association/National Institute
of Neurological and Communicative Disorders and Stroke
(ADRDA/NINCDS) [4] or Diagnostic and Statistical Manual of Mental Disorders, third edition (DSM-111) [51 criteria.
Only patients with Mini-Mental State Examination (MMSE)
s?ores of 10 to 24 [6] and global deterioration ratings [7] of
4 to 5 were admitted to the study. Extensive preoperative
evaluations were performed to rule out, as far as was possible,
other dementia. Details about all patients in the original
study are found in the article by Harbaugh and associates
[2]. Forty-five patients were studied under the present protocol, 35 of whom had a neuropathological diagnosis of AD
determined from their biopsies. Mean age of the patients
with AD was 67 2 1.5 years (mean f SEM). Cognitive performance on the MMSE was obtained, but reliable data for
duration of disease in each patient was not available.
Autopsy AD patients were those who met clinical criteria
for AD during life, who were autopsied within 24 hours after
death, and who met neuropathological criteria for AD 17a).
From these patients, right frontal cortex samples were selected for inclusion in the postmortem AD group. These
patients were selected to be age-equivalent, at the time of
death, to the biopsied patient group. Mean age was 73.4 2
1.8 years (n = 11).
Nonnalcontrols were selected from right frontal cortex samples of patients who died suddenly, without terminal hypoxia,
without prior history of dementia, and whose neuropatholog-
ical examination revealed no evidence of AD or other neurological diseases. Mean age was 68 2 2.4 years (n = 22).
Tissue Acquisition and Sample Preparation
For chemistry, biopsy samples were frozen on dry ice in the
operating room, sealed in airtight containers, and held at
- 70°C until prepared for chemical analysis by batch. Autopsy samples were frozen on dry ice and stored at - 70°C
until analysis.
Samples for histopathological evaluation were immersionfixed in 10% formalin, embedded in paraffin, and stained by
standard neuropathological techniques, including the modified Bielschowsky method for N P counts. Autopsy samples
were treated identically. The surgical protocol called for a
full-thickness sample of cortex, with a small amount of subcortical white matter attached, to facilitate orientation. Subcortical white matter was trimmed before neurochemical
Biochemical Methods
Choline acetyltransferase (ChAT) activity was assayed by the
method of Fonnum [8), as modified by DeKosky and colleagues [9]. Acetylcholinesterase (AChE) activity was assessed by the method of Ellman and co-workers [lo}, also as
modified 191. Total muscarinic cholinergic binding sites were
assessed by use of [3H]quinuclindinyl benzilate (13H]QNB)
[111. The M1 muscarinic binding site subtype was measured
with L3H)pirenzepine (C3H]PZ) [12). Scatchard analyses of
the binding of both ligands were performed on cortical samples taken from autopsied patients with AD and control patients. The Kd for QNB was approximately 150 nM, that for
PZ 12 nM. These are in accord with those for human cortex
previously reported by this laboratory 191 and others [ 11,
127. The {3H]QNB binding assays of the AD biopsy and
control samples were run at saturating concentrations (240
nM). The E3H]PZ assays were run at the Kd. Proteins were
measured by the procedure of Lowry and colleagues [131.
Neuropathological Evaluation
All biopsied patients included in the current study were diagnosed by the neuropathologist at the local study center. A
second neuropathologist (W.R.M.) reviewed 35 of the patients for confirmation; in 2 patients, the diagnosis of AD
was made by the local neuropathologists, but insufficient tissue was available for confirmation by the second neuropathologist. In both patients, tissue fragments insufficient for corroborating diagnosis did have N P noted. Adequate tissue was
available from 24 of the 35 patients with AD to allow the
second neuropathologist to generate a quantitative assessment of NP. N P were manually counted using a 20 x objective ( 2 0 0 ~magnification) with each field representing 0.6
mm2. The number of fields counted varied with the size of
the section.
Clinical-Pathological Acctlracy
A n overall clinical diagnostic accuracy of 78% was
achieved in the study (Table 1). Despite the presence
626 Annals of Neurology Vol 32 N o 5 November 1992
Table 1 , Accuracy of Diagnosis in Biopsied Patients with
Preoperative Clinical Diagnosis of Probable A D
Number of
of Total
- 11-
Total operations
Pathology of AD
Pick‘s disease
No pathological
A D = Alzheimer’s disease.
of features considered typical of AD by the examining
physicians, 2 patients with Pick’s disease were found,
and in 7 patients no neurological abnormality could be
identified in the surgical samples by the neuropathologist.
Autop Controls Blopsy AD
Autopsy AD
Cholinergic Enzymes
There were 32 AD biopsy samples in which ChAT and
AChE were measured; frozen samples for cholinergic
enzyme analysis were available for 8 of the 10 non-AD
biopsied patients. There were no changes in cholinergic enzyme activity (ChAT or AChE) as a function of
patient age in any of the groups (the group spanned
only three decades). Analysis of variance revealed that
the levels of activity of ChAT differed significantly
among the biopsied patients with AD, autopsied patients with AD, and autopsied controls (F = 25.38; p
< 0.0001). Post hoc t tests with Bonferroni correction
for multiple comparisons indicated significant decline
in biopsy AD ChAT activity compared with autopsied
controls ( p < O.OOOl), as well as significant differences
between biopsied patients with AD and autopsied patients with AD (] = 0.0058), indicating likely further
decline in ChAT activity through the subsequent
course of the disease (Fig 1). Autopsied patients with
AD were also significantly lower than autopsied controls ( p < 0.0001). Mean ChAT activity of the 8 patients with non-AD dementia was 4.96 ? 1.0 kmol
of acetylcholine (ACh)/hr/gm of protein, not different
from the normal autopsied controls (6.01 5 0.6 Fmol
of ACh/hr/gm of protein). AChE activity also was significantly different among the three groups ( p <
0.0017); post hoc t tests indicated that biopsied patients with AD were significantly lower in AChE activity than the age-equivalent controls ( p < 0.0021).
There was no further significant decline in AChE activity in the autopsied patients with AD (Fig 2). Mean
AChE activity of the biopsied patients with non-AD
dementia was 0.28 2 0.04 pmol/hr/gm of protein,
not different from the normal age-equivalent controls
(0.23 ? 0.02 pmol/hr/gm of protein). The distribution
Fig I. Choline acetyltransferase (ChAT) activity in the right
frontal cortex of normal autopsied controls, biopsied patients
with Alzheimefs disease (AD), and autopsied patients with
AD. Leueh in the biopsied patients were significantly reduced (p
< 0.0001)to 43% ofthe autopsied control levels. A further
significant decline (p < 0.01 1) was seen in the autopsied patients. ChAT activity is expressed as mean numbers of micromoles of acetylcholine per hour per gram of protein +. SEM. *p
< 0.0001,from autopsied controls. **p < 0.0001,from autopsied controls; and p < 0.01 17, from biopsied patients.
of ChAT activity of the samples from biopsied patients
with non-AD dementia is illustrated in Figure 3.
Cholinergic Receptors
Levels of the total cholinergic receptor binding as indexed by binding of the radiolabeled ligand L3H)QNB
and of the M1 muscarinic subtype-specific ligand
L3H]PZ were compared with those of age-equivalent
controls. Insufficient tissue was available from biopsied
patients to perform a Scatchard analysis, but there was
no difference in the Kd for Q N B binding in autopsy
AD cortex compared with age-equivalent normal autopsy control tissue {9, 11). No change in receptor
number was seen as a function of age in either group.
There were 26 samples from biopsied patients with
AD with sufficient tissue to allow receptor binding
studies. There were no significant differences in the
levels of binding of E3H)QNB between biopsied patients (71.6 -+ 4.25 fmol/mg of protein) and autopsied
controls (82.4 ? 9.6 fmol/mg of protein). E3H]PZ
binding was also unchanged between autopsied con-
DeKosky et
Cerebral Biopsy in Alzheimer’s Disease 627
Autop Controls BIOPSY AD
Autopsy AD
Fig 2. Acetylcholinesterase (AChE) activity in the right frontal
cortex of normal autopsied controls, biopsied patients with Alzheimer's disease (AD), and autopsied patients with AD. I n biopsied patients with A D , AChE was reduced to 66% of autopsied controls, a significant decline (p < 0.001). The further
decline seen in the autopsied patients with A D rompared with
biopsied patients was not statistically significant. AChE activity is expressed aJ mean number of micromoles per hour per
gram ofprotein t SEM. *p < 0.0021,from controls.
**p < 0.0045, from controls.
trols (182 +- I 1 fmol/mg of protein) and samples from
biopsied patients (179 5 13 fmol/mg of protein).
Nezlropathological, Biochemical, and Behavioral
Correlations in the Biopsy Group
There was a significant correlation between the level
of ChAT activity in the biopsy samples and the level
of cognitive function as measured by the MMSE ( r =
0.41,p = 0.0214; see Fig 3). There was no association,
however, between NP counts (9.97 2 0.96 plaques/
field) in the biopsy group) and MMSE ( r = 0.28, NS),
nor between N P counts and levels of ChAT activity ( r
= 0.069, NS). AChE activity did not correlate significantly with MMSE (r = 0.09, NS), nor with plaque
counts (r = 0.289, NS). Cholinergic enzyme data were
available from 8 of the 10 non-AD patients (both patients with Pick's disease and 6 of the 8 patients with
non-AD dementia); these are also illustrated in Figure
3. The patients with Pick's disease had high levels of
ChAT. Among the patients with non-AD dementia,
there was no relationship between enzyme activity and
MMSE (see Fig 3).
ChAT Activity
Fig 3. Choline acetyltransfrase (ChAT) activity in frontal COItex samples from the patients with biopsy-proven Alzheimer's
disease (AD) and patients with non-AD dementia. Filled circla
= AD; open circles = non-AD dementia (no pathological diagnosis in the biopsy); open triangles = Pick's disease. Levels of
ChAT activity in the biopsied patients with A D bad a significant cowelation with the Mini-Mental State Examination
(MMSE); linear regression is shown only for the patients with
A D (F = 5.89640; p = 0.0214; r = 0.405; P = 0.164).
In the patients with non-AD dementia, there was no relationship between ChAT and MMSE.
The present study confirms previous biopsy evaluations showing decline in ChAT activity {141 compared
with non-AD brains of the same age, and additionally
shows that degree of loss of ChAT activity in living
patients correlates with level of cognitive function. The
loss of ChAT even in the biopsy patients (with relatively early disease) is large, and worsens with disease
progression. N P density in the biopsied patients did
not correlate with severity of dementia or with ChAT
Cholinergic Enzyme Alterations
In previous biopsy studies, ACh synthesis in patients
with AD correlated with degree of cognitive loss 115,
161, but loss of ChAT activity itself was not related to
severity of dementia. In 17 biopsied patients with AD,
Neary and co-workers { 171 found no relationship between ChAT activity and mental status even though
other markers (neuronal cell loss, reduction in neuronal nuclear size, neuronal RNA content, and cortical
neuritic plaque counts) correlated with cognitive status.
628 Annals of Neurology Vol 32 No 5 November 1992
Significant correlations of ChAT and mental status before death have been reported, however, in autopsied
patients with AD 118, 191. Correlation of ChAT activity with cognition does not imply that cholinergic deficits are responsible for the dementia; stronger correlations can be demonstrated between mental status and
synapse counts 1201 and mental status and biochemical
markers of synaptic proteins 121) in AD brain.
AChE activity in the AD biopsy samples was decreased significantly, but the correlation of AChE with
mental status did not reach statistical significance.
AChE is not exclusive to the cholinergic system, and
is found in noncholinergic structures. Unlike ChAT,
AChE did not decline further between the cortical biopsy samples and the autopsy samples. It is possible
that much of the cholinergic system-associated AChE
is lost earlier in the course of the disease and the remainder is associated largely with the noncholinergic
sources of the enzyme [22). In addition, AChE may
be downregdated early in the disease in response to
diminished ACh synthesis, in an effort to maintain levels of ACh. Intense AChE staining is found in N P in
patients with AD {23-261; thus, AChE in the plaques
may have contributed to the stabilization of total AChE
in the autopsied patients in the present study. Thus,
the amount of AChE associated with the cholinergic
system may be overestimated in patients with AD,
partly explaining why AChE inhibitors are not effective
as therapeutic measures.
Muscarinic Receptors
Total muscarinic cholinergic receptor binding is normal
in autopsy studies of AD brain 11I, 191, and intralaminar microchemical studies have shown that no focal
areas within the frontal cortical lamina are selectively
depleted [271. The present study confirms the stability
of total muscarinic receptor binding in the biopsied
There are several subtypes of pharmacologically defined muscarinic receptors 128, 291; 80% of the cortical muscarinic cholinergic receptors are the M1 subtype, to which PZ selectively binds. In agreement with
previous autopsy studies 130-321, no M1 receptor loss
was found in the biopsied patients compared with agematched controls. The ability of the M1 cholinergic
receptor to convert to its high-affinity state has been
reported impaired in patients with A D {33}, although
others suggest that the degree of dissociation from the
binding protein is variable [341. Any dissociation of
the receptor from its second messenger would indicate
a postsynaptic, as well as presynaptic, impairment of
cholinergic neurotransmission. Reports of loss of M2
receptors in the cortex of patients with AD 130, 311
suggested that a decrease of total muscarinic cholinergic receptor binding might be expected in cortex, but
the present study and most others have not found such
a decrease in total binding Ell, 19, 27, 351. The population of both total muscarinic receptors (QNB binding) and the M1 receptor subtype (PZ binding) appear
quantitatively unchanged in the biopsied patients, as in
autopsied patients with AD.
NP and Diagnosis of A D
Neuropathological diagnosis of AD remains dependent on demonstration of the presence in the cortex
and hippocampus of a sufficient number of N P 17a,
361. The more recently specified area density of N P
needed to make the diagnosis, as determined by the
Consortium to Establish a Registry for Alzheimer’s
Disease (CERAD) Neuropathology Task Force 1363,
reflects the semiquantitative nature of the diagnostic
determination. The mere presence of N P in the brain
is not sufficient to make the diagnosis of AD, but their
number and location, and whether the patient was clinically demented before death, allow a neuropathological diagnosis of increasing certainty 1367. Plaques are
virtually invariably seen in the right frontal lobe in patients with AD. In normal autopsy cases, N P are rarely
if ever seen in the frontal cortex where the biopsies
were done for the current study 137, 381. In biopsied
patients, the diagnosis is derived from one small sample
of frontal or (in some studies) temporal cortex, so
applying the quantitative criteria for N P density in this
small piece of tissue is a conservative way to make the
diagnosis of AD.
The present study did not find N P correlations with
degree of dementia, although such correlations have
been reported in biopsy series {lS, 381. Some autopsy
studies have found correlation of N P density with dementia severity 1391, whereas many others did not 117,
18, 21, 40-433. Similarly, correlation of N P density
with level of ChAT activity reported by Perry and colleagues 1191was not found by Wilcock and co-workers
118). In milder cases, the density of N P in the cortex
is more variable {391. Threshold effects, producing a
maximal number of countable, distinguishable NP, and
a floor effect produced by inability to quantitatively
measure severe dementia in the late stages, may be
responsible for the varying results in such correlations
118, 391. The technique of quantification, for example,
a global plaque count score {391 versus a single lobe
plaque score 1181, and the inclusion of normal patients
(with few or no NP) in the analysis {39], also affects
such correlations.
Diagnostic Accuracy of the Clinical Assessment
The accuracy of clinical diagnosis achieved in the current study is similar to that of previous biopsy studies
in the literature, which has risen to approximately 80%
(Table 2). This percentage has improved during the
last 25 years, perhaps due to improved neuroimaging
and neuropsychological assessment and more consis-
DeKosky et al: Cerebral Biopsy in Alzheimer’s Disease 629
Table 2. Percent Accuracy of Biopsy-Confirmed Patients with Clinically Diagnosed Alzheimer’s Disease
Smith e t al (1966)
Coblent et al (1973)
Bowen e t al(1982)
Fox et al(1985)
Neary e t al(1986)
Harbaugh et al(1989)
of Patients
Percentage o f
Patients with A D
Clinical Selection
Presenile dementialatrophy
Probable AD
Probable AD
‘‘Typical cases”
Presenile d e m e n t d a t r o p h y
Probable AD
AD = Alzheimer’s disease.
tent criteria for the diagnosis 14, 51. The figures for
clinical diagnostic accuracy of these studies are not exactly comparable because the design of each study affected the likelihood of AD being found. For example,
the report by Bowen and Neary 1151 was largely of
younger patients studied for presenile dementia with
cortical atrophy. Fox and colleagues [441 reported perfect (100%) diagnostic accuracy in 11 patients who
were carefully screened to assure typical features of
AD; they disqualified patients who had more prominent symptoms in one or another cognitive domain.
Autopsy studies have used a variety of clinical and
neuropathological criteria for diagnosis. A review of
clinicopathological accuracy in series reported from
1975 to 1987 showed correlations of from 43% (in a
1975 study that reflected the pre-computed tomographic CT scan era; {45])to 87% (461. In a recent
review of 6 autopsy series reported since 1987 1471,
accuracy of clinical diagnosis ranged from 68 to 10096,
with the 100% being a prospective study of patients
diagnosed as having AD 1481. A prospective European
study had a clinical accuracy of 82% 1491. Thus, careful
evaluation of clinical characteristics leads to high diagnostic accuracy, and although not all such behavioral
presentations are AD { 15}, the clinical diagnostic accuracy in general for AD, given an “AD-like picture,”
continues to range up from 80% in nonselected autopsy cases.
There are few reports of autopsy results from previously biopsied patients with AD (421. No data are
available on any subsequent autopsy diagnoses of the
small but consistent number of patients who had no
pathological diagnosis made from biopsy; this includes
16% of the current series, 25% (6 of 24) in the Bowen
and Neary { l 5 ] study, and 20% as reported by Coblentz and associates 1501.
tion in biopsied patients with AD than does ChAT
activity {20],and levels of the synaptic protein synaptophysin correlate more strongly with mental status than
do NP counts of ChAT activity from autopsy cases
121). Widespread neuronal loss in frontal cortex 1551,
hippocampus {56},amygdala 1571, locus ceruleus [58],
and nucleus basalis of Meynert {59],and the deafferentation of hippocampus by neuron loss in entorhinal
cortex {GO], plus the disruptive presence of N P in the
neuropil and neurofibrillary tangles in neurons, present
challenges for therapeutic approaches that cannot be
addressed purely by neurotransmitter-enhancement
strategies. Such efforts should be accompanied by efforts to preserve neural membrane, retard progression
of the disease, and determine if neurotrophic factors
can slow decline or improve function in patients with
We thank Carter Hackney and John Webb for technical assistance,
and Jeff Howe for aid with data management.
Structural Changes, Cholinergic Dysfunction, and
Therapeutic Implications
Loss of synapses { 5 l f and the synaptic proteins associated with the synapse (52-541 are widespread in patients with AD. Synapse loss in the right frontal lobe
correlates more strongly with level of cognitive func630 Annals of Neurology Vol 32 No 5 November 1992
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correlation, biopsy, neuropathological, cortical, disease, cognitive, alzheimers, neurochemical, diagnostika, accuracy
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