Clinico-Pathological Correlation in Dementias

F. TeixeiraI, E. Alonso2, V. Romerol, A. Ortiz', C. Martinez3, E. Otero4
'Departnents of Experimental Neuropathology and 2Genetics, and the 3Division
of Psychology and
4Neurology, National Institute of Neurology and Neurosurgery, Mexico City,
Mexico

Submitted: February 22, 1994
Accepted: February 9, 1995

The object of this study is to investigate whether or not there are clinical
signs and symptoms in
patients with dementia that, by themselves or jointly, can be associated
with the pathological
diagnosis of Alzheimer's disease. Twelve patients with dementia were
studied, in whom the clinical
diagnosis of Alzheimer's disease was made according to established criteria.
A sample of
leptomeninges, cortex and subcortical white matter was obtained from each
patient and was
processed for light and electron microscopy. In the cases in whom neuritic
plaques and neurofibrilary
tangles were present, pathological changes were quantified. The diagnosis of
Alzheimer's disease
was confirmed in 5 cases, whereas in 3 patients spongiform encephalopathy
was present. In the
remaining patients, the number of neuritic plaques was within normal limits
for the age of the
subjects. Comparison of the data in Alzheimer (n = 5) and non-Alzheimer (n =
7) groups showed an
increased, statistically significant incidence of acalculia, abnormalities
of judgment, impairment of
abstraction and primitive reflexes in the former. Although good fitting
models were obtained, none
achieved perfect discrimination. The model that included alterations
ofjudgment and acalculia gave
the best fit.
Key Words: Alzheimer's disease, dementia
INTRODUCTION
Several signs and symptoms have been described extensively
in the various diseases that lead to dementia. These
symptoms include lack of attention, defective memory, apathy,
emotional lability, judgment changes and delirium (Karp
and Mirra 1986). Many of these characteristics, as well as
electrophysiological changes, are said to be shared by different
forms of dementia (McKhann et al 1984).
It is the object of this paper to investigate whether or not,
in Alzheimer's disease, there is a constellation ofclinical data
that will allow the clinician to reach the diagnosis without the
aid of a brain biopsy.
Address reprint requests to: Dr F Teixeira, Instituto Nacional de
Neurologfa y Neurocirugia, Insurgentes Sur, 3877, Mexico 14269,
DF, Mexico.
METHODS
Twelve patients were studied. Because of degeneration of
the patient's brain functions, a detailed medical history was
obtained from family members. A complete clinical examination
was performed, including cranial nerves, tone,
reflexes, coordination, gait and proprioception. None ofthese
patients had a history or clinical findings suggestive of other
causes of dementia such as cerebral infarction, trauma to the
head, intracranial neoplasia, substance abuse or systemic or
neurological diseases associated with dementia.
Neuropsychological examination was designed by the
Division of Psychology of the National Institute of Neurology
and Neurosurgery so that the exploration could be
adapted to the sociocultural level and schooling of the
patients. Basic neuropsychological exploration investigated
JPsychiatry Neurosci, VoL 20, No. 4, 1995 276
Dementia
Table 1
Degree of psychological deterioration expressed as percentages
Degree of deficit
Marked (%) Moderate/slight (%)
77
82
84
100
60
66
100
23
18
16
0
20
28
0
Nil (%)
0%
0%
0%
0
20
6
0
Gnosias 66 22 12
R & D): repetition and denomination; I & I: ideomotor and ideatory; VI, P &
C: visuomotor integration, perception and coordination.
attention, concentration, memory (immediate, recent, remote
and learning), language (flow, repetition denomination and
comprehension), praxis (ideomotor, ideatory and visuoconstructive)
and all modalities of gnosias. Degrees of impairment
in each patient were qualified as follows, per different
area: 0 = nil, 1 = slight to moderate, and 2 = severe. In
7 patients, a scale was used to assess 5 different aspects of the
ability to perform everyday activities: personal hygiene,
work, interpersonal relation, motor system (abnormal movements,
gait) and memory and visuospacial Qrganization. The
scale consists of 100 tests, each one graded as follows:
0 = normal; I = slight deficit; 2 = moderate deficit, and
3= severe deficit. Normal subjects score 20 points or less.
The patients underwent an extensive battery of laboratory
and neuroimaging studies to evaluate the degree and topography
of cerebral atrophy, to exclude vascular impairment
and causes of partially or completely reversible dementias.
This detailed work-up included a complete blood count,
erythrocyte sedimentation rate, Chem 20, thyroid tests, levels
of B12, syphilis serology, HIV testing, chest X-ray, electrocardiogram,
examination of cerebrospinal fluid, computerized
tomographic scanning, and magnetic resonance
imaging. Baseline electroencephalographic measures were
used to follow the course of the disease. The latency and
amplitude of P 300 cognitive-evoked potential were correlated
with neuropsychological deterioration.
After the studies were completed, the relatives were
briefed on the risks of a brain biopsy and on its nature, i.e.,
that the biopsies are not curative, but part of research protocol
to study changes in blood-brain barrier in Alzheimer's disease
that is still in process. This protocol was approved by the
Committee for Ethics in Biomedical Research from the
National Institute of Neurology and Neurosurgery. After
permission for the biopsy was granted in writing, a sample of
the superior frontal gyrus was taken, as this adds the least
operative time and risk. In addition, quantitative studies by
de la Monte (1989) showed that, in Alzheimer brains, the
regional distribution ofplaques and tangles usually correlates
with the distribution of cerebral atrophy. In all of this study's
patients, neuroimaging studies revealed that the frontal gyri
were severely affected.
The s4mple, which included the leptomeninges, cerebral
cortex and subcortical white matter, was divided into 2 parts.
The first part of the specimen was fixed in buffered formalin
and embedded in paraffin. Sections were stained with hematoxylin
and eosin; luxol fast blue-cresyl violet was used for
myelin and nerve cells; Bielschowsky and Von Braunmuhl
methods were used for neurofibrillary tangles and neuritic
plaques; and Congo Red was used for amyloid. Immunoperoxidase
techniques, using monoclonal mouse antibodies to
human beta amyloid and to amyloyd A4 component (Dako
A/S, Denmark), were also applied. Senile plaques and
neurofibrillary tangles were counted at 100 x power and
400 x power, respectively, on the whole surface of the cortex
contained in sections stained with silver methods or immunoperoxidase
techniques. Their numbers were expressed per
square millimeter unit. The second part of the specimen was
finely sectioned and fixed in 2.5% glutaraldehyde in 0.1 M
cacodylate buffer, pH 7.4, post-fixed in 1% osmium tetroxide
in the same buffer, dehydrated in acetone and embedded in
Epon. Semithin sections were stained with toluidine blue and
examined under a light microscope. Ultrathin sections, in the
silver/grey area of the spectrum of interference colors, were
stained with uranyl acetate and lead citrate and observed
under a Zeiss EMIO transmission electron microscopy.
Attention
Concentration
Memory
Language
Fluidity
R&D
Praxias
I&I
VI, P & C
.-I.. IL I-I
277 July 1995
Journal ofPsychiatry & Neuroscience
The following packages were used for statistical analysis
of the results: BMDP 1990 version on a VAX 11n750, and
GLIM 3.77 version on an AT microcomputer with coprocessor.
Pearson's Chi-Square Test and Fisher's Exact Test
were used to compare clinical features.
RESULTS
The results of clinical and laboratory examinations did not
rule out Alzheimer's disease in any of the patients, according
to established criteria (McKhann et al 1984). There were no
instances of hypothyroidism, or cardiac, renal or hepatic
malfunction. Cerebrospinal fluid examination was normal in
all patients. Computerized tomographic scanning and magnetic
resonance imaging showed, in all individuals, global
cerebral atrophy with marked reduction in overall crosssectional
areas of the brain, an increase of the volume of the
ventricular system and of the subarachnoid space. No areas
of cerebral infarction were seen in any of the images.
Results of the basic neuropsychological exploration are
expressed in Table 1. Eighty-eight percent of the patients
showed a marked deterioration of judgment and a similar
deficit in the performance of abstract tasks and calculation.
The mean score of the 7 subjects tested for everyday activity
scales was 49, which reflects marked deterioration, and indicates
a requirement for permanent assistance and care. In
summary, there was a severe degeneration of superior cerebral
functions involving cortical and subcortical areas. At this
advanced stage of dementia, it is not possible to detect
significant differences of involvement among several areas.
Five patients (numbers 8 to 12) were diagnosed as having
Alzheimer's disease with base on morphologic criteria determined
by Khachaturian et al (1985) and Crystal et al (1988).
They had numerous neuritic plaques and a variable density
of neurofibrillary tangles. Three patients (5 to 7) showed
numerous small (1 to 12 micrometer in diameter) vacuoles,
many of them confluent, which markedly distorted the
neuropil of the cortex. There was severe astrocytic gliosis.
No plaques or tangles were seen in these biopsies, and no
congophilic or A4 positive material was present. Electron
microscopy showed that these vacuoles were located in the
cytoplasm of astrocytes and neurons, and contained cytoplasmic
and membranous debris. These cases were diagnosed as
having Jakob-Creutzfeldt disease. Patients 1 to 3 had few
neuritic plaques; their biopsy was reported as being normal
for their age. In patient 4, many neurons were atrophic, with
dense nuclei and abundant cytoplasmic lipofuscin. These
neurons were located far from the surgical margins of the
specimen and belonged to all cortical layers. In none of the
biopsies were there cytoplasmic or nuclear abnormal bodies,
inflammation, neoplasia or demyelination.
On the basis of the result of the brain biopsy, the patients
were divided into two groups: A (Alzheimer group: patients
8 to 12) and NA (non-Alzheimer group, patients 1 to 7).
Individuals from either group were similar in regard to age
and sex distribution (see Table 2).
In many patients, the number of cortical argyrophilic
plaques exceeded by far the minimum established by
Khachaturian et al (1985) for each age. Differences between
mean numbers ofplaques and neurofibrillary tangles in A and
NA subjects were highly significant.
Time of evolution tended to be shorter in NA cases, but
the difference with the A group was not significant because
of the presence of patient 1, who had an unusually long
course.
Clinico-pathological correlation
Family history
Two patients had one or more first-degree relatives with
dementia. Patient 1 was 83 years old at the time of the biopsy,
and his intellectual deterioration had been progressing for
10 years. His sister, aged 71, had a similar clinical picture
with 15 years' evolution. This patient had few argyrophilic
plaques and no neurofibrillary tangles; this pattern was considered
within normal limits for his age. Patient 9, a 52-yearold
woman whose diagnosis of Alzheimer's disease was
confirmed by brain biopsy, belonged to an extraordinary
family in that her mother, her maternal grandmother, a
brother, a sister and a maternal aunt had all died after presenting
a clinical picture similar to hers. Two other sisters were
demented and still alive. The pattern of inheritance for this
family corresponds to an autosomal dominant. Pearson's
Chi-Square Test showed no statistically significant difference
for this variable between the A group and the NA group.
Seizures
This variable was observed in 3 patients. Patient 8 of the
A group, who had a 36-month history of behavioral changes,
presented 3 episodes of generalized seizures in the last
4 months before being admitted. Patients 5 and 7, with
spongiform encephalopathy, also had convulsive episodes in
the last 5 months before being admitted. The difference of
incidence between the two groups was not significant.
Speech abnormalities
Three out of five patients with Alzheimer's disease presented
with speech abnormalities, characterized by reduced
fluidity and problems for expression and comprehension.
Verbal expression was, in the most severely affected patients,
reduced to stereotypes, with no residual ability to communicate
ideas. Patient 6 of the NA group had marked problems
communicating verbally, and was limited to mumbling one
of the last words said by the interviewer. The statistical
significance for this variable was moderate (p < 0. 1).
278 VoL 20., No. 4,1995
July 1995
Table 2
Clinical and pathological data
Case Diagnosis Age Sex Evolution (months) NFI NP
1 Non-Alzheimer 83 M 120 0 8
2 Non-Alzheimer 68 F 66 3 5
3 Non-Alzheimer 43 M 9 0 1
4 Non-Alzheimer 57 F 15 1 0
S Non-Alzheimer 56 M 16 0 0
6 Non-Alzheimer 68 F 5 0 0
7 Non-Alzheimer 61 F II 0 0
Mean 62.29 34.57 0.57 2.0
sd 12.49 M =43% 43.01 1.13 3.21
8 Alzheimer 77 M 60 2 23
9 Alzheimer 52 F 72 8 16
10 Alzheimer 65 F 36 5 14
11 Alzheimer 69 M 19 3 35
12 Alzheimer 59 F 84 6 21
Mean 64.40 54.20 4.8 21.80
sd 9.53 M = 40% 26.50 2.39 8.23
F= 0.10 0.45 17.1 34.36
p n.s. n.s. n.s. p <0.01 p < 0.01
Age is expressed in years; NFT = numbers of neurofibrillary tangles per
square millimeter; NP = numbers of neuritic plaques per square
millimeter; n.s. = not significant.
Cerebellar changes
All patients with Alzheimer's disease performed adequately
at the tests for coordination, albeit slowly. Among the
NA patients, only one woman (number 6) showed generalized
incoordination, with dysmetria and truncal ataxia. There
was no significant difference between the A group and the
NA group regarding this variable.
Delirium
Relatives of most patients from both groups attested to
delirious episodes, with restlessness, visual and auditory
hallucination and disorientation. There was no significant
difference between the groups.
Abnormal movements
These movements manifested as intentional tremor of
hands. Again, the difference was not significant. None of the
cases diagnosed histologically as Jakob-Creutzfeldt disease
had myoclonic jerks.
Pyramidal abnormalities
Three subjects for each group showed mild generalized
spasticity, gastrocnemial clonus and bilateral Babinski sign.
The difference was not significant.
Primitive reflexes
Suction, searching, palmar and plantar grasping reflexes
were present in all patients with Alzheimer's disease and 3
out of 7 NA individuals. The level of significance was
p <0.04.
Impairment ofmemory
Impairment involves both short-term and long-term memory
consolidation and retrieval. All patients with Alzheimer's
disease were severely affected, as were 5 out of 7 from the
NA group. The remaining 2 NA subjects showed a moderate
to slight impairment. There was no statistically significant
difference between the A group and the NA group.
Impairment ofabstraction, Judgment alterations and acalculia
The first 2 features were characteristic of Alzheimer cases
and were present in all patients. Acalculia was observed in
all patients with Alzheimer's disease but one, in contrast to 1
out of 7 NA cases. In some A individuals, acalculia presented
early in the course of the disease. Regarding all 3 features,
there was a significant difference (p < 0.05) between the A
group and the NA group.
Dementia 279
Journal ofPsychiatry & Neuroscience
Table 3
Summary of clinical variables in Alzheimer (A) and non-Alzheimer (NA)
patients (see text)
A Group NA Group
n=5
Family history
Seizures
Speech changes
Cerebellar abnormalities
Delirium
Abnornal movements
Pyramidal abnormalities
Primitive reflexes
Impaired memory
Impaired abstraction
Judgment alterations
Acalculia
Dysarthria
Apraxia
Agnosia
T-s
1
2
3
0
4
2
3
5
S
S
5
4
2
2
2
Incontinence I
Disorientation 3
Abnormal EEG 5
n.s.: difference statistically not significant; +: 0.05 < p < 0.10; ++: p <
0.05.
n=7
1
1
5
3
3
3
5
2
1
4
3
4
1
3
Significance
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s. ++
n.s.
++
++
++
n.s.
n.s.
n.s.
n.s.
n.s.
Dysarthria, apraxia and agnosia
There was no significant difference in any ofthese features
between the A group and the NA group.
Incontinence
Although this symptom was more common in the NA
group, the difference was, once more, not significant.
Disorientation
Three out of five patients with Alzheimer's disease were
disoriented in time and space, compared with 1 out of 7 NA
patients. The difference was not significant.
Abnormal EEG
Electroencephalographic changes, characterized by deficient
organization and a generalized slow activity was found
in all A patients, and in 3 out of 7 NA patients. The significance
of the difference was moderate (p < 0.07).
None of the patients presented headache, fever, vertigo or
cranial nerve changes. The above discussed variables are
shown in Table 3.
Logistic discriminant functions
The joint effects of the variables were selected in stages
because of the small sample size. Although good fitting
models were obtained, none achieved a perfect discrimination.
Among the models with two variables, alterations in
judgment and acalculia gave the best fit (deviance 4.50 with
9 d]) and only I patient with Alzheimer's disease was misclassified
(see Table 4).
DISCUSSION
The rates of accuracy of the clinical diagnosis of
Alzheimer's disease in several clinico-pathological studies
range from 43% to 87% (Joachim et al 1988; Mosla et al
1985; Muller and Schwartz 1978; Nott and Fleminger 1975;
Sulkava et al 1983; Todorov et al 1975; Wade et al 1987). It
should be interesting, therefore, if selected clinical data could
help to reach this diagnosis without the aid of a brain biopsy.
The results of this study show a very significant association
of Alzheimer's disease with the following variables:
primitive reflexes, impairment of abstraction, changes in
judgment and acalculia. In studying the joint effect of
280 VoL 20, No. 4,1995
July 1995 Dementia 281
Table 4
Fitting model including alteradons ofjudgment
and acalculia
Case Diagnosis Fitted
I NA 0.250
2 NA 0.000
3 NA 0.250
4 NA 0.250
5 NA 0.000
6 NA 0.000
7 NA 0.000
8 A 1.000
9 A 1.000
10 A 1.000
11 A 0.250+
12 A 1.000
NA = non-Alzheimer; A = Alzheimer; + = misclassified Alzheimer
patient
variables, it was seen that alterations of judgment and acalculia
produced the best fit.
The sample in this study may be considered small for the
purpose of selecting a set of signs and symptoms that can
characterize Alzheimer's disease clinically. However, it is
not an easy task to obtain the permission to perform a brain
biopsy which is of no benefit for the patient when the relative
is informed of the risks involved.
The definite diagnosis of Alzheimer's disease depends on
the microscopical examination of brain tissue, either by
autopsy or biopsy. In the USA, the Alzheimer Disease
Research Center of the University of Pittsburgh has launched
a public campaign to encourage relatives of demented patients
to request a postmortem examination of the brain
(Boller et al 1989). However, in Mexico, a similar campaign
has enjoyed little success so far for several reasons. The
patient who suffers from Alzheimer's disease usually dies at
home. The relatives, who are already exhausted by the demands
of caretaking, obtain a death certificate from the
family physician, and proceed quickly to the funeral rites.
The few families who do request an autopsy are almost
invariably denied admission to the hospital where the patient
had been admitted because cadavers without a death certificate
must be sent to the police department for autopsy. Many
patients die in small towns or villages where there are no
pathologists, let alone neuropathologists. Therefore, brain
biopsy remains the only possibility for confirming the clinical
diagnosis. It is true that there is no benefit derived by the
patient from this procedure and that he or she faces surgical
and anesthetic risks. In contrast, brain biopsy allows: 1. the
development of new diagnostic procedures that might, in the
future, replace it; 2. adequate genetic counselling in cases
with an autosomal dominant pattern of inheritance, so that
family members can take part in studies at the molecular
biology level; and 3. the performance of therapeutic trials and
of epidemiological surveys in Mexico.
Familiar aggregation has been demonstrated in 40% of
cases of Alzheimer's disease. In 15% of these cases, the
pattern of inheritance was autosomal dominant (Heston et al
1981). Patient number nine's family is an example of the
latter, and showed an early age of onset.
Vacuolar change, similar to that present in Jakob-
Creutzfeldt disease, has been described in brains of patients
with Alzheimer's disease, especially at the medial temporal
isocortex, where it has a high, statistically significant association
with the presence of large numbers of neurofibrillary
tangles and argyrophilic plaques (Smith et al 1987). This
study considered the possibility that cases 5 to 7, diagnosed
as Jakob-Creutzfeldt disease, could be, in fact, Alzheimer
cases with this peculiar vacuolar change. A good method for
separating the two entities would be the use of antibodies
against prion (Pr-P) proteins (Tateishi et al 1988), which
were, unfortunately, not available to the authors. However,
none of these cases showed positivity for A4 protein, neither
had one single argyrophilic plaque or tangle. Moreover, the
biopsies were taken from the frontal regions, which are
reported to be free of involvement in instances of
Alzheimer's disease with vacuolar changes (Smith et al
1987).
Although the diagnosis of probable Alzheimer's disease
was made in all of the patients in this study, according to the
criteria established by McKhann et al (1984), this diagnosis
was confirmed in only 47.1% of them. This low rate might
be the result of several factors. The National Institute of
Neurology and Neurosurgery in Mexico City is an institution
that concentrates especially on difficult or unusual cases that
are referred from all over the country. Therefore, it received
a biased sample that included as many as 3 cases of spongiform
encephalopathy. In addition, it is important to remember
that a small, 1 cubic centimeter sample of cortex and white
matter may not be representative of the extent of the damage
in other areas of the brain, and so, correlates poorly with the
clinical picture. This illustration is particularly true of cases
1 to 4, which did not fit into any of the pathological entities
that manifest clinically as dementia. To understand more
clearly the relation between damage and clinical impairment,
further prospective studies using autopsy material are needed.
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