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Mohamed Ahmed El-Sayed et al.
35
Clinical, neuropsychological testing, brain MRI and
SPECT in Alzheimer and vascular dementia
Mohamed Ahmed El-Sayed1, Abd El-Hady Taha Emam
2,
Tarek Abd El-Fatah El-Magraby3
Departments of Neurology1, Radiology
2, Oncology and Nuclear Medicine
3, Cairo University
ABSTRACT
Background: Alzheimer’s disease (AD) and cerebrovascular disease (CVD) are the most common
causes of dementia in the world. For several reasons, however, differential diagnosis of AD versus
vascular dementia (VaD) has proved to be difficult. However, their accurate differentiation is of great
importance due to different pharmacoceutical strategies which may modify the course of each disease.
Objective: The objective of this study is to assess the usefulness of clinical neuropsychological testing,
neuro-radiological findings (by MRI) and cerebral blood flow changes (by SPECT) in differentiation of
AD and VaD. And to correlate these results with the severity of the dementia, and to find a possible
correlation between clinical neuro-psychological deficits and structural and functional abnormalities in
MRI and SPECT. Materials and Methods: This study was carried on twenty patients suffering of
dementia for more than 2 years duration and were classified into 2 groups, group I included 10 patients
having possible AD and group II included 10 patients having possible VaD. Patients of either groups
were selected according to the following criteria: DSM-IV for AD, DSM-IV for VaD, Hachnisksi ischemic
scale (HIS), ADDTC scale, NINCDS-ADRDA scale. Patients in this study were subjected to thorough
medical, neurological and neurovascular examination, full laboratory investigations, clinical neuro-
psychological scales and tests including: CAMCOG, DRS, MMSE Hamilton depression scale, blessed
dementia scale, Bristol activities of daily living scale, IDDD and clinical dementia rating (CDR), MRI
brain, functional neuro-imaging using SPECT. Results: This study revealed that vascular risk factors
(predominantly uncontrolled hypertension) and focal neurological symptoms and signs were mainly a
features of VaD and not AD. Patients with AD had significantly more deterioration (P<0.05) in mental
and cognitive functions and activities of daily living compared to those with VaD, while those with VaD
significantly (P<0.05) were more prone to develop depression and behavioral changes. Bilateral cortical
atrophy (especially in the temporo-parietal region) was significantly higher in those with AD (P<0.05)
while that of subcortical type (especially in fronto-temporal region) was higher in those with VaD
(P<0.05). Multiple brain infarcts is a cardinal feature of VaD and not AD, infarctions were multiple,
small, cortical-subcortical mainly in the basal ganglia, thalamus, deep white matter, fronto-temporal
areas. Furthermore, white matter hypodensity was significantly higher in these with VaD (P<0.01).
SPECT examination revealed that cerebral hypoperfusion was significantly higher (P<0.05) in the
posterior parietal, medial temporal regions in patients with AD and higher (P<0.05) in fronto-temporal,
basal ganglionic, thalamic areas in patients with VaD. There was a significant positive correlation
between the severity of the dementia of either types (assessed by DRS, MMSE, blessed dementia scale and
CAMCOG) and cortical involvement and frontal lobe affection in MRI and SPECT examinations. There
was a good correlation between the differences in neuropsychological results in both types of dementia
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
36
and structural and functional abnormalities observed on MRI and SPECT examination. Neuro-
radiological findings recorded by MRI brain examination correlated well with that observed on SPECT
examination, however, SPECT demonstrated more brain areas of dysfunction not detected by MRI
examination. Conclusion: Clinical neuropsychological testing is a fairly good method for differentiation
of the type of dementia (AD versus VaD). However, neuro-imaging and functional imaging add not only a
more precise method of differentiation, but also a method to determine the severity of the disease and
explain its structural and functional background for these clinical abnormalities. . (Egypt J. Neurol.
Psychiat. Neurosurg., 2004, 41(1): 35-58).
INTRODUCTION
Alzheimer disease (AD), the most
common cause of dementia has been studied
extensively, whereas, vascular dementia
(VaD), the second most common cause of
dementia has been studied sparsely1,2
.
Unlike AD, it may be possible to arrest
the progression of VaD1, therefore, the
accurate differentiation of VaD from AD is
essential. The patterns of impairment of
cognition may contribute to this required
differentiation. Moreover the diagnostic
criteria for each condition refer to neuro-
psychological deficits that are presumed to be
characteristic2-5
.
Neuro-imaging is a key procedure in the
assessment of dementia especially for
differential diagnostic evaluations; recently,
interest has focused on neuro-imaging for
distinguishing normal aging from
pathological conditions and for differentiating
the type of dementia such as AD versus
VaD5.
Single Photon Emission Computerized
Tomography (SPECT) is being widely used
for cerebral blood flow (GBF) studies. These
studies provide unique information for the
identification of functional abnormalities
relevant to AD6. Moreover, SPECT provides
a useful method used to differentiate AD from
other types of dementia especially VaD7,8
.
The sensitivity of SPECT when
distinguishing AD from VaD ranged from
43% to 100%8-10
. This rather broad
distribution has been attributed to difference
in SPECT methods11
, and to the clinical
characteristic of the specific population
examined9.
The diagnostic value of SPECT in the
diagnosis of patients with dementia remains
unclear. While bilateral temporo-parietal
abnormalities are common but not specific for
AD, no typical pattern of abnormality was
seen in the VaD12
.
The aim of this study is to assess the
usefulness of clinical neuro-psychological
testing, neuro-radiological findings, and
cerebral blood flow changes in differentiating
patients with AD and VaD, and to correlate
the obtained data with the degree and severity
of dementia in each type.
To find possible correlations between
neuro-psychological deficits recorded
clinically, and structural and functional
abnormalities detected on neuro-imaging
studies (MRI and SPECT of the brain).
PATIENTS AND METHODS
Patients:
* This study was conducted on twenty
Egyptian patients suffering of dementia
for 2 years duration.
* Patients were classified into 2 groups:
- Group I: included 10 patients (7
males and 3 females) diagnosed as
having possible AD. Their ages
ranged from 60-81 years with mean
age 69.6±2.45 years.
Mohamed Ahmed El-Sayed et al.
37
- Group II: included 10 patients (6 males and 4 females) diagnosed as having possible vascular dementia. Their ages ranged from 61-81 years with mean age 70.3±2.29 years.
Patients Selection: Patients were selected and diagnosed as having either possible AD or possible VaD according to the following criteria: 1. Diagnostic and statistical manual of
mental disorders fourth edition revised (DSM-IV) for diagnosis of Alzheimer’s dementia
3.
2. Diagnostic and statistical manual of mental disorders fourth edition revised (DSM-IV) for diagnosis of vascular dementia
3.
3. Hachinski ischemic scale (HIS)13
. 4. California Alzheimer’s disease
diagnostic and treatment centers scale (ADDTC)
14.
5. National Institute of Neurological and Communicative Disorders and Stroke, the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA)
15.
Exclusion Criteria: Excluded from this study: All demented patients not fulfilling the criteria for possible AD or possible VaD in the previous selection criteria. Any patients with severe dysphasia, severe hearing or visual impairment. Patients with disturbed or inconsistent conscious level e.g. delirium. Patients with concomitant medical or metabolic illness known to affect cognition e.g. hypothyroidism, liver or kidney failure. Patients with previous history of other significant neurologic or psychiatric disorders known to cause cognitive impairment e.g. major depression, patients with history of significant head trauma with loss of consciousness.
Patients with history of taking psycho-active drugs or using drugs known to affect mentality and cognition e.g. anti-cholinergics, anti-epileptics, or anti-psychotics. Patients with a history of alcohol or other substance abuse.
Patients with MRI showing structural brain disease other than brain atrophy, ischemic vascular changes, or white mater change.
Methods: All patients in this study were submitted to the following: 1. Thorough history taking from patients or
a near relative using special questionnaire that focuses on vascular risk factors including hypertension, diabetes mellitus. Smoking, ischemic heart disease, previous history of stroke.
2. Thorough medical examination. For detection of vascular risk factors and to exclude other medical causes of cognitive impairment.
3. Thorough neurological examination according to standardized neurological sheet. Neurology Department, Cairo University.
4. Neuro-vascular examination according to standardized neuro-vascular examination sheet. Neurology Department, Cairo University.
5. The following laboratory investigations (for detection of risk factors and to exclude the other causes contributing to cognitive impairment) included: a. Complete blood picture. b. Fasting and 2 hours post-prandial
blood sugar. c. Serum urea, creatinine and uric acid. d. Complete liver function tests. e. Complete lipid profile.
f. Thyroid function test (free T3, T4,
TSH).
6. Clinical neuro-psychological scales and tests:
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
38
They included:
a. Scales to assess the mental and
cognitive functions:
- CAMCOG the cognitive
examination part of a
standardized psychiatric
assessment schedule, CAMDEX
(the Cambridge examination of
mental disorders of the
elderly)16,17
.
- Dementia rating scale (DRS)18
.
- Mini-mental state examination
test19
.
b. Scale to assess the patients’ mood:
Hamilton depression scale20
.
c. Scales to assess the activities of daily
living:
- Blessed dementia scale of daily
living activities21
.
- Bristol activities of daily living
scale22
.
- Interview for deterioration in
daily living activities in dementia
(IDDD)23
.
d. Scale to assess the disease severity:
Clinical dementia rating (CDR)24
.
7. Structural neuro-imaging using MRI
brain. MRI brain was done for all
patients at the Department of
Radiodiagnosis, Cairo University.
Parameters studied were: Brain atrophy,
brain-infarctions and white matter
changes.
8. Functional neuro-imaging using single
photon emission computerized
tomography (SPECT) to assess the
regional CBF. SPECT scans of the brain
were performed for all patients at the
Department of Nuclear Medicine, Cairo
University using Tc99m-Hexamethyul
propylenanine (HMPAO) brain SPECT
(Tc99 HMPAO SPECT). Two
parameters of cerebral blood flow (CBF)
were studied.
* Site of the abnormality: Which for
ease of data analysis the patterns of
CBF abnormality were classified into
left and right frontal, parietal, mesial
temporal, lateral temporal and
occipital areas, in addition to the
basal ganglia, thalamus, and
cerebellar hemispheres, which were
also analyzed for the presence of
hypoperfusion.
* Degree of hypoperfusion: As there is
a normal variability of the uptake of
the radio-active tracer in different
parts of the brain, a cut-off point
value was determined for each region
of the brain, below which
pathological hypoperfusion was
considered (Table 1).
Table 1. Normal quantitative, SPECT value
in different regions of the brain, described as
a percentage from the cerebellum uptake.
Site Normal quantitation %
Frontal lobe 87-105
Parietal lobe 78-90
Occipital lobe 70-90
Caudate 85-100
Thalamus 85-105
Putamen. 80-105
Lateral temporal 70-90
Medial temporal 60-80
In general any activity compared to the
cerebellum that is below 60% is considered
abnormal25
.
RESULTS
I. Age and Sex Distribution:
The mean age of patients with AD
(group I) was 69.6 years ±2.45 SD (their ages
ranged from 60 to 81 years). While that of
Mohamed Ahmed El-Sayed et al.
39
patients with VaD was 70.3 years ±2.29 SD
(their ages ranged from 61 to 81 years).
Patients with AD were 7 males (70%)
and 3 females (30%) while those with VaD
were 6 males (60%) and 4 females (40%).
II. Risk Factors:
As shown in Fig. (1) which demonstrates
the risk factors in patients with dementia in
either group. Comparing the results in both
groups revealed, high statistically significant
difference (P<0.01) between patients with AD
and those with VaD regarding hypertension
and ischemic heart disease being much more
in those with VaD [hypertension in all
patients (100%) and ischemic heart disease in
7 patients (70%) in VaD compared to only 3
patients (30%) for either hypertension or
ischemic heart disease in those with AD].
Moreover, all patients with VaD had
long standing hypertension (10 years
duration), both systolic and diastolic, and
mostly uncontrolled in 6 patients (60%).
Again, there was a significant difference
(P<0.05) regarding cigarette smoking, and
cardiac arrthymia being more in those with
VaD.
On the other hand, no significant
difference (P>0.05) between the 2 groups of
patients was observed regarding other risk
factors studied (DM, hyperlipidemia, and
hyperuricemia). Although diabetic patients
were more in those with VaD while those
with hyperuricemia were more in those with
AD.
III. Clinical Neurological Findings:
Clinical neurological examination
findings as shown in table (2) revealed that,
patients with VaD had much more
neurological deficits on examination than
those with AD (except for the presence of
primitive reflexes being more in those with
AD).
High statistically significant difference
(P<0.01) was observed regarding the presence
of motor deficits, gait disturbance, speech
disturbance, cranial nerves involvement,
incoordination and sensory deficits (mainly of
cortical type) and a significant difference
(P<0.05) regarding the presence of extra-
pyramidal manifestations (mainly rigidity,
flexion attitude, abnormal short gait) being
more in those with VaD.
On the other hand, no significant
difference was found regarding sphincteric
troubles (although being more in those with
VaD mainly in the form of precipitancy) and
presence of primitive reflexes (being more in
patients with AD).
IV. Neuro-Psychological Examination and
Scaling of Dementia:
Table (3) demonstrates the results of
comparison between the 2 groups of patients
(AD and VaD) regarding the mean of scores
different neuropsyhological scales and tests
used in this study.
Comparing the cognitive functions and
mental deficits revealed that the deterioration
of mental functions is much more
significantly affected in those with AD than
with VaD (P<0.01 for CAMCOG and P<0.05
for MMSE and DRS). Moreover, aspects
being mostly affected in AD patients were
orientation, language, memory especially
recent and recall memory, abstract thinking
and prexia, while in those with VaD, were
executive functions mainly verbal memory,
verbal fluency speech, attention, slow
mentation, prexia with less severe memory
affection.
The activities of daily living were much
more significantly disturbed (P<0.05) in those
with AD than with VaD, also patients with
AD become dependent earlier than those with
VaD.
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
40
Regarding the Hamilton depression
scale, the results revealed that patients with
VaD were significantly (P<0.05) more prone
to have depression than those with AD.
The severity of the disease was assessed
using the clinical dementia rating scale
(mainly) and supported by the mean score of
MMSE, CAMCOG scale and blessed daily
living activities scale and demonstrated in
table (4). Two patients (20%) with AD were
categorized as having mild to moderate
dementia while 8 patients (80%) as having
moderate to severe dementia. On the other
hand, in patients with VaD these figures were
4 patients (40%) and 6 patients (60%)
respectively.
V. Neuro-Radiological Results (MRI
findings):
The neuro-radiological findings studied
on MRI examination were: (a) brain atrophy,
(b) brain infarctions and (c) white matter
changes.
Regarding brain atrophy all patients
(100%) of either group had a variable degree
of bilateral brain atrophy.
Patients with AD dementia had cortical
atrophy (only) in 8 patients (80%) and mixed
cortical-subcortical in 2 patients (20%) while
atrophy was cortical (only) in 3 patients
(30%) of those with VaD, subcortical (only)
in 5 patients (50%) and mixed cortical-
subcortical in 2 patients (20%). So cortical
atrophy was significantly higher in those with
AD (P<0.01) while subcortical atrophy was
significantly higher in those with VaD
(P<0.01) (Fig. 2). Moreover, temporo-parietal
atrophy was significantly higher in those with
AD (7 patients 70%) while fronto-temporal
atrophy was significantly higher in those with
VaD (7 patients 70%). Occipital lobe atrophy
and cerebellar atrophy were found only in
patients with VaD (2 patients and 3 patients
respectively) and not in patients with AD
(Fig. 3).
The second radiological finding
examined was brain infarctions, a finding
which was found in all patients with VaD
(100%) and only in 2 patients (20%) with
AD, a difference which reached a highly
significant statistical value (P<0.01).
Infarctions of patients with VaD were
mainly cortical-subcortical (mixed) in 7
patients (70%), cortical only in one patient
(10%) and subcortical in 2 patients (20%)
(Fig. 4), while that of patients of AD were
subcortical.
All patients with VaD had bilateral
multiple brain infarctions which were small in
size in 70% of patients, and mixed small and
large in 30% of patients, while those with AD
had their infarctions small and single.
In VaD patients, deep periventricular,
basal ganglionic, thalamic infarctions each
was found in 9 patients (90%), 6 patients
(60%) had their infarctions in the fronto-
temporal area, 3 patients (30%) in the
temporo-parietal area, 3 patients (30%) in the
occipital area, 2 patients (20%) had brain
stem infarctions and another 2 patients (20%)
had cerebellar infarctions (Fig. 5).
The third finding studied was the white
matter hypodensity (leuco-encephalopathy), a
bilateral nearly symmetrical radiological
finding was found in all patients (100%) with
VaD and only in 3 patients with AD, a
difference which reached a highly significant
value (P<0.01).
VI. MRI Findings and Severity of the
Dementia:
Comparing patients with mild to
moderate VaD to those with moderate to
severe dementia, regarding the radiological
Mohamed Ahmed El-Sayed et al.
41
findings revealed that: those with more severe
degree of dementia had significantly a higher
degree of atrophy which was exclusively
fronto-temporal and mostly with cortical
involvement either alone or with subcortical
involvement in addition). Again, those with
more severe degree of VaD showed
significantly higher bilateral mixed cortical-
subcortical or cortical (only) brain infarctions,
especially of the fronto-temporal area,
especially on left side.
On the other hand, the same comparison
for patients with AD revealed that, the more
severe degree of dementia was significantly
associated with high degree of atrophy which
was exclusively cortical and mainly affecting
the temporo-parietal area bilaterally.
In both group of patients it was observed
that, frontal lobe involvement either by brain
atrophy or brain infarctions is significantly
associated with more severe degree of
dementia, more worsen scores of cognitive
functions and daily living activities.
VII. SPECT Results:
All patients (100%) of both groups of
patients (AD and VaD) had bilateral multiple
area of hypoperfusion on SPECT
examination.
A. Site of hypo-perfusion: (Table 5)
Patients with AD were affected in the
following frequency: Medial temporal in
6 patients (60%), posterior parietal in 5
patients (50%) lateral temporal in 3
patients (30%). Frontal, anterior parietal,
basal ganglionic each in 2 patients
(20%). Cerebellum and thalamus each in
only one patient (10%).
While patients with VaD were
affected in the following frequency;
bilateral patchy deep periventricular
areas of hypoperfusion in all patients
(100%). Basal ganglionic in 8 patients
(80%), thalamic in 7 patients (70%),
frontal in 5 patients (50%), lateral
temporal and anterior parietal each in 4
patients (40%), occipital in 3 patients
(30%), and posterior parietal and medial
temporal each in 2 patients (20%), lastly
cerebellar hypoperfusion was noted in 2
patients (20%). Comparing the results of
both groups revealed that: SPECT
hypoperfusion is significantly higher
(P<0.05) in posterior-parietal, medial
temporal regions for patients with AD
and higher in frontal, anterior parietal,
occipital areas, basal ganglia, and
thalamus in those having VaD.
B. Degree of hypo-perfusion: (Table 6)
Patients with AD showed maximum
degree of affection in the medial
temporal area, posterior-parietal area
followed by frontal area. Whereas;
patients with VaD showed their
maximum degree of abnormality in the
frontal area especially on left side, ant-
parietal area, deep white matter
especially of fronto-parietal area, basal
ganglionic, and thalamic regions.
VIII. SPECT Findings and Severity of the
Dementia:
Comparing the site and degree of
cerebral hypoperfusion in SPECT
examination in both groups in those having
mild to moderate dementia to those having
moderate to severe dementia revealed that:
patients with more severe AD had more
affection of medial temporal and posterior
parietal areas bilaterally, while in patients of
VaD, no characteristic pattern was observed
to be associated with the severity of the
dementia apart from the higher incidence of
frontal lobe involvement (either cortical or
cortical-subcortical) especially on left side.
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
42
Table 2. Clinical neurological findings in both groups of patients with dementia.
Clinical findings
Group I (AD)
(10 patients)
Group II (VaD)
(10 patients)
P value
No. % No. %
Speech disturbance 3 30 7 70 <0.01**
Cranial nerves abnormalities 1 10 8 80 <0.01**
Motor weakness 2 20 10 100 <0.01**
Incoordination 2 20 7 70 <0.01**
Extrapyramidal manifestations 2 20 5 50 <0.05*
Gait disturbance 4 40 10 100 <0.01**
Sensory deficit 1 10 4 40 <0.01**
Sphincter disturbance 5 50 7 70 >0.05
Primitive reflexes 10 100 8 80 >0.05
*Significant **Highly significant
Table 3. Results of neuro-psychological testes and scales in both groups with dementia
Neuropsychological
tests and scales
Group I
(patients with AD)
Group II
(patients with VaD)
P value
Range Mean ±SD Range Mean ±SD
I. Cognitive and mental functions:
1. MMSE
2. CAMCOG
3. D. rating scale
12-16
41-53
9-17
14.3±0.44
47.7±1.42
12.3±1.59
17-21
61-77
1-20
19.0±0.37
68.1±1.7
16.7±0.95
<0.05*
<0.05*
<0.05*
II. Activity of daily living:
1. Blessed D.scale
2. Bristol
3. IDDD
16-19
29-44
52-73
17.5±3.13
36.5±1.48
61.3±2.53
11-17
21-40
33-67
12.3±1.3
26.8±1.5
46.5±2.3
<0.05*
<0.05*
<0.05*
III. Depression:
Hamilton depression scale
20-32
27.1±1.23
22-47
32.2±2.4
<0.05*
* Significant
Table 4. Grading of the disease severity using clinical dementia rating scale.
Grading of dementia
Group I
(patients with AD)
Group II
(patients with VaD)
No. % No. %
Mild to moderate 2 20 4 40
Moderate to severe 8 80 6 60
Mohamed Ahmed El-Sayed et al.
43
Table 5. Sites of hypoperfusion on SPECT examination in both groups of patients with dementia
Hypoperfusion on
SPECT exam
Group I
(patients with AD)
Group II
(patients with VaD)
P value
No. % No. %
Positive
Site:
Frontal
Anterior-parietal
Posterior parietal
Medial temporal
Lateral temporal
Occipital
Thalamic
B.G
Cerebellum
Number:
Patchy
Single
Bilaterality
10
2
2
5
6
3
0
1
2
1
3
7
10
100
20
20
50
60
30
0
10
20
10
30
70
100
10
5
4
2
2
4
3
7
8
2
10
0
10
100
50
40
20
20
40
30
70
80
20
100
0
100
-
<0.05*
<0.05*
<0.05*
<0.05*
>0.05
<0.05*
<0.01**
<0.01**
>0.05
<0.01**
0
0
*Significant **Highly significant
Table 6. Results of degree of hypoperfusion on SPECT examination of both groups of dementia.
Sites of hypoperfusion
Group I
(patients with AD)
Group II
(patients with VaD)
P value
Mean ±SD Mean ±SD
Frontal 85.3±1.23 69.7±1.07 <0.05*
Anterior parietal 80.5±0.27 71.3±0.87 >0.05
Posterior parietal 65.8±1.37 79.2±0.79 <0.05*
Medial temporal 51.2±1.72 69.3±0.84 <0.05*
Lateral temporal 78.3±0.72 77.5±0.82 >0.05
Occipital 81.2±0.92 76.3±0.87 >0.05
Thalamus 91.2±0.37 69.7±1.27 <0.05*
Basal ganglia 90.3±0.42 71.8±1.35 <0.05*
Cerebellum 95.2±0.37 91.3±0.78 >0.05
*Significant
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
44
0
10
20
30
40
50
60
70
80Patients %
Cortical** Subcortical** Mixed
Types of brain atrophy
AD VaD
Fig. (1): Risk factors in patients with dementia (VaD and AD)
Fig. (2): Types of brain atrophy in patients with dementia.
**Highly significant
0
10
20
30
40
50
60
70
80
90
100Patients
Cig
. S
mokin
g
AF
IHD
Hypert
ensio
n
D.M
Hyperu
rcaem
ia
Hyperlip
id
Risk factors
Vascular dementia Alzheimer Dementia
Mohamed Ahmed El-Sayed et al.
45
0
10
20
30
40
50
60
70
%
T.P** F.T** Occipital Cerebellar
Sites of brain atrophy
AD VaD
0
10
20
30
40
50
60
70
80
90
Patients
Dee
p
pe
riv
en
t
Th
ala
mus
B.G F.T
T.P
Oc
cip
ital
B. s
tem
Cere
bell
ar
Site
T.P: Temporo-parietal, F.T: Fronto-temporal
Fig. (3): Sites of brain atrophy in patients with dementia
0
10
20
30
40
50
60
Patients %
Cortical
subcortical
Subcortical Cortical
Depth
Fig. (4): Depth of infarctions in patients with VaD.
Fig. (5): Sites of the infarctions in patients with VaD
**Highly significant
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
46
Fig. (6): Brain MRI showing bilateral temporo-parietal atrophy.
Fig. (7): Brain SPECT showing bilateral medial temporal and posterior parietal areas of hypoperfusion.
Figs. (6 and 7): MRI and SPECT of a patient with AD.
Mohamed Ahmed El-Sayed et al.
47
Fig. (8): Brain MRI showing bilateral periventricular W.M ischemic changes.
Fig. (9): Brain SPECT showing bilateral areas of hypoperfusion of patchy distribution.
Figs. (8 and 9): MRI and SPECT of a patient with VaD.
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
48
DISCUSSION
Alzheimer’s disease (AD) and
cerebrovascular disease (CVD) are the most
common causes of dementia in the world. For
several reasons, however, differential
diagnosis of AD versus vascular dementia
(VaD) has proved to be difficult26,27
.
However, their accurate differentiation is of
great importance, due to different
pharmacoceutical strategies which may
modify the course of each disease26,27
.
In this study we try to assess the utility of
neuro-psychological testing, MRI findings
and SPECT findings to differentiate dementia
due to AD and that is due to VaD and to
throw light on the possible correlation
between these findings in both types of
dementia.
This study revealed a significantly higher
vascular risk factors in patients with VaD
compared to those with AD, and these
findings were supported by the results of
many studies28-30
, who reported that many
atherogenic factors seem to be a risk for
developing VaD, namely hypertension, IHD,
cardiac arrhythmia, heart failure, DM,
cigarette smoking, obesity and
hypercholesterolemia.
One of the most important risk factors
for the development of VaD was
hypertension, which was present in all
patients with VaD. Moreover, all patients had
both systolic and diastolic hypertension for
more than 10 years duration and most of them
(6 patients 60%) were uncontrolled or
irregularly controlled. These findings denote
the importance of uncontrolled long standing
hypertension as a risk factor for developing
VaD. Again, this was in consistent with the
reports of many studies28,31-35
.
On the other hand, different vascular
factors are not significantly related to the
development of AD. However, it is reported
that factors such as family history, sex,
serious head injury, smoking, cholesterol
level and estrogen may modify the APOE-
related risk for AD31
. Moreover, Hoffman et
al.36
and Skoog37
have noted synergy between
E4 and vascular risk factors or multifocal
white matter vascular lesions in increasing the
risk of AD.
The clinical neurological examination
(excluding mental state examination) is very
important item for differentiation of AD from
VaD5. This study revealed that patients with
VaD had significantly much more focal
neurological deficits than those with AD. This
was consistent with that reported by Del Ser
et al.38
who observed that in VaD the
dysfunction is in one or more cognitive
domains with patchy distribution of deficits
and stepwise deterioration course. Focal
neurological symptoms and signs are
frequently present on examination including
weakness of an extremity, exaggeration of
deep tendon reflexes, an extensor plantar
response and gait abnormalities.
On the other hand, neurological
examination of patients with AD is usually
normal. Commonly associated features
include presence of primitive reflexes,
impaired cortical sensation, and less common
features as, extrapyramidal signs, gait
disturbance and Myoclonus39,40
.
The previously reported data were in
accordance with the results of other
studies4,5,41
who reported that focal
neurological deficits is a cardinal features of
vascular and mixed dementia while this is not
the case for AD.
The present study revealed that mental
and cognitive functions were much more
significantly affected in patients with AD
compared to those with VaD. Furthermore,
most aspects being affected in AD disease
patients were mainly in memory (either verbal
Mohamed Ahmed El-Sayed et al.
49
or non-verbal), especially long-term memory
and language, abstract thinking and
orientation with no significant deficits in
perception, construction, attention or
executive functions, while those with VaD
had greater defects in executive functions,
attention, speech, slow mentation with
relative preservation of long term memory,
these findings were in accordance with many
reports26, 42-44
.
Moreover, Roman et al.15
and Tiernery et
al.26
observed that cognitive deficits in
patients with VaD are multifocal and highly
variable (depending on the size and location
of vascular brain injury), and therefore more
varied than generally seen in AD. Memory
deficits may be not as marked as AD and
discrepancies between verbal and non-verbal
elements, or visuospatial dysfunction,
dysphasia, cognitive slowing and impaired
executive function (impairment of frontal lobe
functions) are usually more seen in VaD than
AD, on the other hand deficits in AD is
attributed to selective vulnerability of medial
temporal lobe structures to neuro-fibrillatory
degeneration26
.
On the other hand, the two groups of
patients did not differ significantly on tests of
language, constructional abilities, memory
registration, conceptual functions and
attention44
.
In this study patients with AD were
significantly more handicapped and became
dependent earlier than those with VaD, as
proved by the results of scales for daily living
activities used (Blessed demenetia scale,
Bristol daily activities scale and IDDD). This
was supported by the observations of many
authors31-44
.
Patients with VaD were significantly
more prone to develop depression than those
with AD, a finding which was consistent with
the reports of many studies45-47
who observed
that affective symptoms (such as depression),
psyhotic symptoms and behavioral
alternations such as delusions, agitation and
hallucinations are common complications of
VaD.
Furthermore, other studies46-48
reported
that depressive disorders including major
depression and other less severe but clinically
significant depression are common co-morbid
components or complications of VaD.
Moreover, depression may be premonitory
sign for VaD49
.
The high prevalence of depression in
those having VaD may be explained by the
relative preservation of self-awareness and
insight in those having VaD for relatively
longer time than those with AD.
Not-surprising that, those with moderate
to severe grade of dementia of either types
(AD and VaD) suffered more significantly
from deterioration of cognitive functions and
became more dependent and handicapped.
Conversely with progress of the disease the
incidence and severity of depression and
affective symptoms became less evident while
the psychotic and behavioral symptoms
became more clear45-49
.
Regarding the neuroradiological
findings, this study revealed that bilateral
cortical mainly temporo-parietal atrophy is a
prerequisite for the development of AD. On
the other hand only 50% of patients with VaD
had bilateral cortical (mainly fronto-temporal)
atrophy and the other 50% had exclusively
subcortical atrophy. The previously reported
findings were in accordance with that of
many studies38,40
.
As mentioned above bilateral cortical
atrophy is an essential pre-requisite for the
development of AD. On the other hand,
bilateral multiple brain infarctions is essential
for the diagnosis of VaD which in this study
were mainly cortical-sub-cortical, and mainly
in the following sites basal ganglia, thalamus,
fronto-temporal and temporo-parietal regions.
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
50
These findings were supported by reports of
various studies27-32
.
Again, cortical involvement is the most
important feature for development of
dementia of the either types (bilateral
cortical atrophy in 100% of patients with
AD and 50% of those with VaD, bilateral
cortical infarctions in 80% of patients with
VaD)38-40,42,43
.
Another important finding is the
involvement of temporal lobe in most of
patients of both types (in both groups) either
by atrophy or infarctions, this goes with
Tatemichi et al.49
who reported the
importance of cortical involvement especially
the temporal lobe for the development of AD
or VaD42-44
.
White matter ischemic changes were
common radiological findings in patients with
VaD (100% of patients) and only infrequently
found in those with AD (30% of patients) a
finding which was supported by Boon et al.50
who reported that in VaD periventricle white
matter changes were 11.6 times greater than
in AD and 3.5 times greater than in healthy
people, and subcortical WMLs were 2.6 and
13.5 times respectively.
Kantarci and Juck51
reported that severe
temporal atrophy, hypo-intensities involving
the hippo-campal or insular cortex and gyral
hypo-intensity bands are more frequently
noted in AD. Basal ganglionic/thalamic
hyper-intensities, thromboembolic infarctions,
confluent white matter and irregular
periventricular hyper-intensity are more
common in VaD. These were in accordance
with the study results.
Although Tatemichi et al.49
reported the
importance of cortical involvement for the
development of dementia (an observation
which well documented in this study), Kertesz
et al.52
and Tatemichiet et al.53
reported that
subcortical sites especially grey matter nuclei
or thalamus, or white matter pathways
between association areas e.g. periventricular
zone, centrum semioval or between
subcortical-cortical regions of the limbic
system lead to disconnection syndrome
contributing to various cognitive disturbances
and various neurological deficits on clinical
examination. This subcortical involvement
was found in 90% of patients with VaD.
The radiological findings in patients with
VaD were supported by many
authors5,15,29,49,52
who suggested that the
cumulative burden results from the number of
such lesions with multiple strategically
located infarcts causing cognitive decline.
The total volume of such lesions or both
characteristics reaching a critical threshold
overcoming the brain compensatory
capacities.
Functional imaging of the brain using
SPECT revealed typical hypoperfusion in
bilateral medial-temporal, posterior-parietal
and occasionally frontal regions in patients
with AD. On the other hand, bilateral
periventricular, basal ganglionic, thalamic and
frontal regions are the mostly affected regions
in those with VaD.
The previous results were in accordance
with the SPECT criteria reported by Talbot et
al.8. For differentiating AD form VaD and
these criteria were bilateral posterior CBF
abnormality or bilateral posterior plus
unilateral anterior CBF abnormality provides
support for the diagnosis of AD. By contrast,
bilateral anterior CBF abnormalities or
bilateral anterior CBF plus unilateral posterior
CBF abnormalities or patchy CBF changes
provide support for diagnosis of VaD.
Unilateral posterior, unilateral anterior,
unilateral anterior plus unilateral posterior,
generalized CBF abnormalities and normal
CBF pattern fail to differentiate either
disorders (VaD and AD).
Many studies6,8,9,54-56
reported that
bilateral hypo-perfusion in the association
Mohamed Ahmed El-Sayed et al.
51
cortex of the parietal lobes and the posterior
temporal regions (with or without frontal lobe
perfusion defect) is considered to be the
characteristic SPECT findings in AD. A
finding which was consistent with the study
results.
Our SPECT findings in patients with AD
confirm the currently accepted observation of
a bilateral (either symmetric or asymmetric)
hypoperfusion of the posterior temporal and
parietal areas, as the most typical SPECT
picture in patients with AD with widespread
cognitive deterioration42,43
. Worthnoting that
in AD, brain damage spreads from the
parieto-temporal association cortex to the
occipital and frontal cortex according to the
progression of the disease severity.
On the other hand, no typical pattern of
abnormalities was seen in patients with VaD,
as SPECT findings varied greatly according
to the site and degree of vascular brain
injury12,55,57,58
.
Correlation between MRI findings and
SPECT findings:
The study results revealed a good
significant correlation between the anatomic
disturbances (MRI findings) and functional
abnormality (SPECT findings). Cortical
affection (either by atrophy or brain ischemic
changes), and temporo-parietal region
affection in AD patients, fronto-temporal
region, and deep gray matter substances and
white matter in VaD were nearly consistent in
both neuro-imaging and functional imaging.
However. SPECT can demonstrate a further
areas not detected by neuro-imaging as basal
ganglionic, and thalamic affection in some
patients with AD. Moreover, SPECT can
provide a more clear idea about degree of
functional disturbances compared to MRI.
This was supported by the report of P.
Velakoulis and Lioyd58
who stated that the
pattern of SPECT abnormality was
concordant with structural neuro-imaging in
65% of patients and neuro-psychological
testing in 82% of patients. These were
supported by many studies59-68
.
Correlation between neuropsychological
findings and neuro-imaging findings
(structural and functional) (MRI and SPECT):
Usually there is a close relation between
neuropsychological profiles and neuro-
radiologic findings and patterns of regional
brain dysfunction shown by SPECT42,62,63
.
Firstly, these results emphasis on the
importance of cortical involvement (with
variable degree of subcortical involvement)
for the occurrence of dementia. A finding
which correlated well with the cardinal neuro-
psychological manifestation of dementia of
either type, which was a result of disturbance
in cortical functions or its subcortical
connections especially memory and executive
functions.
This study reported the importance of
involvement of temporal lobe structures in
either type (in addition to parietal in AD and
frontal in VaD). So that demonstrating the
importance of temporal lobe regions for
processing of memory.
Reasons for differences in neuro-
psychological tests performance:
Looi and Sachdev69
reported that, to
understand the pathogenesis of these
differences in the two dementia syndrome,
one must examine their neuro-pathologic
basis. Memory is supported by multiple
neural systems with particular involvement of
the medial temporal and diencephalic
structures39,40,67-74
.
In AD the neuro-pathologic lesions
impact directly and early on structures closely
associated with memory74,75
. It has been
suggested that the initial episodic memory
impairment in AD is due to trans-entorhinal
neuropathology (causing disconnection of the
Egypt J. Neurol. Psychiat. Neurosurg. Vol. 41 (1) – Jan 2004
52
hippocompus). This is followed by semantic
memory deficits reflecting the spread of the
pathology to the adjacent temporal neo-
cortex66,67,76,77
. So, a mesial temporal
localization of brain impairment was already
reported by studies using MRI and SPECT in
patients with AD78
.
It is not surprising that patients with AD
in this study were characterized by deficits in
recognition memory. This pattern is well
established in the AD literature. Poor
recognition memory is considered to reflect
deficits in storage caused by deficient
consolidation of new memory traces26,79
. This,
in turn is often linked to the degeneration of
the mesial temporal areas namely the
hippocampus, and amygdala. These areas are
highly vulnerable to neuro-fibrillarily
degeneration one of the classic neuro-
pathological hallmarks of AD80,81
. Thus poor
recognition memory among patient with AD
is likely due to neuro-fibrillarily degeneration
in the mesial temporal lobes including the
hippocampus.
In contrast, verbal memory may be
relatively spared in VaD due to the
heterogensity of the neuropathology resulting
in lesser impaction on widely distributed
memory system and the frequent sparing of
medial temporal lobe structures. The relative
excess of deficits ascribed to pre-frontal lobe
function in VaD may be explained by the
frequent presence of lesions in structures that
comprise the frontal subcortical circuits.
These frontal subcortical circuits
typically consist of neuronal connections from
the frontal cortex to basal ganglia, down to
the thalamus with feedback flow from the
thalamus to the frontal cortex82-84
.
So dysfunction can occur due to damage
to any part of the circuit. The circuits
disrupted in VaD include: The dorsolateral
prefrontal circuit mediating executive
functions, orbito-frontal circuit mediating
emotional lability and the anterior cingulate
circuit responsible for motivation and
initiation83,84
. Thereby explains the excess
frontal executive dysfunction in VaD
observed in this study. Furthermore, our
results were supported by many authors84-89
who reported that correlated imaging studies
lend support to the conceptualization of VaD
as being characterized by a greater degree of
frontal lobe dysfunction than in AD of the
same severity.
Subcortical infarcts, because of the
characteristics of cerebral-vasculature, tend to
occur within cortico-striato-thalamo-cortical
anatomical loops that support the functioning
of pre-frontal cortex. So dementia may follow
in part due to generalized impact of the loss
of cognitive regulatory functions of the
frontal lobe90,91
. This suggestion was
supported by: empirical description of
cerebral vasculature92
, radiological studies
showing that lacune predominantly occur in
the thalamus, basal ganglia, frontal white
matter (all of which are important
components of frontal-subcortical circuits)
and by functional studies using SPECT which
demonstrated that hypoperfusion was more
frequent in that areas93-95
. Lastly this was
supported by neuro-psychological studies of
VaD that shows the predominance of
symptoms associated with frontal lobe
dysfunctions44,87,91
. Patients with subcortical
ischemic vascular disease tend to show
greater impairment in executive function and
relatively better preservation of recognition
memory28
.
Moreover Obrien et al.62
reported that
functional imaging studies of ischemic VaD
are considerably less uniform in their findings
than are the studies on AD60-64
. However,
recently more consistent findings have been
emerged, and these studies support the idea
that subcortical infarcts impair cognition
through their effects on the cortex, and
Mohamed Ahmed El-Sayed et al.
53
suggest that basal ganglia and prefrontal
cortex are especially hypoactive in VaD. The
previous observations support our SPECT
data in VaD63,70,96
.
White matter ischemic changes which
were observed predominantly in VaD were
correlated with the severity of apathy,
decreased affect, depression, and social
withdrawal in many studies96
.
Although the specific pathophysiology of
apathy, depression or psychomotor slowing is
unknown, recent studies suggest that these
symptoms, may be due to pathological
changes in the frontal-subcortical pathway,
and frontal lobe perfusion deficits and
dysfunction of dopaminergic serotenergic and
nor-adrenergic neuro-transmission96,97
.
Relation between neuro-anatomical
imaging, functional imaging and severity of
dementia:
This study revealed that those with more
severe type of dementia of either types had a
more severe involvement of the temporo-
parietal area in those with AD and deep
periventricular area (especially of prefrontal
area) and thalamic area in VaD. Furthermore,
frontal lobe involvement of both types is
associated with more severe types of
dementia. A result which was supported by
many authors who emphasis the importance
of frontal lobe involvement as a predictor for
the disease severity96,98
.
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