Clinical, neuropsychological testing, brain MRI and … · Clinical, neuropsychological testing,...

24
35 Clinical, neuropsychological testing, brain MRI and SPECT in Alzheimer and vascular dementia Mohamed Ahmed El-Sayed 1 , Abd El-Hady Taha Emam 2 , Tarek Abd El-Fatah El-Magraby 3 Departments of Neurology 1 , 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

Transcript of Clinical, neuropsychological testing, brain MRI and … · Clinical, neuropsychological testing,...

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.

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- 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:

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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.

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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

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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

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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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الملخص العربي التقييم اإلكليىيكي والتقييم العصبي السيكولوجي اإلكليىيكي وأشعة الرويه المغىاطيسي

الىاتج عه مرض الزهايمر على المخ واألشعة بالىظائر المشعة أحادية الفوتون على المخ في العتة

والىاتج عه أمراض األوعية الذموية المخية

2012