Alzheimer’s disease in adults with Down’s syndrome: the relationship between regional cerebral blood flow equivalents and dementia
I
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Deb S, de Silva PN, Gemmell HG, Besson JAO, Smith FW, Ebmeier KP. Alzheimer’s disease in adults with Down’s syndrome: the relationship between regional cerebral blood flow equivalents and dementia. Acta Psychiatr Scand 1992: 86: 340-345. 0 Munksgaard 1992.
S. Deb’, P. N. de Silva H. G. Gemmel12, J. A. 0. Besson F. W. Smith’, K. P. Ebmeier3
Twenty adult patients suffering from Down’s syndrome (DS) were recruited from hospitals and the community, together with 14 age- and sex-matched controls of normal intelligence. Dementia was diagnosed in patients using a structured psychiatric and physical examination as well as a carer interview and case notes. All patients and controls were imaged using single photon emission computerized tomography with 99”Tc-exametazime. Four patients were clinically demented and all of them showed regional cerebral blood flow (rCBF) changes commonly found in patients with Alzheimer’s disease, namely bilateral temporo-parietal deficits. These changes were also observed in about half of the patients without clinical evidence of dementia, but in none of the healthy controls. Across the group of patients, temporo-parietal rCBF deficits were associated with evidence of deterioration, but not with advancing age.
Key words: Down’s syndrome; dementia; Alzheimer’s disease: cerebral blood flow; single photon emission computerized tomography
There is substantial evidence to suggest that adults with Down’s syndrome (DS) are more likely to show features of Alzheimer’s disease (AD) than normal adults and adults with other types of mental handicaps (1,2). The onset of AD, as well as features of aging, also seems to appear in DS subjects at an earlier age than in controls (3). Post-mortem studies show AD-type neuropathology in up to 100% of adult DS patients over 40 years of age (4). Acknowledging the difficulty of diagnosing dementia in DS, Lai & Williams ( 5 ) found that 87; of DS adults between 35-50 years, 50% between 50 and 60 years and 80% over the age of 60 years suffered from clinically detectable dementia. Zigman et al. (6) suggested that 15-40% of DS patients over 40 years show signs of clinical dementia. Franceschi et al. (7) found none of their under-40 and 55% of their 40to 55-year-old patients to be demented. Johanson et al. (8) found a deterioration in visuospatial performance, visuospatial memory, speech and writing in an older (50 8 years) patient group over a period of 6 years but not in a younger (33 4) group over a 5 year follow-up period. At follow-up, older patients had a mean reduction of parietal regional cerebral blood flow (rCBF), whereas younger patients showed no change.
340
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Departments of Mental Health and Nuclear Medicine, University of Aberdeen, MRC Brain Metabolism Unit, Edinburgh, United Kingdom
Dr. Shoumitro Deb, Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN. South Wales, United Kingdom Accepted for publication May 24, 1992
Single photon emission computerized tomography (SPECT) with the radioactive tracer 99”Tcexametazime has been used for the examination of rCBF in dementia. This method has shown with remarkable consistency that about 70% of patients with a clinical diagnosis of Alzheimer’s disease show temporo-parietal reduction in uptake (9-1 1). This contrasts with 10-20% of patients clinically diagnosed as suffering from multiple-infarct dementia who show such changes (9, 12). Temporo-parietal lesions are, by no means, specific; they occasionally occur in controls, in patients with hypoxic cortical infarction and sleep apnea, as well as during frontal lobe seizures, when there is an apparent reduction in temporo-parietal blood flow relative to frontal areas (12). However, a number of authors have found a correlation between various measures of cognitive deterioration and reduction of tracer uptake in temporo-parietal areas of AD patients (13-19). Finally, an improvement of this perfusion deficit with physostigmine has been reported (16,20). All these findings suggest that temporo-parietal lesions observed in patients with clinical Alzheimer’s disease are a reflection of the specific neurodegenerative changes involved. The aims of the present study were:
Down’s syndrome and SPECT
to identify the subjects with clinically detectable dementia in a sample of DS patients over 34 years of age, known to the mental handicap and social services; to determine the frequency of temporo-parietal rCBF deficits suggestive of DAT in this population; to compare the pattern of uptake between patients and matched healthy controls; and to examine the relationship between clinically diagnosed dementia and temporo-parietal uptake deficits in the patients. Material and methods Subjects and clinical assessment
All patients suffering from Down’s syndrome over the age of 34 years without a history of epilepsy who were known to the mental handicap and social work services of the Grampian area were identified. They were clinically diagnosed by consultant psychiatrists in the mental handicap services; trisomy 21 was confirmed in all cases by chromosomal analysis. The patients were either residents in the 2 hospitals for the mentally handicapped in Grampian or attended day hospitals or adult training centres while living in the community with their families or in hostels for the mentally handicapped. A clinical examination was carried out on each patient, which included a physical examination and a psychiatric assessment, including tests of orientation, aphasia, agnosia, apraxia and memory. Further investigations included chromosomal analysis and routine biochemistry and haematology tests, including an assessment of thyroid function. An interview was conducted with the main carer, who had known the subject over the preceding 2 years or more (21). This interview is designed to detect and assess the severity of cases of clinical dementia in mentally handicapped populations. The interviewer initially asks an open question enquiring whether any deterioration in the patient has been noticed over the preceding 12-24 months. The following structured questionnaire allows for the clinical staging of dementia. The first stage is characterized by more subtle deterioration in 4 areas. These include (i) impairment of memory (for example, the patient doesn’t remember names of friends or common objects, forgets words, misplaces objects and loses interest in personal hygiene). The other areas are (ii) spatial disorientation (getting lost in familiar settings, dyspraxias etc.), (iii) lack of spontaneity (both in movement and in reaction to people) and (iv) physical slowing. The second stage is defined by additional observable (v) mental deterioration with (vi) perceptual failure, (vii) speech and language deterioration, (viii) movement disorders or (ix) other
physical dysfunction (such as onset of epilepsy, loss of sphincter control etc.). Each type of behaviour deterioration was scored on a 3-point scale (does not occur = 0, occurs occasionally = 1, occurs frequently=2). A total deterioration score was computed by adding up the scores of the 9 scoring categories (max. score 18). For the diagnosis of AD, findings from the physical and psychiatric examinations, the interview with the carer and information from case notes was combined. Clinical raters as well as relatives and other carers, were blind to the outcome of the SPECT studies; the analysis of images was carried out blind to the clinical diagnosis of dementia. A control group of normal adult subjects with no history of neurological or mental illness was recruited from hospital staff. Imaging protocol and data analysis
Patients and controls were imaged using 750 MBq of 99mTc-exametazime (Ceretec @), which was injected intravenously. Data acquisition started 15 min after the injection. Twenty-five-second frames were required on a 64 x 64 matrix using a high resolution collimator fitted on an IGE 400 ACT rotating gamma camera interfaced to a Link Analytical Maps 50-50 data processor. A set of trans-axial sections through the brain of each subject was obtained by the back projection of profiles filtered by a Hanning weighted ramp filter. Hard copies of these rCBF images were produced in 2 formats, colour prints and black-andwhite films. Each set of images was reported blind by 3 experienced raters (HGG, JAOB, FWS) who were asked to look for the bilateral temporo-parietal deficits as typically seen in DAT and to grade reduction of uptake on a 4-point scale (9). The mean values of the scores of the 3 observers were accepted for the purpose of the current study. Counts in bilateral temporo-parietal regions of interests were then measured and normalized using areas of normal cortical uptake in primary sensory-motor cortex of the same slice. This method combines a clinical approach, using the 4 grades distinguishable by colour or grey scales, with a more quantitative approach. The quantitative uptake ratios for the 4 grades were measured as follows: grade I = uptake between 90 and 100%;grade I1 = uptake between 87 and 95 % ; grade 111= uptake between 75 and 87 % ; grade IV = uptake between 70 and 80%. There was some overlap between grades I and I1 and between grades I l l and IV, but a definite cut-off at around 87% of uptake into sensory-motor cortex between grades I1 and 111. All control scans were scored as grade I or I1 and had uptake ratios 2 90%. Any uptake less than 87 % was, therefore, considered to be abnormal.
341
Deb et al. Written informed consent for the investigations was given either by the subject or their carers following a procedure approved by the joint Ethics Committee of Grampian Health Board and the University of Aberdeen. Results Clinical assessment
Twenty-one patients were identified, of whom one had to be excluded from the study because of epilepsy. Ten patients (5 women, 5 men) were inpatients and the rest (3 women, 7 men) were living in the community. The patients’ mean age was 49 years (SD: 10 years; range: 35-59 years). There were 14 controls (6 female, 8 male) with a mean age of 47 years (SD: 11 years). Patients and controls were, therefore, well matched for age and sex. All patients had IQ scores between 30 and 45 (22-24). Routine biochemical and haematological investigations did not reveal any abnormality. There was also no evidence of any functional mental illness. Four patients were classified as demented (2 inpatients and 2 outpatients). Two, one male patient aged 50 and one female patient aged 53 fell into Stage I of Newroth & Newroth‘s (21) classification and two patients were classified as Stage I1 (one male aged 52 and one female aged 56). Deterioration scores across the 9 items (21) were highly consistent, with a Crohnbach’s a of 0.91. The two patients with Stage 2 dementia had deterioration scores of 10 and 12; the two with Stage 1 dementia had scores of 6 and 7. The scores of nondemented patients ranged from 0 to 2. All three 69-year-old patients were not demented: 2 were women, one had a deterioration score of 0 and the other suffered from occasional lack of spontaneity and physical slowing. The third was a man and had occasionally observed memory loss and physical slowing.
the 69-year-old man had an abnormal reduction in tracer uptake. Imaging data - quantitative uptake ratios
The distribution and association of deterioration scores and exametazime uptake ratios is illustrated in Fig. 2. Only deterioration scores showed a correlation with exametazime uptake (Spearman’s r = - 0.68, d f = 18, P
I
’,
Deb S, de Silva PN, Gemmell HG, Besson JAO, Smith FW, Ebmeier KP. Alzheimer’s disease in adults with Down’s syndrome: the relationship between regional cerebral blood flow equivalents and dementia. Acta Psychiatr Scand 1992: 86: 340-345. 0 Munksgaard 1992.
S. Deb’, P. N. de Silva H. G. Gemmel12, J. A. 0. Besson F. W. Smith’, K. P. Ebmeier3
Twenty adult patients suffering from Down’s syndrome (DS) were recruited from hospitals and the community, together with 14 age- and sex-matched controls of normal intelligence. Dementia was diagnosed in patients using a structured psychiatric and physical examination as well as a carer interview and case notes. All patients and controls were imaged using single photon emission computerized tomography with 99”Tc-exametazime. Four patients were clinically demented and all of them showed regional cerebral blood flow (rCBF) changes commonly found in patients with Alzheimer’s disease, namely bilateral temporo-parietal deficits. These changes were also observed in about half of the patients without clinical evidence of dementia, but in none of the healthy controls. Across the group of patients, temporo-parietal rCBF deficits were associated with evidence of deterioration, but not with advancing age.
Key words: Down’s syndrome; dementia; Alzheimer’s disease: cerebral blood flow; single photon emission computerized tomography
There is substantial evidence to suggest that adults with Down’s syndrome (DS) are more likely to show features of Alzheimer’s disease (AD) than normal adults and adults with other types of mental handicaps (1,2). The onset of AD, as well as features of aging, also seems to appear in DS subjects at an earlier age than in controls (3). Post-mortem studies show AD-type neuropathology in up to 100% of adult DS patients over 40 years of age (4). Acknowledging the difficulty of diagnosing dementia in DS, Lai & Williams ( 5 ) found that 87; of DS adults between 35-50 years, 50% between 50 and 60 years and 80% over the age of 60 years suffered from clinically detectable dementia. Zigman et al. (6) suggested that 15-40% of DS patients over 40 years show signs of clinical dementia. Franceschi et al. (7) found none of their under-40 and 55% of their 40to 55-year-old patients to be demented. Johanson et al. (8) found a deterioration in visuospatial performance, visuospatial memory, speech and writing in an older (50 8 years) patient group over a period of 6 years but not in a younger (33 4) group over a 5 year follow-up period. At follow-up, older patients had a mean reduction of parietal regional cerebral blood flow (rCBF), whereas younger patients showed no change.
340
’,
‘
Departments of Mental Health and Nuclear Medicine, University of Aberdeen, MRC Brain Metabolism Unit, Edinburgh, United Kingdom
Dr. Shoumitro Deb, Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN. South Wales, United Kingdom Accepted for publication May 24, 1992
Single photon emission computerized tomography (SPECT) with the radioactive tracer 99”Tcexametazime has been used for the examination of rCBF in dementia. This method has shown with remarkable consistency that about 70% of patients with a clinical diagnosis of Alzheimer’s disease show temporo-parietal reduction in uptake (9-1 1). This contrasts with 10-20% of patients clinically diagnosed as suffering from multiple-infarct dementia who show such changes (9, 12). Temporo-parietal lesions are, by no means, specific; they occasionally occur in controls, in patients with hypoxic cortical infarction and sleep apnea, as well as during frontal lobe seizures, when there is an apparent reduction in temporo-parietal blood flow relative to frontal areas (12). However, a number of authors have found a correlation between various measures of cognitive deterioration and reduction of tracer uptake in temporo-parietal areas of AD patients (13-19). Finally, an improvement of this perfusion deficit with physostigmine has been reported (16,20). All these findings suggest that temporo-parietal lesions observed in patients with clinical Alzheimer’s disease are a reflection of the specific neurodegenerative changes involved. The aims of the present study were:
Down’s syndrome and SPECT
to identify the subjects with clinically detectable dementia in a sample of DS patients over 34 years of age, known to the mental handicap and social services; to determine the frequency of temporo-parietal rCBF deficits suggestive of DAT in this population; to compare the pattern of uptake between patients and matched healthy controls; and to examine the relationship between clinically diagnosed dementia and temporo-parietal uptake deficits in the patients. Material and methods Subjects and clinical assessment
All patients suffering from Down’s syndrome over the age of 34 years without a history of epilepsy who were known to the mental handicap and social work services of the Grampian area were identified. They were clinically diagnosed by consultant psychiatrists in the mental handicap services; trisomy 21 was confirmed in all cases by chromosomal analysis. The patients were either residents in the 2 hospitals for the mentally handicapped in Grampian or attended day hospitals or adult training centres while living in the community with their families or in hostels for the mentally handicapped. A clinical examination was carried out on each patient, which included a physical examination and a psychiatric assessment, including tests of orientation, aphasia, agnosia, apraxia and memory. Further investigations included chromosomal analysis and routine biochemistry and haematology tests, including an assessment of thyroid function. An interview was conducted with the main carer, who had known the subject over the preceding 2 years or more (21). This interview is designed to detect and assess the severity of cases of clinical dementia in mentally handicapped populations. The interviewer initially asks an open question enquiring whether any deterioration in the patient has been noticed over the preceding 12-24 months. The following structured questionnaire allows for the clinical staging of dementia. The first stage is characterized by more subtle deterioration in 4 areas. These include (i) impairment of memory (for example, the patient doesn’t remember names of friends or common objects, forgets words, misplaces objects and loses interest in personal hygiene). The other areas are (ii) spatial disorientation (getting lost in familiar settings, dyspraxias etc.), (iii) lack of spontaneity (both in movement and in reaction to people) and (iv) physical slowing. The second stage is defined by additional observable (v) mental deterioration with (vi) perceptual failure, (vii) speech and language deterioration, (viii) movement disorders or (ix) other
physical dysfunction (such as onset of epilepsy, loss of sphincter control etc.). Each type of behaviour deterioration was scored on a 3-point scale (does not occur = 0, occurs occasionally = 1, occurs frequently=2). A total deterioration score was computed by adding up the scores of the 9 scoring categories (max. score 18). For the diagnosis of AD, findings from the physical and psychiatric examinations, the interview with the carer and information from case notes was combined. Clinical raters as well as relatives and other carers, were blind to the outcome of the SPECT studies; the analysis of images was carried out blind to the clinical diagnosis of dementia. A control group of normal adult subjects with no history of neurological or mental illness was recruited from hospital staff. Imaging protocol and data analysis
Patients and controls were imaged using 750 MBq of 99mTc-exametazime (Ceretec @), which was injected intravenously. Data acquisition started 15 min after the injection. Twenty-five-second frames were required on a 64 x 64 matrix using a high resolution collimator fitted on an IGE 400 ACT rotating gamma camera interfaced to a Link Analytical Maps 50-50 data processor. A set of trans-axial sections through the brain of each subject was obtained by the back projection of profiles filtered by a Hanning weighted ramp filter. Hard copies of these rCBF images were produced in 2 formats, colour prints and black-andwhite films. Each set of images was reported blind by 3 experienced raters (HGG, JAOB, FWS) who were asked to look for the bilateral temporo-parietal deficits as typically seen in DAT and to grade reduction of uptake on a 4-point scale (9). The mean values of the scores of the 3 observers were accepted for the purpose of the current study. Counts in bilateral temporo-parietal regions of interests were then measured and normalized using areas of normal cortical uptake in primary sensory-motor cortex of the same slice. This method combines a clinical approach, using the 4 grades distinguishable by colour or grey scales, with a more quantitative approach. The quantitative uptake ratios for the 4 grades were measured as follows: grade I = uptake between 90 and 100%;grade I1 = uptake between 87 and 95 % ; grade 111= uptake between 75 and 87 % ; grade IV = uptake between 70 and 80%. There was some overlap between grades I and I1 and between grades I l l and IV, but a definite cut-off at around 87% of uptake into sensory-motor cortex between grades I1 and 111. All control scans were scored as grade I or I1 and had uptake ratios 2 90%. Any uptake less than 87 % was, therefore, considered to be abnormal.
341
Deb et al. Written informed consent for the investigations was given either by the subject or their carers following a procedure approved by the joint Ethics Committee of Grampian Health Board and the University of Aberdeen. Results Clinical assessment
Twenty-one patients were identified, of whom one had to be excluded from the study because of epilepsy. Ten patients (5 women, 5 men) were inpatients and the rest (3 women, 7 men) were living in the community. The patients’ mean age was 49 years (SD: 10 years; range: 35-59 years). There were 14 controls (6 female, 8 male) with a mean age of 47 years (SD: 11 years). Patients and controls were, therefore, well matched for age and sex. All patients had IQ scores between 30 and 45 (22-24). Routine biochemical and haematological investigations did not reveal any abnormality. There was also no evidence of any functional mental illness. Four patients were classified as demented (2 inpatients and 2 outpatients). Two, one male patient aged 50 and one female patient aged 53 fell into Stage I of Newroth & Newroth‘s (21) classification and two patients were classified as Stage I1 (one male aged 52 and one female aged 56). Deterioration scores across the 9 items (21) were highly consistent, with a Crohnbach’s a of 0.91. The two patients with Stage 2 dementia had deterioration scores of 10 and 12; the two with Stage 1 dementia had scores of 6 and 7. The scores of nondemented patients ranged from 0 to 2. All three 69-year-old patients were not demented: 2 were women, one had a deterioration score of 0 and the other suffered from occasional lack of spontaneity and physical slowing. The third was a man and had occasionally observed memory loss and physical slowing.
the 69-year-old man had an abnormal reduction in tracer uptake. Imaging data - quantitative uptake ratios
The distribution and association of deterioration scores and exametazime uptake ratios is illustrated in Fig. 2. Only deterioration scores showed a correlation with exametazime uptake (Spearman’s r = - 0.68, d f = 18, P
