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Cognitive decline and mortality in Alzheimer's disease (AD)
258
NEUROBIOLOGY OF AGING. VOLUME Ii. 1990 ABSTRACTS OF SECOND INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE CLINICAL COURSE 24
22 b~PEARANCEOFNEUROFIBRILIA%RYTANGLES IN NEOCORTEXFOLLOWED BY FIVE YEARS OF MINIMAL COGNITIVE DECLINE. *AW Clark, IM Parhad, EM Pajurkova. University of Calgary, Calgary, Alberta, Canada. The appearance of neurofibrillary tangles in n e o c o r t e x m a y constitute a watershed in the evolution of Alzheimer-type degeneration. Wherea~ non-demented individuals commonly have neOcortical plaques, they rarely have significant numbers of neocorticalneurofibrillarytangles (Tamlinson etal., J Neurol Sci, 1968). We describe a patient evaluated sequentially after biopsy-proven appearance of numerous plaques and tangles in neocortex, who 5 years later failed to meet strict NINCDS criteria for the clinical diagnosis of Alzheimer's disease (McKhann e t a l . , Neurology, 1984). At the age of 63, he had suffered a minor traffic accident and subsequently developed headaches, difficulty concentrating, mew~r y problems, a n d two episodes interpreted as temporal lobe seizures. Radiolagic stutltes revealed ventriculomegaly. Following placement of a ventriculoperitoneal shunt (right parietal) and discovery of xanthochromic fluid in the suboktral space, a cortical biopsy (right frontal) was taken in October 1984. Bielschowskystainedsections rewealednumerous senile plaques and neurofibrillary tangles, the latter most conspicuous in layer 3 of cortex. In June 1988, 3 years 8 months after the biopsy, he attained a WAIS verbal IQ of i08 and performance IQ of 109, showing no significant decline since 1985 testing. Memory function and some p r o b l ~ - s o l v i n g functions had declined, however; and the patient and his wife noted that he had increasing difficulty with playing bridge and dancing. In January1990, 5 years 2 m o n t h s after the biopsy, his mini-mental test score was 28/30. similar cases have been described only infrequently I N e a r y e t al., J Neurol Neurosurg Psychiatry, 1986). We conclude that, in some patients, cognitive functions may show very slow decline for years following the appearance of neurofibrillarytangles in neocortex. In cc=~arison to cases of rapidly pragressive AD, the findings emphasize the dramatic case~to-case differences in temporal evolution at various stages of the disease.
23 COGNITIVE DECLINE AND MORTALITY IN ALZEEIMER'S DISEASE (AD) *A. Burns, R. Jacoby and R. Levy. Section of Old Age Psychiatry, Institute of Psychiatry, De Cresplgny Park, Denmark Hill, London SE5 8AF, UK 178 patients living in the catchment area of the Maudsley ~ospltal in South East London and satisfying NINCDS/ADRDA criteria for AD were enrolled in a prospective longitudinal study to assess the clinical course of the disease, identify predictors of cognitive decline and to identify possible
clinical
subtypes.
The f o l l o w i n g m e a s u r e s ( u s i n g
standardlsed instruments) were made at entry to the study: Cognitive Function (Minl-Mental State Examination, CAMCOG); Current Mental State (Geriatric Mental State Schedule); history (CAMDEX~ Including personal and family history and symptoms since the onset of the disorder such as delusions, hallucinations and mlsldentlflcatlons); current behavlour (Stockton Geriatric Rating Scale) and cranial computed tomography. All patients were followed up for between 12 and 36 months wlth the above measures repeated annually. Scores on all the tests of cognitive function decreased significantly over the follow-up p e r i o d . A c l u s t e r analysis of the scores revealed 3 stable clusters of mild, moderate and severe decline. The following features were predictive of more rapid decline - hallucinations ( p a r t i c u l a r l y audltory hallucinations within 12 mOnths prior to entry into the study), family history of dementia in parents (but not in
siblings
o r 2nd d e g r e e r e l a t i v e s )
and d u r a t i o n
of i l l n e s s
less than 2 years. During the follow up, 84 patients died. Patients more likely to dle included those with a grasp reflex and increased muscle tone at entry to the study and those who developed a snout reflex and extrapyramldal signs during the follow-up. Subjects with misldentiflcations had a lower mortality rate than patients without these symptoms. Three subscales of the Stockton Geriatric Rating Scale (communication failure, apathy and physical disability) were associated wlth an increased death rate. There appears to be clinical heterogeneity in AD wlth features such as family history, psy~hlatrlc symptoms and neurological signs being associated wlth a more rapidly deteriorating clinical course and higher mortality.
STANDING BALANCE MEASURES IN ALZHEIMER'S DISEASE (AD). "Piero G. Antuono, Barbara M. Myklebust, Joel B: Myklebust, Qing-Tang Hu. VA Medical Center and the Medical College of Wisconsin, Milwaukee, Wisconsin, 53295. Standing balance measures were collected from 11 normal subjects and 14 AD patients (NINCDS/ADRDA criteria) with impaired gaR by clinical examination. Deviations of the center of pressure during quiet standing have been characterized for normal adults and normal aging. These measurements have been used to assess neurological disorders of the vestibular and cerebellar systems and lesions of the pyramidal and extrapyramidal systems. We recently developed a method to quantify deviations by determining the fractal dimension D of a curve. In this context D is a measure of the degree to which a curve fills the available space: D = log (n) / [log (n) + log (d/D)]. The subjects were asked to stand quietly on a Kistler force plate for 1 minute with eyes opened, followed by 1 minute with eyes closed. The middle 20 second period was analyzed for each trial. The mean D value for the control group was 1.86 (sd =0.33), and 1.73 (sd =0.18) for the AD group (p<0.05). Among the AD group, balance with eyes closed was less impaired then with eyes opened (r=0.61). This finding may suggest difficulty with integrative cortical functions. Severity of balance impairment correlated significantly with degree of cognitive impairment as measured by the Mini-Mental Status Examination (r=0.61). These preliminary studies indicate that measurements of the fractal dimension are a simple and objective method to assess standing balance and characterize motor abnormalities in Alzheimer's Disease. Supported by the VA Rehabilitation R&D, VA Medical Research Services and Alzheimer's Association S.E. WI Chapter. 25 VASCULAR DEMENTIA EVIDENCE OF A SUBCORTICAL SMALL VESSEL SUBGROUP. *A. Wallin, K. Blennow, C.G. Gottfries. Department of Psychiatry and Neurochemistry, Gothenburg University, S-422 03 Hisings Backa, Sweden. Vascular dementia (VD) was studied with regard to pathogenesis and symptomatology. A clinical VD diagnosis was chosen when the patients showed dementia in combination with cerebral ischemic attacks or other pronounced vascular diseases. On computered tomography, leuko-araiosis was found to be extensive and to occur frequently (85%). In cerebrospinal fluid an increased albumin ratio without relation to cerebral ischemic attacks was found, indicating BBB dysfunction. Intrathecal IgG production was found in 9% of the VD patients; and the IgG index was related to severity of disease and to hypertension. A frontosubcortical symptom complex was the dominating clinical pattern. At postmortem, a small volume of infarcted tissue was found, together with a pronounced decrease in myelin lipids in subcortical areas. The combination of leuko-araiosis, BBB dysfunction, immunological and symptomatological findings and decreased myelin lipids suggests that VD in this study was a subcortical small vessel disorder. Infarcts, when present, were rather endpoint manifestations of the small vessel pathology than the cause of the disease, Today, multi-infarct dementia is looked upon as the main category of VD. Our findings suggest that subcortical small vessel dementia is another important group that ought be be taken into account. 26
PROGRESSIVE APHASIA DUE TO LOBAR ATROPHY. J.S. Snowden. D Neary, D M.A Mann ~ of N e u r O i o g y , ~ ~ a t Infirmary and ~ of P ~ . U ~ of Manchester, Manchester M13 9WL, England. There is increasing evidence ~at foca~ cer~:~al ~ r a t i o n represents a condition which is c l i n ~ and ~ ~ from
NEUROBIOLOGY OF AGING. VOLUME Ii. 1990 ABSTRACTS OF SECOND INTERNATIONAL CONFERENCE ON ALZHEIMER'S DISEASE CLINICAL COURSE 24
22 b~PEARANCEOFNEUROFIBRILIA%RYTANGLES IN NEOCORTEXFOLLOWED BY FIVE YEARS OF MINIMAL COGNITIVE DECLINE. *AW Clark, IM Parhad, EM Pajurkova. University of Calgary, Calgary, Alberta, Canada. The appearance of neurofibrillary tangles in n e o c o r t e x m a y constitute a watershed in the evolution of Alzheimer-type degeneration. Wherea~ non-demented individuals commonly have neOcortical plaques, they rarely have significant numbers of neocorticalneurofibrillarytangles (Tamlinson etal., J Neurol Sci, 1968). We describe a patient evaluated sequentially after biopsy-proven appearance of numerous plaques and tangles in neocortex, who 5 years later failed to meet strict NINCDS criteria for the clinical diagnosis of Alzheimer's disease (McKhann e t a l . , Neurology, 1984). At the age of 63, he had suffered a minor traffic accident and subsequently developed headaches, difficulty concentrating, mew~r y problems, a n d two episodes interpreted as temporal lobe seizures. Radiolagic stutltes revealed ventriculomegaly. Following placement of a ventriculoperitoneal shunt (right parietal) and discovery of xanthochromic fluid in the suboktral space, a cortical biopsy (right frontal) was taken in October 1984. Bielschowskystainedsections rewealednumerous senile plaques and neurofibrillary tangles, the latter most conspicuous in layer 3 of cortex. In June 1988, 3 years 8 months after the biopsy, he attained a WAIS verbal IQ of i08 and performance IQ of 109, showing no significant decline since 1985 testing. Memory function and some p r o b l ~ - s o l v i n g functions had declined, however; and the patient and his wife noted that he had increasing difficulty with playing bridge and dancing. In January1990, 5 years 2 m o n t h s after the biopsy, his mini-mental test score was 28/30. similar cases have been described only infrequently I N e a r y e t al., J Neurol Neurosurg Psychiatry, 1986). We conclude that, in some patients, cognitive functions may show very slow decline for years following the appearance of neurofibrillarytangles in neocortex. In cc=~arison to cases of rapidly pragressive AD, the findings emphasize the dramatic case~to-case differences in temporal evolution at various stages of the disease.
23 COGNITIVE DECLINE AND MORTALITY IN ALZEEIMER'S DISEASE (AD) *A. Burns, R. Jacoby and R. Levy. Section of Old Age Psychiatry, Institute of Psychiatry, De Cresplgny Park, Denmark Hill, London SE5 8AF, UK 178 patients living in the catchment area of the Maudsley ~ospltal in South East London and satisfying NINCDS/ADRDA criteria for AD were enrolled in a prospective longitudinal study to assess the clinical course of the disease, identify predictors of cognitive decline and to identify possible
clinical
subtypes.
The f o l l o w i n g m e a s u r e s ( u s i n g
standardlsed instruments) were made at entry to the study: Cognitive Function (Minl-Mental State Examination, CAMCOG); Current Mental State (Geriatric Mental State Schedule); history (CAMDEX~ Including personal and family history and symptoms since the onset of the disorder such as delusions, hallucinations and mlsldentlflcatlons); current behavlour (Stockton Geriatric Rating Scale) and cranial computed tomography. All patients were followed up for between 12 and 36 months wlth the above measures repeated annually. Scores on all the tests of cognitive function decreased significantly over the follow-up p e r i o d . A c l u s t e r analysis of the scores revealed 3 stable clusters of mild, moderate and severe decline. The following features were predictive of more rapid decline - hallucinations ( p a r t i c u l a r l y audltory hallucinations within 12 mOnths prior to entry into the study), family history of dementia in parents (but not in
siblings
o r 2nd d e g r e e r e l a t i v e s )
and d u r a t i o n
of i l l n e s s
less than 2 years. During the follow up, 84 patients died. Patients more likely to dle included those with a grasp reflex and increased muscle tone at entry to the study and those who developed a snout reflex and extrapyramldal signs during the follow-up. Subjects with misldentiflcations had a lower mortality rate than patients without these symptoms. Three subscales of the Stockton Geriatric Rating Scale (communication failure, apathy and physical disability) were associated wlth an increased death rate. There appears to be clinical heterogeneity in AD wlth features such as family history, psy~hlatrlc symptoms and neurological signs being associated wlth a more rapidly deteriorating clinical course and higher mortality.
STANDING BALANCE MEASURES IN ALZHEIMER'S DISEASE (AD). "Piero G. Antuono, Barbara M. Myklebust, Joel B: Myklebust, Qing-Tang Hu. VA Medical Center and the Medical College of Wisconsin, Milwaukee, Wisconsin, 53295. Standing balance measures were collected from 11 normal subjects and 14 AD patients (NINCDS/ADRDA criteria) with impaired gaR by clinical examination. Deviations of the center of pressure during quiet standing have been characterized for normal adults and normal aging. These measurements have been used to assess neurological disorders of the vestibular and cerebellar systems and lesions of the pyramidal and extrapyramidal systems. We recently developed a method to quantify deviations by determining the fractal dimension D of a curve. In this context D is a measure of the degree to which a curve fills the available space: D = log (n) / [log (n) + log (d/D)]. The subjects were asked to stand quietly on a Kistler force plate for 1 minute with eyes opened, followed by 1 minute with eyes closed. The middle 20 second period was analyzed for each trial. The mean D value for the control group was 1.86 (sd =0.33), and 1.73 (sd =0.18) for the AD group (p<0.05). Among the AD group, balance with eyes closed was less impaired then with eyes opened (r=0.61). This finding may suggest difficulty with integrative cortical functions. Severity of balance impairment correlated significantly with degree of cognitive impairment as measured by the Mini-Mental Status Examination (r=0.61). These preliminary studies indicate that measurements of the fractal dimension are a simple and objective method to assess standing balance and characterize motor abnormalities in Alzheimer's Disease. Supported by the VA Rehabilitation R&D, VA Medical Research Services and Alzheimer's Association S.E. WI Chapter. 25 VASCULAR DEMENTIA EVIDENCE OF A SUBCORTICAL SMALL VESSEL SUBGROUP. *A. Wallin, K. Blennow, C.G. Gottfries. Department of Psychiatry and Neurochemistry, Gothenburg University, S-422 03 Hisings Backa, Sweden. Vascular dementia (VD) was studied with regard to pathogenesis and symptomatology. A clinical VD diagnosis was chosen when the patients showed dementia in combination with cerebral ischemic attacks or other pronounced vascular diseases. On computered tomography, leuko-araiosis was found to be extensive and to occur frequently (85%). In cerebrospinal fluid an increased albumin ratio without relation to cerebral ischemic attacks was found, indicating BBB dysfunction. Intrathecal IgG production was found in 9% of the VD patients; and the IgG index was related to severity of disease and to hypertension. A frontosubcortical symptom complex was the dominating clinical pattern. At postmortem, a small volume of infarcted tissue was found, together with a pronounced decrease in myelin lipids in subcortical areas. The combination of leuko-araiosis, BBB dysfunction, immunological and symptomatological findings and decreased myelin lipids suggests that VD in this study was a subcortical small vessel disorder. Infarcts, when present, were rather endpoint manifestations of the small vessel pathology than the cause of the disease, Today, multi-infarct dementia is looked upon as the main category of VD. Our findings suggest that subcortical small vessel dementia is another important group that ought be be taken into account. 26
PROGRESSIVE APHASIA DUE TO LOBAR ATROPHY. J.S. Snowden. D Neary, D M.A Mann ~ of N e u r O i o g y , ~ ~ a t Infirmary and ~ of P ~ . U ~ of Manchester, Manchester M13 9WL, England. There is increasing evidence ~at foca~ cer~:~al ~ r a t i o n represents a condition which is c l i n ~ and ~ ~ from