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469 Combination of Alzheimer's disease with Creutzfeldt-Jakob disease: A neuropathological study
FIFTH INTERNATIONAL
CONFERENCE
ON ALZHEIMER'S
however, is likely to cause impaired cognition. Presently available data support the view that the occurrence of additional lesions in the form of AD stage III (or more) destruction is the most common cause of intellectual decline in PD. Supported by the Deutsche Forschungsgemeinschaft and the Bundesministerium fiir Forschung und Technologic
468 Clinical and Pathological
Features of Parkinsonism
in
AIzheimer's Disease L. N. Wang and K. W. Htmng Department of Neurology, Chinese PLA General Hospital, Geriatric institute of PLA, 28 Fu-Xing Road, Beijing, China Because patients with Alzheiner's disease often develop clinical menifestations of parkinsonism, 6 cases of Alzheimer's disease confirmed by neuropathological examinations were reviewed. Coexistent of Parkinsonisln was present in 3 cases. Chief clinical features were bradykinesia and stiff muscles, particularly rigidity of neck. Paghologically, nonspecific degeneration, includillg pigqnented neuronal loss and gliosis in the substantia nigaa and locus cendeus in 2 cases and spheroid pigmentary degeneration in one case was found. Our findings revealed that the pathologic con'elates of clinical parkinsonism in A l z h e i m e r ' s disease w e r e h e t e r o g e n o u s and iron m e t a b o l i s m shotdd be considered as one of the risk factors, because of the excessive accumnlatioll of iron pigments in substantial nigra was present in one of our cases. No pathological changes in both substantia niga'a and locus ceruleus were present in the cases of Alzheimer's disease withont clinical featnres o f parkinsonism.
469 Combination of AIzheimer's Disease with Creutzfeldt-Jakob Disease: a Neuropathological Study H. Budka* (1), LA. Hainfellner (1), K. Jellinger (2), and F. Gullotta (3) (1) Institute of Neurology, University of Vienna, A-1097 Wien, and (2) Hospital Lainz, Neurological Department, Vienna, Austria; (3) Institute of Neuropathology, Miinster, FRG Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) are prototypes of non-transmissible and transmissible cerebral amyloidoses, respectively. They share clinical, neuropathological, and pathogenetic features but have undetermined mutual influences. We screened neocortical tissue blocks from 107 neuropathologically proven sporadic.CJD cases with anti-lYA4 immunocytochemistry. These cases comprise 78 consecutive CJD cases neuropathologically diagnosed since 1996 in Austria, and 29 consecutive cases diagnosed in a single neuropathological institution in Germany. In cases with IYA4 deposits, histology was extended to Bielschowsky silver impregnation, and to anti-tau and anti-ubiquitin immanocytochemistry. On selected blocks, anti-13/PrP and alcian blue/anti-PrP double stains were performed. Prion protein (PrP) deposits were visualized by means of anti-PrP immunocytochemistry. The neuropathologieal diagnosis of AD was made according to CERAD criteria. We detected 4 cases (3 females, l male) of definite, 6 cases (all females) of probable, and 2 cases (both females) of possible AD. The age range in definite and probable AD combined with CJD was 64-82 years, and the median age was 72 years; this differs significantly from the median age of 64 years in our Austrian CJD series. Duration of signs and symptoms ranged between 2 and I 1 months, with a median of 5,5 months; in Austrian CJD cases, the median duration is 4 months. Each case had a variable amount of synaptic type and/or plaque type and/or patchy/ perivacuolar PrP deposits in the neocortex. In primitive 13/A4plaques, synaptic type PrP was infrequently detectable. However, at the periphery of mature IYA4 plaques, synaptic type and patchy PrP deposits frequently accumulated. We conclude that the coexistence of sporadic CJD and AD in the same patient is not an exceptional f'mding and primarily occurs in aged patients. Since CERAD criteria for AD include "'presence of other neuropathologic disorders likely to cause dementia", an AD diagnosis in CJD brains is solely based on the densities of argyrophilic plaques; it might include subclinical brain pathology if CJD would not have developed. The contribution of AD vs. CJD changes, respectively, to manifestation of dementia is difficult to assess; the relatively short clinical course of our combination cases argues for CJD as predominant cause of dementia. The accumulation of PrP around g/A4 plaques indicates an effect of B/A4 amyloid deposition on PrP morphogenesis. [This study is supporledby the ELI ConcegedAction "Thehuman prion diseases: from nettrobiologyto pathobiologyand moleculargenetics"(Projectleader: H. Budka)].
DISEASE
S117
470
The Locus Coeruleus in Alzheimer's Disease: the Relation between Cell Death and Depression W J G Hoogendijk x~', I Sommers2, P Eikelenboom2, CW Pool t, DF Swaabt r Graduate School Neurnsciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, The Netherlands; 2 Valerins Clinic, Free University, Amsterdam, The Netherlands It is not known to what extent depression in Alzheimer's disease (AD) is caused by psychological or by biological events. We hypothesize, however, that many symptoms of the depression syndrome in AD have a neurobiological representation in the noradrenergie locus coernieus (LC) and in distinct hypothalamic systems. We are currently studying the noradrenergic LC in depressed and non-depressed AD patients, since noradrenaline is known to play a central role in depression. Two studies dalm that the LC would be more severely affected in depressed AD patients than in non-depressed AD patients. However, it is possible that certain dementia symptoms have been mistaken for depressive symptoms. In the present study we tested 47 AD patients for depression with a 6-month interval, taking symptom overlap into account with the dementia syndrome. At present 29 subjects came to autopsy, 6 of whom suffered from major depression according to DSMIII-R. They were matched with non-depressed AD patients and 6 controls. The left I.,C was dissected and image- analysisassisted morphometry was performed. Preliminary results show that the mean pigmented neuron number in the I.,C is 9.780 in the control group, 7.407 in the depressed AD group and 3.938 in the non-depressed AD group. Concluding, the present study confirms the cell loss in the I.,C in AD as compared to controls, but does not show any difference between depressed and non-depressed AD patients. Several studies have emphasized the anatomical specificity of the noradrenergic inputs to the paraventricular nucleus (PVN). In patients with major depression we recently found activation of AVP-, OXT-, and corticotropin-releasing hormone (CRH)-expressing neurons in the PVN that may be related to cognitive impairment, decreased food intake, and a disturbed dexamethasone suppression test, respectively. We will try to obtain confirmation for the role of CRH in depression by studying the hypothalaml of the same depressed and non-depressed AD patients.
471 T h e e e r e b e l l a r d e n t a t e n u c l e u s in A l z h e i m e r ' s d i s e a s e w i t h and without myoclonus Y. Fukutani ~'2., N. J.Cairns2, I. P. Everall 2, A. Chadwick 2 , K. Isaki~and P. L. Lantos 2 i Department of Neuropsychiatry, Fukui Medical School, Fukui, Japan 2 Department of Neuropathology, Institute of Psychiatry, London, UK Introduction. Although myoclonus is common in the later stages of Alzheimer's disease, its cause and the mechanism of myoclonus are still uncertain. In order to elucidate the pathological basis of myoclonus in Alzheimer's disease, we have quantitatively assessed the neuronal population in the cerebellar dentate nucleus using the stercological probe, the disector. Materials and methods. Formalin-fixed, paraffin-wax embedded brain tissues from 8 sporadic Alzheimer's disease patients with myoclonus, 10 sporadic Alzheimer's disease patients without myoclonus and 9 non-demented age-matched controls without neurological disease were obtained from the Brain Bank, Department of Neuropathology, Institute of Psychiatry. The medial part of the dentate nucleus was cut sagittaly at 20 pm and stained with cresyl violet. The neuronal numerical density of the dentate neurons was investigated using a stereological technique, the optical disector. Small and large neurons were counted separately according to lhe size of the nucleolus and shape of the cytoplasm. Statistical analysis was perlonned by one-way ANOVA. Results. The mean neuronal density of the dentate nucleus in Alzheimer's disease with myoclonus (14,100 cells/mm 3) showed a trend to be greater than in Alzheimer's disease without myoclonus (13,460 cells/ram3; F=I.70, df=24, p=0.08) and controls (13,650 cells/mm3; F=l.70, df=24, p=0.26), suggestive of a reduction in size of the dentate grey matter. The ratio of small neurons to large neurons in Alzheimer's disease with myoclonus (0.46) was significantly lower than in Alzheimer's disease without myoclonus (0.60; F=3.30, dr=24, p=0.02) and controls (0.58; F=3.30, df=24, p=0.049), indicating a preferential loss of small neurons in the dentate nucleus. In all three groups, the neuronal density in the rostral part was lower than in the caudal part. Conclusion. An imbalance in the proportion of small to large neurons in the dentate nucleus may contribute to the pathological substrate of myoclonus in Alzheimer's disease.
CONFERENCE
ON ALZHEIMER'S
however, is likely to cause impaired cognition. Presently available data support the view that the occurrence of additional lesions in the form of AD stage III (or more) destruction is the most common cause of intellectual decline in PD. Supported by the Deutsche Forschungsgemeinschaft and the Bundesministerium fiir Forschung und Technologic
468 Clinical and Pathological
Features of Parkinsonism
in
AIzheimer's Disease L. N. Wang and K. W. Htmng Department of Neurology, Chinese PLA General Hospital, Geriatric institute of PLA, 28 Fu-Xing Road, Beijing, China Because patients with Alzheiner's disease often develop clinical menifestations of parkinsonism, 6 cases of Alzheimer's disease confirmed by neuropathological examinations were reviewed. Coexistent of Parkinsonisln was present in 3 cases. Chief clinical features were bradykinesia and stiff muscles, particularly rigidity of neck. Paghologically, nonspecific degeneration, includillg pigqnented neuronal loss and gliosis in the substantia nigaa and locus cendeus in 2 cases and spheroid pigmentary degeneration in one case was found. Our findings revealed that the pathologic con'elates of clinical parkinsonism in A l z h e i m e r ' s disease w e r e h e t e r o g e n o u s and iron m e t a b o l i s m shotdd be considered as one of the risk factors, because of the excessive accumnlatioll of iron pigments in substantial nigra was present in one of our cases. No pathological changes in both substantia niga'a and locus ceruleus were present in the cases of Alzheimer's disease withont clinical featnres o f parkinsonism.
469 Combination of AIzheimer's Disease with Creutzfeldt-Jakob Disease: a Neuropathological Study H. Budka* (1), LA. Hainfellner (1), K. Jellinger (2), and F. Gullotta (3) (1) Institute of Neurology, University of Vienna, A-1097 Wien, and (2) Hospital Lainz, Neurological Department, Vienna, Austria; (3) Institute of Neuropathology, Miinster, FRG Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) are prototypes of non-transmissible and transmissible cerebral amyloidoses, respectively. They share clinical, neuropathological, and pathogenetic features but have undetermined mutual influences. We screened neocortical tissue blocks from 107 neuropathologically proven sporadic.CJD cases with anti-lYA4 immunocytochemistry. These cases comprise 78 consecutive CJD cases neuropathologically diagnosed since 1996 in Austria, and 29 consecutive cases diagnosed in a single neuropathological institution in Germany. In cases with IYA4 deposits, histology was extended to Bielschowsky silver impregnation, and to anti-tau and anti-ubiquitin immanocytochemistry. On selected blocks, anti-13/PrP and alcian blue/anti-PrP double stains were performed. Prion protein (PrP) deposits were visualized by means of anti-PrP immunocytochemistry. The neuropathologieal diagnosis of AD was made according to CERAD criteria. We detected 4 cases (3 females, l male) of definite, 6 cases (all females) of probable, and 2 cases (both females) of possible AD. The age range in definite and probable AD combined with CJD was 64-82 years, and the median age was 72 years; this differs significantly from the median age of 64 years in our Austrian CJD series. Duration of signs and symptoms ranged between 2 and I 1 months, with a median of 5,5 months; in Austrian CJD cases, the median duration is 4 months. Each case had a variable amount of synaptic type and/or plaque type and/or patchy/ perivacuolar PrP deposits in the neocortex. In primitive 13/A4plaques, synaptic type PrP was infrequently detectable. However, at the periphery of mature IYA4 plaques, synaptic type and patchy PrP deposits frequently accumulated. We conclude that the coexistence of sporadic CJD and AD in the same patient is not an exceptional f'mding and primarily occurs in aged patients. Since CERAD criteria for AD include "'presence of other neuropathologic disorders likely to cause dementia", an AD diagnosis in CJD brains is solely based on the densities of argyrophilic plaques; it might include subclinical brain pathology if CJD would not have developed. The contribution of AD vs. CJD changes, respectively, to manifestation of dementia is difficult to assess; the relatively short clinical course of our combination cases argues for CJD as predominant cause of dementia. The accumulation of PrP around g/A4 plaques indicates an effect of B/A4 amyloid deposition on PrP morphogenesis. [This study is supporledby the ELI ConcegedAction "Thehuman prion diseases: from nettrobiologyto pathobiologyand moleculargenetics"(Projectleader: H. Budka)].
DISEASE
S117
470
The Locus Coeruleus in Alzheimer's Disease: the Relation between Cell Death and Depression W J G Hoogendijk x~', I Sommers2, P Eikelenboom2, CW Pool t, DF Swaabt r Graduate School Neurnsciences Amsterdam, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam ZO, The Netherlands; 2 Valerins Clinic, Free University, Amsterdam, The Netherlands It is not known to what extent depression in Alzheimer's disease (AD) is caused by psychological or by biological events. We hypothesize, however, that many symptoms of the depression syndrome in AD have a neurobiological representation in the noradrenergie locus coernieus (LC) and in distinct hypothalamic systems. We are currently studying the noradrenergic LC in depressed and non-depressed AD patients, since noradrenaline is known to play a central role in depression. Two studies dalm that the LC would be more severely affected in depressed AD patients than in non-depressed AD patients. However, it is possible that certain dementia symptoms have been mistaken for depressive symptoms. In the present study we tested 47 AD patients for depression with a 6-month interval, taking symptom overlap into account with the dementia syndrome. At present 29 subjects came to autopsy, 6 of whom suffered from major depression according to DSMIII-R. They were matched with non-depressed AD patients and 6 controls. The left I.,C was dissected and image- analysisassisted morphometry was performed. Preliminary results show that the mean pigmented neuron number in the I.,C is 9.780 in the control group, 7.407 in the depressed AD group and 3.938 in the non-depressed AD group. Concluding, the present study confirms the cell loss in the I.,C in AD as compared to controls, but does not show any difference between depressed and non-depressed AD patients. Several studies have emphasized the anatomical specificity of the noradrenergic inputs to the paraventricular nucleus (PVN). In patients with major depression we recently found activation of AVP-, OXT-, and corticotropin-releasing hormone (CRH)-expressing neurons in the PVN that may be related to cognitive impairment, decreased food intake, and a disturbed dexamethasone suppression test, respectively. We will try to obtain confirmation for the role of CRH in depression by studying the hypothalaml of the same depressed and non-depressed AD patients.
471 T h e e e r e b e l l a r d e n t a t e n u c l e u s in A l z h e i m e r ' s d i s e a s e w i t h and without myoclonus Y. Fukutani ~'2., N. J.Cairns2, I. P. Everall 2, A. Chadwick 2 , K. Isaki~and P. L. Lantos 2 i Department of Neuropsychiatry, Fukui Medical School, Fukui, Japan 2 Department of Neuropathology, Institute of Psychiatry, London, UK Introduction. Although myoclonus is common in the later stages of Alzheimer's disease, its cause and the mechanism of myoclonus are still uncertain. In order to elucidate the pathological basis of myoclonus in Alzheimer's disease, we have quantitatively assessed the neuronal population in the cerebellar dentate nucleus using the stercological probe, the disector. Materials and methods. Formalin-fixed, paraffin-wax embedded brain tissues from 8 sporadic Alzheimer's disease patients with myoclonus, 10 sporadic Alzheimer's disease patients without myoclonus and 9 non-demented age-matched controls without neurological disease were obtained from the Brain Bank, Department of Neuropathology, Institute of Psychiatry. The medial part of the dentate nucleus was cut sagittaly at 20 pm and stained with cresyl violet. The neuronal numerical density of the dentate neurons was investigated using a stereological technique, the optical disector. Small and large neurons were counted separately according to lhe size of the nucleolus and shape of the cytoplasm. Statistical analysis was perlonned by one-way ANOVA. Results. The mean neuronal density of the dentate nucleus in Alzheimer's disease with myoclonus (14,100 cells/mm 3) showed a trend to be greater than in Alzheimer's disease without myoclonus (13,460 cells/ram3; F=I.70, df=24, p=0.08) and controls (13,650 cells/mm3; F=l.70, df=24, p=0.26), suggestive of a reduction in size of the dentate grey matter. The ratio of small neurons to large neurons in Alzheimer's disease with myoclonus (0.46) was significantly lower than in Alzheimer's disease without myoclonus (0.60; F=3.30, dr=24, p=0.02) and controls (0.58; F=3.30, df=24, p=0.049), indicating a preferential loss of small neurons in the dentate nucleus. In all three groups, the neuronal density in the rostral part was lower than in the caudal part. Conclusion. An imbalance in the proportion of small to large neurons in the dentate nucleus may contribute to the pathological substrate of myoclonus in Alzheimer's disease.