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11 Differential diagnosis: Progressive supranuclear palsy vs postencephalitic parkinsonism
FIFTH INTERNATIONAL
CONFERENCE
ON ALZHEIMER'S
of ACHE, revealed by isoelectric focusing, was found in CSF obtained at necropsy from subjects with confirmed AD (Navaratnam et al. Lancet 1991, 337, 447). The present report describes the results of a longitudinal clinicopathological study to answer the questions: 1. Is there a significant difference between AChE or non-specific cholinasterase activities in lumbar CSF taken in life in confu'med AD compared with other dementias and controls? 2. Is the anomalous molecular form of AChE in lumbar CSF characteristic of confn'med AD? 3. Are these measurements of any diagnostic value? 4. Is there any relationship between CSF cholinesterase activities and apoE ullelotype? Methods as in Appleyard et al. (1987) and Navaratnam et al. above. PatientS: subjects with histopathologieal diagnoses at necropsy: AD alone (37), AD with other pathology (13), other dementias (23). Controls: 61 living subjects without cognitive deficit and 10 dead subjects with no evidence of CNS pathology. AChE activity: controls (21.43:4.8 SD); all AD cases (17.8±4.6) p<0.005; other dementias (19.2±6.9). No signilieant difference in non-specific ChE. Anomalous form of AChE: controls 18/69; all AD cases 13/50; not significantly different. There was n o relationship between the number of ApoE4 alleles and AChE activity or non-specific ChE activity. Conclusion. The overlap between AChE levels is too great for this measurement to be of diagnostic value; likewise, the presence of an anomalous molecular form of AChE is not diagnostic for AID.
WORKSHOP B: HARMONIZATION OF DEMENTIA DRUG GUIDELINES "REPORT OF THE INTERNATIONAL WORKING GROUPS"
DISEASE
$3
Corticobasal degeneration (CBD) and Pick's disease (PD) are rare neurodegenerative diseases that share histopathological features that are demonstrated well with neurofilament (NF) and tan (z) protein immunocytochemistry. Clinically, CBD and PD are not frequently confused, but neither disorder can be diagnosed with certainty before autopsy. PD is a dementing disorder with personality deterioration, but Alzheimer's disease can be clinically similar. Dementia is less common in CBD, where an asymmetrical, rigidity and apraxia syndrome is more usual. Unfortunately, the CBD phenotype has been described in other disorders, most notably asymmetrical progressive supranuclear palsy (PSP). In classical cases, CBD and PD can be differentiated by gross examination of the brain. CBD has asymmetrical, circumscribed atrophy of the frontal lobes, sometimes limited to the premotor gyms; while PD has "knifeedge" atrophy affecting frontal and temporal poles. Cortical neurons in both disorders show ballooning degeneration with strong immunoreactivity for phosphorylated NF. In PD Pick bodies are round X-positive (x÷) inclusions in neurons in the upper cortical layers, dentate fascia and Ammon's horn. A few neurons in CBD may resemble Pick bodies, but the usual x+ neuronal inclusions in CBD are not round and more often fibrillary. Neuronal inclusions are present in deep gray matter and the brainstem in CBD, in a distribution common with PSP. The hallmark of CBD is extensive "c+ inclusions in glial cell bodies and processes. Clusters of x+ glial processes create the so-called "astrocytie plaque". Astrocytes in PD may also have x÷ inclusions, and they rarely form plaque-like lesions. More often they have a tufted appearance similar to "c+ glia in PSP. White matter x+ glia and processes are abundant in CBD, but less common in PD. Oligodendroglial x+ inclusions in CBD are usually perinuclear fibrils, but round x+ inclusions, similar to Pick bodies, are found in PD. Clearly, CBD and PD have overlapping histological features. The major distinctions are restricted cortical involvement in CBD with many x+ inclusions in glia, white matter and deep gray matter and more x+ neuronal inclusions in the cortex in PD.
9 International Working Group on Harmonization of Dementia Drug Guidelines Whitehouse P.J.*, Amaducci, L., Feldman, H., Ferris, S., Gauthier, S., Homma, A., Khachaturian, Z., Levy, R., Orgogozo, J.M., Post, S., Reisberg, B., Rossor, M., Thai, L., Winblad, B The International Working Group on Harmonization of. Dementia Drug Guidelines is a group of academics, industry scientists, and government regulators who are committed to global cooperation in the process of developing more effective medications for Alzheimer's disease and related dementias. Through a series of meetings we have been reviewing the currently existing drug guidelines in the United States, Canada, Europe and Japan. We are actively working to identify differences in these guidelines in order to make the standard for approval more uniform in these major world markets. In addition, we are spending considerable time focusing on practical aspects of multi-site, multinational studies. Our activities are divided into working subgroups who are focusing on Phase III cognitive trials from the point of view of outcome measures and design issues as well as protocols to treat non-cognitive symptoms, slow the progression of disease and ultimately prevent the disorder. Moreover, we have an interest in cultural and ethical issues which may affect the international drug development process.
WORKSHOP C: DIFFERENTIAL DIAGNOSIS OF NON-ALZHEIMER'S DISEASE DEMENTIA 10 Corticobasal Degeneration versus Picks' Disease: An Immunocytochemical Comparison Dennis W. Diekson and Mel B. Feany Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
11 Differential Diagnosis: Progressive Supranuclear Palsy vs Postencephalitic Parkinsonism KA. Jellinger L.B. Institute of Ciinical Neurobiology, Lainz-Hospital, A-I 130 Vienna, Austria Degenerative dementing disorders with neurofibrillary/tan pathology pose significant challenges for neuropathologists. Two disorders sharing widespread distribution of abnormal aggregates of hyperphosphorylated tuu in neurons, neurites and glia showing striking pathological overlaps are progressive supranuclear palsy (PSP) and postencephalitic parkinsonism (PEP), the distinction of which is difficult on the basis of neuropathology alone without clinical information (history of encephalitis lethargica, earlier age of onset, longer disease duration in PEP, etc). Although immunohistochemical and ultrastructural studies are unable to easily differentiate neurofibrillary tangles (NFT) or neuropil threads (NT) in PEP from those in Alzheimer's disease (AD) and PSP, biochemical studies show differences between the double tan isoforms in PSP and the tan protein triplet in AD and PEP. Despite significant overlap in the morphology and distribution pattern &lesions there is differential anatomical susceptibility in the affected regions that is included in the NINDS diagnostic criteria of PSP and related disorders (Litvan et al., JNEP 1996; 55:97-105) and has been confirmed by semiquantitative morphological analysis in PSP (penny et al., JNEP 1996; 55:53-67). Typical PSP is featured by multisystem neuronal loss and gliosis with high density of NFT, NP, and glial tan inclusions in striatum, pallidum, substantia nigra, subthalamic nucleus, pontine basis, oculomotor complex, dentate nucleus and/or medulla, whereas PEP shows no or only minimal affection of the oculomotor complex, troehlear and dentate nuclei, basis pontis, inferior olives, and striatum. Since similar lesion pattern is seen in atypical cases of PSP, these histologie features are usually insufficient for separating PSP from PEP. Nigral cell loss in both disorders involves all parts of zona eompacta with no predilection for the ventral tier. Neocortical tan pathology in both disorders predominates in the hippoeampus and entorhinal region and some neocortical, mainly prefrontal and inferior temporal areas, preferentially in layers II and III, and severe involvement in PSP of the primary motor cortex. This distribution pattern differs from that seen in AD. Although the use of artifical neural networks identified a few histologic features that might help to differentiate PSP and PEP (Litvan et al.; Brain 1996, in press), further studies are necessary to improve the current diagnostic criteria of PEP and PSP.
CONFERENCE
ON ALZHEIMER'S
of ACHE, revealed by isoelectric focusing, was found in CSF obtained at necropsy from subjects with confirmed AD (Navaratnam et al. Lancet 1991, 337, 447). The present report describes the results of a longitudinal clinicopathological study to answer the questions: 1. Is there a significant difference between AChE or non-specific cholinasterase activities in lumbar CSF taken in life in confu'med AD compared with other dementias and controls? 2. Is the anomalous molecular form of AChE in lumbar CSF characteristic of confn'med AD? 3. Are these measurements of any diagnostic value? 4. Is there any relationship between CSF cholinesterase activities and apoE ullelotype? Methods as in Appleyard et al. (1987) and Navaratnam et al. above. PatientS: subjects with histopathologieal diagnoses at necropsy: AD alone (37), AD with other pathology (13), other dementias (23). Controls: 61 living subjects without cognitive deficit and 10 dead subjects with no evidence of CNS pathology. AChE activity: controls (21.43:4.8 SD); all AD cases (17.8±4.6) p<0.005; other dementias (19.2±6.9). No signilieant difference in non-specific ChE. Anomalous form of AChE: controls 18/69; all AD cases 13/50; not significantly different. There was n o relationship between the number of ApoE4 alleles and AChE activity or non-specific ChE activity. Conclusion. The overlap between AChE levels is too great for this measurement to be of diagnostic value; likewise, the presence of an anomalous molecular form of AChE is not diagnostic for AID.
WORKSHOP B: HARMONIZATION OF DEMENTIA DRUG GUIDELINES "REPORT OF THE INTERNATIONAL WORKING GROUPS"
DISEASE
$3
Corticobasal degeneration (CBD) and Pick's disease (PD) are rare neurodegenerative diseases that share histopathological features that are demonstrated well with neurofilament (NF) and tan (z) protein immunocytochemistry. Clinically, CBD and PD are not frequently confused, but neither disorder can be diagnosed with certainty before autopsy. PD is a dementing disorder with personality deterioration, but Alzheimer's disease can be clinically similar. Dementia is less common in CBD, where an asymmetrical, rigidity and apraxia syndrome is more usual. Unfortunately, the CBD phenotype has been described in other disorders, most notably asymmetrical progressive supranuclear palsy (PSP). In classical cases, CBD and PD can be differentiated by gross examination of the brain. CBD has asymmetrical, circumscribed atrophy of the frontal lobes, sometimes limited to the premotor gyms; while PD has "knifeedge" atrophy affecting frontal and temporal poles. Cortical neurons in both disorders show ballooning degeneration with strong immunoreactivity for phosphorylated NF. In PD Pick bodies are round X-positive (x÷) inclusions in neurons in the upper cortical layers, dentate fascia and Ammon's horn. A few neurons in CBD may resemble Pick bodies, but the usual x+ neuronal inclusions in CBD are not round and more often fibrillary. Neuronal inclusions are present in deep gray matter and the brainstem in CBD, in a distribution common with PSP. The hallmark of CBD is extensive "c+ inclusions in glial cell bodies and processes. Clusters of x+ glial processes create the so-called "astrocytie plaque". Astrocytes in PD may also have x÷ inclusions, and they rarely form plaque-like lesions. More often they have a tufted appearance similar to "c+ glia in PSP. White matter x+ glia and processes are abundant in CBD, but less common in PD. Oligodendroglial x+ inclusions in CBD are usually perinuclear fibrils, but round x+ inclusions, similar to Pick bodies, are found in PD. Clearly, CBD and PD have overlapping histological features. The major distinctions are restricted cortical involvement in CBD with many x+ inclusions in glia, white matter and deep gray matter and more x+ neuronal inclusions in the cortex in PD.
9 International Working Group on Harmonization of Dementia Drug Guidelines Whitehouse P.J.*, Amaducci, L., Feldman, H., Ferris, S., Gauthier, S., Homma, A., Khachaturian, Z., Levy, R., Orgogozo, J.M., Post, S., Reisberg, B., Rossor, M., Thai, L., Winblad, B The International Working Group on Harmonization of. Dementia Drug Guidelines is a group of academics, industry scientists, and government regulators who are committed to global cooperation in the process of developing more effective medications for Alzheimer's disease and related dementias. Through a series of meetings we have been reviewing the currently existing drug guidelines in the United States, Canada, Europe and Japan. We are actively working to identify differences in these guidelines in order to make the standard for approval more uniform in these major world markets. In addition, we are spending considerable time focusing on practical aspects of multi-site, multinational studies. Our activities are divided into working subgroups who are focusing on Phase III cognitive trials from the point of view of outcome measures and design issues as well as protocols to treat non-cognitive symptoms, slow the progression of disease and ultimately prevent the disorder. Moreover, we have an interest in cultural and ethical issues which may affect the international drug development process.
WORKSHOP C: DIFFERENTIAL DIAGNOSIS OF NON-ALZHEIMER'S DISEASE DEMENTIA 10 Corticobasal Degeneration versus Picks' Disease: An Immunocytochemical Comparison Dennis W. Diekson and Mel B. Feany Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
11 Differential Diagnosis: Progressive Supranuclear Palsy vs Postencephalitic Parkinsonism KA. Jellinger L.B. Institute of Ciinical Neurobiology, Lainz-Hospital, A-I 130 Vienna, Austria Degenerative dementing disorders with neurofibrillary/tan pathology pose significant challenges for neuropathologists. Two disorders sharing widespread distribution of abnormal aggregates of hyperphosphorylated tuu in neurons, neurites and glia showing striking pathological overlaps are progressive supranuclear palsy (PSP) and postencephalitic parkinsonism (PEP), the distinction of which is difficult on the basis of neuropathology alone without clinical information (history of encephalitis lethargica, earlier age of onset, longer disease duration in PEP, etc). Although immunohistochemical and ultrastructural studies are unable to easily differentiate neurofibrillary tangles (NFT) or neuropil threads (NT) in PEP from those in Alzheimer's disease (AD) and PSP, biochemical studies show differences between the double tan isoforms in PSP and the tan protein triplet in AD and PEP. Despite significant overlap in the morphology and distribution pattern &lesions there is differential anatomical susceptibility in the affected regions that is included in the NINDS diagnostic criteria of PSP and related disorders (Litvan et al., JNEP 1996; 55:97-105) and has been confirmed by semiquantitative morphological analysis in PSP (penny et al., JNEP 1996; 55:53-67). Typical PSP is featured by multisystem neuronal loss and gliosis with high density of NFT, NP, and glial tan inclusions in striatum, pallidum, substantia nigra, subthalamic nucleus, pontine basis, oculomotor complex, dentate nucleus and/or medulla, whereas PEP shows no or only minimal affection of the oculomotor complex, troehlear and dentate nuclei, basis pontis, inferior olives, and striatum. Since similar lesion pattern is seen in atypical cases of PSP, these histologie features are usually insufficient for separating PSP from PEP. Nigral cell loss in both disorders involves all parts of zona eompacta with no predilection for the ventral tier. Neocortical tan pathology in both disorders predominates in the hippoeampus and entorhinal region and some neocortical, mainly prefrontal and inferior temporal areas, preferentially in layers II and III, and severe involvement in PSP of the primary motor cortex. This distribution pattern differs from that seen in AD. Although the use of artifical neural networks identified a few histologic features that might help to differentiate PSP and PEP (Litvan et al.; Brain 1996, in press), further studies are necessary to improve the current diagnostic criteria of PEP and PSP.