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Frontal Cortical Synaptophysin in Lewy Body Diseases: Relation to Alzheimer’S Disease and Dementia

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Frontal Cortical Synaptophysin in Lewy Body Diseases: Relation to Alzheimer’S Disease and Dementia J Neurol Neurosurg Psychiatry 1998;64:653–656 653 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.5.653 on 1 May 1998. Downloaded from Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer’s disease and dementia L A Hansen, S E Daniel, G K Wilcock, S Love Abstract movement disorder, but up to 40% of patients Objectives—Dementia in Alzheimer’s dis- with Parkinson’s disease eventually become ease correlates closely with loss of neocor- demented.1 DLB is a more recently recognised tical synapses. Similar synaptic loss has clinicopathological entity which accounts for been shown in patients whose Alzheimer’s perhaps 20% of dementia in elderly people.2 It disease is also associated with neocortical is typically associated with mild parkinsonism, and brain stem Lewy bodies. The aim was and usually resting tremor is absent. Both Par- to determine if dementia in Lewy body kinson’s disease and DLB show neuronal loss disease was associated with diminished and gliosis in the substantia nigra, locus concentrations of midfrontal cortex syn- ceruleus, and the nucleus basalis of Meynert, aptophysin. accompanied by single or multiple Lewy Methods—An immunobinding assay was bodies in surviving neurons, and at least some used to measure synaptophysin in post- neocortical Lewy bodies can be found in both mortem samples of midfrontal cortex conditions. The neuropathological abnormali- from 89 patients with Alzheimer’s disease ties associated with dementia in Parkinson’s (ages 59–100, mean 79), 22 with combined disease and DLB are variable and complex. Lewy body disease and Alzheimer’s dis- About a third of demented patients with ease (ages 69–103, mean 79), 15 demented Parkinson’s disease have concomitant Alzheim- patients with “pure” Lewy body disease er’s disease at necropsy, another 10% have (ages 57–80, mean 74), nine with neocorti- widespread neocortical Lewy bodies, and most cal and brain stem Lewy bodies who had of the remainder show only the typical pathol- Parkinson’s disease but were not de- ogy of Parkinson’s disease.1 Most DLB brains mented (ages 68–85, mean 79), and 20 neu- have more Alzheimer’s disease pathology than rologically normal controls (ages 58–89, age matched controls, but far less than is mean 75). The diagnosis was confirmed in encountered in typical Alzheimer’s disease.3 Departments of all cases by detailed neuropathological These cases of mixed Lewy body disease and Pathology and Alzheimer’s disease have also been termed Neurosciences, examination of the contralateral hemi- University of brain. Seven of the patients in the pure Lewy body variants of Alzheimer’s disease (LBV).4 Almost 30% of DLB cases, however, California, San Diego, Lewy body disease with dementia group http://jnnp.bmj.com/ La Jolla, California, had initially presented with parkinsonism are free of changes associated with Alzheimer’s USA and eight with dementia. disease. Patients with such pure Lewy body L A Hansen Results—Synaptophysin concentrations disease are less demented than those with both Lewy bodies and Alzheimer’s disease lesions.56 Parkinson’s Disease (arbitrary units (AU)/µg) in patients with Alzheimer’s disease (mean 79 (SD 28)) or Dementia in Alzheimer’s disease correlates Society Brain Bank, 7 London, UK combined Lewy body disease and Alzhe- closely with loss of neocortical synapses, and S E Daniel imer’s disease (mean 83 (SD 33)) were sig- similar synaptic loss has been found in patients with combined Alzheimer’s disease and Lewy nificantly lower than in controls (mean on September 24, 2021 by guest. Protected copyright. Department of Care of 115 (SD 29)) (p=0.002). Synaptophysin body pathology.6 In this study, we sought to the Elderly determine if dementia across the range of Lewy G K Wilcock concentrations in demented patients with pure Lewy body disease (mean 106 SD 39) body diseases, including both Parkinson’s Department of and patients with Lewy body disease who disease and DLB, is associated with loss of Neuropathology, were not demented (mean 101 (SD 18)) did midfrontal cortex synaptophysin, as is the case University of Bristol, not diVer significantly from control values in Alzheimer’s disease. Frenchay Hospital, or from each other. Bristol, UK Materials and methods SLove Conclusion—Loss of midfrontal cortex synapses probably contributes to demen- SUBJECTS Correspondence to: tia in Lewy body disease when Alzheimer’s We evaluated demented and non-demented Dr L A Hansen, Department disease is also present but not to the patients with Lewy body disease to determine if of Pathology, University of synaptophysin loss could explain cognitive California, San Diego, 9500 dementia of pure Lewy body disease. Gilman Drive, La Jolla, dysfunction. To control for the confounding California 92093–0624, (J Neurol Neurosurg Psychiatry 1998;64:653–656) influence of concurrent Alzheimer’s disease USA. Telephone 001 619 pathology, we separated cases of DLB into two 534 6212; fax: 001 619 534 6232; email: Keywords: Lewy body disease; dementia; synaptophysin groups: those with and those without concomi- [email protected] tant lesions of Alzheimer’s disease. Finally, we contrasted the results in these groups with Received 27 August 1997 Lewy body diseases include idiopathic Parkin- those obtained from a cohort of patients with and in revised form 7 October 1997 son’s disease and dementia with Lewy bodies pure Alzheimer’s disease, and results from age Accepted 16 October 1997 (DLB). Parkinson’s disease is primarily a matched non-demented controls. 654 Hansen, Daniel, Wilcock, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.5.653 on 1 May 1998. Downloaded from Mean (SD) concentrations of synaptophysin Alzheimer’s disease pathology was evaluated using either thioflavin-S preparations viewed Mean PM Mean synaptophysin nMeanagedelay (h) (AU/µg) under ultraviolet illumination, or with modified Bielschowsky silver impregnation for plaques LBD without dementia 9 79 (5) 15 (14) 101 (18) and tangles. LBD with dementia 15 74 (7) 26 (17) 106 (39) Mixed LBD + AD 22 79 (8) 11 (10) 83 (33) AD 89 79 (9) NA 79 (28) MIDFRONTAL CORTEX SYNAPTOPHYSIN Controls 20 75 (8) 42 (35) 115 (29) QUANTIFICATION LBD = Lewy body disease; AD = Alzheimer’s disease; NA = not available, but < 24 hours; PM = Specimens from the frozen right hemibrain postmortem. midfrontal cortex were analysed with a dot The non-demented Lewy body disease immunobinding assay for quantification of group consisted of nine patients with clinically synaptophysin-like immunoreactivity. Post- diagnosed idiopathic Parkinson’s disease (age mortem intervals before freezing of the brain range 68–85, mean 74), whose brains showed tissue varied considerably, from two to 103 only typical Parkinson’s disease pathology, hours, but we have shown this method of syn- aptophysin measurement to be stable over pro- including a few neocortical Lewy bodies in 10 every instance, without Alzheimer’s disease longed postmortem intervals, and the con- changes. The DLB group included 37 patients, trols had both the longest average postmortem both those whose initial and primary clinical delay interval (42 hours) and the highest mean diagnosis was dementia, and patients with Par- synaptophysin concentrations (115 arbitrary kinson’s disease who developed dementia units (AU)/µg). Determination of neocortical before death. These 37 DLB specimens were synaptophysin was undertaken by homogenis- separated into those with and those without ing 0.1 g frozen brain tissue in 1 ml cold homogenising buVer with a Dounce glass/glass concomitant Alzheimer’s disease; a neu- × ropathological diagnosis of Alzheimer’s disease tissue grinder. A low speed spin (5000 g 10 was assigned if a brain had enough senile minutes) was performed and the supernatant plaques to meet both National Institute on separated into particulate and cytosolic frac- 8 tions by ultracentrifugation (356 000 g×1h, Aging criteria for Alzheimer’s disease and cri- o teria from the Consortium to Establish a Reg- 4C). After resuspending pellet with buVer, 2 istry for Alzheimer Disease for “definite”, or µg particulate fraction was blotted on to nitro- “probable” Alzheimer’s disease.9 There were cellulose membrane using a dot-blot manifold. 22 such mixed Lewy body disease and A serial dilution of aliquoted control sample Alzheimer’s disease brains. All 22 of these was included as a normalisation standard. patients (age range 69–103, mean 79) had pre- Blots were blocked using phosphate buVered sented with dementia, not Parkinson’s disease. saline (PBS) and 0.1% Tween-20 for two The remaining 15 DLB cases (age range hours. They were then incubated in primary 57–80, mean 74) did not meet the above antibody (antisynaptophysin, Boehringer- described neuropathological criteria for Alzhe- Mannheim Biochemical, Indianapolis, IN, imer’s disease. Seven of these patients had pre- USA, mouse monoclonal, 0.1 µg/ml in PBS- sented initially with Parkinson’s disease, and BSA) for 12–18 hours, followed by rabbit anti- mouse IgG (0.85 µg/ml in PBS-BSA) , and 125I- eight with dementia. The Alzheimer’s disease http://jnnp.bmj.com/ comparison group consisted of 89 patients with protein A (0.1 µCi/ml in PBS-BSA) for two pure Alzheimer’s disease (age range 59–100, hours each. After washing in PBS-Tween, an mean 79). Finally, we also analysed synapto- autoradiogram was produced on a phosphor physin concentrations from 20 age matched imaging screen and quantified on a Molecular non-demented controls (age range 58–89, Dynamics phosphorImager SE using the Im- mean 75). ageQuant Software (Molecular Dynamics, Sunnyvale, CA, USA) . Results are expressed as arbitrary units (AU)/µg blotted protein after on September 24, 2021 by guest. Protected copyright. NEUROPATHOLOGICAL EVALUATION normalising against the standard curve. At necropsy, the brains were divided midsagit- tally, and the right hemibrain was frozen at Results −70°C for neurochemical analysis, and the left The table shows the result of midfrontal cortex was fixed in formalin for 10 days to three weeks synaptophysin assay in each group.
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