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Prevalence of Alzheimer Plaques in AIDS

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Prevalence of Alzheimer Plaques in AIDS J Neurol Neurosurg Psychiatry 1998;65:29–33 29 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.1.29 on 1 July 1998. Downloaded from Prevalence of Alzheimer plaques in AIDS Margaret M Esiri, Simon C Biddolph, Christine S Morris Abstract According to the amyloid hypothesis for the Objectives—Both genetic and environ- pathogenesis of Alzheimer’s disease, diVuse mental risk factors for Alzheimer’s dis- plaques are the initial manifestation of the dis- ease have been identified. The best ease, with neuritic or classic plaques and burnt established environmental risk factor, out plaques developing later.910 Concurrent head trauma, is thought to act through the with plaque accumulation and progression, triggering of an inflammatory response. neurofibrillary tangles, initially appearing only Another stimulus to an inflammatory in the transentorhinal region, become more response in the brain is AIDS. Whether numerous and widespread in the hippocampus there is an increased prevalence of â/A4 and eventually in the neocortex and certain amyloid deposits in the form of argy- subcortical nuclei.11 Typically, the progression rophilic plaques in the brains of patients of disease from the initial, diVuse, plaque stage with AIDS has therefore been investi- to the advanced state with widespread neocor- gated. tical neuritic plaques and neurofibrillary tan- Methods—The prevalence of argyrophilic gles is estimated to take at least 20 years. This amyloid plaques in the cerebral cortex of is based on findings on the prevalence of these frontal and temporal lobes was compared changes in brains from patients of diVering in 97 cases of AIDS dying at ages 30–69 ages with adult Down’s syndrome, who almost years with that in 125 age matched, invariably develop the pathology of Alzheimer’s non-HIV infected controls. disease by late middle age,12 and in elderly Results—In the control group, and in populations.13 14 The early stages of this patho- AIDS, the prevalence of plaques increased logical sequence, before the widespread devel- with age (p=0.005 and 0.048 respectively). opment of neuritic pathology, are largely There was a significantly greater preva- subclinical. lence of argyrophilic plaques in the AIDS Although there is indubitable evidence for an group as a whole (29%) (p< 0.004) and in important genetic influence in the develop- those in the fourth decade (18%) (p<0.014) ment of these changes, both in familial and than in control subjects (13% and 0% sporadic Alzheimer’s disease,15–20 it is also respectively). thought likely that environmental factors play a Conclusion—There is a predisposition to significant part in their development. Three argyrophilic plaque formation in the separate epidemiological studies, among nine brain in AIDS. The findings support the that considered the possibility, have pointed to view that a stimulus to an inflammatory the importance of previous head injury in http://jnnp.bmj.com/ response in the brain favours argyrophilic increasing the risk of developing clinical Alzhe- plaque formation. The clinical relevance imer’s disease.21 One reason for this might be of our findings is, as yet, unclear. that head injury produces irreversible damage (J Neurol Neurosurg Psychiatry 1998;65:29–33) to the brain which reduces its reserve capacity Keywords: AIDS; Alzheimer’s disease; amyloid plaques and makes symptoms develop at an earlier stage in the evolution of the pathology of Alzheimer’s disease.22 However, it is also possi- on September 30, 2021 by guest. Protected copyright. Alzheimer’s disease is characterised pathologi- ble that head injury accelerates, or makes more cally chiefly by the presence of widely distrib- likely, the development of Alzheimer’s disease uted cerebral argyrophilic plaques and neurofi- pathology itself. Thus, in dementia pugilistica, brillary tangles.1 A principal component of pathological features resembling those seen in Department of argyrophilic plaques is â/A4 amyloid, a peptide Alzheimer’s disease develop in boxers sub- Neuropathology and derived from the metabolic processing of a jected to repeated head injury.23 Recent patho- Neurology, RadcliVe larger, glycosylated membrane protein, amy- logical studies exploring a possible link be- Infirmary, Oxford, UK 23 tween head injury and Alzheimer’s disease have M M Esiri loid precursor protein. Argyrophilic plaques S C Biddolph have diVerent morphological forms, classified found an increased prevalence of â/A4 amyloid 4 C S Morris as diVuse, classic, and “burnt out”. DiVuse deposits in subjects dying four hours to 2.5 plaques consist of focal but dispersed deposits years after severe head injury compared with Correspondence to: of â/A4 amyloid, well demonstrated immuno- age matched controls with no history of previ- Professor MM Esiri, 24 25 Neuropathology cytochemically with antibodies to â/A4 protein ous head injury. Possession of the apolipo- 5–8 Department, RadcliVe and with the methenamine silver stain. Clas- protein E gene allele å4 increases both the risk Infirmary, Oxford OX2 6HE, sic plaques have a central, dense core of â/A4 of developing Alzheimer’s disease,19 20 particu- UK. Telephone 0044 1865 larly after head injury,26 and the risk of having 224 403; fax 0044 1865 224 amyloid and a surrounding corona of abnormal 508. neuritic and glial cell processes. Burnt out â/A4 amyloid deposits in the brain after head plaques consist of a dense deposit of â/A4 injury.27 It is hypothesised28 that head injury Received 16 September 1997 amyloid resembling the core of classic plaques provokes enhanced production of amyloid pre- and in revised form 14 November 1997 without the surrounding neuritic and other cell cursor protein as part of an acute phase Accepted 25 November 1997 processes. response, possibly mediated by interleukin-1, 30 Esiri, Biddolph, Morris J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.1.29 on 1 July 1998. Downloaded from Table 1 Plaque distribution and density in HIV infected cases and controls of temporal lobe/hippocampus and frontal lobes, or of hippocampus, entorhinal cortex, HIV + HIV− and temporal lobe were stained with the meth- Temporal lobe and frontal lobe plaques 17 12 enamine silver stain for argyrophilic plaques Only temporal lobe plaques 11* 2 (which stains all â/A4 amyloid plaques)7 and Plaque profile densities (mean (SD))† 2.14 (3.17) 3.40 (3.89) systematically scanned for the presence of *In six cases a frontal lobe section was not available for examination. argyrophilic plaques, without knowledge of †DiVerence NS by Mann-Whitney non-parametric test (p=0.78). the age of each case. All sections were mounted which has been shown to upregulate produc- on APTES (3-aminopropyl-triethoxysilane)- tion of amyloid precursor protein in cultured coated slides and adjacent sections to those cells.29–32 This enhanced production of amyloid used for methenamine silver staining from HIV precursor protein, it is suggested, in turn infected patients and a random selection of results in increased /A4 amyloid deposits in controls were processed for HIV p24 antigen. â + + the brain. Randomly selected HIV , methenamine silver , − + If this hypothesis is correct it might be and control HIV , methenamine silver cases anticipated that other disease processes predis- were also immunostained for âA4. All sections posing to increased interleukin-1 production in were rehydrated, treated with 3% aqueous the brain may likewise result in an enhanced hydrogen peroxide (H2O2) to block endog- risk of developing â/A4 amyloid deposits. The enous peroxidase. Then antigen retrieval for chronic viral infection that causes AIDS, HIV p24 was performed by microwaving for HIV-1, is estimated to infect the brain in 20%– 3×5 minutes on “high” in an 800 W microwave 80% of AIDS cases, depending on the popula- oven, and by pretreating with 98% formic acid tions studied and the sensitivity of the method for five minutes for âA4. After washes in phos- used to detect such infection.33 Furthermore, phate buVered saline containing 0.01% Triton interleukin-1 is one of several cytokines that X-100 (PBST), non-specific binding was has been shown to be produced in increased blocked by incubation with foetal calf serum at amounts in the brain in AIDS.34 These findings 1:20 for 20 minutes, followed immediately by suggest the possibility that patients with AIDS, incubation in the primary antibodies, mouse like those with head injury, may be at increased monoclonal anti-HIV p24 (Dako) diluted 1:20 risk of developing amyloid plaques in the and rabbit anti-âA4 (Insight Biotechnology), cerebral cortex. We have therefore examined diluted 1:100, for one hour. After further sections of cerebral cortex from patients with washes as before, biotinylated goat antimouse AIDS dying from 30 to 69 years of age and immunoglobulins (at 1:200) and biotinylated compared the prevalence of argyrophilic amy- goat antirabbit immunoglobulins at 1:400 loid deposits in those patients with that in age (both from Dako) were applied as the second- matched controls without HIV infection. ary reagents for HIV p24 and âA4 respectively, for 30 minutes. After further washes in PBST, the tertiary reagent, streptavidin horseradish Materials and methods peroxidase (Dako), diluted at 1:300, was Material from 97 patients with HIV-1 infection applied for 30 minutes. The reactions were (10 pre-AIDS, 87 AIDS) (91 men, five visualised with 3-amino-9-ethylcarbazone http://jnnp.bmj.com/ women), aged over 29 years at death (mean (AEC) and lightly counterstained with Mayer’s (SD) 47.6 (10.2), range 30–67 years) was haemalum (Merck, BDH) and mounted in obtained from the MRC AIDS brain bank at glycerol gelatin (Sigma). In sections that the Institute of Psychiatry, London and at its contained plaques, the mean density of plaque satellites in Oxford and Edinburgh, or from the profiles per field averaged from an examination Institute of Neurology, London.
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