Alzheimer Disease: Perry E

Court J, Martin-Ruiz C, Piggott M, Spurden D, Griffiths M, Perry E. · Joint MRC Newcastle University Centre Development in Clinical Brain Aging, Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom. · Biol Psychiatry. · Pubmed #11230868 No free full text.

Abstract: Loss of cortical nicotinic acetylcholine receptors with high affinity for agonists (20-50%) in patients with Alzheimer's disease is a common finding. Recent immunochemical analyses indicate that this deficit is predominantly associated with the loss of alpha4 subunits (30-50%), although modest reductions of alpha3 may occur in some individuals (25-29%). No reduction of beta2 subunit protein expression or levels of alpha3 and alpha4 messenger RNA has been reported. Decline in cortical [(125)I]alpha-bungarotoxin binding and alpha7 protein expression does not appear to be as extensive or widespread as the loss of alpha4 (0-40%), with no reduction in messenger RNA expression. In the thalamus, there was a trend for reduced [(3)H]nicotine binding in the majority of nuclei (0-20%) in Alzheimer's disease; however, there was a significant decline in [(125)I]alpha-bungarotoxin binding in the reticular nucleus. In the striatum [(3)H]nicotine binding was reduced in Alzheimer's disease, and although neuroleptic medication accentuated this change, it occurred in those free of neuroleptics. Changes in nicotinic acetylcholine receptors in Alzheimer's disease are distinct from those in normal aging and are likely to contribute to clinical features and possibly neuropathology.

Perry E, Walker M, Grace J, Perry R. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, UK NE4 6BE. · Trends Neurosci. · Pubmed #10354606 No free full text.

Abstract: The cholinergic system is one of the most important modulatory neurotransmitter systems in the brain and controls activities that depend on selective attention, which are an essential component of conscious awareness. Psychopharmacological and pathological evidence supports the concept of a 'cholinergic component' of conscious awareness. Drugs that antagonize muscarinic receptors induce hallucinations and reduce the level of consciousness, while the nicotinic receptor is implicated as being involved in the mechanism of action of general (inhalational) anaesthetics. In degenerative diseases of the brain, alterations in consciousness are associated with regional deficits in the cholinergic system. In Alzheimer's disease (AD), there is a loss of explicit (more than implicit) memory and hypoactivity of cholinergic projections to the hippocampus and cortex, while the visual hallucinations experienced by subjects with Dementia with Lewy bodies (DLB) are associated with reductions in neocortical ACh-related activity. In Parkinson's disease, the additional loss of pedunculopontine cholinergic neurones, which control REM (rapid eye movement) sleep or dreaming, is likely to contribute to REM abnormalities, which also occur in DLB. Widespread basal-forebrain and rostral brainstem cholinergic pathways, which include converging projections to the thalamus, appear to be located strategically for generating and integrating conscious awareness. Alleviation of a range of cognitive and non-cognitive symptoms by drugs that modulate the cholinergic system, which are being developed for the treatment of AD and related disorders, could be caused by changes in consciousness.

Perry E. · Department of Neurochemical Pathology, Wolfson Research Centre, Institute for Ageing and Health, University of Newcastle, Newcastle General Hospital, Newcastle-upon-Tyne, UK. · J Altern Complement Med. · Pubmed #17480134 No free full text.

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Ziabreva I, Perry E, Perry R, Minger SL, Ekonomou A, Przyborski S, Ballard C. · Institute of Ageing and Health, University of Newcastle Upon Tyne, Newcastle General Hospital, Westgate Road, NE4 6BE Newcastle upon Tyne, UK. · J Psychosom Res. · Pubmed #16938507 No free full text.

Abstract: BACKGROUND: Exciting preliminary work indicates an increase in progenitor activity in the subgranular zone of the dentate gyrus of people with Alzheimer's disease (AD) compared to that of controls. We examine progenitor activity in the other main progenitor niche, the subventricular zone (SVZ), as well as potential associations with key pathological and neurochemical substrates. METHOD: Immunocytochemistry techniques utilizing nestin and Musashi1 antibodies were used to examine progenitor activity in the SVZ and to enable comparisons between seven patients with AD and seven controls, based upon the quantification of the percentage area covered, using the Image Pro Plus v.4.1 image analysis system. AD pathology was staged using the Consortium to Establish a Registry for Alzheimer's Disease and Braak criteria. Choline acetyl transferase (ChAT) was measured in the temporal cortex as an indication of the severity of cortical cholinergic deficits. Glial fibrillary acidic protein (GFAP) was used to label astrocytes. RESULTS: There was a significant ninefold decrease (Z = 2.2, P = .046) of Musashi1 immunoreactivity in the SVZ of patients with AD in comparison with that of controls, but there was a significant increase in nestin immunoreactivity in the same region (Z = 2.2, P = .028) without any significant change in GFAP immunoreactivity. Reduced ChAT enzymatic activity was the main association of Musashi immunoreactivity (R = -.90, P = .03). DISCUSSION: The current results indicate a significant reduction of progenitor cells (as labeled by Musashi1) in the SVZ of patients with AD, but an increase in GFAP-negative astrocyte-like cells with progenitor characteristics. Cortical cholinergic loss was strongly associated with the reduction of progenitors, with potential implications of important treatment targets.

Thomas AJ, Hendriksen M, Piggott M, Ferrier IN, Perry E, Ince P, O'Brien JT. · School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. · Neuropathol Appl Neurobiol. · Pubmed #16640648 No free full text.

Abstract: Previous studies investigating the serotonin transporter (SERT) in depression have been inconsistent and included a large proportion of subjects who had committed suicide. In Alzheimer's disease studies have generally reported a reduction in SERT density but have not compared Alzheimer's disease subjects with and without comorbid major depression. We conducted a post mortem study of SERT density in the prefrontal cortex in normal elderly, a group of elderly depressed subjects and in Alzheimer's disease subjects with and without major depression. A post mortem study comparing SERT density in the prefrontal cortex in elderly controls (n = 10), subjects with major depression (n = 8) and subjects with Alzheimer's disease with (n = 9) and without (n = 5) comorbid major depression. We used autoradiography to measure the density of [3H]CN-IMI binding (non-specific binding determined with citalopram) to the SERT in the prefrontal cortex. We found a marked reduction in specific SERT binding in the prefrontal cortex in Alzheimer's disease subjects compared with both control (P = 0.002) and depressed subjects (P = 0.004) but no difference in SERT binding between depressed and control subjects or between Alzheimer's disease subjects with and without depression. Our study confirms previous reports of a reduction in SERT binding in Alzheimer's disease but indicates this reduction is not greater in Alzheimer's disease subjects who also have had major depression. In a group of subjects more typical of late-life depression we did not identify any alterations in SERT density.

Sahin HA, Emre M, Ziabreva I, Perry E, Celasun B, Perry R. · Department of Neurology, Ondokuz Mayis University, Faculty of Medicine, Kurupelit, 55139, Samsun, Turkey. · Acta Neuropathol. · Pubmed #16468020 No free full text.

Abstract: We studied the distribution pattern of pathology and cholinergic deficits in the subnuclei of the amygdaloid complex (AC) in five patients with Alzheimer's disease (AD), eight with dementia with Lewy bodies (DLB) and five normal controls. In controls, the basal nucleus contained the highest choline acetyltransferase activity; the activity in the lateral and central nuclei and those in the cortical, medial and accessory basal nuclei were comparable. In AD, there was a significant decrease in choline acetyltransferase activity in the accessory basal and lateral nuclei, in DLB a significant decrease was observed in the accessory basal, lateral and cortical nuclei. Compared to controls the hyperphosphorylated tau-pathology burden was significantly higher in the basal, central and medial nuclei in AD and in the central, cortical, lateral and medial nuclei in DLB. The amyloid plaque burden was significantly higher in the accessory basal, basal, lateral and cortical nuclei in AD and in all nuclei in DLB. The alpha-synuclein burden was significantly higher in all nuclei in both AD and DLB. Compared to AD alpha-synuclein burden was higher in all nuclei in DLB. There were no correlations between the distribution pattern of hyperphosphorylated tau-pathology, amyloid plaques and alpha-synuclein-positive structures, and choline acetyltransferase activity, except the lateral nucleus in DLB. In conclusion we found no relationship between the pattern of cholinergic deficits and the distribution pattern of lesions in the AC of patients with AD or DLB. Cholinergic deficits were more prominent in the nuclei of basolateral (BL) group in AD, whereas the nuclei of both BL and corticomedial groups were involved in DLB, which may be due to the involvement of both basal forebrain and brainstem cholinergic nuclei in the latter.

Ballard C, Morris C, Kalaria R, McKeith I, Perry R, Perry E. · Wolfson Centre for Age-Related Diseases, Guys Campus, Kings College London, London, UK. · Dement Geriatr Cogn Disord. · Pubmed #15802910 No free full text.

Abstract: Accumulating evidence suggests that butyrylcholinesterase (BuChE) plays an important role in the progression of cognitive deficits and Alzheimer-type pathology in dementia patients. We examined the relationship between the K variant of BuChE and the severity of deposits of amyloid (Abeta(1-42)) and phosphorylated tau in the temporal cortex (BA36) of 30 prospectively studied autopsy-diagnosed dementia (Alzheimer's disease and dementia with Lewy bodies) patients. There was 42% less phosphorylated tau in BA36 in cases with > or =1 K compared with those with wild-type BuChE alleles (t = 2.2, p = 0.039), but no difference in the extent of Abeta(1-42) deposition. BuChE may play this role in the phosphorylation of tau, relevant to therapeutic inhibition of the enzyme.

Perry E, Ziabreva I, Perry R, Aarsland D, Ballard C. · Newcastle General Hospital, MRC Bldg., Westgate Rd., Newcastle upon Tyne, NE4 6BE, UK. · Neurology. · Pubmed #15642917 No free full text.

Abstract: Choline acetyltransferase in temporal cortex was evaluated as a marker of cholinergic function in autopsied dementia cases (9 vascular dementia [VaD] cases, 12 "mixed" VaD and Alzheimer disease [AD] cases, 10 AD cases, 12 control subjects). Patients with AD (t = 2.5, p = 0.02) and "mixed" VaD and AD (t = 3.8, p = 0.001) had greater cholinergic deficits than age-matched control subjects and patients with "pure" VaD. The absence of cholinergic deficits in "pure" VaD may be relevant to the pharmacologic treatment of these patients.

Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E. · MRC Building, Centre Development in Clinical Brain Aging, Newcastle General Hospital, Newcastle Upon Tyne, UK. · Glia. · Pubmed #12509811 No free full text.

Abstract: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are common forms of dementia in the elderly associated with cholinergic dysfunction, including reductions in nicotinic acetylcholine receptors (nAChRs). In AD, astrocytes are implicated in the formation of senile plaques, one of the core pathological features. Using immunohistochemistry, we have investigated astrocytic expression of the two major nicotinic receptor alpha subunits in the human hippocampus and entorhinal cortex. alpha7, but not alpha4, subunit immunoreactivity was associated with astrocytes. An increase in the proportion of astrocytes expressing alpha7 immunoreactivity was observed in AD compared with age-matched controls. A similar increase was not evident in DLB. Elevated alpha7 nAChRs on astrocytes in AD may contribute to alterations in calcium homeostasis and nitric oxide production, which in turn could affect beta-amyloid-mediated inflammatory processes in AD.

Bednar I, Paterson D, Marutle A, Pham TM, Svedberg M, Hellström-Lindahl E, Mousavi M, Court J, Morris C, Perry E, Mohammed A, Zhang X, Nordberg A. · Divisions of Molecular Neuropharmacology, Occupational Therapy and Elderly Care Research (NEUROTEC), S-141 86 Stockholm, Sweden. · Mol Cell Neurosci. · Pubmed #12093166 No free full text.

Abstract: The nicotinic (nAChRs) and muscarinic (mAChRs) acetylcholine receptors and acetylcholinesterase (AChE) activity were studied in the brains of APP(SWE) transgenic mice (Tg+) and age-matched nontransgenic controls (Tg-) that were between 4 and 19 months of age. A significant increase in the binding of 125I-labeled alpha-bungarotoxin (alpha7 nAChRs) was observed in most brain regions analyzed in 4-month-old Tg+ mice, preceding learning and memory impairments and amyloid-beta (Abeta) pathology. The enhanced alpha7 receptor binding was still detectable at 17-19 months of age. Increase in [3H]cytisine binding (alpha4beta2 nAChRs) was measured at 17-19 months of age in Tg+ mice, at the same age when the animals showed heavy Abeta pathology. No significant changes in [3H]pirenzepine (M1 mAChRs) or [3H]AFDX 384 (M2 mAChRs) binding sites were found at any age studied. The upregulation of the nAChRs probably reflects compensatory mechanisms in response to Abeta burden in the brains of Tg+ mice.

Nordberg A, Hellström-Lindahl E, Lee M, Johnson M, Mousavi M, Hall R, Perry E, Bednar I, Court J. · Karolinska Institutet, NEUROTEC, Division of Molecular Neuropharmacology, Huddinge University Hospital, Stockholm, Sweden. · J Neurochem. · Pubmed #12065674 No free full text.

Abstract: Alzheimer's disease neuropathology is characterised by beta-amyloid plaques and neurofibrillary tangles. Inhibition of beta-amyloid accumulation may be essential for effective therapy in Alzheimer's disease. In this study we have treated transgenic mice carrying the Swedish mutation of human amyloid precursor protein [Tg(Hu.APP695.K670N-M671L)2576], which develop brain beta-amyloid deposits, with nicotine in drinking fluid (200 microg/mL) from 9-14.5 months of age (5.5 months). A significant reduction in amyloid beta peptide 1-42 positive plaques by more than 80% (p < 0.03) was observed in the brains of nicotine treated compared to sucrose treated transgenic mice. In addition, there was a selective reduction in extractable amyloid beta peptides in nicotine treated mice; cortical insoluble 1-40 and 1-42 peptide levels were lower by 48 and 60%, respectively (p < 0.005), whilst there was no significant change in soluble 1-40 or 1-42 levels. The expression of glial fibrillary acidic protein was not affected by nicotine treatment. These results indicate that nicotine may effectively reduce amyloid beta peptide aggregation in brain and that nicotinic drug treatment may be a novel protective therapy in Alzheimer's disease.

Martin-Ruiz C, Court J, Lee M, Piggott M, Johnson M, Ballard C, Kalaria R, Perry R, Perry E. · Joint MRC-Newcastle University Development in Clinical Brain Aging, Newcastle General Hospital, Newcastle upon Tyne, UK. · Acta Neurol Scand Suppl. · Pubmed #11261803 No free full text.

Abstract: OBJECTIVES: Comparisons were made of nicotinic receptors in 3 major forms of dementia in old age. Although it is well established the involvement of nicotinic receptors in Alzheimer's disease (AD), their status in the other two main causes of dementia in old age-dementia with Lewy bodies (DLB) and vascular dementia (VaD) is not widely reported. METHODS: Temporal cortex was examined for epibatidine and alpha-bungarotoxin binding, and immunoreactivity of alpha4 and alpha7 nAChR subunits. RESULTS: There were selective abnormalities in nicotinic receptor subtypes in the disorders examined. In AD there is a loss of high affinity receptor binding, reflecting a selective loss of alpha4 subunit, but no change in alpha7 subunits. Similar abnormalities in ligand binding are also apparent in DLB. In the VaD series, there was no overall loss of epibatidine binding or immunoreactivity for alpha4 or alpha7 subunits. CONCLUSIONS: Loss of cortical receptor alpha4 subunit appears to be a characteristic feature of neurodegenerative dementia but not dementia of vascular origin. Since nicotinic receptors control cerebral vasodilation, the relative integrity of the receptors in VaD may auger well for nicotinic therapy in this disorder in which there is a cholinergic abnormality, to judge by the loss of the presynaptic enzyme.

Perry E, Martin-Ruiz C, Lee M, Griffiths M, Johnson M, Piggott M, Haroutunian V, Buxbaum JD, Nãsland J, Davis K, Gotti C, Clementi F, Tzartos S, Cohen O, Soreq H, Jaros E, Perry R, Ballard C, McKeith I, Court J. · Department of Neuropathology, MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, Newcastle, UK. · Eur J Pharmacol. · Pubmed #10771016 No free full text.

Abstract: Human brain ageing is associated with reductions in a variety of nicotinic receptors subtypes, whereas changes in age-related disorders including Alzheimer's disease or Parkinson's disease are more selective. In Alzheimer's disease, in the cortex there is a selective loss of the alpha4 (but not alpha3 or 7) subunit immunoreactivity and of nicotine or epibatidine binding but not alpha-bungarotoxin binding. Epibatidine binding is inversely correlated with clinical dementia ratings and with the level of Abeta1-42, but not related to plaque or tangle densities. In contrast, alpha-bungarotoxin binding is positively correlated with plaque densities in the entorhinal cortex. In human temporal cortex loss of acetylcholinesterase catalytic activity is positively correlated with decreased epibatidine binding and in a transgenic mouse model over expressing acetylcholinesterase, epibatidine binding is elevated. In Parkinson's disease, loss of striatal nicotine binding appears to occur early but is not associated with a loss of alpha4 subunit immunoreactivity. Tobacco use in normal elderly individuals is associated with increased alpha4 immunoreactivity in the cortex and lower densities of amyloid-beta plaques, and with greater numbers of dopaminergic neurons in the substantia nigra pars compacta. These findings indicate an early involvement of the alpha4 subunit in beta-amyloidosis but not in nigro-striatal dopaminergic degeneration.

Lippa CF, Smith TW, Perry E. · Department of Neurology, MCP-Hahnemann, Philadelphia, PA 19129, USA. · J Neural Transm. · Pubmed #10443555 No free full text.

Abstract: The biological substrate underlying the reduced cortical choline acetyltransferase (ChAT) in dementia with Lewy bodies (DLB) is incompletely understood. We compared cortical ChAT levels with Lewy body densities and neuronal loss in the nucleus basalis of Meynert (nbM) and cerebral cortex in six DLB, seven Alzheimer's disease (AD), and six control cases. We found greater neuronal loss in the nbM in DLB compared to AD (U = 9.500, p = 0.049). Mean ChAT levels in the cortex were lower in dementia patients than controls (t = 17.500, p = 0.001), and DLB cases had slightly lower ChAT levels than AD cases, but this difference was not significant (t = -0.332, p = 0.746). Overall, cortical ChAT levels correlated inversely with neuronal loss in the nbM (Spearman rank correlation coefficient = -0.53). The correlation between ChAT level and the combined factor of nbM LBs and neuronal loss was -0.59. A similar correlation between ChAT level and the combined factor of nbM neurofibrillary tangles and neuronal loss was -0.72. The correlation between ChAT and the combined factor of nbM LBs and neuronal loss was -0.81 when AD cases were excluded from the analysis. Local cortical pathology was not related to ChAT level. We conclude that neuronal loss and Lewy body formation in the nbM may contribute to the reduction in cortical ChAT in DLB.

Ballard C, Holmes C, McKeith I, Neill D, O'Brien J, Cairns N, Lantos P, Perry E, Ince P, Perry R. · Medical Research Council Neurochemical Pathology Unit, Newcastle General Hospital, U.K. · Am J Psychiatry. · Pubmed #10401449 links to  free full text

Abstract: OBJECTIVE: The literature reports considerable variation in the rates of psychiatric morbidity for patients with dementia with Lewy bodies. The authors intended to clarify the frequency of psychiatric morbidity in dementia with Lewy bodies and how it differs from probable Alzheimer's disease. METHOD: The study incorporated two groups--a clinical case register cohort (98 with dementia with Lewy bodies; 92 with Alzheimer's disease) and 80 (40 with dementia with Lewy bodies: 40 with Alzheimer's disease) prospectively studied, neuropathologically confirmed cases. Diagnoses were made by using the McKeith et al. consensus criteria for dementia with Lewy bodies and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for Alzheimer's disease. Neuropathological diagnoses were made by using the consensus criteria for dementia with Lewy bodies and the Mirra et al. protocol for Alzheimer's disease. RESULTS: The occurrence of psychiatric symptoms was reported over 1 month. Hallucinations, depression, delusions, and delusional misidentification were all significantly higher for patients with dementia with Lewy bodies. The differences in frequency between dementia with Lewy bodies and Alzheimer's disease for auditory and visual hallucinations were especially pronounced for patients with mild cognitive impairment. The presence of psychiatric symptoms at presentation was a better discriminator between dementia with Lewy bodies and Alzheimer's disease than occurrence over the course of dementia. CONCLUSIONS: Delusional misidentification and hallucinations in the early stages of dementia may improve differentiation between patients with dementia with Lewy bodies and those with Alzheimer's disease and have important treatment implications.