Alzheimer Disease: Perry R

Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T. · Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle-upon-Tyne NE4 6BE, UK. · J Neurol Sci. · Pubmed #15537525 No free full text.

Abstract: Cerebrovascular disease is highly heterogeneous but can culminate in vascular cognitive impairment or vascular dementia (VaD). As much as the clinical diagnosis warrants scrutiny, the neuropathological substrates of VaD also need to be better defined. Atherosclerosis and small vessel disease are the main causes of brain infarction. Lacunar infarcts or multiple microinfarcts in the basal ganglia, thalamus, brainstem and white matter are associated with more than half of VaD cases consistent with subcortical ischaemic VaD. White matter changes including regions of incomplete infarction are usually widespread in VaD, but their contribution to impairment is not explicit. Other pathologies including hippocampal injury and Alzheimer type of lesions may also modify the course of dementia. Similar to other common dementias consensus criteria for VaD need unambiguous definition to impact on preventative and treatment strategies and are critical for selective recruitment to clinical trials.

McKeith IG, Burn DJ, Ballard CG, Collerton D, Jaros E, Morris CM, McLaren A, Perry EK, Perry R, Piggott MA, O'Brien JT. · Institute for Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Newcastle, UK. · Semin Clin Neuropsychiatry. · Pubmed #12567332 No free full text.

Abstract: The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.

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.

Ballard C, McKeith I, O'Brien J, Kalaria R, Jaros E, Ince P, Perry R. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, UK. · Dement Geriatr Cogn Disord. · Pubmed #10705161 No free full text.

Abstract: The neuropathological substrates of dementia and depression were evaluated in 30 patients with cerebrovascular disease and significant cognitive impairment (VaD), with a particular focus on patients with small infarct volumes (<15 ml). VaD patients with small infarct volumes had a similar degree of cognitive impairment to those with larger infarct volumes (>15 ml) but were significantly more likely to be depressed and to have areas of microinfarction. A review of individual cases with small infarct volumes suggested that the combination of microinfarction, diffuse white matter disease and perivascular changes, or the overlap of neurodegenerative pathologies and microvascular changes were particularly important. Microinfarction was also significantly associated with major depression.

Mukaetova-Ladinska EB, Milne J, Andras A, Abdel-All Z, Cerejeira J, Greally E, Robson J, Jaros E, Perry R, McKeith IG, Brayne C, Xuereb J, Cleghorn A, Doherty J, McIntosh G, Milton I. · Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #18577885 No free full text.

Abstract: BACKGROUND: Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease alpha-synuclein is incorporated within Lewy bodies and alpha-, beta- and gamma-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF. METHODS: A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify alpha- and gamma-synucleins and IgG. RESULTS: We describe for the first time the presence of gamma-synuclein in CSF. There is an elevation of both alpha- and gamma-synucleins in CSF from elderly individuals with Alzheimer's disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. gamma-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of alpha- and gamma-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay. CONCLUSIONS: The reported increases in alpha- and gamma-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.

Walker Z, Jaros E, Walker RW, Lee L, Costa DC, Livingston G, Ince PG, Perry R, McKeith I, Katona CL. · University College London and Royal Free Hospitals, London, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #17353255 links to  free full text

Abstract: BACKGROUND: Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone. METHODS: A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls. RESULTS: Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP-CIT scan for the diagnosis of DLB was 88% and specificity was 100%. CONCLUSION: FP-CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.

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.

Lewis H, Beher D, Cookson N, Oakley A, Piggott M, Morris CM, Jaros E, Perry R, Ince P, Kenny RA, Ballard CG, Shearman MS, Kalaria RN. · Department of Molecular & Cellular Neuroscience, Merck, Sharp & Dohme Research Laboratories, Terlings Park, Essex. · Neuropathol Appl Neurobiol. · Pubmed #16599940 No free full text.

Abstract: Clinicopathological observations suggest there is considerable overlap between vascular dementia (VaD) and Alzheimer's disease (AD). We used immunochemical methods to compare quantities of amyloid-beta (Abeta) peptides in post mortem brain samples from VaD, AD subjects and nondemented ageing controls. Total Abeta peptides extracted from temporal and frontal cortices were quantified using a previously characterized sensitive homogenous time-resolved fluorescence (HTRF) assay. The HTRF assays and immunocapture mass spectrometric analyses revealed that the Abeta(42) species were by far the predominant form of extractable peptide compared with Abeta(40) peptide in VaD brains. The strong signal intensity for the peak representing Abeta(4-42) peptide confirmed that these N-terminally truncated species are relatively abundant. Absolute quantification by HTRF assay showed that the mean amount of total Abeta(42) recovered from VaD samples was approximately 50% of that in AD, and twice that in the age-matched controls. Linear correlation analysis further revealed an increased accumulation with age of both Abeta peptides in brains of VaD subjects and controls. Interestingly, VaD patients surviving beyond 80 years of age exhibited comparable Abeta(42) concentrations with those in AD in the temporal cortex. Our findings suggest that brain Abeta accumulates increasingly with age in VaD subjects more so than in elderly without cerebrovascular disease and support the notion that they acquire Alzheimer-like pathology in older age.

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.

Court JA, Johnson M, Religa D, Keverne J, Kalaria R, Jaros E, McKeith IG, Perry R, Naslund J, Perry EK. · MRC Building, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK. · Neuropathol Appl Neurobiol. · Pubmed #16150123 No free full text.

Abstract: Investigating correlates of tobacco smoking provides the only currently available opportunity of examining effects of long-term exposure of nicotinic receptors on a specific nicotinic agonist in human. Alzheimer-type pathology (Abeta and abnormally phosphorylated tau assessed on the basis of AT8 immunoreactivity) together with vascular markers has been compared in age-matched groups of normal elderly smokers and non-smokers in the entorhinal cortex, an area of noted age-related pathology. The density of total Abeta and diffuse Abeta immunoreactivity, together with formic acid-extractable Abeta42 but not Abeta40, was reduced in smokers (n = 10-18) compared with non-smokers (n = 10-20) (P < 0.05). There was also a reduced percentage of cortical and leptomeningeal vessels with associated Abeta immunoreactivity in smokers (n = 13) compared with non-smokers (n = 14) (P < 0.005 and 0.05, respectively). There was a significant inverse correlation between formic acid-extractable Abeta42 and pack years (n = 34, r = -0.389, P = 0.025), with a similar trend for total Abeta immunoreactivity which did not reach statistical significance (n = 30, r = -0.323, P = 0.082). In contrast, there were no significant group differences for vascular markers (collagen IV, alpha-actin or glucose transporter 1), AT8 immunoreactivity or phosphate-buffered saline-soluble Abeta peptides, and no significant associations with gender for any of the measured parameters. These findings are consistent with previously reported reductions in histologically assessed amyloid plaques in aged human brain associated with tobacco use and dramatic lessening of Abeta deposits in APPsw mice after nicotine treatment. Development of nicotinic drugs to protect against beta-amyloidosis as one of the principal pathological hallmarks of brain ageing and Alzheimer's disease is indicated.

Aarsland D, Perry R, Larsen JP, McKeith IG, O'Brien JT, Perry EK, Burn D, Ballard CG. · Section of Geriatric Psychiatry, Central Hospital, Rogaland, Stavanger, Norway. · J Clin Psychiatry. · Pubmed #15889951 No free full text.

Abstract: BACKGROUND: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD). METHOD: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003. RESULTS: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p = .006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies). CONCLUSIONS: An operationalized evaluation of severe NSR blind to diagnosis confirmed the high prevalence in DLB and identified high frequencies in Parkinson's disease and PDD with important implications for clinical practice.

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.

Aarsland D, Andersen K, Larsen JP, Perry R, Wentzel-Larsen T, Lolk A, Kragh-Sørensen P. · Section of Geriatric Psychiatry, Central Hospital of Rogaland, Stavanger, N-4095 Hillevåg, Norway. · Arch Neurol. · Pubmed #15596611 links to  free full text

Abstract: OBJECTIVES: To measure the rate and predictors of change on the Mini-Mental State Examination in patients with Parkinson disease (PD) and to compare that change with the Mini-Mental State Examination changes of patients with Alzheimer disease and nondemented subjects. PATIENTS: Patients with PD were drawn from a community-based cohort in Rogaland County, Norway. Those who were without cognitive impairment at disease onset and participated in 1 or more assessments after visit 1 were included and examined after 4 years (visit 2) and 8 years (visit 3). Motor, cognitive, and psychiatric symptoms were rated using standardized scales at visit 1. Two population-based cohorts of patients with Alzheimer disease and nondemented control subjects were included for comparison. Data were analyzed using a mixed-effects model. RESULTS: One hundred twenty-nine PD patients (57% women) were included. The mean (SD) Mini-Mental State Examination score at visit 1 was 27.3 (5.7). The mean annual decline in score from visit 1 to visit 3 was 1.1 (95% confidence interval, 0.8 to 1.3; 3.9% change from visit 1). Patients with PD and dementia (n = 49) had an annual decline from visit 1 to visit 2 of 2.3 (95% confidence interval, 2.1 to 2.5; 9.1% change from visit 1), compared with 2.6 (95% confidence interval, 2.3 to 2.8; 10.6% change from visit 1) in the patients with Alzheimer disease (n = 34) (mean annual decline among patients with PD and dementia vs patients with Alzheimer disease, not significant). The change in score for nondemented PD patients (n = 80) was small and similar to that for nondemented control subjects (n = 1621). Old age, hallucinations, and more severe motor symptoms (rigidity and motor scores mediated by nondopaminergic lesions) at visit 1 were significantly associated with a more rapid cognitive decline in patients with PD. CONCLUSIONS: The mean annual decline on the Mini-Mental State Examination for PD patients was 1 point. However, a marked variation was found. In patients with PD and dementia, the mean annual decline was 2.3, which was similar to the decline observed in patients with Alzheimer disease.

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.

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.

O'Brien J, Thomas A, Ballard C, Brown A, Ferrier N, Jaros E, Perry R. · Newcastle General Hospital, Wolfson Research Centre, Institute for the Health of the Elderly, Westgate Road, University of Newcastle upon Tyne, Newcastle upon Tyne NE4 6BE, UK. · Biol Psychiatry. · Pubmed #11164759 No free full text.

Abstract: BACKGROUND: Cognitive impairment is common in depression, but underlying mechanisms remain unknown. We examined whether increases in Alzheimer-type or vascular pathology are associated with cognitive impairments in elderly depressed subjects. METHODS: Eleven subjects who had died during a well-documented episode of DSM-IV major depression were included. Neuropathologic assessments, blind to group membership, included standardized assessment of neuritic plaques, neurofibrillary tangles, and Lewy Bodies in frontal, temporal, parietal, and occipital cortices. Braak staging of Alzheimer pathology was also performed. Cerebral microvascular disease was scored according to a previously validated scale, and a score for cerebral and systemic atheroma of large and medium sized arteries was obtained. RESULTS: No subject had Lewy bodies. Plaque and tangle counts for all subjects were well within published norms for age-matched control subjects. There were no significant differences in plaque or tangle counts between subjects who were cognitively impaired (n = 5) and those who were nonimpaired (n = 6) during their depressive illness. Similarly, neither total microvascular pathology nor deep frontal microvascular pathology differed between the two groups. CONCLUSIONS: Our results indicate that the liability for some patients to develop cognitive impairment during a depressive episode is not related to an increase in Alzheimer-type or vascular neuropathologic change. This indicates that other mechanisms must underlie both the cognitive impairment associated with depression and the observation that depression is a risk factor for dementia.

Ballard C, O'Brien J, Swann A, Neill D, Lantos P, Holmes C, Burn D, Ince P, Perry R, McKeith I. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #10867448 No free full text.

Abstract: The progression of parkinsonism over 1 year was evaluated in a prospective cohort of patients (n = 338), suffering from dementia with Lewy bodies (DLB), Alzheimer's disease (AD) or vascular dementia (VaD). Parkinsonism was assessed using the modified Unified Parkinson's Disease Rating Scale. Significant parkinsonism was significantly commoner in DLB sufferers (71%) than amongst patients with AD (7%) or VaD (10%). DLB patients with established parkinsonism had an annual increase in severity of 9%, but progression was more rapid (49% in 1 year) in patients with early parkinsonism. Parkinsonism was frequent at all severities in DLB patients, but usually only present in other dementias when MMSE <10.

Ballard C, Neill D, O'Brien J, McKeith IG, Ince P, Perry R. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, NE4 6BE, Newcastle upon Tyne, UK. · J Affect Disord. · Pubmed #10837878 No free full text.

Abstract: BACKGROUND: Little is known about psychiatric symptoms in Vascular dementia (VaD). METHOD: 92 patients with VaD, and 92 patients with Alzheimer's disease (AD) are reported. The evaluation included standardised measures of mood and psychosis. RESULTS: 72% of VaD patients and 38% of those with AD had two or more anxiety symptoms. VaD patients with severe dementia (94%) were the most likely to be anxious. Depression was also significantly more common in VaD patients (19% vs. 8%) whereas psychotic symptoms were prevalent in both dementias. CONCLUSION: Psychiatric symptoms are common in VaD, especially in patients with moderate or severe dementia. Rigorous assessment of psychiatric symptoms in VaD should be part of good clinical practice.

O'Brien J, Perry R, Barber R, Gholkar A, Thomas A. · Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. j.t.o' · Ann N Y Acad Sci. · Pubmed #10818542 No free full text.

Abstract: A number of studies have suggested that cerebral changes, particularly deep white matter lesions (WML) visualized on magnetic resonance imaging (MRI), may be involved in the genesis of late life depression. This has been confirmed in a prospective study which also found a relationship between the presence of WML and poor 3-year outcome in elderly depressed subjects. Most studies find these lesions to predominate in frontal lobe and basal ganglia, supporting the hypothesis of "fronto-striatal" dysfunction in depression. To investigate whether WML are associated with mood disturbance in dementia, proton density and T2-weighted images were obtained in 80 subjects with dementia (dementia with Lewy bodies, n = 27; Alzheimer's disease, n = 28; vascular dementia, n = 25) and 26 age-matched normal controls. Periventricular lesions (PVL), white matter lesions (WML), and basal ganglia hyperintensities (BG) were visually rated blind to diagnosis using a semiquantitative scale. Frontal WML were associated with higher depression scores in patients with dementia, implying a common pathophysiology of depression irrespective of diagnosis. Further study of the neurobiological basis of WML is needed. This can best be achieved by serial clinical assessment combined with in vivo and in vitro MRI and neuropathological examination.

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.

Neill D, Curran MD, Middleton D, Mawhinney H, Edwardson JA, McKeith I, Ballard C, Morris C, Ince P, Jaros E, Perry R. · Institute For The Health Of The Elderly, Newcastle General Hospital, Newcastle Upon Tyne, UK. · Neurosci Lett. · Pubmed #10568518 No free full text.

Abstract: The allele frequency of the HLA-DRB1 gene was compared between groups of 48 clinically diagnosed elderly Alzheimer's disease (AD) cases and 44 pathologically confirmed elderly control cases. Specific primers were used to PCR amplify the highly polymorphic second exon of HLA-DRB1 using DNA extracted from blood samples or frozen brain tissue. The allele type was identified using sequence specific oligonucleotide probes. The results showed an increased frequency of DRB1*03 (P < 0.006) and decreased frequency of DRB1*09 (P < 0.049) in the AD cases compared with the controls. The results suggest that DRB1*03 is associated with an increased risk and DRB1*09 a possible decreased risk for the development of late-onset AD with first detectable clinical symptoms occurring at age 75 years or greater.

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.

Barber R, Scheltens P, Gholkar A, Ballard C, McKeith I, Ince P, Perry R, O'Brien J. · Institute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #10369824 links to  free full text

Abstract: OBJECTIVES: Alzheimer's disease and vascular dementia are associated with an increase in changes in white matter on MRI. The aims were to investigate whether white matter changes also occur in dementia with Lewy bodies and to examine the relation between white matter lesions and the cognitive and non-cognitive features of dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. METHODS: Proton density and T2 weighted images were obtained on a 1.0 Tesla MRI scanner in patients with dementia with Lewy bodies (consensus criteria; n=27, mean age=75.9 years), Alzheimer's disease (NINCDS/ADRDA; n=28, mean age=77.4 years), vascular dementia (NINDS/AIREN; n=25, mean age=76.8 years), and normal controls (n=26, mean age=76.2 years). Cognitive function, depressive symptoms, and psychotic features were assessed using a standardised protocol. Periventricular hyperintensities (PVHs), white matter hyperintensities (WMHs) and basal ganglia hyperintensities (BGHs) were visually rated blind to diagnosis using a semiquantitative scale. RESULTS: Periventricular hyperintensities were positively correlated with age and were more severe in all dementia groups than controls. Total deep hyperintensities scores (WMHs plus BGHs) were significantly higher in all dementia groups than controls and higher in patients with vascular dementia than those with dementia with Lewy bodies or Alzheimer's disease. In all patients with dementia, frontal WMHs were associated with higher depression scores and occipital WMHs were associated with an absence of visual hallucinations and delusions. CONCLUSION: In common with Alzheimer's disease and vascular dementia, PVHs and WMHs were significantly more extensive in dementia with Lewy bodies than in controls. This overlap between different dementias may reflect shared pathological mechanisms. The link between frontal WMHs and depression and the absence of occipital WMHs and psychotic symptoms has important implications for understanding the neurobiological basis of these symptoms.

Middleton D, Mawhinney H, Curran MD, Edwardson JA, Perry R, McKeith I, Morris C, Ince PG, Neill D. · Northern Ireland Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, UK. · Neurosci Lett. · Pubmed #10203251 No free full text.

Abstract: The frequency of various allele types of the class I Major Histocompatibility Complex (MHC) genes HLA-A and HLA-B were compared between pathologically confirmed groups of late and early-onset Alzheimer's disease (AD) and a control group. DNA was extracted from frozen brain tissue and the highly polymorphic second and third exons of the HLA-A and HLA-B genes were independently PCR amplified using specific primers. Individual allele types were identified using sequence-specific oligonucleotide probes. The results showed that the main frequency differences occurred between the late-onset AD and the control group however none of these reached statistical significance.