OBJECTIVE:: To investigate normalized I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) single photon emission computed tomography (SPECT) imaging, a marker for the alpha4beta2 nicotinic receptor, as a predictor of cognitive progression in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS:: Thirty-one patients with dementia (16 patients with AD and 15 patients with DLB) underwent I-5IA-85380 SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM2), which involved spatial preprocessing of scans to standard Montreal Neurological Institute space and intensity normalization of each image to its mean global brain activity. RESULTS:: Regression analysis revealed that reduced normalized I-5IA-85380 uptake in left superior, middle, and inferior frontal gyri and prepost central and anterior cingulate regions significantly correlated with decline in executive function in a pooled group comprising AD and DLB. CONCLUSION:: The findings, although preliminary, suggest that the cholinergic system may be more involved in neurodegenerative processes affecting some cognitive processes more than others, as such, this procedure may be useful for increased understanding of the pathophysiological mechanisms responsible for neurodegeneration.

OBJECTIVE: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. METHODS: We carried out whole-genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single-nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. RESULTS: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 x 10(-7)), PDXK (vitamin B6/dopamine metabolism, p = 3.27 x 10(-6)), SRGAP3 (axon guidance, p = 5.65 x 10(-6)), and TRAPPC4 (vesicle transport, p = 5.81 x 10(-6)). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 x 10(-7)(odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18-1.44). INTERPRETATION: We provide an example of how microgenomic genome-wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD.

(99m)Tc-exametazime single photon emission computed tomography (SPECT) scans of 36 patients with Alzheimer's disease (AD) and 30 with dementia with Lewy bodies (DLB) underwent region of interest (ROI) and principal component analysis (PCA). Principal component analysis was performed on the entire ROI data set. Principal components (PCs) were obtained, representing common intercorrelated regions in AD and DLB. Topographic expression that signified the extent to which a participant expressed the topographic covariance pattern was derived and used as a discriminatory variable. Principal components were identified, accounting for 77% of total data variance. Significant (PC x group) interaction was observed (P <.001). Topographic expression was significantly higher in DLB than AD (F(1,64)= 21.6, P <.001), and differentiated DLB from AD with sensitivity 73% specificity 72%. Calculating the topographic expression in an independent data set of 48 patients with AD and 23 with DLB gave sensitivity = 70%, specificity = 67%. Principal component analysis captures additional sources of variance and if perfusion SPECT is the only scan available, this procedure may offer extra information.

OBJECTIVES: Investigate the impact of the changes in eligibility within England and Wales (E&W) for prescription within the UK National Health Service for treatment of Alzheimer's disease (AD). METHODS: A population-based study in England and Wales with 13 004 individuals measured with MMSE at baseline was used to examine the distributions of individuals within eligibility criteria. Information obtained from informants enabled classification of the study defined dementia cases to ICD10 diagnosis of subtype (AD, dementia with vascular risk, both or other). RESULTS: Fifty six per cent of dementia patients (representing 323 000 individuals in E&W) fall into the new MMSE criteria band. A further 120 000, 20% of dementia patients, are estimated to have disease that is considered too mild for treatment. Further examination of type of dementia showed that those with mixed AD and vascular dementia had similar proportions of dementia cases within the treatable MMSE group as the subgroup with AD alone, though with mixed disease individuals more often score below the lower threshold. There is substantial instability in the eligibility groupings over a short time period. CONCLUSIONS: The population impact of new NICE criteria of excluding high MMSE scores is to exclude one in five individuals with AD and a further one in ten of those with a mixed disease. Changing the guidance has almost balanced the loss of treatment for the high MMSE group (13%) with the introduction of treatment for those scoring 10/11 (11%). Copyright (c) 2009 John Wiley & Sons, Ltd.

BACKGROUND: dementia risk conferred by apolipoprotein-E (APOE) and angiotensin-1-converting enzyme (ACE) polymorphisms have been reported for the MRC Cognitive Function and Ageing Study (CFAS) at 6-year follow-up. We concentrate on incident dementia risk over 10 years. METHODS: participants come from MRC CFAS, a multi-centre longitudinal population-based study of ageing in England and Wales. Three follow-up waves of data collection were used: 2, 6 and 10 years. Logistic regressions were undertaken to investigate associations between APOE (n = 955) and ACE (n = 856) alleles/genotypes and incident dementia. Two types of control groups were used: non-demented and highly functioning non-demented. Results were back-weighted. RESULTS: compared to APOE epsilon3, epsilon2 conferred protection of odds ratio (OR)= 0.3 (95% confidence interval, CI = 0.1-0.6) and epsilon4 risk of OR = 2.9 (95% CI = 1.7-4.9) for incident dementia. Compared to epsilon3/epsilon3, the epsilon3/epsilon4 and epsilon4/epsilon4 genotypes conferred risks of OR = 3.6 (95% CI = 1.8-7.3) and OR = 7.9 (95% CI = 1.6-39.2), respectively. The epsilon3/epsilon2 genotype protected against dementia (OR = 0.2, 95% CI = 0.1-0.7), and epsilon2/epsilon2 had a similar protective effect but with wide CIs (OR = 0.3, 95% CI = 0.1-1.7). Restricting the control group accentuated these differentials. The effects of ACE alleles/genotypes on incident dementia risk were small. CONCLUSIONS: APOE but not ACE is associated with late-onset incident dementia in the population. Using longer term follow-up with proper adjustment for attrition and incident cases increases estimates of risk.

BACKGROUND: Dementia drug development aims to modulate pathological processes that cause clinical syndromes. Population data (epidemiological neuropathology) will help to model and predict the potential impact of such therapies on dementia burden in older people. Presently this can only be explored through post mortem findings. We report the attributable risks (ARs) for dementia at death for common age-related degenerative and vascular pathologies, and other factors, in the MRC Cognitive Function and Ageing Study (MRC CFAS). METHODS AND FINDINGS: A multicentre, prospective, longitudinal study of older people in the UK was linked to a brain donation programme. Neuropathology of 456 consecutive brain donations assessed degenerative and vascular pathologies. Logistic regression modelling, with bootstrapping and sensitivity analyses, was used to estimate AR at death for dementia for specific pathologies and other factors. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%). CONCLUSIONS: Such AR estimates cannot be derived from the living population; rather they estimate the relative contribution of specific pathologies to dementia at death. We found that multiple pathologies determine the overall burden of dementia. The impact of therapy targeted to a specific pathology may be profound when the dementia is relatively "pure," but may be less impressive for the majority with mixed disease, and in terms of the population. These data justify a range of strategies, and combination therapies, to combat the degenerative and vascular determinants of cognitive decline and dementia. Please see later in the article for the Editors' Summary.

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is the commonest cause of dementia. Cholinesterase inhibitors, such as donepezil, are the drug class with the best evidence of efficacy, licensed for mild to moderate AD, while the glutamate antagonist memantine has been widely prescribed, often in the later stages of AD. Memantine is licensed for moderate to severe dementia in AD but is not recommended by the England and Wales National Institute for Health and Clinical Excellence. However, there is little evidence to guide clinicians as to what to prescribe as AD advances; in particular, what to do as the condition progresses from moderate to severe. Options include continuing cholinesterase inhibitors irrespective of decline, adding memantine to cholinesterase inhibitors, or prescribing memantine instead of cholinesterase inhibitors. The aim of this trial is to establish the most effective drug option for people with AD who are progressing from moderate to severe dementia despite treatment with donepezil. METHOD: DOMINO-AD is a pragmatic, 15 centre, double-blind, randomized, placebo controlled trial. Patients with AD, currently living at home, receiving donepezil 10mg daily, and with Standardized Mini-Mental State Examination (SMMSE) scores between 5 and 13 are being recruited. Each is randomized to one of four treatment options: continuation of donepezil with memantine placebo added; switch to memantine with donepezil placebo added; donepezil and memantine together; or donepezil placebo with memantine placebo. 800 participants are being recruited and treatment continues for one year. Primary outcome measures are cognition (SMMSE) and activities of daily living (Bristol Activities of Daily Living Scale). Secondary outcomes are non-cognitive dementia symptoms (Neuropsychiatric Inventory), health related quality of life (EQ-5D and DEMQOL-proxy), carer burden (General Health Questionnaire-12), cost effectiveness (using Client Service Receipt Inventory) and institutionalization. These outcomes are assessed at baseline, 6, 18, 30 and 52 weeks. All participants will be subsequently followed for 3 years by telephone interview to record institutionalization. DISCUSSION: There is considerable debate about the clinical and cost effectiveness of anti-dementia drugs. DOMINO-AD seeks to provide clear evidence on the best treatment strategies for those managing patients at a particularly important clinical transition point. Trial registration Current controlled trials ISRCTN49545035.

ABSTRACT: BACKGROUND: Functional disability, the loss of ability to carry out daily tasks unaided, is a major adverse outcome more common with increasing age. The potential contribution of neuropathological changes in subcortical areas of the brain associated with normal ageing may be a contributing factor to this loss of function. This study investigates the clinicopathological relationship between functional ability during life and pathological correlates identified at post mortem in an UK population of older people (66-102 years). The aim is to examine the clinicopathological correlates of functional disability in subcortical neuronal populations of non-demented elderly individuals. METHODS: 156 non-demented participants in the brain donation programme of the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) were included in this study. Neuropathological examination was based on the CERAD protocol; pathologies of interest were amyloid plaques, neurofibrillary tangles, Lewy bodies, vascular disease and neuronal loss. Self-reported functional ability was scored according to a combined activities of daily living and instrumental activities of daily living scale. RESULTS: Functional disability was equally common in men and women over 65 years, and in both sexes disability was more common at older ages. Neuronal loss in several subcortical regions elevated the risk of functional disability by three-fold (95% CI 1.3-6.6). There was evidence for a relationship between Lewy bodies in the SN and functional disability. CONCLUSION: Neuronal loss in subcortical regions is associated with functional disability in the older population. The causal relationships are not defined and require further investigation.

OBJECTIVE: To investigate differences in distribution of alpha4beta2 subtypes of nicotinic acetylcholine receptors (nAChRs) using the ligand (123)I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) and single photon emission computed tomography (SPECT) in subjects with vascular dementia and age-matched controls.(123)I-5IA-85380 binding was compared to corresponding regional cerebral blood flow (rCBF) changes in the same subjects. METHODS: Thirty subjects (14 vascular dementia and 16 controls) underwent (123)I-5IA-85380 and rCBF ((99m)Tc-exametazime) SPECT scanning. Image analysis was performed on voxel basis using statistical parametric mapping (SPM2). RESULTS: Compared to controls, reductions in relative (123)I-5IA-85380 uptake were identified in dorsal thalamus and right caudate in vascular dementia. Increase in scaled (123)I-5IA-85380 uptake in cuneus was also demonstrated in vascular dementia relative to controls. Perfusion deficits in anterior cingulate were apparent in the patient group and did not appear to be associated with (123)I-5IA-85380 changes. CONCLUSIONS: Reduced (123)I-5IA-85380 uptake in vascular dementia was confined to sub-cortical regions, unlike the cortical reductions previously described in Alzheimer's disease. Elevation of normalised (123)I-5IA-85380 uptake in cuneus in vascular dementia could be a compensatory response to reduced cholinergic activity in dorsal thalamus.