Nicola Archer

Glycogen synthase kinase-3 is increased in white cells early in Alzheimer's disease.

Alzheimers disease (AD) is a disorder without a molecular marker in peripheral tissues or a disease modifying treatment. As increasing evidence has suggested a role for glycogen synthase kinase-3 (GSK-3) in the pathogenesis of the condition we measured total GSK-3 protein (alpha and beta isoforms) and GSK-3 activity (serine 9 phosphorylation) in a group of healthy elderly people, in AD and in mild cognitive impairment (MCI). Total GSK-3 protein was increased in both AD and in MCI without a compensatory decrease in activity. These data suggest that GSK-3 assays might be a useful diagnostic marker in a readily available tissue and moreover that GSK-3 activity is increased in the prodromal phase of the disorder suggesting that inhibition of GSK-3 might be a useful therapeutic strategy.

Risk of developing dementia in people with diabetes and mild cognitive impairment

BACKGROUND Diabetes mellitus is associated with cognitive dysfunction, but it is not clear whether the disorder increases the risk of conversion from mild cognitive impairment to dementia. AIMS To determine the association between diabetes mellitus and dementia conversion in people with mild cognitive impairment (Petersons criteria) in a prospective community-based study. METHOD People over 65 years old were approached through primary care practices in south London, UK, and those with mild cognitive impairment (n = 103) were followed up for 4 years. Presence of diabetes was established from self-report and information from general practitioners. RESULTS Nineteen participants progressed to dementia, with the predominant diagnosis being probable or possible Alzheimers disease (in 84%). Only diabetes mellitus was associated with progression to dementia (hazard ratio 2.9, 95% CI 1.1-7.3) after adjustment for sociodemographic factors, APOE4, premorbid IQ and other health conditions. CONCLUSIONS Diabetes mellitus increases not only the risks of dementia and mild cognitive impairment but also the risk of progression from such impairment to dementia.

Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study

Consistent deficits in the cholinergic system are evident in the brains of Alzheimers Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late‐onset AD. A significant association for disease was detected for a non‐coding polymorphism in ChAT (allele χ12 = 12.84, P = 0.0003; genotype χ22 = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele χ12 = 1.02, P=0.32; genotype χ22 = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele χ12 = 12.37, P = 0.0004; genotype χ22 = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K‐variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case‐control samples.

Candidate gene association studies of the alpha 4 (CHRNA4) and beta 2 (CHRNB2) neuronal nicotinic acetylcholine receptor subunit genes in Alzheimer's disease

Consistent deficits in the cholinergic system are evident in Alzheimers disease (AD) patients, including selective loss of alpha4beta2 nicotinic acetylcholine receptors in the brains of AD patients. Knockout mice for the beta2 subunit have impaired neuronal survival in ageing. Accordingly, we have analysed polymorphisms in the genes that encode the alpha4 and beta2 subunits, CHRNA4 and CHRNB2 respectively, for genetic associations with late-onset AD. A significant association for disease was observed for a non-coding polymorphism in CHRNB2 (odds ratio=0.57, 95% confidence interval=0.35-0.95, P=0.024). Replication analysis was performed in two further sample sets. While these did not individually yield significant results, a significant association remained when all samples were pooled (odds ratio=0.70, 95% confidence interval=0.52-0.95, P=0.019). These data suggest that this variant warrants further examination in large case-control series.

Education, occupation and retirement age effects on the age of onset of Alzheimer's disease

To determine the effects of early life education, mid life employment and later life retirement age on the age of onset (AOO) of Alzheimers disease (AD).

Down syndrome with and without dementia: An in vivo proton Magnetic Resonance Spectroscopy study with implications for Alzheimer's disease

It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimers disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS-) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS-, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy (((1))H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS- (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS- and healthy controls. In contrast neither DS+ nor DS- differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS-). Our secondary aim of comparing brain metabolites in DS+ and DS- to Alzheimers disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS-. [mI] may modify risk for dementia in this vulnerable population.

Experiences of young people who have undergone the Lightning Process to treat chronic fatigue syndrome/myalgic encephalomyelitis--a qualitative study.

OBJECTIVES Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a serious condition characterized by debilitating but unexplained fatigue. Treatment alternatives are few, and especially so for young people. The aetiology of CFS/ME is still unclear and controversial, but rehabilitative interventions seem so far most promising. The Lightning Process is a 3-day training programme that has recently become available, but no outcome studies have yet been published. It is a non-medical training programme that combines concepts from Neuro-Linguistic Programming, Life Coaching and Osteopathy. The aim of this study was to explore the experiences of young people with CFS/ME after they had undergone the Lightning Process. DESIGN Qualitative research study. METHODS Semi-structured interviews were conducted with an opportunistic sample recruited through open advertisements of nine young people, aged 14-26, who had undergone the treatment, and three of their parents. Inductive thematic analysis was used to evaluate the content of the interviews. RESULTS Mostly positive experiences were reported of the Lightning Process. Two reported dissatisfaction and no improvement, while seven were satisfied and were much improved. Particular helpful aspects were the theoretical rationale, practical exercises, and the technique they learned. Less helpful aspects were the intensity and short duration of the treatment with little follow-up, the secrecy surrounding it, and feelings of being blamed if the treatment did not work. CONCLUSIONS As this is the first report of young peoples experiences with the Lightning Process, it will be important to consider the helpful and unhelpful treatment components for future refinement of interventions for CFS/ME.

The role of premorbid personality and cognitive factors in awareness of illness, memory, and behavioural functioning in Alzheimer's disease

Introduction. Research has suggested an association between personality factors and awareness in patients with dementia, yet valid measurement of premorbid personality is problematic. The present study aimed to better reveal the relationship between premorbid personality and awareness by using improved methodology. Moreover, the study aims to contrast the strength of the relationship of premorbid personality and awareness with that of cognitive factors. Methods. Awareness of illness, symptoms, mnemonic and behavioural impairments, and treatment compliance were measured in 27 patients with mild-to-moderate Alzheimers disease (AD) diagnosed by standard criteria for probable AD. Participant premorbid personality was measured using average retrospective Neuroticism-Extroversion-Openness Inventory (NEO-FFI) scores from two informants. Correlations were performed to investigate the relationship between awareness and personality dimensions, as well as measures of cognitive style, neuropsychological function, mood, carer burden, and sociodemographic factors. Results. There was little relationship between awareness and personality scores, but modest associations between awareness and mood, age, and age of onset of first symptoms. Awareness of memory was related to memory functioning. Increased carer burden was associated with lack of awareness of cognitive-behavioural deficits but there were only few and weak associations between awareness and measures of cognitive functioning. Conclusions. There was little support for an association between previous personality and awareness in dementia. However, increased carer burden was associated specifically with lack of awareness of cognitive-behavioural deficits not deficits in ADL, whereas lower awareness of ADL and not cognitive-behavioural deficits was associated with age. Awareness of memory appeared to be a metamemory capacity. Mood and age rather than personality and cognition are stronger predictors of awareness in early Alzheimers disease.

Polymorphisms in the phosphate and tensin homolog gene are not associated with late-onset Alzheimer's disease

The varepsilon4 allele of the APOE locus is the only confirmed risk factor for late-onset Alzheimers disease (LOAD). The phosphate and tensin homolog (PTEN) gene is both a biological and positional candidate gene for LOAD. Eight polymorphisms spanning this gene were selected from dbSNP and genotyped in pooled DNA samples of both cases and controls. No evidence for association with LOAD was obtained in this study although further investigation revealed low levels of linkage disequlibrium (LD) between the genotyped SNPs. Our results suggest that it is unlikely that genetic variation within the PTEN gene contributes to risk of LOAD.

P3-043: Do impairments in lexical access predict deterioration in mild cognitive impairment?

Background: Previous studies have reported that individuals with mild cognitive impairment (MCI) who show multiple cognitive deficits are at increased risk of developing Alzheimer’s disease (AD). Language function, and specifically aspects of lexical access have not been studied in detail in MCI, despite word-finding difficulties being a common complaint in individuals attending memory clinics. Objective(s): This study aims to investigate a variety of measures of lexical access in MCI and their relationship to subsequent deterioration over the following 12 months. Methods: 76 subjects with MCI (MMSE 25-27, age 80.0 5.9, education 10.84 2.20), 32 patients with mild AD (MMSE 19-29, age 79.9 5.5, education 10.72 2.73) and 38 age and education matched controls (MMSE 28-30, age 80.4 5.1, 10.68 2.45) were assessed in a crosssectional and prospective longitudinal study design using the following measures: phonemic and semantic fluency, the Boston Naming Test and a novel measurement of the Tip-of-the-tongue-experience (TOT). General cognitive function was assessed using MMSE and CERAD, while NART and WAIS Vocabulary scale were used to determine premorbid verbal intelligence and vocabulary knowledge. Results: Cross-sectionally, significant group differences were found on all measures (One-way ANOVA, p 0.001), with the AD group performing worse than the other two groups in each instance, confirming the sensitivity of the measures to the clinical condition. Relative to the controls, the MCI group was impaired on the verbal fluency tasks and the number of correct responses on the TOT test (but not on the number of tip-of-the-tongue states reported). At follow-up, the MCI group showed significant additional decline relative to controls in word finding as indexed by the number of correct responses on the BNT and TOT test, and a greater number of ‘don’t know’ responses on the BNT. Conclusions: Some aspects of language function sensitive to AD are also impaired in MCI relative to age matched controls. Over a 12-month period, further deterioration is observed in word finding, suggesting that it may be an early marker of incipient dementia in some individuals.