Evaluation of a pilot of a community virtual triage for breast symptoms outside of usual primary or secondary care pathways.

Both primary and secondary care services in the NHS have been overwhelmed with an increase in referrals on the suspected cancer pathways. The years 2020/2021 saw 551,770 symptomatic breast referrals made in England alone. The Wessex Rapid investigations service in conjunction with the local district general hospital and primary care networks instigated a virtual triage for new breast symptoms. Over the course of a year, 664 people were assessed by either telephone or video using specially trained nurses. Appointments were given within 1-2 working days. The service was highly valued by patients and general practitioners. We were unable to confirm a reduction in referral to secondary care as the evaluation occurred during a postpandemic peak in referrals. We found that 10% of patients with new breast symptoms can safely self-manage. This percentage varied with the experience of the triage clinician. A specialist community face-to-face service could reduce further the need for full secondary care evaluation. Better integration and use of information technology systems would improve the service. The rapid responsiveness and length of consultations is valued by patients. Representation with the same symptoms was rare. This pathway utilises staff outside of the usual primary and secondary care providers and thus reduces the pressure on stretched systems.

The investigation and management of unilateral nipple discharge.

INTRODUCTION: Between 16,000 and 48,000 women are estimated to present to UK breast clinics with nipple discharge each year. The incidence of malignancy in these women is 2.7-24.2%. Currently, there is no consensus on the best way to investigate and manage these women. The aim of this study was to assess the rate of malignancy in women presenting with unilateral nipple discharge, and to evaluate the role of examination, imaging and cytology in reliably predicting outcome. METHODS: Breast units were asked to prospectively collect data on all new patients with unilateral nipple discharge. Data collected included discharge colour, whether it was uniductal or multiductal, examination and imaging findings, cytology results and outcome. RESULTS: Complete datasets were submitted by 5 units on 228 patients. The incidence of malignancy was 4.4%. Clinical examination was valuable in detecting malignancy and multiductal discharge was not related to malignancy. The positive predictive value for detecting malignancy for an abnormality found on mammography was 53.5% and for ultrasonography, it was 65.2%. The role of cytology in detecting malignancy was inconclusive with positive predictive values of the presence of red blood cells and epithelial cells at 6.1% and 10.7% respectively. CONCLUSIONS: A large number of women are investigated for nipple discharge (with huge resource implications) but there is little reliable evidence on the best way to investigate and manage these patients. A larger study is needed to evaluate the role of investigations in nipple discharge to produce guidelines on optimal management.

Application of the NIA-AA Research Framework: Towards a Biological Definition of Alzheimer's Disease Using Cerebrospinal Fluid Biomarkers in the AIBL Study.

BACKGROUND: The National Institute on Aging and Alzheimer's Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer's disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer's disease. OBJECTIVES: To stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)). DESIGN: Individuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A-T-(N)-; A+T-(N)-; A+T+(N)-; A+T-(N)+; A+T+(N)+; A-T+(N)-; A-T-(N)+; A-T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers. SETTING: Two study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study. PARTICIPANTS: One-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays. INTERVENTION (if any): Not applicable. MEASUREMENTS: Three CSF biomarkers, namely amyloid ß1-42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test - Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores. RESULTS: Thirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework's definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC scores was observed with increasing abnormal biomarkers; and increased abnormal biomarkers were also associated with increased rates of decline across some cognitive measures. CONCLUSIONS: Increasing biomarker abnormality appears to be associated with worse cognitive trajectories. The implementation of biomarker classifications could help better characterize prognosis in clinical practice and identify those at-risk individuals more likely to clinically progress, for their inclusion in future therapeutic trials.

Long-term effect of oncoplastic breast-conserving surgery using latissimus dorsi miniflaps on mammographic surveillance and the detection of local recurrence.

INTRODUCTION: Latissimus dorsi miniflap is a breast-conserving volume replacement technique for the reconstruction of large breast defects. While mammographic features of miniflap reconstruction have been described, little is known about the incidence, mode of presentation and size of local recurrence after this procedure. This study aimed to investigate the impact of latissimus dorsi miniflap reconstruction on the frequency, presentation and detection of local recurrence. METHODS: Clinical, radiological and pathological data were reviewed in 261 patients. Complete records were available for 11 patients developing local recurrence, including mode, time of presentation and size of the recurrent tumours. All mammograms before and after local recurrence were assessed in relation to a range of specific characteristics including parenchymal density, flap visibility, architectural distortion, mass, calcifications, fat necrosis, skin thickening and breast oedema. RESULTS: Twenty-one patients developed local recurrence at 10.4 years following reconstruction (mean age 49 years, resection weight 182 g and tumour size 33 mm). Following radiotherapy, 0.5% of patients developed local recurrence each year, which increased five-fold when radiotherapy was omitted (HR 4.99). Local recurrences were diagnosed in five patients by mammography alone, in three by mammography and palpable lump, and in three by palpable lump alone. They were detected when small (15 mm) and were associated with new mammographic abnormalities in 10 patients. CONCLUSIONS: Long follow-up demonstrates that latissimus dorsi miniflap reconstruction allows oncologically safe breast conservation when combined with postoperative radiotherapy. Local recurrences are detected early, either by mammography, clinical examination or both, and detection is not compromised by the presence of a flap.

The impact of tamoxifen brand switch on side effects and patient compliance in hormone receptor positive breast cancer patients.

BACKGROUND: In 2006 Nolvadex was discontinued and replaced by a variety of alternative generic tamoxifen brands for the adjuvant treatment of breast cancer. Anecdotally, patients are switching brands and taking alternative medications to reduce treatment related symptoms. Nevertheless, more severe side effects may equate to better relapse prevention. This study evaluates generic tamoxifen adherence and its correlation with side effects and brand switch. METHODS: Consecutive disease free ER positive patients (stage I-III) were invited to respond to a questionnaire. 165 of 327 questionnaires were returned (50% response). Pearson's Chi Square test was used for data analysis. RESULTS: 63 patients (38%) reported a switch between generic tamoxifen. 59% of all patients experienced side effects associated with tamoxifen treatment of which 53% were severe. Patients experiencing differential symptoms dependent on tamoxifen brand reported more severe side effects (p = 0.02). Non-prescribed supplements were taken by 42% of all patients with no significant improvement in climacteric symptoms (p = 0.05). The concomitant use of SSRIs appeared to have no effect on symptoms. A significant number of patients considered discontinuing tamoxifen because of the side effects (p = 0.001), yet this did not translate into discontinuation or non-adherence (p = 0.8 and 0.08 respectively). CONCLUSION: Severe tamoxifen side effects are commonly experienced by breast cancer patients and can be significantly altered by change in tamoxifen brand. Most patients will continue to take tamoxifen, despite side effects to avoid cancer relapse. Supplementation and antidepressants did not improve tamoxifen related side effects in our cohort.

Resource implications of risk-reducing mastectomy and reconstruction.

AIM: Risk-reducing mastectomy (RRM) is on the increase, now frequently combined with breast reconstruction (BR). However, the resource implications associated with bilateral mastectomy and reconstruction are unknown. This study assessed the overall cost of performing risk-reducing surgery. METHODS: All cases of RRM and BR performed between 1991 and 2011 at this hospital were identified from a prospectively collected database. All patients undergoing bilateral mastectomy were included, when at least one mastectomy was risk-reducing. Overall treatment costs for all surgical procedures, complications, revisional procedures and outpatient attendances were calculated and compared to the National Tariff allowed. Mann-Whitney U and Fischer's exact tests were used to calculate levels of significance. RESULTS: Fifty patients underwent bilateral mastectomy and BR (median follow up 20 [range 1-106] months), 72 were Latissimus Dorsi reconstructions (LDR) and 28 were Subpectoral reconstructions (SPR). LDR took longer than SPR (p = 0.001), with a greater length of stay (p = 0.024). Nine percent of patients returned to theatre for early complications, but the type of BR did not influence the early complication rate (LDR versus SPR, p = 0.345) or the need for additional unplanned procedures (LDR versus SPR, p = 0.671). The overall mean cost for bilateral RRM and BR was £14,797 per patient. The inpatient cost for bilateral RRM and LDR was £10,082 compared with £5,905 SPR. Both procedures exceeded the £5,697 tariff allowed in the UK. CONCLUSION: Bilateral RRM and BR is a safe procedure, but the resource implications are considerable and exceed the tariff allowed, particularly when performing more complex techniques.

APOE and BDNF polymorphisms moderate amyloid ß-related cognitive decline in preclinical Alzheimer's disease.

Accumulation of ß-amyloid (Aß) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aß-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aß neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aß positron emission tomography neuroimaging was used to classify participants as Aß(-) or Aß(+). Relative to Aß(-)ɛ4(-), Aß(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aß(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aß(-)ɛ4(-) and Aß(-)ɛ4(+) groups. Among Aß(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aß-related cognitive decline. Aß(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aß(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aß(-) and Aß(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

A blood-based predictor for neocortical Aß burden in Alzheimer's disease: results from the AIBL study.

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aß (extracellular ß-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aß accumulation, therefore, providing a platform for developing a population-based screen.

Associations between gonadotropins, testosterone and ß amyloid in men at risk of Alzheimer's disease.

Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of ß amyloid (Aß) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Aß levels have focused primarily on plasma Aß(1-40) and not on the more pathogenic Aß(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Aß levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Aß(1-40) and Aß(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Aß(1-40); beta=0.208, P=0.017; Aß(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-ɛ4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-ɛ4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease.

Physical activity and amyloid-ß plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing.

Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-ß (Aß) and Aß brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aß and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aß levels were measured in fasting blood samples. A subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aß1-42/1-40 ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aß from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ε4 carriers. Lower plasma Aß1-42/1-40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.

Olfactory discrimination predicts cognitive decline among community-dwelling older adults.

The presence of olfactory dysfunction in individuals at higher risk of Alzheimer's disease has significant diagnostic and screening implications for preventive and ameliorative drug trials. Olfactory threshold, discrimination and identification can be reliably recorded in the early stages of neurodegenerative diseases. The current study has examined the ability of various olfactory functions in predicting cognitive decline in a community-dwelling sample. A group of 308 participants, aged 46-86 years old, were recruited for this study. After 3 years of follow-up, participants were divided into cognitively declined and non-declined groups based on their performance on a neuropsychological battery. Assessment of olfactory functions using the Sniffin' Sticks battery indicated that, contrary to previous findings, olfactory discrimination, but not olfactory identification, significantly predicted subsequent cognitive decline (odds ratio = 0.869; P<0.05; 95% confidence interval = 0.764-0.988). The current study findings confirm previously reported associations between olfactory and cognitive functions, and indicate that impairment in olfactory discrimination can predict future cognitive decline. These findings further our current understanding of the association between cognition and olfaction, and support olfactory assessment in screening those at higher risk of dementia.

Breast reconstruction using permanent Becker expander implants: an 18 year experience.

BACKGROUND: Single-stage reconstruction using permanent expander implants is an established technique following mastectomy. Short and long-term outcome data following breast reconstruction using Becker tissue expanders is limited. METHOD: A retrospective case note review of patients undergoing expander-based procedures between 1989 and 2007 was undertaken. Data recorded included postoperative symptoms and complications, the use of radiotherapy, revisional surgery, and device failure. RESULTS: Three hundred and thirteen expanders were used in 276 patients with a mean age of 48.3 (17-78) years, over the 18 year study period. The mean follow up period was 64.6 (1-199) months. 256 Becker expanders were used during 175 latissimus dorsi (LD) and 52 subpectoral (SP) reconstructions, 13 contralateral augmentations and 16 implant replacements. The postoperative infection rate was 5.8%, leading to an expander loss rate of 3.8%. The use of prophylactic antibiotics was associated with an increased postoperative infection rate (p = 0.046). Six haematomas (2.5%) and 12 cases of skin envelope necrosis (5.0%) required unscheduled intervention. Symptoms of pain, distortion and hardness were experienced by 21.3% of patients, and radiotherapy was associated with a significantly higher risk of adverse symptoms (p < 0.0001). No patient developed symptomatic implant rupture or silicone granuloma but 17.9% of reconstructions underwent revisional surgery, the rate being highest following SP reconstruction (p = 0.029). Nine patients developed injection port complications (3.8%), and the overall device failure rate was 1.3%. The original expander has been retained by 74.2% of women. CONCLUSION: The Becker permanent expander is a reliable implant associated with a low complication rate and a high retention rate when used during breast reconstruction.

Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging.

OBJECTIVE: There is mounting evidence for the contribution of apoE to the pathophysiology of Alzheimer disease (AD). Studies also indicate that plasma apoE levels may reflect disease status, suggesting that apoE is a potential AD biomarker. However, while some studies of apoE levels in plasma have presented correlations with AD pathology, others have not. Thus, there is a lack of consensus as to the suitability of plasma apoE as an AD biomarker. The major objective of this cross-sectional study was to investigate total plasma apoE as well as levels of the apoE4 form in a large, highly characterized cohort which included both healthy controls and participants with early-stage AD. METHODS: Total apoE and apoE4 were measured in 1,079 individuals drawn from the highly characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Total and isoform-specific plasma apoE levels were then compared with cerebral Aß load, as assessed by PET using Pittsburgh compound B (PiB). RESULTS: Total apoE and apoE4 levels were found to be significantly lower in patients with AD in the entire cohort, and decrease with Aß load in the PiB-PET subset. ApoE levels were significantly lower among ε4 homozygous individuals. In APOE ε3/ε4 heterozygote carriers, apoE4 levels decrease, indicating that apoE3 levels increase with disease. CONCLUSION: Analysis of cross-sectional data from the AIBL study indicates that plasma apoE levels are altered in AD and correlate with AD pathology level. The significance of these findings will be determined in the AIBL longitudinal study of aging.

Lack of evidence to support the association of polymorphisms within the alpha- and beta-secretase genes (ADAM10/BACE1) with Alzheimer's disease.

Cleavage of the amyloid precursor protein (APP) occurs through either an amyloidogenic or a non-amyloidogenic pathway. The first results in the generation of beta-amyloid (Aß) and is initiated through cleavage by the beta-site amyloid beta A4 precursor protein-cleaving enzyme 1 (BACE1). The second precludes the formation of Aß through cleavage by alpha-secretase, an enzyme's activity demonstrated in a disintegrin metalloproteinase, ADAM10. To assess the contribution of variants in the BACE1 and ADAM10 genes we used a detailed fine mapping approach. Genotyping of 11 single nucleotide polymorphisms covering the complete BACE1 gene, and 27 covering the entire ADAM10 gene, revealed no single-marker or haplotypic association with AD. We conclude that, in this present study, neither ADAM10 nor BACE1 present with any evidence to suggest that they are major candidate genes involved in conferring risk for AD.

No association of Tachykinin receptor 2 (TACR2) polymorphisms with Alzheimer's disease.

The Tachykinin Receptor 2 (TACR2) located at chromosome 10q21.3 belongs to a class of receptors that bind members of the tachykinin neurotransmitter family. The TACR2 binds neurokinin A, also known as substance K, and is expressed in distinct parts of the human brain. Functionally, the TACR2 has been implicated in stress induced hippocampal acetylcholine release and the gene TACR2 is located within a previously identified linkage region for Alzheimer's disease (AD) on chromosome 10q21. Together, both facts make the TACR2 a reasonable positional and functional candidate gene for AD. Genotyping of 13 single nucleotide polymorphisms (SNPs) covering the entire gene and haplotypic analysis revealed no association with AD. Thus, we conclude that TACR2 can be excluded as a major susceptibility gene conferring risk to AD.

Examination of the current top candidate genes for AD in a genome-wide association study.

With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the 'Top Results' list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case-control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.

No association of lipase C polymorphisms with Alzheimer's disease.

Hepatic lipase, also known as hepatic triglyceride lipase (LIPC), much like the major genetic risk factor for Alzheimer's disease (AD), apolipoprotein E (APOE), is associated with altered lipid metabolism. As such this link makes LIPC a potential functional candidate for AD risk. Previously, three single nucleotide polymorphisms (SNPs) have been investigated in AD with a lack of association reported. To rule out a possible contribution of other variants in LIPC, located at 15q21-q23, we used a detailed fine mapping approach in a German case-control sample. Genotyping of 25 single nucleotide polymorphisms covering the complete LIPC gene and haplotypic analysis revealed no association with AD. Thus, we conclude that LIPC can be excluded as a major functional candidate gene conferring risk to AD.

Novel phage peptides attenuate beta amyloid-42 catalysed hydrogen peroxide production and associated neurotoxicity.

Amyloid-beta (Abeta) peptides play a central role in the pathogenesis of Alzheimer's disease. There is accumulating evidence that supports the notion that the toxicity associated with human Abeta (both 40 and 42) is dependent on its superoxide dismutase (SOD)-like activity. We developed a novel screening method involving phage display technology to identify novel peptides capable of inhibiting Abeta's neurotoxicity. Two random peptide libraries containing 6-mer and 15-mer peptide inserts were used and resulted in the identification of 25 peptides that bound human Abeta (40 or 42). Here, we show that two of the three most enriched peptides obtained significantly reduced Abeta42's SOD-like activity. A 15-mer peptide reduced Abeta42 neurotoxicity in a dose-dependent manner as evidenced by a reduction in LDH release. These findings were confirmed in the independent MTT assay. Furthermore, comparative analysis of the 15-mer peptide with Clioquinol, a known inhibitor of Abeta's metal-mediated redox activity, showed the 15-mer peptide to be equipotent to this metal chelator, under the same experimental conditions. These agents represent novel peptides that selectively target and neutralise Abeta-induced neurotoxicity and thus provide promising leads for rational drug development.