Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.

BACKGROUND: Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer's disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer's disease. METHODS: We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer's disease. Patients concomitantly using other medicines for Alzheimer's disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer's disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer's Disease Co-operative Study-Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11). FINDINGS: Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31-7·34]: 75 mg LMTM twice a day [n=257] -0·02, -1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] -0·43, -2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [-8·22, 95% CI -9·63 to -6·82]: 75 mg LMTM twice a day -0·93, -3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day -0·34, -2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. INTERPRETATION: The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer's disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer's disease will be reported soon. FUNDING: TauRx Therapeutics.

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aß42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

Role of depression in predicting time to conversion to mild cognitive impairment.

OBJECTIVE: To establish whether, in a cohort with normal cognition, severity of depressive symptoms at baseline was related to the time taken for conversion to mild cognitive impairment (MCI) and whether this interacted with other potential risk factors, including APOE ε4 status and demographic and cognitive variables. METHODS: In a population-based cohort study, 126 cognitively normal subjects were assessed for depressive symptoms at baseline using the Geriatric Depression Scale (GDS) and were then followed over 20 years with regular cognitive assessments. The interval-censored accelerated failure time model was used to establish whether GDS and other factors, including APOE ε4 status, predicted the median time to development of MCI. RESULTS: Fifty subjects developed MCI. In APOE ε4 noncarriers, the degree of depressive symptoms at baseline predicted the time to development of MCI: An increase in GDS of 1 standard deviation (3.85) was associated with shortening of the median time to conversion to MCI by 25.4% (p = 0.0024, z = -5.6). This relationship remained statistically significant after controlling for cognitive and other confounding variables. The relationship was not significant in APOE ε4 carriers. CONCLUSION: Depressive symptoms (measured by GDS) predict time to conversion to MCI in cognitively normal people who do not carry the APOE ε4 allele. This may explain conflicting results of previous studies where APOE ε4 status was not taken into account when exploring the relationship between depression and MCI. It may also have a clinical application in helping to identify people at greater risk of developing MCI.

Cerebral subcortical small vessel disease in subjects with pathologically confirmed Alzheimer disease: a clinicopathologic study in the Oxford Project to Investigate Memory and Ageing (OPTIMA).

The understanding of how cerebrovascular disease (CVD) contributes to dementia is hampered by a lack of agreed and validated pathologic methods to accord weight to the contribution of different aspects of CVD to dementia. A previous study from the Oxford Project to Investigate Memory and Ageing (OPTIMA) validated a scheme for assessing the contribution of subcortical small vessel disease (SVD) toward dementia in the elderly by showing a significant inverse relationship between the severity of SVD and cognition in subjects without any other dementia pathology using this method. In the present paper, the method has been used to assess severity of SVD in 161 cases of neuropathologically confirmed Alzheimer disease. The results showed there was no relationship between the SVD score and cognitive scores acquired in the last 2 years of life. SVD scores were significantly related to age (P<0.0017) and were slightly but significantly higher in females than males (P<0.049). SVD scores were not related to blood pressure at entry to OPTIMA and were significantly lower when compared with the cohort of OPTIMA cases with only CVD (mean 5.06 ± 1.85 vs. 5.9 ± 2.67; P<0.0065). We conclude that when Alzheimer disease pathology is present in elderly subjects, it overwhelms the modest contribution that SVD makes to cognitive impairment.

The development and validation of a patient-reported quality of life measure for people with mild cognitive impairment.

BACKGROUND: No validated patient-reported outcome measure (PROM) exists specifically to assess quality of life in mild cognitive impairment (MCI); we report a study conducted to develop such a measure. METHODS: Semi-structured in-depth interviews were carried out with 23 people with MCI in order to determine items for a draft questionnaire. These interviews were audio-recorded, transcribed, and content analyzed. The draft questionnaire was refined following feedback from a focus group. 280 questionnaires were posted to subjects recruited from memory clinics and research databases, the response rate was 56% i.e. 146 questionnaires were included in the final analysis. The completed questionnaires were analyzed using factor analytic techniques to produce the final measure; construct validity was assessed by correlation with a generic patient-reported outcome measure, the SF-12v2. RESULTS: Factor analysis produced a 13-item measure tapping two domains of patient-reported quality of life ("Emotional Effects" and "Practical Concerns"). Internal consistency reliability was high for both domains (α was 0.91 and 0.85 respectively). Both dimensions were highly and significantly correlated with the Mental Component Summary score of the SF-12v2 ("emotional effects" ρ = -0.43, p < 0.001 and "practical concerns" ρ = -0.56, p < 0.001). CONCLUSIONS: The Mild Cognitive Impairment Questionnaire (MCQ) is a 13-item measure developed specifically to measure patient-reported outcomes in people with MCI. It was created on the basis of patient report and has been shown to have good psychometric properties. It is likely to prove valuable in the evaluation of treatment regimes in this patient group.

Exploring the experiences of people with mild cognitive impairment and their caregivers with particular reference to healthcare - a qualitative study.

BACKGROUND: The aim of this study was to investigate the experiences of people with mild cognitive impairment (MCI; PWMCI) and their "advocates," particularly within healthcare services. METHODS: Semi-structured interviews were conducted with 23 PWMCI diagnosed ≤6 months ago and 20 advocates recruited via patients. The resulting data were content-analyzed. RESULTS: PWMCI interviewed rarely reported negative impressions of their general practitioner (GP). Reports regarding memory services were more mixed: positive impressions related to finding the service to be "well run" and the staff "pleasant," negative ones to the assessment process or a perceived lack of feedback. Aside from improved information provision, most PWMCI had no suggestions for improvements to their healthcare. However, these results should be interpreted with caution as many of the PWMCI interviewed displayed evidence of impaired recall and/or insight relating to their condition and healthcare. Advocates generally reported more negative impressions of both contact with the PWMCI's GP (most commonly reporting a "dismissive" attitude) and memory services (with common complaints relating to the assessments used in clinics and lengthy waiting times). This group generally had suggestions for improvements to services - particularly regarding information provision, changes in the assessment process, and improvements in communication by services. CONCLUSIONS: To our knowledge, this is the first in-depth study of the difficulties experienced by PWMCI and their advocates which includes the context of healthcare provision. The specific needs of these groups, as described here, as well as those of people with dementia, should be considered when designing memory clinics and other related services.

Population-based case-control study of white matter changes on brain imaging in transient ischemic attack and ischemic stroke.

BACKGROUND AND PURPOSE: White matter changes (WMC) are a common finding on brain imaging and are associated with an increased risk of ischemic stroke. They are most frequent in small vessel stroke; however, in the absence of comparisons with normal controls, it is uncertain whether WMC are also more frequent than expected in other stroke subtypes. Therefore, we compared WMC in pathogenic subtypes of ischemic stroke versus controls in a population-based study. METHODS: We evaluated the presence and severity of WMC on computed tomography and on magnetic resonance brain imaging using modified Blennow/Fazekas scale and age-related white matter changes scale, respectively, in a population-based study of patients with incident transient ischemic attack or ischemic stroke (Oxford Vascular Study) and in a study of local controls (Oxford Project to Investigate Memory and Ageing) without history of transient ischemic attack or ischemic stroke, with stratification by stroke pathogenesis (Trial of Org10172 in Acute Stroke Treatment classification). RESULTS: Among 1601 consecutive eligible patients with first-ever ischemic events, 1453 patients had computed tomography brain imaging, 562 had magnetic resonance imaging, and 414 patients had both. Compared with 313 controls (all with computed tomography and 131 with magnetic resonance imaging) and after adjustment for age, sex, diabetes mellitus, and hypertension, moderate/severe WMC (age-related white matter changes scale) were more frequent in patients with small vessel events (odds ratio, 3.51 [95% confidence interval, 2.13-5.76]; P<0.0001) but not in large artery (odds ratio, 1.03 [95% confidence interval, 0.64-1.67]), cardioembolic (odds ratio, 0.87 [95% confidence interval, 0.56-1.34]), or undetermined (odds ratio, 0.90 [95% confidence interval, 0.62-1.30]) subtypes. Results were consistent for ischemic stroke and transient ischemic attack, for other scales, and for magnetic resonance imaging and computed tomography separately. CONCLUSIONS: In contrast to small vessel ischemic events, WMC were not independently associated with other pathogenic subtypes, suggesting that WMC are unlikely to be an independent risk factor for nonsmall vessel events.

Use of whole blood for analysis of disease-associated biomarkers.

Analyses for diagnosis and monitoring of pathological conditions often rely on blood samples, partly due to relative ease of collection. However, many interfering substances largely preclude the use of whole blood itself, necessitating separation of plasma or serum. We present a feasibility study demonstrating potential use of fresh or frozen whole blood to detect soluble biomarkers using an enzyme-linked immunosorbent assay (ELISA)-based method. Good correlation between levels of soluble CD25 in plasma and whole blood of healthy individuals or Alzheimer's patients was established. These results provide a basis for development of a novel biosensor approach for disease-associated biomarker detection in whole blood.

Single-domain amnestic mild cognitive impairment identified by cluster analysis predicts Alzheimer's disease in the european prospective DESCRIPA study.

BACKGROUND/AIMS: To identify prodromal Alzheimer's disease (AD) subjects using a data-driven approach to determine cognitive profiles in mild cognitive impairment (MCI). METHODS: A total of 881 MCI subjects were recruited from 20 memory clinics and followed for up to 5 years. Outcome measures included cognitive variables, conversion to AD, and biomarkers (e.g. CSF, and MRI markers). Two hierarchical cluster analyses (HCA) were performed to identify clusters of subjects with distinct cognitive profiles. The first HCA included all subjects with complete cognitive data, whereas the second one selected subjects with very mild MCI (MMSE ≥28). ANOVAs and ANCOVAs were computed to examine whether the clusters differed with regard to conversion to AD, and to AD-specific biomarkers. RESULTS: The HCAs identified 4-cluster solutions that best reflected the sample structure. One cluster (aMCIsingle) had a significantly higher conversion rate (19%), compared to subjective cognitive impairment (SCI, p < 0.0001), and non-amnestic MCI (naMCI, p = 0.012). This cluster was the only one showing a significantly different biomarker profile (Aß42, t-tau, APOE ε4, and medial temporal atrophy), compared to SCI or naMCI. CONCLUSION: In subjects with mild MCI, the single-domain amnestic MCI profile was associated with the highest risk of conversion, even if memory impairment did not necessarily cross specific cut-off points. A cognitive profile characterized by isolated memory deficits may be sufficient to warrant applying prevention strategies in MCI, whether or not memory performance lies below specific z-scores. This is supported by our preliminary biomarker analyses. However, further analyses with bigger samples are needed to corroborate these findings.

An assessment of neurocognitive speed in relation to frailty.

OBJECTIVES: to evaluate the relationship between neurocognitive speed (NCS) and frailty; to consider how this relationship is affected by how frailty is operationalised. DESIGN: secondary analysis of the baseline cohort of the Oxford Project To Investigate Memory and Aging (OPTIMA), a longitudinal observational cohort. SUBJECTS: of 388 participants who underwent a comprehensive intake assessment followed by an annual follow-up for at least 3 years, data on all measures were available on 164 people. MEASUREMENTS: NCS was defined as a combined score of <18 on the pattern comparison test (<11 is abnormal) and letter comparison test (<7 is abnormal). Frailty was defined from a modified Phenotype model, the Edmonton Frailty Scales (EFS) and a frailty index (FI); the latter two were adapted here to exclude cognitive measures. RESULTS: in multivariate logistic (NCS as < or ≥18) and linear regression (NCS as continuous variable), only the FI (OR = 0.87) was significant (P < 0.05). When all frailty measures were included in the multivariate analysis only, FI (OR = 0.88) was significant (P < 0.05). Mini-mental Status Examination remained significantly related to NCS throughout all analysis. CONCLUSION: NCS slows with increasing frailty as shown with the FI.

Designing drug trials for Alzheimer's disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force.

An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer's disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit.

Interaction of insulin and PPAR-α genes in Alzheimer's disease: the Epistasis Project.

Altered glucose metabolism has been described in Alzheimer's disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.

Is MRI better than CT for detecting a vascular component to dementia? A systematic review and meta-analysis.

BACKGROUND: Identification of causes of dementia soon after symptom onset is important, because appropriate treatment of some causes of dementia can slow or halt its progression or enable symptomatic treatment where appropriate. The accuracy of MRI and CT, and whether MRI is superior to CT, in detecting a vascular component to dementia in autopsy confirmed and clinical cohorts of patients with VaD, combined AD and VaD ("mixed dementia"), and AD remain unclear. We conducted a systematic review and meta-analysis to investigate this question. METHODS: We searched eight databases and screened reference lists to identify studies addressing the review question. We assessed study quality using QUADAS. We estimated summary diagnostic accuracy according to imaging finding, and ratios of diagnostic odds ratios (RDORs) for MRI versus CT and high versus low risk of bias. RESULTS: We included 7 autopsy and 31 non-autopsy studies. There was little evidence that selective patient enrolment and risk of incorporation bias impacted on diagnostic accuracy (p = 0.12 to 0.95). The most widely reported imaging finding was white matter hyperintensities. For CT (11 studies) summary sensitivity and specificity were 71% (95% CI 53%-85%) and 55% (44%-66%). Corresponding figures for MRI (6 studies) were 95% (87%-98%) and 26% (12%-50%). General infarcts was the most specific imaging finding on MRI (96%; 95% CI 94%-97%) and CT (96%; 93%-98%). However, sensitivity was low for both MRI (53%; 36%-70%) and CT (52%; 22% to 80%). No imaging finding had consistently high sensitivity. Based on non-autopsy studies, MRI was more accurate than CT for six of seven imaging findings, but confidence intervals were wide. CONCLUSION: There is insufficient evidence to suggest that MRI is superior to CT with respect to identifying cerebrovascular changes in autopsy-confirmed and clinical cohorts of VaD, AD, and 'mixed dementia'.

A comparison of screening tools for the assessment of mild cognitive impairment: preliminary findings.

We report a pilot investigation into the utility of screening tools in Mild Cognitive Impairment (MCI). The Addenbrooke's Cognitive Examination-Revised (ACE-R), Montreal Cognitive Assessment (MoCA) and the novel Computer-Administered Neuropsychological Screen for Mild Cognitive Impairment (CANS-MCI) were administered to 20 elderly controls and 15 MCI cases. Non-parametric Mann-Whitney U-tests showed significant differences between groups (p < .0001) on the CANS-MCI and MoCA. The ACE-R and MoCA total scores showed high sensitivity (90%) to MCI. Area under the curve was consistently significant in discriminating controls and MCI for memory scores across all screening instruments. A useful profile of quantitative and qualitative information pertaining to cognitive functioning in MCI can be obtained with the MoCA, ACE-R, and CANS-MCI.

Living with mild cognitive impairment: the patient's and carer's experience.

BACKGROUND: Mild cognitive impairment (MCI) is a relatively common condition and rates of diagnosis are likely to increase in the near future. Little is known about the experiences of patients with MCI and their carers nor about the most appropriate interventions to support this group. METHODS: The existing literature on this topic up to July 2011 was identified via systematic searches of the Embase and Medline databases, the Cochrane Library and relevant sections of the National Electronic Library for Health. The main search term "mild cognitive impairment" was used in combination with other relevant terms. The reference lists of reviewed articles were also examined for any additional papers of significance. Papers identified by this method were examined and those deemed relevant were included in this review. RESULTS: Twenty-one suitable papers were identified for inclusion in this review, a relatively small number. The studies reviewed suggest that patients with MCI and their carers face a variety of practical and emotional challenges. No interventional studies of support have been undertaken, but the authors of relevant observational studies have suggested provision of information, psychosocial support and strategies to enhance patient interaction with carers and social contacts. CONCLUSIONS: MCI results in significant challenges for both patients and their carers. Further work is required in order to establish the best way to help patients and carers meet these challenges.

Cognitive lifestyle and long-term risk of dementia and survival after diagnosis in a multicenter population-based cohort.

An active cognitive lifestyle has been linked to dementia incidence and survival, but the separate and combined effects of its subcomponents are not clear. Data were derived from the Medical Research Council Cognitive Function and Ageing Study, a population-based study of 13,004 individuals in England and Wales first interviewed in 1991-1992 and followed over a 10-year period for dementia incidence and 12 years for mortality. A Cognitive Lifestyle Score (CLS), defined as a composite of cognitive activity including education, occupational complexity, and social engagement, was available for 12,600 individuals in 3 stages of life. A higher CLS was protective of dementia (odds ratio = 0.6, 95% confidence interval: 0.4, 0.9). Sensitivity analyses found this main effect to be reliable and replicable even when considering just 2 components of the score, either education and occupation or education and late-life social engagement. No single CLS factor was associated with dementia incidence on its own. Survival differences did not reach statistical significance. Our data suggest that more years of education, as well as further stimulatory experiences in either midlife or late life. are necessary for a protective link with dementia incidence. There was little evidence of an effect of cognitive lifestyle on survival after dementia diagnosis.

Donepezil for the treatment of agitation in Alzheimer's disease.

BACKGROUND: Agitation is a common and distressing symptom in patients with Alzheimer's disease. Cholinesterase inhibitors improve cognitive outcomes in such patients, but the benefits of these drugs for behavioral disturbances are unclear. METHODS: We randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a brief psychosocial treatment program to receive 10 mg of donepezil per day (128 patients) or placebo (131 patients) for 12 weeks. The primary outcome was a change in the score on the Cohen-Mansfield Agitation Inventory (CMAI) (on a scale of 29 to 203, with higher scores indicating more agitation) at 12 weeks. RESULTS: There was no significant difference between the effects of donepezil and those of placebo on the basis of the change in CMAI scores from baseline to 12 weeks (estimated mean difference in change [the value for donepezil minus that for placebo], -0.06; 95% confidence interval [CI], -4.35 to 4.22). Twenty-two of 108 patients (20.4%) in the placebo group and 22 of 113 (19.5%) in the donepezil group had a reduction of 30% or greater in the CMAI score (the value for donepezil minus that for placebo, -0.9 percentage point; 95% CI, -11.4 to 9.6). There were also no significant differences between the placebo and donepezil groups in scores for the Neuropsychiatric Inventory, the Neuropsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change. CONCLUSIONS: In this 12-week trial, donepezil was not more effective than placebo in treating agitation in patients with Alzheimer's disease. (ClinicalTrials.gov number, NCT00142324 [ClinicalTrials.gov].).

The dopamine ß-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.

BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine ß-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

Retrospective evaluation of revised criteria for the diagnosis of Alzheimer's disease using a cohort with post-mortem diagnosis.

OBJECTIVE: The criteria currently used to diagnose Alzheimer's disease (AD) require the presence of dementia, i.e. cognitive impairment sufficient to affect normal social and/or occupational function. Dubois et al. (Dubois et al., 2007) have recently proposed a set of revised criteria that may aid the diagnosis of the earlier stages of AD, and do not require the presence of dementia. We aimed to evaluate the new predementia-AD criteria through their retrospective application to the OPTIMA cohort with post-mortem (PM) confirmed diagnoses. METHODS: The criteria were evaluated for sensitivity and specificity using cognitive, neuroimaging and cerebrospinal fluid data and clinical information for exclusion criteria. Limitations in choice of cognitive test, use of CT scans rather than MRI and missing CSFs affected the outcomes. Analyses were carried out for the whole cohort (n = 243) and on a mild-stage subgroup (n = 99) defined by MMSE ≥ 21. RESULTS: Of the four options for fulfilling the revised-criteria, the best results for the whole cohort were achieved using memory and CSF data with exclusion criteria applied (.68 sensitivity and .93 specificity). The pattern was similar for the mild cohort, but with lower sensitivity. Specificities of 1.0 were reached with supportive criteria, CSF and CSF plus MTL. CONCLUSIONS: The revised-criteria, when applied to our cohort, offer good specificity and reasonable sensitivity when compared with the gold standard of PM diagnosis. The criteria were not more effective for early stage dementia.

A Machine Learning Approach to Identify a Circulating MicroRNA Signature for Alzheimer Disease.

BACKGROUND: Accurate diagnosis of Alzheimer disease (AD) involving less invasive molecular procedures and at reasonable cost is an unmet medical need. We identified a serum miRNA signature for AD that is less invasive than a measure in cerebrospinal fluid. METHODS: From the Oxford Project to Investigate Memory and Aging (OPTIMA) study, 96 serum samples were profiled by a multiplex (>500 analytes) microRNA (miRNA) reverse transcription quantitative PCR analysis, including 51 controls, 32 samples from patients with AD, and 13 samples from patients with mild cognitive impairment (MCI). Clinical diagnosis of a subset of AD and the controls was confirmed by postmortem (PM) histologic examination of brain tissue. In a machine learning approach, the AD and control samples were split 70:30 as the training and test cohorts. A multivariate random forest statistical analysis was applied to construct and test a miRNA signature for AD identification. In addition, the MCI participants were included in the test cohort to assess whether the signature can identify early AD patients. RESULTS: A 12-miRNA signature for AD identification was constructed in the training cohort, demonstrating 76.0% accuracy in the independent test cohort with 90.0% sensitivity and 66.7% specificity. The signature, however, was not able to identify MCI participants. With a subset of AD and control participants with PM-confirmed diagnosis status, a separate 12-miRNA signature was constructed. Although sample size was limited, the PM-confirmed signature demonstrated improved accuracy of 85.7%, largely owing to improved specificity of 80.0% with comparable sensitivity of 88.9%. CONCLUSION: Although additional and more diverse cohorts are needed for further clinical validation of the robustness, the miRNA signature appears to be a promising blood test to diagnose AD.