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Background: Previous research has identified a small subgroup of older adults that maintain a high level of cognitive functioning well into advanced age. Investigation of those with superior cognitive performance (SCP) for their age is important, as age-related decline has previously been thought to be inevitable. Objective: Preservation of cortical thickness and volume was evaluated in 76 older adults with SCP and 100 typical older adults (TOAs) assessed up to five times over six years. Methods: Regions of interest (ROIs) found to have been associated with super-aging status (a construct similar to SCP status) in previous literature were investigated, followed by a discovery phase analyses of additional regions. SCPs were aged 70 + at baseline, scoring at/above normative memory (CVLT-II) levels for demographically similar individuals aged 30–44 years old, and in the unimpaired range for all other cognitive domains over the course of the study. Results: In linear mixed models, following adjustment for multiple comparisons, there were no significant differences between rates of thinning or volume atrophy between SCPs and TOAs in previously identified ROIs, or the discovery phase analyses. With only amyloid-β negative individuals in the analyses, again there were no significant differences between SCPs and TOAs. Conclusion: The increased methodological rigor in classifying groups, together with the influence of cognitive reserve, are discussed as potential factors accounting for our findings as compared to the extant literature on those with superior cognitive performance for their age.

Background CSF biomarkers are well-established for routine clinical use, yet a paucity of comparative assessment exists regarding CSF extraction methods during lumbar puncture. Here, we compare in detail biomarker profiles in CSF extracted using either gravity drip or aspiration. Methods Biomarkers for β-amyloidopathy (Aβ1–42, Aβ1–40), tauopathy (total tau), or synapse pathology (BACE1, Neurogranin Trunc-p75, α-synuclein) were assessed between gravity or aspiration extraction methods in a sub-population of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study (cognitively normal, N = 36; mild cognitive impairment, N = 8; Alzheimer’s disease, N = 6). Results High biomarker concordance between extraction methods was seen (concordance correlation > 0.85). Passing Bablock regression defined low beta coefficients indicating high scalability. Conclusions Levels of these commonly assessed CSF biomarkers are not influenced by extraction method. Results of this study should be incorporated into new consensus guidelines for CSF collection, storage, and analysis of biomarkers.

BackgroundPhysical inactivity has been consistently linked to increased risk of cognitive decline; however, studies examining the impact of exercise interventions on cognition have produced inconsistent findings. Some observational studies suggest exercise intensity may be important for inducing cognitive improvements; however, this has yet to be thoroughly examined in older adult cohorts. The objective of the current study was to evaluate the effect of systematically manipulated high-intensity and moderate-intensity exercise interventions on cognition.MethodsThis multi-arm pilot randomised clinical trial investigated the effects of 6 months of high-intensity exercise and moderate-intensity exercise, compared with an inactive control, on cognition. Outcome measures were assessed at pre- (baseline), post- (6 months), and 12 months post-intervention. Ninety-nine cognitively normal men and women (aged 60–80 years) were enrolled from October 2016 to November 2017. Participants that were allocated to an exercise group (i.e. high-intensity or moderate-intensity) engaged in cycle-based exercise two times per week for 6 months. Cognition was assessed using a comprehensive neuropsychological test battery. Cardiorespiratory fitness was evaluated by a graded exercise test.ResultsThere was a dose-dependent effect of exercise intensity on cardiorespiratory fitness, whereby the high-intensity group experienced greater increases in fitness than the moderate-intensity and control groups. However, there was no direct effect of exercise on cognition.ConclusionsWe did not observe a direct effect of exercise on cognition. Future work in this field should be appropriately designed and powered to examine factors that may contribute to individual variability in response to intervention.Trial registrationThis study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000643370). Registered on 3 May 2017—retrospectively registered.https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372780

Background: Using immunoprecipitation-mass spectrometry, we recently developed and validated a plasma composite biomarker for the assessment of amyloid-β (Aβ) levels. However, as yet, its relationship with clinical outcomes remains unclear. Objective: We aimed to examine the relationship between this plasma Aβ composite biomarker and cognitive function in cognitively normal older adults in two independent cohorts. Methods: Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and the National Centre for Geriatrics and Gerontology (NCGG) study had undergone Aβ neuroimaging using positron emission tomography (PET), cognitive assessments and provided blood samples. We derived a high-performance plasma Aβ composite biomarker by immunoprecipitation with mass-spectrometry. Results: Both continuous and categorical measures of the plasma Aβ composite biomarker were significantly related to decline in episodic memory and executive function. The magnitude of effects of the plasma Aβ composite on episodic memory and executive function were comparable to that observed for the effects of PET Aβ levels on these same outcome measures. Conclusion: Several plasma Aβ biomarkers have been developed, but none have yet been applied to investigate their relationship with cognitive outcomes. Our results have important implications for the use of this biomarker in the detection of at-risk individuals.

ObjectiveTo explore whether the plasma total β-amyloid (Aβ) Aβ42/Aβ40ratio is a reliable predictor of the amyloid-PET status by exploring the association between these 2 variables in a subset of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging cohort.MethodsTaking plasma samples at 3 separate time points, month 18 (n = 176), month 36 (n = 169), and month 54 (n = 135), we assessed the total Aβ42/Aβ40ratio in plasma (TP42/40) with regard to neocortical Aβ burden via PET standardized uptake value ratio (SUVR) and investigated both association with Aβ-PET status and correlation (and agreement) with SUVR.ResultsThe TP42/40 plasma ratio was significantly reduced in amyloid-PET–positive participants at all time points (p< 0.0001). Adjusting for covariates age, gender,APOEε4 allele status, and clinical classification clearly affects the significance, withpvalues reduced and only comparisons at 54 months retaining significance (p= 0.006). Correlations with SUVR were similar across each time point, with Spearman ρ reaching −0.64 (p< 0.0001). Area under the curve values were highly reproducible over time points, with values ranging from 0.880 at 36 months to 0.913 at 54 months. In assessments of the healthy control group only, the same relationships were found.ConclusionsThe current study demonstrates reproducibility of the plasma assay to discriminate between amyloid-PET positive and negative over 3 time points, which can help to substantially reducing the screening rate of failure for clinical trials targeting preclinical or prodromal disease.Classification of evidenceThis study provides Class II evidence that plasma total Aβ42/Aβ40ratio is associated with neocortical amyloid burden as measured by PET SUVR.

Background Delays in Crohn's disease (CD) diagnosis are positively associated with ileal location and an increased risk of complications. Aim To develop a simple risk assessment tool to enable primary care physicians to recognise potential ileal CD earlier, shortening the delay to specialist investigation METHODS: Three cohorts were acquired for this study. Cohort 1 included 61 patients retrospectively identified with ileal CD between 2000 and 2010 and 78 matched controls drawn from a cohort referred for investigation of abdominal symptoms. Cohort 2 included 42 individuals diagnosed with ileal CD and 57 controls identified prospectively. Cohort 3 included an additional 84 individuals with ileal CD and 495 without CD referred for colonoscopy. Clinical symptoms and serological biomarkers were acquired and used to develop a risk prediction algorithm. The algorithm was trained independently on each of the three cohorts and tested on the latter two cohorts. Results Altered bowel habit with abdominal pain combined with derangements in white cell count (WCC), albumin and platelet counts were important features in predicting ileal CD (AUC = 0.92, 95% CI = 0.89-0.92). This was validated in cohorts 2 (AUC = 0.96, 95% CI = 0.95-0.98) and 3 (AUC = 0.94, 95% CI = 0.92-0.96). C-reactive protein was independently associated with ileal CD but non-signficant in a multivariate model. Conclusion A web-based risk stratification tool for ileal CD has been developed from objective and symptom-based criteria. This tool enables primary care physicians to more confidently request urgent specialist assessment for patients identified as at high risk for ileal CD.

Ulcerative colitis (UC) is a major form of inflammatory bowel disease with increasing global incidence. There is significant phenotypic heterogeneity defined by a range of clinical variables including age of onset and disease extent. Clinical outcomes range from long-term remission on minimal therapy to surgical resection. Close to 70% of UC risk can be attributed to genetics and understanding the genetic mechanisms contributing to this risk and disease heterogeneity is vital for understanding disease pathogenesis and improving patient outcomes through targeted screening and therapies. This study aims to characterise the genetic heterogeneity of UC by identifying genomic risk variants specific to mild and/or severe forms of UC, exploring variations in the effect size of known risk variants and assessing the clinical value of a genetic risk score (GRS). We conducted genome-wide association (GWA) analyses in 287 patients with mild UC, 311 patients with severe UC and 583 age- and gender-matched controls. Odds ratios (OR) for mild vs control, severe vs control and combined mild and severe UC vs control were calculated. Using the combined UC data, two independent loci in the HLA region reached genome-wide significance. An additional genome-wide significant signal on chromosome 1 was identified in severe cases only. OR for known risk loci varied between mild and severe patients and were similar to previously published results. Effect estimates from the most recent UC GWA meta-analysis were used to calculate a GRS for each individual. A higher mean GRS was observed in both mild and severe UC cases compared to controls however, there was no difference between the mean GRS for mild and severe UC. Heterogeneity in effect sizes of UC associated variants between mild and severe disease burden suggests the presence of genetically distinct signatures. While large consortium data are needed to identify genome-wide significant variants, additional risk loci may be identified by targeted recruitment of individuals with a history of severe disease.Author SummaryUlcerative colitis (UC) is a chronic and often debilitating form of inflammatory bowel disease affecting approximately 0.3% of the population in industrialized economies. The disease displays significant clinical heterogeneity including age at presentation, disease severity, and the propensity to develop disease-related complications. Several previous studies have demonstrated the heritability of UC, identifying over 30 loci specific to the disease. The majority of these loci have small to modest effect sizes other than those within the Human Leucocyte Antigen (HLA) region on chromosome 6. Using stringent clinical criteria for defining mild and severe forms of UC in an extremes of phenotype approach, we undertook a genome wide association study in a dataset of 1222 participants to investigate genetic heterogeneity in this disease. We demonstrated substantial differences in genetic associations in severe UC as compared to mild UC. While over 2,000 SNPs achieved genome-wide significance in the severe UC analysis, none reached significance for mild UC. These results were reflected in significant differences in odds ratios. We identified Complement Factor B (CFB) as a potential susceptibility gene for severe UC in the Caucasian population with additional tissue gene expression demonstrating a positive correlation with disease severity.

BackgroundOngoing research seeks to identify blood-based biomarkers able to predict the onset and progression of Alzheimer’s disease (AD). A potential biomarker is the unfolded conformational variant of p53, previously observed in individuals in the prodromal and clinical AD stages. In this retrospective study, we compare diagnostic and prognostic performances of measures of the amyloid β load with those of a conformational variant of U-p53 in plasma samples from individuals participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) cohort.MethodsImmunoprecipitation (IP) followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing in plasma samples from the AIBL study identified the clinically relevant AZ 284®peptide, representing a measure of the U-p53 conformational variant (U-p53AZ). Based on U-p53AZquantification via IP/LC electrospray ionisation-coupled MS/MS (AlzoSure®Predict test) on 515 samples from 482 individuals from the AIBL cohort, the predictive performance of U-p53AZwas assessed and compared with amyloid load as measured by amyloid β-positron emission tomography (Aβ-PET). Its predictive performance was determined at 36, 54, 72 and 90 months following baseline assessment.ResultsU-p53AZwas able to identify individuals with AD dementia with an area under the receiver operating characteristic curve (AUC) of 99%. U-p53AZoutperformed the conventional Aβ-PET measures in predicting the onset of AD dementia both from preclinical (AUC=98%) and prodromal stages (AUC=89%), even 90 months prior to onset (AUC=99%). Additionally, the estimated predictive performance of U-p53AZwas superior (AUC ≥98%) to other risk factors (i.e., gender, Aβ-PET andAPOEε4 allele status) in identifying individuals at high risk for progression to AD.ConclusionThese findings support use of U-p53AZas blood-based biomarker predicting if individuals, at both asymptomatic and MCI stages, would progress to AD at least six years prior to the onset of clinical AD dementia.

Introduction Superior cognitive performance in older adults may reflect underlying resistance to age-associated neurodegeneration. While elevated amyloid β (Aβ) deposition (Aβ+) has been associated with increased cortical atrophy, it remains unknown whether “SuperAgers” may be protected from Aβ-associated neurodegeneration. Methods Neuropsychologically defined SuperAgers (n = 172) and cognitively normal for age (n = 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Aβ status. Results Of the case-matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aβ+. Rates of age- and Aβ-associated atrophy did not differ between the groups on any measure. Aβ− individuals displayed the slowest rates of atrophy. Discussion Maintenance of superior memory in late life does not reflect resistance to age- or Aβ-associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aβ deposition (i.e. Aβ−) displayed reduced rates of cortical atrophy.

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 β1-42, 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.

Patients with inflammatory bowel disease (IBD) often have subjective symptoms for months or years prior to their diagnosis. Blood tests taken prior to diagnosis may provide objective evidence of duration of pre-diagnosis disease. We aim to describe the pre-diagnosis laboratory pattern of patients with IBD. A total of 838 patients diagnosed with IBD between 01/01/1996 and 01/03/2014, with pre-diagnosis laboratory testing available, contributed data for analysis. C-reactive protein, erythrocyte sedimentation rate, hemoglobin level, mean cell volume (MCV) platelet count, white blood cell count, neutrophil count, albumin level, ferritin level, serum iron level, alanine transaminase level, and fecal calprotectin were examined in the 24 months leading up to diagnosis and compared to baseline data taken between 24 and 36 months prior to diagnosis. For patients with Crohn’s disease, a significant drop in serum albumin and MCV levels and a significant rise in platelet count were observed between 115 and 385 days prior to diagnosis (p

Accumulating research has linked Mediterranean diet (MeDi) adherence with slower cognitive decline and reduced Alzheimer’s disease (AD) risk. However, no study to-date has examined the relationship between MeDi adherence and accumulation of cerebral Aβ-amyloid (Aβ; a pathological hallmark of AD) in older adults. Cognitively normal healthy control participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing completed the Cancer Council of Victoria Food Frequency Questionnaire at baseline, which was used to construct a MeDi score for each participant (score range 0–9; higher score indicating higher adherence). Cerebral Aβ load was quantified by Pittsburgh Compound B positron emission tomography at baseline, 18 and 36 months: Only individuals categorised as “Aβ accumulators”, and thus considered to be on the AD pathway, were included in the analysis (N = 77). The relationship between MeDi adherence, MeDi components, and change in cerebral Aβ load (baseline to 36 months) was evaluated using Generalised Linear Modelling, accounting for age, gender, education, Apolipoprotein E ε4 allele status, body mass index and total energy intake. Higher MeDi score was associated with less Aβ accumulation in our cohort (β = −0.01 ± 0.004, p = 0.0070). Of the individual MeDi score components, a high intake of fruit was associated with less accumulation of Aβ (β = −0.04 ± 0.01, p = 0.00036). Our results suggest MeDi adherence is associated with reduced cerebral AD pathology accumulation over time. When our results are considered collectively with previous data linking the MeDi to slower cognitive decline, it is apparent that MeDi adherence warrants further investigation in the quest to delay AD onset.

Characterisation and diagnosis of idiopathic Parkinson’s disease (iPD) is a current challenge that hampers both clinical assessment and clinical trial development with the potential inclusion of non-PD cases. Here, we used a targeted mass spectrometry approach to quantify 38 metabolites extracted from the serum of 231 individuals. This cohort is currently one of the largest metabolomic studies including iPD patients, drug-naïve iPD, healthy controls and patients with Alzheimer’s disease as a disease-specific control group. We identified six metabolites (3-hydroxykynurenine, aspartate, beta-alanine, homoserine, ornithine (Orn) and tyrosine) that are significantly altered between iPD patients and control participants. A multivariate model to predict iPD from controls had an area under the curve (AUC) of 0.905, with an accuracy of 86.2%. This panel of metabolites may serve as a potential prognostic or diagnostic assay for clinical trial prescreening, or for aiding in diagnosing pathological disease in the clinic.

Despite the increasing number of individuals affected by Alzheimer’s disease (AD) every year, no effective therapy has been developed to treat this neurodegenerative disease yet. The current methods for AD diagnosis are effective for clinical confirmation of the disease only when symptoms become apparent, years after molecular damage started within the patients’ brains. As higher expression of a conformationally altered p53 has been correlated with AD, we developed a mass spectrometry-based method for highly sensitive, specific, and reproducible quantification of a p53 conformational variant in plasma samples of patients with known clinical outcome. In particular, we tested the prognostic performance of an AD-specific 2D3A8-immunoselected p53 peptide (AZ 284™) in different sets of individuals progressing from both cognitively unimpaired (CU) and mild cognitive impairment (MCI) patients progressing to AD dementia. Our data showed that quantitative analysis of AZ 284™ is a reliable tool for predicting AD progression up to 6 years prior to dementia onset with AUC >90%. Taken together, these results support the implementation of p53 conformational variant quantification as an affordable and powerful diagnostic tool for early, non-invasive AD diagnosis.

Background Telemonitoring studies in chronic heart failure are characterized by mixed mortality and hospitalization outcomes, which have deterred the uptake of telemonitoring in clinical practice. These mixed outcomes may reflect the diverse range of patient management strategies incorporated in telemonitoring. To address this, we compared the effects of different telemonitoring strategies on clinical outcomes. Objective The aim of this systematic review and subgroup meta-analysis was to identify noninvasive telemonitoring strategies attributing to improvements in all-cause mortality or hospitalization outcomes for patients with chronic heart failure. Methods We reviewed and analyzed telemonitoring strategies from randomized controlled trials (RCTs) comparing telemonitoring intervention with usual care. For each strategy, we examined whether RCTs that applied the strategy in the telemonitoring intervention (subgroup 1) resulted in a significantly lower risk ratio (RR) of all-cause mortality or incidence rate ratio (IRR) of all-cause hospitalization compared with RCTs that did not apply this strategy (subgroup 2). Results We included 26 RCTs (N=11,450) incorporating 18 different telemonitoring strategies. RCTs that provided medication support were found to be associated with a significantly lower IRR value than RCTs that did not provide this type of support (P=.01; subgroup 1 IRR=0.83, 95% CI 0.72-0.95 vs subgroup 2 IRR=1.02, 95% CI 0.93-1.12). RCTs that applied mobile health were associated with a significantly lower IRR (P=.03; IRR=0.79, 95% CI 0.64-0.96 vs IRR=1.00, 95% CI 0.94-1.06) and RR (P=.01; RR=0.67, 95% CI 0.53-0.85 vs RR=0.95, 95% CI 0.84-1.07). Conclusions Telemonitoring strategies involving medication support and mobile health were associated with improvements in all-cause mortality or hospitalization outcomes. These strategies should be prioritized in telemonitoring interventions for the management of patients with chronic heart failure.

Background β-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer’s disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology. Methods Using automated Elecsys® assays (Roche Diagnostics) for Aβ (1–42) (Aβ42), Aβ (1–40) (Aβ40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging. Results Ratios Aβ42/Aβ40, tTau/Aβ42 and pTau/Aβ42 had higher receiver operator characteristic—area under the curve (all 0.94), and greater concordance with Aβ-PET (overall percentage agreement ~ 90%), compared with individual biomarkers. Conclusion Strong concordance between CSF biomarkers and Aβ-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.

Alzheimer's disease (AD) has a long pathological process, with an approximate lead-time of 20 years. During the early stages of the disease process, little evidence of the building pathology is identifiable without cerebrospinal fluid and/or imaging analyses. Clinical manifestations of AD do not present until irreversible pathological changes have occurred. Given an opportunity to provide treatment prior to irreversible pathological change, this study aims to identify a subgroup of cognitively normal (CN) participants from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), where subtle changes in cognition are indicative of early AD-related pathology. Using a Bayesian method for unsupervised clustering via mixture models, we define an aggregate measure of posterior probabilities (AMPP score) establishing the likelihood of pre-clinical AD. From Baseline through to 54 months, visuo-spatial function had the greatest contribution to the AMPP score, followed by attention and processing speed and visual memory. Participants with the highest AMPP scores had both increasing neo-cortical amyloid burden and decreasing hippocampus volume over 54 months, compared to those in the lowest category with stable amyloid burden and hippocampus volume. The identification of a possible pre-clinical stage in CN participants via this method, without the aid of disease specific biomarkers, represents an important step in utilizing the strength of cognitive composite scores for the early detection of AD pathology.

Plasma amyloid-β peptide concentration has recently been shown to have high accuracy to predict amyloid-β plaque burden in the brain. These amyloid-β plasma markers will allow wider screening of the population and simplify and reduce screening costs for therapeutic trials in Alzheimer’s disease. The aim of this study was to determine how longitudinal changes in blood amyloid-β track with changes in brain amyloid-β. Australian Imaging, Biomarker and Lifestyle study participants with a minimum of two assessments were evaluated (111 cognitively normal, 7 mild cognitively impaired, 15 participants with Alzheimer’s disease). Amyloid-β burden in the brain was evaluated through PET and was expressed in Centiloids. Total protein amyloid-β 42/40 plasma ratios were determined using ABtest® assays. We applied our method for obtaining natural history trajectories from short term data to measures of total protein amyloid-β 42/40 plasma ratios and PET amyloid-β. The natural history trajectory of total protein amyloid-β 42/40 plasma ratios appears to approximately mirror that of PET amyloid-β, with both spanning decades. Rates of change of 7.9% and 8.8%, were observed for total protein amyloid-β 42/40 plasma ratios and PET amyloid-β, respectively. The trajectory of plasma amyloid-β preceded that of brain amyloid-β by a median value of 6 years (significant at 88% confidence interval). These findings, showing the tight association between changes in plasma and brain amyloid-β, support the use of plasma total protein amyloid-β 42/40 plasma ratios as a surrogate marker of brain amyloid-β. Also, that plasma total protein amyloid-β 42/40 plasma ratios has potential utility in monitoring trial participants, and as an outcome measure., Total protein amyloid β42/40 plasma ratios determined by the ABtest® assay were able to effectively map and track longitudinal amyloid PET accumulation. This adds to the body of information that blood-based biomarkers hold utility for diagnosis, prognosis, monitoring and, thus, treatment in the field of Alzheimer’s., Graphical Abstract Graphical Abstract

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-β deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-β positron-emission tomography (PET) imaging or measurement of amyloid-β in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-β markers. Here we demonstrate the measurement of high-performance plasma amyloid-β biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-β precursor protein (APP)669-711/amyloid-β (Aβ)1-42 and Aβ1-40/Aβ1-42 ratios, and their composites, to predict individual brain amyloid-β-positive or -negative status was determined by amyloid-β-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-β burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-β-PET burden and levels of Aβ1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-β burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-β by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-β to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-β load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-β positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [β(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [β(standard error) = -0.139 (0.048), P = 0.004), and attention [β(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [β(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [β(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-β to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-β positron emission tomography to stratify individuals at risk of decline.

Background Hypothalamic-pituitary-adrenal axis dysregulation, which is typically assessed by measuring cortisol levels, is associated with cognitive dysfunction, hippocampal atrophy, and increased risk for mild cognitive impairment and Alzheimer’s disease (AD). However, little is known about the role of hypothalamic-pituitary-adrenal axis dysregulation in moderating the effect of high levels of amyloid-β (Aβ+) on cognitive decline in the preclinical phase of AD, which is often protracted, and thus offers opportunities for prevention and early intervention. Methods Using data from a 6-year multicenter prospective cohort study, we evaluated the relation between Aβ level, plasma cortisol level, and cognitive decline in 416 cognitively normal older adults. Results Results revealed that Aβ+ older adults experienced faster decline than Aβ− older adults in all cognitive domains (Cohen’s d at 6-year assessment = 0.37–0.65). They further indicated a significant interaction between Aβ and cortisol levels for global cognition ( d = 0.32), episodic memory ( d = 0.50), and executive function ( d = 0.59) scores, with Aβ+ older adults with high cortisol levels having significantly faster decline in these domains compared with Aβ+ older adults with low cortisol levels. These effects were independent of age, sex, APOE genotype, anxiety symptoms, and radiotracer type. Conclusions In cognitively healthy older adults, Aβ+ is associated with greater cognitive decline and high plasma cortisol levels may accelerate the effect of Aβ+ on decline in global cognition, episodic memory, and executive function. These results suggest that therapies targeted toward lowering plasma cortisol and Aβ levels may be helpful in mitigating cognitive decline in the preclinical phase of AD.

Background Maintenance anti-tumour necrosis factor-α (anti-TNFα) treatment for Crohn's disease is the standard of care for patients with an inadequate response to corticosteroids and immunomodulators. Aim To compare the efficacy and safety of infliximab and adalimumab in clinical practice and assess the value of concomitant immunomodulator therapy. Methods We performed an observational cohort study in consecutive patients with Crohn's disease qualifying for anti-TNFα treatment in Australia and New Zealand between 2007 and 2011. Demographic and clinical data were prospectively recorded to identify independent factors associated with induction and maintenance of response to infliximab or adalimumab, or to either anti-TNFα therapy. Results Three hundred and twenty-seven patients (183 infliximab, 144 adalimumab) successfully applied for treatment. Eighty-nine percent responded in all groups and median maintenance of response was similar for the two agents. Concomitant immunomodulator with infliximab, but not adalimumab, demonstrated a significantly longer response overall (P = 0.002), and significantly fewer disease and treatment-related complications (P = 0.017). Corticosteroids at baseline, and/or in the preceding 12 months, were associated with a 9–13 times greater risk of disease flare during maintenance treatment as compared to no corticosteroids (P < 0.0001). Maintenance of response was similar in the anti-TNF naive and anti-TNF experienced subgroups. Conclusions In this large, real-life study, we demonstrate infliximab and adalimumab to have similar response characteristics. However, infliximab requires concomitant immunomodulator to achieve optimal maintenance of response comparable to adalimumab monotherapy. The results of this study will assist clinicians in further optimising patient care in their day-to-day clinical practice.

Understanding the relationships between the structure and function of the brain largely relies on the qualitative assessment of Magnetic Resonance Images (MRIs) by expert clinicians. Automated analysis systems can support these assessments by providing quantitative measures of brain injury. However, the assessment of deep gray matter structures, which are critical to motor and executive function, remains difficult as a result of large anatomical injuries commonly observed in children with Cerebral Palsy (CP). Hence, this article proposes a robust surrogate marker of the extent of deep gray matter injury based on impingement due to local ventricular enlargement on surrounding anatomy. Local enlargement was computed using a statistical shape model of the lateral ventricles constructed from 44 healthy subjects. Measures of injury on 95 age-matched CP patients were used to train a regression model to predict six clinical measures of function. The robustness of identifying ventricular enlargement was demonstrated by an area under the curve of 0.91 when tested against a dichotomised expert clinical assessment. The measures also showed strong and significant relationships for multiple clinical scores, including: motor function (r = 0.62, P < 0.005), executive function (r = 0.55, P < 0.005), and communication (r = 0.50, P < 0.005), especially compared to using volumes obtained from standard anatomical segmentation approaches. The lack of reliance on accurate anatomical segmentations and its resulting robustness to large anatomical variations is a key feature of the proposed automated approach. This coupled with its strong correlation with clinically meaningful scores, signifies the potential utility to repeatedly assess MRIs for clinicians diagnosing children with CP. Hum Brain Mapp 37:3795–3809, 2016.

Background: Many patients presenting with an acute severe ulcerative colitis to a regional hospital are transferred to a metropolitan hospital for specialised care.Aims: To evaluate the outcomes and characteristics of these patients.Method: A retrospective observational cohort study was conducted to examine the 30-day colectomy rate using prospectively collected data on 69 consecutive index cases of acute severe ulcerative colitis transferred from regional hospitals to our metropolitan hospital meeting Truelove and Witts criteria. Those that avoided colectomy were followed out to 1 year to examine outcomes.Results: The 30-day colectomy rate was 46.4% (32/69) in regional transfer patients. Rescue therapy was administered to 65% (45/69) of patients after transfer to our metropolitan hospital. Colectomy was avoided in 55% of these patients at 30 days. Colectomy free status was maintained in 78%(29/39) of these patients. Mortality was 0% at 30 days and 1 year.Conclusion: Over 50% of the patients failing therapy in a regional centre and requiring transfer avoided short term colectomy with co-ordinated referral for rescue therapy in a tertiary metropolitan inflammatory bowel disease unit. These patients would have ultimately required colectomy in their regional hospital without intervention.

Objective:We assessed a blood-based signature, which previously demonstrated high accuracy at stratifying individuals with high or low neocortical β-amyloid burden (NAB), to determine whether it could also identify individuals at risk of progression to Alzheimer disease (AD) within 54 months.Methods:We generated the blood-based signature for 585 healthy controls (HCs) and 74 participants with mild cognitive impairment (MCI) from the Australian Imaging, Biomarkers and Lifestyle Study who underwent clinical reclassification (blinded to biomarker findings) at 54-month follow-up. The individuals were split into estimated high and low NAB groups based on a cutoff of 1.5 standardized uptake value ratio. We assessed the predictive accuracy of the high and low NAB groupings based on progression to mild cognitive impairment or AD according to clinical reclassification at 54-month follow-up.Results:Twelve percent of HCs with estimated high NAB progressed in comparison to 5% of HCs with estimated low NAB (odds ratio = 2.4). Forty percent of the participants with MCI who had estimated high NAB progressed in comparison to 5% of the participants with MCI who had estimated low NAB (odds ratio = 12.3). These ratios are in line with those reported for Pittsburgh compound B–PET results. Individuals with estimated high NAB had faster rates of memory decline than those with estimated low NAB.Conclusion:These findings suggest that a simple blood-based signature not only provides estimates of NAB but also predicts cognitive decline and disease progression, identifying individuals at risk of progressing toward AD at the prodromal and preclinical stages.

Congenital brain lesions result in a wide range of cerebral tissue alterations observed in children with cerebral palsy (CP) that are associated with a range of functional impairments. The relationship between injury severity and functional outcomes, however, remains poorly understood. This research investigates the differences in cortical shape between children with congenital brain lesions and typically developing children (TDC) and investigates the correlations between cortical shape and functional outcome in a large cohort of patients diagnosed with unilateral CP. Using 139 structural magnetic resonance images, including 95 patients with clinically diagnosed CP and 44 TDC, cortical segmentations were obtained using a modified expectation maximization algorithm. Three shape characteristics (cortical thickness, curvature, and sulcal depth) were computed within a number of cortical regions. Significant differences in these shape measures compared to the TDC were observed on both the injured hemisphere of children with CP (P

White and grey matter lesions are the most prevalent type of injury observable in the Magnetic Resonance Images (MRIs) of children with cerebral palsy (CP). Previous studies investigating the impact of lesions in children with CP have been qualitative, limited by the lack of automated segmentation approaches in this setting. As a result, the quantitative relationship between lesion burden has yet to be established. In this study, we perform automatic lesion segmentation on a large cohort of data (107 children with unilateral CP and 18 healthy children) with a new, validated method for segmenting both white matter (WM) and grey matter (GM) lesions. The method has better accuracy (94%) than the best current methods (73%), and only requires standard structural MRI sequences. Anatomical lesion burdens most predictive of clinical scores of motor, cognitive, visual and communicative function were identified using the Least Absolute Shrinkage and Selection operator (LASSO). The improved segmentations enabled identification of significant correlations between regional lesion burden and clinical performance, which conform to known structure-function relationships. Model performance was validated in an independent test set, with significant correlations observed for both WM and GM regional lesion burden with motor function (p, Graphical abstract Image 1, Highlights • Presents an automated lesion segmentation approach tailored to cerebral palsy • Demonstrates the utility of quantifying lesions from MRI • Illustrates the influence that grey matter lesions have on functional impairments

Introduction For early detection of Alzheimer's disease (AD), the field needs biomarkers that can be used to detect disease status with high sensitivity and specificity. Apolipoprotein J (ApoJ, also known as clusterin) has long been associated with AD pathogenesis through various pathways. The aim of this study was to investigate the potential of plasma apoJ as a blood biomarker for AD. Methods Using the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, the present study assayed plasma apoJ levels over baseline and 18 months in 833 individuals. Plasma ApoJ levels were analyzed with respect to clinical classification, age, gender, apolipoprotein E (APOE) ε4 allele status, mini‐mental state examination score, plasma amyloid beta (Aβ), neocortical Aβ burden (as measured by Pittsburgh compound B‐positron emission tomography), and total adjusted hippocampus volume. Results ApoJ was significantly higher in both mild cognitive impairment (MCI) and AD groups as compared with healthy controls (HC; P

Multifactorial pathological processes of Alzheimer's disease (AD) begin decades prior to clinical onset. Early identification of patients at risk of developing AD using biomarkers reflecting various aspects of pathogenesis is necessary for prevention and early intervention. Cortical β-amyloid (Aβ) burden assessed by positron emission tomography (PET) or cerebrospinal fluid (CSF) levels of Aβ42 are validated biomarkers for early identification. Recently, alterations in levels of neuronal proteins, neuronal pentraxin receptor (NPTXR) and neurofilament light (NfL), in the CSF have emerged as promising AD biomarkers. However, their association with Aβ deposition is not well understood. In this pilot study, we evaluate whether CSF NfL and NPTXR are associated with PET-Aβ imaging and core CSF biomarkers (Aβ42, T-tau, and P-tau). CSF samples were collected from a sub-cohort of participants from the Australian Imaging Biomarkers and Lifestyle study of aging (AIBL) and categorized as either PET-Aβ positive (n = 15) or negative (n = 15). NPTXR was significantly lower in PET-Aβ positive than negative individuals (p = 0.04), and correlated with Aβ42 (rho = 0.69, p 0.0001), T-tau (rho = 0.45, p = 0.01), and P-tau (rho = 0.51, p = 0.004). However, CSF NfL was not significantly different between PET-Aβ positive and negative individuals and did not correlate with any of the core CSF biomarkers. Similar associations of NPTXR and the core CSF biomarkers persisted in the cognitively normal individuals. Together, NPTXR concentration in CSF may be more sensitive NfL to identify AD risk during the preclinical stage, warranting further investigation into its contribution to AD pathogenesis.

Higher cardiorespiratory fitness has been associated with better cognitive function in older adults; yet, this relationship demonstrates a degree of variability across the older adult population. Thus, it is hypothesised that variation in genetic factors may influence the relationship between fitness and cognitive health. One such genetic factor is the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism, which has previously been shown to moderate the relationship between self-reported physical activity and memory performance. In this study we aim to investigate the interaction between BDNF Val66Met polymorphism and objectively-measured cardiorespiratory fitness on performance on tasks assessing verbal and visuospatial memory. Data from ninety-nine cognitively normal men and women aged 60–80 years were used. Fitness was assessed by peak oxygen consumption, and verbal and visuospatial memory were evaluated using well-validated measures. Participants were categorised into: lower-fit Met carriers, higher-fit Met carriers, lower-fit Val/Val, or higher-fit Val/Val. Higher-fit individuals performed better on a task assessing visuospatial memory, compared with lower-fit individuals. Furthermore, an interaction between BDNF Val66Met and fitness was observed in terms of visuospatial memory performance on a continuous paired associate learning task; whereby lower-fit Met carriers performed 1 standard deviation worse than higher-fit Met carriers. No differences were observed between the higher-fit and lower-fit Val/Val homozygotes. Future intervention studies should evaluate the effect of structured exercise on cognitive health between BDNF Val66Met carriers and Val/Val homozygotes.

Background: Patients on immunosuppression at the time of acute severe ulcerative colitis have been suggested to be at a higher risk of colectomy than those who are treatment-naïve. The aim of this study was to examine the effect of immunosuppressive therapy on the risk of colectomy. Method: We conducted a retrospective observational cohort study using prospective data examining the 30 day and 1 year colectomy rates of 200 consecutive patients with an index episode of acute severe ulcerative colitis as defined by the Truelove and Witts criteria. Results: Immunosuppression on admission was shown not to increase colectomy rate at 30 days post-admission (immunomodulator: p = 0.422, oral steroids: p = 0.555). A total of 24 patients underwent colectomy between 30 days and 1 year. A three-fold higher risk of colectomy at 1 year was seen in those requiring an immunomodulator prior to the index admission compared with those started de novo during the index admission [41% versus 14% odds ratio (OR): 2.93 (1.19–7.24 p = 0.016)]. Factors most predictive of colectomy at 30 days were abdominal radiographic colonic dilation ⩾5.5 cm, first presentation of ulcerative colitis, C-reactive protein ⩾ 45 mg/l on day 3 of therapy and bowel frequency ⩾8 on day 3. Conclusion: The need for an immunomodulator prior to admission with acute severe ulcerative colitis increases the medium-term colectomy rate by three-fold at 1 year. Prospective studies are needed to confirm these findings and develop strategies to reduce the high risk in this subgroup of patients.

BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial. OBJECTIVE: Assessing levels of Aβ-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aβ-amyloid (32 Aβ-amyloid-and 45 Aβ-amyloid+), as well as concordance between CSF biomarker levels and PET Aβ-amyloid imaging. METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging. RESULTS: Across all three platforms, the T-tau/Aβ42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aβ42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aβ-amyloid-and Aβ-amyloid+ groups were strongest for the Aβ42/Aβ40 and T-tau/Aβ42 ratios (p

Introduction Inconsistent results from previous studies of exercise and cognitive function suggest that rigorously designed randomized controlled trials are urgently needed. Here, we describe the design of the Intense Physical Activity and Cognition (IPAC) study, which will assess the impact of a 6-month high-intensity exercise intervention on cognitive function and biomarkers of dementia risk, compared with a 6-month moderate-intensity exercise intervention and control group (no study-related exercise). Methods One-hundred and five cognitively healthy men and women aged between 60 and 80 years are randomized into a high-intensity exercise, moderate-intensity exercise, or control group. Individuals randomized to an exercise intervention undertake 6 months of cycle-based exercise twice a week, at 50 minutes per session. All participants undergo comprehensive neuropsychological testing, blood sampling, brain magnetic resonance imaging, fitness testing, and a body composition scan at baseline, 6 months (immediately after intervention), and 18 months (12 months after intervention). Discussion The IPAC study takes a multidisciplinary approach to investigating the role of exercise in maintaining a healthy brain throughout aging. Rigorous monitoring of exertion and adherence throughout the intervention, combined with repeated measures of fitness, is vital in ensuring an optimum exercise dose is reached. Results from the IPAC study will be used to inform a large-scale multicentre randomized controlled trial, with the ultimate aim of pinpointing the frequency, duration, and intensity of exercise that provides the most benefit to the brain, in terms of enhancing cognitive function and reducing dementia risk in older adults.

BACKGROUND: The cerebrospinal fluid (CSF) amyloid-β (Aβ)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. METHODS: Aβ pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹⁸F-flutemetamol, or ¹⁸F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ(1-42) >544 ng/L, T-tau

Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic anemia. We examined iron-binding plasma proteins from AD patients and healthy controls from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing using size exclusion chromatography-inductively coupled plasma-mass spectrometry. Peak area corresponding to transferrin (Tf) saturation was directly compared to routine pathological testing. We found a significant decrease in transferrin-associated iron in AD that was missed by routine pathological tests of transferrin saturation, and that was able to discriminate between AD and controls. The AD cases showed no significant difference in transferrin concentration, only a decrease in total transferrin-bound iron. These findings support that a previously identified decrease in plasma iron levels in AD patients within the AIBL study is attributable to decreased loading of iron into transferrin, and that this subtle but discriminatory change is not observed through routine pathological testing.

Objective: This study investigated the retinal arteriolar central reflex (CR, the central reflection observed in photographs of retinal vessels), which may provide information about micro-vascular health in the retina and also the brain, due to the homology between these vascular networks. The study also describes a novel computer based semi-automated technique that accurately quantifies retinal arteriolar CR and vessel width, and calculates the CR to vessel width ratio (CRR) from digital retinal photographs. Methods: Digital retinal photographs were collected from participants in the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL), including 25 participants diagnosed with Alzheimer’s disease (AD) (age 72.4 ± 7.5 yrs, 12 male, 13 female) and 123 elderly participants without dementia (cognitively normals: CN) (age 71.6 ± 5.6 yrs, 55 male, 68 female). Using a sub-cohort of 144 (22 AD, 122 CN) with the novel CRR measures, we identified significantly higher CRR levels in AD participants (mean CRR 0.253 (SD 0.04)) as compared with CN’s (mean CRR 0.231 (SD 0.04), p = 0.025). Adjustment for APOE e4 allele status however, reduced the significance (p = 0.081). CRR was significantly higher in APOE e4 allele carriers (mean CRR 0.254 (SD 0.03) as compared with non-carriers (mean CRR 0.224 (SD 0.05), p < 0.0001). Results: These data indicate that CRR is strongly linked to APOE e4 status and exhibits a weaker, independent trend with AD diagnosis. The retina may be useful as a novel model for non-invasive monitoring of the effects of APOE e4 on the central nervous system, particularly in cerebrovascular disease.

Background It is common for older adults to experience decline in some cognitive functions with increasing age. Importantly, a subset, usually referred to as super-agers (SA; Rogalski, et al., 2013, J Cog Neurosc, 25: 29-36) live to an old age whilst continuing to maintain cognitive function at levels similar to demographically-matched peers at least 20-30 years their junior. The current study reports trajectories of change in cortical thickness on a well-defined group of SAs vs. typical agers (TA) followed longitudinally over six years in the Australian Imaging, Biomarkers & Lifestyle Study (AIBL) (Ellis et al., 2009, Int Psychogeriat, 2: 672-87). Methods Super-Agers were defined as individuals aged 60+ who scored in the normative range for individuals aged 30 – 44 on the CVLT-II, a test of verbal episodic memory, at baseline and two consecutive time-points 18 months apart. SAs additionally must have performed in the unimpaired range in all other cognitive domains, as compared to same-aged peers. Typical agers must have scored within the normal range on all cognitive measures compared with same-aged peers. This report describes data from 21 SAs and 24 TAs. The TAs were chosen from a larger group matched on age, education and gender to the SA group. All participants completed brain magnetic resonance imaging every 18 months for six years. We conducted multiple linear mixed models analyses to assess the association between preservation of cortical thickness in SAs and TAs. Results From 34 regions of interest identified as potentially differentiating SAs from TAs from previous neuroimaging studies, our results were consistent in finding greater cortical thinning amongst TAs in 20 of these regions (p-values ranging between ≤ .000 and .047), with an additional five regions at trend level (p-values ranging between ≥ .05 and .073). Using false discovery rates, we found significantly preserved thickness in three regions not previously reported including left superior parietal gyrus, left precuneus, and left paracentral lobule. Conclusions SAs and TAs displayed similar cortical thickness at baseline (p >.40), but showed different trajectories over time. The findings will be discussed in the context of current models of cognitive and brain reserve.

Previous studies have proposed that the early elucidation of brain injury from structural Magnetic Resonance Images (sMRI) is critical for the clinical assessment of children with cerebral palsy (CP). Although distinct aetiologies, including cortical maldevelopments, white and grey matter lesions and ventricular enlargement, have been categorised, these injuries are commonly only assessed in a qualitative fashion. As a result, sMRI remains relatively underexploited for clinical assessments, despite its widespread use. In this study, several automated and validated techniques to automatically quantify these three classes of injury were generated in a large cohort of children (n = 139) aged 5–17, including 95 children diagnosed with unilateral CP. Using a feature selection approach on a training data set (n = 97) to find severity of injury biomarkers predictive of clinical function (motor, cognitive, communicative and visual function), cortical shape and regional lesion burden were most often chosen associated with clinical function. Validating the best models on the unseen test data (n = 42), correlation values ranged between 0.545 and 0.795 (p

We examined the distribution of zinc in the periphery (erythrocytes and serum) in a large, well-characterised cohort, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, in order to determine if there is systemic perturbation in zinc homeostasis in Alzheimer's disease (AD). We observed an age dependent decrease in serum zinc of approximately 0.4% per year. When correcting for the age dependent decline in serum zinc no significant difference between healthy controls (HC), mildly cognitively impaired (MCI) or AD subjects was observed.

The pre-mortem clinical diagnosis of Creutzfeldt-Jakob disease (CJD) is supported by biomarkers, especially cerebrospinal fluid (CSF) 14-3-3 and total tau (Tau) protein levels. These CSF biomarkers have proven the most useful prior to transitioning to powerful next generation diagnostics employing protein amplification techniques such as the real time quaking-induced conversion (RT-QuIC) assay. To enhance national diagnostic capacity while transitioning to RT-QuIC assays an optimized CSF Tau cutoff was determined and shown to usefully supplement 14-3-3 protein detection.

Background Up to 40% of patients who present with acute severe ulcerative colitis (UC) fail to make an adequate response to intravenous corticosteroids. Ciclosporin or infliximab are currently employed as salvage therapy in this clinical scenario. Aim To compare clinical outcomes in patients treated with ciclosporin or infliximab in the setting of steroid-refractory acute severe UC. Methods A prospective study of 83 consecutive presentations of steroid-refractory acute severe UC from 1999 to 2009 was conducted. All study participants satisfied the Truelove and Witts' criteria for acute severe UC. The primary outcome measures were rates of colectomy at discharge from hospital and at 3 months and 12 months following admission. Results Eighty-three steroid-refractory acute severe UC events were generated by 83 patients. Salvage therapy was instituted with ciclosporin in 45 patients and infliximab in the remaining 38 patients. Of those patients who received ≥72 h of ciclosporin (2-4 mg/kg), 56% (24/43) avoided colectomy at the time of discharge, while this figure was 84% (32/38) for those administered one dose of infliximab (5 mg/kg) (P = 0.006). At 3 months, the colectomy-free rate was 53% for ciclosporin (23/43) vs. 76% for infliximab (28/37) (P = 0.04), and 42% (18/43) vs. 65% (24/37) at 12 months (P = 0.04). There were no deaths and two serious adverse events, both occurring in the ciclosporin group. Conclusions In this large cohort of patients presenting with acute severe UC, we have observed that infliximab salvage therapy is associated with lower rates of both severe adverse events and colectomy than ciclosporin in the short-term and medium-term.

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 Aβ (extracellular β-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 Aβ accumulation, therefore, providing a platform for developing a population-based screen.