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Background: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear. Objective: The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease. Methods: We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted utilizing mass spectrometry methods and data combined using pathway analysis. Results: We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis could be used to provide separation of the three groups. Conclusion: This study found significant changes in metabolites and proteins from multiple cellular pathways in saliva. These changes were associated with AD, demonstrating that this approach might prove useful to identify new biomarkers based upon integration of multi-omics parameters.

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

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.

The degeneration of the human brain is a complex process, which often affects certain brain regions due to healthy aging or disease. This degeneration can be evaluated on regions of interest (ROI) in the brain through probabilistic networks and morphological estimates. Current approaches for finding such networks are limited to analyses at discrete neuropsychological stages, which cannot appropriately account for connectivity dynamics over the onset of cognitive deterioration, and morphological changes are seldom unified with connectivity networks, despite known dependencies. To overcome these limitations, a probabilistic wombling model is proposed to simultaneously estimate ROI cortical thickness and covariance networks contingent on rates of change in cognitive decline. This proposed model was applied to analyze longitudinal data from healthy control (HC) and Alzheimer's disease (AD) groups and found connection differences pertaining to regions, which play a crucial role in lasting cognitive impairment, such as the entorhinal area and temporal regions. Moreover, HC cortical thickness estimates were significantly higher than those in the AD group across all ROIs. The analyses presented in this work will help practitioners jointly analyze brain tissue atrophy at the ROI-level conditional on neuropsychological networks, which could potentially allow for more targeted therapeutic interventions.

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.

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.

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.

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.

Background: Research continues to search for blood-based biomarkers sensitive to Alzheimer’s disease (AD) pathology during the initial stages when symptoms of cognitive decline are not yet apparent. A blood-based biomarker candidate is metalloprotein p53, the conformation of which was previously found to be altered in peripheral cells from individuals with mild cognitive impairment (MCI) and AD, presenting as an unfolded p53 (U-p53) conformational variant. Methods: Plasma samples from the well-characterized Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort were used to identify the clinically relevant AZ 284® peptide, specifically present in samples from individuals with symptomatic AD. The AZ 284® peptide, which is a marker of the U-p53 conformational variant (U-p53AZ), was identified by immunoprecipitation (IP) with a novel U-p53 conformational variant-specific antibody followed by liquid chromatography (LC) tandem mass spectrometry (MS/MS) and protein sequencing. Using IP-LC surface-activated chemical ionization (SACI) MS/MS analysis, the prognostic and diagnostic performance of U-p53AZ were examined in the longitudinal AIBL cohort, including 252 plasma samples derived from 214 elderly individuals. For the prognostic analyses, U-p53AZ levels were assessed at 36, 72, and 90 months after baseline assessment. Results: The prognostic performance of U-p53AZ to predict the progression to AD from preclinical or prodromal AD was high, with area under the receiver operating characteristic curve (AUC) values close to or above 0.90. Furthermore, U-p53AZ predicted the progression to AD more than 6 years prior to symptom onset with positive and negative predictive values of about 90%. Additionally, the estimated prognostic performance of U-p53AZ was superior to other main risk factors (i.e., age, sex, and either alone or in combination with amyloid status. Furthermore, U-p53AZ had high diagnostic performance to differentiate cognitively normal individuals from those with AD (AUC values >0.88). Conclusion: These findings support the use of U-p53AZ as a prognostic blood-based biomarker accurately predicting the progression to AD dementia during the preclinical and prodromal stages at least 6 years before receiving the clinical diagnosis of AD dementia.

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.

NAbs to different epitopes of Aβ are differentially associated with the severity and progression of Alzheimer’s disease., The pathological relevance of naturally occurring antibodies to β-amyloid (NAbs-Aβ) in Alzheimer’s disease (AD) remains unclear. We aimed to investigate their levels and associations with Aβ burden and cognitive decline in AD in a cross-sectional cohort from China and a longitudinal cohort from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. NAbs-Aβ levels in plasma and cerebrospinal fluid (CSF) were tested according to their epitopes. Levels of NAbs targeting the amino terminus of Aβ increased, and those targeting the mid-domain of Aβ decreased in both CSF and plasma in AD patients. Higher plasma levels of NAbs targeting the amino terminus of Aβ and lower plasma levels of NAbs targeting the mid-domain of Aβ were associated with higher brain amyloidosis at baseline and faster cognitive decline during follow-up. Our findings suggest a dynamic response of the adaptive immune system in the progression of AD and are relevant to current passive immunotherapeutic strategies.

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.

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

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer’s disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.

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.

Background: Total tau (tTau) and phosphorylated 181P tau (pTau) are supportive diagnostic cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease. Manual CSF tau assays are limited by lot-to-lot and between-laboratory variability and long incubation/turnaround times. Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF immunoassays were developed for fully automated cobas e analyzers, allowing broader access in clinical practice and trials. Methods: Analytical performance, reproducibility, method comparisons with commercially available assays, and lot-to-lot and platform comparability (cobas e 601/411) of the Elecsys® CSF assays were assessed. Tau distributions and concentration ranges were evaluated in CSF samples from two clinical cohorts. Results: Both assays showed high sensitivity (limit of quantitation [LoQ]: 63 pg/mL [tTau]; 4 pg/mL [pTau]) and linearity over the measuring range (80–1300 pg/mL; 8–120 pg/mL), which covered the entire concentration range measured in clinical samples. Lot-to-lot and platform comparability demonstrated good consistency (Pearson's r: 0.998; 1.000). Multicenter evaluation coefficients of variation (CVs): repeatability, < 1.8%; intermediate precision, < 2.8%; between-laboratory variability, < 2.7% (both assays); and total reproducibility, < 6.7% (tTau) and < 4.7% (pTau). Elecsys® CSF assays demonstrated good correlation with commercially available tau assays. Conclusions: Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF assays demonstrate good analytical performance with clinically relevant measuring ranges; data support their use in clinical trials and practice.

Background Alzheimer's disease (AD) biomarkers, such as cerebrospinal fluid (CSF) amyloid-β (1–42; Aβ42), can provide high diagnostic accuracy. Several immunoassays are available for Aβ42 quantitation, but standardisation across assays remains an issue. We compared the Elecsys® β-Amyloid (1–42) CSF assay with three assays and two liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Methods Three method comparison studies evaluated the correlation between the Elecsys® β-Amyloid (1–42) CSF assay versus: INNOTEST® β-AMYLOID(1–42) (860 samples) and the Roche Diagnostics-developed LC-MS/MS method (250 samples); INNO-BIA AlzBio3 and the University of Pennsylvania (UPenn)-developed LC-MS/MS method (250 samples); and ADx-EUROIMMUN Beta-Amyloid (1–42) enzyme-linked immunosorbent assay (ELISA) (49 samples). Results High correlation was demonstrated between Elecsys® β-Amyloid (1–42) CSF and comparator assays: INNOTEST® β-AMYLOID(1–42) (Spearman's ρ, 0.954); INNO-BIA AlzBio3 (Spearman's ρ, 0.864); ADx-EUROIMMUN Beta-Amyloid (1–42) ELISA (Pearson's r, 0.925). Elecsys® assay and LC-MS/MS measurements were highly correlated: Pearson's r, 0.949 (Roche Diagnostics-developed method) and 0.943 (UPenn-developed method). Conclusion Findings from this multicentre evaluation further support use of the Elecsys® β-Amyloid (1–42) CSF assay to aid AD diagnosis. CSF-based certified reference materials should improve agreement across assays and mass spectrometry-based methods, which is essential to establish a global uniform CSF Aβ42 cut-off to detect amyloid pathology.

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.

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.

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.

Higher cardiorespiratory fitness has been associated with enhanced cognitive function in older adults; yet, this relationship demonstrates a degree of variability. Thus, it is hypothesised that variation in genetic factors may influence the relationship between fitness and cognitive health. In this study we evaluate whether the BDNF Val66Met polymorphism moderates the relationship between cardiorespiratory fitness and 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. A significant interaction was observed between BDNF Val66Met and fitness on visuospatial memory performance; whereby lower-fit Met carriers performed 1SD lower than higher-fit Met carriers (p=0.04). We observed higher levels of fitness mitigated the deleterious effect of BDNF Met allele carriage on visuospatial memory. 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.