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Summary: Background: Plasma phospho-tau 217 (pTau217) assays can accurately detect Alzheimer's disease (AD) pathology, but clinical application is limited by the need for specialised equipment. This study tests the performance of a plasma pTau217 assay performed on the Lumipulse-G® platform, that is in widespread clinical use, for selecting patients for therapy based on β-amyloid (Aβ) status and tau staging. Methods: Participants included 388 individuals with 18F-NAV4694 Aβ-PET and 18F-MK6240 tau-PET. Association of pTau217 with PET was examined using Spearman's correlation. Discriminative performance for Aβ and tau PET status as well as tau staging was assessed using Receiver Operating Characteristic analysis. Findings: Plasma pTau217 had a high correlation with both Aβ Centiloid (r = 0.76) and tau SUVRmeta-temporal (r = 0.78). Area under curve (AUC) was 0.93 for Aβ− vs Aβ+ and 0.94 for tau− vs tau+. Applying one threshold (Youden's index), pTau217 was 87% accurate in classification of participants to Aβ− vs Aβ+. Applying two thresholds to classify participants into Low, Indeterminate, and High zones, 17.8% had Indeterminate results and among Low/High zone participants, 92% were correctly classified as Aβ− or Aβ+. The assay accurately discriminated moderate/high neocortical tau from no tau or tau limited to mesial-temporal lobe (AUC 0.97) and high neocortical tau from all others (AUC 0.94). Interpretation: Plasma pTau217, measured by the widely-available, fully-automated Lumipulse®, was a strong predictor of both Aβ and tau PET status and demonstrated strong predictive power in identifying individuals likely to benefit the most from anti-Aβ treatments. Funding: NHMRC grants 1132604, 1140853, 1152623 and AbbVie.

Abstract INTRODUCTION Mounting evidence suggests that certain comorbidities may influence the clinical evolution of Alzheimer's dementia (AD). METHODS We conducted logistic regression analyses on the medical history and cognitive health diagnoses of participants in the Australian Imaging, Biomarker & Lifestyle study (n = 2443) to investigate cross‐sectional associations between various comorbidities and mild cognitive impairment (MCI)/AD. RESULTS A mixture of associations were observed. Higher comorbidity of anxiety and other neurological disorders was associated with higher odds of AD, while arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD. DISCUSSION This study underscores the links between specific comorbidities and MCI/AD. Further research is needed to elucidate the longitudinal comorbidity‐MCI/AD associations and underlying mechanisms of these associations. Highlights Comorbidities that significantly increased AD odds included anxiety and other neurological disorders. Arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD. Alcohol consumption had the most significant confounding effect in the study. Visual‐AD association was modified by age, sex, and APOE ε4 allele status. Anxiety‐AD and depression‐AD associations were modified by sex.

BackgroundWith an aging population, the prevalence of hearing loss and dementia are increasing rapidly. Hearing loss is currently considered the largest potentially modifiable risk factor for dementia. The effect of hearing interventions on cognitive function should therefore be investigated, as if effective, these may be successfully implemented to modify cognitive outcomes for older adults with hearing loss.MethodsThis prospective longitudinal observational cohort study compared outcomes of a convenience sample of prospectively recruited first-time hearing aid users without dementia from an audiology center with those of community-living older adults participating in a large prospective longitudinal cohort study with/without hearing loss and/or hearing aids. All participants were assessed at baseline, 18 months, and 36 months using the same measures.ResultsParticipants were 160 audiology clinic patients (48.8% female patient; mean age 73.5 years) with mild–severe hearing loss, fitted with hearing aids at baseline, and 102 participants of the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging (AIBL) (55.9% female patient; mean age 74.5 years). 18- and 36-month outcomes of subsets of the first participants to reach these points and complete the cognition assessment to date are compared. Primary comparative analysis showed cognitive stability for the hearing aid group while the AIBL group declined on working memory, visual attention, and psychomotor function. There was a non-significant trend for decline in visual learning for the AIBL group versus no decline for the hearing aid group. The hearing aid group showed significant decline on only 1 subtest and at a significantly slower rate than for the AIBL participants (p

BackgroundWe sought to understand how safety culture may evolve during disruption, by using the COVID-19 pandemic as an example, to identify vulnerabilities in the system that could impact patient outcomes.MethodsA cross-sectional analysis of transplant personnel at a high-volume transplant center was conducted using the Safety Attitudes Questionnaire (SAQ). Survey responses were scaled and evaluated pre- and post-COVID-19 (2019 and 2021).ResultsTwo-hundred and thirty-eight responses were collected (134 pre-pandemic and 104 post-pandemic). Represented organ groups included: kidney (N = 89;38%), heart (N = 18;8%), liver (N = 54;23%), multiple (N = 66;28%), and other (N = 10;4%). Responders primarily included nurses (N = 75;34%), administration (N = 50;23%), and physicians (N = 24;11%). Workers had high safety, job satisfaction, stress recognition, and working conditions satisfaction (score >75) both before and after the pandemic with overlapping responses across both timepoints. Stress recognition, safety, and working conditions improved post-COVID-19, but teamwork, job satisfaction, and perceptions of management were somewhat negatively impacted (all p > 0.05).ConclusionsDespite the serious health care disruptions induced by the pandemic, high domain ratings were notable and largely maintained in a high-volume transplant center. The SAQ is a valuable tool for healthcare units and can be used in longitudinal assessments of transplant culture of safety as a component of quality assurance and performance improvement initiatives.

Summary: Background: Tau positron emission tomography (PET) imaging enables longitudinal observation of tau accumulation in Alzheimer's disease (AD). 18F-MK6240 is a high affinity tracer for the paired helical filaments of tau in AD, widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the natural history of tau accumulation, and the impact of disease stage and reference region on the magnitude and effect size of regional change. Methods: One hundred and eighty-four participants: 89 cognitively unimpaired (CU) beta-amyloid negative (Aβ−), 44 CU Aβ+, 51 cognitively impaired Aβ+ (26 with mild cognitive impairment [MCI] and 25 with dementia) had follow-up 18F-MK6240 PET for one to four years (median 1.48). Regional standardised uptake value ratios (SUVR) were generated. Two reference regions were examined: cerebellar cortex and eroded subcortical white matter. Findings: CU Aβ− participants had very low rates of tau accumulation in the mesial temporal lobe (MTL). In CU Aβ+, significantly higher rate of accumulation was seen in the MTL (particularly the amygdala), extending into the inferior temporal lobes. In MCI Aβ+, the rate of accumulation was greatest in the lateral temporal, parietal and lateral occipital cortex, and plateaued in the MTL. Accumulation was global in AD Aβ+, except for a plateau in the MTL. The eroded subcortical white matter reference region showed no significant advantage over the cerebellar cortex and appeared prone to spill-over in AD participants. Data fitting suggested approximately 15–20 years to accumulate tau to typical AD levels. Interpretation: Tau accumulation occurs slowly. Rates vary according to brain region, disease stage and tend to plateau at high levels. Rates of tau accumulation are best measured in the MTL and inferior temporal cortex in preclinical AD and in large neocortical areas, in MCI and AD. Funding: NHMRC; Cerveau Technologies.

Objectives An increasing number of people are undergoing lumbar puncture (LP) for the purposes of research. Performing LP for research purposes introduces considerations that differ from LP performed for clinical, diagnostic or therapeutic reasons. The demand for research LP will greatly increase as biomarkers are used to both diagnose and monitor disease progression in clinical trials. Minimising adverse events is paramount because research participants receive no clinical benefit and often need repeat procedures. We describe the experience of performing LP for research by anaesthetists.Methods We reviewed the clinical protocol and incidence of adverse events in 326 research LP in an anaesthesia department.Results There was a lower incidence of adverse events compared with previous reports when LP was undertaken for clinical reasons. The incidence of severe post-LP headache was 1.3% when an atraumatic spinal needle with a 27 gauge tip and a 22 gauge shaft was used.Conclusions We describe the practice to sample cerebrospinal fluid (CSF) by LP for research purposes. Specific practices include the sitting position of the participant, aspiration rather than passive CSF withdrawal, attention to the sterility of the procedure, monitoring of vital signs and importantly the use of 22/27 gauge microtip spinal needle.Trial registration numbers ACTRN12612000493842, NCT04623242.

Abstract Background Peripheral blood microRNAs (miRNA) have been identified as potential biomarkers for Alzheimer’s disease (AD). Study results have generally been inconsistent and limited by sample heterogeneity. The aim of this study is to establish candidate blood miRNA biomarkers for AD by comparing differences in miRNA expression between participants with brain amyloid imaging-defined AD and normal cognition. Methods Blood RNA was extracted from a subset of participants from the Australian Imaging Biomarkers Lifestyle Study of Ageing cohort (AIBL) with brain amyloid imaging results. MiRNA profiling was performed using small RNA sequencing on 71 participants, comprising 40 AD with high brain amyloid burden on imaging (amyloid positive) and 31 cognitively normal controls with low brain amyloid burden (amyloid negative). Cross-sectional comparisons were made between groups to examine differential miRNA expression levels using Fisher’s exact tests. Replication of results was undertaken using a publicly available dataset of blood miRNA data of AD and controls. In silico analysis of downstream messenger RNA targets of candidate miRNAs was performed to elucidate potential biological function. Results After quality control, 816 miRNAs were available for analysis. There were 71 significantly differentially expressed miRNAs between the AD and control groups (p

Background: Worldwide, coffee is one of the most popular beverages consumed. Several studies have suggested a protective role of coffee, including reduced risk of Alzheimer’s disease (AD). However, there is limited longitudinal data from cohorts of older adults reporting associations of coffee intake with cognitive decline, in distinct domains, and investigating the neuropathological mechanisms underpinning any such associations.Methods: The aim of the current study was to investigate the relationship between self-reported habitual coffee intake, and cognitive decline assessed using a comprehensive neuropsychological battery in 227 cognitively normal older adults from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, over 126 months. In a subset of individuals, we also investigated the relationship between habitual coffee intake and cerebral Aβ-amyloid accumulation (n = 60) and brain volumes (n = 51) over 126 months.Results: Higher baseline coffee consumption was associated with slower cognitive decline in executive function, attention, and the AIBL Preclinical AD Cognitive Composite (PACC; shown reliably to measure the first signs of cognitive decline in at-risk cognitively normal populations), and lower likelihood of transitioning to mild cognitive impairment or AD status, over 126 months. Higher baseline coffee consumption was also associated with slower Aβ-amyloid accumulation over 126 months, and lower risk of progressing to “moderate,” “high,” or “very high” Aβ-amyloid burden status over the same time-period. There were no associations between coffee intake and atrophy in total gray matter, white matter, or hippocampal volume.Discussion: Our results further support the hypothesis that coffee intake may be a protective factor against AD, with increased coffee consumption potentially reducing cognitive decline by slowing cerebral Aβ-amyloid accumulation, and thus attenuating the associated neurotoxicity from Aβ-amyloid-mediated oxidative stress and inflammatory processes. Further investigation is required to evaluate whether coffee intake could be incorporated as a modifiable lifestyle factor aimed at delaying AD onset.

Age-related macular degeneration (AMD) is characterized by the accumulation of debris in the posterior eye. In this study we evaluated peripheral blood monocyte phagocytic function at various stages of AMD and in aged matched control participants. Real-time tri-color flow cytometry was used to quantify phagocytic function of peripheral blood monocyte subsets (non-classic, intermediate and classic) isolated from subjects with intermediate or late AMD and compared with age matched healthy controls. Assessment of phagocytic function of monocytes isolated from those with and without reticular pseudodrusen was also made, and the effect of glatiramer acetate on phagocytic function assessed. Phagocytic function was reduced in all subjects with AMD, irrespective of stage of disease. However, there was no correlation between phagocytic function and drusen load, nor any difference between the level of phagocytosis in those with or without reticular pseudodrusen. Treatment with glatiramer acetate increased phagocytosis of classical and non-classical monocytes, normalizing the reduction in phagocytosis observed in those with AMD. These findings suggest that defective systemic phagocytosis is associated with both intermediate and late stages of AMD, highlighting a potential role in the accumulation of debris that occurs early in the disease process. Assessing peripheral monocyte phagocytic function provides further insights into the etiology of this disease and offer a novel therapeutic target.

Abstract Introduction In cognitively normal (CN) adults, increased rates of amyloid beta (Aβ) accumulation can be detected in low Aβ (Aβ–) apolipoprotein E (APOE) ε4 carriers. We aimed to determine the effect of ε4 on the ability to benefit from experience (ie, learn) in Aβ– CNs. Methods Aβ– CNs (n = 333) underwent episodic memory assessments every 18 months for 108 months. A subset (n = 48) completed the Online Repeatable Cognitive Assessment‐Language Learning Test (ORCA‐LLT) over 6 days. Results Aβ– ε4 carriers showed significantly lower rates of improvement on episodic memory over 108 months compared to non‐carriers (d = 0.3). Rates of learning on the ORCA‐LLT were significantly slower in Aβ– ε4 carriers compared to non‐carriers (d = 1.2). Discussion In Aβ– CNs, ε4 is associated with a reduced ability to benefit from experience. This manifested as reduced practice effects (small to moderate in magnitude) over 108 months on the episodic memory composite, and a learning deficit (large in magnitude) over 6 days on the ORCA‐LLT. Alzheimer's disease (AD)–related cognitive abnormalities can manifest before preclinical AD thresholds.

PurposeThere has been increasing interest in identifying non-invasive, imaging biomarkers for neurodegenerative disorders of the central nervous system (CNS). The aim of this proof-of-concept study was to investigate whether corneal sensory nerve and dendritic cell (DC) parameters, captured using in vivo confocal microscopy (IVCM), are altered in individuals with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).MethodsFifteen participants were recruited from the Australian Imaging Biomarkers and Lifestyle (AIBL) study in Melbourne, VIC, Australia. The cohort consisted of cognitively normal (CN) individuals (n = 5), and those with MCI (n = 5) and AD (n = 5). Participants underwent a slit lamp examination of the anterior segment, followed by corneal imaging using laser-scanning in vivo confocal microscopy (IVCM) of the central and inferior whorl regions. Corneal DC density, field area, perimeter, circularity index, aspect ratio, and roundness were quantified using Image J. Quantitative data were derived for corneal nerve parameters, including nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and diameter.ResultsCorneal DC field area and perimeter were greater in individuals with MCI, relative to CN controls, in both the central and inferior whorl regions (p < 0.05 for all comparisons). In addition, corneal DCs in the whorl region of MCI eyes had lower circularity and roundness indices and a higher aspect ratio relative to CNs (p < 0.05 for all comparisons). DC density was similar across participant groups in both corneal regions. There was a trend toward lower quantitative parameters for corneal nerve architecture in the AD and MCI groups compared with CN participants, however, the inter-group differences did not reach statistical significance. Central corneal nerve diameters were similar between groups.ConclusionThis study is the first to report morphological differences in corneal DCs in humans with MCI. These differences were evident in both the central and mid-peripheral cornea, and in the absence of significant nerve abnormalities or a difference in DC density. These findings justify future large-scale studies to assess the utility of corneal IVCM and DC analysis for identifying early stage pathology in neurodegenerative disorders of the CNS.

Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03–2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31–17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.

Abstract Introduction This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. Methods CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results CSF NfL levels as well as NfL/amyloid β (Aβ42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aβ42). CSF NfL and NfL/Aβ42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aβ42 predicted cortical amyloid load, brain atrophy, and cognition. Discussion CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.

Abstract Introduction Plasma amyloid β (Aβ) peptides have been previously studied as candidate biomarkers to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Methods Free and total Aβ42/40 plasma ratios (FP42/40 and TP42/40, respectively) were determined using ABtest assays in cognitively normal subjects from the Australian Imaging, Biomarker and Lifestyle Flagship Study. This population was followed‐up for 72 months and their cortical Aβ burden was assessed with positron emission tomography. Results Cross‐sectional and longitudinal analyses showed an inverse association of Aβ42/40 plasma ratios and cortical Aβ burden. Optimized as a screening tool, TP42/40 reached 81% positive predictive value of high cortical Aβ burden, which represents 110% increase over the population prevalence of cortical Aβ positivity. Discussion These findings support the use of plasma Aβ42/40 ratios as surrogate biomarkers of cortical Aβ deposition and enrichment tools, reducing the number of subjects submitted to invasive tests and, consequently, recruitment costs in clinical trials targeting cognitively normal individuals.

Abstract Background The purpose of the present study was to identify variations in emotional dysregulation patterns among adults diagnosed with borderline personality disorder (BPD), with an eye toward implications for treatment. Methods Latent profile analysis (LPA) was utilized to classify 156 inpatients with BPD, based on patterns of Difficulties in Emotion Regulation Scale (DERS; Gratz and Roemer, J Psychopathol Behav Assess 26: 41-54, 2004) subscale scores. Results Results revealed that a three class solution best fit the sample (Low Impairment, Global Dysregulation, and Emotionally Aware). Further analysis of the classes at admission revealed that the Global Dysregulation group reported significantly higher suicidal ideation than either the Low Impairment or Emotionally Aware groups, and that the Global Dysregulation group reported significantly higher functional impairment than the Low Impairment group. Conclusions All three groups improved greatly over the course of hospital treatment, although they remained distinguishable at discharge, retaining their positions symptomatically relative to one another. Limitations, implications, and future directions are discussed.