Kelly K. Pertile

Plasma Amyloid-β as a Biomarker in Alzheimer's Disease: The AIBL Study of Aging

Amyloid-beta (Abeta) plays a central role in the pathogenesis of Alzheimers disease (AD) and has been postulated as a potential biomarker for AD. However, there is a lack of consensus as to its suitability as an AD biomarker. The objective of this study was to determine the significance of plasma Abeta as an AD biomarker and its relationship with Abeta load and to determine the effect of different assay methods on the interpretation of Abeta levels. Plasma Abeta1-40, Abeta1-42, and N-terminal cleaved fragments were measured using both a commercial multiplex assay and a well-documented ELISA in 1032 individuals drawn from the well-characterized Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Further, Abeta levels were compared to Abeta load derived from positron-emission tomography (PET) with the Pittsburgh compound B (PiB). Lower Abeta1-42 and Abeta1-42/1-40 ratio were observed in patients with AD and inversely correlated with PiB-PET derived Abeta load. However, assay methodology significantly impacted the interpretation of data. The cross-sectional analysis of plasma Abeta isoforms suggests that they may not be sufficient per se to diagnose AD. The value of their measurement in prognosis and monitoring of AD interventions needs further study, in addition to future longitudinal comparisons together with other predictors, which will determine whether plasma Abeta has diagnostic value in a panel of biomarkers.

Changes in plasma amyloid beta in a longitudinal study of aging and Alzheimer's disease

A practical biomarker is required to facilitate the preclinical diagnosis of Alzheimers disease (AD).

Homocysteine, Vitamin B12, and Folic Acid Levels in Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Elderly: Baseline Characteristics in Subjects of the Australian Imaging Biomarker Lifestyle Study.

There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimers disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.

An anemia of Alzheimer's disease

Lower hemoglobin is associated with cognitive impairment and Alzheimers disease (AD). Since brain iron homeostasis is perturbed in AD, we investigated whether this is peripherally reflected in the hematological and related blood chemistry values from the Australian Imaging Biomarker and Lifestyle (AIBL) study (a community-based, cross-sectional cohort comprising 768 healthy controls (HC), 133 participants with mild cognitive impairment (MCI) and 211 participants with AD). We found that individuals with AD had significantly lower hemoglobin, mean cell hemoglobin concentrations, packed cell volume and higher erythrocyte sedimentation rates (adjusted for age, gender, APOE-ɛ4 and site). In AD, plasma iron, transferrin, transferrin saturation and red cell folate levels exhibited a significant distortion of their customary relationship to hemoglobin levels. There was a strong association between anemia and AD (adjusted odds ratio (OR)=2.43, confidence interval (CI) (1.31, 4.54)). Moreover, AD emerged as a strong risk factor for anemia on step-down regression, even when controlling for all other available explanations for anemia (adjusted OR=3.41, 95% CI (1.68, 6.92)). These data indicated that AD is complicated by anemia, which may itself contribute to cognitive decline.

Longitudinal Analysis of Serum Copper and Ceruloplasmin in Alzheimer's Disease

BACKGROUND Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimers disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects. METHODS Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status. RESULTS There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003). CONCLUSION Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD.

Peripheral α-defensins 1 and 2 are elevated in Alzheimer's disease.

Biomarkers enabling the preclinical identification of Alzheimers disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and neuroimaging modalities. The current study aimed to replicate our earlier reports of altered binding within the AD-affected blood cellular fraction to copper-loaded immobilized metal affinity capture (IMAC) arrays. IMAC and anti-amyloid-β (Aβ) antibody arrays coupled with mass spectrometry were used to analyze blood samples collected from 218 participants from within the AIBL Study of Aging. Peripheral Aβ was fragile and prone to degradation in the AIBL samples, even when stored at -80°C. IMAC analysis of the AIBL samples lead to the isolation and identification of alpha-defensins 1 and 2 at elevated levels in the AD periphery, validating earlier findings. Alpha-defensins 1 and 2 were elevated in AD patients indicating that an inflammatory phenotype is present in the AD periphery; however, peripheral Aβ levels are required to supplement their prognostic power.

Alzheimer's disease is associated with lower hemoglobin levels and anemia: The Australian Imaging Biomarker Lifestyle (AIBL) study of aging

Initiative. Ventricle sub-volume segmentation was performed in all images using semi-automated software. Longitudinal volume enlargement was evaluated using a repeated-measures ANOVA for each sub-region for a total of 30 analyses. Paired t-tests were used as a post-hoc analysis to each ANOVA performed and Bonferroni correction factors were applied. Rates of temporal horn change were calculated as a percentage change from baseline. Results: In the AD group, all sub-regions except the RLA were significant larger in at least one pair-wise comparison, where p < 0.05. The RLP, LLM, LLP regions were significantly larger at all three time points. The RLM, LLA, LAH, LPH, RAH were all significantly larger from baseline compared to 12-month and from baseline compared to 24-month but not between 12month and 24-month. The RPH experienced significant enlargement from baseline to 24-month but not in any other pair-wise comparison. The MCI and NEC groups had no significant enlargement in any sub-region longitudinally. AD subjects experienced the greatest percent change in temporal horn enlargement in all temporal horn regions (LAH, RAH, LPH, RPH) compared to baseline. Conclusions: Significant enlargement longitudinally within ventricle sub-regions in AD subjects suggest that AD patients experience the greatest rate in volumetric change. Larger groups are needed to better understand changes in MCI and NEC populations. In conclusion, sub-region ventricle segmentation may provide additional information in regional volume differences between patient populations over time.

Concordance Between Cerebrospinal Fluid Biomarkers with Alzheimer’s Disease Pathology Between Three Independent Assay Platforms

BACKGROUND To enhance the accuracy of clinical diagnosis for Alzheimers 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 < 0.0001); however, comparison of predictive models for PET Aβ-amyloid showed no difference between Aβ42 alone and the T-tau/Aβ42 ratio. CONCLUSION This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.

ELEVATED BLOOD HDL AND HDL-ASSOCIATED LIPOPROTEINS IN HEALTHY CONTROLS WHO RAPIDLY CONVERT TO ALZHEIMER'S DISEASE IN THE AIBL COHORT

Figure 1. VEGF levels in the serum of patients of AD without depression, AD with depression, and control subjects. The levels of serum VEGF in patients with AD with depression was significant higher than that in the AD without depression as well as control. (F(2,72) 1⁄43.51, p< .05). The levels of serum VEGF in patients with AD without depression were no significant difference compared to the control subjects. Christopher James Fowler, Luz Fernanda Yevenes, Alan Rembach, Noel Garry Faux, Brett Trounson, Kelly Pertile, Rebecca Rumble, Kathryn A. Ellis, David Ames, Ashley I. Bush, Ralph Martins, Colin Louis Masters, Florey Institute of Neuroscience, Melbourne, Australia; Florey Institute of Neuroscience andMental Health, Melbourne, Australia; Florey Institute of Neuroscience and Mental Health, Parkville, Australia; St Georges Hospital, Parkville, Australia; National Ageing Research Institute Inc. (NARI), Parkville, Australia; Florey Institute of Neuroscience & Mental Health, Parkville, Australia; Edith Cowan University, Joondalup, Australia. Contact e-mail: christopher.fowler@ florey.edu.au