Systemic perturbations of the kynurenine pathway precede progression to dementia independently of amyloid-ß.

Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-ß and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease.

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 Aß-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.

Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies.

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-ß peptide (also known as Aß or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aß 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 Aß.

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

BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial. OBJECTIVE: Assessing levels of Aß-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aß-amyloid (32 Aß-amyloid-and 45 Aß-amyloid+), as well as concordance between CSF biomarker levels and PET Aß-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/Aß42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ= 0.69-0.8) as compared with Aß42 alone (ρ= 0.66-0.75). Differences in CSF biomarker levels between the PET Aß-amyloid-and Aß-amyloid+ groups were strongest for the Aß42/Aß40 and T-tau/Aß42 ratios (p < 0.0001); however, comparison of predictive models for PET Aß-amyloid showed no difference between Aß42 alone and the T-tau/Aß42 ratio. CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aß-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.

A randomized, exploratory molecular imaging study targeting amyloid ß with a novel 8-OH quinoline in Alzheimer's disease: The PBT2-204 IMAGINE study.

INTRODUCTION: We are developing a second generation 8-OH quinoline (2-(dimethylamino) methyl-5, 7-dichloro-8-hydroxyquinoline [PBT2, Prana Biotechnology]) for targeting amyloid ß (Aß) in Alzheimer's disease (AD). In an earlier phase IIa, 3 month trial, PBT2 lowered cerebrospinal fluid Aß by 13% and improved cognition (executive function) in a dose-related fashion in early AD. We, therefore, sought to learn whether PBT2 could alter the Aß-PET signal in subjects with prodromal or mild AD, in an exploratory randomized study over a 12-month phase in a double-blind and a 12-month open label extension phase trial design. METHODS: For inclusion, the usual clinical criteria for prodromal or probable AD, Mini-Mental State Examination ≥20, and global Pittsburgh compound B (PiB)-PET standardized uptake volume ratio (SUVR) >1.7 were used. As this was an exploratory study, we included contemporaneous matched control data from the Australian Imaging Biomarker and Lifestyle Study (AIBL). Other measures included fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging volumetrics, blood Aß biomarkers, and cognition and function. RESULTS: Forty subjects completed the first 12-month double-blind phase (placebo = 15, PBT2 = 25), and 27 subjects completed the 12-month open label extension phase (placebo = 11, PBT2 = 16). Overall, PTB2 250 mg/day was safe and well tolerated. The mean PiB-PET SUVR at baseline was 2.51 ± 0.59. After adjusting for baseline SUVR, in the double-blind phase, the placebo group showed a nonsignificant decline in PiB-PET SUVR, whereas the PBT2 group declined significantly (P = .048). Subjects who did not enter or complete the extension study had a significantly higher 12-month Aß-PET SUVR (2.68 ± 0.55) compared with those who completed (2.29 ± 0.48). Both groups differed significantly from the rate of change over 12 months in the AIBL control group. In the open label 12-month extension study, the PiB-SUVR stabilized. There were no significant differences between PBT2 and controls in fluorodeoxyglucose-positron emission tomography, magnetic resonance imaging volumetrics, blood Aß biomarkers, or cognition/function over the course of the double-blind phase. DISCUSSION: There was no significant difference between PBT2 and controls at 12 months, likely due to the large individual variances over a relatively small number of subjects. PBT2 was associated with a significant 3% PiB-PET SUVR decline in the double-blind phase and a stabilization of SUVR in the open-label phase. From this exploratory study, we have learned that the entry criterion of SUVR should have been set at ≥ 1.5 and <2.0, where we know from the AIBL study that subjects in this band are accumulating Aß in a linear fashion and that subjects who withdrew from this type of study have much higher SUVRs, which if not taken into account, could distort the final results. Because of large individual variations in SUVR, future studies of PBT2 will require larger numbers of subjects (n > 90 per arm) over a longer period (18 months or more). Further evaluation of higher doses of PBT2 in earlier stages of AD is warranted. TRIAL REGISTRATION: ACTRN 12611001008910 and ACTRN 12613000777796.

Biochemically-defined pools of amyloid-ß in sporadic Alzheimer's disease: correlation with amyloid PET.

We fractionated frontal cortical grey matter from human Alzheimer's disease and control subjects into four biochemically defined pools that represent four distinct compartments: soluble/cytosolic, peripheral membrane/vesicular cargo, integral lipid/membranous pools and aggregated/insoluble debris. Most of the readily extractable amyloid-ß remains associated with a lipid/membranous compartment. There is an exchange of amyloid-ß between the biochemical pools that was lost for the amyloid-ß42 species in Alzheimer's disease, consistent with the peptide being irreversibly trapped in extracellular deposits. The quantitative amyloid-ß data, combined with magnetic resonance imaging volumetric analysis of the amount of cortical grey matter in brain, allowed us to estimate the total mass of amyloid-ß in Alzheimer's disease (6.5 mg) and control (1.7 mg) brains. The threshold positron emission tomography standard uptake value ratio of 1.4 equates to 5.0 µg amyloid-ß/g of grey matter and the mean Alzheimer's disease dementia standard uptake value ratio level of 2.3 equates to 11.20 µg amyloid-ß/g of grey matter. It takes 19 years to accumulate amyloid from the threshold positron emission tomography standard uptake value ratio to the mean value observed for Alzheimer's disease dementia. This accumulation time window combined with the difference of 4.8 mg of amyloid-ß between Alzheimer's disease and control brain allows for a first approximation of amyloid-ß accumulation of 28 ng/h. This equates to an estimated 2-5% of the total amyloid-ß production being deposited as insoluble plaques. Understanding these rates of amyloid-ß accumulation allows for a more quantitative approach in targeting the failure of amyloid-ß clearance in sporadic Alzheimer's disease.

Amyloid burden and incident depressive symptoms in cognitively normal older adults.

OBJECTIVE: Several studies have reported that non-demented older adults with clinical depression show changes in amyloid-ß (Aß) levels in blood, cerebrospinal fluid and on neuroimaging that are consistent with those observed in patients with Alzheimer's disease. These findings suggest that Aß may be one of the mechanisms underlying the relation between the two conditions. We sought to determine the relation between elevated cerebral Aß and the presence of depression across a 54-month prospective observation period. METHODS: Cognitively normal older adults from the Australian Imaging Biomarkers and Lifestyle study who were not depressed and had undergone a positron emission tomography scan to classify them as either high Aß (n = 81) or low Aß (n = 278) participated. Depressive symptoms were assessed using the Geriatric Depression Scale - Short Form at 18-month intervals over 54 months. RESULTS: Whilst there was no difference in probable depression between groups at baseline, incidence was 4.5 (95% confidence interval [CI] 1.3-16.4) times greater within the high Aß group (9%) than the low Aß group (2%) by the 54-month assessment. CONCLUSIONS: Results of this study suggest that elevated Aß levels are associated with a 4.5-fold increased likelihood of developing clinically significant depressive symptoms on follow-up in preclinical Alzheimer's disease. This underscores the importance of assessing, monitoring and treating depressive symptoms in older adults with elevated Aß. Copyright © 2016 John Wiley & Sons, Ltd.

Rubidium and potassium levels are altered in Alzheimer's disease brain and blood but not in cerebrospinal fluid.

Loss of intracellular compartmentalization of potassium is a biochemical feature of Alzheimer's disease indicating a loss of membrane integrity and mitochondrial dysfunction. We examined potassium and rubidium (a biological proxy for potassium) in brain tissue, blood fractions and cerebrospinal fluid from Alzheimer's disease and healthy control subjects to investigate the diagnostic potential of these two metal ions. We found that both potassium and rubidium levels were significantly decreased across all intracellular compartments in the Alzheimer's disease brain. Serum from over 1000 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), showed minor changes according to disease state. Potassium and rubidium levels in erythrocytes and cerebrospinal fluid were not significantly different according to disease state, and rubidium was slightly decreased in Alzheimer's disease patients compared to healthy controls. Our data provides evidence that contrasts the hypothesized disruption of the blood-brain barrier in Alzheimer's disease, with the systemic decrease in cortical potassium and rubidium levels suggesting influx of ions from the blood is minimal and that the observed changes are more likely indicative of an internal energy crisis within the brain. These findings may be the basis for potential diagnostic imaging studies using radioactive potassium and rubidium tracers.

Innate phagocytosis by peripheral blood monocytes is altered in Alzheimer's disease.

Sporadic Alzheimer's disease (AD) is characterised by the deposition and accumulation of specific protein aggregates. Failure of clearance could underlie this process, and recent genetic association studies point towards involvement of the phagocytosis and autophagy pathways. We developed a real-time tri-color flow cytometry method to quantitate the phagocytic function of human peripheral blood monocyte subsets including non-classic CD14(dim)CD16(+), intermediate CD14(+)CD16(+) and classic CD14(+)CD16(-) monocytes. Using this method, we have measured the phagocytic ability of fresh monocytes in a study of preclinical, prodromal and clinical AD, matched with cognitively normal healthy control subjects. Basal levels of phagocytosis in all three subsets of monocytes were similar between healthy controls and AD patients, while a significant increase of basal phagocytosis was found in subjects with high Aß-amyloid burden as assessed by PET scans. Pre-treating cells with Copaxone (CPX, to stimulate phagocytosis) or ATP (an inhibitor of P2X7-mediated phagocytosis) showed a differential response depending on clinical or Aß-burden status, indicating a relative functional deficit. Overall the results are consistent with a perturbation of basal and stimulated innate phagocytosis in sporadic AD.

Plasma apolipoprotein J as a potential biomarker for Alzheimer's disease: Australian Imaging, Biomarkers and Lifestyle study of aging.

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 (Aß), neocortical Aß 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 < .0001). ApoJ significantly correlated with both "standardized uptake value ratio" (SUVR) and hippocampus volume and weakly correlated with the plasma Aß1-42/Aß1-40 ratio. Plasma apoJ predicted both MCI and AD from HC with greater than 80% accuracy for AD and greater than 75% accuracy for MCI at both baseline and 18-month time points. DISCUSSION: Mean apoJ levels were significantly higher in both MCI and AD groups. ApoJ was able to differentiate between HC with high SUVR and HC with low SUVR via APOE ε4 allele status, indicating that it may be included in a biomarker panel to identify AD before the onset of clinical symptoms.

High Content, Multi-Parameter Analyses in Buccal Cells to Identify Alzheimer's Disease.

Alzheimer's disease (AD) is a degenerative brain disorder and is the most common form of dementia. Minimally invasive approaches are required that combine biomarkers to identify individuals who are at risk of developing mild cognitive impairment (MCI) and AD, to appropriately target clinical trials for therapeutic discovery as well as lifestyle strategies aimed at prevention. Buccal mucosa cells from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing cohort (n=60) were investigated for cytological markers that could be used to identify both MCI and AD individuals. Visual scoring of the buccal cytome demonstrated a significantly lower frequency of basal and karyorrhectic cells in the MCI group compared with controls. A high content, automated assay was developed using laser scanning cytometry to simultaneously measure cell types, nuclear DNA content and aneuploidy, neutral lipid content, putative Tau and amyloid-ß (Aß) in buccal cells. DNA content, aneuploidy, neutral lipids and Tau were similar in all groups. However, there was significantly lower Tau protein in both basal and karyolytic buccal cell types compared with differentiated buccal cells. Aß, as measured by frequency of cells containing Aß signal, as well as area and integral of Aß signal, was significantly higher in the AD group compared with the control group. Buccal cell Aß was correlated with mini-mental state examination (MMSE) scores (r = -0.436, P=0.001) and several blood-based biomarkers. Combining newly identified biomarkers from buccal cells with those already established may offer a potential route for more specific biomarker panels which may substantially increase the likelihood of better predictive markers for earlier diagnosis of AD.

Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-ß Burden.

BACKGROUND: APOEɛ4 genotype and aging have been identified as risk factors for Alzheimer's disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning. OBJECTIVE: To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-ß (Aß) burden in cognitively normal elderly. METHODS: 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aß pathology. RESULTS: Odds of high Aß burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aß burden. Stratified analyses showed that odds of SMC for high Aß burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01). CONCLUSION: Aging, APOEɛ4 genotype, and SMC were associated with high Aß burden. SMC were especially indicative of high Aß burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aß burden eligible for secondary prevention trials.

The Emerging Role of Metalloproteomics in Alzheimer's Disease Research.

Metals are increasingly recognized to have an important role in molecular processes underlying Alzheimer's disease (AD). This chapter discusses the current role of metals in AD and expands on the development of metalloproteomics and how the recent advances in analytical technology will allow detailed investigation of metalloproteins. Investigation of individual metalloproteins will yield new mechanistic details about the role of metals in AD.

Alzheimer's disease cerebrospinal fluid biomarkers are not influenced by gravity drip or aspiration extraction methodology.

INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers, although of established utility in the diagnostic evaluation of Alzheimer's disease (AD), are known to be sensitive to variation based on pre-analytical sample processing. We assessed whether gravity droplet collection versus syringe aspiration was another factor influencing CSF biomarker analyte concentrations and reproducibility. METHODS: Standardized lumbar puncture using small calibre atraumatic spinal needles and CSF collection using gravity fed collection followed by syringe aspirated extraction was performed in a sample of elderly individuals participating in a large long-term observational research trial. Analyte assay concentrations were compared. RESULTS: For the 44 total paired samples of gravity collection and aspiration, reproducibility was high for biomarker CSF analyte assay concentrations (concordance correlation [95%CI]: beta-amyloid1-42 (Aß42) 0.83 [0.71 - 0.90]), t-tau 0.99 [0.98 - 0.99], and phosphorylated tau (p-tau) 0.82 [95 % CI 0.71 - 0.89]) and Bonferroni corrected paired sample t-tests showed no significant differences (group means (SD): Aß42 366.5 (86.8) vs 354.3 (82.6), p = 0.10; t-tau 83.9 (46.6) vs 84.7 (47.4) p = 0.49; p-tau 43.5 (22.8) vs 40.0 (17.7), p = 0.05). The mean duration of collection was 10.9 minutes for gravity collection and <1 minute for aspiration. CONCLUSIONS: Our results demonstrate that aspiration of CSF is comparable to gravity droplet collection for AD biomarker analyses but could considerably accelerate throughput and improve the procedural tolerability for assessment of CSF biomarkers.

Self and informant memory concerns align in healthy memory complainers and in early stages of mild cognitive impairment but separate with increasing cognitive impairment.

BACKGROUND: Information provided by an informant about a patient with cognitive change is an essential component of clinical history taking. How an informant's report relates to the patient's phenomenological experience of memory loss is yet to be understood. The aim was to examine patterns of relationships between self and informant reports from a phenomenological perspective. METHODS: Forty-three healthy non-memory complainers (HC-NMC), 37 healthy subjective memory complainers (HC-SMC) and 43 individuals with mild cognitive impairment (MCI) were administered a semi-structured interview, which measured their concerns of frequency of memory lapses and impact on mood. Informants responded to questionnaires. RESULTS: Self-reported concerns of increasing frequency and impacted mood related to informant concerns in HC-SMCs. MCI with lower informant concern showed a similar pattern to HC-SMCs on complaints of increasing frequency. In those with higher informant concern, self-reports markedly separated from informant concern. The MCI group with greater informant concern performed comparatively poor on verbal and non-verbal memory measures. CONCLUSIONS: Our results suggest that the association between self-reported and informant memory concerns is moderated by MCI severity. Self and informant reports of increasing memory lapse frequency aligned in HC-SMC and MCIs with low informant concern, suggesting a similar dyadic experience of memory change. In MCIs with greater informant concern, the pattern changed exposing a changing insight with advancing memory impairment. These individuals are potentially reflecting a 'forgetting that they forget' phenomenon in elements of their concern.

Comparative analysis of the Cancer Council of Victoria and the online Commonwealth Scientific and Industrial Research Organisation FFQ.

FFQ are commonly used to examine the association between diet and disease. They are the most practical method for usual dietary data collection as they are relatively inexpensive and easy to administer. In Australia, the Cancer Council of Victoria FFQ (CCVFFQ) version 2 and the online Commonwealth Scientific and Industrial Research Organisation FFQ (CSIROFFQ) are used. The aim of our study was to establish the level of agreement between nutrient intakes captured using the online CSIROFFQ and the paper-based CCVFFQ. The CCVFFQ and the online CSIROFFQ were completed by 136 healthy participants. FFQ responses were analysed to give g per d intake of a range of nutrients. Agreement between twenty-six nutrient intakes common to both FFQ was measured by a variety of methods. Nutrient intake levels that were significantly correlated between the two FFQ were carbohydrates, total fat, Na and MUFA. When assessing ranking of nutrients into quintiles, on average, 56 % of the participants (for all nutrients) were classified into the same or adjacent quintiles in both FFQ, with the highest percentage agreement for sugar. On average, 21 % of participants were grossly misclassified by three or four quintiles, with the highest percentage misclassification for fibre and Fe. Quintile agreement was similar to that reported by other studies, and we concluded that both FFQ are suitable tools for dividing participants' nutrient intake levels into high- and low-consumption groups. Use of either FFQ was not appropriate for obtaining accurate estimates of absolute nutrient intakes.

Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-ß Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

BACKGROUND: The cerebrospinal fluid (CSF) amyloid-ß (Aß)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aß imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aß amyloid ligands. METHODS: Aß pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹8F-flutemetamol, or ¹8F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aß(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. RESULTS: CSF Aß(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aß(1-42) provided greater accuracy, predicting MCI/AD with Aß pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aß(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity. CONCLUSIONS: CSF Aß(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aß imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.

Buccal Cell Cytokeratin 14 Correlates with Multiple Blood Biomarkers of Alzheimer's Disease Risk.

Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as Alzheimer's disease (AD). Our hypothesis was that cytokeratin 14 (CK14) expression could be used with blood-based biomarkers such as homocysteine, vitamin B12, and folate to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Buccal cells from 54 individuals were analyzed by a newly developed method that is rapid, automated, and quantitative for buccal cell CK14 expression levels. CK14 was negatively correlated with plasma Mg²âº and LDL, while positively correlated with vitamin B12, red cell hematocrit/volume, and basophils in the MCI group and positively correlated with insulin and vitamin B12 in the AD group. The combined biomarker panel (CK14 expression, plasma vitamin B12, and homocysteine) was significantly lower in the MCI (p = 0.003) and AD (p = 0.0001) groups compared with controls. Receiver-operating characteristic curves yielded area under the curve (AUC) values of 0.829 for the MCI (p = 0.002) group and 0.856 for the AD (p = 0.0003) group. These complex associations of multiple related parameters highlight the differences between the MCI and AD cohorts and possibly an underlying metabolic pathology associated with the development of early memory impairment. The changes in buccal cell CK14 expression observed in this pilot study supports previous results suggesting the peripheral biomarkers and metabolic changes are not restricted to brain pathology alone in MCI and AD and could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD.