Blood-based molecular biomarkers for Alzheimer\u27s disease

A major barrier to the effective conduct of clinical trials of new drug candidates against Alzheimer\u27s disease (AD) and to identifying patients for receiving future disease-modifying treatments is the limited capacity of the current health system to find and diagnose patients with early AD pathology. This may be related in part to the limited capacity of the current health systems to select those people likely to have AD pathology in order to confirm the diagnosis with available cerebrospinal fluid and imaging biomarkers at memory clinics. In the current narrative review, we summarize the literature on candidate blood tests for AD that could be implemented in primary care settings and used for the effective identification of individuals at increased risk of AD pathology, who could be referred for potential inclusion in clinical trials or future approved treatments following additional testing. We give an updated account of blood-based candidate biomarkers and biomarker panels for AD-related brain changes. Our analysis centres on biomarker candidates that have been replicated in more than one study and discusses the need of further studies to achieve the goal of a primary care-based screening algorithm for AD

Getting to the Root of Bacterial Hairs: What is “s”?

An atomic force microscope (AFM) was used to measure the steric forces of lipopolysaccharides (LPS) on the biofilm-forming bacteria, Pseudomonas aeruginosa. It is well known that LPS play a vital role in biofilm formation. These forces were characterized with a modified version of the Alexander and de Gennes (AdG) model for polymers, which is a function of equilibrium brush length, L, probe radius, R, temperature, T, separation distance, D, and an indefinite density variable, s. This last parameter was originally distinguished by de Gennes as the root spacing or mesh spacing depending upon the type of polymer adhesion; however since then it has been commonly thought of as the root spacing. This study aims to clarify the ambiguity of this parameter as a first step in characterizing biofilm formation. Varying the temperature and pH at which the steric forces of the LPS are measured and then analyzing the produced force curves with Matlab, should allow us to measure s. The Matlab program has been written to crop large numbers of force curves in accordance with the Alexander and de Gennes polymer model objectively and quickly. If s is the root spacing it should remain constant regardless of the changing polymer lengths, on the other hand if it is the mesh spacing it will be proportional to the temperature and pH. Preliminary data suggest that the LPS vary with temperature and pH. The data also suggest that s represents the mesh spacing. Once s has been described, further studies can be done to determine how environmental changes influence L, and s and consequently biofilm formation

Home sick: impacts of migratory beekeeping on honey bee (Apis mellifera) pests, pathogens, and colony size

Honey bees are important pollinators of agricultural crops and the dramatic losses of honey bee colonies have risen to a level of international concern. Potential contributors to such losses include pesticide exposure, lack of floral resources and parasites and pathogens. The damaging effects of all of these may be exacerbated by apicultural practices. To meet the pollination demand of US crops, bees are transported to areas of high pollination demand throughout the year. Compared to stationary colonies, risk of parasitism and infectious disease may be greater for migratory bees than those that remain in a single location, although this has not been experimentally established. Here, we conducted a manipulative experiment to test whether viral pathogen and parasite loads increase as a result of colonies being transported for pollination of a major US crop, California almonds. We also tested if they subsequently transmit those diseases to stationary colonies upon return to their home apiaries. Colonies started with equivalent numbers of bees, however migratory colonies returned with fewer bees compared to stationary colonies and this difference remained one month later. Migratory colonies returned with higher black queen cell virus loads than stationary colonies, but loads were similar between groups one month later. Colonies exposed to migratory bees experienced a greater increase of deformed wing virus prevalence and load compared to the isolated group. The three groups had similar infestations of Varroa mites upon return of the migratory colonies. However, one month later, mite loads in migratory colonies were significantly lower compared to the other groups, possibly because of lower number of host bees. Our study demonstrates that migratory pollination practices has varying health effects for honey bee colonies. Further research is necessary to clarify how migratory pollination practices influence the disease dynamics of honey bee diseases we describe here

Decreased Serum Zinc Is An Effect Of Ageing And Not Alzheimer\u27s Disease

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

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development

Visually identified Tau 18F-MK6240 PET patterns in symptomatic Alzheimer\u27s disease

Background: In Alzheimer\u27s disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. Objective: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. Methods : Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. Results: Visual rating resulted in 59.6 % classified as Typical, 17.9 % as MTL-sparing, 9.9 % LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen\u27s kappa values of 0.89 and 0.86 respectively). Tracer retention in a hook -like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High crtical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. Conclusion: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition

Using imputation to provide harmonized longitudinal measures of cognition across AIBL and ADNI

To improve understanding of Alzheimer’s disease, large observational studies are needed to increase power for more nuanced analyses. Combining data across existing observational studies represents one solution. However, the disparity of such datasets makes this a non-trivial task. Here, a machine learning approach was applied to impute longitudinal neuropsychological test scores across two observational studies, namely the Australian Imaging, Biomarkers and Lifestyle Study (AIBL) and the Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) providing an overall harmonised dataset. MissForest, a machine learning algorithm, capitalises on the underlying structure and relationships of data to impute test scores not measured in one study aligning it to the other study. Results demonstrated that simulated missing values from one dataset could be accurately imputed, and that imputation of actual missing data in one dataset showed comparable discrimination (p \u3c 0.001) for clinical classification to measured data in the other dataset. Further, the increased power of the overall harmonised dataset was demonstrated by observing a significant association between CVLT-II test scores (imputed for ADNI) with PET Amyloid-β in MCI APOE-ε4 homozygotes in the imputed data (N = 65) but not for the original AIBL dataset (N = 11). These results suggest that MissForest can provide a practical solution for data harmonization using imputation across studies to improve power for more nuanced analyses

Follow-up Plasma Apolipoprotein e Levels In The Australian Imaging, Biomarkers And Lifestyle Flagship Study of Ageing (AIBL) Cohort

Introduction: Alzheimer\u27s disease (AD) is a growing socioeconomic problem worldwide. Early diagnosis and prevention of this devastating disease have become a research priority. Consequently, the identification of clinically significant and sensitive blood biomarkers for its early detection is very important. Apolipoprotein E (APOE) is a well-known and established genetic risk factor for late-onset AD; however, the impact of the protein level on AD risk is unclear. We assessed the utility of plasma ApoE protein as a potential biomarker of AD in the large, well-characterised Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) cohort. Methods: Total plasma ApoE levels were measured at 18-month follow-up using a commercial bead-based enzyme-linked immunosorbent assay: the Luminex xMAP human apolipoprotein kit. ApoE levels were then analysed between clinical classifications (healthy controls, mild cognitive impairment (MCI) and AD) and correlated with the data available from the AIBL cohort, including but not limited to APOE genotype and cerebral amyloid burden. Results: A significant decrease in ApoE levels was found in the AD group compared with the healthy controls. These results validate previously published ApoE protein levels at baseline obtained using different methodology. ApoE protein levels were also significantly affected, depending on APOE genotypes, with ε2/ε2 having the highest protein levels and ε4/ε4 having the lowest. Plasma ApoE levels were significantly negatively correlated with cerebral amyloid burden as measured by neuroimaging. Conclusions: ApoE is decreased in individuals with AD compared with healthy controls at 18-month follow-up, and this trend is consistent with our results published at baseline. The influence of APOE genotype and sex on the protein levels are also explored. It is clear that ApoE is a strong player in the aetiology of this disease at both the protein and genetic levels. © 2015 Gupta et al.; licensee BioMed Central

COMT val158met is not associated with Aβ-amyloid and APOE ε4 related cognitive decline in cognitively normal older adults

The non-synonymous single nucleotide polymorphism (SNP), Val158Met within the Catechol-O-methyltransferase (COMT) gene has been associated with altered levels of cognition and memory performance in cognitively normal adults. This study aimed to investigate the independent and interactional effects of COMT Val158Met on cognitive performance. In particular, it was hypothesised that COMT Val158Met would modify the effect of neocortical Aβ-amyloid (Aβ) accumulation and carriage of the apolipoprotein E (APOE) ε4 allele on cognition in preclinical Alzheimer’s disease (AD). In 598 cognitively normal older adults with known neocortical Aβ levels, linear mixed modelling revealed no significant independent or interactional associations between COMT Val158Met and cognitive decline. These findings do not support previous associations between COMT Val158Met and cognitive performance and suggest this variant does not influence Aβ-amyloid or APOE ε4 driven cognitive decline in a well characterised cohort of cognitively normal older adults

Plasma glial fibrillary acidic protein is associated with 18F-SMBT-1 PET: Two putative astrocyte reactivity biomarkers for Alzheimer\u27s disease

Background: Astrocyte reactivity is an early event along the Alzheimer\u27s disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD. Objective: The objective of this study was to evaluate the association between the abovementioned astrocyte reactivity biomarkers. Methods: Plasma GFAP and Aβ were measured using the Simoa® platform in participants who underwent brain 18F-SMBT-1 and Aβ-PET imaging, comprising 54 healthy control (13 Aβ-PET+ and 41 Aβ-PET-), 11 mild cognitively impaired (3 Aβ-PET+ and 8 Aβ-PET-) and 6 probable AD (5 Aβ-PET+ and 1 Aβ-PET-) individuals. Linear regressions were used to assess associations of interest. Results: Plasma GFAP was associated with 18F-SMBT-1 signal in brain regions prone to early Aβ deposition in AD, such as the supramarginal gyrus (SG), posterior cingulate (PC), lateral temporal (LT) and lateral occipital cortex (LO). After adjusting for age, sex, APOE ɛ4 genotype, and soluble Aβ (plasma Aβ42/40 ratio), plasma GFAP was associated with 18F-SMBT-1 signal in the SG, PC, LT, LO, and superior parietal cortex (SP). On adjusting for age, sex, APOE ɛ4 genotype and insoluble Aβ (Aβ-PET), plasma GFAP was associated with 18F-SMBT-1 signal in the SG. Conclusion: There is an association between plasma GFAP and regional 18F-SMBT-1 PET, and this association appears to be dependent on brain Aβ load