Alison L. Baird

Plasma proteins predict conversion to dementia from prodromal disease

The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia.

Blood-Based Proteomic Biomarkers of Alzheimer's Disease Pathology.

The complexity of Alzheimer’s disease (AD) and its long prodromal phase poses challenges for early diagnosis and yet allows for the possibility of the development of disease modifying treatments for secondary prevention. It is, therefore, of importance to develop biomarkers, in particular, in the preclinical or early phases that reflect the pathological characteristics of the disease and, moreover, could be of utility in triaging subjects for preventative therapeutic clinical trials. Much research has sought biomarkers for diagnostic purposes by comparing affected people to unaffected controls. However, given that AD pathology precedes disease onset, a pathology endophenotype design for biomarker discovery creates the opportunity for detection of much earlier markers of disease. Blood-based biomarkers potentially provide a minimally invasive option for this purpose and research in the field has adopted various “omics” approaches in order to achieve this. This review will, therefore, examine the current literature regarding blood-based proteomic biomarkers of AD and its associated pathology.

Blood protein predictors of brain amyloid for enrichment in clinical trials

Measures of neocortical amyloid burden (NAB) identify individuals who are at substantially greater risk of developing Alzheimers disease (AD). Blood‐based biomarkers predicting NAB would have great utility for the enrichment of AD clinical trials, including large‐scale prevention trials.

Circadian rhythms and attention deficit hyperactivity disorder: The what, the when and the why.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterised by impulsivity, inattention and hyperactivity. Aside from these core psychopathologies, sleep disturbances are found to be highly comorbid with ADHD, and indeed dysregulated sleep may contribute to some of the symptoms of the disorder. It is not clear how sleep disturbances come to be so common in ADHD, but one putative mechanism is through the circadian timekeeping system. This system underpins the generation of near 24-hour rhythms in a host of physiological, behavioural and psychological parameters, and is a key determinant of the sleep/wake cycle. In this paper we review the evidence for sleep and circadian rhythm disturbance in ADHD, examine the possible mechanistic links between these factors and the disorder and discuss future directions through which the circadian clock can be targetted for ADHD symptom relief.

Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly

Increasingly, clinical trials for Alzheimers disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

ZNF804A Genotype Modulates Neural Activity during Working Memory for Faces

Background: Genetic susceptibility to schizophrenia (SZ) has been suggested to influence the cortical systems supporting working memory (WM) and face processing. Genetic imaging studies link the SZ risk variant rs1344706 on the ZNF804A gene to psychosis via alterations in functional brain connectivity during WM, but no work has looked at the effects of ZNF804A on WM with face-processing components. Methods: We therefore investigated healthy controls that were genotyped for rs1344706 with a face WM task during functional magnetic resonance imaging. We suggested that variation at the rs1344706 locus would be associated with similar alterations as patients previously tested using the same WM task for faces. Results: The rs1344706 risk allele was indeed associated with altered activation in the right dorsolateral prefrontal (rDLPFC) cortex. We established that the rDLPFC was activated in a task-dependent manner, suggesting that the differences in activation between rs1344706 genotype groups reflected alterations in task processing. Furthermore, we demonstrated that the rDLPFC region showed significant volumetric overlap with the rDLPFC which had previously been reported to be altered during task processing for patients with SZ. Conclusions: The findings support an association between rs1344706 and alterations in DLPFC activity during WM for faces. We further suggest that WM for faces may be a useful intermediate phenotype in the investigation of genetic susceptibility to psychosis.

Blood metabolite markers of neocortical amyloid-β burden: discovery and enrichment using candidate proteins.

We believe this is the first study to investigate associations between blood metabolites and neocortical amyloid burden (NAB) in the search for a blood-based biomarker for Alzheimers disease (AD). Further, we present the first multi-modal analysis of blood markers in this field. We used blood plasma samples from 91 subjects enrolled in the University of California, San Francisco Alzheimers Disease Research Centre. Non-targeted metabolomic analysis was used to look for associations with NAB using both single and multiple metabolic feature models. Five metabolic features identified subjects with high NAB, with 72% accuracy. We were able to putatively identify four metabolites from this panel and improve the model further by adding fibrinogen gamma chain protein measures (accuracy=79%). One of the five metabolic features was studied in the Alzheimers Disease Neuroimaging Initiative cohort, but results were inconclusive. If replicated in larger, independent studies, these metabolic features and proteins could form the basis of a blood test with potential for enrichment of amyloid pathology in anti-amyloid trials.

A Decade of Blood Biomarkers for Alzheimer's Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication.

Blood-based biomarkers represent a less invasive and potentially cheaper approach for aiding Alzheimer’s disease (AD) detection compared with cerebrospinal fluid and some neuroimaging biomarkers. Acknowledging that many in the field have made great progress, here we review some of the work that our group has pursued to identify and validate blood-based proteomic biomarkers through both case control and AD pathology endophenotype-based approaches. Our focus is primarily to identify a minimally invasive and hopefully cost-effective blood-based biomarker to reduce screen failure in clinical trials where participants have prodromal or even pre-clinical disease. We summarize some of the key findings and approaches taken in these biomarker studies, while addressing the main challenges, including that of limited replication in the field, and discuss opportunities for biomarker development.

PLASMA PRIMARY FATTY AMIDES ASSOCIATE TO CSF AMYLOID LEVELS AND ALZHEIMER’S DISEASE PROGRESSION IN THE EMIF-AD BIOMARKER DISCOVERY COHORT

with albumin ratio (r1⁄40.28, p1⁄40.006). We observed no independent effects, but a synergistic effect of IL-6 and albumin ratio on Aß (Z1⁄4-2.72, p1⁄40.006). The JN-analyses showed that the association between albumin ratio and Aßwas significant for IL-6 levels 3.48 pg/ml. We found no direct relation between the albumin ratio and p-Tau levels (p1⁄40.91), but mediation analyses indicated that the mediation of Aß,on the association between BBB dysfuction and p-Tau, was contingent on elevated IL-6 levels (indirect effect for IL-6: mean-1s (b1⁄40.026, Z1⁄40.075, p1⁄40.94), mean (b1⁄41.16, Z1⁄41.64, p1⁄40.09), mean+1s (b1⁄43.51, Z1⁄40.197, p1⁄40.049)). There is a negative relationship between Aß and pTau (p<0.001). Conclusions: The results suggest a link between BBB-dysfunction and markers of neurodegeneration via Aßmediated mechanisms in the presence of elevated IL-6 levels, indicating that inflammation and BBB-dysfunction, in addition to Aß are important components in the path to neurodegeneration. These results fit with autopsy studies reporting a common cooccurrence of Aß and vascular pathology in AD-type dementia.

GENOMICS AND EPIGENOMICS ANALYSES IN THE EMIF-AD MULTIMODAL BIOMARKER DISCOVERY STUDY

These associations were stronger in MCI compared to CN. The multi-variable SVM classifier provided an area under the curve (AUC) of 0.74 6 0.08 in CN (Figure 1) and an AUC of 0.79 6 0.08 in MCI (Figure 2). Conclusions:Amyloid pathology is associated with changes in structural MRI measures in preclinical and prodromal AD. An automated classifier based on clinical and imaging variables can identify the presence of amyloid pathology with a moderate level of accuracy. These results could be used in trial design to pre-screen subjects for enrolment.