Thomas D. Parker

Study protocol: Insight 46 – a neuroscience sub-study of the MRC National Survey of Health and Development

BackgroundIncreasing age is the biggest risk factor for dementia, of which Alzheimer’s disease is the commonest cause. The pathological changes underpinning Alzheimer’s disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment – including β-amyloid depostion, vascular disease, network breakdown and atrophy – to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms.Methods/designThis paper outlines the clinical, cognitive and imaging protocol of “Insight 46”, a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71xa0years, a small fraction have overt dementia, but estimates suggest that ~1/3 of individuals in this age group may be in the preclinical stages of Alzheimer’s disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60–64xa0years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24xa0month) data collection covering clinical, neuropsychological, β-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73).DiscussionThrough the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69xa0years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer’s disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.

Cortical microstructure in young onset Alzheimer's disease using neurite orientation dispersion and density imaging

Alzheimers disease (AD) is associated with extensive alterations in grey matter microstructure, but our ability to quantify this in vivo is limited. Neurite orientation dispersion and density imaging (NODDI) is a multi‐shell diffusion MRI technique that estimates neuritic microstructure in the form of orientation dispersion and neurite density indices (ODI/NDI). Mean values for cortical thickness, ODI, and NDI were extracted from predefined regions of interest in the cortical grey matter of 38 patients with young onset AD and 22 healthy controls. Five cortical regions associated with early atrophy in AD (entorhinal cortex, inferior temporal gyrus, middle temporal gyrus, fusiform gyrus, and precuneus) and one region relatively spared from atrophy in AD (precentral gyrus) were investigated. ODI, NDI, and cortical thickness values were compared between controls and patients for each region, and their associations with MMSE score were assessed. NDI values of all regions were significantly lower in patients. Cortical thickness measurements were significantly lower in patients in regions associated with early atrophy in AD, but not in the precentral gyrus. Decreased ODI was evident in patients in the inferior and middle temporal gyri, fusiform gyrus, and precuneus. The majority of AD‐related decreases in cortical ODI and NDI persisted following adjustment for cortical thickness, as well as each other. There was evidence in the patient group that cortical NDI was associated with MMSE performance. These data suggest distinct differences in cortical NDI and ODI occur in AD and these metrics provide pathologically relevant information beyond that of cortical thinning.

Navigating Genetic Influences on the Topography of Alzheimer’s Disease

JMS has received research funding and PET tracer from AVID Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly); has consulted for Roche, Eli Lilly, Biogen and Merck; received royalties from Oxford University Press and Henry Stewart Talks; given education lectures sponsored by Eli Lilly and Biogen; and serves on a Data Safety Monitoring Committee for Axon Neuroscience SE. TDP has no disclosures

DIFFERENTIAL HIPPOCAMPAL SUBFIELD LOSS IN DIFFERENT PHENOTYPES OF YOUNG ONSET ALZHEIMER’S DISEASE

to controls. Connections were predominantly impaired in frontal and occipital junctions. There was a graduation from controls to MCI and from MCI to AD. CSF markers differed not between AD and MCI. For all subjects a low correlation was observed for MMSE and CSF tau and a number of connections including fronto-parietal and fronto-occipital. Conclusions: In this investigation with an rs-fNIRS it was demonstrated a good feasibility of the method. Moreover it turned out to be sufficient to detect substantial differences between controls andMCI subjects, and AD patients, respectively. For further longitudinal studies it may be worth to explore whether rs-fNIRS has the capability to predict thoseMCI subjects that convert into AD.

INFLUENCES OF BLOOD PRESSURE AND BLOOD PRESSURE TRAJECTORIES ON CEREBRAL PATHOLOGY AT AGE 70: RESULTS FROM A BRITISH BIRTH COHORT

Whole brain volume inml, mean (sd) 1102.2 (99.6) Figure 2. Relationship between the ratios of blood omega3 (PC 20.5, 22.6) and omega6 (PC 22.4, 20.4) and the disease stage associated with each individual. For all the considered cases there is a significant inverse relationship between the (log-) ratio omega3/omega6 and the individual stage identified by our model. Podium Presentations: Monday, July 23, 2018 P626

LONGITUDINAL CORTICAL THICKNESS IN SPORADIC YOUNG ONSET ALZHEIMER’S DISEASE

MRI from 1713 ADNI subjects; 11593 T1-MRI from 5389 Rotterdam-Study-Scan (Ikram et al, 2015) aging subjects; 244 T1-MRI from 64 PPMS subjects of the Institute of Neurology-UCL; we analyzed 24 T1-MRI and DTI of HCP subjects to estimate an average structural connectome. Results: The mechanistic profile identified by our model (Fig 2) agrees with current results that identify transneuronal spread from and to hubs as the principal mechanism underlying neurodegeneration in AD (Cope et al, 2018). Interestingly, the model points out that we can’t neglect the component of neurodegeneration due to nodal stress – vulnerability of hubs due to increased metabolic demand. The proximity mechanism identified in HA suggests a more uniform brain-loss, while the presence of an un-explained term indicates that the hypothetical mechanisms utilized are not sufficient to fully explain the aging process. In PPMS the profile is a combination of apparently discordant (nodal stress and trophic failure) mechanisms: it is possible that the focal inflammatory component of MS, although not strong in our progressive cohort, plays a role in complicating the patterns of neurodegeneration. Conclusions:Our results suggest that neurodegeneration in AD and PPMS is not simply an acceleration of the aging process: the two diseases have distinct spreading mechanisms underlying neurodegeneration.

EXPLORING THE POPULATION PREVALENCE OF β-AMYLOID BURDEN: AN ANALYSIS OF 250 INDIVIDUALS BORN IN MAINLAND BRITAIN IN THE SAME WEEK IN 1946

that is associated with frontal lobe change. Traditional neuropsychological tests examining frontal dysfunction, such as the Stroop and the Trail Making tests, measure individual’s top-down control ability by comparing the time taken to complete the task in control condition and the interference condition. Trial-by-trial intra-individual reaction time (RT) variability in cognitive control tasks, however, could also be a sensitive measure of frontal integrity, since it has been shown that frontal involvement is critical in maintaining cognitive stability by minimizing fluctuation of cognitive performance. In this study, we purported to investigate the neural correlates of intra-individual RT variability in an experimental cognitive control task, namely the Multi-Source Interference Task (MSIT).Methods:Utilizing functional magnetic resonance imaging (fMRI), we investigated the brain regions activated when healthy older adults (n1⁄452) performed the MSIT, which consists of interference and control conditions. Regional activation that was significantly different in the interference condition compared to the control condition was examined to find brain regions involved in inhibitory control. Within the regions found to be involved in inhibitory control, we identified regions that were specifically associated with the intra-individual RT variability. Results: Inhibitory success was correlated with smaller intra-individual variability of RT, while themagnitude of the variability was reflected in the activation of the frontal regions, such as the left middle and left inferior frontal gyri, as well as the left supramarginal gyrus. Conclusions: Individuals with greater intra-individual variability during the MSIT activated the inhibitory control network to a greater magnitude, possibly reflecting the increased demand for cognitive control network due to their less efficient inhibitory control system. This is consistent with previous findings that showed greater intra-individual variability in dementia patients with frontal involvement compared to those with Alzheimer’s disease. Increase in intra-individual variability of RT has also been shown to be observed in people with MCI, suggesting the measure as a promising behavioral index that reflects frontal or frontoparietal integrity.