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

Abstract

Background: Increasing 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/design: This 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 71 years, 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 60-64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) 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).

Discussion: Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, 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.

Keywords: Epidemiology, Life course, Genetics, Alzheimer’s Disease, Ageing, Magnetic resonance imaging, Positron emission tomography, Cognition, Vascular disease, Birth cohort.

Fig. 1

Flowchart for Insight 46

Fig. 2

Novel computerised tests (a) Irrelevant Distractor. An example stimulus display (not to scale) with an irrelevant distractor in the low load condition. Note that the specific cartoon image shown here as an irrelevant distractor is included for illustrative purposes only, in order to avoid violating copyright for the images used in the experiment. Figure reprinted from [64] with permission from American Psychological Association (b) Visuomotor Integration apparatus. Note that in the indirect condition, the participant’s hand is covered by a box, not shown here. Figure reprinted from [61], Copyright, with permission from Elsevier. (c) ‘What was where?’ task. Figure reprinted from [56] available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360752/, American Psychological Association, copyright under the Creative Commons Attribution License https://creativecommons.org/licenses/by/3.0/ (d) Task-set Switching / Response Inhibition. An example stimulus display for an incongruent word trial

Fig. 3

Improved PET reconstruction using the pCT method. Examples of attenuation maps obtained with the multi-atlas CT synthesis method (pCT) and the UTE method and the corresponding florbetapir PET images generated with each method (10-min frame 50 min post-injection). Difference maps are also shown (pCT – UTE) to better visualise the improved PET reconstruction accuracy

Fig. 4

Volumetric T1 pre-processing and segmentation in Insight 46. Examples of axial (top row), coronal (middle row) and sagittal (bottom row) slices from an original MPRAGE volumetric T1 scan (left column), pre-processed T1 (distortion and bias field corrected) (middle column), and with the GIF parcellation overlaid on top (right column)

Fig. 5

Representative diffusion images in Insight 46. Examples of diffusion images at the two b values, b = 700 and 2000 s/mm², with their corresponding derived MD and FA maps (left) and NODDI metrics (right)

Fig. 6

Brain volumes derived from first 100 Insight 46 volumetric T1 scans. Violin plots demonstrating total brain and lobar volumes (left) and regional lobar volumes (right) calculated on the first 100 T1 scans in Insight 46 using the automated segmentation pipeline