Abstract
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 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).DiscussionThrough 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.
Highlights
Increasing age is the biggest risk factor for dementia, of which Alzheimer’s disease is the commonest cause
Alzheimer’s disease (AD) is characterised histopathologically by the accumulation of senile plaques mainly composed of amyloid β (Aβ), neurofibrillary tangles composed of hyperphosphorylated tau [4], and excess neuronal cell loss in vulnerable regions, notably the medial temporal lobe and parietal association cortices
Positron emission tomography (PET) using amyloid-specific tracers allows for quantification of fibrillar amyloid burden; and modern multi-modal magnetic resonance imaging (MRI) offers a non-invasive way of determining brain volumes, cerebrovascular disease, white matter tract integrity, brain perfusion, functional connectivity, and brain microstructure
Summary
Insight 46 intends to integrate the NSHD data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with data on genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, to inform what influences the entire spectrum of changes that occur as the brain ages: from healthy through to pathological ageing, with a specific focus on AD. Abbreviations 3 T: 3 Tesla (magnetic field strength); ACE-III: Addenbrooke’s Cognitive Examination 3rd revision; AD: Alzheimer’s disease; ASL: arterial spin labelling; AxD: axial diffusivity; Aβ: beta-amyloid; BRAIN: BRadykinesia Akinesia INcoordination test; CBF: cerebral blood flow; CDR: Clinical Dementia Rating scale; DICOM: Digital Imaging and Communications in Medicine, a standard for handling, storing, printing, and transmitting information in medical imaging; DVAR: variance of signal change from average signal in fMRI; DW MRI: diffusion-weighted MRI; EDTA: ethylenediaminetetraacetic acid; EPI: echo planar imaging; FA: fractional anisotropy; FLAIR: fluid attenuated inversion recovery MRI; fMRI: functional MRI; FNAME-12A: 12-item Face-Name Associative Memory Exam; FNAME-16: 16-item Face-Name Associative Memory Exam; FWHM: full width at half maximum (spatial resolution); GIF: geodesic information flow, an in-house method of MRI segmentation; GRAPPA: GeneRalized Autocalibrating Partial Parallel Acquisition, an MRI multi-coil parallel imaging technique; GRASE: gradient- and spin-echo MRI; GWAS: genome wide association study; ICA: independent component analysis; MCI: mild cognitive impairment; MD: mean diffusivity; MMSE: mini-mental state examination; MPRAGE: magnetisation prepared rapid gradient echo MRI; MRC: Medical Research Council; MRI: magnetic resonance imaging; NDI: neurite density index; NODDI: neurite orientation dispersion and density index; NRES: National Research Ethics Service; NSHD: National Survey of Health and Development; ODI: orientation dispersion index; pCASL: pseudo-Continuous Arterial Spin Labelling; PD: Parkinson’s disease; PEEK: Portable Eye Examination Kit; PET: positron emission tomography; PHI: protected health information; QC: quality control; RD: radial diffusivity; REC: research ethics committee; REM: rapid eye movement; SCD-Q: Subjective Cognitive Decline Questionnaire; SNR: signal-to-noise ratio; SPACE: Sampling Perfection with Application optimized Contrasts using different flip angle Evolution MRI; SST: serum-separator tube; SUVR: standardised uptake value ratio; T1: MRI spin–lattice or longitudinal relaxation time; T2*: MRI measure of loss of phase coherence among spins oriented at an angle to the static magnetic field due to a combination of magnetic field inhomogeneities and the spin-spin relaxation; T2: MRI spin-spin or transverse relaxation time; TE: MRI echo time; TR: MRI repetition time; TSH: thyroid-stimulating hormone; UCL: University College London; UPDRS: Unified Parkinson’s Disease Rating Scale; UPSIT: University of Pennsylvania Smell Identification Test; UTE: MRI ultrashort TE; WAIS-R: Wechsler Adult Intelligence Scale-Revised; WASI: Wechsler Abbreviated Scale of Intelligence; WMS-R: Wechsler Memory Scale-Revised; XNAT: an open-source imaging informatics software platform
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
