Title: Developing novel neuroimaging biomarkers of Alzheimer's disease in people with Down syndrome using functional near infrared spectroscopy (fNIRS)
Funder: Department of Health and Social Care

Abstract: Research questionCan functional near infrared spectroscopy (fNIRS) be used to measure early neuroimaging biomarkers of Alzheimer's disease (AD) in people with Down syndrome (DS)? BackgroundDS, caused by triplication of Chromosome 21, is the most common genetic cause of Alzheimer's disease, with AD neuropathology near-universally present before age 40. Research interest in AD in DS is growing, however, people with DS remain under-represented in neuroimaging research. With predictable AD-outcomes, their inclusion could accelerate the development of biomarkers that are measurable before cognitive decline becomes apparent. Magnetic resonance imaging (MRI) and Positron Emission Tomography (PET) studies are being pursued with individuals who can tolerate scans, but for many, such restrictive modalities are inaccessible.Developing more accessible neuroimaging methods could improve inclusivity. FNIRS offers a silent, cost-effective method of measuring cortical activity that has already been established for studies of neurodevelopment, stroke and drug response. It could be a valuable tool for establishing early neuroimaging biomarkers of AD in this high-risk population.Aims and objectives Develop an annotated, anatomical atlas of the DS brain to facilitate future neuroimaging research, including spatial registration of fNIRS dataEstablish key metrics of resting-state brain activity in Down syndrome using existing functional MRI data (rs-fMRI) to inform development of similar metrics with fNIRSDetermine the resting-state and task-based fNIRS metrics that are most sensitive to dementia in people with DS. Methods Existing structural MRI data from the Alzheimer's Biomarker Consortium will be used. Data from healthy individuals with DS under age 35 will be prioritised. Amyloid- and tau- PET scan data is available to exclude those with substantial AD neuropathology. rs-fMRI data from the same study will be used to determine key features of resting-state activity in adults with DS with and without dementia (Expected N = 400; 10% dementia cases). Functional connectivity and data decomposition approaches will be used. Cortical results will inform a resting-state fNIRS pilot study. N=20 adults with DS without dementia. 44 fNIRS channels covering frontal, parietal, temporal and occipital cortices. 12-minute data acquisition (eyes open). Resting-state, plus executive function and memory task-based fNIRS measures will be collected from 40 adults with DS without dementia, 15 prodromal, and 15 with diagnosed dementia. Optimal sensitivity to dementia status will be determined. 12-month follow-up will assess predictive capacity of baseline fNIRS measurements in relation to cognitive decline.Timelines for deliveryYear 1: Neuroimaging and leadership training, atlas structure complete, rs-fMRI analyses completeYear 2: fNIRS pilot complete and main study underwayYear 3: Baseline fNIRS study complete and published; annotation of atlas complete and published, follow-up study complete and publications underway. Impact and Dissemination Atlas: will offer improved interpretation of clinical scans, and facilitate further neuroimaging research. Promoted through publications, conferences. Open-source sharing via GitHub, OpenNeuro. Imaging studies: improved knowledge of brain function in DS and AD, development of novel, cost-effective and accessible neuroimaging biomarkers of AD. Potential new avenue for inclusive neuroimaging studies. Disseminated through publications, conferences, clinical groups, Down syndrome associations. Workshops developed for knowledge transfer.

Lay abstract: Aims This research will develop patient-friendly ways of measuring changes in the brain caused by Alzheimer's disease. I will work with people with Down syndrome, who all develop Alzheimer's disease, to find the best measures for showing if someone has Alzheimer's disease or not. This could bring new ways to predict dementia, or measure if a treatment is working. Background Dementia is a devastating condition with no current cure, that causes people to progressively lose their skills and independence. Different brain diseases can cause dementia, but the most common is Alzheimer's disease. It is very difficult to find treatments for Alzheimer's disease and check that they work, because most cases happen by chance and dementia develops many years after the first signs of Alzheimer's disease in the brain. Down syndrome is a very important condition for research because everybody with Down syndrome develops Alzheimer's disease by age 40. However, people with Down syndrome, who may also have learning disabilities, are often excluded from research - especially when it involves brain imaging. More patient-friendly brain-imaging methods might help more people participate. I tried a method called 'functional near infrared spectroscopy' (fNIRS) during my PhD. fNIRS uses small lights in a comfortable cap to measure activity in the outside layer of the brain. This is called the cortex, and it is where a lot of our thinking takes place. Nearly everyone I saw with Down syndrome was able to complete an fNIRS 'scan' so this could be a good tool for research. Methods This research programme will have 3 stages. Stage 1: I will develop an 'atlas' of the Down syndrome brain. This will help future brain imaging research because standard brain imaging tools do not always fit the unique brain shape seen in people with Down syndrome. I will use data that has already been collected from people with Down syndrome who can tolerate MRI scans. These scans take detailed 3-D pictures of the brain, but you have to stay very still inside a noisy scanner with a strong magnet, which is not possible for everyone.Stage 2: I will use more existing MRI data to learn about how the brain works in people with Down syndrome when someone is just relaxing. This is called the 'resting-state'. It can tell us about how brain functions are organised, which can change when Alzheimer's disease develops. I will use these results to then try and find similar patterns using fNIRS.Stage 3: I will use fNIRS to measure brain activity in people with Down syndrome when relaxing, and when doing computer games. I will look for differences in brain activity between participants with and without dementia. I will see these same people again 12 months later to see if any of these fNIRS measurements can also predict future cognitive decline. Patient involvement In my PhD, I interviewed some people with Down syndrome and found that many wanted to be included in brain imaging research, but for a minority of people, MRI scanners were too scary. These discussions helped me design the first fNIRS studies. Now, I am organising a new learning disability advisory group so people with learning disability can tell researchers whether their study sounds suitable and check that their information is easy to understand. Dissemination I will share the results in scientific journals and conferences, and by talking to clinicians and people with Down syndrome and their carers. I will share the atlas online for other researchers to use. I will deliver workshops to teach other people how to use fNIRS for clinical research.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;CONGENITAL DISORDERS