Topic 5 - Longitudinal Cohorts

Longitudinal cohorts - in general

There is a lot still to be learned about how FTD, PSP, CBD, and related illnesses change over time - why do some people progress faster than others? Why do symptoms change so much over time? Why do two different diseases sometimes look alike? What should we measure to know if a treatment is slowing the illness down?

To answer these questions, and to know how to build better clinical trials of the right drug in the right patients, and the right outcomes, we have established several key longitudinal cohorts, working with patients and families to study the illnesses over years. This is critical to identify new biomarkers, distinguish different types of dementia, predict outcomes, and design better trials. 

The NTAD Study

New Therapeutics in Alzheimer’s Disease Study (NTAD), is a longitudinal multimodal and multicentre neuroimaging study aiming to develop an early, reliable and disease-specific biomarker platform for Alzheimer’s disease. NTAD brings academic and industry scientists together to aid faster turnover of clinical trials and increased the range of drugs tested.

Since the start in 2018, NTAD operates across two recruitment sites in Cambridge and Oxford, working with a team of experts from Cardiff, AstraZeneca, Janssen and Lilly. Funded by the Dementia’s Platform UK and Alzheimer’s Research UK, NTAD aims to recruit 100 amyloid-positive participants with early Alzheimer’s disease and mild cognitive impairment, and 30 healthy controls. The study incorporates structural and functional MRI, amyloid PET, CSF, EEG/MEG, genetics, plasma, COVID19 serology and cognitive tests. MRI, EEG/MEG and plasma and cognitive tests are collected longitudinally in the patient group one year apart.

NTAD is the first study aiming to quantify and assess the test-retest reliability of the EEG/MEG markers in Alzheimer’s disease. To allow this, a subset of the patients repeat the EEG/MEG protocol two-weeks apart. Test-retest comparisons will help us find a set of robust and replicable biomarkers to be taken forward to the longitudinal comparisons.

NTAD has a specific focus on early neurophysiological and synaptic changes in Alzheimer’s disease, because these changes precede the deterioration in behaviour, cognition and atrophy. Using EEG and MEG, we can measure task related and resting state oscillations, frequency spectra, time dependent amplitude, and network connectivity. E/MEG protocol is comprised of audio-visual task measuring low level sensory processing, Roving mismatch negativity task, two in-house hippocampal tasks called the scene repetition and the visual-auditory oddball task, and finally eyes-open and closed resting state recordings. E/MEG protocol is aligned partially with the CamCAN (large scale healthy ageing study), CamCAN Frail (a branch of CamCAN study focusing on cognitive frailty and Alzheimer’s disease), and Deep and Frequent Phenotyping study (large scale multicentre biomarker study of asymptomatic individuals with genetic risk of Alzheimer’s disease).

In 2020, NTAD has started acquiring PET scans with a novel [¹¹C]UCB-J ligand in a subset of controls and the patients to measure Alzheimer’s-related changes in synaptic density in relation to EEG/MEG and MRI biomarkers.

Since 2018, NTAD has completed the baseline scans, two-week test-retest scans and annual follow-up scans of over 60% of the sample, aiming to complete the study by 2021.

Study Team: 

Cambridge: Prof James B Rowe (CI & Cambridge PI), Prof Rik Henson, Dr Ece Kocagoncu, Melek Karadag, Michelle Naessans, Juliette Lanskey

Oxford: Prof Kia Nobre (Oxford PI), Prof Mark Woolrich, Dr Vanessa Raymont, Dr Andrew Quinn, Jemma Pitt 

Industry partners: Dr John Isaac (Janssen Pharmaceuticals), Dr Stephen Lowe, (Lilly), Dr Michael Perkinton (AstraZeneca)

If you like more information or you would like to volunteer, please contact Dr Ece Kocagoncu (ek390@cam.ac.uk) or Prof James Rowe (james.rowe@mrc-cbu.cam.ac.uk).

The PiPPIN-3 Study

The PiPPIN (PIck's disease and Progressive supranuclear palsy Prevalence and INcidence) study is an observational study of patients with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) in Cambridgeshire and Norfolk.

The first cohort of of 204 patients was recruited between January 2013 and December 2014 (PiPPIN-1 cohort). The second cohort recruited a further 200 patients between 2017-2018 (PiPPIN-2 cohort).

We are currently recruiting for in a 3rd study phase (2021-2023).

The overall aim is to establish the frequency and characteristics of FTD/PSP/CBD, and to study in detail the causes of apathy and impulsivity, which affect many FTD/PSP/CBD patients.

The study has 3 stages:

a) Minimum data set with information from neurological and psychiatric services;

b) Diagnostic validation, neuropsychological and cognitive testing;

c) Brain imaging, biomarkers from blood, neuropathology, and naturalistic activity monitoring.

If you would like participate in this study, please contact Dr Katherine Stockton (kcg30@medschl.cam.ac.uk)

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The GENFI-2 Initiative (a multi-centre study)

The Genetic Frontotemporal dementia Initiative (GENFI) is a multi-centre study across Europe and Canada with expertise in familial frontotemporal dementia (FTD). It is coordinated by Dr Jonathan Rohrer at University College London.

The major aim of the study is to investigate genetic frontotemporal dementia, with healthy people and patients in families where someone has a mutation in the progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9ORF72) genes. GENFI investigates people who have developed symptoms already and their healthy relatives. 

Importantly, healthy relatives in GENFI do not need to know their genes and will not find out about their genes as a result of taking part.  This means that one can take part with confidence, helping research into the illness without having to worry about gene testing. 

If you would like to know more, please contact Carolyn Timberlake (cmc38@medschl.cam.ac.uk). 

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PROSPECT-M-UK (a multi-centre study)

PROSPECT-M-UK is a multi-centre longitudinal study conducted at seven sites in the UK and coordinated by the PSP Association national research network, founded in 2014.  The overall aim is to improve the early diagnosis of PSP, MSA, and CBD, advance the understanding of these diseases, and establish a platform for clinical trials. 

Participants are invited to either a "light" participation, with registration of their illness and home based questionnaires, or a "full" study assessment with:

• clinical assessment
• blood sample
• neuropsychological ('memory') testing
• questionnaires
• an up to date  MRI brain scan

If you would like to know more, please contact Carolyn Timberlake (cmc38@medschl.cam.ac.uk).

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The NIMROD Project

The NIMROD (Neuroimaging of Inflammation in MemoRy and Other Disoders) project is a longitudinal study for patients with neurodegenerative disease, dementia, and depression. It is led by Professor John T. O'Brien and Professor James B. Rowe.

The main objective of this study is to determine the role of inflammation in the development of different types of dementia. Data from patients with Alzheimer's disease, Lewy Body dementia, Progressive Supranuclear Palsy, mild cognitive impairment, Parkinson's disease, late life depression, and vascular dementia are annually assessed by means of brain imaging, neuropsychology, and blood biomarker analyses.

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MLSE Language Assessment for patients with Primary Progressive Aphasia (PPA)

This study is a collaboration between Professor Peter Garrard at the St George's University in London, Professor James B. Rowe and Professor Karalyn Patterson in Cambridge. The primary aim of this project is to develop and fully validate a short but effective language test kit, for patients with primary progressive aphasia (PPA). The instrument is called Mini Linguistic State Examination (MLSE) and will be validated in English and Italian by means of questionnaires, neuropsychological tasks, and brain imaging.

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Diagnosis and prognosis in frontotemporal dementia, progressive supranuclear palsy and corticobasal degeneration. 

This study has been running since 2007, and is largely superseded by PIPPIN, GENFI-2 and PROSPECT-M-UK studies, in assessing diagnostic and prognostic biomarkers in these related illnesses.  Data from this study have been instrumental in understanding the impact of disease on cognition, brain networks, and survival, as well as providing the essential context in which to interpret neuropathology studies at the Cambridge Brain Bank. 

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Selected publications

• Passamonti, L., Vazquez Rodriguez, P., Hong, Y. T., Allinson, K. S., Williamson, D., Borchert, R. J., Sami, S., Cope, T. E., Bevan-Jones, W. R., Jones, P. S., Arnold, R., Surendranathan, A., Mak, E., Su, L., Fryer, T. D., Aigbirhio, F. I., O'Brien, J. T., & Rowe, J. B. (2017). 18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy. Brain, 140(3), 781-791. doi:10.1093/brain/aww340 PMID: 28122879 PMC5382948
• Bevan-Jones, W. R., Surendranathan, A., Passamonti, L., Vazquez Rodriguez, P., Arnold, R., Mak, E., Su, L., Coles, J. P., Fryer, T. D., Hong, Y. T., Williams, G., Aigbirhio, F., Rowe, J. B., & O'Brien, J. T. (2017). Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study protocol: a deep phenotyping cohort study of the role of brain inflammation in dementia, depression and other neurological illnesses. BMJ Open, 7(1), e013187. doi:10.1136/bmjopen-2016-013187 PMID: 28064175 PMC5223666
• Lansdall, C. J., Coyle-Gilchrist, I. T. S., Jones, P. S., Vazquez Rodriguez, P., Wilcox, A., Wehmann, E., Dick, K. M., Robbins, T. W., & Rowe, J. B. (2017). Apathy and impulsivity in frontotemporal lobar degeneration syndromes. Brain, 140(6), 1792-1807. doi:10.1093/brain/awx101 PMID: 28486594
• Mutsaerts, H., Petr, J., Thomas, D. L., De Vita, E., Cash, D. M., van Osch, M. J. P., Golay, X., Groot, P. F. C., Ourselin, S., van Swieten, J., Laforce, R., Jr., Tagliavini, F., Borroni, B., Galimberti, D., Rowe, J. B., Graff, C., Pizzini, F. B., Finger, E., Sorbi, S., Castelo Branco, M., Rohrer, J. D., Masellis, M., MacIntosh, B. J., & investigators, G. (2017). Comparison of arterial spin labeling registration strategies in the multi-center GENetic frontotemporal dementia initiative (GENFI). J Magn Reson Imaging. doi:10.1002/jmri.25751 PMID: 28480617
• Premi, E., Grassi, M., van Swieten, J., Galimberti, D., Graff, C., Masellis, M., Tartaglia, C., Tagliavini, F., Rowe, J. B., Laforce, R., Jr., Finger, E., Frisoni, G. B., de Mendonca, A., Sorbi, S., Gazzina, S., Cosseddu, M., Archetti, S., Gasparotti, R., Manes, M., Alberici, A., Cardoso, M. J., Bocchetta, M., Cash, D. M., Ourselin, S., Padovani, A., Rohrer, J. D., Borroni, B., & Genetic, F. T. D. I. (2017). Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study. Brain, 140(6), 1784-1791. doi:10.1093/brain/awx103 PMID: 28460069 PMC5445253
• Sudre, C. H., Bocchetta, M., Cash, D., Thomas, D. L., Woollacott, I., Dick, K. M., van Swieten, J., Borroni, B., Galimberti, D., Masellis, M., Tartaglia, M. C., Rowe, J. B., Graff, C., Tagliavini, F., Frisoni, G., Laforce, R., Jr., Finger, E., de Mendonca, A., Sorbi, S., Ourselin, S., Cardoso, M. J., Rohrer, J. D., & Genetic Ftd Initiative, G. (2017). White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort. Neuroimage Clin, 15, 171-180. doi:10.1016/j.nicl.2017.04.015 PMID: 28529873 PMC5429247
• Su, L., Faluyi, Y. O., Hong, Y. T., Fryer, T. D., Mak, E., Gabel, S., Hayes, L., Soteriades, S., Williams, G. B., Arnold, R., Passamonti, L., Rodriguez, P. V., Surendranathan, A., Bevan-Jones, R. W., Coles, J., Aigbirhio, F., Rowe, J. B., & O'Brien, J. T. (2016). Neuroinflammatory and morphological changes in late-life depression: the NIMROD study. Br J Psychiatry, 209(6), 525-526.
• Coyle-Gilchrist, I. T., Dick, K. M., Patterson, K., Vazquez Rodriquez, P., Wehmann, E., Wilcox, A., Lansdall, C. J., Dawson, K. E., Wiggins, J., Mead, S., Brayne, C., & Rowe, J. B. (2016). Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology, 86(18), 1736-1743. doi:10.1212/WNL.0000000000002638 PMID: 27037234 PMC4854589
• Rohrer, J. D., Nicholas, J. M., Cash, D. M., van Swieten, J., Dopper, E., Jiskoot, L., van Minkelen, R., Rombouts, S. A., Cardoso, M. J., Clegg, S., Espak, M., Mead, S., Thomas, D. L., De Vita, E., Masellis, M., Black, S. E., Freedman, M., Keren, R., MacIntosh, B. J., Rogaeva, E., Tang-Wai, D., Tartaglia, M. C., Laforce, R., Jr., Tagliavini, F., Tiraboschi, P., Redaelli, V., Prioni, S., Grisoli, M., Borroni, B., Padovani, A., Galimberti, D., Scarpini, E., Arighi, A., Fumagalli, G., Rowe, J. B., Coyle-Gilchrist, I., Graff, C., Fallstrom, M., Jelic, V., Stahlbom, A. K., Andersson, C., Thonberg, H., Lilius, L., Frisoni, G. B., Pievani, M., Bocchetta, M., Benussi, L., Ghidoni, R., Finger, E., Sorbi, S., Nacmias, B., Lombardi, G., Polito, C., Warren, J. D., Ourselin, S., Fox, N. C., Rossor, M. N., & Binetti, G. (2015). Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol, 14(3), 253-262. doi:10.1016/S1474-4422(14)70324-2 PMID: 25662776

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