Diffusion tensor imaging in familial Alzheimer's disease: Longitudinal and cross-sectional studies of early change

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Diagnosis of Alzheimer‘s disease, the most common form of dementia, is difficult in its earlier stages. A number of different brain scanning techniques have recently been developed which may pick up very early changes in these individuals. One of these techniques is called diffusion imaging. This examines the microscopic structure of brain tissue, non-invasively. It also allows assessment of connections between parts of the brain - so called white matter tracts. Diffusion imaging therefore allows not just the assessment of how particular areas of brain may be degenerating, but also how the connections between areas are being affected.

Familial Alzheimer‘s disease is a rare form of Alzheimer‘s where the disease is inherited at a young age. Individuals from families with known genetic mutations have generously agreed to take part in prospective longitudinal studies. We propose to study individuals who are well, but who are at known risk of developing Alzheimer‘s disease. This will allow us to acquire high resolution brain scans, including this new technique of diffusion imaging in conjunction with detailed clinical and psychological assessments. We will examine whether this technique detects early changes and how this matches with the onset and progression of clinical cognitive problems.

Technical Summary

As increasing numbers of therapies promising disease modification in Alzheimer‘s disease (AD) undergo development, the need for reliable biomarkers has never been more relevant. Targeting therapies to the early stages of the disease where they are most likely to be effective, and monitoring their effect on the pathological process, demands sensitive markers of early manifestation and progression of disease. Although rare, familial Alzheimer‘s disease (FAD) provides the unique opportunity to carry out prospective longitudinal study of individuals who are cognitively normal but are destined to develop the disease.

Diffusion imaging allows assessment of alterations in tissue microstructure which may be an early marker of pathological change. Diffusion tensor imaging (DTI) extends the modality to examine the integrity of white matter pathways and allows the assessment of connections between degenerating regions. It is now well established that grey matter losses and neuropsychological deficits are detectable many years prior to symptom onset in FAD mutation carriers. Degeneration of white matter tracts connecting these cortical areas and the concomitant effects of loss of connectivity have been less well studied, however there is evidence that these changes occur early.

The aim of this study is to investigate markers of early change using DTI in presymptomatic individuals at risk of FAD and in individuals mildly affected by familial and sporadic AD. We will use serial volumetric MRI and diffusion imaging, together with clinical and neuropsychological assessments, to study presymptomatic FAD mutation carriers, mildly affected individuals with FAD and young-onset sporadic AD, and age-matched controls. We will combine volumetric imaging and DTI to assess the relative contributions to, and relationship between, grey and white matter damage. In the FAD cohort, we will also have the opportunity to compare these results with changes detectable on amyloid imaging thr PET scanning using the C11-PIB ligand.

In addition, we will, for the first time, look at longitudinal changes in diffusion and correlate these with changes in clinical and cognitive measures over time. Measurement of within-individual changes on imaging avoids some of the natural between-individual variability and may be a more sensitive and relevant marker of pathological change than a single assessment.

This study will derive new imaging biomarkers for the detection of early change in AD, and provide more general insights into the pathobiology of neurodegenerative disease.
 
Description Alzheimer's Association International Conference Travel Fellowship
Amount £1,800 (GBP)
Organisation Alzheimer's Association 
Sector Charity/Non Profit
Country United States
Start 07/2012 
End 07/2012
 
Description Brain Exit Fellowship
Amount £61,025 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 02/2016
 
Description European Federation of Neurological Societies 2010 Congress Bursary/European Federation of Neurological Societies
Amount £762 (GBP)
Organisation European Federation of Neurological Societies (EFNS) 
Sector Charity/Non Profit
Country Austria
Start 05/2010 
End 05/2010
 
Description European Federation of Neurological Societies 2014 Congress Bursary
Amount £800 (GBP)
Organisation European Federation of Neurological Societies (EFNS) 
Sector Charity/Non Profit
Country Austria
Start 05/2014 
End 05/2014
 
Description ISTAART (International society to advance alzheimer research and treatment) travel fellowship
Amount £2,000 (GBP)
Organisation Alzheimer's Association 
Sector Charity/Non Profit
Country United States
Start 07/2010 
End 07/2010
 
Description University of London Chadburn Academic Clinical Lectureship in Medicine
Amount £250,000 (GBP)
Funding ID 177549 
Organisation University of London 
Sector Academic/University
Country United Kingdom
Start 08/2018 
End 08/2023
 
Description Amyloid imaging in familial Alzheimer's disease mutation carriers 
Organisation Hammersmith Hospital
Department Centre for Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution This study aimed to investigate the timing and anatomical distribution of cerebral amyloid deposition, as measured by Pittsburgh compound B positron emission tomography (PIB-PET) scanning, in familial Alzheimer's disease (FAD) mutation carriers. Myself and a clinician colleague were responsible for recruiting subjects to this study from our own longitudinal study of FAD and conducting their clinical assessments.
Collaborator Contribution Amyloid imaging was provided by and conducted at the Hammersmith Hospital.
Impact Our findings from this study were published in the journal Brain (21084313)
Start Year 2008
 
Description Dominantly Inherited Alzheimer Network (DIAN) study 
Organisation Washington University in St Louis
Country United States 
Sector Academic/University 
PI Contribution In response to a call for international collaboration on familial Alzheimer's disease (FAD) from the US National Institutes of Health, the Dominantly Inherited Alzheimer Network (DIAN) grant was awarded. Professor Morris of Washington University is principal investigator for this international collaborative study, which includes centres in the United States, Australia and ourselves here in the UK. The DIAN study collects longitudinal clinical and biomarker data from individuals at risk and affected by FAD and includes MRI. Diffusion tensor imaging was not initially included in the DIAN MRI protocol, making the work of my fellowship particularly complementary. We have been recruiting individuals from our own longitudinal study of FAD into DIAN since 2010 and I have been responsible for conducting the subjects' clinical assessments.
Collaborator Contribution DIAN collates all the data collected from the different sites and covers the costs of the imaging and patient travel. Funding from DIAN has therefore directly supported the research that I am doing with these subjects as part of my fellowship.
Impact This is a multi-disciplinary collaboration, bringing together a range of disciplines including neurology, genetics, pathology and imaging. I have been a co-author on a number of studies utilising DIAN data that have now been published - a volumetric imaging study published in Neurology in 2013 (PMID: 24049139 ) and a study of white matter hyperintensities in FAD published in Annals of Neurology in 2016.
Start Year 2010
 
Description Induced pluripotent stem cells derived from patients with Familial Alzheimer's disease and other dementias as novel cell models for neurodegeneration 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution In this collaborative research project with Professor John Hardy and Dr Selina Wray at UCL Institute of Neurology, individuals with mutations known to cause familial Alzheimer's disease (FAD) are invited to undergo a skin biopsy under local anaesthetic. From these biopsies, fibroblasts may be cultivated and, when cultured in a specific way, converted to stem cells and subsequently neurons. I have been responsible for recruiting FAD mutation carriers to this study from our ongoing longitudinal study of FAD and performing the skin biopsies.
Collaborator Contribution Dr Selina Wray and colleagues in the Department of Molecular Neuroscience culture the fibroblasts and perform all of the cellular work.
Impact This is a multi-disciplinary collaboration between Neurologists at our centre and Cellular Biologists in the Department of Molecular Neuroscience. A paper has been published describing the preliminary work on the project (PMID: 22952635), which is creating an open-access resource of fibroblasts for use by the scientific community. In 2015, another paper resulting from this collaboration was published (PMID: 26136155 ) and, together with Professor Nick Fox and Dr Lashley, Dr Wray and I submitted a proposal to Alzheimer's Research UK for a PhD studentship, which was awarded in February 2016. The PhD studentship, entitled 'Deciphering pathological heterogeneity in familial Alzheimer's disease' will investigate the pathological and molecular mechanisms underlying phenotypic heterogeneity in familial Alzheimer's disease, utilising brain tissue and iPSCs from PSEN1 and APP mutation carriers.
Start Year 2010
 
Description International PCA working party 
Organisation Alzheimer's Association
Country United States 
Sector Charity/Non Profit 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation Claude Bernard University Lyon 1 (UCBL)
Department Department of Neurology and Stroke Center
Country France 
Sector Academic/University 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation Mayo Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation Mayo Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation Pitié-Salpêtrière Hospital
Country France 
Sector Hospitals 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation University of California, Los Angeles (UCLA)
Country United States 
Sector Academic/University 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation University of Milan
Department Department of Neurology
Country Italy 
Sector Academic/University 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation University of Toronto
Department Division of Neurology
Country Canada 
Sector Academic/University 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description International PCA working party 
Organisation VU University Medical Center
Department Department of Neurology
Country Netherlands 
Sector Academic/University 
PI Contribution I participated in the first international PCA (posterior cortical atrophy) working party at the Alzheimer's Association International Conference (AAIC) in Vancouver, July 2012. PCA is an under-diagnosed variant of Alzheimer's disease causing initial deficits in visuoperceptual and visuospatial skills, with relative preservation of memory. The aim of the working party was to bring together a multi-disciplinary group of professionals from international clinical and research centres of excellence with an interest in PCA. The initial meeting aimed to identify areas for improvement and harmonisation within existing diagnostic criteria and to publish recommendations in a consensus statement. The group will provide a forum for active collaboration in which projects requiring multi-centre expertise and large sample sizes can be realised. It will also provide opportunities to raise awareness about the condition. I have continued to participate in this group's annual meetings, most recently at the 2015 Alzheimer's Association International Conference in Washington DC.
Collaborator Contribution A number of potential collaborative projects were discussed at the initial meeting. Our group suggested pooling DNA samples for a multi-centre study of genetic risk factors for PCA. The other group members agreed to donate their samples to us in order to start this project. This study has now been completed and the paper accepted for publication in the journal Alzheimer's and Dementia
Impact We successfully applied for status as an Alzheimer's Association Professional Interest Area (PIA), which will provide funding for future meetings and a dedicated research symposium at future AAIC. Our most recent meeting as a PIA took place at the 2014 AAIC. A perspective paper, detailing the motivation for and discussions at the PCA working party was published in the journal Alzheimer's and Dementia in 2013 (PMID: 23274153), a paper reporting the results of the genetics study was published in this journal in 2016 (PMID: 26993346 ) and the same journal has recently accepted a paper reporting our PCA consensus statement. The collaboration is multi-disciplinary, in that it brings together neurologists, psychiatrists, psychologists and basic scientists with a research and clinical interest in PCA.
Start Year 2012
 
Description Pathological investigations in familial Alzheimer's disease 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution During my MRC clinical research training fellowship, I became increasingly interested in exploring the insights into pathology that my imaging studies suggested and therefore established a collaboration with Dr Tammaryn Lashley and Professor Tamas Revesz in the Institute of Neurology brain bank to examine familial Alzheimer's disease brain tissue. I have worked with my collaborators in the brain bank to establish a cohort of cases and have provided the detailed phenotypic information that we have used to develop research questions, which we have been addressing with pathological investigations.
Collaborator Contribution My collaborators in the Institute of Neurology brain bank have provided and analysed the pathological material with immunohistochemical methods.
Impact This is a multi-disciplinary collaboration between neurologists and neuropathologists. Our collaboration began with a detailed investigation of a single case and a short report describing this entitled 'Spontaneous ARIA (amyloid-related imaging abnormalities) and cerebral amyloid angiopathy related inflammation in Presenilin 1-associated familial Alzheimer's disease' was published in the Journal of Alzheimer's disease in 2015 (PMID: 25408217). We followed this work with am imaging and neuropathological study of cerebral amyloid angiopathy in familial Alzheimer's disease and the resulting paper, entitled 'Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease' was also published in 2015 in Neurobiology of Aging (PMID: 26410308). Our collaboration also contributed to the paper we published in Lancet Neurology in 2016 'Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series' Ryan NS et al. (PMID 27777022) as this includes the neuropathological analysis of two individuals with novel Presenilin 1 mutations. In 2014, I co-supervised a UCL Biomedical Sciences MSc student with my collaborator Dr Tammaryn Lashley, to work on our project. She was awarded a prize for her MSc thesis 'Pathological investigations in familial Alzheimer's disease'. I went on to present this study at the Alzheimer's Association International Conference in Washington DC in 2015. In order to continue and expand our collaboration, Dr Lashley and I, together with Professor Nick Fox and our collaborator Dr Selina Wray, successfully applied for a PhD Studentship from Alzheimer's Research UK entitled 'Deciphering pathological heterogeneity in familial Alzheimer's disease, which was awarded in February 2016.
Start Year 2011
 
Description Presenilin 1 function in familial Alzheimer's disease mutations 
Organisation University of Leuven
Country Belgium 
Sector Academic/University 
PI Contribution The collaboration developed from a mutual interest in how the effects of different Presenilin 1 mutations give rise to variable clinical phenotypes in familial Alzheimer's disease. We have provided brain tissue and clinical phenotype information on a cohort of familial Alzheimer's disease cases and have developed research questions through discussions with Professors Bart de Strooper and Lucia Chavez Gutierrez in the University of Leuven. Prof de Strooper has held a joint appointment at UCL and was appointed as Director of the new UK Dementia Research Institute in December 2016.
Collaborator Contribution Analysis of gamma-secretase activity in the familial Alzheimer's disease brain tissue.
Impact Papers published in the Journal of Experimental Medicine on gamma-secretase activity in familial Alzheimer's disease brains (PMID: 26481686) and in Cell (28753424) on how PSEN1 mutations destabilise gamma-secretase.
Start Year 2013
 
Description ADAD (Autosomal Dominant Alzheimer Disease) forum working group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Our collaborators from the Dominantly Inherited Alzheimer study in the US are working with the Alzheimer's Association to establish the 'ADAD (autosomal dominant alzheimer diseae) forum', which will constitute a website and message board for use by individuals from families affected by familial Alzheimer's disease worldwide. I was invited to join the working group who are putting together this project, which meets in regular teleconferences.


Family members, some of whom are already research participants, have expressed enthusiasm for this project, which will ultimately raise awareness of the disease and the opportunities for families affected by it to participate in research.
Year(s) Of Engagement Activity 2010
 
Description Familial Alzheimer's disease support group meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I organised the first familial Alzheimer's disease (FAD) support group meeting for families affected by the disease, together with a psychologist colleague, which took place in July 2010. In addition to organising the event and schedule for the day, I gave a talk to the group about opportunities for people at risk of and affected by the disease to take part in research. In this presentation, I outlined both my own MRC-funded research project and the other local and international research projects that we are in collaboration with, which aim to recruit these individuals. The day also included talks from invited speakers on familial AD and open discussions amongst the group on a range of topics including issues surrounding genetic counselling, diagnosis and support. The day was attended by around 20 family members and 10 professionals including the carers of individuals with FAD and members of the Alzheimer's Research Trust.

I have helped to organise the annual support group meeting every year since.


Feedback from family members attending the meeting was very positive. During the day the group expressed interest in having annual support group meetings of this kind with newsletters and establishment of a dedicated website for the group. We have started work on the planning of the next meeting, the newsletter and website, all of which will provide forums for further dissemination of the research. (2010)

The support group has continued to grow and we appointed a Nurse Advisor to run the grou
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014,2015,2016,2017,2018,2019
URL http://www.fadsupportgroup.org.uk
 
Description Familial Alzheimer's disease support group newsletter 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I have prepared and edited the content of the annual newsletter that is sent to all members of our familial Alzheimer's disease support group, since we started the group in 2010.

The newsletters have been very well received and members of the group have requested that previous years issues are available on the support group website for reference.
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014,2015,2016,2017,2018,2019
URL http://www.fadsupportgroup.org.uk/
 
Description Familial Alzheimer's disease support group website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I wrote the majority of the content for the Familial Alzheimer's disease (FAD) support group website, which was launched in February 2013. The website was designed and built by two family members from the support group and we had several meetings to plan and develop the site. The website aims to provide information and support to people affected by FAD, their families, friends and healthcare professionals. We are now (in 2019) further developing our website as the FAD support group has become part of 'Rare dementia support'. I am part of the working group developing plans to establish a new dedicated centre of excellence for rare dementia support and expand our digital presence.

The website was launched at the 2013 FAD support group meeting and received a very positive response from the group members.
Year(s) Of Engagement Activity 2013,2014,2019
URL http://www.fadsupportgroup.org.uk/
 
Description Film on living with familial Alzheimer's disease 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact I collaborated with a professional film-maker to make a short film in which I interviewed people at risk of familial Alzheimer's disease (FAD) on their views about various issues including their feelings about participating in research and clinical trials. The film was shown at a meeting held by the Eupopean Medicines Agency (EMA) to discuss the prospect of presymptomatic treatment trials in FAD in order to represent the views of the people that would enter such trials if they were established. This film will also feature on the FAD support group website we are building.


The film stimulated a lot of interest and discussion at the EMA meeting. The EMA subsequently approved the launch of a presymptomatic treatment trial for individuals at risk of familial Alzheimer's disease (DIAN-TU).
Year(s) Of Engagement Activity 2010
 
Description Plenary talk at Austrian Alzheimer Society annual meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was invited to give a plenary talk on young onset dementia at the 2018 Austrian Alzheimer Society meeting, attended by Austrian neurologists, psychiatrists and dementia researchers. In the talk, I discussed a clinical approach to young onset dementia and the importance of investigating for a genetic cause. I then presented some of my MRC-funded research on familial Alzheimer's disease and talked about how my work demonstrates how detailed investigation of clinical phenotype and imaging changes in patients with genetic dementias can provide insights into underlying disease mechanisms, and the relevance of this to current trials of disease-modifying therapies.
Year(s) Of Engagement Activity 2018
 
Description Presentation at Familial Alzheimer's disease support group meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact At the inaugural familial Alzheimer's disease support group meeting, I gave a talk about opportunities for people at risk of and affected by the disease to take part in research. In this presentation, I outlined both my own MRC-funded research project and the other local and international research projects that we are in collaboration with, which aim to recruit these individuals.

I gave a further talk on Neuroimaging research in familial Alzheimer's disease at the 2015 support group meeting and on how families participating in research has advanced the field in 2018.

Recruitment or participants to our familial Alzheimer's disease research programme has steadily increased since the support group was launched.
Year(s) Of Engagement Activity 2010,2015,2018
 
Description Presentation at posterior cortical atrophy patient support group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Around 60 patients and carers affected by the posterior cortical atrophy (PCA) variant of Alzheimer's disease attended this National support group meeting in London on 26th October 2012. A number of patients from Manchester and Australia also listened via a skype link-up. I was invited to give a talk entitled 'Neurological symptoms in PCA and an update on research into why they occur', followed by a question and answer session.

The talk sparked a lot of discussion and questions and patients approached me afterwards to express their interest in taking part in research. The presentation and an audio recording of the talk have been uploaded to a PCA members forum on the internet so that those unable to attend the meeting in person can also hear it.
Year(s) Of Engagement Activity 2012