Early macrostructural and microstructural cortical changes in Alzheimer's disease: longitudinal and cross-sectional studies of early change

Alzheimer's disease is the commonest cause of dementia. Not only is Alzheimer's disease devastating for individuals and families but also represents a growing public health problem. Dementia research is therefore a key national and global priority. Alzheimer's disease is associated with the build up of abnormal proteins in the brain and loss of brain cells, both of which precede the onset of memory problems, probably by many years. Once loss of brain cells occurs, the damage is irreversible. Therefore, when drugs that can stop or slow the progression of Alzheimer's disease become available, ideally we would want to be able to identify and treat individuals at risk of developing dementia before symptoms had started. However, exactly how early this irreversible damage begins to occur is currently unclear, and detecting these early changes is difficult. Better techniques are urgently needed for identifying individuals at risk of Alzheimer's, for staging their disease, and for monitoring its progression.

The cerebral cortex is the thin outermost layer of neural tissue (grey matter) on the brain's surface. The cerebral cortex plays a key role in our thought processes, from language and calculation to planning and attention. Abnormalities within the cerebral cortex occur very early in Alzheimer's disease. A number of new brain scanning techniques which may be able to detect very early changes in both the thickness and structure of the cortex, and its connections with other brain areas, have been developed. In addition to these brain scanning techniques, new memory tests have been developed which may be able to detect very early changes as the brain structures starts to become impaired. Taken together, these brain imaging techniques and memory tests may provide important information about the brain changes in Alzheimer's disease.

Familial Alzheimer's disease is a rare form of the disease (accounting for less than 1% of cases) where the disease is inherited - usually at a young age - due to a genetic defect. Individuals from families with known genetic mutations have generously agreed to take part in longitudinal studies, which we have been running at the Dementia Research Centre for many years.

We propose to evaluate the techniques described above to study individuals from families affected by familial Alzheimer's who are well, but who are at high risk of developing Alzheimer's disease. We will also assess people who already have symptomatic Alzheimer's disease and some healthy individuals for comparison. We will do this by acquiring detailed (MRI) brain scans, including the new techniques, in conjunction with detailed clinical and psychological assessments. We will examine how well each of these techniques can detect the earliest features of Alzheimer's disease, and how good each is at measuring change over time. We will also aim to improve our understanding of how early and where in the brain the first damage begins to occur. This information will be used to determine how best to run clinical trials in individuals at risk of developing Alzheimer's disease, which will ultimately increase our chances of finding an effective treatment.

Evidence suggests that Alzheimer's disease (AD) is associated with a long period of progressive accumulation of molecular pathology, followed by increasing neuronal damage, before symptoms appear. The best chance of successful treatment may therefore come from offering therapies as early as possible. In order to do so we need to be able to identify those at risk, to stage their disease, and to track progression with robust and precise methods.

Although rare, familial AD (FAD) provides a unique opportunity for prospective study of individuals who are cognitively normal but are destined to develop the disease. Whilst rates of brain atrophy increase prior to symptom onset, detecting subtle changes in cortical grey matter may be a more sensitive and earlier marker of neurodegeneration. Recent advances in imaging have led to the development of techniques for high quality macroscopic (cortical thickness) and microscopic (diffusion) measures of cortical change.

Whilst by definition asymptomatic, those who have prodromal AD may have subtle cognitive deficits. Novel neuropsychological tests have been able to detect subtle abnormalities in memory, including binding of short-term memory and accelerated long-term forgetting, in other conditions involving mesial temporal cortex. These tests may also be useful in early AD.

The aims of this study are:
1. To use serial MRI to investigate cross-sectional and longitudinal markers of early cortical and juxtacortical change using sensitive metrics (cortical thickness and diffusion) in those at-risk of developing FAD, those mildly affected by FAD and sporadic AD, and controls;
2. To evaluate the sensitivity of novel neuropsychological tests of mesial temporal dysfunction at detecting differences in these groups;
3. To evaluate how these markers of early degenerative change compare temporally to one another, and to more established cognitive and imaging outcomes; and how these correlate with molecular markers of AD pathology.

Key stakeholders - AD patients and families

FAD patients and families - Whilst this work is observational and not of direct benefit to the individual participants, in the longer term we hope the most direct beneficiaries of this work will be patients with FAD and their families. This diseases strikes younger people in the prime of their working lives and exacts a devastating human and socioeconomic cost for these individuals, their extended families, and their support networks. For these stakeholders, benefits from this work will include patient and carer education, and hopefully earlier diagnosis, better staging of disease (informing prognosis) and ultimately development of effective pharmacological treatments.

SAD patients and families - SAD is the commonest cause of dementia. It is currently estimated to affect half a million people in the United Kingdom, and is expected to rise exponentially over the coming decades. Our work will inform how findings from FAD can be applied to SAD, and ultimately improve diagnosis and treatment of the people affected. Through this our work will benefit wider society from an educational, health and economic standpoint.


Improved public awareness

Dementia presents a huge challenge to society, both now and increasingly in the future. The recent Department of Health National Dementia Strategy highlighted as its first objective "Improving public and professional awareness and understanding of dementia". The research supported by this Fellowship will be actively promulgated in public engagement activities extending those already in place at the host Centre including lay lectures, media releases and support group out-reach activities. These activities engage a range of nonmedical groups. An improved public awareness of Alzheimer's disease and other dementias is essential in order to improve awareness of the importance of early diagnosis and treatment and reduce social exclusion and discrimination.


Impact on collaborations with other academic partners and with industry

Collaboration with other academic partners and with industry is important in order to facilitate large multicentre therapeutic trials. The DRC continues to take a lead role in such collaborations. The findings of the research proposed will directly inform the planning of such trials, thereby increasing the potential benefits of such collaborations.


Impact on other neurodegenerative diseases

Alzheimer's is the most common of a number of neurodegenerative illnesses that affect the cerebral cortex. By developing new, more sensitive methods at detecting degeneration of the cortex, the outcomes of the proposed research will not only help in the earlier diagnosis and improved monitoring of AD, but could also potentially be utilised in a number of other neurodegenerative conditions. This wider applicability beyond only AD will significantly increase the number of potential beneficiaries.


Impact on government health policy

Dementia currently costs the UK over £23 billion per year. In recent years, dementia (of which AD is the most common), has become an increasing priority to the NHS and Department of Health. The DRC actively engages with national and international policy makers. It is anticipated that the outcomes of the current research, as with other research done at the DRC, will help to inform and guide those who formulate national and international health policies, including helping to meet the Prime Minister's Dementia Challenge. By developing methods of detecting AD earlier and monitoring potential responses to novel treatments, we aim to help improve the options available for those who develop management guidelines for dementia, both in the NHS and beyond.