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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Patterns and mechanisms of brain atrophy in healthy aging and dementia: Why is the aging brain susceptible to Alzheimers Disease?

Alternative title: null

Awarded: NOK 6.0 mill.

The prevalence of Alzheimer disease increases sharply after 60 years of age. Among the oldest old, the prevalence is close to 50%. At the same time, about half of healthy,, non-demented older adults report to be worried about their own memory. In this project, we have focused on understanding why it is the aging brain that is vulnerable to Alzheimer, and what is the brain basis for the cognitive changes we observed in Alzheimer vs. the changes we observe in otherwise healthy older adults. We have especially focused on the relationship between what we call episodic memory, brain integrity and accumulation in the brain of a special protein called amyloid. We examine this in participants with different risk factors for AD. The most important results from the project can be summed as follows: (1) Methodological development We have developed an analysis stream for the different types of information we use, especially MRI-measures of brain integrity and PET measures of amyloid accumulation. During the project, we developed a good procedure for coordinate the analyses of MRI and PET-data. This was done in collaboration with our international partners, especially at the Martinos Center for Biomedical Imaging, Harvard Medical School. As a part of the project we developed and tested an analysis stream for functional connectivity, which aso have yielded exciting results. Methodologically we tested how different ways of analyzing structural MRIs may affect the classification of Alzheimer patients and patients with mild cognitive impairment from healthy older adults. This is important, because earlier studies have suggested that some of the mostly used tools for analysis of morphometric MRI-data may yield variable results. We found hat the ability to classify Alzheimer patients from healthy older adults was very robust and good, and also that the ability to distinguish patients with mild cognitive impairment from older adults was good. (2) Establishment of a database We have collected and coordinated data from different research centers around the world, including Norway, Europe and USA. All together, these data constitute a very valuable database, which we will continue to take advantage of also after the end of the project. Data include different measures of amyloid plaque accumulation, MRI examinations of the brain and clinical/ cognitive information. (3) Examples of scientific findings from the project (a) As part of the project, we showed that reduced memory in older adults are related to changes in functional connectivity ? how different brain regions communicate ? during rest. This was true both within the cerebral cortex and between the cerebral cortex and deeper regions of the brain. Further, we have developed a good paradigm for measuring brain activity during different types of memory, which we now are using in examinations of adult participants of different age. (b) We found that in older adults with high levels of amyloid, there is a relationship between sleep problems, memory and other measures of brain health. Since both amyloid and sleep problems are associated with Alzheimer, this is important knowledge for diagnosis, prognosis and intervention. (c) There is a known relationship between accumulation of amyloid and sleep problems in older adults. We studied where this relationship existed, i.e. in which regions of the brain are sleep problems related to accumulation of amyloid. We found extensive brain regions where this was the case. We then tested a sample of Alzheimer patients, and found that sleep problems and accumulation of amyloid in cognitive healthy older adults happens in the same regions where Alzheimer patients showed increased amyloid accumulation. Further, we found that this overlapped with regions with high expression of the HOMER1 gene. HOMER1 is involved in sleep and in processing of amyloid, and may be a molecular mechanism between sleep problems and accumulation of amyloid in Alzheimer. This knowledge may contribute to better understanding of why some older adults accumulate more amyloid than others do, and therefore have higher likelihood of a clinical Alzheimer diagnosis. (d) We calculated where in the brain participants tend to have increased accumulation of amyloid. This was tested against expression of different genes in the cerebral cortex from an international database (Allen Brain Atlas). This showed that expression of 8 different genes are anatomically related to accumulation of amyloid. This work may increase our understanding of the molecular foundation for amyloid accumulation, and contribute to a better mapping of risk factors for AD. (e) Older adults with mild cognitive impairment or subjective mild cognitive impairment were divided in two groups based on levels of amyloid. We found that accumulation of amyloid was associated with reduced structural brain integrity, possibly related to more extended demyelination and axonal loss.


The prevalence of Alzheimer's Disease (AD) increases sharply from 60 years, reaching about 50% in 90 year olds. At the same time, 50% of healthy elderly report worries about their own memory function. Thus, understanding the neural foundation for cognitiv e decrements in both demented and healthy aging is among the most important tasks for research in neuroscience. At the heart of this question is the role of amyloid protein in neurodegeneration and memory decline in both AD and healthy aging. Current mode ls hold that the influence of amyloid on the brain is largest in very early phases of AD, years before clinical symptoms become manifest, so it is paradoxical that the influence of amyloid on brain atrophy and memory problems in healthy elderly is little researched and with inconsistent results. Progress is hindered by methodological differences and statistically under-powered studies due to very costly data collection. The main objective of this project is to make a leap forward with researchers at the f orefront of aging and AD, by launching a large database including 500 healthy and 500 patients. Focus is on 3 major events common to normal aging and AD, the EBA triad: disturbance of Episodic memory function, reduced Brain integrity and accumulation of A myloid. The database will include measures of brain atrophy (MRI), amyloid (CSF and/ or PiB PET) and memory for asymptomatic elderly and patients with mild cognitive impairment and AD. Based on these biomarkers, cognitive scores and genetic profiles, part icipants will be divided into groups, spanning from very low to extremely high AD risk. This yields a unique possibility to identify commonalities and differences between amyloid and brain atrophy and memory problems across groups with different AD risks. The statistical power of this project to detect effects in healthy elderly is excellent, enabling this novel strategy.

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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering