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Disentangling the contributions of dopamine and amyloid burden to age-related changes in cognition and brain network connectivity in healthy older adults

Final Report Summary - AMYDA (Disentangling the contributions of dopamine and amyloid burden to age-related changes in cognition and brain network connectivity in healthy older adults)

Alzheimer’s disease and Parkinson’s disease are the two most common neurodegenerative disorders in old age. With a steadily increasing elderly population, the prevalence of these diseases has sharply risen. It is predicted that by 2040 the number of people in Europe that will receive a diagnosis of Alzheimer’s disease will be 10.000.000 which will put immense pressure on European healthcare systems.
The current targets for treatment of Alzheimer’s disease and Parkinson’s disease are to identify the disease as early as possible and administer symptomatic treatment that may postpone the progression of the disease. State-of-the-art research on early diagnosis has emphasized minimally invasive imaging of the aging brain. This research has revealed that an aging brain is characterized by prominent neurobiological change, even in the absence of a clinical diagnosis: White matter lesion are commonly observed on brain scans in older adults. Neurotransmitter functions decrease over the adult lifespan, affecting particularly the dopamine system. And around 20-50% of clinically normal older adults show signs of amyloid deposition, the hallmark pathology of Alzheimer’s disease.
Over the last decade, several reviews of the neurocognitive aging literature have discussed the hypothesis that declines in markers of the dopamine system, accumulation of amyloid burden and white matter damage in aging reflect independent neurobiological cascades, each representing a potential early indicator of an age-related neurological disorder that impacts cognition. To date, however, in vivo imaging studies of human aging have generally used a single neurobiological marker, with comparisons only possible across studies.
Leveraging a unique data collection at Harvard University and Massachusetts General Hospital, the project AMYDA was in the position to assess multiple imaging markers of the aging brain within the same individuals and to investigate their joint and independent functional consequences.
In line with prior review studies, we expected that dopamine transporter density, amyloid deposition and white matter damage reflect independent biomarkers of brain aging. Interestingly, our experiments uncovered that this is likely not the case. First, markers of white matter damage and markers of dopamine functions appear to reflect partly the same neurobiological cascade. Because prior models have assumed these markers to be independent, we further explored possible shared factors that may explain these results. This investigation revealed the integrity of the dopamine system was negatively influence by high systolic blood pressure, mirroring the established correlation between white matter integrity and cardiovascular health. Second, while prior studies in normal older individuals have also shown little evidence for an association between markers of Alzheimer’s risk and white matter integrity, we were able to show that accumulation of cortical amyloid and white matter changes are not independent processes in individuals at increased risk for Alzheimer’s disease.
To this date, hypotheses regarding brain aging have often focused on the heterogeneity that characterizes brain aging and how different cascades may independently contribute to behavioral outcomes. With imaging methods now developed to a point where it is possible to begin to separate normal aging from preclinical disease, our results suggest that brain biomarkers in aging are instead characterized by an increasing dedifferentiation and inter-relation.
In the final set of experiments, we began to explore the functional implications of aging-related brain changes. We found that, although neurobiological cascades in aging are in part inter-related, they may have dissociable functional implications. We also found that state-of-the-art biomarkers of brain function (fMRI functional connectivity) were more sensitive than standard
neuropsychological tests, which are rarely “pure” measures of
one specific brain network over the other. Our results suggeste that studying the integrity of brain networks using fMRI may offer an opportunity to differentiate the functional consequences of amyloid accumulation, white matter damage and dopamine depletion in older adults prior to onset of clinical decline. Finally, we explored the specificity with which fMRI is sensitive to underlying neurobiological change in a sample of patients with Parkinson’s disease. Histopathology studies have shown specific losses of dopaminergic nigro-striatal projections in Parkinson’s disease and dementia with Lewy bodies that are dissociable from normal aging. Our results suggest that the dissociation of normal aging and disease within the substantia nigra is also reflected in dissociable patterns of fMRI connectivity, which again highlights the potential usefulness for fMRI functional connectivity as a biomarker of underlying pathology.
The findings of the AMYDA project help to differentiate neurobiological processes and their functional consequences that occur as part of healthy aging (e.g. dopamine loss) from those that may indicate incipient neuropathology (i.e. Alzheimer’s disease or Parkinson’s disease). We believe that our findings will be of key importance for furthering research on neurobiological processes and their functional consequences that occur
as part of healthy aging and in the quest to delineate them from incipient neuropathology. With the prevalence of Alzheimer’s disease and Parkinson’s disease increasing steadily in European countries and the rest of the world, understanding the contributions of amyloid burden and loss of dopamine to age-related cognitive decline is crucial to identifying early diagnostic markers of neurodegenerative disease and targets for interventions.

Results have been published in the following articles:
Rieckmann, A. Van Dijk., Sperling, R.A. Johnson, K.A. Buckner, R.L. Hedden, T. (2016): Accelerated decline in white matter integrity in clinically normal individuals at risk for Alzheimer’s disease. Neurobiology of Aging.

Rieckmann, A., Hedden, T., Younger, A.P. Sperling, R.A. Johnson, K.A. Buckner, R.L. (2015): Dopamine transporter availability in clinically normal aging is associated with individual differences in white matter integrity. Human Brain Mapping http://doi/10.1002/hbm.23054

Rieckmann, A., Gomperts, S.N. Johnson, K.A. Growdon, J.H. Van Dijk, K.R.A (2015): Putamen–midbrain functional connectivity is related to striatal dopamine transporter availability in patients with Lewy body diseases. NeuroImage Clin, 8, 554-559.