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Final Report Summary - VASCAMY (Vascular and Aymloid Predictors of Neurodegeneration and Cognitive Decline in Nondemented Subjects.)

Alzheimer’s disease (AD) is a neurodegenerative disease that is characterized by the accumulation of the protein amyloid-beta (Aβ) in the brain. The development of Aβ, however, often coincides with the presence of white matter degeneration. It is a major question whether Aβ pathology and white matter alterations are associated with each other and contribute to disease progression in AD. The major aim of the VASCAMY study was to assess the association between global Aβ levels and fiber-tract changes and their impact on neurodegeneration and cognitive decline in AD. To this end, the VASCAMY study assessed biomarkers of Aβ (as measured in cerebrospinal fluid (CSF) or by amyloid PET) and white matter changes (as measured by MRI) during the course of AD. Furthermore, given previous findings suggesting that some subjects may cope better with developing brain pathology to maintain cognitive performance, we applied resting-state and task-based functional MRI to identify those brain changes that underlie reserve capacity in AD.
White matter hyperintensities (WMH) are a gross radiological marker of white matter alterations. Although WMH have been previously associated with increased risk of dementia, the impact of WMH onto functional networks underlying cognition are not well understood in AD. Here, we assessed both regional WMH and global levels Aβ as predictors of functional-MRI assessed integrity of neural networks in collaboration with the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Resting-state fMRI and WMH were assessed in seventy-eight participants with abnormally high amyloid levels as measured by AV-45 PET in different clinical stages of AD. WMH volume was determined for major white matter fiber tracts that connect regions within the default mode network, i.e. a large-scale functional network known to undergo pathological alterations in AD. The WMH volume was highest within the inferior fronto-occipital fasciculus (IFOF), a tract that connects frontal and occipito-parietal brain regions. Higher WMH exclusively in the IFOF was associated with reduced functional connectivity between the projection areas of that tract in the default mode network. For global AV-45 PET, higher levels were associated with reduced FC in IFOF-connected, temporal and parietal DMN areas independently from WMH. These results suggest that apart from abnormally high Aß deposition, white matter alterations are associated with reduced integrity of a major functional network, and thus reveal a potential pathway for the effect of WMH on cognitive abilities in AD.
In order to understand the development of both Aβ and fiber tract changes during the course of AD, VASCAMY teamed up with the international multicenter Dominantly Inherited Alzheimer’s Network (DIAN) which obtained both AV-45 PET and MRI in autosomal dominantly inherited mutations that cause AD (N = 59) and controls (N = 44). In the genetically caused, familial form of AD, the onset of dementia symptoms can be estimated years in advance, thus allowing to assess brain changes at the presymptomatic stage of AD. We analyzed diffusion weighted MRI to detect microstructural white matter alterations in mutation carriers compared to controls. In mutation carriers, increased mean diffusivity (MD), i.e. higher white matter degeneration, emerged about 10 years before the estimated onset of dementia symptom, particularly in posterior parietal white matter. Consistent with our results on the effects of WMH on functional integrity in sporadic AD (see above), we found increased MD to be associated with reduced grey matter volume integrity in projection areas of those white matter tracts that showed altered MD. Notably, the increase in MD was found not only in WMH areas, but also the normal appearing white matter, suggesting that subtle white matter alterations are already detectable in early phases of AD. Increased deposition of Aβ was observed about 10 years before the first emergence of MD alterations in the mutation carriers. Abnormal biomarker levels Aβ were associated with higher MD. Together, the results suggest that that primary AD pathology such as Aβ may contribute to white matter alterations in AD.
In addition to Aβ, we assessed the association between a CSF CSF TREM2, i.e. marker of microglia activation, and MD in the white matter. TREM2 is a protein that serves as a receptor almost exclusively expressed by microglia in the brain. Loss-of-function mutations in the TREM2 gene are associated with a dramatic increase in the risk of AD (odds ratio ~3.6) that is comparable to that of the most important genetic risk factor of AD, i.e. ApoE 4 allele. We previously reported CSF TREM2 levels to be abnormally increased about 5-10 years before the estimated age of dementia onset. Here, we found that higher CSF sTREM2 levels were associated with higher MD values particularly in the medial frontal and posterior parietal brain regions. These results suggest that abnormally high microglia activation may contribute to white matter alterations in AD.
In conclusion, our findings suggest that white matter alterations are early presymptomatic brain abnormality during the course of AD. Our findings encourage preventative measures focusing on the reduction of amyloid-beta as well as risk factors associated with higher WMH, such as smoking, high blood pressure or the metabolic syndrome. Furthermore, we demonstrated an association between microglia activity/inflammation (CSF TREM2) and white matter alterations. Microglia have been shown to be involved in axonal repair in the brain, where impaired microglia activity such as induced by TREM2 mutations entail reduced chemotaxis and migration of microglia for the removal of cell debris. The current results encourage future therapeutic approaches to target the neuroimmune system as a secondary preventative approach to enhance white matter integrity and prevent or slow down neurodegeneration.
Recent evidence suggests environmental and life style factors that are associated with enhanced resilience of cognitive abilities against the impact of brain pathology in AD. From a therapeutic point of view, the identification of brain mechanisms that underlie such enhanced resilience would provide novel targets to enhance cognitive abilities in AD. We reasoned that particularly functional networks in the prefrontal cortex, which are relatively spared in AD, support reserve. Specifically, we focussed on global functional connectivity of a hub in the left frontal cortex (LFC, Broca area 6/44), which is part of the cognitive control network. In young adults, this hub has been associated with higher IQ, i.e. a protective factor against dementia risk in later life (Cole et al., 2012). We asked the question whether higher LFC hub connectivity buffers the detrimental impact of AD pathology on memory performance in elderly subjects. In a series of studies including resting-state fMRI obtained in elderly controls, participants with mild cognitive impairment or AD dementia, we found that higher global LFC hub connectivity was associated with higher memory performance at given level of AD brain pathology (such as measured by CSF tau or FDG-PET). These results suggest that higher LFC hub connectivity is associated with higher resilience of memory against developing neurodegeneration in AD. In further support of these findings from resting-state fMRI, we found that higher task-fMRI related LFC connectivity during episodic memory encoding was associated with higher memory performance at a given level of grey matter atrophy in HC and MCI. Together, these results suggest that LFC hub connectivity is a putative functional brain mechanism that may support higher reserve capacity during the course of AD.
These results are of interest for health care providers and patients since a large number of studies demonstrated life style and environmental factors such as education, physical activity or higher general cognitive abilities are associated with higher reserve. However, while such life-style and societal factors may be difficult to change, our findings of global connectivity of the LFC as a highly feasibly and likely candidate of reserve provides the basis developing novel therapeutic and preventative interventions to directly enhance resilience in AD. Studies testing non-invasive intervention such as transcranial magnetic stimulation of LFC connectivity to enhance cognitive abilities in AD are under way. For more information on VASCAMY, please visit:

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