NOMAD · Network Neurodegeneration in Alzheimer's Disease

Network Neurodegeneration in Alzheimer's Disease

Summary description of the project objectives Alzheimer’s disease (AD) is a fatal neurodegenerative disease characterized by progressive loss of cognitive functions and brain vitality. The two major pathological hallmarks of AD are extracellular senile plaques consisting of amyloid-β (Aβ) and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau. The most supported hypothesis for the pathogenesis of AD, the “amyloid cascade hypothesis”, proposes that Aβ starts to accumulate approximately 15 years before the onset of symptoms and triggers a cascade of pathological events, including aggregation of tau. Toxicity of Aβ and tau may 1) disrupt functional connectivity (the brain consists of networks of spatially independent regions that activate simultaneously), 2) lead to neurodegeneration (progressive reductions in gray matter density), and 3) eventually result in cognitive loss. The interactions between Aβ, tau and neurodegeneration and how they relate to the functional organization of the brain are poorly understood. This is illustrated by one of the most striking neuroimaging findings in the past decade, which is the dissociation between the distribution of Aβ and patterns of brain atrophy. Aβ is deposited relatively diffuse and symmetrically, while brain degeneration parallels clinical symptoms and is more asymmetric and focal. Based on the close association of tau with neuronal injury and cognitive status in post-mortem studies, it may be hypothesized that tau pathology is the missing link that ties Aβ deposition to neurodegeneration. The relationships between tau pathology and other molecular, structural and functional processes have not yet been investigated in much detail, however, due to lack of suitable biomarkers for the detection of tangle pathology. Previous positron emission tomography (PET) tracers for tau showed insufficient specific binding and measuring tau levels in cerebrospinal fluid only provides whole-brain measures rather than crucial regional information. With the recent development of tau tracer [18F]T807, however, it is now possible to probe pathological burden (Aβ and tau), neurodegeneration and functional connectivity in the living human brain. [18F]T807 binds with high affinity to aggregates of tau, which can be visualized and quantified when imaged using PET. Since 2004, presence of fibrillar Aβ can be measured using Pittsburgh compound-B (PIB) and PET. Neurodegeneration and functional connectivity can be measured using structural and functional magnetic resonance imaging (MRI), respectively. This combination of advanced neuroimaging techniques allow for the very first time testing of the amyloid cascade hypothesis during life. Our incomplete understanding of disease mechanisms may partially account for the lack of successful treatment options in AD to date. Most attention has been devoted to advance the clearance of Aβ or inhibit its production, with the idea that reducing parenchymal Aβ prevents further progress of the cascade. In advanced stages of AD this approach appeared ineffective and trials in prodromal and even preclinical stages of AD are currently ongoing. Treating Aβ may thus be useful early, targeting tau may show beneficial effects in the symptomatic stage and offers great potential for novel therapeutic agents. Tau imaging will add indispensable knowledge to current literature and can be used to address fundamental questions about the mechanisms that drive clinical, anatomical, and functional diversity in AD. Therefore, we will apply multi-modal neuroimaging to elucidate the relationships between AD pathology, neurodegeneration and network integrity in a heterogeneous sample of AD patients. The main aim of this proposal is to study how tau, Aβ, and neurodegeneration relate to each other and to brain connectivity. The following key objectives flow from this approach: 1) To investigate spatial relationships between brain atrophy, Aβ and tau deposition; 2) To investigate how the brain’s functional architecture shapes vulnerability to Aβ, tau and neurodegeneration in AD. Description of the work performed since the beginning of the project 1. Directly related to this project a) The researcher has acquired new knowledge and skills for analysis of structural and functional MRI data, and on how to combine this with PET imaging. b) The findings with regard to objective 1 have recently been published (Ossenkoppele et al. Brain [2016] and Ossenkoppele et al. Annals of Neurology [2015]) and presented at two international conferences. c) The findings with regards to objective 2 have been presented at two international conferences and two manuscripts have been submitted. d) Objective 2 will also be approached using graph analytical techniques. These analyses are finalized and we are currently preparing the publication. 2. Indirectly related to this project The researcher has applied his new neuroimaging skills to address scientific questions closely related to the main objectives of this project. For example, the researcher performed voxel-based morphometry analyses on structural MRI data to investigate the origin and spread of brain atrophy in distinct variants of AD (Ossenkoppele et al. Human Brain Mapping [2015]) and correlated these findings to amyloid-β and tau levels in cerebrospinal fluid (Ossenkoppele et al. Neurobiology of Aging [2015]). Furthermore, he applied similar techniques to assess the neuroimaging (in addition to clinical and pathological) features of the frontal variant of AD, a relatively rare subtype of AD characterized by behavioral and/or dysexecutive deficits (Ossenkoppele et al. Brain [2015]. Finally, the researcher utilized the networks of VUMC and UCSF to conduct a large meta-analysis on amyloid PET and CSF data in >8000 non-demented subjects (Jansen, Ossenkoppele et al. JAMA [2015] and >2000 patients with dementia (Ossenkoppele, Jansen et al. JAMA [2015]. Description of the main results achieved so far Objective 1: relationships between tau, Aβ and neurodegeneration In an individual with posterior cortical atrophy (“visual variant of AD”, Figure 1, Ossenkoppele et al. Annals of Neurology [2015]) we showed that the pattern of glucose hypometabolism ([18F]FDG PET) and the clinical symptoms strongly corresponded to patterns of tau pathology ([18F]AV1451 PET), and not to amyloid-β pathology ([11C]PIB PET). These findings were replicated and extended in a larger sample and in multiple variants of Alzheimer’s disease (Figure 2, Ossenkoppele et al. Brain [2016]). Objective 2: functional connectivity and tau pathology We found that the spatial pattern of tau observed in AD patients does resemble the functional organization of the healthy brain, supporting the notion that tau pathology spreads through circumscribed brain networks (Figure 3). The expected final results and their potential impact and use The results can have an impact on several levels: 1. Tau imaging with PET – the “missing link”?: The dissociation between Aβ deposition and neurodegeneration is a longstanding debate in AD research. We showed that tau – another AD hallmark protein – is potentially the missing link between molecular pathology and degenerative phenotype, which provides important leads about the pathogenesis of AD. 2. Appropriate use criteria for amyloid imaging: Another important aspect of this proposal is imaging of Aβ plaques. Its emergence has caused a major paradigm shift in diagnostic thinking (from AD solely being a clinical entity towards inclusion of biomarkers) and is now used as a diagnostic tool in the memory clinic. This has recently led to the proposal of “appropriate use criteria” for amyloid imaging [26]. One of the recommendations was to apply Aβ imaging in EO-AD, probably due to diagnostic dilemmas caused by their atypical presentations. This study adds to the understanding of the role of Aβ in young AD patients and can be used to further specify diagnostic procedures in EO-AD. Furthermore, this initial work on tau PET may facilitate future clinical implementation as a potential diagnostic or prognostic marker. 3. Therapy: Understanding which protein is driving neurodegeneration is highly relevant for effective therapies. Many clinical trials that assessed Aβ treatments in mild-to-moderate AD patients have failed and can be summarized as “too little, too late”. Therapies tailored at reducing tau pathology are ongoing and may have great potential in the symptomatic stage. This study adds to our understanding of the role of tau and its association with Aβ, neurodegeneration and brain connectivity.

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