Detecting and tracking early neurodegeneration in familial Alzheimer’s disease

Alzheimer’s disease (AD) is recognized to have a long presymptomatic period, with initial deposition of extracellular amyloid and intracellular tau, followed by downstream neurodegeneration and cognitive decline. There is great interest in testing potential disease-modifying treatments for AD prior to the onset of symptoms, when minimal neuronal loss has occurred. To facilitate this, robust and sensitive methods are needed to identify at-risk individuals, stage their disease, and track progression. Familial Alzheimer’s disease (FAD) shares many features, clinically, radiologically, and neurophysiologically, with the more common sporadic form of disease. Carriers of autosomal dominantly inherited mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes have relatively predictable ages at symptom onset, based on family history. Study of FAD mutation carriers therefore provides the opportunity for the prospective study of asymptomatic individuals with known underlying AD pathology prior to the onset of clinical disease. The studies presented herein aim to improve the identification and characterization of early FAD neurodegenerative change and its earliest downstream cognitive effects. A multimodal approach is taken, with both presymptomatic and mildly symptomatic individuals included. Chapter one provides an introduction to AD and methods for measuring early neurodegeneration. Chapter two then outlines the general methodological approach across the different studies. Chapters three and four present results of magnetic resonance imaging studies of macrostructural (cortical thickness) and microstructural (diffusion-weighted imaging) cortical change. Chapter five reports results for a new blood-based biomarker of neurodegeneration – serum neurofilamentlight. Chapter six investigates a novel approach to presymptomatic cognitive testing – 6 assessing accelerated long-term forgetting. In all studies, significant differences between mutation carriers and non-carrier controls are detectable during the presymptomatic period. The thesis draws together these different approaches and discusses how they advance our understanding of the neurobiology of AD and their potential utility in both clinical assessment and presymptomatic therapeutic trials

Evo-devo and the search for homology (“sameness”) in biological systems

Developmental biology and evolutionary studies have merged into evolutionary developmental biology ("evo-devo”). This synthesis already influenced and still continues to change the conceptual framework of structural biology. One of the cornerstones of structural biology is the concept of homology. But the search for homology ("sameness”) of biological structures depends on our favourite perspectives (axioms, paradigms). Five levels of homology ("sameness”) can be identified in the literature, although they overlap to some degree: (i) serial homology (homonomy) within modular organisms, (ii) historical homology (synapomorphy), which is taken as the only acceptable homology by many biologists, (iii) underlying homology (i.e., parallelism) in closely related taxa, (iv) deep evolutionary homology due to the "same” master genes in distantly related phyla, and (v) molecular homology exclusively at gene level. The following essay gives emphasis on the heuristic advantages of seemingly opposing perspectives in structural biology, with examples mainly from comparative plant morphology. The organization of the plant body in the majority of angiosperms led to the recognition of the classical root-shoot model. In some lineages bauplan rules were transcended during evolution and development. This resulted in morphological misfits such as the Podostemaceae, peculiar eudicots adapted to submerged river rocks. Their transformed "roots” and "shoots” fit only to a limited degree into the classical model which is based on either-or thinking. It has to be widened into a continuum model by taking over elements of fuzzy logic and fractal geometry to accommodate for lineages such as the Podostemacea