Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus

MORPHOLOGICAL CLASSIFICATION OF SUBTYPES OF VOLUMETRIC PROJECTION NEURONS FROM MOUSE BRAIN SCANS

Automated annotation and identification tools for quantitative study of the brain are in demand. Robust and scalable models for classification of neuron morphologies are necessary for the automation. The goal of this thesis is to introduce a robust and fast methodology based on minute local level features of 3D projection neurons for classification of into subtypes. This study proposes a "Codebook" or "Periodic Table" of local features of volumetric neurons. The idea is that every neuron subtype will have a unique combination of features from the Codebook to create its morphological features. Existing image segmentation based labeling and probabilistic models to assign neuroanatomical labels do not take into account morphological features at a local level. Morphological features of a neuron at a local level like axon-soma linkages and dendrite-soma linkages are crucial in determining the neuron morphology and hence its label or location. This thesis also highlights the potential of semi-supervised segmentation of volumetric (3D) neurons for automatic region identification and labeling with minimal data annotation