Sub-Regional Hippocampal Injury is Associated with Fornix Degeneration in Alzheimer's Disease.

We examined in vivo evidence of axonal degeneration in association with neuronal pathology in Alzheimer's disease (AD) through analysis of fornix microstructural integrity and measures of hippocampal subfield atrophy. Based on known anatomical topography, we hypothesized that the local thickness of subiculum and CA1 hippocampus fields would be associated with fornix integrity, reflecting an association between AD-related injury to hippocampal neurons and degeneration of associated axon fibers. To test this hypothesis, multi-modal imaging, combining measures of local hippocampal radii with diffusion tensor imaging (DTI), was applied to 44 individuals clinically diagnosed with AD, 44 individuals clinically diagnosed with mild cognitive impairment (MCI), and 96 cognitively normal individuals. Fornix microstructural degradation, as measured by reduced DTI-based fractional anisotropy (FA), was prominent in both MCI and AD, and was associated with reduced hippocampal volumes. Further, reduced fornix FA was associated with reduced anterior CA1 and antero-medial subiculum thickness. Finally, while both lesser fornix FA and lesser hippocampal volume were associated with lesser episodic memory, only the hippocampal measures were significant predictors of episodic memory in models including both hippocampal and fornix predictors. The region-specific association between fornix integrity and hippocampal neuronal death may provide in vivo evidence for degenerative white matter injury in AD: axonal pathology that is closely linked to neuronal injury.

Spatially localized hippocampal shape analysis in late-life cognitive decline.

We present a method for generating data-driven, concise, and spatially localized parameterizations of hippocampal (HP) shape, and use the method to analyze HP atrophy in late-life cognitive decline. The method optimizes a set of shape basis vectors (shape components) that strike a balance between spatial locality and compact representation of population shape characteristics. The method can be used for exploratory analysis of localized shape deformations in any population of HP on which point-to-point correspondence mappings have been established via anatomical landmarking or high-dimensional warping. Experiments combine the method with an automated HP to HP mapping method to analyze tracings of 101 elderly subjects with normal cognition, mild cognitive impairment, and Alzheimer's Disease (AD) from an AD Center population. Results suggest that shape components corresponding to atrophy to the CA1 and subiculum HP fields--where early AD pathology is located--correlate strongly with robust measures of the cognitive dysfunction that is typical of early AD. Furthermore, the energy function minimized by the shape component optimization technique is shown to be smooth with few local minima, suggesting that the method may be relatively easy to apply in practice.

New candidate genes for sex-comb divergence between Drosophila mauritiana and Drosophila simulans.

A large-effect QTL for divergence in sex-comb tooth number between Drosophila simulans and D. mauritiana was previously mapped to 73A-84AB. Here we identify genes that are likely contributors to this divergence. We first improved the mapping resolution in the 73A-84AB region using 12 introgression lines and 62 recombinant nearly isogenic lines. To further narrow the list of candidate genes, we assayed leg-specific expression and identified genes with transcript-level evolution consistent with a potential role in sex-comb divergence. Sex combs are formed on the prothoracic (front) legs, but not on the mesothoracic (middle) legs of Drosophila males. We extracted RNA from the prothoracic and mesothoracic pupal legs of two species to determine which of the genes expressed differently between leg types were also divergent for gene expression. Two good functional candidate genes, Scr and dsx, are located in one of our fine-scale QTL regions. In addition, three previously uncharacterized genes (CG15186, CG2016, and CG2791) emerged as new candidates. These genes are located in regions strongly associated with sex-comb tooth number differences and are expressed differently between leg tissues and between species. Further supporting the potential involvement of these genes in sex-comb divergence, we found a significant difference in sex-comb tooth number between co-isogenic D. melanogaster lines with and without P-element insertions at CG2791.