Radiological Pathological Correlations in Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that has been increasingly linked to traumatic brain injury. The neuropathology that distinguishes CTE from other tauopathies includes hyperphosphorylated tau (pTau) tangles and tau positive astrocytes irregularly distributed in cortical sulcal depths and clustered around perivascular foci. These features are clearly identified using immunohistochemistry, but are undetectable to current clinical imaging methods. Diffusion imaging has been proposed as a noninvasive method to detect the pathognomonic lesion of CTE in vivo because of its high sensitivity to microstructural alterations in tissue structure. While several diffusion imaging approaches, ranging from diffusion tensor imaging (DTI) to more advanced schemes such as generalized q-sampling imaging (GQI) and diffusion kurtosis imaging (DKI) may prove useful, the relationship between changes in diffusion-derived metrics and the underlying pathology remains unknown. We have developed and implemented a method of perform radiological-pathological correlations in tissues with diagnoses of CTE, aimed to determine whether high spatial resolution diffusion imaging is capable of sensitively detecting pTau pathology. Human ex vivo cortical tissues diagnoses with Stage III/IV CTE, Alzheimer’s disease (AD) or frontotemporal lobar dementia (FTLD) were scanned in an 11.74T Agilent MRI scanner using DTI, GQI and DKI acquisition schemes with isotropic in-plane spatial resolution of 250µm and 500µm slice thickness. Following image acquisition, tissues were sectioned and stained for histopathological markers including AT8 (pTau), GFAP (astrocytes) and Myelin Black Gold II (myelinated white matter). A custom script was used to co-register histological to MRI images, allowing for the ability to perform high spatial resolution correlations of histological with diffusion metrics. Using this approach, we found no relationship between pTau in sulcal depths and any of our DTI, GQI and DKI based measures. Interestingly, we found that white matter underlying sulcal depths in CTE tissues showed signs of disruption, a finding that we did not observe in AD or FTLD tissues. Furthermore, white matter integrity in these regions was correlated with fractional anisotropy. These findings demonstrate that high spatial resolution diffusion imaging is capable of detecting white matter disorganization closely related to pTau pathology in CTE, and may provide a more sensitive and specific means of diagnosing CTE

Analytic Continuation of Resolvent Kernels on noncompact Symmetric Spaces

Let X=G/K be a symmetric space of noncompact type and let L be the Laplacian associated with a G-invariant metric on X. We show that the resolvent kernel of L admits a holomorphic extension to a Riemann surface depending on the rank of the symmetric space. This Riemann surface is a branched cover of the complex plane with a certain part of the real axis removed. It has a branching point at the bottom of the spectrum of L. It is further shown that this branching point is quadratic if the rank of X is odd, and is logarithmic otherwise. In case G has only one conjugacy class of Cartan subalgebras the resolvent kernel extends to a holomorphic function on a branched cover of the complex plane with the only branching point being the bottom of the spectrum.Comment: 16 pages, 3 figures, LaTe

Minimal long-term neurobehavioral impairments after endovascular perforation subarachnoid hemorrhage in mice

AbstractCognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.</jats:p

The Morphology of Reionization in a Dynamically Clumpy Universe

A recent measurement of the Lyman-limit mean free path at $z = 6$ suggests it may have been very short, motivating a better understanding of the role that ionizing photon sinks played in the reionization process. Accurately modeling the sinks in reionization simulations is challenging because of the large dynamic range required if gas structures on scales $\sim 10^4-10^8 M_{\odot}$ contributed significant opacity. As a result, there is no consensus on how important the sinks were in shaping reionization's morphology and its observables. We address this question with a recently developed radiative transfer code that includes a dynamical sub-grid model for the sinks based on radiative hydrodynamics simulations. Compared to assuming a fully pressure-smoothed IGM, our dynamical treatment reduces the predicted sizes of ionized bubbles by $10-20\%$ under typical assumptions about reionization's sources. Near the midpoint of reionization, the 21 cm power at $k \sim 0.1$ $h$Mpc$^{-1}$ is reduced by a similar factor. These effects are more modest than the $25-45\%$ power suppression resulting from the much higher recombination rate in models that neglect pressure smoothing entirely. Whether the sinks played a significant role in reionization's morphology depends on the nature of its sources. For example, if reionization was driven by bright ($M_{\rm UV} < -17$) galaxies, the sinks reduce the large-scale 21 cm power by at most $15\%$, even if pressure smoothing is neglected. Conveniently, when bright sources contribute significantly, the morphology in our dynamical treatment can be reproduced to high accuracy with a uniform sub-grid clumping factor that yields the same ionizing photon budget. By contrast, if $M_{\rm UV} \sim -13$ galaxies drove reionization, an accurate model of the sinks' dynamics is more important, with the uniform clumping model erring at the $20\%$ level.Comment: 17 pages, 12 figures, prepared for submission to MNRAS. Comments welcom