Faculty Bibliography

Alzheimer's disease (AD) is the most common form of dementia. Despite many years of intense research, there is currently still no effective treatment. Multiple cell types contribute to disease pathogenesis, with an increasing body of data pointing to the active participation of astrocytes. Astrocytes play a pivotal role in the physiology and metabolic functions of neurons and other cells in the central nervous system. Because of their interactions with other cell types, astrocyte functions must be understood in their biologic context, thus many studies have used mouse models, of which there are over 190 available for AD research. However, none appear able to fully recapitulate the many functional changes in astrocytes reported in human AD brains. Our review summarizes the observations of astrocyte biology noted in mouse models of familial and sporadic AD. The limitations of AD mouse models will be discussed and current attempts to overcome these disadvantages will be described. With increasing understanding of the non-neuronal contributions to disease, the development of new methods and models will provide further insights and address important questions regarding the roles of astrocytes and other non-neuronal cells in AD pathophysiology. The next decade will prove to be full of exciting opportunities to address this devastating disease.

PURPOSE/OBJECTIVE:This study reports on the development of a novel 3D procedure planning technique to provide pre-ablation treatment planning for partial gland prostate cryoablation (cPGA). METHODS:Twenty men scheduled for partial gland cryoablation (cPGA) underwent pre-operative image segmentation and 3D modeling of the prostatic capsule, index lesion, urethra, rectum, and neurovascular bundles based upon multi-parametric MRI data. Pre-treatment 3D planning models were designed including virtual 3D cryotherapy probes to predict and plan cryotherapy probe configuration needed to achieve confluent treatment volume. Treatment efficacy was measured with 6 month post-operative MRI, serum prostate specific antigen (PSA) at 3 and 6 months, and treatment zone biopsy results at 6 months. Outcomes from 3D planning were compared to outcomes from a series of 20 patients undergoing cPGA using traditional 2D planning techniques. RESULTS:Forty men underwent cPGA. The median age of the cohort undergoing 3D treatment planning was 64.8 years with a median pretreatment PSA of 6.97 ng/mL. The Gleason grade group (GGG) of treated index lesions in this cohort included 1 (5%) GGG1, 11 (55%) GGG2, 7 (35%) GGG3, and 1 (5%) GGG4. Two (10%) of these treatments were post-radiation salvage therapies. The 2D treatment cohort included 20 men with a median age of 68.5 yrs., median pretreatment PSA of 6.76 ng/mL. The Gleason grade group (GGG) of treated index lesions in this cohort included 3 (15%) GGG1, 8 (40%) GGG2, 8 (40%) GGG3, 1 (5%) GGG4. Two (10%) of these treatments were post-radiation salvage therapies. 3D planning predicted the same number of cryoprobes for each group, however a greater number of cryoprobes was used in the procedure for the prospective 3D group as compared to that with 2D planning (4.10 ± 1.37 and 3.25 ± 0.44 respectively, p = 0.01). At 6 months post cPGA, the median PSA was 1.68 ng/mL and 2.38 ng/mL in the 3D and 2D cohorts respectively, with a larger decrease noted in the 3D cohort (75.9% reduction noted in 3D cohort and 64.8% reduction 2D cohort, p 0.48). In-field disease detection was 1/14 (7.1%) on surveillance biopsy in the 3D cohort and 3/14 (21.4%) in the 2D cohort, p = 0.056) In the 3D cohort, 6 month biopsy was not performed in 4 patients (20%) due to undetectable PSA, negative MRI, and negative MRI Axumin PET. For the group with traditional 2D planning, treatment zone biopsy was positive in 3/14 (21.4%) of the patients, p = 0.056. CONCLUSIONS:3D prostate cancer models derived from mpMRI data provide novel guidance for planning confluent treatment volumes for cPGA and predicted a greater number of treatment probes than traditional 2D planning methods. This study prompts further investigation into the use of 3D treatment planning techniques as the increase of partial gland ablation treatment protocols develop.

The precuneus (PreC; Brodmann area 7), a key hub within the default mode network (DMN) displays amyloid and tau-containing neurofibrillary tangle (NFT) pathology during the onset of Alzheimer's disease (AD). PreC layer III projection neurons contain lysosomal hydrolase cathepsin D (CatD), 14)a marker of neurons vulnerable to NFT pathology. Here we applied single population laser capture microdissection coupled with custom-designed microarray profiling to determine the genetic signature of PreC CatD-positive-layer III neurons accrued from postmortem tissue obtained from the Rush Religious Orders Study (RROS) cases with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD. Expression profiling revealed significant differential expression of key transcripts in MCI and AD compared to NCI that underlie signaling defects, including dysregulation of genes within the endosomal-lysosomal and autophagy pathways, cytoskeletal elements, AD-related genes, ionotropic and metabotropic glutamate receptors, cholinergic enzyme and receptors, markers of monoamine neurotransmission as well as steroid-related transcripts. Pervasive defects in both MCI and AD were found in select transcripts within these key gene ontology categories, underscoring the vulnerability of these corticocortical neurons during the onset and progression of dementia. Select PreC dysregulated genes detected via custom-designed microarray analysis were validated using qPCR. In summary, expression profiling of CatD positive PreC layer III neurons revealed significant dysregulation of a mosaic of genes in MCI and AD that were not previously appreciated in terms of their indication of systems-wide signaling defects in a key hub of the DMN. This article is protected by copyright. All rights reserved.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Aggression is a social behavior essential for securing resources and defending oneself and family. Thanks to its indispensable function in competition and thus survival, aggression exists widely across animal species, including humans. Classical works from Tinbergen and Lorenz concluded that instinctive behaviors including aggression are mediated by hardwired brain circuitries that specialize in processing certain sensory inputs to trigger stereotyped motor outputs. They further suggest that instinctive behaviors are influenced by an animal's internal state and past experiences. Following this conceptual framework, here we review our current understanding regarding the neural substrates underlying aggression generation, highlighting an evolutionarily conserved 'core aggression circuit' composed of four subcortical regions. We further discuss the neural mechanisms that support changes in aggression based on the animal's internal state. We aim to provide an overview of features of aggression and the relevant neural substrates across species, highlighting findings in rodents, primates and songbirds.

Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. PNI induced afterdischarge in A high threshold mechanoreceptors (AHTMRs), mechanical sensitization (i.e., decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low threshold mechanoreceptors (LTMRs). PNI resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically-insensitive and electrically-unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BACKGROUND:Despite innovations in left ventricular assist devices (LVAD) technology, stroke remains a leading cause of morbidity and mortality in this population. Major clinical trials of LVAD have used various definitions and approaches to measuring stroke outcomes which may limit comparison of stroke risk between different devices. METHODS:Data from the five major LVAD randomized, controlled, trials was abstracted to compare definitions of stroke (composite, ischemic, hemorrhagic and disabling) and stroke event rates across trials. Methodological limitations and suggestions to improve research and clinical practices for stroke and LVAD were identified. RESULTS:Comparison of stroke events across LVAD clinical trials is confounded by methodological variability including heterogeneity in stroke definitions, non-standardized evaluation of stroke etiology, oversimplification of stroke severity classification, and inconsistent event rate reporting due to data censoring at the time of death or transplant. Variability in the study of stroke in LVAD patients limits the ability to compare devices and design prevention strategies to mitigate stroke risk. CONCLUSIONS:Based on this review, we propose that future clinical trials: 1) utilize standardized stroke definitions and define stroke subtypes, 2) ensure that neurologists are integrated in study design and event adjudication, 3) include more thorough evaluations of stroke etiology using multimodality techniques, and 4) adopt the National Institutes of Health Stroke Scale to define stroke severity.