Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:The basal forebrain contains multiple structures of great interest to emerging functional neurosurgery applications, yet many neuroradiologists are unfamiliar with this neuroanatomy because it is not resolved with current clinical MR imaging. MATERIALS AND METHODS/METHODS:= 13) to demonstrate and characterize the detailed anatomy of the basal forebrain using a clinical 3T MR imaging scanner. We measured the size of selected internal myelinated pathways and measured subthalamic nucleus size, oblique orientation, and position relative to the intercommissural point. RESULTS:= .084 and .047, respectively). Individual variability for the subthalamic nucleus was greatest for angulation within the sagittal plane (range, 15°-37°), transverse dimension (range, 2-6.7 mm), and most inferior border (range, 4-7 mm below the intercommissural plane). CONCLUSIONS:Direct identification of basal forebrain structures in multiple planes using the TSE T2 sequence makes this challenging neuroanatomy more accessible to practicing neuroradiologists. This protocol can be used to better define individual variations relevant to functional neurosurgical targeting and validate/complement advanced MR imaging methods being developed for direct visualization of these structures in living patients.

Background: Alzheimer's disease (AD) is the most common form of dementia affecting 5.7 million individuals in the U.S. alone. While treatment approaches have predominantly focused on the reduc-tion of amyloid beta plaques, there has been a concerted shift to also target tau pathology, another major pathological marker of AD. There is no current treatment for AD, however profound efforts have been made in developing an immunotherapy approach. We have focused on activating Toll-like receptor 9 (TLR9), a stimulatory receptor of the innate immune system, in attempts to ameliorate the immune system's dysfunctional clearance. Our earlier studies revealed that stimulation of the innate immunity via TLR9 agonist, CpG ODN, in 3xTg-AD mice can alleviate all pathological hallmarks of AD (Ab, tau, CAA) and improve behavioral deficits without toxicity. Given the importance of tau related pathology, we designed an experiment to more directly determine the effect of CpG-ODN on tau pathology. This was done through rTg4510 mice, a tauopathy mouse model which develops robust forebrain tangle pathology without concurrent amyloid pathology.
Method(s): The rTg4510 mice were injected with either the TLR9 agonist Class B CpG-ODN or saline at monthly intervals (3 to 11 months of age). After the treatment period, immunohistochemistry and biochemical analyses (western blot) were performed. Peripheral immune response analyses (Th1/Th2 Luminex technology) are underway.
Result(s): Histological evaluation of CpG-ODN effect on hippo-campal and cortical brain regions revealed region specific reductions in PHF1 and MC1 immunoreactivity in CpG-ODN treated animals. Preliminary western blot analyses showed a significant reduction in total PHF1 phospho-tau levels (low-speed supernatant fraction) in the CpG-ODN-treated group in comparison to the saline-treated animals. Additionally, CpG-ODN treatment was not associated with increased insoluble tau pathology in sarcosyl fractions. Unlike previous attempts to simulate innate immunity, our method of immunomodulation demonstrated a modest, yet beneficial, effect on tau related pathology.
Conclusion(s): Overall, the present findings, together with our earlier research, demonstrate promising preclinical evidence for the potential use of TLR9 ligand CpG ODN as a disease modifying drug for Alzheimer's disease and other tau related dementias

BACKGROUND AND PURPOSE/OBJECTIVE:The brain stem is compactly organized with life-sustaining sensorimotor and autonomic structures that can be affected by numerous pathologies but can be difficult to resolve on conventional MR imaging. MATERIALS AND METHODS/METHODS:We applied an optimized TSE T2 sequence to washed postmortem brain samples to reveal exquisite and reproducible brain stem anatomic MR imaging contrast comparable with histologic atlases. This resource-efficient approach can be performed across multiple whole-brain samples with relatively short acquisition times (2 hours per imaging plane) using clinical 3T MR imaging systems. RESULTS:< .10). CONCLUSIONS:Compared with traditional atlases, multiplanar MR imaging contrast has advantages for learning and retaining brain stem anatomy for clinicians and trainees. Direct TSE MR imaging sequence discrimination of brain stem anatomy can help validate other MR imaging contrasts, such as diffusion tractography, or serve as a structural template for extracting quantitative MR imaging data in future postmortem investigations.

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that modify extracellular matrix components and play crucial roles in development and numerous diseases. ADAMTS18 is a member of the ADAMTS family, and genome-wide association studies made an initial association of ADAMTS18 with white matter integrity in healthy people of 72-74 years old. However, the potential roles of ADAMTS18 in central nervous system remain unclear. In this study, we showed that Adamts18 mRNA is highly abundant in developing brains, especially in the cerebellum granular cell layer and the hippocampus dentate gyrus (DG) granular cell layer. Adamts18 knockout (KO) mice displayed higher dendritic branching complexity and spine density on hippocampal DG granular cells. Behavioral tests showed that Adamts18 KO mice had reduced levels of depression-like behaviors compared to their wild-type (WT) littermates. The increased neurite formation could be attributed in part to reduced phosphorylation levels of the collapsin response mediator protein-2 (CRMP2) due to activation of the laminin/PI3K/AKT/GSK-3β signaling pathway. Our findings revealed a critical role of ADAMTS18 in neuronal morphogenesis and emotional control in mice.

The purpose of this study was to evaluate changes in the prevalence and risk factors of cognitive impairment (CI) by analyzing and comparing two cross-sectional epidemiological surveys of CI and its subtypes were performed in a rural area of northern China between 2010 and 2015. Residents aged ≥60 years were drawn in northern China. The Mini Mental State Examination (MMSE) is recommended to test for CI. Dementia was further categorised into Alzheimer's disease (AD), vascular dementia (VaD), and dementia caused by other diseases (ODs). Mild cognitive impairment (MCI) was classified into MCI caused by AD (MCI-A), MCI caused by VaD (MCI-VD), and MCI caused by ODs (MCI-O). The prevalence of CI increased in China. The prevalence of all-cause CI was 30·5% (22.9% MCI and 7.6% dementia) in 2010. The prevalence of all-cause CI was 38.3% (27.8% MCI and 10.5% dementia) in 2015. Similar increases were observed for the prevalence of subtypes of dementia and MCI. These findings suggest an increasing prevalence of CI and its subtypes in China, which may be related to alterations in sociodemographic factors, vascular risk factors and lifestyle changes over time in these cohorts.

There are growing genetic, transcriptomic and proteomic data pointing to the complexity of Alzheimer's disease (AD) pathogenesis. Unbiased "omics" approaches are essential for the future development of effective AD research, which will need to be combined and personalized, given that multiple distinct pathways can drive AD pathology. It is essential to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity, as well as the common presence of mixed pathologies. These nonmutually exclusive therapeutic approaches include the targeting of multiple toxic oligomeric species concurrently, targeting the apolipoprotein E/amyloid β interaction and the modulation of innate immunity, as well as more "out of the box" ideas such as targeting infectious agents that may play a role in AD.

Traumatic brain injury (TBI) is a risk factor for a group of neurodegenerative diseases termed tauopathies, which includes Alzheimer's disease and chronic traumatic encephalopathy (CTE). Although TBI is stratified by impact severity as either mild (m), moderate or severe, mTBI is the most common and the most difficult to diagnose. Tauopathies are pathologically related by the accumulation of hyperphosphorylated tau (P-tau) and increased total tau (T-tau). Here we describe: (i) a novel human tau-expressing transgenic mouse model, TghTau/PS1, to study repetitive mild closed head injury (rmCHI), (ii) quantitative comparison of T-tau and P-tau from brain and plasma in TghTau/PS1 mice over a 12 month period following rmCHI (and sham), (iii) the usefulness of P-tau as an early- and late-stage blood-based biochemical biomarker for rmCHI, (iii) the influence of kinase-targeted therapeutic intervention on rmCHI-associated cognitive deficits using a combination of lithium chloride (LiCl) and R-roscovitine (ros), and (iv) correlation of behavioral and cognitive changes with concentrations of the brain and blood-based T-tau and P-tau. Compared to sham-treated mice, behavior changes and cognitive deficits of rmCHI-treated TghTau/PS1 mice correlated with increases in both cortex and plasma T-tau and P-tau levels over 12 months. In addition, T-tau, but more predominantly P-tau, levels were significantly reduced in the cortex and plasma by LiCl + ros approaching the biomarker levels in sham and drug-treated sham mice (the drugs had only modest effects on the T-tau and P-tau levels in sham mice) throughout the 12 month study period. Furthermore, although we also observed a reversal of the abnormal behavior and cognitive deficits in the drug-treated rmCHI mice (compared to the untreated rmCHI mice) throughout the time course, these drug-treated effects were most pronounced up until 10 and 12 months where the abnormal behavior and cognition deficits began to gradually increase. These studies describe: (a) a translational relevant animal model for TBI-linked tauopathies, and (b) utilization of T-tau and P-tau as rmCHI biomarkers in plasma to monitor novel therapeutic strategies and treatment regimens for these neurodegenerative diseases.