Faculty Bibliography

One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The squirrel monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.

Cerebrovascular ischaemia is potentiated by hyperthermia, and even mild temperature elevation has proved detrimental to ischaemic brain. Infarction progression following endovascular reperfusion relates to multiple patient-specific and procedural variables; however, the potential influence of mild systemic temperature fluctuations is not fully understood. This study aims to assess the relationship between systemic temperatures in the early aftermath of acute ischaemic stroke and the loss of at-risk penumbral tissues, hypothesizing consumption of the ischaemic penumbra as a function of systemic temperatures, irrespective of reperfusion status. A cross-sectional, retrospective evaluation of a single-institution, prospectively collected endovascular therapy registry was conducted. Patients with anterior circulation, large vessel occlusion acute ischaemic stroke who underwent initial CT perfusion, and in whom at least four-hourly systemic temperatures were recorded beginning from presentation and until the time of final imaging outcome were included. Initial CT perfusion core and penumbra volumes and final MRI infarction volumes were computed. Systemic temperature indices including temperature maxima were recorded, and pre-defined temperature thresholds varying between 37°C and 38°C were examined in unadjusted and adjusted regression models which included glucose, collateral status, reperfusion status, CT perfusion-to-reperfusion delay, general anaesthesia and antipyretic exposure. The primary outcome was the relative consumption of the penumbra, reflecting normalized growth of the at-risk tissue volume ≥10%. The final study population comprised 126 acute ischaemic stroke subjects (mean 63 ± 14.5 years, 63% women). The primary outcome of penumbra consumption ≥10% occurred in 51 (40.1%) subjects. No significant differences in baseline characteristics were present between groups, with the exception of presentation glucose (118 ± 26.6 without versus 143.1 ± 61.6 with penumbra consumption, P = 0.009). Significant differences in the likelihood of penumbra consumption relating to systemic temperature maxima were observed [37°C (interquartile range 36.5 - 37.5°C) without versus 37.5°C (interquartile range 36.8 - 38.2°C) with penumbra consumption, P = 0.001]. An increased likelihood of penumbra consumption was observed for temperature maxima in unadjusted (odds ratio 3.57, 95% confidence interval 1.65 - 7.75; P = 0.001) and adjusted (odds ratio 3.06, 95% confidence interval 1.33 - 7.06; P = 0.009) regression models. Significant differences in median penumbra consumption were present at a pre-defined temperature maxima threshold of 37.5°C [4.8 ml (interquartile range 0 - 11.5 ml) versus 21.1 ml (0 - 44.7 ml) for subjects not reaching or reaching the threshold, respectively, P = 0.007]. Mild fever may promote loss of the ischaemic penumbra irrespective of reperfusion, potentially influencing successful salvage of at-risk tissue volumes following acute ischaemic stroke.

Background/UNASSIGNED:Maladaptive reactivity to sensory inputs is commonly observed in neurodevelopmental disorders (e.g., autism, ADHD). Little is known, however, about the underlying neural mechanisms. For some children, atypical sensory reactivity is the primary complaint, despite absence of another identifiable neurodevelopmental diagnosis. Studying Sensory Processing Disorder (SPD) may well provide a window into the neuropathology of these symptoms. It has been proposed that a deficit in sensory integration underlies the SPD phenotype, but objective quantification of sensory integration is lacking. Here we used neural and behavioral measures of multisensory integration (MSI), which would be affected by impaired sensory integration and for which there are well accepted objective measures, to test whether failure to integrate across the senses is associated with atypical sensory reactivity in SPD. An autism group served to determine if observed differences were unique to SPD. Methods/UNASSIGNED:= 44). Participants performed a simple reaction-time task to the occurrence of auditory, visual, and audiovisual stimuli presented in random order, while high-density recordings of electrical brain activity were made. Results/UNASSIGNED:tests suggested the possibility of enhanced MSI in SPD in timeframes consistent with cortical sensory registration (∼60 ms), followed by reduced MSI during a timeframe consistent with object formation (∼130 ms). The ASD group also showed reduced MSI in the later timeframe. Conclusion/UNASSIGNED:testing pointed to periods of potential differential processing. While these exploratory electrophysiological observations point to potential sensory-perceptual differences in multisensory processing in SPD, it remains equally plausible at this stage that later attentional processing differences may yet prove responsible for the multisensory behavioral deficits uncovered here.

BACKGROUND:Depression is associated with a broad range of cognitive deficits, including processing speed (PS) and executive functioning (EF). Cognitive symptoms commonly persist with the resolution of affective symptoms and increase risk of relapse and recurrence. The cognitive control network is comprised of brain areas implicated in EF and mood regulatory functions. Prior research has demonstrated the effectiveness of computerized cognitive training (CCT) focused on PS and EF in mitigating both cognitive and affective symptoms of depression. METHODS:Ninety participants aged 18-29 with a current diagnosis of major depressive disorder or persistent depressive disorder, or a Hamilton Depression Rating Scale score ≥12, will be randomized to either PS/EF CCT, verbal CCT, or waitlist control. Participants in the active groups will complete 15 min of training 5 days/week for 8 weeks. Clinical and neuropsychological assessments will be completed at baseline, week 4, week 8, and 3-month follow-up. Structural and functional magnetic resonance imaging (fMRI) will be completed at baseline and week 8. We will compare changes in mood, cognition, daily functioning, and fMRI data. We will explore cognitive control network functioning using resting-state and task-based fMRI. RESULTS:Recruitment began in October 2019; we expect to finish recruitment by April 2022 and subsequently begin data analysis. CONCLUSIONS:This study is innovative in that it will include both active and waitlist control conditions and will explore changes in neural activation. Identifying the neural networks associated with improvements following CCT will allow for the development of more precise and effective interventions. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT03869463; https://clinicaltrials.gov/ct2/show/NCT03869463.

Pediatric multiple sclerosis (MS) is an increasingly recognized rare subgroup of patients presenting with a unique set of diagnostic challenges. Understanding the early development of MS may offer a window into the pathogenesis of disease; however further research is needed, particularly within the field of genetics and to understand the complex environmental and biological interactions at work. Acute disseminated encephalomyelitis (ADEM) remains a hallmark presentation of early pediatric disease and can be a monophasic illness or end up being reclassified as a relapsing disorder. The clinical expression is shaped in part by the prepubertal or postpubertal state of the patient. Other syndromes can also present with ADEM, and a specific differential diagnosis exists for children presenting with any initial demyelinating event (IDE). New definitions and criteria have allowed early detection of MS. However applying adult criteria to very young children should be approached with caution. There is now a major effort in studying disease-modifying therapy (DMT) in children due to requirements from regulatory authorities. Pediatric patients respond well to therapy and often do best with an interdisciplinary approach focusing on social aspects, cognition, and fatigue which enhances the achievement of successful outcomes.
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