Faculty Bibliography

Inflammation is a significant component of Alzheimer's disease pathology. While neuroprotective microglia are important for containment/clearance of Amyloid plaques and maintaining neuronal survival, Alzheimer inflammatory microglia may play a detrimental role by eliciting tau pathogenesis and accelerating neurotoxicity. Regulatory T cells have been shown to suppress microglia-mediated inflammation. However, the role of regulatory T cells in ameliorating the proinflammatory immune response in Alzheimer's disease requires further investigation. Forty-six patients with Alzheimer disease, 42 with mild cognitive impairment and 41 healthy controls were studied. The phenotypes of peripheral regulatory T cells were assessed with multicolour flow cytometry. Regulatory T cells were co-cultured with responder T cells and proliferation was determined by ³H-thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell-derived pro-inflammatory macrophages and changes in interleukin-6/tumour necrosis-alpha transcripts and protein levels were measured. Freshly isolated regulatory T cells were expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin-2 and rapamycin to promote their suppressive function. We found that the suppressive function of regulatory T cells on responder T-cell proliferation was compromised at the Alzheimer disease stage, compared with mild cognitive impairment and healthy controls. CD25 mean fluorescence intensity in regulatory T-cell population was also reduced in Alzheimer dementia patients. Regulatory T cells did not suppress pro-inflammatory macrophages at baseline. Following ex vivo expansion, regulatory T-cell suppression of responder T-cell proliferation and pro-inflammatory macrophage activation increased in both patients and controls. Expanded regulatory T cells exerted their immunoregulatory function on pro-inflammatory macrophages through a contact-mediated mechanism. In conclusion, regulatory T-cell immunophenotype and function are compromised in Alzheimer's disease. Following ex vivo expansion, the immunomodulatory function of regulatory T cells is enhanced even at advanced stages of Alzheimer's disease. Restoration of regulatory T-cell function could be explored as a means to modulate the inflammatory status of Alzheimer's disease.

Nearly 380,000 U.S. service members between 2000 and 2017 were, and at least 300,000 athletes annually are, diagnosed with concussion. It is imperative to establish a gold-standard diagnostic test to quickly and accurately diagnose concussion. In this non-randomized, prospective study, we examined the reliability and validity of a novel neurocognitive assessment tool, the Defense Automated Neurobehavioral Assessment (DANA), designed to be a more sensitive, yet efficient, measure of concussion symptomatology. In this study, the DANA Brief version was compared to an established measure of concussion screening, the Military Acute Concussion Evaluation (MACE), in a group of non-concussed service members. DANA Brief subtests demonstrated low to moderate reliability, as measured by intra-class correlation coefficient (ICC; values range: 0.28-0.58), which is comparable to other computerized neurocognitive tests that are widely-implemented to diagnose concussion. Statistically significant associations were found between learning and memory components of the DANA Brief and the diagnostic MACE cognitive test score (DANA Brief subtests: CDD: R ² = 0.05, p = 0.023; CDS: R ² = 0.10, p = 0.010). However, a more robust relationship was found between DANA Brief components involving attention and working memory, including immediate memory, and the MACE cognitive test score (DANA Brief subtests: GNG: R ² = 0.08, p = 0.003; PRO: R ² = 0.08, p = 0.002). These results provide evidence that the DANA Rapid version, a 5-min assessment self-administered on a hand-held portable device, based on the DANA Brief version, may serve as a clinically useful and improved neurocognitive concussion screen to minimize the time between injury and diagnosis in settings where professional medical evaluation may be unavailable or delayed. The DANA's portability, durability, shorter test time and lack of need for a medical professional to diagnose concussion overcome these critical limitations of the MACE.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies.

Guillain-Barré Syndrome is a popular eponym that comes from a 1916 paper by Drs. Guillain, Barré, and Strohl. These physicians described two soldiers in the French Sixth Army during World War I who developed acute progressive motor weakness. Although Drs. Guillain and Barré have continued to be included in the syndrome's eponym, Dr. Strohl has been forgotten despite having strongly contributed to the original paper. The reasons previously mentioned for Dr. Strohl's absence appear trivial in contemporary practice and thus, his name deserves to be reintroduced to Guillain-Barré-Strohl Syndrome.