We recently developed a CD8 T cell-induced mouse model that recapitulates definitive hallmarks of Alzheimer's disease (AD) and allowed prediction of previously unknown properties of human sporadic AD (DOI: 10.1073/pnas.2401420121). Identification of a peptide antigen to which the inducing T cells respond in this model (a non-Aβ epitope on Amyloid Precursor Protein [APP]) allowed us to quantify analogous T cells in human brain and blood, using an APP 471-479 /Human Leukocyte Antigen(HLA)-A2 multimer (pHLA) and flow cytometry on blood. Blood levels of these T cells distinguished AD and related MCI from normal aging controls with high accuracy (AUC: 0.883-0.892), but the assay is currently suitable only for HLA-A2-positive (about half of all) patients due to HLA subtype-restricted binding. CD8 T cell binding to a non-self ( ALIAPVHAV /HLA-A0201) multimer correlated with APP multimer binding in HLA-A2-positive patients (0.42-0.58x relative to APP/HLA-A2; r = 0.81; P  < 0.001). Surprisingly, the same non-self multimer bound at similar levels to HLA-A2-negative patients’ Tcells. We thus quantified levels of age-related, KLRG1 + CD8 T cells binding to this multimer in HLA-A2-positive ( n  = 79) and -negative ( n  = 44) subjects by flow cytometry from Alzheimer's disease (AD) and normal aging control cohorts, and assessed their correspondence to disease status. As with the APP pHLA reagent, levels of T cells binding to the non-self pHLA multimer were significantly diminished in AD irrespective of HLA subtype ( P  < 0.015 by 2-sided T-Test). In receiver operating characteristic (ROC) analysis of the HLA-negative cohort, area under the curve (AUC) was 0.878 for AD ( P  < 0.00001) with 79.4% sensitivity and 98.6% specificity, nearly identical to the APP-specific CD8 T cells in HLA-A2-positive individuals (AUC 0.88; 72.2% sensitivity, 97.2 specificity). Moreover, disease correspondence of the non-self pHLA-reactive T cells was improved in HLA-A2-positive patients as well (AUC 0.912). Subtype-independent pHLA binding by CD8 T cells strongly corresponds to AD status in HLA-A2-negative and HLA-positive individuals, providing a working basis for expanding our AD biomarker assay to all patients. Ongoing work will focus on increasing the sensitivity of HLA-independent multimer binding to further increase assay utility.

The progressive aggregation of amyloid beta (Aβ) monomers into oligomers is a critical factor in Alzheimer's disease (AD) pathogenesis. Although mutated forms of Aβ have been shown to display altered aggregation dynamics, the specific effects of deamidated Aβ on microglial function remain understudied. Our research group previously found that the deamidated variant Aβ-42-N27D modified Aβ aggregation, reduced neurotoxicity, and reduced microglial reactivity, but the impact of Aβ-42 side chain deamidation in general on such parameters remained unclear. Here, we expanded on our prior work by investigating how two site-specific Aβ-42 mutations (Q15E & N27D), where neutral amide side chains are replaced with negatively charged carboxylic acids, affect aggregation and microglial immune response using a mouse microglial cell line. Size exclusion chromatography revealed that Aβ-42-Q15E and Aβ-42-N27D exhibit distinct aggregation profiles compared to Aβ-42 wild type (WT). Multiplexed analysis of 8 cytokines secreted into the culture medium revealed that Aβ-42-Q15E and Aβ-42-N27D decrease the expression of inflammatory cytokines such as IL-6, IP-10, and MIP-1α relative to Aβ-42-WT. Immunocytochemistry revealed that Aβ-42-Q15E and Aβ-42-N27D decrease CD68 expression relative to Aβ-42-WT. These findings demonstrate that deamidation significantly alters Aβ-42 aggregation and microglial activation, suggesting structural modifications to Aβ-42 modulate inflammatory signaling in AD. This work provides a foundation for future studies on Aβ-42 post-translational modifications as potential therapeutic targets in AD.S.

Alzheimer's disease (AD) is a growing global challenge that imposes a tremendous burden on society and economies. Though recently approved anti-amyloid β (Aβ) immunotherapies show effectiveness in clearing amyloid and slowing cognitive decline, the removal of cerebral Aβ can also cause serious adverse events (SAEs). Therefore, decreasing the detrimental effects of Aβ in the brain without promoting SAEs is an unmet need in AD treatment. Here, we show that deamidation of Asparagine 27(N27) in Aβ1-42 can significantly reduce Aβ's neurotoxicity and decrease selective microglial pro-inflammatory cytokine production. We also show that deamidation of N27 produces a pronounced decrease in Aβ's aggregation propensity and decreases soluble oligomer formation, suggesting a potential mechanism for its mitigation of Aβ's detrimental cellular effects. Modulation of these Aβ properties by N27 deamidation represents a proof of concept for a potential strategy to alter the detrimental effects of Aβ that may not require its removal from the brain. Our findings on reducing Aβ's toxic properties by N27 deamidation may provide a basis for future therapeutic interventions.

Amyloid aggregation is a key feature of Alzheimer's disease (AD) and a primary target for past and present therapeutic efforts. Recent research is making it increasingly clear that the heterogeneity of amyloid deposits, extending past the commonly targeted amyloid-β (Aβ), must be considered for successful therapy. We recently demonstrated that amyloid-α (Aα or p3), a C-terminal peptidic fragment of Aβ, aggregates rapidly to form amyloids and can expedite the aggregation of Aβ through seeding. Here, we advance the understanding of Aα biophysics and biology in several important ways. We report the first cryogenic electron microscopy (cryo-EM) structure of an Aα amyloid fibril, proving unambiguously that the peptide is fibrillogenic. We demonstrate that Aα induces Aβ to form amyloid aggregates that are less toxic than pure Aβ aggregates and use nuclear magnetic resonance spectroscopy (NMR) to provide insights into specific interactions between Aα and Aβ in solution. This is the first evidence that Aα can coassemble with Aβ and alter its biological effects at relatively low concentrations. Based on the above, we urge researchers in the field to re-examine the significance of Aα in AD.

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer’s disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models. The precise impact of T cells downstream of Aβ/pTau, however, appears to vary depending on the animal model. Our prior work suggested that antigen-specific memory CD8 T (“ hi T”) cells act upstream of Aβ/pTau after brain injury. Here, we examine whether hi T cells influence sporadic AD-like pathophysiology upstream of Aβ/pTau. Examining neuropathology, gene expression, and behavior in our hi T mouse model we show that CD8 T cells induce plaque and tangle-like deposition, modulate AD-related genes, and ultimately result in progressive neurodegeneration with both gross and fine features of sporadic human AD. T cells required Perforin to initiate this pathophysiology, and IFNγ for most gene expression changes and progression to more widespread neurodegenerative disease. Analogous antigen-specific memory CD8 T cells were significantly elevated in the brains of human AD patients, and their loss from blood corresponded to sporadic AD and related cognitive decline better than plasma pTau-217, a promising AD biomarker candidate. We identify an age-related factor acting upstream of Aβ/pTau to initiate AD-like pathophysiology, the mechanisms promoting its pathogenicity, and its relevance to human sporadic AD.

The promise of adaptive cancer immunotherapy in treating highly malignant tumors such as glioblastoma multiforme (GBM) can only be realized through expanding its benefits to more patients. Alleviating various modes of immune suppression has so far failed to achieve such expansion, but exploiting endogenous immune enhancers among mutated cancer genes could represent a more direct approach to immunotherapy improvement. We found that Isocitrate Dehydrogenase-1 (IDH1), which is commonly mutated in gliomas, enhances glioma vaccine efficacy in mice and discerns long from short survivors after vaccine therapy in GBM patients. Extracellular IDH1 directly enhanced T cell responses to multiple tumor antigens, and prolonged experimental glioma cell lysis. Moreover, IDH1 specifically bound to and exhibited sialidase activity against CD8. By contrast, mutant IDH1R132H lacked sialidase activity, delayed killing in glioma cells, and decreased host survival after immunotherapy. Overall, our findings identify IDH1 as an immunotherapeutic enhancer that mediates the known T cell-enhancing reaction of CD8 desialylation. This uncovers a new axis for immunotherapeutic improvement in GBM and other cancers, reveals novel physiological and molecular functions of IDH1, and hints at an unexpectedly direct link between lytic T cell function and metabolic activity in target cells.

Supplementary Figure 1: spheroid growth in VersaGel using tumor cell lines. A) HepG2 hepatocarcinoma cell line; B) LN18 glioblastoma cell line. Scale bar = 1 millimeter. Supplementary Figure 2: VersaGel vs. BME (Matrigel) for Patient 4, Partial Responder (A) and Patient 5, Responder (B).

We previously engineered mice to accumulate elevated levels of age-related, antigen-specific memory CD8 T cells as in humans. These mice spontaneously develop all major hallmarks of AD with aging. Analogous T cells reactive to an epitope on Amyloid Precursor Protein (APP) were found in aging humans, accumulated in AD brain, and decreased in AD blood. Here, we examine whether their levels are associated with established AD biomarkers in CSF. Antigen-specific CD8 T cells in blood were quantified by flow cytometric analysis after staining with anti-CD8, anti-KLRG1 and APP peptide-HLA-A2 multimers in normal aging, MCI with or without AD biomarkers, and confirmed late-onset AD patient cohorts (n = 50). Aβ1-42, total Tau, and pTau181 were quantified in CSF, and cognitive performance assessed by MMSE. Percentage of APP-specific memory CD8 T cells was significantly decreased with dementia (0.68 + 0.29% for MMSE <25; 1.63 + 0.32% for MMSE >24), reaching minimal levels in AD blood, which precluded meaningful correlations in AD patients. Nevertheless, increasing levels of APP-specific memory CD8 T cells in blood from all subjects combined corresponded with increased CSF Aβ1-42 (r = 0.373, P < 0.0004) and decreased total Tau but not pTau181 or MMSE (r = -0.234, P < 0.0292; r = -0.208, P < 0.0531; and r = -0.009, P < 0.9410, respectively). Decreases in the larger parental (KLRG1 + ) memory CD8 T cell population also correlated with decreased CSF Aβ1-42 in AD patients alone (r = 0.511, P = 0.003 for % KLRG1 + of CD8 T cells; r = 0.682, P < 0.00009 for % KLRG1 + CD8 + cells; n = 31). Our results reveal that age-related memory CD8 T cells in blood decrease with dementia, and in proportion to decreased CSF Aβ1-42 and total Tau in all patients, while their parental KLRG1 + population is directly proportional to Aβ1-42 in AD patients only. This validates our previous findings that loss of APP-specific memory CD8 T cells from blood accurately tracks the AD continuum, and support the notion that antigen-specific memory CD8 T cells are associated with the earliest detectable pathologic changes in AD.

Sporadic Alzheimer’s disease, the most common neurodegenerative disorder of aging, is characterized by cerebral plaques and neurofibrillary tangles. Experimental rodents develop plaques but neither tangles nor substantial neurodegeneration under conditions that guarantee Alzheimer’s in humans, suggesting rodents lack critical co-initiation factors. Accumulation of antigen-reactive memory CD8 T cells increases with aging, and was recently revealed as a hallmark of human Alzheimer’s. The impact of this process on disease initiation, however, has not been established because age-related T cell changes are muted in rodents. We developed a mouse model of human-like CD8 T cell aging that promotes antigen-reactive memory CD8 T cell accumulation. Here we show that these “hiT” mice develop all major hallmarks of Alzheimer’s with aging, including tangle-like inclusions and substantial neurodegeneration. Antigen-reactive CD8 T cells analogous to those in hiT mice increased in Alzheimer’s brain, but decreased earlier in blood, where their loss effectively distinguished the Alzheimer’s continuum from aging controls. Our findings establish a clinically relevant mouse model for sporadic Alzheimer’s and show that age-related immune dysfunction critically contributes to its initiation. They also identify useful immune-based targets to track and potentially treat human Alzheimer’s, while validating a model system to examine age-related disease immuno-biology more generally.

We previously engineered mice to accumulate age-related, antigen-specific memory CD8 T cells as in humans. These mice spontaneously develop all major hallmarks of AD with aging. Analogous T cells reactive to an epitope on Amyloid Precursor Protein (APP) were found in aging humans, accumulated in AD brain, and decreased in AD blood where their levels accurately tracked the disease in initial analysis. Here, we examine whether levels of these blood T cells are associated with established AD biomarkers. Antigen-specific CD8 T cells in blood were quantified by flow cytometric analysis after staining with anti-CD8, anti-KLRG1 and APP peptide-HLA-A2 multimers in normal aging, MCI with or without AD biomarkers, and confirmed late-onset AD patient cohorts (n = 50). Aβ1-42, total Tau, and pTau181 were quantified in CSF, and cognitive performance assessed by MMSE. Percentage of APP-specific memory CD8 T cells was significantly decreased with dementia (0.68 + 0.29% for MMSE <25; 1.63 + 0.32% for MMSE >24), reaching minimal levels in AD. Although the paucity of APP-specific CD8 T cells in AD blood precluded meaningful correlations, decreases in the larger parental (KLRG1 + ) memory CD8 T cell population correlated with decreased CSF Aβ1-42 in AD (r = 0.511; P = 0.003; n = 31). Decreasing APP-specific CD8 T cells in blood also correlated with lower CSF Ab1-42 in normal aging patients (r = 0.518; P = 0.028; n = 18). No significant correlations between T cell levels and total Tau or pTau181 were observed. Our results reveal that age-related memory CD8 T cells in blood decrease with dementia, and in proportion to decreased CSF Aβ1-42 in both AD and normal aging. Given that decreased CSF Aβ1-42 is among the earliest biomarkers for AD, this validates our previous findings that loss of APP-specific memory CD8 T cells from blood accurately tracks the AD continuum in humans. Our findings also support the notion that antigen-specific memory CD8 T cells are associated with the earliest detectable pathologic changes in AD, and as such may represent novel cause-associated biomarker candidates to predict and track the disease.

Neurological disorders significantly impact the world's economy due to their often chronic and life-threatening nature afflicting individuals which, in turn, creates a global disease burden. The Group of Twenty (G20) member nations, which represent the largest economies globally, should come together to formulate a plan on how to overcome this burden. The Neuroscience-20 (N20) initiative of the Society for Brain Mapping and Therapeutics (SBMT) is at the vanguard of this global collaboration to comprehensively raise awareness about brain, spine, and mental disorders worldwide. This paper aims to provide a comprehensive review of the various brain initiatives worldwide and highlight the need for cooperation and recommend ways to bring down costs associated with the discovery and treatment of neurological disorders. Our systematic search revealed that the cost of neurological and psychiatric disorders to the world economy by 2030 is roughly $16T. The cost to the economy of the United States is $1.5T annually and growing given the impact of COVID-19. We also discovered there is a shortfall of effective collaboration between nations and a lack of resources in developing countries. Current statistical analyses on the cost of neurological disorders to the world economy strongly suggest that there is a great need for investment in neurotechnology and innovation or fast-tracking therapeutics and diagnostics to curb these costs. During the current COVID-19 pandemic, SBMT, through this paper, intends to showcase the importance of worldwide collaborations to reduce the population's economic and health burden, specifically regarding neurological/brain, spine, and mental disorders.

High grade gliomas are associated with poor prognosis and high mortality. Conventional treatments and management of high grade gliomas have shown little improvement in 5-year overall survival. This phase I trial evaluated the safety, immunogenicity, and potential synergy of surgical resection with Gliadel Wafer implantation, followed by autologous tumor lysate-pulsed dendritic cell (DC) vaccine in patients with malignant glioma. Primary end points of this study were safety and surrogate markers of immunogenicity, overall survival, and progression free survival. Following surgical resection, Gliadel Wafers were placed along the resection cavity. Patients subsequently received intradermal injections of autologous tumor lysate-pulsed DC vaccines 3 times at 2 week intervals. Treatment response was evaluated clinically and through MRI at regular intervals. Twenty-eight patients received Gliadel Wafers and DC vaccination: 11 newly diagnosed (8 glioblastoma [GBM], 2 anaplastic astrocytoma [AA], and 1 anaplastic oligodendroglioma [AO]) and 17 recurrent (15 GBMs, 1 AA, and 1 AO) high grade gliomas. Immunogenicity data was collected for 20 of the 28 patients. Five of 20 patients showed elevated IFN-gamma responses following vaccination. Median progression-free survival and overall survival for all GBM patients in the trial from the start of vaccination were 3.6 months and 16.9 months respectively. Comparisons between vaccine responders and non-vaccine responders were not statistically significant. Adjuvant autologous dendritic cells pulsed with tumor-lysate following resection and Gliadel Wafer placement is safe, elicits modest immunogenicity and shows similar clinical outcomes in patients who had DC vaccination in previous studies. (C) 2020 Published by Elsevier Ltd.

The incidence of autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), which frequently co-occur, are both rising. The causes of ASD and ADHD remain elusive, even as both appear to involve perturbation of the gut-brain-immune axis. CD103 is an integrin and E-cadherin receptor most prominently expressed on CD8 T cells that reside in gut, brain, and other tissues. CD103 deficiency is well-known to impair gut immunity and resident T cell function, but it's impact on neurodevelopmental disorders has not been examined. We show here that CD8 T cells influence neural progenitor cell function, and that CD103 modulates this impact both directly and potentially by controlling CD8 levels in brain. CD103 knockout (CD103KO) mice exhibited a variety of behavioral abnormalities, including superior cognitive performance coupled with repetitive behavior, aversion to novelty and social impairment in females, with hyperactivity with delayed learning in males. Brain protein markers in female and male CD103KOs coincided with known aspects of ASD and ADHD in humans, respectively. Surprisingly, CD103 deficiency also decreased age-related cognitive decline in both sexes, albeit by distinct means. Together, our findings reveal a novel role for CD103 in brain developmental function, and identify it as a unique factor linking ASD and ADHD etiology. Our data also introduce a new animal model of combined ASD and ADHD with associated cognitive benefits, and reveal potential therapeutic targets for these disorders and age-related cognitive decline.

Mitigating effects of aging on human health remains elusive because aging impacts multiple systems simultaneously, and because experimental animals exhibit critical aging differences relative to humans. Separation of aging into discrete processes may identify targetable drivers of pathology, particularly when applied to human-specific features. Gradual homeostatic expansion of CD8 T cells dominantly alters their function in aging humans but not in mice. Injecting T cells into athymic mice induces rapid homeostatic expansion, but its relevance to aging remains uncertain. We hypothesized that homeostatic expansion of T cells injected into T-deficient hosts models physiologically relevant CD8 T cell aging in young mice, and aimed to analyze age-related T cell phenotype and tissue pathology in such animals. Indeed, we found that such injection conferred uniform age-related phenotype, genotype, and function to mouse CD8 T cells, heightened age-associated tissue pathology in young athymic hosts, and humanized amyloidosis after brain injury in secondary wild-type recipients. This validates a model conferring a human-specific aging feature to mice that identifies targetable drivers of tissue pathology. Similar examination of independent aging features should promote systematic understanding of aging and identify additional targets to mitigate its effects on human health.

Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially reported in Wuhan, China in December 2019 was first detected in the United States on January 20, 2020 in a long-term care facility near Seattle, Washington. The virus spread quickly, and the World Health Organization declared a pandemic on March 11, 2020. On September 30, 2020 there were over 33.8 million cases and 1,013,000 deaths worldwide (130 deaths/million, 7.8 billion people), and over 7 million confirmed cases and 207,000 deaths in the United States (621 deaths/million, 333 million people) (data sources; for review, see Yamamoto et al1Yamamoto V Bolanos JF Fiallos J et al.COVID-19: review of a 21st century pandemic from etiology to neuro-psychiatric implications.J Alzheimers Dis. 2020; 77: 459-504Crossref PubMed Scopus (55) Google Scholar). The virus has high infectivity, with rapid contagion related to conditions favoring airborne spread, for example, congregate living facilities, long-term care facilities, and prisons. Traditional measures of social isolation (distancing), sanitation (hand washing/masks), and contact tracing have been implemented with variable success. However, 3 characteristics of COVID-19: 1) international variation; 2) age-related mortality; and 3) sequence homology between the fusion proteins of SARS-CoV-2 and measles and mumps viruses, and sequence homology between the Macro domains of SARS-CoV-2 and the rubella virus, suggest the Measles-Mumps-Rubella (MMR) vaccine may mitigate COVID-19 spread and severity. 1) COVID-19 has severely affected some countries and spared others. On September 30, 2020, China reported only 90,545 cases and 4739 deaths. Most deaths were in Hubei Province (population 59 million; 4512 deaths; 79 deaths/million), whose capital is Wuhan. Outside of Hubei Province, China (population nearly 1.4 billion) has reported only 227 deaths (0.16 deaths/million). China and the 36 other countries and regions in the World Health Organization Western Pacific Region (WPR) have the fewest cases and deaths per population unit. Most countries in Asia and Africa also have low COVID-19 rates. By contrast, the United States, other countries of the Americas, and Europe, have >50 times the death rate of WPR countries. Measles epidemics leading to measles elimination programs with mass MMR vaccination may explain part of the observed international variations, suggesting that MMR vaccine may provide strong protection from COVID-19 spread and mortality (first reported by Gold et al2Gold JE Tilley LP Baumartil WH MMR vaccine appears to confer strong protection from COVID-19: few deaths from SARS-CoV-2 in highly vaccinated populations.ResearchGate. 2020; (Available at:)https://www.researchgate.net/publication/341354165_MMR_Vaccine_Appears_to_Confer_Strong_Protection_from_COVID-19_Few_Deaths_from_SARS-CoV-2_in_Highly_Vaccinated_PopulationsDate accessed: October 26, 2020Google Scholar in March 2020; see also Franklin et al3Franklin R Young A Neumann B et al.Homologous protein domains in SARS-CoV-2 and measles, mumps, and rubella viruses: preliminary evidence than MMR vaccine might provide protection against COVID-19.medRxiv. 2020; (Available at)https://www.medrxiv.org/content/10.1101/2020.04.10.20053207v1.full.pdfDate accessed: October 26, 2020Google Scholar). Supporting the potential anti-COVID-19 benefit of MMR vaccine, the WPR has successfully reduced measles through extensive MMR vaccination programs.4Ma C Rodewald L Hao L et al.Progress toward measles elimination - China, January 2013-June 2019.MMWR Morb Mortal Wkly Rep. 2019; 68: 1112-1116Crossref PubMed Scopus (32) Google Scholar There are similar reports of measles epidemics and eradication efforts from other parts of Asia and across Africa. By contrast, MMR vaccination programs have been problematic in the United States,5Qian M Chou SY Lai EK Confirmatory bias in health decisions: evidence from the MMR-autism controversy.J Health Econ. 2020; 70102284Crossref PubMed Scopus (13) Google Scholar the rest of the Americas, and Europe.6Siciliani L Wild C McKee M et al.Strengthening vaccination programmes and health systems in the European Union: a framework for action.Health Policy. 2020; 124: 511-518Crossref PubMed Scopus (54) Google Scholar While travel restrictions, control of congregate living conditions, and governmental interventions play roles in controlling the COVID-19 spread, it is possible that MMR vaccination programs are the basis for the huge international variation. 2) In the United States, COVID-19 penetration has been extensive. Across all states, disease severity and mortality has been worst in the elderly, from the first reported deaths in nursing homes in Washington State until the present. Early deaths occurred at the end of March, peaked between mid-April and mid-May, then decreased prior to surging through July. While the number of deaths varied, the actual proportion of deaths related to COVID-19 across age groups changed very little (Centers for Disease Control [CDC] data). On September 30, 2020 the CDC reported 194,091 deaths, categorized by age and sex. Of these deaths, 20 were under 1 year of age and 47 were between 1 and 15 years (0.035% of all COVID-19 deaths, 60 million children, 1.1 deaths/million). All individuals under 45 years of age (190 million) accounted for <3% of the deaths (5898; 31 deaths/million), but those over 45 years (135 million) accounted for more than 97% of the deaths (188,193; 1394 deaths/million). After a large jump from 5 to 20 years of age, the death rate increased for those over age 30 years at an exponential age-related rate, doubling every 7.4 years. This rate exceeds the base rate of the exponential increase of total deaths with age (only doubling every 9 years after age 30, see Ashford7Ashford JW APOE genotype effects on Alzheimer's disease onset and epidemiology.J Mol Neurosci. 2004; 23: 157-165Crossref PubMed Scopus (201) Google Scholar). Accordingly, the vulnerability to COVID-19 is closely related to age but exceeds the increase of the established comorbid illnesses (obesity, hypertension, diabetes, vascular disease) with age. Unexpectedly, the percentage of COVID-19 deaths relative to all deaths increases most sharply between 15 and 45 years, but over 45 there is a relatively stable percentage of COVID-19 deaths in this older population, ranging between 8.4% and 9.8%. This discrepancy suggests that the strong relationship with comorbidities occurs because of a confound with age, while some other factor is causally involved. As observed internationally, MMR vaccination could also potentially contribute to the US age distribution. The low infection rates and mild presentations in children >1 year of age may be due to childhood vaccinations. The CDC recommends that children get 2 MMR doses, at 12-15 months of age and 4-6 years. Double childhood MMR vaccination can generate antibodies lasting for 20 or more years.8Davidkin I Jokinen S Broman M Leinikki P Peltola H Persistence of measles, mumps, and rubella antibodies in an MMR-vaccinated cohort: a 20-year follow-up.J Infect Dis. 2008; 197: 950-956Crossref PubMed Scopus (266) Google Scholar Yet, some children do not get vaccinated at all.5Qian M Chou SY Lai EK Confirmatory bias in health decisions: evidence from the MMR-autism controversy.J Health Econ. 2020; 70102284Crossref PubMed Scopus (13) Google Scholar Further, long-term benefit declines with age, as evidenced by many women presenting for prenatal care who have lost MMR-related immunity.9Haas DM Flowers CA Congdon CL Rubella, rubeola, and mumps in pregnant women: susceptibilities and strategies for testing and vaccinating.Obstet Gynecol. 2005; 106: 295-300Crossref PubMed Scopus (34) Google Scholar This pattern is consistent with the observed progressive increase of COVID-19 infection and death rates up to 45 years of age (CDC data). The stabilization of the percentage increase in COVID-19 mortality with more advanced age may be due to long-lasting immune responses to now-rare childhood infections,10Mina MJ Kula T Leng Y et al.Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens.Science. 2019; 366: 599-606Crossref PubMed Scopus (232) Google Scholar but which are less protective against COVID-19. 3) There are reports that appear to suggest that several currently available vaccines already established as "safe" (including polio, Haemophilus influenzae type-B, MMR, and pneumococcal) may offer significant protection against COVID-19 via a nonspecific "innate immunity."11Fidel Jr, PL Noverr MC Could an unrelated live attenuated vaccine serve as a preventive measure to dampen septic inflammation associated with COVID-19 infection?.mBio. 2020; 11: e00907-e00920Crossref PubMed Scopus (78) Google Scholar, 12Pawlowski C Puranik A Bandi H et al.Exploratory analysis of immunization records highlights decreased SARA-CoV-2 rates in individuals with recent non-COVID-19 vaccinations.medRxiv. 2020; (Available at:)https://www.medrxiv.org/content/10.1101/2020.07.27.20161976v1.full.pdfDate accessed: October 26, 2020Google Scholar, 13Root-Bernstein R Age and location in severity of COVID-19 pathology: do lactoferrin and pneumococcal vaccination explain low infant mortality and regional differences?.Bioessays. 2020; (Available at:)https://onlinelibrary.wiley.com/doi/full/10.1002/bies.202000076Date accessed: October 26, 2020Crossref PubMed Scopus (33) Google Scholar However, these findings may actually be reflecting a response to MMR vaccination, which is often administered in conjunction with these others. More directly, there is evidence that rubella virus has a 29% sequence homology with a SARS-CoV-2 surface protein.3Franklin R Young A Neumann B et al.Homologous protein domains in SARS-CoV-2 and measles, mumps, and rubella viruses: preliminary evidence than MMR vaccine might provide protection against COVID-19.medRxiv. 2020; (Available at)https://www.medrxiv.org/content/10.1101/2020.04.10.20053207v1.full.pdfDate accessed: October 26, 2020Google Scholar,14Sidiq KR Sabir DK Ali SM Kodzius R Does early childhood vaccination protect against COVID-19?.Front Mol Biosci. 2020; 7: 120Crossref PubMed Scopus (40) Google Scholar Accordingly, the rubella component of the MMR vaccine may confer specific protection against COVID-19. These findings suggest the MMR vaccine may protect against COVID-19, including high-risk individuals, such as elderly with comorbidities, and health care workers and first responders with COVID-19 patients, especially individuals living in long-term care facilities and the related institutional staff. Clinicians who are caring for such high-risk patients should consider the benefit/cost ratios of MMR vaccination to justify use of this simple, low-risk intervention to reduce COVID-19 disease, especially until a specific vaccine is approved. Clinical trials to confirm this speculation are now being conducted. Data Sources, most recently accessed 9/30/2020: Center for Disease Control and Prevention (CDC): www.cdc.gov United States Census Bureau: www.census.gov Worldometer: https://www.worldometers.info/coronavirus Johns Hopkins Coronavirus Resource Center: https://coronavirus.jhu.edu/map.html

While autosomal dominant mutations that promote amyloid deposition guarantee rare genetically‐determined Alzheimer’s disease (AD), discrete factors promoting more prominent sporadic AD have not been identified. Evidence from mice, and more recently from a patient resistant to autosomal dominant AD, suggests that an age‐sensitive factor missing from mice links amyloid deposition to NFTs and neurodegeneration in AD, and is critical for AD development. We previously engineered mice that possess human‐like predominance of an age‐related resident memory CD8 T cell population (hiTRM mice), and exhibit antigen‐specific CD8 T cell accumulation in brain, as well as sporadic amyloid deposition linked to NFT‐like structures and neurodegeneration.

Abstract A cell culture platform that enables ex vivo tissue growth from patients or patient-derived xenograft (PDX) models and assesses sensitivity to approved therapies (e.g., temozolomide) in a clinically relevant time frame would be very useful in translational research and personalized medicine. Here, we present a novel three-dimensional (3D) ECM hydrogel system, VersaGel, for assaying ex vivo growth and therapeutic response with standard image microscopy. Specifically, multicellular spheroids deriving from either 5 patients with glioblastoma (GBM) or a renal cell carcinoma (RCC) PDX model were incorporated into VersaGel and treated with temozolomide and several other therapies, guided by the most recent advances in GBM treatment. RCC ex vivo tissue displayed invasive phenotypes in conditioned media. For the GBM patient tumor testing, all five clinical responses were predicted by the results of our 3D-temozolomide assay. In contrast, the MTT assay found no response to temozolomide regardless of the clinical outcome, and moreover, basement membrane extract failed to predict the 2 patient responders. Finally, 1 patient was tested with repurposed drugs currently being administered in GBM clinical trials. Interestingly, IC50s were lower than Cmax for crizotinib and chloroquine, but higher for sorafenib. In conclusion, a novel hydrogel platform, VersaGel, enables ex vivo tumor growth of patient and PDX tissue and offers insight into patient response to clinically relevant therapies. We propose a novel 3D hydrogel platform, VersaGel, to grow ex vivo tissue (patient and PDX) and assay therapeutic response using time-course image analysis.

INTRODUCTION: We conducted a single-institution phase 1 trial of a dendritic cell immunotherapy targeting glioblastoma stem-like cells for patients with either newly diagnosed or recurrent glioblastoma. Following gross total or near-gross total resection, patients who consented to participate in this trial underwent leukapheresis for isolation of peripheral blood mononuclear cells, which were then differentiated into dendritic cells in culture, pulsed with lysate derived from an allogeneic glioblastoma stem-like cell line, and administered by intradermal injection weekly x 4 weeks, then every other month until disease progression or vaccine depletion. Patients with newly diagnosed glioblastoma were treated with standard-of-care chemoradiation, with vaccine injections beginning 1 week following the completion of radiation therapy. Patients with recurrent disease received no other disease-directed therapy while on trial. From December 2013 to February 2018, 38 patients enrolled in this trial -- 12 patients with newly diagnosed glioblastoma and 26 with recurrent disease. Median age 57 (range 19–77), median KPS 80 (range 70–100), 66% male. Survival functions were estimated using the Kaplan-Meier method. For newly diagnosed patients, median Time-to-Progression (TTP) was 8.86 mo, and median Overall Survival (OS) was 21.1 mo. For patients with recurrent glioblastoma, median TTP was 3.14 mo and median OS was 12.0 mo. Treatment was well-tolerated with no related grade 3/4 toxicities. As of this analysis, 7 patients are still alive, and 2 patients in the newly diagnosed glioblastoma cohort are still progression-free. Immune response studies and tumor antigen profiling are ongoing. CONCLUSION: Consistent with other previously completed dendritic cell immunotherapy trials, this phase 1 trial demonstrates improved TPP and OS for patients with either newly diagnosed or recurrent glioblastoma compared to historical controls. Ongoing efforts include characterizing and expanding the subset of patients who most benefit from immunotherapy.