Citations

Abstract The contribution of antiviral resident memory T cells (TRM) to blood-brain barrier disruption has not been defined despite the implication of this lymphocyte in clinical encephalitis. We therefore evaluated the capacity of TRM cells to induce CNS vascular permeability in mice which resolved Theiler’s murine encephalomyelitis (TMEV) infection. Following TMEV infection of the brain, persistent populations of virus antigen specific resident memory T cells are induced within the brain. This population of resident memory T cells can be further reactivated at 60 dpi through administration of the cognate immunodominant virus peptide antigen, VP2, inducing blood brain barrier disruption in the process. We determined that brain resident memory T cells expand following reactivation with administered VP2 peptide. This reactivation is associated with infiltration of T cells, and inflammatory myeloid cells into the brain. Importantly, using depletion and T cell sequestrating strategies with low dose anti CD8 antibodies and FTY720, we determined that TRM induced blood-brain barrier disruption is independent of peripheral T cells. We conclude that reactivation of brain TRM cells during peptide administration occurs without dependency on peripheral responses, highlighting the importance of this cell type in inducing neuroinflammation and underlying neuropathology.

Abstract Immunosuppression following damage to the CNS is a common, yet poorly understood, feature of neurological diseases as diverse as stroke, traumatic brain injury, and glioblastoma. This immunosuppression is a barrier to successful patient outcomes. We sought to define the effect of various brain insults on the thymus and T-cell responses. We tested thymic function following various neurological insults, including viral infection, brain tumor, sterile inflammation, physical injury, and seizures. All brain insults resulted in significant thymic involution that was reversible if the insult was cleared. Thymic involution did not occur following similar peripheral insults. Using parabiosis, we demonstrated that thymic involution was transferable via circulatory routes from glioma-bearing to non-tumor-bearing parabionts. Similarly, serum obtained from mice with ongoing neurological insults potently inhibited T-cell proliferation in vitro. We next fractionated the serum based on molecular weight and tested the resulting fractions’ immunosuppressive potential. Interestingly, we found that serum fractions with large molecular weights of greater than 100 kiloDaltons were responsible for the immunosuppressive properties of serum obtained from glioma-bearing mice. In short, CNS-specific insults, regardless of nature, induce immunosuppression by prompting thymic involution and systemic immunosuppression mediated through circulating factors with large molecular weight. These studies provide evidence of the mechanisms leading to immune deficiencies observed in patients following neurological injuries.

Abstract Systemic immunosuppression following neurological insults including stroke, traumatic brain injury, and glioblastoma mutiforme (GBM) causes mortality and leads to failure of therapies. Exact immunological nature and the underlying mechanisms of this immunosuppression are unknown. Our goal was to define effects of neurological insults given exclusively to the brain on the thymus; a primary immune organ. Specifically, we evaluated the effects on the thymus following physical injury with intracranial PBS injection, intracranial (ic) Theiler’s Murine Encephalomyelitis Virus infection, intracranial injection with lipopolysaccharide, CNS tumors (B16 melanoma and GL261 glioma ic), and seizure induction with intraperitoneal Kainic acid injection. These insults resulted in significant thymic involution that is reversible upon clearance of the neurological insult. The extent of thymic involution correlated with the extent of brain injury. Further analysis of the brain-thymus axis in mice with GL261 gliomas was conducted using RNA-Seq. Principle component analysis of RNA-Seq data revealed unbiased separation of thymi of naïve and glioma harboring mice, suggesting that thymus is directly affected by brain injury. To determine the extent to which thymic involution was caused by a soluble factor, we employed parabiosis. This approach demonstrated a soluble factor is responsible for thymic involution. These findings are the first demonstration that neurological insults ubiquitously contribute to immune suppression. We also provide evidence that thymic involution is mediated by a soluble factor, the identification of which could be critical for ameliorating the effect of neurological injuries on immune suppression.

Abstract Background The criteria for the selection of COVID‐19 patients that could benefit most from ECMO organ support are yet to be defined. In this study, we evaluated the predictive performance of ECMO mortality predictive models in patients with COVID‐19. We also performed a cost–benefit analysis depending on the mortality predicted probability. We conducted a retrospective cohort study in COVID‐19 patients who received ECMO at two tertiary care hospitals between March 2020 to July 2021. Materials and Methods We evaluated the discrimination (C‐statistic), calibration (Cox calibration), and accuracy of the prediction of death due to severe ARDS in V‐V ECMO score (PRESERVE), the Respiratory Extracorporeal Membrane Oxygenation Survival Score (RESP) score, and the PREdiction of Survival on ECMO Therapy‐Score (PRESET) score. In addition, we compared the RESP score with Plateau pressure instead of Peak pressure. Results We included a total of 36 patients, 29 (80%) of them male and with a median (IQR) APACHE of 10 (8–15). The PRESET score had the highest discrimination (AUROCs 0.81 [95%CI 0.67–0.94]) and calibration (calibration‐in‐the‐large 0.5 [95%CI −1.4 to 0.3]; calibration slope 2.2 [95%CI 0.7/3.7]). The RESP score with Plateau pressure had higher discrimination than the conventional RESP score. The cost per QALY in the USA, adjusted to life expectancy, was higher than USD 100 000 in patients older than 45 years with a PRESET > 10. Conclusion The PRESET score had the highest predictive performance and could help in the selection of patients that benefit most from this resource‐demanding and highly invasive organ support.

Background: Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials. Methods: The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point. Results: MVP was associated with DMR absent/mild (ERO <20 mm 2 ) in 50%, moderate (ERO 20–40 mm 2 ) in 25%, and severe or higher (ERO ≥40 mm 2 ) in 25%, with mean ERO 24±24 mm 2 , regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%–90% range, 0–9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; P < 0.0001) but with wide overlap (10%–90% range, 4–11 versus 0–7) and mediocre correlation ( R 2 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29–1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11–1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02–1.14]) or ≥1% (hazard ratio, 1.11 [1.08–1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10–1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10–1.16], all per 1-point increment with P <0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all P <0.0001). Conclusions: This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.

AbstractBackgroundGiven the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development.MethodWe assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40.ResultThe relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5).ConclusionThese results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.

AbstractBackgroundThe ability to detect malformed prion proteins using real‐time quaking‐induced conversion (RT‐QuIC) assays has transformed the diagnostic approach to sporadic Creutzfeldt‐Jakob disease (CJD), facilitating earlier recognition of affected patients. Recognizing this, we evaluated the frequency of clinical features and biomarker results at initial evaluation in patients with CJD and determined the relationship between these early features and CJD diagnosis and prognosis.MethodClinical data were extracted from the electronic medical records of patients with probable or definite (pathologically confirmed) CJD assessed at Mayo Clinic from 2014‐2021. Diagnoses of probable CJD were established by clinical consensus, referencing the Centers for Disease Control and Prevention diagnostic criteria. Clinical features and biomarkers results were evaluated at presentation, and associations with CJD diagnosis and symptomatic disease duration determined.ResultOne‐hundred fifteen patients were included (40, [35%] with definite CJD). Mean age‐at‐symptom onset was 64.8±9.4 years; 68 patients were female (59%). The sensitivity of clinical markers (myoclonus) and tests historically considered in patients with suspected CJD (e.g., stereotyped EEG abnormalities (16%), CSF 14‐3‐3 (60%)) was poor. Biomarkers with good diagnostic sensitivity included RT‐QuIC (93%), t‐tau levels >1149 pg/mL (88%), and characteristic signal abnormalities on MRI (77%). Multivariable linear regression confirmed shorter survival for patients with myoclonus (125.9 days, 95%CI 23.3‐15.5, p=0.026), visual/cerebellar signs (180.19 days, 95%CI 282.2‐78.2, p<0.001), positive 14‐3‐3 (193 days, 95%CI 304.9‐82.9; p<0.001), and elevated t‐tau levels (each 1000 pg/ml increase was associated with a nine‐day shorter time‐to‐death, 95%CI 1‐18; p=0.041).ConclusionCSF RT‐QuIC and elevated t‐tau levels, and stereotyped MRI abnormalities continue to be strongly associated with the diagnosis in the modern era, while other clinical findings (myoclonus) and biomarkers results traditionally ascribed to CJD (e.g., PSWC on EEG, 14‐3‐3) offered less value in the diagnostic evaluation. Detection of visual or cerebellar features, myoclonus, CSF 14‐3‐3, and t‐tau levels may predict disease duration, justifying inclusion in the evaluation of CJD‐suspected patients.

AbstractBackgroundEvent‐related‐potentials (ERPs) during cognitive tasks are sensitive measures of cognitive decline [1]‐[2] and could quantitatively measure the trajectory of disease progression or response to clinical interventions. In this longitudinal study, we aimed to compare ERPs between individuals with mild cognitive impairment (MCI) and controls, and to demonstrate the test‐retest reliability of ERP measures to assess their potential utility for future observational studies and treatment trials.MethodsParticipants included individuals with mild cognitive impairment (MCI, n=31) and healthy controls stratified by age: HC2 (n=46, 40‐60 yrs.), HC3 (n=56, 60‐90 yrs.). ERPs during attention, image recognition, and verbal memory tasks were recorded using a wireless EEG to determine amplitudes and latencies of the P200 and late positive potential (LPP) ERP components in response to target (memorized) and non‐target (novel) stimuli. Differences between MCI and HC3 groups were characterized at the initial visit, and longitudinal changes in ERP components were determined at 1‐year follow‐up for both groups. Reliability of ERP measures was demonstrated by computing intraclass correlation coefficient (ICC) measures of test‐retest variability in all healthy controls (HC2 and HC3) from initial visit to 1‐year follow‐up.ResultsAt the initial visit, the MCI group demonstrated reduced LPP amplitude (Hedges‐g=0.8, p=10‐3) and delayed P200‐latency (Hedges‐g=0.89, p=10‐4) when compared to HC3. Reliability in healthy controls was high for LPP (0.85 and 0.75 for target and non‐target stimuli, respectively) and moderate for P200‐latency (0.67 and 0.53 for target and non‐target stimuli, respectively), without longitudinal changes after 1‐year follow‐up. Individuals with MCI demonstrated increased P200‐latency (Hedges‐g= 1.05, p=0.02, df=8).ConclusionsIndividuals with MCI demonstrated quantifiable memory ERP deficits at baseline with detectable change in the P200 component at 1‐year follow‐up, demonstrating that ERPs are sensitive measures for quantifying mild cognitive impairment. Test‐retest reliability of these measures was good or moderate after 1‐year, supporting their feasibility for longitudinal monitoring of patients during disease progression or quantifying the cognitive impact of potential interventions.

AbstractBackgroundDelirium and dementia are common causes of cognitive impairment in older adults and frequently co‐exist. Delirium is associated with poor clinical outcomes when comorbid with dementia. Identifying delirium superimposed on dementia (DSD) is clinically challenging given the overlap in symptoms, including inattention, cognitive impairment, and altered level of consciousness, especially in advanced stages of dementia. Recognition of delirium is also critical in ADRD (Alzheimer’s Disease and Related Dementias) clinical trials for both validity and safety reasons. The ECT‐AD study is one such trial investigating the safety and efficacy of electroconvulsive therapy (ECT) for treatment‐refractory agitation and aggression in individuals with advanced ADRD. Herein we review the Confusion Assessment Method (CAM) for identifying delirium in the ECT‐AD study.MethodInclusion criteria for ECT‐AD are hospitalized individuals diagnosed with ADRD (ages 55–89, MMSE ≤ 15) and refractory agitation/aggression, as measured by the Cohen‐Mansfield Agitation Inventory (CMAI). Procedures for detecting baseline and treatment‐emergent delirium involve a 3‐step approach conducted by raters trained in the CAM, which assesses inattention, disorganized thinking, altered levels of consciousness, and fluctuating mental status. Step 1 involves gathering information from nurse informants regarding the patient’s mental status over the past 24 hours. Step 2 involves collecting observational data through informal patient interaction (e.g., brief conversation). Step 3 is an objective assessment of cognitive status using the Severe Impairment Battery – 8 Item (SIB‐8), while also making qualitative observations about delirium features (e.g., level of consciousness). The rater then codes the CAM and determines delirium status based on these 3 steps.ResultOf our 6 consented subjects, 1 experienced delirium detected by the CAM during the Randomization Phase. The subject received three positive CAMs on consecutive treatment days, citing change in mental status, inability to arouse, restlessness, psychomotor agitation, and swearing. ECT/S‐ECT was held each treatment day and the subject was withdrawn from the Randomization Phase.ConclusionIdentifying DSD is challenging due to overlapping symptoms and the fluctuating nature of delirium. The CAM may be useful in this regard by using a multi‐step approach that incorporates observations from reliable informants, direct patient interactions, and structured cognitive assessments.

AbstractBackgroundThe coarse‐grained plaque (CGP) is a divergent plaque‐type recently described in Alzheimer’s disease (AD)1. In the current study, we studied the CGPs distribution over the brain, and its association with APOE, p‐tau, and neuroinflammation.MethodThe cohort (N = 60) was selected from the Mayo Clinic brain bank in Jacksonville, USA. Brain tissue from the frontal ‐, parietal ‐, temporal cortex, and the hippocampus was immunohistochemically stained for Aβ (6F/3D), p‐tau (AT8), CD68, and GFAP. The CGP and classic cored plaque (CCP) were scored as previously described1. Total plaque burden was expressed as the sum of all cortical regions.ResultThe CGP was predominantly located in the neocortex and present in ∼60% of AD cases, who were younger at onset (p<0.05) and had a lower brain weight (p<0.05) than CGP negative cases. When stratified for APOE Ɛ4+ and Ɛ4‐, CGP burden was only in Ɛ4+ positively correlated with p‐tau, Aβ, and GFAP burden in the frontal and parietal cortex (Table 1). CGP burden was not correlated with CD68. The CCP was negatively correlated with p‐tau, and not with GFAP, Aβ or CD68 (Table 1). In APOE Ɛ4+ cases, the burden of CGPs was negatively correlated with the burden of CCPs (Fig.1).ConclusionThe neocortical CGP is correlated with increased p‐tau burden and astrogliosis in APOE Ɛ4+. The CGP is inversely correlated with the common CCP, suggesting an opposite effect of Aβ‐induced tau‐toxicity for the CGP versus the CCP. 1Boon et al., Acta Neuropathologica, 2020