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Background: Hippocampal formation atrophy is a well‐established imaging biomarker of several neurological diseases, including Alzheimer's disease, temporal lobe epilepsy, and schizophrenia. The hippocampus is divided into subfields that have different functions and vary in sensitivity to different diseases. This study investigates the potential interaction between COVID‐19 and the various hippocampus subfields, which may shed light on the long‐term neurological consequences of the virus. Method: We obtained high‐resolution T1‐weighted (T1w) and T2‐weighted (T2w) MRI images using 7T scanners located at three sites in two countries: Pittsburgh (n = 14) and Texas (San Antonio and Houston) (n = 40) in the USA, and Nottingham, UK (n = 33). We evaluated the hippocampus subfields using the ASHS package [1‐3]. Imaging sets of 51 subjects with minimal or no manual segmentation corrections (Figures 1 and 2) were included in the analysis. We conducted T‐tests with Bonferroni correction, adjusting for age and intracranial volume to identify the differences in hippocampus subfield volumes across groups. Result: Participants who needed admission into the ICU due to Covid‐19 showed a significantly lower (p‐value = 0.0034) left CA1 volume compared to participants who did not require ICU (Figure 3). In addition, several other non‐significant trends were observed. Conclusion: Our preliminary findings suggest that Covid‐19 may impact the hippocampus, particularly in patients who required intensive care. However, the study ‐ as of to date ‐ has a small sample size and lacks a comparison group with patients who were admitted into ICU for acute illnesses other than Covid‐19. Additionally, longitudinal data is needed to track the long‐term effects of the disease on the hippocampal subfields. Funding: NIH R56AG074467, R01MH111265 and R01AG063525 References: 1. Berron et al. Neuroimage 2017 2. Yushkevich et al. Human Brain Mapping 2015 3. Santini et al. Neuroimage: clinical 2021 [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has disproportionately affected ethno‐racial minority populations and people with greater social deprivation. It is unknown whether such disparities influence research participation for investigations of long‐term neuro‐cognitive effects of SARS‐CoV‐2 infection. Method: Across 3 US and 1 UK sites, we are enrolling a multi‐racial cohort of SARS‐CoV‐2 infected individuals and age, sex, race‐matched non‐infected controls. Utilizing harmonized protocols for cognitive assessments and 7‐Tesla MRI, we aim to provide ultra‐high‐field data on natural history of COVID‐19 driven microstructural and microvascular cerebral changes and associated cognitive trajectories. We will also compare the imaging markers to those observed in an existing cohort of early onset Alzheimer's Disease and Related Dementias (ADRD). We analyzed screening and enrollment data to determine potential age, sex, race, ethnicity, and social deprivation disparities in research participation. We derived address‐based Area Deprivation Index (ADI) (scale 1 ‐10), with higher ADI indicating greater deprivation. Logistic regression models were fit to evaluate associates of non‐response and refusal. Odds Ratios (OR) and 95% confidence intervals (CI) are reported. Result: Over a 11‐month period, at a single US site, a total of 1,046 SARS‐CoV‐2 infected people and their controls were contacted, and 379 (36.2%) responded. In univariable analyses, non‐response was associated with younger age, male sex, non‐White race, and higher ADI (Table 1). In the fully adjusted model, non‐White race was independently associated with higher likelihood of non‐response [OR (CI) for Black vs. White: 1.49 (1.04, 2.12) and for Asian vs. White: 1.88 (1.28, 2.76)]., Independent of race, higher ADI was also associated with likelihood of non‐response (Table 2 and Figure 1). Among the responders, 228 (60.2%) refused. Although, no socio‐demographic factors were significantly associated with likelihood of refusal, the point estimates in the fully adjusted model suggest potential racial disparities in providing consent (Tables 1 and 2). Aggregated data from all sites will be presented. Conclusion: It is imperative to recognize and mitigate persistent disparities in the COVID‐19 pandemic, particularly pertaining to participation in long‐COVID research. Mechanisms of such persistent disparities need to be studied in context of cultures, beliefs, access, and clinical factors. [ABSTRACT FROM AUTHOR]

Background: Regulatory T cells (Tregs) play a neuroprotective role by suppressing inflammation. We previously documented that Treg immunomodulatory mechanisms are compromised in people with Alzheimer's disease (AD) and are associated with activation of peripheral monocytes and upregulation of inflammatory mediators. In this original study, we investigated the feasibility and potential impact of low‐dose IL‐2 immunotherapy on restoring Tregs and modifying inflammation in an AD clinical setting. Method: Eight patients with mild‐to‐moderate AD dementia (MMSE:12‐25) were enrolled in a phase 1, open‐label, feasibility study of IL‐2 treatment. The presence of elevated brain amyloid, as demonstrated by either CSF or amyloid positron emission tomography (PET) scan, was confirmed in all participants. Enrolled individuals received monthly five‐day‐courses of subcutaneous IL‐2 (1 million units/day) for four months and were followed for an additional two months post‐treatment. Treg immunophenotype and functional analysis were obtained serially at screening, day 1 (before IL‐2 treatment) and day 8 (three days after the fifth dose) of each treatment cycle during therapy, and then at weeks 17 and 24. Two‐sided paired t‐tests were used to assess the statistical significance of changes in each analyte or clinical outcome at each timepoint. Result: Overall, low‐dose IL‐2 immunotherapy was well‐tolerated and all patients received the treatment as planned. The number of CD4+CD25highFoxP3+ Tregs increased two to three‐fold after each IL‐2 treatment cycle (p<0.01) and returned to baseline before the next cycle. Treg suppressive function on responder T cell (Tresp) proliferation also progressively increased through the four‐month IL‐2 treatment phase (p<0.01). IL‐2 treatment down‐regulated IL‐1β, IL‐6 and TNFa transcripts in circulating monocytes and modulated plasma pro‐inflammatory chemokines and cytokines (IL‐15, CCL2, CCL4, CCL11 and FLT3LG; p<0.01). Clinical benefits (mean change ± SE) were observed on the Mini‐Mental State Exam (+2.25 ± 0.59, p = 0.007) and the Clinical Dementia Rating Sum of Boxes (‐0.56 ± 0.24; p = 0.051). Conclusion: IL‐2 immunotherapy restored peripheral Treg function and ameliorated systemic pro‐inflammatory mediators in AD patients. The results of this study warrant conducting a well‐controlled clinical study to further evaluate the safety and efficacy of low‐dose IL‐2 as a potential treatment for AD. [ABSTRACT FROM AUTHOR]

Background: Globally, over six hundred million cases of SARS‐CoV‐2 have been confirmed. As the number of individuals in recovery rises, examining long‐term neurological effects, including cognitive impairment and cerebral microstructural and microvascular changes, has become paramount., We present preliminary cognitive findings from an ongoing multi‐site study investigating the long‐term neurological impacts of COVID‐19 using 7 Tesla MRI‐based neuroimaging. Methods: Across 3 US and 1 UK sites, we identified adult (> = 18) COVID‐19 survivors (CS) and healthy controls (HC) without significant pre‐existing medical, neurological, or psychiatric illness. Using the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS‐3) battery and Norms Calculator, 12 cognitive scores were adjusted for age, sex, and education and classified as either unimpaired or mild (<9th percentile), moderate (<2nd percentile), or severely impaired (<1st percentile). The observed frequency of impairment across the two groups is reported along with proportional differences (PD) and confidence intervals (CI). Illness severity and time since infection were evaluated as potential associates of cognitive impairment. Results: Over a period of 11 months, we enrolled 108 participants. At the time of reporting, 80 (46.3% female; mean age: 60.3 ± 8.6; 61 CS, 19 HC) had completed cognitive assessments. Of the participants for whom we ascertained time since symptom onset and illness severity (n = 51 and 43, respectively), 31.4% had their index COVID‐19 infection within the past year, and 60.5% had a severe to critical infection (Table 1). Table 2 reports observed frequency of impairment for each metric. Aggregating all 12 cognitive metrics, we found 45 (73.8%) of CS had at least one impairment [vs HC: 10 (52.6%)]. A significantly greater proportion of CS had at least one moderate to severe or severe impairment (Figure 1). CS also had significantly higher frequencies of presenting with two or more mild to severe impairments [PD 0.33 (0.13, 0.54)]. Illness severity and time since infection were not significantly associated with cognitive impairment. Conclusion: Our preliminary results are consistent with potentially sustained COVID‐associated cognitive impairment in a subset of participants. Enrollment in the multi‐site cohort is ongoing, and updated results will be presented along with ultra‐high field MRI‐based neuroimaging correlates. [ABSTRACT FROM AUTHOR]

Background: The SARS‐CoV‐2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID‐19 survivors and controls. Method: Participants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR‐imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID‐19 survivors, 6 controls; Figure 1). COVID‐19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID‐19. Healthy controls were required to have no significant pre‐existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT‐TFL sequence (0.4×0.4×0.5mm). A site‐specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel‐wise integrity values were compared between COVID‐19 survivors and controls using a robust linear regression (age‐controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman's rank correlation. Result: Average LC integrity was not correlated with age, sex, or Hispanic ethnicity (p>0.3). COVID‐19 survivors did not differ from Controls when examining the entire LC (p = 0.54). Voxel‐wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID‐19 survivors exhibited lower LC integrity than controls (p = 0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p = 0.9). LC integrity did not correlate with cognitive performance within the COVID‐19 survivors (Trail Making Test B: p = 0.43; Craft Story delayed recall p = 0.47; MoCA p = 0.84). Conclusion: Consistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS‐CoV‐2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID‐19. [ABSTRACT FROM AUTHOR]

Introduction: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two‐phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS‐1) and protocols (VICCCS‐2) for diagnosis of VCI. We present VICCCS‐2. Methods: We used VICCCS‐1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. Results: Six survey rounds comprising 65–79 participants agreed guidelines for diagnosis of VICCCS‐revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders–Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. Discussion: The VICCCS‐2 suggests standardized use of the National Institute of Neurological Disorders–Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration. [ABSTRACT FROM AUTHOR]

Introduction Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. Methods The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. Results VICCCS had a mean of 122 (98–153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. Discussion VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research. [ABSTRACT FROM AUTHOR]