Effects of COVID-19 on preclinical and clinical research in neurology: Examples from research on neurodegeneration and Alzheimer’s disease
Authors: B. Joy Snider, David M. Holtzman
Journal: Neuron (2021)

The COVID-19 pandemic has had a profound impact on neuroscientists, including those involved in translational research. In this NeuroView, we discuss the positive and negative effects of the pandemic on preclinical research and clinical studies in humans. The COVID-19 pandemic has had a profound impact on neuroscientists, including those involved in translational research. In this NeuroView, we discuss the positive and negative effects of the pandemic on preclinical research and clinical studies in humans. The coronavirus disease 2019 (COVID-19) pandemic has had a huge impact on societies around the world. This has also been the case for translational neuroscience research that involves cellular and animal studies as well as for clinical research and clinical trials in humans. We discuss some of the observations we have made in living through the pandemic from the perspectives of a laboratory-based and a clinical researcher at Washington University in St. Louis, Missouri, United States. As in most academic institutions in the United States, by mid-March of 2020, drastic changes in laboratory-based research began to take place. At Washington University, for a few weeks, only scientists doing “essential” work, such as maintaining valuable animal colonies, were allowed to work on site for limited periods of time with masking and social distancing requirements. At some institutions, valuable colonies of mice were required to be sacrificed with researchers losing years of productivity and time. This was particularly problematic for mouse colonies involving neurological and neurodegenerative diseases that not only require complicated genetic breeding schemes but also are often age related. As an example, in our own lab, it took 2 years to generate P301S Tau transgenic mice that were crossed to both human APOE knockin mice with floxed alleles with an astrocyte-specific inducible Cre driver followed by aging the mice for almost another year before analysis (Wang et al., 2021Wang C. Xiong M. Gratuze M. Bao X. Shi Y. Andhey P.S. Manis M. Schroeder C. Yin Z. Madore C. et al.Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia.Neuron. 2021; 109: 1657-1674.e7https://doi.org/10.1016/j.neuron.2021.03.024Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). At our institution, sacrificing animals prematurely was not required. However, most scientists were not allowed back to the laboratory until almost May of 2020—a 2-month period. After that time, scientists were allowed to come back to the labs in person only when adequate protections against SARS-CoV-2 could be assured, including masking and social distancing that necessitated working in shifts to limit human-human contact. These requirements, which remained in place until the spring of 2021, made it difficult to be in person in the lab for more than 6 h at a time. This not only slowed down the career and scientific progress of graduate students, post-doctoral fellows, and faculty, but it also prevented undergraduate researchers from working in the lab for about a year in our institution. It also either delayed or prevented altogether the ability of scientists in one country to move to a lab in another country for a new position, especially affecting post-doctoral fellows and international students. For many scientists with children, the added burden during the pandemic was substantial, affecting not only financial and psychological well-being, but also productivity—compounding uncertainty around career development. This particularly affected women faculty (Krukowski et al., 2021Krukowski R.A. Jagsi R. Cardel M.I. Academic Productivity Differences by Gender and Child Age in Science, Technology, Engineering, Mathematics, and Medicine Faculty During the COVID-19 Pandemic.J. Womens Health (Larchmt.). 2021; 30: 341-347https://doi.org/10.1089/jwh.2020.8710Crossref PubMed Scopus (76) Google Scholar)—and likely women scientists in general—more than men. Most universities, including ours, extended the tenure clock for faculty as well as extending allowable time to complete PhD and post-doctoral training. All in all, along with the direct and immediate human costs arising from the pandemic, the slowed pace of experimental work—including the development of new diagnostics and treatments for neurological and neurodegenerative diseases that often start in cellular and animal models before moving to humans—will have repercussions that will likely affect our laboratory-based community of translational scientists for years to come. Apart from experimental work, while the lack of having in-person laboratory and smaller group meetings for more than a year has clearly led to some communication gaps, the rapid implementation of video conferencing tools such as Zoom and Microsoft Teams quickly allowed intra- and interlaboratory meetings to resume within days after lockdowns began. Not only did this facilitate local communication, but it also allowed for quick resumption of local, national, and international interactions and conferences, usually with greater participation than has ever occurred. As an example, our department’s neurology grand rounds was usually attended by ∼70 people per week prior to the pandemic. Our first virtual grand rounds after the lockdown began was attended by more than 300 people, and our attendance has remained very high over the last year. While there are key interpersonal interactions that occur at national and international conferences that one simply cannot replace by attending virtually, it has been incredibly empowering and helpful to be able to attend the myriad translational-neuroscience-related conferences and symposia virtually for well over a year now. Not only did established meetings continue in this fashion, but a number of translational neuroscientists at different institutions started new weekly seminar series open to anyone from around the world. These virtual meetings have definitely mitigated many of the effects of scientific isolation and have allowed rapid communication of findings between labs and neuroscientists worldwide. The attendance at these conferences has usually been as high as or higher than when these meetings were in person. When in-person conferences resume in the future, it seems likely that many will remain hybrid or at least video recorded. It also seems likely that travel for scientific purposes and exchange will decrease post pandemic with the realization that communication can often occur as effectively without the extra time, cost, and environmental impact of travel to conferences. While laboratory-based research was slowed during the pandemic, there were a number of positives that also emerged. Many translational neuroscientists who conduct computational/bioinformatics-type research could work from home as effectively as previously. In addition, with less time for neuroscientists to be physically present in the labs, many were able to focus their efforts on completing data analyses and writing and submitting manuscripts. In 2020, submission rates to most journals, including those that cover translational neuroscience, were up substantially. There are still many unknowns around how severely the translational neuroscience research pipeline has been affected not only around setbacks to the progression of promising diagnostic and therapeutic candidates but also around setbacks to career progression. We are buoyed by support from our community to adopt practices to ensure a healthy research—and researcher—pipeline. Meanwhile, clinical research and trials were also significantly affected. The COVID-19 pandemic had profound effects on clinical research in Alzheimer’s disease (AD). Some were obvious negative effects, such as missed drug administrations and outcome measures with impacts on trial integrity and data analysis; there were also less obvious but equally concerning effects on the morale of participants and staff. There was an atmosphere of great uncertainty early in the pandemic, when individual trial centers were grappling with decisions around how to keep participants safe while maintaining trial integrity and complying with protocols. For therapeutic trials under the auspices of the US Food and Drug Administration (FDA), there was little flexibility in screening windows or assessment timelines. FDA guidance appropriately placed participant safety first and allowed for the possibility of protocol changes without prior authorization (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency), but most sponsors from the pharmaceutical industry were reluctant to make major changes without regulatory input, and although they worked hard to develop guidelines and amend protocols, the process was slow and often left trial sites with little guidance. At most institutions and trial sites, participant visits were stopped relatively abruptly in early 2020 as the global pandemic spread. Our experience at the Knight Alzheimer Disease Research Center (ADRC) at Washington University in St. Louis was likely typical. The Knight ADRC conducts observational studies in older adults, and the Knight ADRC Clinical Trials Unit (CTU) conducts interventional studies in people with presymptomatic or symptomatic AD. Decisions about whether to conduct study visits were made with participant safety as the highest priority. We weighed the potential benefits of a study visit for participants against the risk of exposure to COVID-19 created by study visits and procedures—mindful that, early in the pandemic, it was apparent that older adults were among the most vulnerable. This calculation was somewhat different for observational studies (minimal benefit to participants) and interventional studies (more potential benefit to participants). Rising numbers of COVID-19 cases in the region in early March 2020 initially prompted the ADRC and CTU to institute enhanced screening and infection prevention protocols. The ADRC halted all in-person visits for observational studies on March 17, 2020. These visits did not resume until a year later, April 16, 2021. Based on university guidance, the CTU changed to remote visits when possible. In-person visits required consideration of the individual participant’s risk profile and weighing of the potential benefits of the visit, including patient safety and possible benefits to the participant. Trial integrity and data collection were not considered in making these decisions. Given that many trials involved interventions that required MRI imaging for safety monitoring (e.g., amyloid antibody studies where amyloid-related imaging abnormalities [ARIA] were a concern), there were discussions about whether it was safe for participants to visit our imaging facility. The Center for Clinical Imaging Research at the Mallinckrodt Institute of Radiology (CCIR) is housed inside Barnes Jewish Hospital, a tertiary referral hospital that cared for the most affected COVID-19 patients in the region. The CCIR is located across the hall from an intensive care unit that ultimately became a dedicated COVID ICU, making the physical proximity of older adult trial participants to COVID patients a grave concern. We ultimately stopped all in-person visits and had clinical trial staff work from home beginning April 7, 2020, as COVID-19 numbers increased and university guidelines evolved. As at other sites, trial coordinators remained in contact with participants through phone calls, conducting safety assessments and promoting participant engagement (Abdelnour et al., 2020Abdelnour C. Esteban de Antonio E. Pérez-Cordón A. Lafuente A. Buendía M. Pancho A. Jofresa S. Aguilera N. Ibarria M. Cuevas R. et al.Research Center and Memory Clinic, Fundació ACEManaging Clinical Trials for Alzheimer’s Disease During the COVID-19 Crisis: Experience at Fundació ACE in Barcelona, Spain.J. Alzheimers Dis. 2020; 77: 1805-1813https://doi.org/10.3233/JAD-200750Crossref PubMed Scopus (4) Google Scholar). Clinical trial staff had added administrative burdens during this time, for example, spending time locating and then setting up alternative imaging facilities, working to orient and supervise home health nurses (HHNs), and preparing for remote rather than in-person monitoring. In one case, setting up an alternate imaging facility took over a year. Like most clinical trial sites, participant visits for interventional studies, including imaging, resumed as COVID-19 numbers in the region declined, staff and facilities became more confident in infection prevention strategies, and institutions developed policies for resuming research activities. The Knight ADRC CTU resumed in-person participant visits on June 17, 2020, for interventional trials in presymptomatic and symptomatic AD, more than 10 weeks after suspending these visits. We gradually resumed recruiting new participants for ongoing studies and resumed screening visits for those not yet randomized. Observational studies, even those that were designed to enroll participants into interventional studies (e.g., the Dominantly Inherited Alzheimer Network [DIAN] cognitive roll-in study, NCT01760005, or the TRC-PAD study for presymptomatic Alzheimer disease, NCT04004767), were not approved for enrollment until August and September 2021, respectively. For some studies, the delay in randomization meant that participants had to repeat screening procedures when protocols had limits on how long screening could take. During and after the suspension of in-person visits, several studies initiated or expanded the availability of HHNs for blood collection as well as infusions or injections of parenteral medications. The HHN approach can be helpful but has its own challenges of insuring adequately trained staff and timely delivery of study medications, as well as study participants and partners who have varying degrees of comfort with having an HHN in their home. For most studies, there was less flexibility around outcome measures, with most cognitive and clinical measures remaining in person. Because many study interventions are monthly, the number of missed doses may be relatively low at sites that were able to resume study visits within a few months (Abdelnour et al., 2020Abdelnour C. Esteban de Antonio E. Pérez-Cordón A. Lafuente A. Buendía M. Pancho A. Jofresa S. Aguilera N. Ibarria M. Cuevas R. et al.Research Center and Memory Clinic, Fundació ACEManaging Clinical Trials for Alzheimer’s Disease During the COVID-19 Crisis: Experience at Fundació ACE in Barcelona, Spain.J. Alzheimers Dis. 2020; 77: 1805-1813https://doi.org/10.3233/JAD-200750Crossref PubMed Scopus (4) Google Scholar). The impact will be more substantial when study drug administration is more common (e.g., biweekly) or when sites suspend visits for many months or even years. This may be a more significant issue for studies in presymptomatic AD, such as the A4 study, NCT02008357, which involves antibody infusions, because many sites, like ours, weighed the risk/benefit analysis differently for those with and without symptoms of AD. Prolonged site closures could also affect participant retention, but, encouragingly, this was not an issue at the Knight ADRC CTU, where we had no attrition of clinical trial participants because of COVID. Other trial sites reported similarly low rates of attrition, such as the Fundacio ACE in Barcelona, where only one participant out of 108 randomized patients left a clinical trial study during the COVID-19 pandemic (Abdelnour et al., 2020Abdelnour C. Esteban de Antonio E. Pérez-Cordón A. Lafuente A. Buendía M. Pancho A. Jofresa S. Aguilera N. Ibarria M. Cuevas R. et al.Research Center and Memory Clinic, Fundació ACEManaging Clinical Trials for Alzheimer’s Disease During the COVID-19 Crisis: Experience at Fundació ACE in Barcelona, Spain.J. Alzheimers Dis. 2020; 77: 1805-1813https://doi.org/10.3233/JAD-200750Crossref PubMed Scopus (4) Google Scholar). Anecdotally, we found that participants with symptomatic AD and their caregivers believed they received benefit from participating in blinded randomized trials. This is consistent with the finding that participants and caregivers who missed trial visits had increased hopelessness and felt a loss of support (Weinberg et al., 2020Weinberg M.S. Patrick R.E. Schwab N.A. Owoyemi P. May R. McManus A.J. Gerber J. Harper D.G. Arnold S.E. Forester B. Clinical Trials and Tribulations in the COVID-19 Era.Am. J. Geriatr. Psychiatry. 2020; 28: 913-920https://doi.org/10.1016/j.jagp.2020.05.016Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). The impact of the pandemic on retention of participants in observational studies and on their willingness to undergo in-person study procedures like cognitive assessments, imaging, and spinal fluid and blood collection remains to be seen. Missing doses and missing outcome measures may require new statistical analysis approaches. Several new approaches have been proposed (Geerts and van der Graaf, 2020Geerts H. van der Graaf P. A modeling informed quantitative approach to salvage clinical trials interrupted due to COVID-19.Alzheimers Dement. (N. Y.). 2020; 6: e12053https://doi.org/10.1002/trc2.12053Crossref PubMed Scopus (2) Google Scholar), and many studies are revising analysis plans. The ultimate impact of the pandemic on clinical trial outcomes will likely not be clear for several years. The pandemic also had negative effects on monitoring for clinical trials. Our institution stopped allowing visitors on campus unless critical for patient and participant safety, so monitoring visits were conducted remotely or not at all; these restrictions were relaxed in the spring of 2021 and monitor visits have resumed, but monitoring remains behind in some studies in which source materials and trial documents remain on paper. Despite all the negative effects of the pandemic on clinical research in AD, there are some potentially positive repercussions. Particularly for interventional studies, many study sponsors have been reluctant to consider remote outcome assessments (e.g., via phone, video conferencing, online, or smart phones and other devices). The limited literature on remote assessments in dementia suggests that some measures can be adapted to phone or video administration (Marra et al., 2020Marra D.E. Hamlet K.M. Bauer R.M. Bowers D. Validity of teleneuropsychology for older adults in response to COVID-19: A systematic and critical review.Clin. Neuropsychol. 2020; 34: 1411-1452https://doi.org/10.1080/13854046.2020.1769192Crossref PubMed Scopus (82) Google Scholar; Wadsworth et al., 2018Wadsworth H.E. Dhima K. Womack K.B. Hart Jr., J. Weiner M.F. Hynan L.S. Cullum C.M. Validity of Teleneuropsychological Assessment in Older Patients with Cognitive Disorders.Arch. Clin. Neuropsychol. 2018; 33: 1040-1045https://doi.org/10.1093/arclin/acx140Crossref PubMed Scopus (59) Google Scholar), and there is rapidly increasing interest and technology to support remote monitoring devices as outcome measures, although much more work needs to be done. Some studies support the adaptation of well-established AD-specific measures like the ADAS-Cog for remote administration (Schwab et al., 2020Schwab N.A. DesRuisseaux L.A. Weinberg M.S. Arnold S.E. Saving cognitive outcome data in Alzheimer’s disease clinical trials during the COVID-19 pandemic: Commentary on the virtual administration of the ADAS-Cog.Alzheimers Dement. (N. Y.). 2020; 6: e12081https://doi.org/10.1002/trc2.12081Crossref PubMed Google Scholar; Yoshida et al., 2020Yoshida K. Yamaoka Y. Eguchi Y. Sato D. Iiboshi K. Kishimoto M. Mimura M. Kishimoto T. Remote neuropsychological assessment of elderly Japanese population using the Alzheimer’s Disease Assessment Scale: A validation study.J. Telemed. Telecare. 2020; 26: 482-487https://doi.org/10.1177/1357633X19845278Crossref PubMed Scopus (10) Google Scholar). Observational studies have generally been nimbler at adapting intervention and outcome measures to remote administration. The world-wide FINGERS study, NCT01041989, for example, was able to adapt the study’s lifestyle interventions so that many interventions could be continued during the pandemic (Röhr et al., 2021Röhr S. Arai H. Mangialasche F. Matsumoto N. Peltonen M. Raman R. Riedel-Heller S.G. Sakurai T. Snyder H.M. Sugimoto T. et al.World-Wide FINGERS Study GroupImpact of the COVID-19 pandemic on statistical design and analysis plans for multidomain intervention clinical trials: Experience from World-Wide FINGERS.Alzheimers Dement. (N. Y.). 2021; 7: e12143https://doi.org/10.1002/trc2.12143Crossref PubMed Scopus (5) Google Scholar). In the long term, remote assessments will be less expensive and potentially more robust (e.g., could be done more frequently at lower cost). Remote assessments and in-home study interventions may be more convenient for participant and care partners and are likely to increase recruitment and retention. The specter of future pandemics may provide the impetus needed to conduct the studies needed to ensure that these remote measures are robust and reproducible enough to be more widely accepted. As with basic science research, the pandemic made it clear that many clinical trial administrative activities can be conducted remotely, including monitoring, trial staff meetings, and study start-up meetings. This may help reduce costs for future trials. Trial sponsors and regulators, as well as study staff, are now more comfortable with electronic signatures through platforms such as DocuSign or Adobe. More trial documents are now becoming electronic, including some source and regulatory documents, reducing the need for storerooms full of trial binders and saving resources and energy. As clinical trial data become virtually all electronic, this should also improve data integrity and sharing. The COVID-19 pandemic offered many lessons for clinical research in AD that may be applicable for most clinical research for neurological disorders. Initially, the pandemic brought out the fragility of clinical trial infrastructure, invoking concern from researchers and participants alike about potential negative impacts on trials where interventions and outcome measures were interrupted. However, this is likely to bring about greater incorporation of remote assessments, electronic data collection, and storage as well as more flexibility from sponsors and regulators. There was great uncertainty early in the pandemic as site staff, institutional review boards, sponsors, and regulators took time to understand the severity of the pandemic and its impact on the conduct of trials. The biggest lesson from the pandemic was the amazing resilience and dedication around the world of trial participants and trial staff. D.M.H. is an inventor on a patent licensed by Washington University to C2N Diagnostics and subsequently to AbbVie on the therapeutic use of anti-tau antibodies. D.M.H. is an inventor on a patent licensed by Washington University to Eli Lilly on a humanized anti-amyloid-β antibody. D.M.H. co-founded and is on the scientific advisory board to C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali and Cajal Neurosciences and consults for Genentech, Takeda, and Eli Lilly. The lab of D.M.H. receives research funding to Washington University from C2N Diagnostics, Novartis, and NextCure. B.J.S. is on the Biogen advisory board.