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INTRODUCTION: The WHO estimates that 55 million people worldwide have dementia and this number is expected to increase to 139 million by 2050. Founded in 1980, the Alzheimer's Association is the world's leading voluntary health organization in AD/ADRD care, support and research. METHODS: Alzheimer's Association-led funding opportunities and awards, conferences and other activities beginning with the COVID-19 pandemic were reviewed. RESULTS: The Association remains committed to funding, convening, leading and implementing research studies that accelerate the global effort to eliminate Alzheimer's and all other dementia. DISCUSSION: This manuscript describes funding, convening and other global initiatives, influenced in part by the COVID-19 pandemic, to strengthen and drive research forward.
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Background SARS‐CoV‐2 causes neurological, psychiatric and neurocognitive deficits in a large proportion of patients via direct or indirect viral invasion, systemic or intracranial inflammation, micro‐ or macrovascular pathologies, and hypoxic or systemic metabolic complications. The insult to brain function during the acute phase of COVID‐19 may accelerate neurodegenerative process and potentially increase the risk of Alzheimer's Disease or Related Dementias. Ultrahigh Field (7T) MRI has an enhanced sensitivity and spatial resolution over and above clinical 3T MRI, allowing detection of small changes in brain sub‐structures and integrity. Methods The 7T COVID Consortium is an international collaboration across 5 sites which aims to study Ultrahigh Field neuroimaging correlates of clinical phenotypes, neuroimmunology, viral and host genetics, and neurodegenerative markers in a diverse, multi‐ethnic cohort of adults following SARS‐CoV2 infection. Multiple population cohorts include matched individuals following a clinically similar non‐COVID19 illness, and healthy controls including Framingham cohort and further comparative data from an independently‐funded genetically inherited Alzheimer's disease. Synergized imaging sequences across the sites with Ultrahigh Field (7T) facilities, standardized bio‐sampling protocols, and adaptation of centralised REDCAP with WHO protocols and other studies within the COVID consortia1permit harmonised data analyses. Results Pilot data from the UK site, in Nottingham, included individuals who presented with neurological disorders associated with SARS‐CoV2 Alpha variant of concern (B.1.1.7). Clinical phenotypes and biochemical measures of patients during the acute phase of COVID‐19 were documented2and a prospective follow up for neurocognitive assessments and 7T MRI were arranged. Compared with healthy controls, hospitalised patients showed neuroimaging features of cerebral white matter hyperintensities suggestive of neurovascular ischaemia or neuroinflammation. These radiological cerebral white matter hyperintensities could progress 7 months after the acute illness despite clinical silence. Long COVID appeared to have increased susceptibility, that is suggestive of iron accumulation or inflammation, within the basal ganglia structures. Conclusion Pilot data suggest persistent or emergent neuroimaging abnormalities within a year after SARS‐CoV2 infection. Serial follow up may clarify long‐term impact of COVID‐19. Funding: NIH/NIA, USA (R56AG074467), Nottingham Biomedical Research Centre (NIHR), Medical Research Council, UK (MR/T005580/1). References: 1.de Erausquin, et al. http://doi.org/10.1002/alz.12255 2.Dhillon, et al. https://doi.org/10.3389/fneur.2021.640017
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Background COVID‐19 has affected more than 380 million people. Infections may result in long term sequelae, including neuropsychiatric symptoms. In older adults COVID‐19 sequelae resemble early Alzheimer's disease, and may share risk factors and blood biomarkers with it. The Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) established harmonized definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with exposure to COVID‐19. We present one year data in a prospective cohort from Argentina. Method Participants (n = 766) are older adults (≥60 years) recruited from the provincial health registry containing all SARS‐CoV‐2 testing data. We randomly invite older adults stratified by PCR COVID‐19 testing status regardless of symptom severity, between 3 and 6 months after recovery. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale (CDR);neurocognitive assessment;emotional reactivity scale;and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. Result We assessed 88.4% infected participants and 11.6 % controls. Education is 10.36 ± 5.6 years and age is 66.9 ± 6.14 years. Level of care during COVID‐19 is described in Figure 1. Normalized cognitive Z‐scores categorize the cohort in 3 groups with decreased performance compared to normal cognition: memory only impairment (Single‐domain,11.7%);impairment in attention+executive function without memory impairment (Two‐domain, 8.3%);and multiple domain impairment (Multiple domain,11.6%). Logistic regression showed that severity of anosmia, but not clinical status, significantly predicts cognitive impairment. No controls had olfactory dysfunction. Cognitive impairment is defined as Z‐scores below (‐ 2) (Table 1). Clinical assessment with SCAN revealed functional memory impairment in two thirds of infected patients (CDR ≥ 1), which was severe in half of them. Phone‐based follow up at 1 year revealed high adherence (4 participants declined). Five were deceased at follow up. Rates of re‐infection (between 10 and 23%) were not affected by the vaccination schedule (Table 2). Conclusion The longitudinal cohort had very high adherence. Persistent cognitive and functional impairment after SARS‐CoV‐2 infection is predicted by persistent anosmia but not by the severity of the initial COVID‐19 disease.
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Epidemiological, clinical, and radiological studies have provided insights into the phenomenology and biological basis of cognitive impairment in COVID-19 survivors. Furthermore, its association with biomarkers associated with neuroinflammation and neurodegeneration supports the notion that it is a distinct aspect of LongCOVID syndrome with specific underlying biology. Accounting for the latter, translational studies on SARS-CoV-2's interactions with its hosts have provided evidence on type I interferon dysregulation, which is seen in neuroinflammatory and neurodegenerative diseases. To date, studies attempting to describe this overlap have only described common mechanisms. In this manuscript, we attempt to propose a mechanistic model based on the host-virus interaction hypothesis. We discuss the molecular basis for a SARS-CoV-2-associated neurocognitive disorder (SAND) focusing on specific genes and pathways with potential mechanistic implications, several of which have been predicted by Vavougios and their research group. Furthermore, our hypothesis links translational evidence on interferon-responsive gene perturbations introduced by SARS-CoV-2 and known dysregulated pathways in dementia. Discussion emphasizes the crosstalk between central and peripheral immunity via danger-associated molecular patterns in inducing SAND's emergence in the absence of neuroinfection. Finally, we outline approaches to identifying targets that are both testable and druggable, and could serve in the design of future clinical and translational studies.
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Background U.S. POINTER is testing whether multidomain lifestyle interventions focused on physical exercise, nutrition, cognitive challenge, and risk factor management reduces risk of cognitive decline in a heterogeneous population of at-risk older adults in America. The study adapts the FINGER (Finnish Intervention Geriatric Study to Prevent Cognitive Impairment and Disability) interventions to fit the United States culture and delivers the intervention within the community at 5 sites across the country. Method U.S. POINTER is a 2-year RCT that will enroll 2000 cognitively unimpaired older adults who are at risk for cognitive decline due sedentary lifestyle, poor diet and other factors. Participants are randomized to one of two lifestyle intervention groups that differ in format and intensity. In 2020, the COVID-19 pandemic presented a number of challenges for the study that affected recruitment, assessment schedules, and intervention delivery. Result As of March 2020, when COVID-19 incidence was on an exponential rise in the US, 240 participants had been enrolled in U.S. POINTER. In response to local and national safety mandates, study activities were paused from March 23rd to July 13th. During the pause, sites remained in contact with study candidates and enrolled participants to provide ongoing support to keep them engaged in the trial. Enrollees also received regular telephone calls to encourage continued adherence to their assigned lifestyle intervention. In response to the multiple pandemic-related challenges, study protocols and procedures were adapted to facilitate and encourage participant adherence to intervention activities. At study re-start, retention was 98%. Despite climbing COVID-19 infection rates nationwide, enrollment at all 5 sites has continued at a steady rate (N=540 as of Jan2021), virtual Team Meeting attendance for both lifestyle groups exceeds 80%, and participants continue to successfully work toward their intervention goals. Conclusion The COVID-19 pandemic presented unprecedented challenges, but it also provided a unique opportunity to adapt intervention delivery so that a nonpharmacological community-based trial could continue ? even during a debilitating global health crisis. U.S. POINTER?s adaptations to pandemic-related challenges may ultimately increase the resilience of its interventions to even the most challenging of circumstances that older adults will face now and in the future.
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Background The coronavirus disease-19 (COVID-19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. Method World-Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at-risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened forums for researchers to discuss statistical design and analysis issues they faced during the pandemic. We will provide an updated report on experiences of trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. Result The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessments protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within site stratification, interim power projections, and sensitivity analyses. Conclusion Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The World Wide Network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.
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Background COVID-19 has affected more than 150 million people. The causal coronavirus, SARS-CoV-2 has infected twice as many individuals who have remained asymptomatic. COVID-19 includes central nervous system (CNS) manifestations and may result in chronic neuropsychiatric sequelae. Risk factors for COVID-19 sequelae overlap with those for Alzheimer?s disease (AD), particularly older age and ApoE4 status. The Alzheimer?s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) established harmonized definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with variable exposure to COVID-19. We present preliminary data from CNS SC2 in a prospective cohort of 234 older adult Amerindians from Argentina. Method Participants are ≥ 60 years recruited from the health registry of the Province of Jujuy containing all SARS-CoV-2 testing data (regardless of clinical status and of the result of the testing). We randomly invite older adults stratified by testing status regardless of symptom severity, a minimum of 3 months after clinical recovery (maximum 6 months);refusal to participate is <45%. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale;neurocognitive assessment;emotional reactivity scale;and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. We present here the results of olfactory testing and cognitive assessments. Result We assessed 233 infected participants and 64 controls. Average duration of formal learning is 9.35 ± 2.6 years and mean age is 66.7 ± 5.13 years. Normative data for the local population were available for Word list, Corsi Blocks, Oral Trails and Five Digit Tests and were used to normalize Z-scores and categorize the sample in 3 groups: normal cognition (NC,44.6%);memory only impairment (MOI,21%);and multiple domain impairment (MDI,34.4%). Individuals with MDI presented severe alterations in short-term memory;semantic memory;naming;executive function and attention compared to NC or MO groups (Table 1). Severity of cognitive impairment was significantly correlated with severity of olfactory dysfunction (?2 = 13.82;p= 0.003) but not severity of acute COVID-19. Conclusion Older adults frequently suffer persistent cognitive impairment after recovery from SARS-CoV-2 infection;cognitive impairment is correlated with persistent anosmia.
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The COVID-19 pandemic has disproportionately affected more vulnerable populations, including those living with dementia. Over 50 million individuals worldwide are living with Alzheimer's disease (AD) or other dementia, and it is crucial to continue the fight against the condition during the global pandemic. Since the start of mandated lockdowns in March 2020, charity and non-profit organizations that fund AD and related dementia research continue to respond to the needs of the AD research community, ensuring the momentum continues and accelerates. Members of the International Alzheimer's and Related Dementia Research Funder Consortium, a group of nearly 40 funding organizations that informally convene throughout the year to share updates and information, have taken a number of steps to ensure the continued support of the research community. Even during times of uncertainty, it is essential that the field moves forward to uncover preventions, diagnoses, and treatments for these diseases that affect many millions globally.
Subject(s)
Alzheimer Disease , COVID-19 , Alzheimer Disease/diagnosis , Communicable Disease Control , Humans , PandemicsABSTRACT
INTRODUCTION: The coronavirus disease-19 (COVID-19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. METHODS: World-Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at-risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report on experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. RESULTS: The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessment protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within-site stratification, interim power projections, and sensitivity analyses. DISCUSSION: Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The world-wide network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.
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Abstract Background The pandemic of SARS-CoV-2 is focusing all energies on the impact on survival of affected individuals, treatment and prevention, but increasingly attention is focusing on its enduring consequences. We established a global consortium to study a longitudinal representative cohort of individuals, to characterize neurological and neuropsychiatric sequalae from direct viral, immune-, vascular- or accelerated neurodegenerative injury to the central nervous system (CNS). Method We propose to characterize the neurobehavioral phenomenology associated with SARS-CoV-2 in a large, multinational, longitudinal cohort of post COVID-19 infection patients following three sampling strategies: 1) Opportunity sample of patients discharged after hospital admission for COVID-19 related symptoms. 2) A stratified random sample from COVID-19 testing registries (including asymptomatic and negative participants). 3) Ascertaining COVID-19 exposure (antibody) status in ongoing longitudinal, community-based cohort studies that are already collecting biosamples, cognitive, behavioral and neuroimaging data. We will obtain core data within 6 months of discharge or testing. Core characterization will include interviews with the Schedules of Clinical Assessment in Neuropsychiatry (SCAN), neurological exams, emotional reactivity scales and a neurocognitive assessment. Wherever feasible, we will also collect neuroimaging, biosamples and genetic data. Longitudinal follow up will be conducted at 9 and 18 months of the initial evaluation. An mHealth keeping-in-touch process will be set up to minimize attrition rates. The population cohorts provide a large, unbiased, normative and validation sample, albeit with more heterogenous outcome ascertainment. They also permit examination of pre- and post-COVID trends in symptoms and biomarkers. Since some ethnic groups, as well as in individuals with blood type A, are at higher risk of COVID-19 infection and death, a role of genetics in determining susceptibility to infection and poor outcomes seems well supported. We will collect genome-wide genotypes from our cohort individuals to address the role of ancestry and genetic variation on susceptibility to neuropsychiatric sequelae. High rates of mutation in COVID-19 strongly suggest that viral infectivity, including neurotropism, may not be uniform across countries affected by the pandemic. Results Pending. Conclusion Our consortium is in a unique position to address the interaction between genetics (including ancestral DNA), and viral strain variation on CNS sequelae of SARS-CoV-2.