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Measuring the cognitive costs of the COVID-19 pandemic
Molecular Neurodegeneration ( IF 15.1 ) Pub Date : 2021-09-23 , DOI: 10.1186/s13024-021-00492-x
Gregory S Day ₁

Affiliation

Numbers of positive PCR tests, hospital visits, available intensive care beds and ventilators, and lives lost are frequently used to approximate the costs of the Coronavirus Disease 2019 (COVID-19) pandemic. Yet, as weeks turn to months, and months stretch into years, it is becomingly increasingly apparent that the real costs of the pandemic are only just beginning to be counted. This is especially true when considering the neurological consequences of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to prominent systemic inflammation, with direct virus infiltration and proliferation within the central nervous system limited to select cases.[1, 2] Despite this observation, neurologic and psychiatric symptoms and signs are common in patients with COVID-19, including persistent deficits in memory and attention.[3, 4] The high morbidity and burden associated with caring for these patients exemplifies the need to determine the prevalence of cognitive impairment following SARS-CoV-2, and to identify the factors that influence outcomes in recovering patients. In response to this need, Liu and colleagues present cross-sectional data summarizing cognitive outcomes in older patients evaluated 6-months following hospitalization and treatment at one of three COVID-19-designated hospitals in Wuhan, China.[5].

In total, 1,539 participants with COVID-19 were enrolled between February and April 2020. Participants were 60-years or older, without preexisting subjective or diagnosed dementia, or a family history of dementia. Comparison data were obtained from unaffected spousal controls (n = 466). All participants completed a telephone survey, incorporating validated measures of cognition (Telephone Interview of Cognitive Status-40 [TICS-40], Chinese-language version), with family members providing collateral history informing post-COVID-19 cognitive changes. Surprisingly, 35.7 % of patients with severe COVID-19—defined as cases with fever or suspected respiratory infection with objective evidence of respiratory compromise—had clinically meaningful cognitive impairment (mild cognitive impairment or dementia). This number was substantially greater than that observed in uninfected spousal controls (4.3 %; p < 0.001). No association was observed between non-severe COVID-19 infections and clinically meaningful declines on the TICS-40, although family members were more likely to score non-severe cases (versus spousal controls) within a range associated with clinically meaningful impairment on standardized questionnaires. In subsequent analyses, age, COVID-19 severity, requirement for intensive care unit admission, delirium, and history of stroke, coronary heart disease, and chronic obstructive pulmonary disease were associated with worse TICS-40 score. Greater years of education and use of high flow oxygen therapy were associated with a better TICS-40 score. Similar associations were reported when longitudinal declines were estimated through informant questionnaires.[5] These findings indicate that cognitive impairment is prevalent in older individuals following hospitalization and treatment for COVID-19.

Closer consideration of patient- and disease-associated factors offers additional insights into the potential drivers of cognitive impairment in recovering COVID-19 patients. Disease severity, intensive care unit admission, and chronic obstructive pulmonary disease may identify patients at the greatest risk of clinically significant hypoxemia, and resultant cerebral hypoxia and ischemia. Vascular risk factors may further compound this risk, explaining the increased odds of cognitive impairment in patients with these historical risk factors.[5] Although neuroimaging results were not reported in this study, microstructural damage and disruption of functional brain integrity were noted in studies performing neuroradiological assessments 3-months following SARS-CoV-2 infection.[6] More obvious cerebrovascular disruption may also occur following SARS-CoV-2 infection. Indeed, arterial and venous cerebrovascular thrombotic events are commonly reported in patients hospitalized with COVID-19, including young patients without traditional vascular risk factors.[7] These findings suggest that SARS-CoV-2 infection contributes to a hyperinflammatory and hypercoagulable state that may, in turn, lead to thromboembolic events, cerebrovascular changes, and neuronal loss in susceptible patients.

Neuroinflammation is a well-established contributor to neuropathology in Alzheimer disease and related dementias. Genetic variants altering microglial and astrocyte activation influence the risk of Alzheimer disease in large cohort studies, while abnormal activation of microglia and astrocytes promotes the formation and spread of amyloid-beta and tau pathology in animal and in vitro models (for review, see [8]). Prolonged immune activation may also predispose to hippocampal atrophy, tau accumulation and cognitive deficits in older patients recovering from antibody-mediated encephalitis.[9] It is not surprising, therefore, that pathways associated with neuroinflammation and neurodegeneration are upregulated in biofluids and tissues from patients with COVID-19,[1] or that activated microglia feature prominently within the brains of patients who died due to complications of COVID-19.[2] Acute increases in serum neurofilament light chain—a marker of neuroaxonal loss—are also seen in patients hospitalized with COVID-19, with higher levels predicting more severe disease and worse motor outcomes at discharge.[10] Whether neuroinflammation and microglial activation contribute to acute neuronal loss, chronic neurodegenerative changes, or both, remains to be demonstrated in surviving COVID-19 patients.

Longitudinal studies in recovering patients are needed to provide access to data and tissue specimens that will drive discovery and inform the contributors to post-COVID-19 neurological sequelae. These studies should incorporate serial cognitive and clinical assessments, along with structural and molecular (e.g., amyloid-beta and tau) neuroimaging, and biofluid biomarkers of neuroinflammation and neurodegeneration. It will be especially important to obtain these measures early in the disease course, allowing SARS-CoV-2-associated changes in amyloid-beta, tau, and vascular neuropathology to be appreciated through follow-up. In this way, the COVID-19 pandemic presents a unique opportunity to untangle the complex relationship between neurovascular changes, neuroinflammation, and neurodegeneration in an expanding cohort of patients of all ages exposed to SARS-CoV-2. Future studies encompassing broader geographic areas are also needed to ensure the generalizability of results and to validate prevalence estimates of cognitive impairment in other populations affected at other timepoints. This statement acknowledges that much has changed since early 2020, when the cohort reported by Liu et al. was hospitalized.[5] The emergence of new SARS-CoV-2 variants, advances in treatment of severe COVID-19, and the advent and broad dissemination of effective vaccinations may all modify the response to COVID-19, including the risk of post-infectious neurologic sequelae.

A clearer understanding of the drivers of post-COVID-19 cognitive impairment is integral to the development of testable hypotheses and therapeutic approaches to ameliorate neurovascular changes and neuroinflammation, and to slow or stop neurodegeneration in surviving patients. The benefits of this knowledge are likely to extend beyond patients with COVID-19, with the potential to inform approaches to treatment, and improve long-term outcomes in patients with rare(er) autoimmune brain diseases and the millions of individuals worldwide with Alzheimer disease and related dementias. This possibility offers an unexpected upside to an otherwise devastating and costly worldwide pandemic.

Not applicable.

COVID-19:: Coronavirus Disease 2019
SARS-CoV-2:: Severe acute respiratory syndrome coronavirus 2
TICS-40:: Telephone Interview of Cognitive Status-40

1.
Zhou Y, Xu J, Hou Y, Leverenz JB, Kallianpur A, Mehra R, Liu Y, Yu H, Pieper AA, Jehi L, et al. Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimers Res Ther. 2021;13(1):110.
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Matschke J, Lutgehetmann M, Hagel C, Sperhake JP, Schroder AS, Edler C, Mushumba H, Fitzek A, Allweiss L, Dandri M, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19(11):919–29.
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Liu YH, Wang YR, Wang QH, Chen Y, Chen X, Li Y, Cen Y, Xu C, Hu T, Liu XD, et al. Post-infection cognitive impairments in a cohort of elderly patients with COVID-19. Mol Neurodegener. 2021;16(1):48.
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6.
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Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease. Mol Neurodegener. 2020;15(1):40.
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Prudencio M, Erben Y, Marquez CP, Jansen-West KR, Franco-Mesa C, Heckman MG, White LJ, Dunmore JA, Cook CN, Lilley MT, et al. Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19. Sci Transl Med. 2021;13(602).

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GSD is supported by a career development grant from the NIH (K23AG064029).

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Department of Neurology, Mayo Clinic in Florida, Jacksonville, Florida, USA
Gregory S Day

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Gregory S DayView author publications
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GSD: Conception and design, revision, and finalization of the manuscript. The author(s) read and approved the final manuscript.

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Correspondence to Gregory S Day.

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Competing interests

He owns stock (>$10,000) in ANI Pharmaceuticals (a generic pharmaceutical company). He serves as a topic editor for DynaMed (EBSCO), overseeing development of evidence-based educational content, a consultant for Parabon Nanolabs (advice relevant to NIH small business grant submission), and as the Clinical Director of the Anti-NMDA Receptor Encephalitis Foundation, Inc, Canada (uncompensated).

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Day, G.S. Measuring the cognitive costs of the COVID-19 pandemic. Mol Neurodegeneration 16, 67 (2021). https://doi.org/10.1186/s13024-021-00492-x

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Received: 28 August 2021
Accepted: 10 September 2021
Published: 23 September 2021
DOI: https://doi.org/10.1186/s13024-021-00492-x

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Keywords

COVID-19
SARS-CoV-2
Coronavirus
Pandemic
Mild cognitive impairment
Dementia
Cognitive impairment

中文翻译：

衡量 COVID-19 大流行的认知成本

PCR 检测呈阳性的次数、就诊次数、可用的重症监护病床和呼吸机以及死亡人数经常被用来估算 2019 年冠状病毒病 (COVID-19) 大流行的成本。然而，随着几周变成几个月，几个月变成几年，越来越明显的是，大流行的实际成本才刚刚开始计算。考虑到 COVID-19 的神经学后果时尤其如此。

严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 感染会导致明显的全身炎症，病毒在中枢神经系统内的直接浸润和增殖仅限于特定病例。 [1, 2] 尽管有这种观察，神经系统和精神症状和症状在 COVID-19 患者中很常见，包括持续的记忆力和注意力缺陷。 [3, 4] 与照顾这些患者相关的高发病率和负担说明需要确定 SARS-CoV-2 后认知障碍的患病率，并确定影响康复患者结果的因素。针对这一需求，

在 2020 年 2 月至 2020 年 4 月期间，共有 1,539 名 COVID-19 参与者被招募。参与者年龄在 60 岁或以上，没有预先存在主观或诊断的痴呆症，或痴呆症的家族史。比较数据来自未受影响的配偶对照（n = 466）。所有参与者都完成了一项电话调查，其中包括经过验证的认知测量（认知状态电话访谈-40 [TICS-40]，中文版)，家庭成员提供旁系病史，告知 COVID-19 后的认知变化。令人惊讶的是，35.7% 的重度 COVID-19 患者（定义为发烧或疑似呼吸道感染并有呼吸道损害的客观证据）具有临床意义的认知障碍（轻度认知障碍或痴呆）。这个数字大大高于未感染配偶对照中观察到的数字 (4.3 %; p < 0.001)。未观察到非严重 COVID-19 感染与 TICS-40 有临床意义的下降之间存在关联，尽管家庭成员更有可能在与标准化问卷中具有临床意义的损害相关的范围内对非严重病例（相对于配偶对照）进行评分. 在随后的分析中，年龄、COVID-19 严重程度、入住重症监护病房的要求、谵妄、中风史、冠心病和慢性阻塞性肺病与更差的 TICS-40 评分相关。更长的教育年限和高流量氧疗的使用与更好的 TICS-40 评分相关。当通过线人问卷估计纵向下降时，报告了类似的关联。

仔细考虑与患者和疾病相关的因素，可以进一步了解 COVID-19 患者康复过程中认知障碍的潜在驱动因素。疾病严重程度、重症监护病房入院和慢性阻塞性肺疾病可能会识别出临床显着低氧血症以及由此导致的脑缺氧和缺血风险最大的患者。血管风险因素可能进一步加剧这种风险，解释了具有这些历史风险因素的患者认知障碍的几率增加。 [5] 尽管本研究未报告神经影像学结果，但在 SARS-CoV-2 感染 3 个月后进行神经放射学评估的研究中发现了显微结构损伤和脑功能完整性的破坏。[6] SARS-CoV-2感染后也可能发生更明显的脑血管破坏。事实上，动脉和静脉脑血管血栓形成事件在 COVID-19 住院患者中很常见，包括没有传统血管危险因素的年轻患者。 [7] 这些发现表明，SARS-CoV-2 感染会导致高炎症和高凝状态，进而可能导致易感患者的血栓栓塞事件、脑血管变化和神经元丢失。

神经炎症是阿尔茨海默病和相关痴呆症中神经病理学的公认因素。在大型队列研究中，改变小胶质细胞和星形胶质细胞激活的遗传变异会影响阿尔茨海默病的风险，而小胶质细胞和星形胶质细胞的异常激活会促进淀粉样蛋白 β 和 tau 病理学在动物和体外的形成和传播模型（审查，见[8]）。在从抗体介导的脑炎中恢复的老年患者中，长时间的免疫激活也可能导致海马萎缩、tau 蛋白积累和认知缺陷。 [9] 因此，与神经炎症和神经变性相关的通路在 COVID-19 患者的生物体液和组织中上调，[1] 或因 COVID-19 并发症而死亡的患者大脑中激活的小胶质细胞特征显着也就不足为奇了.[2] 在 COVID-19 住院患者中也观察到血清神经丝轻链的急性增加（神经轴突丧失的标志物），较高的水平预示着更严重的疾病和出院时更差的运动结果。 [10] 神经炎症和小胶质细胞激活是否会导致急性神经元丢失、慢性神经退行性变化、

需要对康复患者进行纵向研究，以提供对数据和组织标本的访问，这将推动发现并为 COVID-19 后神经系统后遗症的贡献者提供信息。这些研究应包括连续的认知和临床评估，以及结构和分子（如淀粉样蛋白 β 和 tau）神经影像学以及神经炎症和神经变性的生物流体生物标志物。在病程早期获得这些措施尤为重要，以便通过随访了解与 SARS-CoV-2 相关的淀粉样蛋白 β、tau 和血管神经病理学变化。通过这种方式，COVID-19 大流行提供了一个独特的机会来解开神经血管变化、神经炎症、越来越多的暴露于 SARS-CoV-2 的所有年龄段患者的神经退行性疾病。未来的研究还需要涵盖更广泛的地理区域，以确保结果的普遍性，并验证在其他时间点受影响的其他人群中认知障碍的患病率估计。该声明承认自 2020 年初以来发生了很大变化，当时 Liu 等人报告的队列。住院了。 [5] 新的 SARS-CoV-2 变异体的出现、严重 COVID-19 治疗的进步以及有效疫苗的出现和广泛传播都可能改变对 COVID-19 的反应，包括感染后神经系统后遗症的风险。未来的研究还需要涵盖更广泛的地理区域，以确保结果的普遍性，并验证在其他时间点受影响的其他人群中认知障碍的患病率估计。该声明承认自 2020 年初以来发生了很大变化，当时 Liu 等人报告的队列。住院了。 [5] 新的 SARS-CoV-2 变异体的出现、严重 COVID-19 治疗的进步以及有效疫苗的出现和广泛传播都可能改变对 COVID-19 的反应，包括感染后神经系统后遗症的风险。未来的研究还需要涵盖更广泛的地理区域，以确保结果的普遍性，并验证在其他时间点受影响的其他人群中认知障碍的患病率估计。该声明承认自 2020 年初以来发生了很大变化，当时 Liu 等人报告的队列。住院了。 [5] 新的 SARS-CoV-2 变异体的出现、严重 COVID-19 治疗的进步以及有效疫苗的出现和广泛传播都可能改变对 COVID-19 的反应，包括感染后神经系统后遗症的风险。

更清楚地了解 COVID-19 后认知障碍的驱动因素对于开发可测试的假设和治疗方法以改善神经血管变化和神经炎症以及减缓或停止幸存患者的神经变性至关重要。这些知识的好处可能会扩展到 COVID-19 患者之外，有可能为治疗方法提供信息，并改善罕见（er）自身免疫性脑病患者和全球数百万阿尔茨海默病患者的长期预后和相关的痴呆症。这种可能性为原本具有破坏性且代价高昂的全球大流行病提供了意想不到的好处。

不适用。

新冠肺炎：: 2019冠状病毒病
SARS-CoV-2：: 严重急性呼吸系统综合症冠状病毒 2
TICS-40：: 认知状态电话采访-40

1.
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文章谷歌学术
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文章谷歌学术
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他拥有 ANI Pharmaceuticals（一家仿制药公司）的股票（> 10,000 美元）。他担任 DynaMed (EBSCO) 的主题编辑、监督循证教育内容的开发、Parabon Nanolabs 的顾问（与 NIH 小企业赠款提交相关的建议）以及抗 NMDA 受体脑炎基金会的临床主任, Inc, 加拿大（无偿）。

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