Cognitive Impairment and Altered Cerebral Glucose Metabolism in the Subacute Stage of COVID-19

Jonas A. Hosp; Andrea Dressing; Ganna Blazhenets; Tobias Bormann; Alexander Rau; Marius Schwabenland; Johannes Thurow; Dirk Wagner; Cornelius Waller; Wolf D. Niesen; Lars Frings; Horst Urbach; Marco Prinz; Cornelius Weiller; Nils Schroeter; Philipp T. Meyer


Brain. 2021;144(4):1263-1276. 

In This Article

Abstract and Introduction


During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.


During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the emergence of neurological symptoms increasingly moved into the focus of interest.[1,2] Altogether, 37% (inpatients[3]) to 84% [intensive care unit (ICU) treatment[4]] of coronavirus disease-19 (COVID-19) patients show neurological symptoms, and these symptoms are not restricted to a severe course of disease. In line with these observations, elevated serum markers of axonal injury (neurofilament light chain protein) and astrocytic activation (glial fibrillary acidic protein, GFAP) have been detected in mild-to-moderate[5] and moderate-to-severe cases of COVID-19,[6] indicating an effect on the CNS. Apart from embolic cerebral infarctions and the involvement of peripheral nerves, 20–70% of patients with COVID-19 show a quantitative or qualitative disturbance of consciousness during the acute phase.[3,4] Peri-infectious encephalopathies can lead to cognitive impairment or pass into dementia[7,8] and have been observed in past coronavirus-related epidemics.[9] The neuroinvasive propensity of human betacoronavirus clades has been described repeatedly.[10–12] Olfactory and gustatory dysfunction, which occurs in up to 85%[13,14] of COVID-19 patients, could indicate trafficking of the virus into the CNS[12] as demonstrated in murine models of coronavirus infection.[11] Furthermore, a systemic inflammatory response to SARS-CoV-2 infection may elicit a 'cytokine-storm'[15] that could alter homeostatic processes within the CNS similar to septic encephalopathy.[7]

Guided by these considerations and with the intention to assess the impact of SARS-CoV-2 infection on the CNS, COVID-19 inpatients at the subacute stage were examined for disturbances of gust, olfaction and other neurological signs. The cognitive state was tested using the Montreal Cognitive Assessment (MoCA). Patients showing more than one new neurological symptom (≥2) were eligible for further investigations: a neuropsychological test battery, analysis of the CSF, structural MRI and PET with 18fluorodeoxyglucose (18FDG) to assess regional cerebral glucose metabolism. 18FDG PET is not only an established biomarker of neuronal function[16] and neuronal injury,[17] respectively, but also of CNS inflammation even in the absence of typical MRI findings.[18] Using this multimodal approach, we aimed to comprehensively characterize the neurological sequelae of COVID-19 in the subsample of patients affected severely enough to require inpatient treatment.