Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19

Abstract

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.

Keywords: 18FDG PET; COVID-19; Montreal Cognitive Assessment; cognition; neurology.

Figure 1

Flow chart indicating the enrolment of COVID-19 patients and the investigations that were performed. NPSY = detailed neuropsychological battery.

Figure 2

Individual ¹⁸FDG PET scans grouped according to the visual ratings. Transaxial ¹⁸FDG PET images of COVID-19 patients that were rated as normal (left column) or abnormal (middle and right columns) in consensus. Image count rates were normalized to total brain parenchyma for comparable display (see heat bars) in analogy to the procedure used in clinical routine [radiological orientation, i.e. left image side corresponds to patient’s right body side; numbers denote the axial (z) position in millimetres; scores denote the results of visual ratings separately for each rater]. The last row shows transaxial sections of group-averaged spatially-normalized ¹⁸FDG PET scans. Given the apparent involvement of grey matter on individual visual reads, all scans were normalized to white matter (SPM white matter mask, white matter probability > 50%) for the calculation of group averages.

Figure 3

Result of ¹⁸FDG PET group analysis. Top and middle row: Transaxial sections of group averaged, spatially normalized ¹⁸FDG PET scans in COVID-19 patients and controls. Given the apparent involvement of grey matter on individual visual reads, all scans were normalized to white matter (SPM white matter mask, white matter probability > 50%). Bottom row: COVID-19-related spatial covariance pattern of cerebral glucose metabolism constructed by PCA of the aforementioned groups. For illustration purposes, the spatial covariance pattern was restricted to voxels of the highest quartile of covariance of voxel weights (positive and negative; note that all brain voxels contribute to the pattern expression score according to their weights) and overlaid onto an MRI template. Voxels with negative region weights are colour-coded in cool colours, and regions with positive region weights in hot colours [neurological orientation, i.e. left image side corresponds to patient’s left body side; numbers denote the axial (z) position in millimetres].

Figure 4

Association between the expression of COVID-19-related covariance pattern (quantified by the so-called pattern expression score; see text) and the MoCA score adjusted for years of education. Each dot represents an individual patient’s data; the line (grey shaded area) corresponds to the fit of a linear regression (95% confidence interval; see Figure for R² and P-value).

Figure 5

Results of confirmatory ¹⁸FDG PET analyses. (A) Results of confirmatory SPM analysis. Illustrated are regions that showed significant decreases of normalized ¹⁸FDG uptake in COVID-19 patients compared to control patients [SPM (T) values are colour-coded and overlaid onto an MRI template; two-sample t-test adjusted for age, FDR P < 0.01; neurological orientation, i.e. left image side corresponds to patient’s left body side; numbers denote the axial (z) position in millimetres]. (B) Results of confirmatory PCA relying on healthy controls from the ADNI database. Shown are voxels of the highest quartile of covariance voxel weights, both for negative and positive voxel weights, of the COVID-19 related covariance pattern overlaid onto an MRI template [voxels with negative region weights are colour-coded in cool colours, those with positive region in hot colours; neurological orientation, i.e. left image side corresponds to patient’s left body side; numbers denote the axial (z) position in millimetres].

Figure 6

Distribution pattern of microglia activation. Immunohistochemical reactions for human leukocyte antigen DR isotype (brown), counterstaining with haematoxylin (blue) in different regions of the CNS. Microgliosis and formation of microglia nodules are confined to the white matter, whereas grey matter regions are largely unaffected. Scale bars = 500 µm, 100 µm and 10 µm in the insets, respectively.