Persistent dysfunctions of brain metabolic connectivity in long-covid with cognitive symptoms, 2024, Martini et al.

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Persistent dysfunctions of brain metabolic connectivity in long-covid with cognitive symptoms
Martini, Anna Lisa; Carli, Giulia; Caminiti, Silvia Paola; Kiferle, Lorenzo; Leo, Andrea; Perani, Daniela; Sestini, Stelvio

PURPOSE
Our study examines brain metabolic connectivity in SARS-CoV-2 survivors during the acute-subacute and chronic phases, aiming to elucidate the mechanisms underlying the persistence of neurological symptoms in long-COVID patients.

METHODS
We perfomed a cross-sectional study including 44 patients (pts) with neurological symptoms who underwent FDG-PET scans, and classified to timing infection as follows: acute (7 pts), subacute (17 pts), long-term (20 pts) phases. Interregional correlation analysis (IRCA) and ROI-based IRCA were applied on FDG-PET data to extract metabolic connectivity in resting state networks (ADMN, PDMN, EXN, ATTN, LIN, ASN) of neuro-COVID pts in acute/subacute and long-term groups compared with healthy controls (HCs). Univariate approach was used to investigate metabolic alterations from the acute to sub-acute and long-term phase.

RESULTS
The acute/subacute phase was characterized by hyperconnectivity in EXN and ATTN networks; the same networks showed hypoconnectivity in the chronic phase. EXN and ATTN hypoconnectivity was consistent with clinical findings in long-COVID patients, e.g. altered performances in neuropsychological tests of executive and attention domains. The ASN and LIN presented hyperconnectivity in acute/subacute phase and normalized in long-term phase. The ADMN and PDMN presented a preseverved connectivity. Univariate analysis showed hypometabolism in fronto-insular cortex in acute phase, which reduced in sub-acute phase and disappeared in long-term phase.

CONCLUSIONS
A compensatory EXN and ATTN hyperconnectivity was found in the acute/subacute phase and hypoconnectivity in long-term. Hypoconnectivity and absence of hypometabolism suggest that connectivity derangement in frontal networks could be related to protraction of neurological symptoms in long-term COVID patients.

Link | PDF (European Journal of Nuclear Medicine and Molecular Imaging)

 

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Methods —

We included forty-four neuro-COVID patients (age 69.31 ± 12.25 years; 22/22 male/female; all right-handed) affected by SARS-CoV-2 infection. These patients were prospectively recruited in the Neurology Unit of Ospedale Santo Stefano Prato, Italy, from October 2020 to May 2023.

The inclusion criteria were adults over 18 years old with a history of SARS-CoV-2 infection confirmed by a positive RT-PCR assay from a nasopharyngeal swab sample, the absence of neurological or psychiatric [symptoms] in patient’s medical history and current health status suggesting the presence of neuro-degenerative or other neurological and psychiatric diseases before the infection of SARS-CoV-2, a medical and neuropsychological evaluation for new-onset cognitive impairment or neurological signs in the context of acute/subacute and long COVID phases that were not explained by an alternative diagnosis, and [18F]FDG-PET scan performed within 2-weeks from clinical/neurological assessment.

We included 125 healthy controls (HC) from the AIMN (Associazione Italiana di Medicina Nucleare ed Imaging Molecolare) database, available on the AIMN website. The HC dataset (age, mean ± SD: 65.78 ± 11.33; sex: 58 male/67 female; education, mean ± SD: 10.5 ± 4.29) has been previously validated for extracting SPM-based brain metabolism maps in patients. These subjects exhibited no global cognitive impairment (MMSE, mean ± SD: 28.75 ± 1.69) and maintained cognitive stability after an average 4-year clinical follow-up.

COVID-19 patients underwent [18F]FDG-PET scans

We conducted a brain metabolic connectivity analysis to examine the integrity of large-scale resting-state networks (RSNs) in neuro-COVID patients, including 24 acute-subacute patients (1, 2, and 3 months) and 20 long-COVID patients (4, 5–6, and 7–12 months), compared to 30 age matched HC.

 

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Results —

The hypometabolism commonality analysis performed in 44 patients confirmed the fronto-insular cortex as the hypometabolic hallmark for the “whole group”. More in detail, all patients shared hypometabolism in the orbitofrontal cortex; inferior, superior and middle frontal gyri; medial pre-frontal cortex; insula and in the angular gyrus. When we quantified the severity of hypometabolism (mean) in the fronto-insular-parietal cortex we found that it significantly (p = 0.0001) decreased from the acute (1.66 ± 0.29) to sub-acute (1-m: 1.54 ± 0.52; 2-m: 1.41 ± 0.52; 3-m: 1.13 ± 0.34) and long-term phases (4-m: 0.93 ± 0.21; 5–6m: 0.74 ± 0.13; 7–12-m: 0.46 ± 0.07). Specifically, acute and subacute patients showed significantly more severe brain hypometabolism than long-COVID patients (p = 0.0001).

EXN is executive network
ATTN is attentive network
LIN is limbic network
ASN is anterior salience network

EXN and ATTN are the most affected network in both acute/subacute (DC EXN = 0.23, e.g. poor overlap; DC ATTN = 0.39, e.g. fair overlap) and chronic (DC EXN = 0.31, e.g. fair ovelap; DC ATTN = 0.38, e.g. fair overlap) groups, but with opposite directions of changes. Acute/subacute patients showed a more extended EXN (NCV EXN = 19,240; Δ EXN = + 27%) and ATTN (NCV ATTN = 18,614; Δ EXN = + 20%) than HCs (NCV EXN = 13,877; NCV ATTN = 14,790), thus suggesting the presence of hyperconnectivity. On the contrary, long-COVID patients presented a reduced extention of EXN (NCV EXN = 8181; Δ EXN =—41%) and ATTN (NCV ATTN = 10,765; Δ ATTN =—27%) than HCs, thus suggesting hypoconnectitìvity.

ASN and LIN are affected during the acute/subacute phase (DC ASN = 0.32, e.g. fair overlap; DC LIN = 0.35, e.g. fair overlap) but tend to normalize in the chronic phase (DC ASN = 0.50, e.g. moderate overlap; DC LIN = 0.59, e.g. good overlap).

 

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Discussion —

Results of multivariate approach revealed that EXN and ATTN are the most affected networks. An enhanced functional communication namely hyperconnectivity between EXN and ATTN regions is present in the acute/subacute group in response to neuropathology of disease with the primary goal of sustaining communication through network hubs therefore maximizing information transfer and minimizing behavioral deficit.

In the long-term phase, a progressive decline of functional connectivity is observed in those cortical regions previously characterised by hyperconnectivity, thus suggesting that these two periods of disease may have differential effects on functional connectivity.

The presence of EXN and ATTN hypoconnectivity in long-COVID patients is consistent with our clinical findings showing that these patients present with loss of attention and altered performances in neuropsychological tests of executive, abstract reasoning and attention domains as well as brain fog and reduction in processing speed.

Taken together, results of univariate and multivariate approaches could support the hypothesis that neurological symptoms in long-COVID patients could mainly reflect a neural disorganization of EXN and ATTN, alone or together with a residual neuro-vascular unit dysregulation.