Hippocampal subfield abnormalities and biomarkers of pathologic brain changes: from acute infection to post-COVID syndrome, 2023, Díez-Cirarda et al.

[SNT Gatchaman]

Hippocampal subfield abnormalities and biomarkers of pathologic brain changes: from SARS-CoV-2 acute infection to post-COVID syndrome
Maria Díez-Cirarda; Miguel Yus-Fuertes; Rafael Sanchez-Sanchez; Javier J. Gonzalez-Rosa; Gabriel Gonzalez-Escamilla; Lidia Gil-Martínez; Cristina Delgado-Alonso; Maria Jose Gil-Moreno; Maria Valles-Salgado; Fatima Cano-Cano; Denise Ojeda-Hernandez; Natividad Gomez-Ruiz; Silvia Oliver-Mas; María Soledad Benito-Martín; Manuela Jorquera; Sarah de la Fuente; Carmen Polidura; Belén Selma-Calvo; Juan Arrazola; Jorge Matias-Guiu; Ulises Gomez-Pinedo; Jordi A. Matias-Guiu

Background
Cognitive deficits are among the main disabling symptoms in COVID-19 patients and post-COVID syndrome (PCS). Within brain regions, the hippocampus, a key region for cognition, has shown vulnerability to SARS-CoV-2 infection. Therefore, in vivo detailed evaluation of hippocampal changes in PCS patients, validated on post-mortem samples of COVID-19 patients at the acute phase, would shed light into the relationship between COVID-19 and cognition.

Methods
Hippocampal subfields volume, microstructure, and perfusion were evaluated in 84 PCS patients and compared to 33 controls. Associations with blood biomarkers, including glial fibrillary acidic protein (GFAP), myelin oligodendrocyte glycoprotein (MOG), eotaxin-1 (CCL11) and neurofilament light chain (NfL) were evaluated. Besides, biomarker immunodetection in seven hippocampal necropsies of patients at the acute phase were contrasted against eight controls.

Findings
In vivo analyses revealed that hippocampal grey matter atrophy is accompanied by altered microstructural integrity, hypoperfusion, and functional connectivity changes in PCS patients. Hippocampal structural and functional alterations were related to cognitive dysfunction, particularly attention and memory. GFAP, MOG, CCL11 and NfL biomarkers revealed alterations in PCS, and showed associations with hippocampal volume changes, in selective hippocampal subfields. Moreover, post mortem histology showed the presence of increased GFAP and CCL11 and reduced MOG concentrations in the hippocampus in post-mortem samples at the acute phase.

Interpretation
The current results evidenced that PCS patients with cognitive sequalae present brain alterations related to cognitive dysfunction, accompanied by a cascade of pathological alterations in blood biomarkers, indicating axonal damage, astrocyte alterations, neuronal injury, and myelin changes that are already present from the acute phase.

Link | PDF (Lancet: eBioMedicine)

 

[SNT Gatchaman]

PCS patients were recruited at mean of 11.08 ± 4.47 months after first symptoms, and had a mean of 50.89 ± 11.25 years old and 69% (58/84) were women.

PCS patients presented with lower volume in almost all subfields of the hippocampus as compared to HC, except for CA3 body and parasubiculum subfields.

Regarding possible effects of disease severity, hippocampal volume differences were more accentuated in hospitalized patients compared to non-hospitalized patients in most of the hippocampal subfields. However, hospitalized patients also showed increased volume in specific subfields, such as presubiculum and subiculum of the head and body of the hippocampus.

 

[SNT Gatchaman]

Regarding hippocampal perfusion, PCS patients showed lower perfusion in the hippocampus compared to HC (PCS = 28.94 ± 6.94; HC = 30.79 ± 7.73; F = 9.023; p < 0.001; η p 2 = 0.137). Reduced perfusion was related to memory performance, specifically to Rey Figure Recognition (r = 0.267; p = 0.016) and FCSRT Total Recall (r = 0.218; p = 0.050). Hospitalized patients compared to non-hospitalized patients showed lower hippocampal perfusion values (F = 5.413; p = 0.006; η p 2 = 0.118), and increased FICVF (F = 7.085; p = 0.001; η p 2 = 0.152) and ODI values (F = 12.176; p < 0.001; η p 2 = 0.236).

Regarding GFAP, PCS patients showed signficant, positive, and moderate correlation with whole hippocampal volume (r = 0.345; p = 0.010)

MOG showed significant, positive, and large correlation with whole hippocampal volume (r = 0.597; p < 0.001). [...] MOG revealed significant associations with almost all hippocampal volume subfields

 

[SNT Gatchaman]

Seven autopsies of patients diagnosed with COVID-19 (dead in acute phase), and eight donors considered as controls were analysed. Control patients had no history of neurological disease or with a cause of death unrelated to any neurological condition, including 4 women with an age range of 30–72 years and 4 men from 50 to 65 years of age. COVID-19 patients included 3 women with an age range of 22–33 years and 4 men from 62 to 73 years of age. All patients died due to complications of COVID-19 infection.

In general, perivascular infiltrates and an increase in microglial cells were observed in COVID-19 patients. An interesting histological finding is the apparent neuronal loss in the granular neurons of the dentate gyrus, observing the neuropil loosed and oedematous.

Regarding the GFAP expression in the hippocampus, we found in patients with SARS-CoV-2 infection a marked increase in the number of astrocytic cells, which also showed an increase in the expression of their cytoskeleton visualized with GFAP immunostaining

immunomarking for MOG (mainly in subiculum, CA1, alveus, fimbria) compared to controls [..] At the same time, COVID-19 patients presented with higher expression of CCL11 in neurons and dendrites,

 

[SNT Gatchaman]

FICVF = intracellular volume fraction
ODI = orientation dispersion index

Relates to the NODDI model
See —
NODDI in clinical research (2020, Journal of Neuroscience Methods, paywall)
NODDI: Practical in vivo neurite orientation dispersion and density imaging of the human brain (2012, NeuroImage, paywall)
Functional Consequences of Neurite Orientation Dispersion and Density in Humans across the Adult Lifespan (2015, Journal of Neuroscience)

The lower hippocampal volume in PCS was accompanied by GM microstructural alterations, specifically with increased FICVF and ODI values. ODI is a measure of dispersion of dendrites and axons. Usually FICVF is interpreted as “neurite density” and appears to be reduced in neurodegenerative diseases. However, in the present study, PCS patients showed higher FICVF compared to controls, which was more accentuated in hospitalized patients, and inversely correlated with cognition, suggesting that increased FICVF in PCS is related to greater cognitive decline.

A previous study suggested that SARS-CoV-2 infection may be linked to a vasoconstricting effect which triggers a reduced blood flow. In addition, a potential role of the glymphatic system and the interplay with perivascular spaces and choroid plexus in the homeostasis of fluid circulation and metabolic waste could be hypothesized to explain these findings.

A recent PET study with translocator protein total distribution volume (TSPO VT ) radiotracer, a marker of gliosis, revealed increased TSPO V T in PCS patients compared to controls, in several areas including the hippocampus.

On the other hand, MOG biomarker has been linked to myelination, and PCS patients showed increased MOG values compared to controls and large associations with hippocampal volume, showing that the higher the MOG values, the greater the hippocampal volume, and this relationship was signficant for all the hippocampal subfields. Moreover, higher MOG values were also related to higher white matter volume and lower FICVF. In this case, FICVF change might be understood as deterioration of the intracellular space volume, which may suggest neuroinflammation at this level.

 

[SNT Gatchaman]

The specific alterations suggest grey and white matter changes, including axonal damage, astrocyte alterations, neuronal injury, and myelin changes. All these changes appear to be present also in necropsies from acute COVID-19 patients after death, therefore, these alterations are present in the acute phase but also at longitudinal follow-up after 11 months.

These processes may be summarised in the following three main hypotheses.

acute damage, such as hypoxia or acute neuroinflammation

the presence of some activated mechanisms over time, especially neuroinflammatory. The presence of biomarker changes several months after the infection and the long-lasting nature of symptoms support this hypothesis. Persistent activation of the immunological system could induce blood-brain barrier disruption, neuroinflammation and brain damage

the possibility of unchaining neurodegenerative mechanisms

The fact that these patients are relatively young could suggest that is less probable the hypothesis of unmasked neurodegeneration as the main cause of cognitive deficits in post-COVID syndrome, and points towards an actual association between PCS and cognitive dysfunction by other mechanisms such as neuroinflammation.

 

[Hutan]

It's quite a full-on abstract, in terms of the impacts it is suggesting.

The healthy controls weren't allowed to have had a history of Covid-19, so it's harder to say for sure that the brain findings are related to the persisting cognitive issues.

I'm also a bit suspicious that the people who were hospitalised in the PCS group might be skewing the findings. That is, they had a more severe illness, and so their brains could look more like those of the people who died during acute COVID-19. There were 28 hospitalised patients (9 ventilated) and 56 non-hospitalised. There were only 57 patients providing blood samples, and it isn't clear what percentage of those had been hospitalised during acute covid-19.

The hospitalised people were a lot more likely to have diabetes, high blood pressure, dyslipidemia (the paper says they were similar in clinical symptoms, but they weren't). They were also older and there was a significantly higher percentage of men.

Hospitalized patients compared to non-hospitalized patients showed lower hippocampal perfusion values (F = 5.413; p = 0.006; ηp2 = 0.118), and increased FICVF (F = 7.085; p = 0.001; ηp2 = 0.152) and ODI values (F = 12.176; p < 0.001; ηp2 = 0.236).

Regarding possible effects of disease severity, hippocampal volume differences were more accentuated in hospitalized patients compared to non-hospitalized patients in most of the hippocampal subfields. However, hospitalized patients also showed increased volume in specific subfields, such as presubiculum and subiculum of the head and body of the hippocampus. Supplementary Fig. S3 shows significant volume differences between hospitalized and non-hospitalized patients (p < 0.05).

Also, hospitalized patients showed increased GFAP and NfL values compared to non-hospitalized patients (GFAP: F = 7.086; p = 0.002; ηp2 = 0.208; NfL: F = 4.090; p = 0.023; ηp2 = 0.141).

 

[rvallee]

brain alterations related to cognitive dysfunction, accompanied by a cascade of pathological alterations in blood biomarkers, indicating axonal damage, astrocyte alterations, neuronal injury, and myelin changes that are already present from the acute phase

I think that kids these days are calling this "functional". Just mild alterations of no significance, nothing that CBT can't fix with some gum and plasticity, or whatever.