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

SNT Gatchaman · Jul 17, 2023

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 · Jul 17, 2023

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.
Click to expand...

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

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.
Click to expand...

SNT Gatchaman · Jul 17, 2023

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).
Click to expand...

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

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
Click to expand...

SNT Gatchaman · Jul 17, 2023

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.
Click to expand...

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.
Click to expand...

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
Click to expand...

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,
Click to expand...

SNT Gatchaman · Jul 17, 2023

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.
Click to expand...

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.
Click to expand...

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.
Click to expand...

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.
Click to expand...

SNT Gatchaman · Jul 17, 2023

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.
Click to expand...

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

acute damage, such as hypoxia or acute neuroinflammation
Click to expand...

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
Click to expand...

the possibility of unchaining neurodegenerative mechanisms
Click to expand...

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.
Click to expand...

Hutan · Jul 17, 2023

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).
Click to expand...

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).
Click to expand...

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).
Click to expand...

rvallee · Jul 17, 2023

The paper said: ↑

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
Click to expand...

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.

Log in or Sign up

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

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

Hutan Moderator Staff Member

rvallee Senior Member (Voting Rights)

Share This Page

Log in or Sign up

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

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

SNT Gatchaman Senior Member (Voting Rights)

Hutan Moderator Staff Member

rvallee Senior Member (Voting Rights)

Share This Page

Useful Searches