Detrimental effects of COVID-19 on ageing brains: Clinical, pathological, and psychosocial consequences

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COVID-19 has significantly affected the elderly population, particularly those with cognitive impairment, who frequently presented with acute behavioural changes (namely delirium) as a symptom of disease onset. To understand how, Dr Tino Emanuele Poloni and his colleagues at the Istituto Geriatrico Camillo Golgi, Abbiategrasso, Milan, Italy, studied inflammatory processes in the brain to verify the impact of SARS-CoV-2 on dementia and delirium. They found biological and psychosocial detrimental effects. They observed excessive innate immune response with severe brain inflammatory changes, especially in the brainstem. On the other hand, they noted the inability of elderly people affected by neurocognitive disorders to adapt to COVID-19 and lockdown, leading to depression and cognitive worsening. Nevertheless, they did not find neuropathological evidence for a direct SARS-CoV-2 brain invasion.

Throughout history populations have been scourged by infectious diseases. The most effective preventative measures throughout the centuries have been isolation (isolating the sick) and quarantine (stopping the movement of people who may spread the infection). In contemporary society we use these same proven techniques, as seen in the current pandemic. Italy was the first European country to be severely attacked by the global pandemic labelled COVID-19, a disease recognised as due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A shocking 27,955 Italians had succumbed to the disease by 1 May 2020, and it continues to be a devastating global burden despite the development of new vaccinations.

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COVID-19 symptoms and effects

The most common symptoms of COVID-19 are fever, cough, fatigue, and shortness of breath, but some go on to experience a severe inflammatory state and acute respiratory distress syndrome due to pneumonia, leading to lack of oxygen and multiple organ failure. Moderate to severe lowering of oxygen in the blood especially affects the kidney, heart, and central nervous system (CNS). Neurological phenomena have also been observed during the course of the disease, such as CNS symptoms (psychomotor retardation, dizziness, confusion, delirium, ataxia, encephalitis, stroke, seizures) and vegetative or peripheral manifestations (vomiting, hypotension, lack of respiratory drive, severe asthenia, myalgia, neuralgia, headache, olfactory, and gustatory dysfunction, Guillain-Barré syndrome).

“Neurological phenomena have also been observed after the acute phase of COVID-19.”

Delirium and dementia

In Italy, the median age of death through COVID-19 was 81; these older people were already at higher risk of developing delirium and dementia. Delirium, involving acute behavioural changes frequently called an acute confusional state, has been one of the presenting symptoms of COVID-19 in the elderly. Dr Tino Emanuele Poloni and his colleagues from the Istituto Geriatrico Camillo Golgi, Abbiategrasso, identified that delirium occurrence in elderly people with dementia may represent a prodromal phase – changes that occur prior to the classic symptoms of the disease. They found elderly people initially had symptoms of alterations in behaviour or alertness, up to 72 hours before the appearance of alterations of breathing and vegetative functions (eg., blood pressure), hypoxia and a generalised inflammatory state. This increases the spread of the virus in nursing homes, complicates diagnosis and care of COVID-19, and reduces the chance of survival, especially in people who also have dementia.

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The significantly higher risk of mortality associated with delirium thus deserves special attention, especially in those with severe lymphopenia, reduced lymphocytes, a crucial element of the immune system. Typically, delirium occurs alongside other neurocognitive disorders such as dementia but can be experienced in isolation triggered by trauma or medical interventions. Delirium can be either hypoactive (ideomotor slowdown, lethargy) or hyperactive (agitation, psychosis), indicating the possible involvement of different brain areas. It can also present as a mixture of the two, further indicating the involvement of different brain areas.

Neuropathology of elderly COVID-19 patients

Dr Poloni and his colleagues’ neuropathological investigations into elderly people with COVID-19 revealed increased inflammatory activation in the brain, probably due to a ‘cytokines’ storm. This is where the body’s innate immune system triggers a massive release of molecules called cytokines throughout the body including the brain. They are a normal part of the immune system, but an extreme cytokine outpouring can lead to organ failure and death. This large inflammatory activation induces amoeboid microglial cells (cells involved in the detection and destruction of bacteria and other harmful organisms), which form nodules. Dr Poloni and his colleagues found significant numbers of these nodules, most prominently in the brainstem and in the hippocampus of patients who were experiencing delirium.

The brainstem is involved in the regulation of alertness and vegetative states, and the hippocampus is a central hub in the limbic system, involved in memory, emotions, and behaviour. The nodules on the brainstem and hippocampus, the researchers hypothesised, probably represent the neuropathological basis of ‘COVID-19 encephalopathic syndrome’, the brain disorder caused by COVID-19.

Figure 1. One of the rare nodules containing some lymphocytes that are highlighted by brownish staining (B-lymphocyte specific antibodies: anti-CD20). (a) Very rare and small clusters of SARS-Cov-2 positive neurons, which were detected only in the lower brainstem (anti-SARS-CoV-2 nucleocapsid protein). (b) Hematoxylin & eosin staining reveals diffuse cortical oedema due to extreme hypoxia (cortical swelling with spongiosis and severe neuronal rarefaction). (c) The typical feature of a microglial nodule into the brainstem showing amoeboid cells emphasised by the brown colour (anti-CD68 antibody, specific for microglia). (d) A picture of neuronophagia is observable.

SARS-CoV-2 and brain damage

The role of SARS-CoV-2 in brain damage is still controversial, but Dr Poloni and colleagues’ data demonstrate that it induces a boosting of innate immunity and reduction in adaptive immunity in the brain. This is demonstrated through the large numbers of microglial nodules and the small number of lymphocytes the researchers found in the brain [Fig 1a].

They also found that COVID-19 viral inclusions, where proteins from the virus localise within the host cells, are exceedingly rare in the brain and they only appear in the lower brainstem [Fig 1b]. There was no evidence found of viral encephalitis (inflammation of the brain due to active viral replication). Moreover, the presence of any SARS-CoV-2 genome in the brain was minimal. The evidence of SARS-CoV-2 genetic material that was found in the brain probably came from the circulation of blood and was only detectable with an extremely sensitive methodological approach, confirming the lack of viral replication. Therefore, the virus was not found to be living and reproducing in the brain.

The most distinctive signature of COVID-19 in the brain is the prominent lack of oxygen leading to cortical oedema (brain swelling) [Fig 1c], and the microglial nodules in the brainstem [Fig 1d]. This COVID-specific phenomenon is probably related to the movement of viral fragments from the pharyngeal and respiratory tract through the cranial nerves activating innate immunity at their entry zones in the brainstem.

Profiles of the 204 subjects who participated in the study grouped based on their cognitive state. At the end of the lockdown, they showed different socio-behavioural, mood and lifestyle responses, similar in people without cognitive impairment (NOLD) or with mild cognitive impairment (mild-NCD), much worse in people with dementia.

Cortical microglial boosting

When comparing the frontal cortex, the front part of the brain, in people diagnosed with COVID-19 with matched controls, Dr Poloni and his team found that cortical microglial boosting (an increase in innate immune nodules on the brain) is not only related to COVID-19 but also to pre-existing neurodegeneration such as dementia. They found that microglial hyperactivation in the frontal cortex and hippocampus was clearly associated with the neurodegenerative load regardless of the SARS-CoV-2 infection. In those with both dementia and COVID-19 these nodules were mostly due to the pre-existing neurodegenerative condition, but worsened by the infection. Indeed, in people with COVID-19 complicated by hyperactive delirium, there was a larger number of microglia nodules in the hippocampus. This makes elderly people who are at higher risk for delirium and dementia more prone to neuroinflammation and COVID-19 neurological consequences.

The whole transcriptome (all the genetic messengers) sequencing in the frontal cortex of people diagnosed with COVID-19 shows the turning off of the hypoxia inducing factor (HIF) system (a system which regulates oxygen in cells) and the increase of microglial modulators (microglial controllers). These findings are consistent respectively with the extreme cortical hypoxia and the inflammatory response (amoeboid microglial cells nodules) observed.

“Those with cognitive deficits such as dementia struggled to understand the pandemic and had difficulties following lockdown policies.”

Lockdown and depression

COVID-19 has affected elderly people not only directly through viral invasion of the body but also through the effects of lockdown: currently the strongest form of quarantine in history. Elderly people with mild or no neurocognitive disorders showed a good tolerance to lockdown by maintaining physical and mental activities. For those with dementia, however, the situation was vastly different. They were not only more vulnerable to the infection initially but also were less able to adapt to the social changes. Elderly people with dementia experienced clinical levels of depression and other cognitive complaints.

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Those with cognitive deficits such as dementia struggled to understand the pandemic and had difficulties following lockdown policies. Adapting to the necessary lifestyle changes, particularly maintaining relationships remotely, was a significant problem. It precipitated increased depression especially when associated with sleep and physical health problems. Elderly people with dementia also stated that their memory and other symptoms of dementia deteriorated.

These long-term cognitive consequences are still emerging, but it appears COVID-19 may have accelerated neurodegeneration through cortical hypoxia and inflammation (leading to brain oedema and microglial nodules), and it has reduced functional capacity through isolation. These post COVID-19 consequences are generally described as long-COVID but, according to Dr Poloni’s recent findings, long-COVID does not imply a direct SARS-CoV-2 brain invasion.


Do your investigations suggest that those with delirium and dementia have these microglial nodules on the hippocampus but perhaps when a person recovers from delirium that the nodules disperse?

Microglia is an extremely dynamic entity and promptly responds to inflammatory and immunological stresses affecting the brain. Thus, microglial nodules are likely to regress once the inflammatory stimulus ceases and this pathological process is potentially reversible, at least partially. However, the intense inflammation seen in COVID-19 may have produced worsening of neurodegeneration with probable long-term consequences in patients with dementia. I frequently observe both cognitive and motor regression in these patients with worsening disability. The effects of isolation further worsen the clinical picture. Therefore, it is important to invest in rehabilitation interventions, as in many cases a recovery is possible.

 

References

  • Carlos, A. F., et al. (2021) Life during COVID-19 lockdown in Italy: the influence of cognitive state on psychosocial, behavioral and lifestyle profiles of older adults, Aging & Mental Health, DOI: 10.1080/13607863.2020.1870210
  • Gagliardi, S., et al. (2021) Detection of SARS-CoV-2 genome and whole transcriptome sequencing in Frontal Cortex of COVID-19 patients, Brain, Behavior, and Immunity (2021), DOI: doi.org/10.1016/j.bbi.2021.05.012
  • Poloni, T. E., et al. (2020) Prevalence and prognostic value of Delirium as the initial presentation of COVID-19 in the elderly with dementia: An Italian retrospective study. EClinicalMedicine. DOI: doi.org/10.1016/j.eclinm.2020.100490
  • Poloni, T.E., Medici, V., Moretti, M., et al. (2021) COVID-19-related neuropathology and microglial activation in elderly with and without dementia. Brain Pathology. 2021:00:e12997. DOI: doi.org/10.1111/bpa.12997
DOI
10.26904/RF-137-1587353291

Research Objectives

The medical and psychological effects of COVID-19 on the elderly.

Funding

This study was partially supported by ‘Fondo di Beneficenza’ Intesa Sanpaolo, Italy. Project code: B/2020/0045.

Collaborators

Valentina Medici, Arenn Faye Carlos, Matteo Moretti, Silvia Damiana Visonà, Alice Cirrincione, Annalisa Davin, Elena Rolandi, Stella Gagliardi, Marco Cairati, Chiara Cutaia, Danila Ferrari, Silvia Vitali, Arcangelo Ceretti, Mauro Colombo, Antonio Guaita & Mauro Ceroni.

Bio

Tino Emanuele Poloni is a physician, neurology specialist, and very keen on neuropathology. He is an experienced skier, and Gospel singer. He works as a consultant neurologist at the Golgi-Redaelli Rehabilitation Hospital and is the Chief of the Abbiategrasso Brain Bank at the Neuropathology Department of the Golgi-Cenci Foundation.

Tino Emanuele Poloni

Contact
Golgi Cenci Foundation, Corso San Martino 10 – 20081 Abbiategrasso, Milan, Italy.

E: e.poloni@golgicenci.it
T: +39 0294 66409
W: www.golgicenci.it
W: www.jove.com/institutions/EU-europe/IT-italy/29520-golgi-cenci-foundation

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