The infection with severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) can lead to a new disease called long-COVID or post-acute COVID-19 syndrome (PACS). Symptoms generally appear to improve over time, but in some individuals, they may persist for years. Long/post-COVID, evidently represents a heterogeneous nosological entity, despite similar or overlapping symptoms between patients, and clear diagnostic criteria are yet to be established. The neurologic manifestations of long-COVID, also known as “neuro-long COVID,” may be particularly debilitating and contribute to a significant proportion of the morbidity and disability. This study by authors from the United States aimed to characterize the age-related differences in neurological symptoms, neurological examination findings, self-rated quality of life, and cognitive performance in hospitalized and non-hospitalized COVID patients affected by neuro-long COVID. They hypothesized that older individuals could be more severely affected.
It seems that SARS-CoV-2 exploits various neuroinvasive strategies and pathways to enter the central nervous system (CNS), such as the infection of the nasal olfactory epithelium and axonal transport along the olfactory nerve, retrograde axonal transport, the invasion through the impairment of the blood-brain barrier, and using infected hematopoietic cells as “Trojan horses” (haematogenic pathway). A recent study has shown that the neurotoxin-like region of the SARS-CoV-2 interacts with nicotinic acetylcholine receptors (nAChRs), which have important physiological functions, including mediating the cholinergic excitatory neurotransmission, synchronization of neuronal activity, and regulation of essential physiological functions such as cognition, arousal, sleep, fatigue, anxiety, nutrition, central processing of pain, attention, and behavior (aggression, mood, and impulsivity). This study discovered that the target for the SARS-CoV-2 glycoprotein is the α7 nAChR, one of the common nAChRs in the CNS, linked to hyperactivity, aggression, and anxiety. Furthermore, the neurotoxin-like region of SARS-CoV-2 exerted an opposing, bimodal, and concentration-specific effect on the α7 nAChR: a high concentration of the neurotoxin-like region of SARS-CoV-2 significantly inhibited α7 nAChR and reduced acetylcholine potency, whereas low concentrations potentiated acetylcholine-induced currents. https://discovermednews.com/sars-cov-2-and-nicotinic-acetylcholine-receptors/
As neurodegeneration is one of the aging processes in which the CNS is engaged, numerous data demonstrated the participation of nicotinic acetylcholine receptors in aging and neurodegeneration. These processes affect two main CNS nicotinic acetylcholine receptor subtypes α7 and α4β2. It was suggested that the loss of these receptor subtypes during normal aging is one of the reasons for the cognitive impairments and the pathogenesis of age-related neurodegenerative diseases. (Utkin YN. Aging Affects Nicotinic Acetylcholine Receptors in Brain. Cent Nerv Syst Agents Med Chem. 2019: 19(2):119-124.)
About the study
This cross-sectional study enrolled 1,300 patients with a history of clinical manifestations of COVID-19 confirmed by SARS-CoV-2 reverse transcription polymerase chain reaction or rapid antigen test, and/or by subsequent positive SARS-CoV-2 total antibodies (before COVID-19 vaccinations) or anti- SARS-CoV-2 nucleocapsid antibodies (before or after COVID-19 vaccinations), and with persistent neurological symptoms lasting ≥6 weeks after onset of COVID-19.
Patients were categorized into the hospitalized neuro-long COVID group and the non-hospitalized neuro-long COVID group. All patients were evaluated by a neurologist, either in-person or by video-based telehealth visit. Parts of the neurologic examination (full cranial nerve exam, muscle strength, tone, reflexes, and sensation) were limited during telehealth visits, but full neurologic exams were performed during in-person visits.
Patients filled out questionnaires based on the patient-reported outcomes measurement information system (PROMIS), including cognitive functions, fatigue, sleep disturbance, anxiety, and depression. A more detailed assessment of cognitive functions was performed using the National Institute of Health (NIH) Toolbox (version 2.1) that evaluates processing speed (Pattern comparison processing speed test), attention (Flanker inhibitory control and attention test), executive functions (Dimensional change card-sorting test), and working memory (List-sorting working memory test).
Results
1,300 patients were divided into younger (18–44 years), middle-aged (45–64 years), and older (65+ years) groups. Younger and middle-aged individuals accounted for 71% of the hospitalized neuro-long COVID group and 91% of non-hospitalized neuro-long COVID patients. The mean age of the hospitalized neuro-long COVID patients was 55.6 years and of the non-hospitalized patients 46.2 years.
Age-related differences in the prevalence of comorbidities such as hypertension, dyslipidemia, and cancer were observed in both groups. Significant age-related differences in the prevalence of pre-existing autoimmune diseases, type 2 diabetes, other endocrine disorders, chronic kidney diseases, and cardiovascular and peripheral vascular diseases were found in the non-hospitalized neuro-long COVID patients only.
Age-related differences in manifestations of neuro-long COVID
Neurologic and non-neurologic symptoms were more prevalent in the younger individuals with neuro-long COVID. Age-related differences were found for headache, chest pain, and dysautonomia in both groups, for numbness/tingling, dysgeusia, anosmia, and depression/anxiety in the non-hospitalized patients with neuro-long COVID, and for blurred vision and insomnia in the hospitalized patients with neuro-long COVID. Lower prevalences of these symptoms were observed in the older individuals diagnosed with neuro-long COVID.
On the contrary, abnormal results of a neurological examination were more prevalent among older patients. Age-related differences were observed in gait disturbances in both groups, abnormal general neurological examination in hospitalized patients, and sensory and motor dysfunction in non-hospitalized patients. Higher prevalences of these findings were observed in the older group.
Quality of life assessment was based on the PROMIS questionnaire. Age-related differences in fatigue and sleep disturbance were found in the non-hospitalized patients with neuro-long COVID, reflecting lower self-rated quality of life in younger patients. There were no age-related differences in quality of life in the hospitalized patients.
NIH Toolbox assessment revealed that age-related differences in executive functions were borderline among hospitalized patients, whereas in the non-hospitalized patients with neuro-long COVID, age-related differences in executive function and working memory were significant. The worst performance was found in the younger group.
Conclusion
This study showed that younger and middle-aged patients diagnosed with neuro-long COVID were more affected than older patients, regardless of the severity of acute COVID-19 and their hospitalization status. Neurological symptoms were more prevalent in younger and middle-aged patients, and they reported lower quality of life in domains of fatigue and sleep disturbance than older patients with neuro-long COVID. Younger and middle-aged non-hospitalized patients with neuro-long COVID also had poorer cognitive performance and executive function than the older group. However, older neuro-long COVID patients had a higher prevalence of abnormal neurological examinations, likely due to pre-existing comorbidities.
Since the loss of α7 nAChR during normal aging is one of the reasons for the cognitive impairments, we could hypothesize that inhibition of α7 nAChR by a high concentration of the neurotoxin-like region of SARS-CoV-2 plays a role in the cognitive deterioration and a higher prevalence of neurological symptoms observed in younger and middle-aged patients with neuro-long COVID.
This article was published in Annals of Neurology.
Journal Reference
Choudhury NA, Mukherjee S, Singer T et al. Neurologic Manifestations of Long COVID Disproportionately Affect Young and Middle-Age Adults. ANN NEUROL 2024;00:1–15 (Open Access). https://doi.org/10.1002/ana.27128
