A new study led by the U.S. Department of Defense involving researchers, famous neurodegenerative disease specialists and pathologists from the Uniformed Services University of the Health Sciences- Maryland, the Icahn School Of medicine At Mount Sinai-New York and Columbia University-New York have in a new study alarmingly found that COVID-19 infected individuals younger than 60 years are developing beta-amyloid deposits
The study findings were published on a preprint server by lancet and is currently being peer reviewed. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4003213
Cognitive dysfunction, sometimes described as “brain fog”, has become well recognized as a persistent symptom in a substantial fraction of patients who survive SARS-CoV-2 infection [1-3].
These are a heterogenous group of patients with a wide variety of comorbidities and there are undoubtably multiple pathophysiologic mechanisms responsible for their neurological symptoms (for review see Nalbandian et al. (2021) ).
In this report we describe the serendipitous observation of large numbers of focal β-amyloid deposits in the neocortex of autopsied COVID-19 patients. We also found similar deposits in the brains of non- COVID patients who had suffered significant hypoxia, suggesting that this response is hypoxia driven and not specific to a SARS-CoV-2 infection.
Convenience cohort of hospitalized COVID patients
To determine whether this histologic finding is common in patients who died from COVID-19 infection we examined the superior frontal cortex of brains of an additional ten young (< 60 y/o) COVID-19 patients. This was a convenience cohort – the only selection criterion was that they were young COVID- 19 patients who had been autopsied at NY Presbyterian Hospital/Columbia Irving Medical Center or at Mount Sinai Hospital, New York (see Table 1 for patient demographics. Several of these patients were recently described in ). All of them had thioflavin-negative β-amyloid immunoreactive, focal deposits histologically similar to those seen in the index patient (Figure 1b), giving us a small series in which 10 out of 10 patients had this finding. One of the sections contained rare tau+ neuropil threads in the cortex, otherwise, sections were tau-negative. Several of these patients’ brains revealed small infarcts, but the sections taken for amyloid stain did not show these.
Convenience cohorts of non-COVID patients
To determine whether this histologic finding is found only in patients who died from COVID-19 we examined the brains of five patients who died of Adult Respiratory Distress Syndrome (ARDS) in 2016- 2019, before the COVID pandemic. This was also a convenience cohort – the only selection criterion was that the tissue was readily available in the archival collection at Columbia (see Table 2 for patient demographics). All of them also had focal, thioflavin-negative, β-amyloid immunoreactive deposits in the frontal cortex, histologically similar to those seen the COVID-19 patients (Figure 2). As another control, we examined two surgical biopsies of the cerebral cortex of patients who were diagnosed with acute to subacute infarcts. Both of these revealed similar amyloid deposits to those present in the brains of patients with COVID-19 and ARDS (not shown).
In addition, because all of the autopsy patients, both mTBI patients and neurologically normal controls, in the DoD military TBI cohort had 4G8 β-amyloid immunohistochemical studies as a routine test in that protocol, those patients also represent a convenience cohort of relatively young patients that was used to see how common this histologic finding is in the absence of severe respiratory disease. These amyloid deposits were present in only 5/61 patients enrolled in the DoD cohort between January 1, 2020 and December 31, 2020 and of those five patients, only one was under the age of 55. The detailed
examination of the clinical histories of these unusual patients with this finding is in progress. But for the purpose of this study, the importance of that observation is that it documents that these amyloid deposits are rare in young patients and not a technical artifact present in all autopsy brains.
This report describes a relatively young (< 60 y/o) COVID patient without known clinical evidence of dementia who at autopsy had large numbers of thioflavin-negative, immunoreactive β-amyloid deposits in her neocortex. In a small convenience cohort, 10 out of 10 COVID additional patients of a similar age range who came to autopsy had this pathology. We deliberately examined the cortex of patients in this age group because they are far less likely to contain β-amyloid deposits than older patients.
Nevertheless, we would expect COVID-19 patients of any age to contain such deposits. Indeed, older patients do show these deposits, although it is difficult to distinguish them from age-related β-amyloid plaques (unpublished observations). In addition, we found that autopsies and biopsies of patients who had suffered from hypoxic brain damage also contained similar β-amyloid deposits.
There is a growing body of literature regarding cognitive problems in post-acute COVID patients (“brain fog”), as well as epidemiologic evidence suggesting that neurocognitive deficits are common in COVID survivors [2-4, 12, 13]. Furthermore, long-term cognitive impairment is common after ARDS  and the presence of these deposits in non-COVID brains of patients with ARDS shows that they are not specific to SARS-CoV-2 infections. Rather, it is likely that the deposits correlate with hypoxic damage, since our COVID-19 patients all sustained some degrees of hypoxia and the brains contained widespread hypoxic pathology . This idea is consistent with studies describing a HIF-1α mediated increase in β- amyloid production [15-17] as well as a hypoxia-induced reduction in β-amyloid degradation .
An important limitation of this study is that it is an autopsy-based study and therefore included only the most severely affected COVID patients. As tempting as it is to extrapolate these results to patients who recover from their COVID infection, that is not necessarily justified. Moreover, because this is not a
longitudinal study there is no way of knowing whether the β-amyloid deposits described here would have persisted had the patients survived or whether they are perhaps a transient phenomenon. The fact that these deposits are thioflavin-negative supports the latter possibility. These deposits may be amyloid plaque precursors that, because they have relatively little β-pleated sheet structure, are relatively labile. It will be important to determine how frequently these deposits occur in the brains of patients who recover from COVID-19 and then expire months or years later from other causes
This report suggests a potential pathophysiologic basis for those symptoms. More importantly, this hypothesis suggests that COVID encephalopathy may respond to treatment with anti-amyloid therapeutics.
Table 1: COVID Autopsies from Columbia & Mount Sinai cohort
|H/I acute; athero mild, arterio moderate||HTN, gout, cardiac arrest, cough for two weeks prior to death||57M||Sup Fr Ctx|
|H/I severe; intraparenchymal hemorrhage, SAH, metabolic encephalopathy||Autoimmune hepatitis; S/P liver transplant; ARDS; infections; coagulopathy; 3 weeks in hospital||38F||Sup Fr Ctx|
|H/I moderate; arterio moderate; metabolic encephalopathy||DM2 with DKA; ARDS; 2 month hospitalization||58M||Sup Fr Ctx|
|Infarctions, microscopic, multiple||History breast cancer 14 years prior to death; 1 ½ month hospitalization||50F||Sup Fr Ctx|
|Hemorrhagic infarct of the cerebellum; H/I acute; athero,artrio mild||DM2, sarcoid, CKD; ARDS; 4-5 month hospitalization with multiple problems||45M||Sup Fr Ctx|
|Subacute infarcts; H/I mild; arterio mild||MVA 10 years prior to death; weakness, seizures; COVID+ then to rehabilitation; readmitted 1 day with hematemesis to hospital||41M||Sup Fr Ctx|
|H/I acute, severe; athero severe, arterio moderate||HTN, cardiac arrest; < 1 day in hospital||48M||Sup Fr Ctx|
|H/I, mild||Hypoxia COVID pneumonia; 2 ½ weeks in hospital||37F||Sup Fr Ctx|
|SAH, acute; arterio, mild||HIV; HTN; hyperlipidemia, seizures; adrenal adenomas; septic shock; 4 weeks hospital||53M||Sup Fr Ctx|
|Intracranial hemorrhage, subacute and chronic; remote microinfarct; arterio, mild||HTN; CKD; morbid obesity; CHF; AF; CVA with residual left hemiparesis; asthma; COPD; aortic dissection; 4 weeks in hospital||52F||Sup Fr Ctx|
Table 2; Non-COVID ARDS Autopsies
|SAH; H/I subacute||ARDS, sepsis||62F||Sup Fr Ctx|
|Edema; H/I acute||ARDS||33F||Sup Fr Ctx|
|Microinfarcts striatum, H/I acute; athero/arterio||ARDS, treated sepsis||66F||Sup Fr Ctx|
|H/I mild;arterio||Acute arrest, >12 hours||57M||Sup Fr Ctx|
Abbreviations: H/I, hypoxia/ischemia; athero, atherosclerosis; arterio, arteriolosclerosis; HTN, hypertension; SAH, subarachnoid hemorrhage; Sup Fr Ctx, superior frontal cortex; ARDS, adult respiratory distress syndrome; DM2, Type 2 diabetes; DKA, diabetic ketoacidosis; CKD, chronic kidney disease; MVA, motor vehicle accident.