07 Apr 2021

Part 1 of a two-part story. Click here for Part 2.

As COVID-19 drove yet another conference online, it was also the topic of discussions there—held from the dull safety of researchers' home screens. At the 15th International Conference on Alzheimer's and Parkinson's Diseases, held virtually March 9–14, clinicians grappled with neurological symptoms they see in people with the disease, and they discussed what COVID complications could mean for people with preclinical dementia. Researchers pointed to activated microglia as the culprit behind COVID delirium. Trial investigators also described how they minimized lockdown disruptions and debated how to include people who had COVID in future trials (see Part 10 of this conference series).

Information continues to come in about what SARS-CoV-2 does to the brain. Previously, scientists reported that it could impair short- and long-term memory, increase brain-damage markers in the cerebrospinal fluid and blood, and, in severe cases, cause transient brain or vascular damage (Jan 2021 news). Genetic risk plays a role, such that people homozygous for ApoE4 are more likely to be infected with this new coronavirus and die from COVID-19 than noncarriers (Jan 2021 news). What else have researchers learned since then?

COVID Worsens Neurological Problems
On March 31st, scientists at the CDC's National Center for Health Statistics published U.S. mortality data for the year 2020 (Ahmad and Anderson, 2021). In addition to the 345,323 deaths from COVID-19 itself, there were 133,382 deaths attributable to Alzheimer's disease in 2020, compared to 121,499 deaths from AD in 2019, and 122,019 in 2018. At 9.7 percent, this represents a far larger year-on-year increase than in the years between 2015 and 2019. Among the country's 11 leading causes of death, only the “unintentional injury” category, which includes drug overdoses, rose as much as Alzheimer's in 2020 compared to the year before.

Amid this terrible toll, how do COVID-19 and Alzheimer's interact? It's not clear but at AD/PD, scientists reported that COVID-19 can cause serious neurological symptoms in some people. Why is that? Rocksy Situmeang, a neurologist at Siloam Hospitals Lippo Village, Tangerang, Indonesia, presented observations from her site. Her team collected medical records, laboratory tests, and brain scans of 22 people ages 26 to 98 who had COVID-19 with neurological symptoms and were referred to neurologists at the Siloam Hospitals Mampang, South Jakarta, from April to July 2020. Thirteen were women; the average age was 60. Eighteen had a history of health problems: six had hypertension; four had ischemic stroke or cancer, respectively; three, diabetes. Two each had Alzheimer's, Parkinson's, or sepsis. One person each had atrial fibrillation, pulmonary embolism, a heart attack, myocarditis, a ruptured aneurysm, or a broken leg.

After contracting SARS-CoV-2, half the participants complained of altered mental status, six of weakness on one side of the body. Five had tremors, four were in pain. Blood tests revealed that 11 participants had increased neutrophil-to-lymphocyte ratios, a marker of inflammation; 10 were anemic; nine had a high white-blood-cell count, another marker of infection or inflammation; six had low blood sodium, and four had low potassium levels. At Situmeang's clinic, six participants were newly diagnosed with ischemic stroke, three with electrolyte imbalances that affect brain function, three with AD, three with parkinsonism, and two with metastatic brain tumors. Where available, CT scans confirmed the strokes and tumors, and revealed chronic brain bleeds in one. Three participants had normal brain CT scans.

"I was not surprised that stroke and ischemic complications were the most frequent neurological issues," Dietmar Thal, KU Leuven, Belgium, told Alzforum. "Low blood oxygen seen in some COVID patients, coupled with existing small-vessel disease or cerebral amyloid angiopathy, may easily affect susceptible brain areas." Roger Nitsch, Neurimmune, Switzerland, agreed. "Virus-induced small-blood-vessel damage on top of CAA can have detrimental effects on blood supply in the brain," he told Alzforum.

Situmeang believes that neurological symptoms appear because inflammation caused by the virus aggravates pre-existing conditions. For example, people with dementia were 2.8 times more likely to catch COVID-19, 2.6 times more likely to become severely ill, and 2.6 times more likely to die, she recently reported (Hariyanto et al., 2021). 

If people with dementia fare worse, could the virus affect the trajectory of the disease in people with presymptomatic Alzheimer's? "People with tau and amyloid pathology may experience worse symptoms due to inflammation triggered by COVID-19," Thal said, and Nitsch agreed, noting that brain damage, such as that caused by a stroke, is known to trigger rapid decline in people with mild or moderate dementia. "I would not be surprised if the same happens in COVID-19 patients, especially those with existing small vascular disease and hyperinflammation," he said.

Situmeang noticed that people who suffered a stroke while sick with COVID-19 had increased blood levels of D-dimer, a clotting marker, suggesting that they may be at risk of multi-infarct dementia caused by many small strokes. "We do not know how widespread small-vessel blood clots are in the brains of COVID-19 patients, but it is plausible if there are lots of clots," Johannes Attems, Newcastle University, U.K., said.

Delirium, Dementia—Are Microglia the Instigators?
Tino Emanuele Poloni, Golgi Cenci Foundation, Milan, Italy, and colleagues reported other serious consequences of the virus in people with dementia. As did other groups, they identified that delirium precedes better-known COVID-19 symptoms, such as trouble breathing. Some patients were only delirious, never developing the telltale COVID symptoms. People who were delirious deteriorated faster and were more likely to die than those without delirium (Poloni et al., 2020; commentary by Wang, 2020; Kennedy et al., 2020). In older people hospitalized with COVID-19, those with dementia were three times as likely to be delirious as cognitively normal people (Harb et al., 2021). "People with dementia can suddenly become delirious, lethargic, and have rapidly worsening memory, which caregivers may just attribute to their dementia, not COVID-19," James Galvin, University of Miami, said at AD/PD.

What could be causing the delirium? Poloni searched for answers in brain tissue. At AD/PD, he described differences in autopsy samples from older people with or without COVID-19; some had also had dementia. The scientists obtained brain tissue from six non-COVID cases in the Abbiategrasso Brain Bank (Poloni et al., 2020) and from nine COVID-19 autopsies completed between April and June 2020 at the Institute of Legal Medicine, University of Pavia.

"Autopsies on COVID-19 patients have been discouraged due to the risk of spreading disease, but these cases were selected for forensic autopsies ordered by the state prosecutor," Poloni told Alzforum. COVID safety protocols included immediately fixing the brain in formalin and freezing only a small sample of fresh tissue for biochemical analysis. The researchers looked at the brain stem, cerebellum, frontal cortex, temporal and parieto-occipital cortices, and hippocampus. Four COVID-19 cases and three non-COVID cases had moderate to severe AD pathology.

The COVID-19 brains were swollen and inflamed, with CD68-positive activated microglia and GFAP-positive reactive astrocytes flooding the basal ganglia and hippocampus. Ameboid microglia were seen in the pons, frontal cortex, midbrain, medulla oblongata, and olfactory bulb, as well. The pathologists spotted abnormal, tuft-like capillaries in the pons and T- and B-cells surrounding blood vessels.

This matches what others have found. In a larger series, autopsies of 184 COVID-19 brains showed activated microglia in 43 percent, acute hypoxic changes in 30 percent, and dead tissue around blood clots in 21 percent of cases (Lou et al., 2021). "Poloni's autopsy findings and Situmeang's report of ischemic complications in COVID-19 cases fit well with one another and with other studies," Thal noted.

Poloni also found evidence linking activated microglia to delirium. He saw more of these cells in the hippocampi of the five cases with delirium before they died than the four cases without. Tau neuropathology showed a trend whereby people with more tangles were more likely to have become delirious early on in their bouts of COVID. Those with few or no tangles tended not to have been delirious.

One case stood out. Brain tissue from a young man who had died in an accident turned out to be positive for SARS-CoV-2. To Poloni's surprise, his pons and frontal lobe lit up with active microglia, even though the man had had no COVID symptoms and an otherwise healthy brain.

Many questions remain. "There is so little COVID-19 autopsy data that it is not always clear if the findings are related to the disease or to pre-existing conditions," Thal explained. Ronald Petersen, Mayo Clinic, Rochester, Minnesota, added, "A key unresolved point is whether COVID's neurological effects are due to direct viral infection of the brain, blood-brain barrier breakdown, or secondary effects of systemic inflammation."

In his series, Poloni found traces of the virus in lower brainstem tissue from only one COVID-19 case, leading him to doubt that it was actively replicating in the central nervous system. Likewise, other researchers found the virus and its spike protein in the lower brainstems and cranial nerves from 21 of 40 people who died of COVID-19 (Matschke et al., 2020). This hints that the virus or viral antigens may pass from the respiratory tract through the lower cranial nerves and inflame the lower brainstem. Definitive evidence for direct viral invasion of the brain is lacking (Boldrini et al., 2021). 

Meddling Microglia
COVID delirium is the latest addition to the plethora of problems caused by activated microglia. In response to cell damage or infection, the inflammasome protein complex assembles in microglia, triggering them to crank out cytokines. This complex has been linked to AD by prompting tangle and plaque formation (Dec 2017 news; Nov 2019 news). 

Could activated microglia in the COVID-19 brain be using the inflammasome to cause damage? Michael Heneka, German Center for Neurodegenerative Diseases (DZNE), Bonn, did not discuss COVID-19 directly at AD/PD, but thinks this is entirely possible. "If COVID-19 aggravates microglia, maybe it can trigger damage via the inflammasome, such as exacerbating tau pathology over time," Thal agreed.

Heneka mentioned two studies that will look at the immune system and lingering cognitive effects of COVID-19 in people with "long-COVID." The NIH-funded U.S. study, based at the University of Massachusetts Medical School, Worcester, will follow long-COVID patients for 18 months, testing their cognition and collecting MRI scans and blood samples. A similar study at the University of Bonn will track long-haulers for 12 months. "The U.S. study has not begun enrolling yet, and the German study is working its way through ethics approval," Heneka told Alzforum. In February, the NIH announced a major initiative to study long-COVID. It will provide $1.15 billion in funding over the next four years.— Chelsea Weidman Burke

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References

News Citations

1. Clinical Trials in COVID Era: How To Keep Moving Forward 7 Apr 2021
2. How Does COVID-19 Affect the Brain? 29 Jan 2021
3. APOE Tied to Increased Susceptibility to SARS-CoV-2 29 Jan 2021
4. Do Microglia Spread Aβ Plaques? 21 Dec 2017
5. Microglia Inflammasome Stokes Tau Phosphorylation, Tangles 22 Nov 2019

Paper Citations

1. Ahmad FB, Anderson RN. The Leading Causes of Death in the US for 2020. JAMA. 2021 Mar 31; PubMed.
2. Hariyanto TI, Putri C, Arisa J, Situmeang RF, Kurniawan A. Dementia and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review and meta-analysis. Arch Gerontol Geriatr. 2021 Mar-Apr;93:104299. Epub 2020 Nov 19 PubMed.
3. Poloni TE, Carlos AF, Cairati M, Cutaia C, Medici V, Marelli E, Ferrari D, Galli A, Bognetti P, Davin A, Cirrincione A, Ceretti A, Cereda C, Ceroni M, Tronconi L, Vitali S, Guaita A. Prevalence and prognostic value of Delirium as the initial presentation of COVID-19 in the elderly with dementia: An Italian retrospective study. EClinicalMedicine. 2020 Sep;26:100490. Epub 2020 Jul 30 PubMed.
4. Wang H. Delirium: A suggestive sign of COVID-19 in dementia. EClinicalMedicine. 2020 Sep;26:100524. Epub 2020 Aug 24 PubMed.
5. Kennedy M, Helfand BK, Gou RY, Gartaganis SL, Webb M, Moccia JM, Bruursema SN, Dokic B, McCulloch B, Ring H, Margolin JD, Zhang E, Anderson R, Babine RL, Hshieh T, Wong AH, Taylor RA, Davenport K, Teresi B, Fong TG, Inouye SK. Delirium in Older Patients With COVID-19 Presenting to the Emergency Department. JAMA Netw Open. 2020 Nov 2;3(11):e2029540. PubMed.
6. Harb AA, Chen R, Chase HS, Natarajan K, Noble JM. Clinical Features and Outcomes of Patients with Dementia Compared to an Aging Cohort Hospitalized During the Initial New York City COVID-19 Wave. J Alzheimers Dis. 2021;81(2):679-690. PubMed.
7. Poloni TE, Medici V, Carlos AF, Davin A, Ceretti A, Mangieri M, Cassini P, Vaccaro R, Zaccaria D, Abbondanza S, Bordoni M, Fantini V, Fogato E, Cereda C, Ceroni M, Guaita A. Abbiategrasso Brain Bank Protocol for Collecting, Processing and Characterizing Aging Brains. J Vis Exp. 2020 Jun 3;(160) PubMed.
8. Lou JJ, Movassaghi M, Gordy D, Olson MG, Zhang T, Khurana MS, Chen Z, Perez-Rosendahl M, Thammachantha S, Singer EJ, Magaki SD, Vinters HV, Yong WH. Neuropathology of COVID-19 (neuro-COVID): clinicopathological update. Free Neuropathol. 2021 Jan 18;2 PubMed.
9. Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, Mushumba H, Fitzek A, Allweiss L, Dandri M, Dottermusch M, Heinemann A, Pfefferle S, Schwabenland M, Sumner Magruder D, Bonn S, Prinz M, Gerloff C, Püschel K, Krasemann S, Aepfelbacher M, Glatzel M. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020 Nov;19(11):919-929. Epub 2020 Oct 5 PubMed.
10. Boldrini M, Canoll PD, Klein RS. How COVID-19 Affects the Brain. JAMA Psychiatry. 2021 Mar 26; PubMed.

External Citations

1. major initiative

Further Reading

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