Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5221_Библиотеки_им_академика_М_И_Перельмана.pdf
Infectious Disease and Neurocognition
common cause of delirium is infection. Importantly, delirium increases the risk of
dementia (Fong & Inouye, 2022). In clinical practice, delirium is also referred to as
altered mental status or encephalopathy.
Common infections
As noted, a comprehensive review of all possible infectious diseases possibly associated with dementia is beyond the scope of a single chapter. However, common infectious diseases and their association with dementia are reviewed here.
Human immunodeficiency virus and AIDS
HIV- associated neurocognitive disorder (HAND) is well characterized in the research literature (Antinori et al., 2007). HAND is associated with cognitive impairment and increased risk of dementia (i.e., HIV- associated dementia) (Bobrow
et al., 2020). CNS involvement of HIV and AIDS is less common now than in
the past because of the availability of combination antiretroviral therapy (cART)
(Crum- Cianone et al., 2013). With nonadherence or lack of availability of these
therapies, HIV can negatively impact CNS function. Even with cART treatment,
HIV remains a risk factor for mild to moderate declines in cognition (Bobrow
et al., 2020). Prior to the development of cART in the 1990s, 50 percent of individuals with HIV infection developed dementia (Heaton et al., 2011). HAND can
cause white matter damage in the brain (HIV- associated leukoencephalopathy),
with multiple neurological and psychiatric symptoms (Cliord et al., 2017).
Individuals with HAND oen have decits in executive function, which negatively impact their ability to encode and retrieve information. us, memory difculties are typically dysexecutive in nature. Neuropsychiatric features are also
common, including apathy and depression (Pope et al., 2020). Studies demonstrate that this may be related to injury to, or white matter disconnection from,
subcortical structures, including the basal ganglia and nucleus accumbens
(Cliord et al., 2017). Lastly, individuals with CNS involvement from HIV may
experience parkinsonism, particularly older individuals (Tisch & Brew, 2009).
While cART drastically improved survival rates of individuals with HIV, it also
means that many individuals with this condition must deal with persistent cognitive diculties over several years, with increased odds of cognitive impairment being related to advanced age and comorbid infections, such as hepatitis
C, syphilis, or cytomegalovirus (McArthur et al., 2010). A meta- analysis by Deng
et al. (2021) demonstrated that individuals with HIV are more likely to have
neurocognitive impairment relative to their same- age healthy counterparts, including performing signicantly worse in areas of executive function, processing
speed, verbal skills, and recall.
Dementia Risk Associated Infectious Disease 309
Hepatitis C
Hepatitis C is most associated with chronic liver disease. Without treatment, many
individuals go on to develop cirrhosis and even hepatocellular carcinoma. With
further damage to the liver, individuals with hepatitis C can develop portal hypertension and subsequent encephalopathy (Bostan & Mahmood, 2010). Hepatitis C
can also be associated with an increased risk of neuropathy and stroke (Acharya &
Pacheco, 2008). As noted above, hepatitis C is oen comorbid with HIV, with individuals having both conditions oen showing worse outcomes and more involvement with CNS function. While most studies have focused on how hepatitis C
negatively impacts the liver and subsequent CNS function, it is important to note
that hepatitis can also replicate in peripheral blood and inltrate macrophages and
microglia within the CNS (Forton et al., 2006). e main mechanism of action for
hepatitis C is that it leads to neuroinammation, increased oxidative stress, and a
direct impact on the CNS. Hepatitis C is associated with an increased risk of mild
cognitive impairment and dementia (Hilsabeck et al., 2002).
Neurosyphilis
Syphilis is caused by the bacterium Treponema pallidum, which may involve the CNS
at any point during the infection process. Neurosyphilis is sometimes referred to as
general paresis or dementia paralytica (Jay et al., 2016). Untreated neurosyphilis can
result in meningitis and meningovascular syphilis, which can damage vessels and
cause strokes. General paresis includes personality changes, disorientation, hostility,
and cognitive decline. Lastly, late- stage neurosyphilis can be associated with tabes
dorsalis, in which the infection damages portions of the spinal cord and peripheral
nerves. As a result of damage to the dorsal column, there are multiple sensory and
perceptual changes, with symptoms including pain and neuropathy, and reduced coordination. ere may also be incontinence of bowel and bladder due to damage to
the autonomic nervous system portions of the spinal cord. Neurosyphilis is associated with personality changes, depression, pseudobulbar aect, apathy, and mania.
Along with cognitive changes, individuals may experience disorientation, memory
loss, or dementia (Jay et al., 2016; Mehrabian et al., 2012).
Herpes simplex encephalitis
HSV- 1 and HSV- 2 can directly impact the CNS. Herpes simplex encephalitis
commonly occurs with HIV. Early symptom presentation includes fever, seizure,
and cognitive complaints (Jay et al., 2016). Unfortunately, this virus can also result in severe liver damage. As noted above, HSV can result in meningitis. HSV
has a predilection for orbital frontal and medial temporal lobes; damage to these
Infectious Disease and Neurocognition
regions oen impacts social function, inhibition, limbic function, and memory
(Utley et al., 1997). e transmission of infectious diseases can occur directly or
indirectly. As it pertains to HSV, there can be direct neurotoxicity in which the
virus replicates within neurons, resulting in necrosis, inammation, and cognitive consequences (Hokkanen & Launes, 2000). With the indirect pathway,
HSV also results in chronic inammation, and this prolonged inammation and
subsequent immune activation will damage neurons. ere is also vascular inammation, with subsequent damage to endothelial cells and reduced integrity
of the blood– brain barrier (Jay et al., 2016). A 2015 meta- analysis of over 3000
cases explored the association between HSV and Alzheimer’s disease. is study
showed that reinfection of HSV- 1 is associated with an increased risk of developing Alzheimer’s disease longitudinally (hazard ratio: 1.9). A population- based
study of dementia risk found that those with HSV had a hazard ratio of 2.56,
indicating a signicantly increased risk of dementia. Additionally, the study demonstrated that among those with HSV infection who then subsequently received
anti- herpetic medication, there was a reduced risk of dementia, with a hazard
ratio of 0.092 (Tzeng et al., 2018).
Prion diseases
Prion diseases, while rare, are fatal and result in rapid development of dementia and
subsequent death, typically in less than 1 year. ese protein- based conditions result in innumerable vacuoles throughout the CNS, giving CNS tissue a spongiform
appearance. As such, they are oen referred to as spongiform encephalopathies
(Takada & Geschwind, 2016). e most common form of prion disease in humans
is Creutzfeldt– Jakob disease, but others include Gertsmann– Straussler– Scheinker
syndrome, kuru, and fatal familial insomnia. Creutzfeldt– Jakob disease etiology
may be familial, acquired, or sporadic. In familial cases, there is a normal cellular
precursor for the prion protein, and a pathological process is initiated by mutation,
causing the proliferation of the diseased protein. Acquired cases are thought to be
related to exposure (such as exposure to infected cerebrospinal uid) to the prion
disease that then propagates within the CNS. Sporadic cases occur when the natural
cellular precursor for the protein spontaneously converts to the pathological form
(Takada & Geschwind, 2016).
Toxoplasmosis
A parasitic agent known as Toxoplasma gondii can occur as an opportunistic infec-
tion among immunocompromised individuals. It is a common parasite, present in
25– 30 percent of the world population (Daher et al., 2021). It may result in acute
illness but may also be dormant. Additionally, it can also infect immunocompetent
Dementia Risk Associated Infectious Disease 311
people and result in neurobehavioral and cognitive changes, even in the absence
of symptoms during acute infection. ere are elevated risks among older adults
due to their immunosenescence (Gale et al., 2020). Although the eects were marginal, two separate meta- analyses published in the same year suggest there may
be an increased risk of Alzheimer’s disease associated with toxoplasmosis (Bayani
et al., 2019; Chegeni et al., 2019). Additionally, a more recent study using a large
population data approach (n = 800) demonstrated that toxoplasmosis was associated with a hazard ratio of 2.5– 2.8 for an increased risk of dementia. A post hoc
analysis of this data also demonstrated that other factors increasing the risk of
dementia aer infection include male sex, more health comorbidities, and old age
(Yang et al., 2021).
Severe acute respiratory syndrome coronavirus 2
(SARS- CoV- 2, Covid- 19)
To date, the research on the association between Covid- 19 and dementia risk is in its
infancy, and studies are ongoing. However, the epidemiology literature on Covid- 19
demonstrates that older adults and individuals with multiple medical comorbidities
are at the highest risk of infection. Additionally, relative to older adults without dementia, those already diagnosed with dementia are at an increased risk of acquiring
Covid- 19, developing severe symptoms, and dying from the illness (Bianchetti et al.,
2020; Hariyanto et al., 2021). ose with pre- existing dementia are also at risk of accelerated cognitive decline following Covid- 19 infection compared to individuals
with dementia who do not contract the disease (Dubey et al., 2023). Multiple studies
have demonstrated the cognitive consequences of Covid- 19 illness, particularly
among older adults with severe forms of the illness (Liu et al., 2022). is appears to
be because Covid- 19 might be neuroinvasive. e mechanism of action is thought
to be related to the angiotensin- converting enzyme 2 (ACE2), which is the main
receptor of the virus. e Covid- 19 spike protein binds to ACE2, and transmembrane enzymes allow the virus to enter host cells and proliferate. ACE2 is commonly
found in the lungs, endothelial cells, and other parts of the body. Additionally, ACE2
is found in several areas of the brain, which suggests the virus can directly impact
the CNS.
Although most studies on Covid- 19 and dementia to date have been small, there
is converging evidence that the virus increases the risk of dementia (Achar & Ghosh,
2020; Fu et al., 2022; Verkhratsky et al., 2020). In fact, in a retrospective study of
over 6 million older adults, L. Wang et al. (2022) demonstrated that Covid- 19 significantly increased the risk of a new diagnosis of Alzheimer’s disease within a year of
infection (hazard ratio: 1.69, 95 percent condent interval: 1.53– 1.72). Additionally,
the risk of dementia aer Covid- 19 is likely related to pre- existing factors, such as
age, frailty, and medical comorbidities, and not all individuals with the illness will
develop long- term cognitive sequelae (Goncalves et al., 2023).
Infectious Disease and Neurocognition
Conclusion
In summary, with the increasing age of the global population and with natural
immunosenescence and common comorbidities in aging, infectious diseases are
common in older adults. Such illnesses can directly impact the CNS, or indirectly increase inammation systemically and negatively impact the CNS and neuropsychological function. ere is overwhelming evidence that a broad range of infectious
diseases can increase the risk of dementia, including even common conditions like
inuenza. Importantly, most of the epidemiology research literature on this topic
points out that most of the illnesses studied are preventable (e.g., contraception to
reduce the risk of sexually transmitted infections and vaccinations to reduce the
population risk of easily transmissible illnesses like Covid- 19 and inuenza). is
is supported by evidence that the use of antiviral medication reduces the risk of dementia (Chen et al., 2017; Tzeng et al., 2018). As such, public health measures to
reduce infection in older adults will likely be important to reduce population incidence rates of dementia.
References
ACHAR, A. & GHOSH, C. 2020. COVID- 19- associated neurological disorders: e potential route of
CNS invasion and blood- brain barrier relevance. Cells, 9, 2360.
ACHARYA, J. N. & PACHECO, V. H. 2008. Neurologic complications of hepatitis C. Neurologist, 14,
151– 156.
ALMEIDA, O. P. & LAUTENSCHLAGER, N. T. 2005. Dementia associated with infectious diseases.
Int Psychogeriatr, 17, S65– S77.
ANTINORI, A., ARENDT, G., BECKER, J. T., BREW, B. J., BYRD, D. A., CHERNER, M., CLIFFORD,
D. B., CINQUE, P., EPSTEIN, L. G., GOODKIN, K., GISSLEN, M., GRANT, I., HEATON, R.
K., JOSEPH, J., MARDER, K., MARRA, C. M., MCARTHUR, J. C., NUNN, M., PRICE, R. W.,
PULLIAM, L., ROBERTSON, K. R., SACKTOR, N., VALCOUR, V. & WOJNA, V. E. 2007. Updated
research nosology for HIV- associated neurocognitive disorders. Neurology, 69, 1789– 1799.
BAYANI, M., RIAHI, S. M., BAZRAFSHAN, N., GAMBLE, H. R. & ROSTAMI, A. 2019. infection and
risk of Parkinson and Alzheimer diseases: A systematic review and meta- analysis on observational
studies. Act a Tro p, 196, 165– 171.
BEYDOUN, M. A., BEYDOUN, H. A., WEISS, J., HOSSAIN, S., EL- HAJJ, Z. W. & ZONDERMAN,
A. B. 2021. Periodontal pathogens, and their interactive association with incident all- cause and
Alzheimer’s disease dementia in a large national survey. Mol Psychiatry, 26, 6038– 6053.
BIANCHETTI, A., ROZZINI, R., GUERINI, F., BOFFELLI, S., RANIERI, P., MINELLI, G.,
BIANCHETTI, L. & TRABUCCHI, M. 2020. Clinical presentation of COVID19 in dementia pa-
tients. J Nutr Health Aging, 24, 560– 562.
BLUMENFELD, H. 2010. Neuroanatomy rough Clinical Cases, 2. Sinauer Associates.
BOBROW, K., XIA, F., HOANG, T. D., VALCOUR, V. & YAFFE, K. 2020. HIV and risk of dementia in
older veterans: Epidemiology/ risk and protective factors in MCI and dementia. Alzheimers Dement,
16, e041515.
BOHN, B., LUTSEY, P. L., MISIALEK, J. R., WALKER, K. A., BROWN, C. H., HUGHES, T. M.,
ISHIGAMI, J., MATSUSHITA, K. & DEMMER, R. T. 2023. Incidence of dementia following hos-
pitalization with infection among adults in the atherosclerosis risk in Communities (ARIC) Study
Cohort. JAMA Network Open, 6, e2250126.
Dementia Risk Associated Infectious Disease 313
BOSTAN, N. & MAHMOOD, T. 2010. An overview about hepatitis C: A devastating virus. Crit Rev
Microbiol, 36, 91– 133.
BURT, T. D., AGAN, B. K., MARCONI, V. C., HE, W., KULKARNI, H., MOLD, J. E., CAVROIS, M.,
HUANG, Y., MAHLEY, R. W., DOLAN, M. J., MCCUNE, J. M. & AHUJA, S. K. 2008. Apolipoprotein
(apo) E4 enhances HIV- 1 cell entry in vitro, and the APOE epsilon4/ epsilon4 genotype accelerates
HIV disease progression. Proc Natl Acad Sci U S A, 105, 8718– 8723.
CAMPOS, E. M. N., RODRIGUES, L. D., OLIVEIRA, L. F. & SANTOS, J. C. C. D. 2021. Dementia
and cognitive impairment in adults as sequels of HSV- 1- related encephalitis: A review. Dement
Neuropsychol, 15, 164– 172.
CENTERS FOR DISEASE CONTROL AND PREVENTION. 2020. 10 Leading Causes of Death for Ages
65+ , United States [Online]. Center for Disease Control and Prevention. Available: https:// wisq ars.
cdc.gov/ data/ lcd/ drill- down- age?ageLa bel= 65%2B [Accessed December 1, 2023].
CHEGENI, T. N., SARVI, S., MOOSAZADEH, M., SHARIF, M., AGHAYAN, S. A., AMOUEI,
A., HOSSEININEJAD, Z. & DARYANI, A. 2019. Is Toxoplasma gondii a potential risk factor for
Alzheimer’s disease? A systematic review and meta- analysis. Microb Pathog, 137, 103751.
CHEN, V. C.- H., WU, S.- I., HUANG, K.- Y., YANG, Y.- H., KUO, T.- Y., LIANG, H.- Y., HUANG, K.- L. &
GOSSOP, M. 2017. Herpes zoster and dementia: A nationwide population- based cohort study. J Clin
Psychiatry, 79, 8164.
CLIFFORD, K. M., SAMBOJU, V., COBIGO, Y., MILANINI, B., MARX, G. A., HELLMUTH, J.
M., ROSEN, H. J., KRAMER, J. H., ALLEN, I. E. & VALCOUR, V. G. 2017. Progressive brain atrophy despite persistent viral suppression in HIV over age 60. J Acquir Immune Dec Syndr, 76,
289– 297.
CRUM- CIANFLONE, N. F., MOORE, D. J., LETENDRE, S., POEHLMAN ROEDIGER, M., EBERLY,
L., WEINTROB, A., GANESAN, A., JOHNSON, E., DEL ROSARIO, R., AGAN, B. K. & HALE, B. R.
2013. Low prevalence of neurocognitive impairment in early diagnosed and managed HIV- infected
persons. Neurology, 80, 371– 379.
DAHER, D., SHAGHLIL, A., SOBH, E., HAMIE, M., HASSAN, M. E., MOUMNEH, M. B., ITANI,
S., EL HAJJ, R., TAWK, L., EL SABBAN, M. & EL HAJJ, H. 2021. Comprehensive overview of
Toxoplasma gondii- induced and associated diseases. Pathogens, 10, 1351.
DE COCK, A. M., STRENS, D., VAN OSTA, P. & STANDAERT, B. 2022. Infections and hospital bed-
days among aging adults: A ve- year retrospective study in a Belgian general hospital. Front Med
Te ch n ol , 4, 912469.
DE VLIEGER, L., VANDENBROUCKE, R. E. & VAN HOECKE, L. 2022. Recent insights into viral in-
fections as a trigger and accelerator in Alzheimer’s disease. Drug Discov Today, 27, 103340.
DENG, L. J., ZHANG, X. Z. X., GAO, Y. X., TURNER, D., QIAN, F., LU, H., VERMUND, S. H., ZHANG,
Y. & QIAN, H. Z. 2021. Association of HIV infection and cognitive impairment in older adults: A
meta- analysis. Ageing Res Rev, 68, 101310.
DOUROS, A., SANTELLA, C., DELL’ANIELLO, S., AZOULAY, L., RENOUX, C., SUISSA, S. &
BRASSARD, P. 2021. Infectious disease burden and the risk of Alzheimer’s disease: A populationbased study. J Alzheimers Dis, 81, 329– 338.
DUBEY, S., DAS, S., GHOSH, R., DUBEY, M. J., CHAKRABORTY, A. P., ROY, D., DAS, G., DUTTA, A.,
SANTRA, A., SENGUPTA, S. & BENITO- LEÓN, J. 2023. e eects of SARS- CoV- 2 infection on
the cognitive functioning of patients with pre- existing dementia. J Alzheimers Dis Rep, 7, 119– 128.
DUGGAN, M. R., PENG, Z. S., AN, Y., TRIOLO, M. H. K., SHAFER, A. T., DAVATZIKOS, C., ERUS,
G., KARIKKINETH, A., LEWIS, A., MOGHEKAR, A. & WALKER, K. A. 2022. Herpes viruses in
the Baltimore Longitudinal Study of Aging associations with brain volumes, cognitive performance,
and plasma biomarkers. Neurology, 99, E2014– E2024.
DUNN, N., MULLEE, M., PERRY, V. H. & HOLMES, C. 2005. Association between dementia and in-
fectious disease— Evidence from a case- control study. Alzheimer Dis Associated Disord, 19, 91– 94.
ERICKSON, M. A. & BANKS, W. A. 2019. Age- associated changes in the immune system and blood-
brain barrier functions. Int J Mol Sci, 20, 1632.
FANI, L., WOLTERS, F. J., IKRAM, M. K., BRUNO, M. J., HOFMAN, A., KOUDSTAAL, P. J., MURAD,
S. D. & IKRAM, M. A. 2018. Helicobacter pylori and the risk of dementia: A population- based study.
Alzheimers Dement, 14, 1377– 1382.
Infectious Disease and Neurocognition
FARMEN, K., TOFIÑO- VIAN, M. & IOVINO, F. 2021. Neuronal damage and neuroinammation, a
bridge between bacterial meningitis and neurodegenerative diseases. Front Cell Neurosci, 15, 680858.
FONG, T. G. & INOUYE, S. K. 2022. e inter- relationship between delirium and dementia: e im-
portance of delirium prevention. Nat Rev Neurol, 18, 579– 596.
FORTON, D. M., TAYLOR- ROBINSON, S. D. & THOMAS, H. C. 2006. Central nervous system
changes in hepatitis C virus infection. Eur J Gastroenterol Hepatol, 18, 333– 338.
FU, Y. W., XU, H. S. & LIU, S. J. 2022. COVID- 19 and neurodegenerative diseases. Eur Rev Med
Pharmacol Sci, 26, 4535– 4544.
GALE, S. D., ERICKSON, L. D., THACKER, E. L., MITCHELL, E. L., BROWN, B. L. & HEDGES, D.
W. 2020. Toxoplasma gondii seropositivity and serointensity and cognitive function in adults. PLoS
Negl Trop Dis, 14, e0008733.
GAVAZZI, G. & KRAUSE, K. H. 2002. Ageing and infection. Lancet Infect Dis, 2, 659– 666.
GONCALVES, N. G., ALIBERTI, M. J. R., BERTOLA, L., AVELINO- SILVA, T., DIAS, M. B.,
APOLINARIO, D., BUSATTO, G., FORLENZA, O., NITRINI, R., BRUCKI, S. M. D., BRUNONI,
A. R., VIDAL, K. S. M., JACOB- FILHO, W., SUEMOTO, C. K. & CO- FRAIL STUDY GROUP FOR
THE COVID HCFMUSP STUDY GROUP. 2023. Dissipating the fog: Cognitive trajectories and risk
factors 1 year aer COVID- 19 hospitalization. Alzheimers Dement, 19, 3771– 3782.
HARIYANTO, T. I., PUTRI, C., ARISA, J., SITUMEANG, R. F. V. & KURNIAWAN, A. 2021. Dementia
and outcomes from coronavirus disease 2019 (COVID- 19) pneumonia: A systematic review and
meta- analysis. Arch Gerontol Geriatr, 93, 104299.
HEATON, R. K., FRANKLIN, D. R., ELLIS, R. J., MCCUTCHAN, J. A., LETENDRE, S. L., LEBLANC,
S., CORKRAN, S. H., DUARTE, N. A., CLIFFORD, D. B., WOODS, S. P., COLLIER, A. C., MARRA,
C. M., MORGELLO, S., MINDT, M. R., TAYLOR, M. J., MARCOTTE, T. D., ATKINSON, J. H.,
WOLFSON, T., GELMAN, B. B., MCARTHUR, J. C., SIMPSON, D. M., ABRAMSON, I., GAMST,
A., FENNEMA- NOTESTINE, C., JERNIGAN, T. L., WONG, J., GRANT, I., CHARTER GROUP &
HNRC GROUP. 2011. HIV- associated neurocognitive disorders before and during the era of com-
bination antiretroviral therapy: Dierences in rates, nature, and predictors. J Neurovirol, 17, 3– 16.
HILSABECK, R. C., PERRY, W. & HASSANEIN, T. I. 2002. Neuropsychological impairment in patients
with chronic hepatitis C. Hepatology, 35, 440– 446.
HOKKANEN, L. & LAUNES, J. 1997. Cognitive recovery instead of decline aer acute encephalitis: A
prospective follow up study. J Neurol Neurosurg Psychiatry, 63, 222– 227.
HOKKANEN, L. & LAUNES, J. 2000. Cognitive outcome in acute sporadic encephalitis. Neuropsychol
Re v, 10, 151– 167.
JAY, C. A., HO, E. L. & HALPERIN, J. 2016. Infectious causes of dementia. In: GESCHWIND, M. D.
& RACINE BELKOURA, C. (Eds.), Non‐Alzheimer’s and Atypical Dementia. Chichester: Wiley, pp.
170– 185.
JHA, S. & PATEL, R. 2004. Some observations on the spectrum of dementia. Neurol India, 52, 213– 214.
JOHNSON, T. P., LARMAN, H. B., LEE, M. H., WHITEHEAD, S. S., KOWALAK, J., TORO, C., LAU,
C. C., KIM, J., JOHNSON, K. R., REOMA, L. B., FAUSTIN, A., PARDO, C. A., KOTTAPALLI,
S., HOWARD, J., MONACO, D., WEISFELD- ADAMS, J., BLACKSTONE, C., GALETTA, S.,
SNUDERL, M., GAHL, W. A., KISTER, I. & NATH, A. 2019. Chronic dengue virus panencephalitis
in a patient with progressive dementia with extrapyramidal features. Ann Neurol, 86, 695– 703.
KUO, C. L., PILLING, L. C., ATKINS, J. L., MASOLI, J. A. H., DELGADO, J., KUCHEL, G. A. &
MELZER, D. 2020. APOE e4 genotype predicts severe COVID- 19 in the UK Biobank community
cohort. J Gerontol Series A Biol Sci Med Sci, 75, 2231– 2232.
LEVINE, K. S., LEONARD, H. L., BLAUWENDRAAT, C., IWAKI, H., JOHNSON, N., BANDRES-
CIGA, S., FERRUCCI, L., FAGHRI, F., SINGLETON, A. B. & NALLS, M. A. 2023. Virus exposure
and neurodegenerative disease risk across national biobanks. Neuron, 111, 1086– 1093.e2.
LIU, Y. H., CHEN, Y., WANG, Q. H., WANG, L. R., JIANG, L., YANG, Y., CHEN, X., LI, Y., CEN, Y.,
XU, C., ZHU, J., LI, W., WANG, Y. R., ZHANG, L. L., LIU, J., XU, Z. Q. & WANG, Y. J. 2022. One- year
trajectory of cognitive changes in older survivors of COVID- 19 in Wuhan, China: A longitudinal
cohort study. JAMA Neurol, 79, 509– 517.
LOVHEIM, H., GILTHORPE, J., ADOLFSSON, R., NILSSON, L. G. & ELGH, F. 2015a. Reactivated
herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement, 11, 593– 599.
Dementia Risk Associated Infectious Disease 315
LOVHEIM, H., GILTHORPE, J., JOHANSSON, A., ERIKSSON, S., HALLMANS, G. & ELGH, F.
2015b. Herpes simplex infection and the risk of Alzheimer’s disease: A nested case- control study.
Alzheimers Dement, 11, 587– 592.
MCARTHUR, J. C., STEINER, J., SACKTOR, N. & NATH, A. 2010. Human immunodeciency virus-
associated neurocognitive disorders: Mind the gap. Ann Neurol, 67, 699– 714.
MEHRABIAN, S., RAYCHEVA, M., TRAYKOVA, M., STANKOVA, T., PENEV, L., GRIGOROVA, O.
& TRAYKOV, L. 2012. Neurosyphilis with dementia and bilateral hippocampal atrophy on brain
magnetic resonance imaging. BMC Neurol, 12, 96.
MOUTON, C. P., BAZALDUA, O. V., PIERCE, B. & ESPINO, D. V. 2001. Common infections in older
adults. Am Fam Physician, 63, 257– 268.
NELSON, R. E., HYNN, D., JEZEK, A. & SAMORE, M. H. 2022. Mortality, length of stay, and health-
care costs associated with multidrug- resistant bacterial infections among elderly hospitalized patients in the United States. Clin Infect Dis, 74, 1070– 1080.
OU, Y. N., ZHU, J. X., HOU, X. H., SHEN, X. N., XU, W., DONG, Q., TAN, L. & YU, J. T. 2020.
Associations of infectious agents with Alzheimer’s disease: A systematic review and meta- analysis. J
Alzheimers Dis, 75, 299– 309.
POPE, C. N., MONTOYA, J. L., VASQUEZ, E., PÉREZ- SANTIAGO, J., ELLIS, R., MCCUTCHAN, J.
A., JESTE, D. V., MOORE, D. J. & MARQUINE, M. J. 2020. Association of HIV serostatus and metabolic syndrome with neurobehavioral disturbances. J Neurovirol, 26, 888– 898.
ROTSTEIN, A. & LEVINE, S. Z. 2021. Childhood infectious diseases and old age cognitive functioning: A
nationally representative sample of community- dwelling older adults. Int Psychogeriatr, 33, 75– 82.
TAKADA, L. T. & GESCHWIND, M. D. 2016. Prion diseases and rapidly progressive dementias.
In: GESCHWIND, M. D. & RACINE BELKOURA, C. (Eds.), Non‐Alzheimer’s and Atypical
Dementia. Chichester: Wiley, pp. 103– 122.
TISCH, S. & BREW, B. 2009. Parkinsonism in HIV- infected patients on highly active antiretroviral
therapy. Neurology, 73, 401– 403.
TZENG, N. S., CHUNG, C. H., LIN, F. H., CHIANG, C. P., YEH, C. B., HUANG, S. Y., LU, R. B., CHANG,
H. A., KAO, Y. C., YEH, H. W., CHIANG, W. S., CHOU, Y. C., TSAO, C. H., WU, Y. F. & CHIEN, W. C.
2018. Anti- herpetic medications and reduced risk of dementia in patients with herpes simplex virus
infections— A nationwide, population- based cohort study in Taiwan. Neurotherapeutics, 15, 417– 429.
UTLEY, T. F., OGDEN, J. A., GIBB, A., MCGRATH, N. & ANDERSON, N. E. 1997. e long- term
neuropsychological outcome of herpes simplex encephalitis in a series of unselected survivors.
Neuropsychiatry Neuropsychol Behav Neurol, 10, 180– 189.
VARMA, A. & GAUR, K. J. 2002. e clinical spectrum of neurocysticercosis in the Uttaranchal region.
J Assoc Physicians India, 50, 1398– 400.
VERKHRATSKY, A., LI, Q., MELINO, S., MELINO, G. & SHI, Y. 2020. Can COVID- 19 pandemic
boost the epidemic of neurodegenerative diseases? Biol Direct, 15, 1– 8.
WANG, L., DAVIS, P. B., VOLKOW, N. D., BERGER, N. A., KAELBER, D. C. & XU, R. 2022. Association
of COVID- 19 with new- onset Alzheimer’s disease. J Alzheimers Dis, 89, 411– 414.
WANG, X., JIANG, D., LI, T., ZHANG, X., WANG, R., GAO, S., YANG, F., WANG, Y., TIAN, Q. & XIE,
C. 2022. Association between microbiological risk factors and neurodegenerative disorders: An umbrella review of systematic reviews and meta- analyses. Front Psychiatry, 13, 991085.
WARREN- GASH, C., FORBES, H. J., WILLIAMSON, E., BREUER, J., HAYWARD, A. C.,
MAVRODARIS, A., RIDHA, B. H., ROSSOR, M. N., THOMAS, S. L. & SMEETH, L. 2019. Human
herpesvirus infections and dementia or mild cognitive impairment: A systematic review and metaanalysis. Sci Rep, 9, 4743.
YANG, H. Y., CHIEN, W. C., CHUNG, C. H., SU, R. Y., LAI, C. Y., YANG, C. C. & TZENG, N. S. 2021.
Risk of dementia in patients with toxoplasmosis: A nationwide, population- based cohort study in
Taiwan. Parasit Vectors, 14, 435.
YOSHIKAWA, T. T. 2000. Epidemiology and unique aspects of aging and infectious diseases. Clin Infect
Dis, 30, 931– 933.
20
Multiple Sclerosis
Nicky Dunn and Anna Fogdell- Hahn
Introduction to multiple sclerosis and infectious diseases
Multiple sclerosis (MS) is considered an autoimmune disease, where the immune
system destroys the brain’s white matter, the myelin surrounding the axons, and impairs neuronal signaling. Symptoms vary depending on the location of the lesions
but commonly include motor and sensory disabilities, cognitive decline, and debilitating fatigue. Histopathologically, myelin staining of MS brains shows characteristic sharp- edged plaques in the central nervous system (CNS), where axonal myelin
insulation is missing. What activates the immune system and directs it to specically
destroy the myelin produced by oligodendrocytes in MS remains unknown. Both
anti- myelin T and B cells are found in MS patients, and treatments targeting these
cells are currently used to successfully reduce the symptoms (Atteld et al., 2022). It is
generally agreed that the disease is triggered by environmental factors in genetically
susceptible individuals (Olsson et al., 2016). e strongest genetical risk factor is the
human leukocyte antigen (HLA), and both an HLA class II haplotype (DRB1*15:01)
increasing the risk and an HLA class I protective allele (HLA- A*02:01) decreasing
the risk have been identied and independently veried in several studies (Brynedal
et al., 2007; Fogdell- Hahn et al., 2000; Sawcer et al., 2011). Several environmental
factors are associated with an increased risk of MS, like smoking, shi work, and vitamin D deciency (Olsson et al., 2016). However, infections remain the most viable
hypothesis for explaining the molecular and cellular immunological events that lead
to this debilitating chronic neurological disease.
Epidemiological data support infections as a plausible triggering factor for MS.
e geographical distribution of MS is strikingly uneven, with higher rates of cases
toward the poles compared to regions closer to the equator. Data from migration
studies suggest environmental factors are essential (Gale & Martyn, 1995). ese
studies show that moving to a high- risk country before adolescence results in a
higher risk of developing MS, indicating that exposure to a potential triggering environmental factor is likely required during childhood. Additionally, more extensive
studies now show that long- term residence in high- risk areas also seems to increase
the risk (Pugliatti & Ferri, 2020; Rotstein et al., 2019). Clusters of outbreaks have
also been reported, including in the Faroe Islands, where MS was rst detected when
Nicky Dunn and Anna Fogdell- Hahn, Multiple Sclerosis In:
DOI: 10.1093/ oso/ 9780192870414.003.0021
Multiple Sclerosis 317
soldiers arrived during World War II (Kurtzke & Heltberg, 2001). However, no specic agent was identied, and studies among these families of MS patients have challenged this example (Binzer et al., 2010).
Of infectious agents reported to be associated with MS, viruses are the most
prevalent. e list is extensive; however, Epstein– Barr virus (EBV) and human herpesvirus (HHV)- 6A and HHV- 6B are among some of the strongest and interesting
candidates. When considering potential viral candidates as an etiological agent
for MS, they likely need to be ubiquitous, highly prevalent in the general population, and associated with a broad spectrum of symptoms ranging from asymptomatic to severe CNS diseases in permissive individuals (Kakalacheva et al., 2011;
Leibovitch & Jacobson, 2018). Many viruses fulll these criteria, although the concept violates the rst of Koch’s postulates that the agent should not be found in
asymptomatic healthy individuals. However, we need a broader concept for plausible viral etiologies in MS. Koch’s postulates are too simplistic when considering
ubiquitous viral infections that have successfully established themselves in the
human population. Most common viruses cause relatively minor symptoms or
asymptomatic infections in the majority of the population and severe illness in the
minority. Furthermore, it is unlikely that a single agent will explain all cases of MS,
and MS should instead be considered a syndrome potentially caused by several
dierent mechanisms leading to the self- destruction of myelin. However, stepwise
deduction and identication of causative agents in subgroups are also valuable and
will eventually reduce the disease burden and lead us to more specic treatments
of the subgroups.
Potential mechanisms by which viruses might induce MS and other autoimmune
diseases are still unknown but have mainly been claimed to be through molecular
mimicry, bystander activation, or epitope spreading (Sanderson et al., 2017). In this
chapter, we are not going to explain these hypotheses, which have already been reviewed in detail elsewhere (Fujinami et al., 2006; Mentis et al., 2017; Sospedra &
Martin, 2005), but present the incorporation theory, as an alternative mechanism
underpinning viral triggering of MS.
Viral infections in the central nervous system
Several viral infections are known to cause diseases of the CNS, both in human and
animal models. Herpes simplex viruses (HSV)- 1 and HSV- 2 infection can cause
acute encephalitis or meningitis, whereas chronic sequelae from measles infection
can cause postinfectious encephalomyelitis or subacute sclerosing panencephalitis.
ese are severe, life- threatening illnesses that are distinctly dierent from MS;
however, they share the similarity of having HLA associations (Kachuri et al.,
2020) and have oligoclonal immunoglobulin (Ig)- G/ IgM bands in cerebrospinal
uid (Vaheri et al., 1982), one of the diagnostic tools used for MS (Olsson et al.,
1984). Oligoclonal bands are generally considered to be directed against viruses in