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Infectious Disease and Neurocognition
100.0%
20 30 40 50 60 70 80 90
12.9%
9.8%
11.0%
9.3%
10.9%
13.0%
12.1%
11.3%
9.7%
Elbers JM, 2007
Zhang R, 2016
Lahat E, 1999
He
Weight
Events per 100
Stud
Events per 100
100.0%
Y
Zhang R, 2016
Wa
Schleede L, 2012
Elbers JM, 2007
Chen
K
Lahat E, 1999
Woźniak
Random eects model
Random eects model
Quality =
Quality = P
He
He
He
Residual heterogeneity: I2 = 65%, p < 0.01
Random eects model
Study
Schleede L, 2012 18
Yoshinori I, 1998
Chen T, 2018
Kumar R, 2018
Woźniakowska-Gesicka T, 1996
Ward KN, 2011
Random eects model 217 50.7 [39.2; 62.2]
terogeneity: I2 = 63%, τ2 = 0.3199, p < 0.01
Events Events 95%-CI
Total
32
10
16
17
24
10
15
7
23
13
36
10
28
8
24
14
19
observations
56.2
62.5
70.8
66.7
30.4
36.1
35.7
33.3
73.7
[37.7; 73.6]
[35.4; 84.8]
[48.9; 87.4]
[38.4; 88.2]
[13.2; 52.9]
[20.8; 53.8]
[18.6; 55.9]
[15.6; 55.3]
[48.8; 90.9]
Figure 2.3 Forest plot of general prevalence of neurological sequelae. CI, confidence interval.
Source: Rocha, N. D., De Moura, S. K., Da Silva, G. A. B., Mattiello, R., & Sato, D. K. 2023. Neurological sequelae
aer encephalitis associated with herpes simplex virus in children: Systematic review and meta- analysis. BMC
Infect Dis, 23, 55. https:// doi.org/ 10.1186/ s12 879- 023- 08007- 3. https:// crea tive comm ons.org/ licen ses/ by/ 4.0/
y Events Events 95%-CI Weight
Fair
T, 2018
umar R, 2018
owska-Gesicka T, 1996
terogeneity: I2 = 51%, τ2 = 0.2049, p = 0.07
oor
oshinori I, 1998
rd KN, 2011
terogeneity: I2 = 80%, τ2 = 0.7349, p < 0.01
terogeneity: I2 = 63%, τ2 = 0.3199, p < 0.01
Total
32
18
16
10
15
10
23
7
28
10
24
8
138
24
17
36
13
19
14
79
observations
20 30 40 50 60 70 80 90
56.2
[37.7; 73.6]
62.5
[35.4; 84.8]
66.7
[38.4; 88.2]
30.4
[13.2; 52.9]
35.7
[18.6; 55.9]
33.3
[15.6; 55.3]
46.3 [34.2; 58.9] 66.2%
70.8 [48.9; 87.4] 11.0%
36.1
[20.8; 53.8]
73.7
[48.8; 90.9]
60.0 [33.5; 81.7] 33.8%
50.7217 [39.2; 62.2]
12.9%
9.8%
9.3%
10.9%
12.1%
11.3%
13.0%
9.7%
Figure 2.4 Forest plot of general prevalence of neurological sequelae according to the quality
of the studies. CI, confidence interval.
Source: Rocha, N. D., De Moura, S. K., Da Silva, G. A. B., Mattiello, R., & Sato, D. K. 2023. Neurological sequelae
aer encephalitis associated with herpes simplex virus in children: Systematic review and meta- analysis. BMC
Infect Dis, 23, 55. https:// doi.org/ 10.1186/ s12 879- 023- 08007- 3. https:// crea tive comm ons.org/ licen ses/ by/ 4.0/
acuity, eye movement disorders), (4) mental disabilities (e.g., global development
delay, memory loss, cognitive dysfunction, executive dysfunction), and (5) others
(e.g., areexia, hyperreexia, sensory disturbances). In total, nine studies were included in the analysis, which included 217 children with HSV infection. Overall,
the prevalence estimate for neurological complications was 50.7 percent (95 percent
CI: 39.2– 62.2) (Figure 2.3).
Good- quality studies had a lower prevalence estimate compared to poor- quality
studies (Figure 2.4).
Herpes Simplex Viruses 29
Events per 100
Schleede L, 2012
100.0%
Elbers JM, 2007
Residual heterogeneity: I2 = 51% p = 0.04
Study Events Events 95%-CI Weight
Classification = Developed
Yoshinori I, 1998
Lahat E, 1999
Ward KN, 2011
Random eects model
Heterogeneity: I
Classification = Developing
Chen T, 2018
Kumar R, 2018
Zhang R, 2016
Woźniakowska-Gesicka T, 1996
Random eects model
Heterogeneity: I2 = 45%, τ2 = 0.1570, p = 0.14
Random eects model
Heterogeneity: I2 = 63%, τ2 = 0.3199, p < 0.01
2
= 55%, τ2 = 0.2358, p = 0.06
Total
18
10
17 24
10
14
119
10
7
13
8
32
16
28
19
15
23
36
24
98
observations
20 30 40 50 60 70 80 90
56.2
[37.7; 73.6]
62.5
[35.4; 84.8]
70.8
[48.9; 87.4] 11.0%
35.7
[18.6; 55.9]
73.7
[48.8; 90.9]
59.1 [44.8; 72.0] 55.4%
66.7
[38.4; 88.2]
30.4
[13.2; 52.9]
36.1
[20.8; 53.8]
33.3
[15.6; 55.3]
39.6 [26.9; 53.9] 44.6%
50.7217 [39.2; 62.2]
12.9%
9.8%
12.1%
9.7%
9.3%
10.9%
13.0%
11.3%
Figure 2.5 Forest plot of general prevalence of neurological sequelae according to the Human
Development Index of the countries. CI, confidence interval.
Source: Rocha, N. D., De Moura, S. K., Da Silva, G. A. B., Mattiello, R., & Sato, D. K. 2023. Neurological sequelae
aer encephalitis associated with herpes simplex virus in children: Systematic review and meta- analysis. BMC
Infect Dis, 23, 55. https:// doi.org/ 10.1186/ s12 879- 023- 08007- 3. https:// crea tive comm ons.org/ licen ses/ by/ 4.0/
In addition, studies from developed countries had higher prevalence compared
to studies from developing countries (Figure 2.5). e most common complication was mental disability, with a prevalence of 42.1 percent (95 percent CI: 30–
55.2) (Figure 2.6) (Rocha et al., 2023).
Psychological conditions
A large cohort study from the Netherlands aimed to link childhood life events and
the subsequent development of psychiatric disorders (Jonker et al., 2017). ere were
1084 adolescents with a mean age of 19 years (54.3 percent female) included in the
study. Life events during childhood were assessed at ages 12, 14, 16, and 19 years. e
activation of the immune system was assessed by the levels of immunoglobulin G
(IgG) HSV- 1. Psychological conditions were diagnosed at age 19 years based on the
World Health Organization Composite International Diagnostic Interview Version
3.0. Statistical analysis showed that HSV- 1 was not linked to any mood disorder
(odds ratio (OR): 1.06, 95 percent CI: 0.55– 2.02); however, anxiety was more likely
(OR: 1.21, 95 percent CI: 0.64– 2.30) but the association did not reach statistical signicance. e analysis was adjusted for sex, ethnicity, socioeconomic status, lifetime
diagnosis, body mass index, nicotine use, and alcohol use. Overall, these ndings
suggested that HSV- 1 was not linked with the development of anxiety or mood disorders (Jonker et al., 2017).
Infectious Disease and Neurocognition
Study
Weight
Events per 100
Schleede L, 2012
Schleede L, 2012
T
T
T
T
Schleede L, 2012
T
Schleede L, 2012
Schleede L, 2012
2.2%
4.3%
4.3%
3.6%
4.2%
3.6%
5.2%
27.5%
5.7%
3.1%
4.8%
2.1%
4.5%
2.1%
5.8%
28.2%
5.3%
4.0%
5.2%
2.2%
4.0%
6.2%
3.4%
4.9%
3.9%
5.8%
32.6%
5.5%
100.0%
5.5%
Wa
Elbers JM, 2007
Chen
K
Lahat E, 1999
Woźniak
Wa
Wa
Elbers JM, 2007
Chen
K
Lahat E, 1999
Woźniak
Random eects mode
He
Random eects mode
Random eects mode
He
Wa
Elbers JM, 2007
Chen
K
Lahat E, 1999
Woźniak
Random eects mode
Random eects mode
He
He
He
Random eects mode
He
Residual heterogeneity:
= 53%, p < 0.01
Figure 2.6 Forest plot of prevalence by type of disability. CI, confidence interval.
Source: Rocha, N. D., De Moura, S. K., Da Silva, G. A. B., Mattiello, R., & Sato, D. K. 2023. Neurological sequelae
aer encephalitis associated with herpes simplex virus in children: Systematic review and meta- analysis. BMC
Infect Dis. 23, 55. https:// doi.org/ 10.1186/ s12 879- 023- 08007- 3. https:// crea tive comm ons.org/ licen ses/ by/ 4.0/
Adult population
Neurocognitive deficits
A recent study from Sweden assessed the relationship between HSV- 1 and cognitive
outcomes based on interactions with the apolipoprotein E epsilon 4 allele (APOE ɛ4)
(Weidung et al., 2023). e prospective population- based study consisted of 849 individuals aged 75– 80 years who were assessed via the Mini- Mental State Examination
(MMSE), trail- making test (TMT) A and B, and the 7- minute screening test (7MS).
e results indicate that anti- HSV- 1 IgG seropositivity was linked with a worse performance on all the tests (i.e., MMSE, TMT-
ype = Seizure
T, 2018
umar R, 2018
owska-Gesicka T, 1996
rd KN, 2011
terogeneity: I2 = 65%, τ2 = 0.6373, p < 0.01
ype = Motor disabilities
T, 2018
umar R, 2018
owska-Gesicka T, 1996
rd KN, 2011
terogeneity: I2 = 38%, τ2 = 0.1561, p = 0.14
ype = Visual impairments
rd KN, 2011
terogeneity: I2 = 0%, τ2 = 0, p = 0.39
ype = Mental disabilities
T, 2018
umar R, 2018
owska-Gesicka T, 1996
rd KN, 2011
terogeneity: I2 = 55%, τ2 = 0.2697, p = 0.04
ype = Others
terogeneity: not applicable
terogeneity: I2 = 64%, τ2 = 0.4616, p < 0.01
l
l
l
l
l
l
2
I
Events Events 95%-CI
Total
351
137
4
25
5
9
4
19
3
12
7
40
153
3515
132
6
25
1
9
5
19
1
12
16
40
153
351
403
75
358
134
15
25
3
9
10
19
8
12
14
40
153
10 35
35
569
observations
20 40 60 80
2.9 [0.1; 14.9]
53.8 [25.1; 80.8]
16.0 [4.5; 36.1]
55.6 [21.2; 86.3]
21.1 [6.1; 45.6]
25.0
17.5 [7.3; 32.8]
24.2
42.9 [26.3; 60.6]
15.4 [1.9; 45.4]
24.0 [9.4; 45.1]
11.1 [0.3; 48.2]
26.3 [9.1; 51.2]
8.3
40.0 [24.9; 56.7]
28.9 [19.8; 40.1]
2.9 [0.1; 14.9]
7.5 [1.6; 20.4]
5.9 [2.2; 14.6]
22.9 [10.4; 40.1]
30.8 [9.1; 61.4]
60.0 [38.7; 78.9]
33.3 [7.5; 70.1]
52.6 [28.9; 75.6]
66.7
35.0 [20.6; 51.7]
42.1 [30.0; 55.2]
28.6 [14.6; 46.3]
28.6 [16.1; 45.4]
28.2 [21.6; 36.0]
[5.5; 57.2]
[13.1; 40.3]
[0.2; 38.5]
[34.9; 90.1]
Herpes Simplex Viruses 31
MMSE
Verbal fluency
40
30
20
10
7MS
–10
–20
–30
–40
Clock drawing
0
7
6
5
4
3
2
1
0
**
75 years
ns
75 years
0
75 years
*
Free
ns
****
80 years
ns
Cued (75 years)
TMT-B
Enhanced recall
400
350
300
250
200
150
100
50
15.0
12.5
10.0
7.5
5.0
2.5
0.0
30
25
20
15
10
0
0
40
35
30
25
20
15
10
5
0
75 years
75 years
80 years
***
300
250
200
150
TMT-A
100
50
Temporal orientation
0
4
3
2
1
0
ns
ns
*
80 years
75 years
ns
75 years
Anti–HSV-1 IgG- Anti–HSV-1 IgG+
ns
*
Figure 2.7 Distribution of cognitive outcomes with respect to anti- HSV- 1 IgG positivity. HSV- 1,
herpes simplex virus type 1; IgG, immunoglobulin G; MMSE, Mini- Mental State Examination;
TMT, trail- making test; 7MS, 7- minute screening test. Arrows indicate the direction of greater
cognitive ability. Significance testing was performed using multiple mixed and linear
regression. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001; ns, not significant.
Source: Weidung, B., Josefsson, M., Lyttkens, P., Olsson, J., Elgh, F., Lind, L., Kilander, L., & Lövheim, H. 2023.
Longitudinal eects of herpesviruses on multiple cognitive outcomes in healthy elderly adults. J Alzheimers
Dis, 94, 751– 762. https:// doi.org/ 10.3233/ JAD- 221 116. https:// crea tive comm ons.org/ licen ses/ by/ 4.0/
enhanced free recall, and verbal uency tests but not for the orientation or clockdrawing assessments. At prospective follow- up, there was no change in the cognitive
scores based on HSV- 1 positivity. However, the TMT- A performance was worse when
the HSV- 1 IgG interacted with APOE ɛ4, but there was an improved recall. Overall,
this cohort study provided evidence that HSV- 1 is associated with worse cognition in
cognitively healthy elderly adults, including cognitive decits in executive function,
memory, and expressive language (Weidung et al., 2023).
Another study investigated the relationship between HSV- 1 and schizophrenia
(SZ) in terms of cognitive functions (omas et al., 2013). e patient samples consisted of 198 individuals with SZ and 100 controls that were not statistically signicantly dierent in terms of age, education level, and HSV- 1 status; however, the SZ
patients were more likely to be male and less likely to be married. HSV- 1 positivity
was based on serum HSV- 1 antibody titers; cognitive function was assessed using
the Penn Computerized Neurocognitive Battery. ose who were HSV- 1 positive
had reduced cognitive function in the overall sample. Moreover, there were no statistically signicant dierences between HSV- 1 exposure and SZ case status. However,
HSV- 1 exposure did not increase the risk for SZ, but it was linked with reduced function in specic cognitive domains independent of SZ diagnostic status.
Amnestic mild cognitive impairment (aMCI) is a specic cognitive impairment
that has been associated with the later onset of Alzheimer’s disease (AD) (Agostini
Infectious Disease and Neurocognition
converters
converters
converters
converters
p<0.0001p<0.0001
(a)(a) (b)(b)
AD
patients
patients
p = 0.001p = 0.001
aMCI-
aMCI-
converters
converters
p = 0.0018p = 0.0018
aMCI-
aMCI-
non-
non-
p = 0.009p = 0.009
HCHC
1414
1212
1010
HSV-1 lgG titers, AIHSV-1 lgG titers, AI
p<0.0001p<0.0001
p<0.0001p<0.0001
100100
9595
9090
88
66
44
22
00
AD
AD
patients
patients
aMCI-
aMCI-
converters
converters
aMCI-
aMCI-
non-
non-
HCHC AD
8585
8080
7575
7070
HSV-1 lgG avidity index (%)HSV-1 lgG avidity index (%)
6565
6060
5555
Figure 2.8 HSV- 1 IgG antibody titers (A) and avidity index (B) in AD patients, aMCI- converters,
aMCI- non- converters and healthy controls (HC). Horizontal lines represent the median value.
Statistical significance was evaluated using the Mann– Whitney test U. In (A), the dotted line
represents the threshold value of HSV- 1 seropositivity (Antibody Index (AI) > 1.1).
Source: Agostini, S., Mancuso, R., Baglio, F., Cabinio, M., Hernis, A., Costa, A. S., Calabrese, E., Nemni, R., &
Clerici, M. 2016. High avidity HSV- 1 antibodies correlate with absence of amnestic mild cognitive impairment
conversion to Alzheimer’s disease. Brain Behav Immun, 58, 254– 260. Reprinted with permission from Elsevier.
https:// www.scienc edir ect.com/ jour nal/ brain- behav ior- and- immun ity
aMCI and later AD is a study that aimed to determine if HSV- 1 and APOE ɛ4 play a
pathogenetic role in the conversion from aMCI to AD. e study consisted of four
groups: aMCI individuals (n = 36), aMCI- converters (n = 21), aMCI- non- converters
(n = 15), and healthy controls (n = 25). e ndings showed that HSV- 1 IgG antibody
titers were increased at baseline in MCI- non- converters and that the avidity index for
these antibodies was statistically signicant for an MCI- non- converter compared to
an MCI- converter (p = 0.0018) (Figure 2.8) (Agostini et al., 2016). is suggests that
HSV- 1 plays an important role in the pathogenesis of AD.
Dementia
Currently, the pathogenesis of AD remains to be elucidated (Bruno et al., 2023; Piekut
et al., 2022). e idea that an infectious agent might be responsible for AD is not new and
is one of several hypotheses being examined. However, the process of associating AD
with an infectious pathogen is not a simple one, and there are many issues that need to be
addressed if the Bradford Hill criteria are to be met (Hill, 1965). e initial idea regarding
the possible link between HSV and AD was proposed more than four decades ago by
Melvyn Ball, a Canadian neuropathologist (Ball, 1982). His hypothesis article proposed
that pathognomonic lesions were found in the limbic system of the brain and that the
trigeminal ganglia were very oen aected by HSV, an idea that is still being tested today.
ere is evidence supporting such a hypothesis. A comprehensive meta- analysis
investigated the link between HSV- 1 and AD among 780 AD cases and 1631 controls (n = 18 studies) (Steel & Eslick, 2015; see Table 2.1). In this meta- analysis,
Table 2.1 HSV- 1 studies from Steel and Eslick’s 2015 meta- analysis
Herpes Simplex Viruses 33
Author
(year)
Beert et al.
(1998b)
Hemling
et al. (2003)
Itabashi
et al. (1997)
Lin et al.
(1998)
Lin et al.
(1997)
Kobayashi
et al. (2013)
Jamieson
et al. (1992)
Mori et al.
(2004)
AD cases HSV- 1
positive
cases
52 23 47 23 PCR FC, TC Autopsy Canada No
34 1 40 10 PCR FC, HC,
46 36 44 28 PCR FC, TC Autopsy Japan Ye s
15 9 4 2 PCR FC, TC, HCAutopsy England Ye s
17 13 12 8 PCR FC, TC, HCAutopsy England No
85 65 28 21 Serology Blood Clinical
21 14 15 9 PCR FC, TC,
5 5 6 0 PCR FC, TC Autopsy Japan No
To ta l
controls
HSV- 1
positive
controls
Detection
method
Region of
brain
TC, ACG
HC, OC
Conrmation
of AD
Autopsy Finland Ye s
diagnosis
Autopsy England No
Country APOE ε4
Japan No
assessment
Itzhaki et al.
(1997)
Lin et al.
(1996)
Mann et al.
(1983)
Marques
et al. (2001)
Ounanian
et al. (1990)
Wozniak
et al. (2005)
Bertrand
et al. (1993)
46 36 44 28 PCR FC, TC, HCAutopsy England Ye s
36 28 36 23 PCR – Autopsy England Ye s
13 1 7 1 IHC TC, HC,
amygdala
15 1 15 1 PCR FC, TC Autopsy USA No
19 16 21 19 Serology Blood Clinical
27 14 13 9 Serology Blood Clinical
98 73 57 41 PCR HC, FC,
OC,
cerebellum,
striatum
Autopsy England No
France No
diagnosis
England
diagnosis
Autopsy Canada No
& USA
Ye s
Infectious Disease and Neurocognition
Table 2.1 Continued
Author
(year)
Beert et al.
(1998a)
Letenneur
et al. (2008)
Mancuso
et al. (2014)
Abbreviations: ACG, anterior cingulate gyrus; FC, frontal cortex; HC, hippocampus; occipital cortex; PCR, polymerase chain
reaction; TC, temporal cortex; USA, United States of America.
Adapted from Steel and Eslick (2015). https:// doi.org/ 10.3233/ JAD- 140 822
AD cases HSV- 1
positive
cases
74 54 36 26 PCR FC, OC,
77
83 31 51 14 Serology Blood Clinical
–
To ta l
controls
413
HSV- 1
positive
controls
–
Detection
method
Serology Blood Clinical
Region of
brain
cerebellum,
HC,
striatum
Conrmation
of AD
Autopsy Canada Ye s
diagnosis
diagnosis
Country APOE ε4
assessment
France Ye s
Italy No
individuals who were HSV- 1 positive were more likely to have AD (OR: 1.38, 95 percent CI: 1.03– 1.84). Moreover, the level of heterogeneity was low and not statistically
signicant (I2 = 16.49, p = 0.26).
Interestingly, additional data support Melvin Ball’s hypothesis regarding the effects of HSV on the trigeminal ganglion. e results of an analysis consisting of 43
AD cases and 78 controls (n = 2 studies) suggest that individuals with AD could
be more likely to have HSV- 1 in their trigeminal ganglion (OR: 2.34, 95 percent
CI: 0.68– 8.10) (Steel & Eslick, 2015), although this nding did not reach statistical
signicance, possibly because of the small sample size from the two studies. In addition, there was low heterogeneity for this analysis, which was not statistically signicant (I2 = 43.83, p = 0.18).
A separate subgroup analysis assessed the potential role of HSV- 1 and APOE ε4
in the subsequent development of AD. is analysis consisted of 320 AD cases and
481 individuals with APOE ε4 (n = 8 studies). e analysis revealed that there was
an increased likelihood of AD among patients with HSV- 1 and APOE ε4 (OR: 2.25,
95 percent CI: 0.69– 2.00) (Steel & Eslick, 2015), although again this did not reach
statistical signicance. However, in a subset of AD patients, the likelihood of HSV- 1
infection was increased in APOE ε4 carriers (OR: 2.71, 95 percent CI: 1.08– 6.80).
ere were very few APOE ε4- negative AD cases who were infected with HSV- 1. In
a subset there was an increased likelihood of AD in APOE ε4 carriers in the absence
of HSV- 1 infection (OR: 5.89, 95 percent CI: 2.82– 12.28) (Steel & Eslick, 2015). is
proposed mechanism appears very important for the link between HSV- 1 and AD
(Figure 2.9).
ere have been additional systematic reviews and meta- analyses examining the
association between HSV- 1 and AD, the ndings of which are essentially the same
Herpes Simplex Viruses 35
Figure 2.9 The pathomechanism of virus- associated neurodegeneration. HSV- 1 resides in
neurons and may induce aggregation of Aβ in Alzheimer’s disease (AD) by various mechanisms
that may be facilitated by the presence of the APOE E4 genotype. HSV- 1 may aect turnover
of amyloid precursor protein (APP) to produce more amyloid β (Aβ); subsequently, viral
glycoprotein B might serve as a primal starter for Aβ aggregation. HSV- 1 may also influence
APP and tau protein phosphorylation mediated by calcium ions (Ca
induced by viral kinases, that lead to neuronal degeneration. Furthermore, HSV- 1 may activate
plasma cells to produce immunoglobulin M (IgM), whose increased levels have been linked to
AD pathology.
Source: Piekut, T., Hurła, M., Banaszek, N., Szejn, P., Dorszewska, J., Kozubski, W., & Prendecki, M. 2022.
Infectious agents and Alzheimer’s disease. J Integr Neurosci, 21, 73. https:// doi.org/ 10.31083/ j.jin 2102 073.
https:// crea tive comm ons.org/ licen ses/ by/ 4.0/
2+
). The process may be
in terms of HSV- 1 and AD: (1) OR: 1.40, 95 percent CI: 1.13– 1.75, I2 = 3.00 percent,
p = 0.42 (21 studies) (Wu et al., 2020); and (2) OR: 1.34, 95 percent CI: 1.02– 1.75,
I2 = 0.00 percent, p = 1.00 (Ou et al., 2020).
e epidemiological evidence suggests an association between HSV- 1 and AD
(Steel & Eslick, 2015). is eld is very dynamic, and new studies continue to provide novel information regarding this link and its potential mechanisms. Some researchers feel that the relationship is most likely causal (Itzhaki, 2021) and that the
next steps involve prevention options with a vaccine and treatment options with
long- term antiviral drugs among those at risk (i.e., APOE ε4 carriers) (Hemmingsson
et al., 2021; Itzhaki, 2021; Steel & Eslick, 2015).
Infectious Disease and Neurocognition
Psychiatric illness
A recent study sought to determine the association between pathogen exposure and
mental health, using HSV- 1 as the organism and depression and mental health as
the outcomes (Lu et al., 2022). is was a cohort study from Singapore and included
884 individuals with a mean age of 68 years. Mental health was assessed using the
Geriatric Depression Scale score at baseline and at 3– 4 and 6– 8 years of follow- up.
Baseline measurement also included the mental component score of the 12- Item
Short Form Survey (SF- 12). In this study, HSV- 1 was associated with depression
(OR: 5.15, 95 percent CI: 1.01– 26.32) but not with impaired mental health (OR: 1.07,
95 percent CI: 0.49– 2.35) (Lu et al., 2022) in models adjusted for age, sex, ethnicity,
education, marital status, living alone, and smoking status.
A study in the United States of older (age > 60 years) adults aimed to identify
novel risk factors for depression (Simanek et al., 2019). The sample consisted
of incident depression with a follow- up period of 10 years. In analyses adjusted
for age, sex, education level, income level, and marital status, HSV- 1 positivity
slightly increased the likelihood of depression, but this result did not reach statistical significance (OR: 1.26, 95 percent CI: 0.91– 1.74). In addition, the HSV1 IgG antibody level was not associated with depression (OR: 0.99, 95 percent
CI: 0.89– 1.11). The findings from this study did not support a possible relationship between HSV- 1 status and the development of depression in older adults
(Simanek et al., 2019).
A cross- sectional study aimed to determine the relationship between the infections HSV- 1 and HSV- 2 and depression using data from the United States’
National Health and Nutrition Examination Survey (NHANES) (Gale et al., 2018).
Information from the survey included depression status of individuals, antidepressant use, HSV- 1/ HSV- 2 status, and general demographic factors (mean age: 30 years,
51 percent female). e regression model adjusted for age, sex, socioeconomic
status, race/ ethnicity, education level, smoking status, and sexual behavior (i.e., sexually transmitted diseases). Individuals with a high HSV- 2 antibody level (n = 331)
were more likely to have depression (OR: 2.00, p = 0.02), although there was no association between HSV- 1 and depression. ese results suggest that younger individuals (approximately aged 30 years) who are HSV- 2 positive are more likely to
develop depression (Gale et al., 2018).
In a cohort study, 8028 individuals over the age of 30 years were followed up for
11 years to assess whether HSV- 1 status could predict the development of newonset anxiety and depression (Markkula et al., 2020). All participants had a diagnostic interview for anxiety and depression. During the follow- up, there were 126
new cases of depression and 84 new cases of anxiety disorders. Males who were
HSV- 1 seropositive were more likely to develop new- onset depressive disorders
(OR: 1.77, 95 percent CI: 0.85– 3.68), although this was not statistically signicant,
and new- onset anxiety disorders (OR: 3.43, 95 percent CI: 1.33– 8.83). Conversely,
Herpes Simplex Viruses 37
for females, being HSV- 1 seropositive provided a possible protective eect for
new- onset depression (OR: 0.63, 95 percent CI: 0.39– 1.01) (not statistically signicant) and no dierence was observed for new- onset anxiety (Markkula et al.,
2020). is model adjusted for age, sex, educational level, region of residence, and
marital status.
Conclusion
HSV- 1 is one of the most studied infections associated with neurological complications from childbirth, through adolescence, and into adulthood. Although not
all ndings are consistent, the evidence overall suggests that HSV- 1 is an important
contributor in a variety of cognitive and psychiatric conditions. e association of
HSV- 1 and AD seems robust, and the overall hypothesis for a link between HSV- 1
and AD in terms of the proposed mechanism— that is, involvement with APOE ε4
carriers— augments the evidence required to support the hypothesis.
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