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
Deshayes et al. (2016), accurate diagnosis requires the following four ndings: (1)
blood and/ or CSF eosinophilia; (2) hypodense lesions on brain computed tomography, and/ or hyperintense lesions on T2- weighted brain or spine magnetic resonance imaging; (3) high titer of anti- To x oc a ra antibodies in blood and CSF; and
(4) above all, clinical and/ or radiological improvement aer anthelmintic treatment.
Such investigations require specialist knowledge and equipment, both of which are
less likely to be available in the Global South.
Numbers of cases of cerebral toxocariasis in the
published literature
Evidence for cerebral toxocariasis in humans has always been dicult to assess, especially at the population level. Most information is gained from case reports in the published literature. In 1997, Magnaval et al. reviewed the literature published in English
from the early 1950s to 1997 and found only 12 published cases of neurological toxocariasis as determined by nding Tox o c ar a larvae in the CSF or in the brain and/ or by
immunodiagnosis of the CSF. In contrast, Fan et al. (2015) and Deshayes et al. (2016)
retrieved 86 and 100 reports, respectively, indicating how greater awareness of the condition and improved diagnosis are yielding an increasing number of such reports.
Association between toxocariasis and
neurocognitive function
Evidence from humans
As early as 1997, Magnaval and colleagues sought to characterize a recognizable
cerebral or neurological syndrome among Tox o ca r a seropositive French adults
(Magnaval et al., 1997). Utilizing a case– control study design, the authors compared
seropositive cases, with neurological symptoms in the absence of an etiological diagnosis, with controls matched by age, sex, ethnicity, and travel history outside the
European community. e authors did not nd evidence for a recognizable neurological syndrome, but the relatively small number of subjects (27) should be noted.
Two early American studies focused upon the relationship between To x oc a ra
seropositivity and neuropsychological parameters in young children. Worley
et al. (1984) failed to demonstrate a relationship between To x oc a ra seropositivity
(at 5.4 percent) and cognitive abnormalities, but aer controlling for social class in
333 children aged 5– 7 years, Marmor et al. (1987) suggested a role for toxocariasis in
subtle eects on cognition. Sera were obtained from 4652 children aged 1– 15 years
as part of the New York City Department of Health Lead Screening Program.
Seropositivity was relatively high at 23.1 percent. A total of 155 cases were matched
with controls by age, sex, lead category, and time of sampling. Aer adjustment for
Toxocara 249
ethnicity, socioeconomic status, and current lead status, seropositive children performed less well on several measures of neuropsychological tests.
In a detailed prospective study of preschool children deemed to be disadvantaged,
seropositivity was assessed when children were aged 2, 3, and 4 years, 10 months
(Nelson et al., 1996). Seropositivity rose with age from 2 percent to 14.5 percent.
Initial results found a link between To xo c ar a seropositivity and lower initial intelligence and less advantageous child rearing, but, aer controlling for confounding
variables, statistical signicance was not achieved. However, the authors highlighted
the possibility of partial reverse causality, that is, whether the eects were due to
the exposure itself or to the initial pre- exposure lower intelligence. Furthermore, the
failure to reach statistical signicance may have been inuenced by a sample size
that was too small for the detection of what may be small dierences between seropositive and seronegative groups.
In a signicant departure in terms of scale, several investigators have taken advantage of the National Health and Nutrition Examination Survey (NHANES), which is
a nationally representative cross- sectional survey of over 33,000 people designed to
collect health statistics from a large sample of people representative of the civilian,
non- institutionalized general population in the United States. e third such survey
took place between 1988 and 1994, and serum samples were analyzed for the presence of Tox o ca ra antibodies.
In the rst contribution to utilize the NHANES data set, Walsh and Haseeb (2012)
measured the Wechsler Intelligence Scale for Children— Revised (WISC- R) and the
Wide Range Achievement Test— Revised (WRAT- R) in children aged 6– 16 years.
Children seropositive for To xo c ar a (n = 688) had signicantly lower scores for both
the WISC- R and the WRAT- R compared with seronegative children (n = 3261) aer
controlling for important potentially confounding variables such as socioeconomic
status, sex, ethnicity, residence, cytomegalovirus, and blood lead levels. e overall
seroprevalence for this group was 13.4 percent.
ese ndings were later extended to both young and middle- aged adults
(Erickson et al., 2015) and older adults (Erickson et al., 2022), studies that also utilized the invaluable NHANES database. Erickson et al. (2015) utilized three measures of computer- administered tests of cognitive function in 4279 adults aged
21– 59 years: simple reaction time, symbol– digit substitution, and serial digit
learning. e overall seroprevalence for this group of adults was 16 percent, but
striking dierences in certain groups were observed. For example, seroprevalence
reached 21 percent in non- Hispanic Black, versus 12.8 percent and 13 percent for
Hispanic and non- Hispanic White participants, respectively. Furthermore, for those
living in poverty, seroprevalence was 22.4 percent, in contrast to 12 percent for those
not in poverty. Aer controlling for sex, age, blood lead concentration, educational
attainment, ethnic background, and the poverty- to- income ratio, the authors found
that toxocariasis predicted worse performance on the symbol– digit substitution test
but not on the simple reaction time or the serial digit learning test. Importantly, seropositivity interacted signicantly with host factors such as sex, age, and educational
Infectious Disease and Neurocognition
attainment indicating that, for certain groups, the impact of toxocariasis on cognition may be enhanced.
Most recently, Erickson et al. (2022) extended their observations to older adults
(aged 60 years and over), utilizing 1350 subjects from the 2013– 2014 NHANES
survey. e measures of cognition included assessment of memory function using the
word list memory test, executive function by means of verbal uency, and the digit–
symbol coding test (evaluation of processing speed). e overall seroprevalence for
this group of adults was 8 percent. Tox o c ar a seropositivity was associated with worse
performance on both the verbal uency task and on the digit– symbol coding task.
Furthermore, To x oc a ra sero- intensity was associated with worse performance on the
digit– symbol coding task. Age was found to signicantly inuence the observed relationships, but sex, educational achievement, and income did not. No relationship
between Tox o c ar a seropositivity and tasks that measured memory were observed.
ese three important studies emphasize the need for the large sample sizes in order
to include a sucient number of seropositive cases, the importance of the inclusion of
potential confounding variables, and the utilization of a diversity of appropriate tests
of cognition. Walsh and Haseeb (2012) have highlighted the cross- sectional design of
such studies as an important limitation, as the data cannot be used to draw direct causal
conclusions from the associations observed. ese authors also discuss the possibility
of reverse causality— that is, that those children who are cognitively disabled may
be at greater risk of exposure to To x oc a ra species and hence lead to an increased cooccurrence of toxocariasis and poor cognitive function. Nevertheless, they conclude
that the operation of sensitivity analysis precludes the likelihood of reverse causality.
Gillespie (1993) suggested that the relationship between To x oc a ra and neurological
decits in humans is likely to remain obscure until individual children with mild or
asymptomatic disease are studied in some detail, over the course of their infection, in
contrast to matched controls. However, for ethical and logistical reasons such a study
is unlikely to be undertaken, especially as our understanding of ocular toxocariasis
and its potentially devastating sequelae remains obscure. is highlights the myriad of
challenges that investigators of such studies face, as mirrored in the literature on cognitive development and geohelminth infections (Kvalsvig & Albonico, 2013).
However, to conclude, we do now possess good- quality evidence from large- scale
human studies that exposure to Tox o ca r a does have implications for human cognition. Animal models may hold the key to understanding the mechanisms behind the
perturbations observed in humans.
Evidence from animal models
Mice as the main species for investigation: Evidence for larval
accumulation in the murine brain
As described above, our knowledge of cerebral toxocariasis in humans remains
Toxocara 251
the addition of large psychometric associational studies. A range of animals has
been infected with Tox o ca r a (predominantly T. c an is ) under laboratory conditions, including mice, rats, guinea pigs, hamsters, gerbils, chickens, quail, pigeons,
rabbits, pigs, monkeys, and earthworms (Holland & Hamilton, 2006). Holland
and Hamilton (2006) emphasized that for many of these hosts, larval numbers in
the brain were either not investigated or no evidence for accumulation was found.
However, in contrast, signicant numbers of Tox o ca ra larvae are detected in the murine brain. As early as 1955, Sprent described greater numbers of T. c an is larvae in
the murine brain compared to other ascarid species (Sprent, 1955). Burren (1971)
explored the location of To xo c ar a larvae in the murine brain and reported higher
numbers of larvae in the cerebellum. In an important paper, Dunsmore et al. (1983)
infected Canberra C57BL mice with varying doses of To xo c ar a ova and established
quantitative evidence for accumulation of T. ca ni s larvae in the brains of mice. Other
investigators have described signicant variation in the numbers of larvae detected
in the brains of individual outbred mice, indicating the likely role of host heterogeneity in genetics and immunological response (Cox & Holland, 2001a; Skerrett &
Holland, 1997). Mice, therefore, represent useful model systems to explore the impact of To x oc a ra on brain biology and behavior and provide possible insights into
human cerebral toxocariasis.
Behavioral alterations in T oxocara- infected mice
Although we lack information on behavioral changes in humans exposed to
To xo c ar a , there is now considerable evidence to demonstrate that both outbred and
inbred laboratory mice infected with To x oc ar a exhibit a range of behavioral alterations. A number of key studies have explored the impact of Tox oc ar a infection on
murine behaviors, including baseline activity, exploration, response to novelty, anxiety, learning and memory, and social behavior (Table 16.1). Furthermore, in cases
where larval burden has been determined, the magnitude of these alterations can
be linked to the numbers of To xo c ar a larvae detected in the murine brain. In one
of the earliest studies, Dolinsky et al. (1981) described decreased exploratory behavior, motor performance, and spatial awareness among infected outbred mice.
In an extension of these observations, Burright et al. (1982) infected outbred mice
with a range of doses of Tox o ca r a ova and found that mice infected with the highest
dose never entered the novel environment compared to mice exposed to the lower
doses and control mice. In contrast, and perhaps suggestive that the observations
of Burright et al. (1982) may relate to morbidity in the higher- dose group, Hay and
Aitken (1984) found that infected mice showed a greater preference for exposed
areas and less caution when presented with a novel stimulus. ese mice received
an infective dose of 1000 ova. is was the rst of the early studies to assess larval
burden in the brain (Table 16.1). However, no statistically signicant correlation was
found between the numbers of larvae in the brain and behavioral alterations.
Several studies have provided evidence that T. c an is - infected mice are less active
Infectious Disease and Neurocognition
Table 16.1 Studies on the relationship between Toxocara infection and behavioral
alterations in mice
Author
(year)
Dolinsky
et al. (1981)
Burright
et al. (1982)
Hay &
Aitken
(1984)
Hay et al.
(1985)
Dolinsky
et al. (1985)
Mouse strain Dose Assessment of
Behavioral tests Method
larval burden
in the brain
Oubred
Binghampton
Outbred
Binghampton
Strain A 1000 Ye s Motor performance
1000 NA Activity
Response to novelty
250, 500,
1000
NA Exploration
Novel environment
Ambulation &
Home cage
Novel cage
Home cage
a
Open eld
Rotating cylinder
Open box Y- maze
preference for
exposed areas
Response to novelty
Strain A 1000 NA Activity (running) Exercise wheel
Outbred
Binghampton
1000 Histopathology Activity &
exploration of novel
environments
Sensorimotor
assessments
Home cage
& upper
home cage
Open eld Chain
orientation
Forelimb grasp
Geotaxis response
Chain balance test
Shock & swim-
temp reactivity
Hay et al.
Inbred STR 1000 NA Activity (short
(1986)
Cox &
Holland
(1998)
Outbred LACA 100,
1000,
3000,
Ye s Social behavior
250 × 4
Cox &
Holland
(2001a)
Cox &
Holland
(2001b)
Outbred
LACA
Inbred
NIH
Outbred
LACA
100,
1000,
3000,
250 × 4
100,
1000,
3000,
Ye s Activity Home cage
Ye s Exploration &
250 × 4
Hamilton
et al. (2006)
Inbred
BALB/ c
2000 Ye s Activity
NIH
Janecek
et al. (2017)
Inbred
C57BL/
2000 bHistology Activity
6JRccHsd
Notes: a Modied to include two levels. b T. ca ni s and T. ca ti .
bouts)
Anxiety
novelty
Learning & memory
Anxiety
Learning & memory
Sensorimotor
function
Memory
Home cage
Home cage
Light/ dark
apparatus &
predator odor
“T” maze
Water- nding test
Elevated plus
maze
Home cage
Water- nding test
Home cage
Tape removal
Maze test/ food
reward
Toxocara 253
2017). However, in contrast, two studies provided evidence for increased activity
in To xo c ar a - infected mice (Hay et al., 1985) and hyperactivity as determined by an
evaluation of short bouts of activity (Hay et al., 1986). ese studies utilized both
outbred and inbred strains of mice (Table 16.1).
Studies using mouse models have also explored the impact of To xo ca r a infection on learning and memory, which is likely to be particularly important for humans. In an important contrast, two studies— one utilizing outbred Laca mice (Cox
& Holland, 2001b) and another utilizing two strains of inbred mice (one susceptible and one resistant) (Hamilton et al., 2006)— illustrated the signicance of mouse
strain selection in studies of this kind. In an earlier study (Cox & Holland, 2001a),
Laca mice infected with low, medium, high, and trickle doses of To x oc a ra ova were
exposed to a water- nding apparatus as a means of assessing learning and memory.
e latency to relocate the water tube, aer a period of deprivation, was taken as an
indication of memory impairment. Mice with moderate and high larval numbers in
the brain showed a latency to enter the alcove, nd the water tube, and drink from it,
although these observations did not attain statistical signicance.
Hamilton et al. (2006) assessed the progression of To x oc ar a infection in seven
strains of mice in order to select a susceptible and a resistant strain of mouse to larval
establishment in the brain. BALB/ c mice were selected as the susceptible strain,
and NIH mice were deemed to be resistant. e choice of strains was supported by
previous studies, where BALB/ c mice have been reported to be more susceptible to
T. ca ni s infection (Bardón et al., 1994; Epe et al., 1994), and NIH mice demonstrated
a higher resistance to T. ca ni s infection than outbred CD1 mice (Abo- Shehada &
Herbert, 1989). When the experiments described above were repeated in the inbred
BALB/ c and NIH mice using the same protocol, the susceptible BALB/ c mice infected with To x oc a ra took statistically signicantly longer to drink from the water
bottle than control BALB/ c mice and infected NIH mice, suggesting a degree of
memory impairment. Infected BALB/ c mice also took longer to enter the alcove and
locate the water bottle in comparison to control mice, but these dierences were not
statistically signicant. An alternative explanation for these observations could be
lethargy or anorexia induced by To x oc a ra infection. However, activity was also recorded in these experiments, and infected BALB/ c mice were more ambulatory than
their uninfected counterparts and spent less time immobile, suggesting that they
were not lethargic (Hamilton et al., 2006). ese contrasting studies emphasize how
investigating behavior in inbred strains of mice is attractive as any infection- induced
behavioral alterations that could be masked in heterogeneous outbred mice may appear more pronounced (Holland & Hamilton, 2013).
In an important development, Strube and colleagues began to investigate the differences between T. c an is and T. ca ti in a mouse model. In their rst comparative
study, Janecek et al. (2014) infected separate groups of C57Bl/ 6j mice with T. c an is
and T. ca ti respectively. Higher numbers of T. ca ni s were detected in the brains of
mice compared to T. c at i, mirroring the observations of Havasiovareiterova et al.
(1995). Extending their work, Janecek et al. (2017) infected inbred C57BL/ 6JRccHsd
Infectious Disease and Neurocognition
mice, with separate groups of mice infected with T. c an is and T. ca ti . ey observed
reduced exploration and memory impairment in both groups of mice, but in T. ca ti infected mice, onset was delayed with less severe progression. Furthermore, T. cati-
infected mice displayed reduced fear- related and ight- related reactions rather than
motor and neurological disorders (Janecek et al., 2017). ese comparative observations emphasize that despite the evidence that fewer T. cat i migrate to the brain
in mice, T. cati can still provoke behavioral changes in an animal model and should
not, therefore, be discounted as an etiological agent in cerebral toxocariasis (Janecek
et al., 2017; Maciag et al., 2022).
It is possible that the position of the larvae in the brain may inuence the observed
behavioral alterations. Previous studies have reported the presence of larvae in the
telencephalon (Good et al., 2001) and the cerebellum (Burren, 1971), both areas of
the brain being associated with learning and memory and the coordination and control of voluntary movement. However, Janecek et al. (2014) found signicantly more
T. c an is larvae in the cerebra of infected mice whereas T. ca ti larvae were mainly lo-
cated in the cerebellum.
Overall, the ndings of behavioral alterations in mice associated with To xo c ar a
infection suggest the possibility that To xo ca r a infection in humans could be associated with behavioral alterations and even neuropsychiatric diseases, although little
research to date has addressed this question. Additional research is warranted to investigate associations between To x oc a ra infection and human behavioral alterations
and neuropsychiatric disease.
Cerebral immunity in T oxocara- infected mice and
the investigation of biomarkers of brain injury
Our understanding of the cerebral immune response to To x oc a ra is undoubtedly
less than that of the systemic immune response (Resende et al., 2015). However,
more recently, there has been an increasing focus on the impact of To x oc a ra infection on murine cerebral immunity and biomarkers of brain injury (Table 16.2). As
was the case for the behavioral investigations, various parameters— the choice of
mouse strain, infective dose, duration of infection and whether larval burden was
determined— vary between the studies performed.
Experiments performed in T. c an i s- infected BALB/ c and NIH mice, deemed to
be susceptible and resistant, respectively, revealed a mixed response, with generally
higher levels of mRNA for interleukin (IL)- 5, IL- 10, interferon gamma (IFN- γ), and
inducible nitric oxide synthase (iNOS) in BALB/ c mice compared with NIH mice
(Hamilton et al., 2008). Of particular interest was the observation that infected BALB/
c mice displayed signicantly higher levels of all cytokines and iNOS on days 35 and
42 post infection. is signicant upregulation coincided with the behavioral alterations observed in infected mice, most notably the impairment of memory (Hamilton
et al., 2006, 2008). Furthermore, preliminary data on a small number of mice revealed
Toxocara 255
Table 16.2 Studies on the relationship between Toxocara infection and pathological and
immunological parameters in mice
Author
(year)
Hamilton
et al.
(2008)
Liao et al.
(2008)
Othman
et al.
(2010)
Eid et al.
(2015)
Mouse strain Dose Assessment
Measures Method
of larval
burden in
the brain
Inbred
BALB/ c
NIH
2000 Ye s Cytokines:
IL- 5, IL- 10, IFN- γ
Brain injury biomarker:
iNOS
Outbred 250 Ye s Brain injury biomarkers:
GFAP, NF- L, tTG,
AβPP, S100B TGFβ1, tau, UPS, GFAP
Outbred
Swiss albino
1000 Ye s Cytokines:
IL- 6, TNF- α
Brain injury biomarkers:
iNOS, GFAP
Neurotransmitters:
GABA, glutamate,
dopamine,
norepinephrine,
serotonin
Outbred
Swiss albino
1000 Ye s Cytokines:
a
IL- 5
Brain injury biomarkers:
GFAP
Semi- quantitative
RT- PCR
RT- PCR
Western blot & ELISA
Immunohistochemistry
Semi- quantitative RT- PCR
Immunohistochemistry
Reverse- phase HPLC
Spectrouorometry
Semi-
quantitative RT- PCR
Immunohistochemistry
Chou et al.
b,c
(2017)
Waindok
& Strube
c
(2019)
Waindok
et al.
c
(2019)
Outbred
ICR
Inbred
C57BL/ 6j
Inbred
C57BL/ 6j
250,
Ye s Brain injury biomarkers:
500,
1000
TGF- β1, S100B, GFAP,
TG2, claudin- 5,
SP, IL- 1β, UPS, Aβ
aggregation*
2000 No Cytokines:
G- CSF, GM- CSF, IFN-
γ, IL- 1α, IL- 1β, IL- 2,
IL- 3, IL- 4, IL- 5, IL- 6,
IL- 7, IL, 8, IL- 9, IL10, IL- 11, IL- 12(p40),
IL- 12(p70), IL- 13,
IL- 17A, TNF- α
Chemokines:
CCL11, KC, CXCL1,
MCP- 1, CCL2, MIP1α, CCL3, MIP- 1β,
CCL4, RANTES,
CCL5
2000 No Oxylipins:
Prostanoids,
leukotrienes,
HETEs,NPD1, 13HODE, 9- HODE
Western blotting
*Modied western
blotting via SDD- AGE
Multiple bead array assay
Liquid chromatography
coupled to electrospray
ionization tandem mass
spectrometry
(continued)
Infectious Disease and Neurocognition
Table 16.2 Continued
Author
(year)
Springer
et al.
(2019)
Notes: a Both immunocompetent and immunocompromised mice. b Learning and memory assessed by Morris
Water Maze. c Both T. ca ni s & T. ca ti . d Same mice as for Janecek et al. (2014).
Abbreviations: ELISA, enzyme- linked immunosorbent assay; HPLC, high- performance liquid chromatography;
RT- PCR, reverse transcription polymerase chain reaction; SDD- AGE, semi- denaturating detergent agarose gel
electrophoresis.
Mouse strain Dose Assessment
c
Inbred
C57BL/
6JRccHsd
2000 No Iba- 1, β- APP,
d
Measures Method
of larval
burden in
the brain
Immunohistochemistry
histopathology
a signicant positive correlation between increased time spent to drink and cytokine
levels for both IL- 10 and IFN- γ. Both sets of data were expressed as a percentage increase relative to controls for comparability (Holland & Hamilton, 2013).
In contrast to the work of Hamilton and colleagues, Liao and colleagues infected
IRC mice with a low dose of To x oc a ra ova (Table 16.2), arguing that the eects of
To xo c ar a in the brain in humans are likely to be too cryptic to be clinically detected
because the parasite burden is light but that such subtle eects may be deduced from
a murine model (Liao et al., 2008). Larval recovery was found to be correspondingly low (average of three larvae per brain)— a level similar to that described from
low- dose laboratory infections (Cox & Holland, 2001a) and wild rodents (Dubinsky
et al., 1995). In a detailed study, each mouse brain was divided into four parts to obtain histology and immunohistochemistry, larval recovery, western blotting, and reverse transcription polymerase chain reaction data. e authors observed increases
in several brain injury- associated biomarkers in infected mice including glial brillary acidic protein (GFAP), transforming growth factor beta 1, S100B, neurolament
light chain, tissue transglutaminases, beta- amyloid precursor proteins, and p- tau.
e authors concluded that further work is required to link this observed enhanced
expression of brain injury- associated biomarkers with behavioral alterations in experimental cerebral toxocariasis.
In a study that provided novel insights on neurotransmitters, Othman et al. (2010)
focused upon proinammatory cytokines and abnormalities in neurotransmitters in
a murine model of cerebral toxocariasis. Levels of iNOS and GFAP were also monitored. Infected mice demonstrated increased levels of proinammatory cytokines
(IL- 6, tumor necrosis factor alpha, and iNOS) as well as signicant disturbances in
neurotransmitter proles. Gamma amino butyric acid levels were depressed, exhibiting a signicant decline over time, whereas levels of glutamate were increased in
infected animals. Dopamine and serotonin demonstrated a signicant reduction at
2 weeks post infection. ese changes were most pronounced at the chronic stage
of infection. Astrocyte activation as evidenced by enhanced expression of GFAP
Toxocara 257
was also observed in infected animals. is parallels the observations of Liao et al.
(2008). Changes in the patterns of neurotransmitters have been linked to a range
of complex perturbations in humans, including seizures, behavioral disturbances,
and changes in appetite and sleep. ese observations taken together with those on
cytokines may explain the behavioral, sleep, and cognitive impairments observed in
To xo c ar a - infected humans (Othman et al., 2010). Taking a dierent approach, Eid
et al. (2015) infected both immunocompetent and immunosuppressed Swiss albino
mice with T. can is (Table 16.2). ese authors observed signicant increases in brain
larval counts, reactive gliosis, and a reduction in IL- 5 in the chronic phase of infection in immunosuppressed mice.
In a wide- ranging study that encompassed both behavioral observations and
measurement of neurodegeneration, Chou et al. (2017) infected ICR mice with low,
medium, and high doses of T. c an is . Of importance was the nding that irrespective
of dose, enhanced expression of neurodegeneration- associated factors, persistent
ubiquitin– proteasome system impairment, and excess amyloid beta accumulation
was observed in infected mice. Interestingly, learning and memory capacity was
measured using a Morris water maze, but no eect was detected. e authors concluded that despite the failure to link the observed abnormalities to memory impairment, these neurodegenerative observations may silently progress to Alzheimer’s
disease if chronic cerebral toxocariasis persists.
In an important series of studies by the Strube group, all utilizing the T. c an is /
T. cat i comparison, Springer et al. (2019), using both immunohistochemistry and
histopathology, added weight to the ndings of Chou and colleagues but in a different strain of mouse (Table 16.2). Beta amyloid precursor protein was enhanced
in T. c ani s- infected but not in T. c at i- infected mice, and earlier and more significant neurodegeneration was observed in mice infected with T. ca ni s. Waindok
and Strube (2019) explored a wide range of cytokines and chemokines by means
of a multiplex bead array assay (Table 16.2). In contrast to the ndings of other
investigators (Eid et al., 2015; Hamilton et al., 2008; Othman et al., 2010), concentrations of proinammatory cytokines were not elevated during To xo ca ra
species infection, in contrast to those of IL- 4 and IL- 5 in T. ca ni s- infected but
not in T. cat i- infected mice. Investigation of chemokines, which act as important signaling mediators, revealed that levels of proinammatory macrophage
inammatory protein MIP- 1 alpha were consistently elevated in both T. ca ni sinfected and T. cat i- infected mice, as was anti- inammatory eotaxin (Waindok &
Strube, 2019).
Furthermore, Waindok et al. (2019) extended their observations to the exploration of oxylipins— bioactive regulatory lipids that are involved in complex molecular
signaling during infection and inammation (Strube et al., 2020)— to investigate
lipidomic proles in the T. ca ni s- infected and T. ca ti - infected brain. Signicant increases in lipoxygenase pathways were observed in both infected groups indicating a
predominantly anti- inammatory response.