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Infectious Disease and Neurocognition
Box 10.1 Neurological and neuropsychiatric phenomenology of
Whipple’s disease of the brain
• Amnesia
• Rapidly progressive dementia
• Prosopagnosia
• Frontotemporal dementia
• Korsako’s syndrome
• Klüver– Bucy syndrome
• Lewy body like syndrome
• Progressive supranuclear palsy- like
• Limbic encephalitis
• Normal- pressure encephalitis
• Dementia– parkinsonism– amyotrophic lateral sclerosis
• Rhombencephalitis.
lateral sclerosis- like picture, and rhombencephalitis have been described in WD of the
brain in both its primary and secondary forms (Box 10.1).
T. whipplei is a bacterium with a trilaminar cell wall that invades neurons and glia
aer blood– brain barrier disruptions. In WD, macrophage inltration contributes
to the pathological reaction, with macrophages containing the bacillus. is leads
to an inammatory reaction with neuronal loss, disruption of the neuropil, and loss
of brain function (Bai et al., 2004) with resulting atrophy in target structures, like
the hippocampus. MRI signal changes reective of inammatory processes in the
mesial temporal lobes, orbitofrontal gyrus, basal ganglia, and midbrain may explain
dysfunction such as memory decits, apathy, hallucinations, executive dysfunction,
confabulation, and delusions. Lentiform nucleus inammatory lesions have been associated with cognitive dysfunction, poor visual memory, constructional apraxia,
impaired calculation, and word- nding diculties; cerebral cortical atrophy has
been associated with a dementing syndrome including hypophonia and echolalia,
and diuse subcortical inammatory lesions can result in a dementia syndrome.
Bilateral mesial temporal ring- enhancing lesions can cause a Klüver– Bucy syndrome with prosopagnosia reecting involvement of the temporal facial recognition
system, and frontal and temporal inammatory lesions have been associated with a
frontotemporal dementia- like picture. Cerebral atrophy with FLAIR intensities in
the corpus callosum and subcortical white matter is related to the neuropathological reaction of neuronal loss and gliosis. T2 hyperintensities in the striatum and
hippocampal gyrus can be associated with rapidly progressive dementia. Limbic encephalitis with enhanced T2 signals can be found in the amygdalae and hippocampi.
e syndrome of normal- pressure hydrocephalus with hypersomnolence can occur
secondary to WD inammatory lesions obstructing the ow of CSF.
Whipple’s Disease 139
A dementia– parkinsonism– amyotrophic lateral sclerosis syndrome can be associated with cerebral atrophy. Inammatory contrast- enhancing lesions in the pons,
medulla, and cerebellum can result in rhombencephalitis. Direct inammatory structural abnormalities do not explain the clinical phenomenology in all cases, as it may be
normal. e cellular inammatory inltrate might initiate a cytokine reaction, resulting
in neuronal dysfunction and eventual neuronal and glial loss as in viral infections like
Covid- 19 (Dewanjee et al., 2021). Other mechanisms like obstructive sleep apnea
(Panegyres & Goh, 2015), Wernicke– Korsako syndrome secondary to thiamine deciency from malabsorption, and epileptic seizures, through inammatory mechanisms,
and hippocampal sclerosis may contribute to and exacerbate cognitive diculties, as
do mood disturbances linked to the neuroanatomical and neuropathological substrates
(Miller, 2021). Immune reconstitution inammatory syndrome, which may complicate
treatment initiation with antibiotics in WD and which may lead to a worsening of a
patient’s neurological state— even though reported in systemic WD— has yet to be observed in primary WD of the brain but could be fatal, especially in those previously
treated with immunosuppression (Biagi et al., 2012; El- Abassi et al., 2017).
Recent studies suggest that stroke of cardioembolic origins from T. whipplei
endocarditis may complicate the neurological presentations and further compromise cognitive function. Further, the T. whipplei endocarditis may be occult
(Mecklenburg et al., 2023). T. whipplei PCR positivity identies the pathogen in the
CNS and implies direct infection. However, T. whipplei PCR positivity does not pre-
dict neurological phenomena, and T. whipplei in the CNS does not necessarily result
in neurological phenomena. Intrathecal immunoglobulin G synthesis, as detected
by measuring oligoclonal bands, may be low, implying an impaired antibody and
immune response in individuals developing CNS WD (Mecklenburg et al., 2023).
CNS vasculitis may complicate CNS WD, compromising brain function and adding
to diagnostic and management complexity (Giollo et al., 2020) (Figure 10.2).
Direct invasion
Seizures
Obstructive
sleep apnea
Thiamine
deficiency
Vasculitis
Figure 10.2 Neurological and neuropsychiatric mechanisms of Whipple’s disease.
WHIPPLE’S DISEASE
• Neurology
• Neuropsychiatry
Stroke
Immune
response
Inflammatory
response
Immune
reconstitution
syndrome
Infectious Disease and Neurocognition
Conclusion
WD of the brain in its primary and secondary forms may mimic almost the entire
spectrum of neurodegenerative disorders, including prion diseases. A high index of
suspicion for CNS WD is necessary especially if there are unusual clinical features,
like oculomasticatory myorhythmia. However, despite the literature, this is not pathognomonic, and the majority of patients with neuro- WD do not have it (Panegyres
et al., 2006). When imaging features suspicious of an inammatory granulomatous
process are present in a patient with a neurodegenerative- like presentation, CSF
PCR for WD and brain biopsy must be considered. CNS WD is particularly taxing as
imaging studies may be normal. In dicult cases, pointers like gastrointestinal and
joint symptoms may provide hints to the diagnosis. As WD of the brain is curable,
early diagnosis and treatment may minimize disability, save lives, and reverse a dementia syndrome especially in those presenting with dementia, ophthalmoplegia,
and myoclonus. Early diagnosis and recognition are fundamental to the elimination
of neuro- WD. In a diagnostically challenging patient with neurodegenerative features always ask: could it be WD?
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11
Helicobacter pylori and
Cognitive Dysfunction
May A. Beydoun and Ziad W. El- Hajj
Introduction
Helicobacter pylori (Hp), a curved Gram- negative bacterium, is found in approximately 50 percent of human gastric mucosa (Marshall & Warren, 1984). It was rst
described in 1984 as a bacterium in the stomachs of patients with gastritis and peptic
ulceration (Marshall & Warren, 1984). Worldwide, it is one of the most common infectious agents (Marshall & Warren, 1984), with a prevalence estimated to be as high
as 80– 90 percent in developing countries and ranging between 35 and 40 percent
in the United States and Europe (Lacy & Rosemore, 2001; Roubaud- Baudron et al.,
2012). With an estimated incidence in the United States of 0.5– 1.0 percent/ year (Lacy
& Rosemore, 2001), infection with Hp is oen acquired during childhood, becoming
chronic during adulthood with failed treatment (Lacy & Rosemore, 2001). Hp seroprevalence increases markedly with age, with low iron stores potentially protecting
individuals against a chronic infection state, and iron deciency anemia observed
during acute infection (DiGirolamo et al., 2007). Despite a large body of research,
Hp transmission routes and reservoirs are still not fully understood (Garcia et al.,
2014). Direct person- to- person transmission is thought to be the most common
route (Kayali et al., 2018). Although environmental transmission (from drinking
contaminated water) has not been completely ruled out, it remains controversial
(Eusebi et al., 2014). Patterns of transmission seem to greatly vary with living conditions, with horizontal (familial) transmission being prevalent in developed urban
environments, but vertical transmission is much more extensive in rural developing
countries (Schwarz et al., 2008). Hp infections are oen seen in animals, but although
cross- species transmission has been theorized, no direct evidence for it has been
found (Payao & Rasmussen, 2016). Estimates that half the world’s population harbor
Hp in their stomach led to the belief that this was the main reservoir, but this is being
challenged by many studies of Hp infections in the oral cavity, especially ndings
that periodontal Hp may drive gastric reinfection even aer its eradication from the
stomach (Payao & Rasmussen, 2016). Recurrence in the rst year aer the initial infection is oen due to recrudescence, or the reappearance of the original strain due to
low- ecacy treatments that suppress but fail to eradicate the infection (Kayali et al.,
May A. Beydoun and Ziad W. El- Hajj, Helicobacter pylori and Cognitive Dysfunction In:
Medicine
DOI: 10.1093/ oso/ 9780192870414.003.0012
Helicobacter pylori 143
2018). True reinfection is oen a problem and can occur at high frequency in some
countries even aer high- ecacy treatments, though the reinfections do not seem
to trigger a recurrence of ulcers or aggravation of existing ones (Ryu et al., 2010). In
addition to its primary role in the etiology of peptic ulcers and gastritis (Marshall
& Warren, 1984), Hp infection accounts for 70– 90 percent of primary duodenal ulcers (Kate et al., 2013), and its chronic form compounded by an early age of onset
can trigger gastric carcinoma (Pandey et al., 2010) and mucosal- associated lymphoid
tumor (Bayerdorer et al., 1995). Hp seroprevalence is also higher under poor socioeconomic conditions, crowding, poor hygiene conditions, and among minority
groups (Beydoun et al., 2013; Burucoa & Axon, 2017; Grad et al., 2012). Over the
past decade, studies have linked chronic Hp infection with various extra- digestive
manifestations, including atherosclerosis (Szwed et al., 2021; Wang et al., 2020a), hypertension (Fang et al., 2022; Yue et al., 2023), and stroke (Doheim et al., 2021), with
a growing body of evidence suggesting that this infection may play a causal role in
neurocognitive and neuropsychiatric disorders, including all- cause and Alzheimer’s
disease (AD) dementia, Parkinson’s disease (PD), multiple sclerosis (MS), and depression. erefore, prevention of chronic Hp infection can potentially have a
marked impact on these disorders and their prognosis. e following chapter reviews
the most recent literature and consensus ndings based mainly on meta- analyses,
describing in detail biological mechanisms behind those associations.
Helicobacter pylori and neurocognitive and
neuropsychiatric mechanisms
Disruption of vitamins and homocysteine metabolism
e potential link of Hp with various neurocognitive and neuropsychiatric disorders, including AD, all- cause dementia, PD, MS, and depression, was suggested to
be triggered by several mechanisms that ultimately aect the brain and its vascular
system (Figure 11.1). ese mechanisms broadly fall under two major categories: (1)
disruption in the availability of certain nutrients (specically vitamins and homocysteine (Hcy)) due to endothelial damage, and (2) apoptosis caused by several factors including T- cell- mediated immune response (Beydoun et al., 2024).
Persistent Hp infections oen lead to atrophic gastritis, or chronic inammation
of the mucous membrane of the stomach. e resulting endothelial damage to this
layer disrupts absorption of essential nutrients, including malabsorption of folate and
vitamin B12. ese vitamins are involved in Hcy metabolism; Hcy is synthesized from
methionine, but cells can also recycle it back into methionine to prevent Hcy accumulation through a methylation reaction involving 5- methyl- tetrahydrofolic acid
and vitamin B12. Deciencies in folate and vitamin B12 therefore lead to the increased
concentration of Hcy (Malaguarnera et al., 2004; Santarelli et al., 2004), and this is
thought to be a risk factor in the development of a variety of diseases. Hcy has been
H. pylori
neuron
Degenerated
bacteria
Periodontal
Cognitive
LPS
Dementia
impairment
Periphery
Brain
microglia
Activated
↑Hp IgG
Plasma cell
IL-6, TNF-α
↑CRP, IL-1, IL-1β,
. The immune response to Hp itself involves production of anti- Hp
12
Neuron
GSK-3β
tau
APP
Disease
Alzheimer’s
β
A
PSEN1
plaque
β
A
Neuroinflammation
↑IL-1β, IL-8, TNF-α
Oxidative stress
↑ CXL-13
Folate
and vitamin B-12
malabsorption
12
vitamin B
↓ blood folate and
↑ blood homocysteine
Blood vessel
Figure 11.1 The mechanism behind bacteria- associated neurodegeneration: the case of Helicobacter pylori (Hp). The lipopolysaccharide of Hp triggers the
production of inflammation mediators, including C- reactive protein, several interleukins (IL- 1, IL- 1β, and IL- 6), and tumor necrosis factor alpha (TNF- α). This
increases expression of chemokine ligand 13, which activates microglia, and these in turn induce a neuroinflammatory response. Hp infections also lead to
activation of presenilin 1 and subsequent release of amyloid beta (Aβ), as well as GSK- 3β- mediated hyperphosphorylation of tau protein. Gastrointestinal
infections by Hp also impair the absorption of vitamins such as folate and vitamin B
immunoglobulin G (IgG). Overproduction of IgG, vitamin deficiencies, neuroinflammation, accumulation of Aβ plaques, and tau tangles are all hallmarks of
dementia and are linked to neurodegeneration and subsequent cognitive impairment.
Source: Created with BioRender.com. Adapted from Piekut T., Hurla, M., Banaszek, N., Szejn, P., Dorszewska, J., Kozubski, W. & Prendecki, M. 2022. Infectious agents and Alzheimer’s
disease. J Integr Neurosci, 21, 73.
Helicobacter pylori 145
linked to oxidative stress pathways through its interaction with highly reactive transition metals such as copper. Hcy can enhance copper toxicity and precipitate endothelial damage and neurodegeneration through oxidative injury, which can lead to both
cardiovascular- related damage as well as dementia (White et al., 2001). B vitamins
are important cofactors in many reactions such as neurotransmitters and myelin
synthesis, energy pathways, and other functions of the nervous system (Dominguez
et al., 2006). Vitamin B12 deciency in particular may give rise to cognitive impairment ranging from memory loss to potentially reversible dementia (Nagga et al.,
2003). Among B vitamins, folate deciency was also shown to increase the risk for
mood disorders, particularly depression with multiple pathways involved (Bo et al.,
2020; Wu et al., 2022). Specically, folate aids in the synthesis of neurotransmitters by
promoting tetrahydrobiopterin’s (BH4) production, a co- factor for converting phenylalanine to tyrosine and the hydroxylation of tyrosine and tryptophan (Levitt et al.,
1965). ese two reactions are limiting steps in the synthesis of many key neurotransmitters including dopamine, norepinephrine (noradrenaline), and serotonin. In fact,
reductions in biopterin excretion were found in depressed patients (Anderson et al.,
1992; Coppen et al., 1989), indicating poor BH4 bioavailability.
Apoptosis
e other major mechanism linking Hp with the brain and its vascular system is apoptosis caused by either T- cell- mediated immune response, overexpression of nitric
oxide, or molecular mimicry of host structures. Hp- induced inammation around
the gastric mucosa can occur from a combination of these factors such as when the
molecular mimicry between Hp epitopes and gastric H+ / K+ - ATPase causes the latter
to be targeted as an autoantigen by cytolytic T lymphocytes (D’Elios et al., 2005).
Serum parietal cell autoantibodies also correlated with the serological titer of Hp,
which provides additional evidence for molecular mimicry (Sheu et al., 1997). An
analogous case of molecular mimicry is also seen with Campylobacter jejuni, the
main cause of gastroenteritis, which is now known as the most common antecedent
to Guillain– Barré syndrome, an autoimmune neuropathy (Moran & Prendergast,
2001). Recent evidence suggests that immunoglobulin (Ig)- G antibodies targeting
VacA, an exotoxin secreted by Hp, can cross- react with human Na+ / K+ - ATPase
A subunits in Schwann cells and lead to demyelination in some patients, a phenomenon that is also relevant to MS (Chiba et al., 2002). is nding suggests a possible
cross- reaction between Hp and ganglion cells in AD neuropathy (Kountouras et al.,
2007b). More generally, molecular mimicry, if present, has the ability to impart a
chronic low- grade inammation that should be considered among potential mechanisms for the Hp– AD as well as the Hp– MS association (Piekut et al., 2022). Hp
might be linked to the pathogenesis of PD by crossing the blood– brain barrier aer
ingestion or inhalation, or via circulating monocytes, and subsequently triggering
apoptosis in nerve cells (Camci & Oguz, 2016).
Infectious Disease and Neurocognition
Finally, Hp also triggers other inammatory responses through multiple pathways
such as cytokines (interleukin (IL)- 1, IL- 6, IL- 8, IL- 10, IL- 12, tumor necrosis factor
alpha, interferon gamma), platelet activation, acute phase proteins (brinogen, Creactive protein), and eicosanoids (leukotrienes, prostaglandins), all of which lead to
both apoptosis and thrombosis or vascular lesion (Kountouras et al., 2007b). IL- 10 is
particularly intriguing when assessing the eect of Hp on dierent neurological diseases because of its role as an anti- inammatory interleukin. Hp induces IL- 10 production to suppress the antibacterial T cells, which allows it to propagate and increase
Hcy levels as previously discussed; the resulting damage to the blood– brain barrier
and accumulation of amyloid beta (Aβ) are hallmarks of AD (Kountouras et al.,
2007b). However, this suppression mechanism also decreases the neuroinammation
caused by these same T cells and that is oen associated with MS, which led to the
suggestion that Hp may in fact act as a protective factor against MS (Park et al., 2017).
A few hypotheses have been advanced to explain the high co- prevalence of Hp
and PD. In addition to the apoptotic pathway discussed earlier, glycolipids that are
unique to Hp may be involved (Hirai et al., 1995). Mice fed with sterol glucosides
puried from cycads, which are very similar to those found in Hp, develop both behavioral symptoms as well as disruption of dopamine signaling, both hallmarks of
PD (Schulz et al., 2006). Similar experiments using the Hp glucosides would be more
conclusive, but no data are yet available.
Helicobacter pylori and neurocognitive and
neuropsychiatric disorders: Animal models and
in vitro studies
Two recent animal model studies suggest a link between Hp infection and Aβ
and p- tau AD pathology (Harris & Harris, 2015). e rst one used mouse neuroblastoma N2a cells transfected with human Aβ precursor protein (AβPP) to
overexpress AβPP (Wang et al., 2014). Incubating these cells with Hp ltrate increased the production of presenilin- 2 and Aβ42 (Wang et al., 2014). e same study
showed that intraperitoneal injection of Hp ltrate in rats leads to spatial learning
and memory decits, abnormal hippocampal dendritic spine maturation, and increased presenilin- 2 and Aβ42 in the hippocampus and brain cortex (Wang et al.,
2014). Presenilin- 2 is a key component of the gamma secretase enzyme complex,
which cleaves AβPP to produce Aβ, and mutations in the presenilins have been
shown to increase accumulation of Aβ in AD (Citron et al., 1997) and potentially
in other neurological diseases such as PD (Meeus et al., 2012). In another study, Hp
ltrate activated glycogen synthase kinase- 3 beta in N2a cells, which induced significant hyperphosphorylation at several AD- related phosphorylation sites in tau protein (Wang et al., 2015). is study also used intraperitoneal injection of Hp ltrate
in rats, and here the authors observed signicant tau hyperphosphorylation in the
hippocampus of the injected rat brains, which agrees with their cell culture results
Helicobacter pylori 147
(Wang et al., 2015). However, they did not see any microglial activation or elevated
cytokine levels in the brain or plasma. e authors concluded that soluble Hp exotoxins may induce tau hyperphosphorylation and that tau aggregation could be prevented by Hp eradication (Wang et al., 2015).
e potential preventative eect of Hp on MS has been observed several times in mice
models. One study found that ingestion of Hp reduced prevalence of EAE (a common
mouse model of MS); these mice had reduced numbers of several T- cell types in the
spleen and the central nervous system, the same cells usually found in MS patients and
thought to contribute through inammation and demyelination (Cook et al., 2015).
Epidemiological evidence
Alzheimer’s disease and related dementias
Dementia is a severe global ability loss in several domains of cognition coupled with
dependence in activities of daily living in previously healthy individuals (Huang
et al., 2014). It has an estimated prevalence in adults over 60 years of 4.7 percent
(Sosa- Ortiz et al., 2012) with 4.6– 7.7 million cases added each year worldwide (3.5–
10.5 per 1000) (Ferri et al., 2005; Prince et al., 2013; Sosa- Ortiz et al., 2012; Beydoun
et al., 2023). Approximately 60– 80 percent of dementia is of the AD subtype (SosaOrtiz et al., 2012), a progressive neurodegenerative disorder known for its multifactorial etiology, and manifesting with episodic memory deterioration followed by
impairment in other cognitive domains (Lindeboom & Weinstein, 2004; Beydoun
et al., 2023). ought to be caused by age- dependent and progressive Aβ- amyloid
brain deposition— “the amyloid cascade hypothesis” (Hardy & Selkoe, 2002), AD is
also characterized by a second pathological hallmark, namely neurobrillary tangles
that arise from hyperphosphorylated tau protein (Turner, 2003). AD is the leading
cause of old age disablement (Helmer et al., 2006) and in developed countries, carries
the greatest healthcare burden ($236 billion in long- term care and hospice care cost
in the United States in 2016 ascribed to dementia) (Alzheimer’s Association, 2016;
Honjo et al., 2009). Moreover, it is the sixth leading cause of death in the United States
(Alzheimer’s Association, 2016). Around 5.4 million older Americans currently
have AD, and 13.8 million may have this disease by 2050 (Alzheimer’s Association,
2016). Since no eective treatment is currently available, prevention of AD and allcause dementia is crucial, thus the need to uncover modiable risk factors. While
late- onset AD has been associated with certain genetic factors (e.g. apolipoprotein
E epsilon 4 allele), a Lancet Commission reported in 2020 that about 40 percent of
dementia- population attributable risk is explained by factors such as early- life education, mid- life hearing loss, traumatic brain injury, hypertension, alcohol use, and
obesity, as well as later- life smoking, depression, social isolation, physical inactivity,
air pollution, and diabetes, while 60 percent remains unexplained (Livingston et al.,
2020; Beydoun et al., 2023). Identication of novel mid- life risk factors is thereby