(H. pylori, due to its’ ubiquitous nature, its’ capacity to generate large amounts of endotoxin, and its known link to PD, is a prime candidate.)

7: Helicobacter pylori:
1: FEMS Immunol Med Microbiol. 2005 May 1;44(2):129-35.

Role of inflammation in gastrointestinal tract in aetiology and pathogenesis of
idiopathic parkinsonism.

Dobbs SM, Dobbs RJ, Charlett A, Bjarnason IT.

Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College,
London SE5 8AF, UK.

Idiopathic parkinsonism (IP) is a common disorder, conventionally regarded as
neurodegenerative. Its cardinal features, poverty and slowness of movement,
muscle rigidity, postural abnormality and a characteristic tremor, are
associated with loss of dopaminergic neurones in the substantia nigra of the
brain. Genetic factors explain only a minority of cases, and a common toxic
environmental insult remains elusive. We propose that IP is a systemic disorder
resulting from a ubiquitous peripheral infection, and that only the tip of the
iceberg comes to diagnosis. There is evidence for inflammatory/immune activation
peripherally and in the brain. We have used statistical modelling to explore
links with non-specific and specific systemic markers of inflammation/infection
in IP probands, and explore whether their partners and siblings have a frank or
pre-presentation parkinsonian state. Critical to this approach is continuous
objective measures of the facets of IP. Hypotheses on causality and mechanism
are based on the statistical models. There is pathological and clinical evidence
for direct involvement of the gastrointestinal tract in IP. The candidacy of
Helicobacter pylori infection as a trigger event or driving infection is
relatively high. We have found that eliminating infection in late parkinsonism
with cachexia, a stage usually considered intractable, can result in a U-turn.
However, eradication therapy may not provide a complete solution. Persistence of
antibody against cytotoxin-associated antigen (CagA), increases the predicted
probability of being labelled as having parkinsonism. Evidence for autoimmunity
and immunocompromise is used to build schemes for the natural history. We
conclude that current classifications of neuropsychiatric disease may not prove
the best with respect to defining sub-clinical disease, prophylaxis or halting
progression.

Publication Types:
Review

PMID: 15866206 [PubMed - indexed for MEDLINE]



(Other bacteria and viruses have been linked to PD although the exact mechanism is not known. An inflammatory action would explain the association.)

8. Nocardia:
1: Braz J Med Biol Res. 2004 Apr;37(4):539-48. Epub 2004 Mar 23.

Nocardia otitidiscaviarum (GAM-5) induces parkinsonian-like alterations in
mouse.

Diaz-Corrales FJ, Colasante C, Contreras Q, Puig M, Serrano JA, Hernandez L,
Beaman BL.

Laboratorio de Fisiologia de la Conducta, Facultad de Medicina, Universidad de
Los Andes, Merida, Venezuela.

Parkinson's disease, a major neurodegenerative disorder in humans whose etiology
is unknown, may be associated with some environmental factors. Nocardia
otitidiscaviarum (GAM-5) isolated from a patient with an actinomycetoma produced
signs similar to Parkinson's disease following iv injection into NMRI mice. NMRI
mice were infected intravenously with a non-lethal dose of 5 x 10(6) colony
forming units of N. otitidiscaviarum (GAM-5). Fourteen days after bacterial
infection, most of the 60 mice injected exhibited parkinsonian features
characterized by vertical head tremor, akinesia/bradykinesia, flexed posture and
postural instability. There was a peak of nocardial growth in the brain during
the first 24 h followed by a decrease, so that by 14 days nocardiae could no
longer be cultured. At 24 h after infection, Gram staining showed nocardiae in
neurons in the substantia nigra and occasionally in the brain parenchyma in the
frontal and parietal cortex. At 21 days post-infection, tyrosine hydroxylase
immunolabeling showed a 58% reduction of tyrosine hydroxylase in the substantia
nigra, and a 35% reduction of tyrosine hydroxylase in the ventral tegmental
region. Dopamine levels were reduced from 110 +/- 32.5 to 58 +/- 16.5 ng/mg
protein (47.2% reduction) in brain from infected mice exhibiting impaired
movements, whereas serotonin levels were unchanged (191 +/- 44 protein in
control and 175 +/- 39 ng/mg protein in injected mice). At later times,
intraneuronal inclusion bodies were observed in the substantia nigra. Our
observations emphasize the need for further studies of the potential association
between Parkinson's disease or parkinsonism-like disease and exposure to various
nocardial species.

PMID: 15064817 [PubMed - indexed for MEDLINE]



(It has long been known that living in a rural environment increases the likelihood of PD. Increased endotoxic exposure is an obvious explanation.)

9. LPS and agricultural exposure:
1: Occup Environ Med. 2006 Jan;63(1):59-67.

Agricultural seed dust as a potential cause of organic dust toxic syndrome.

Smit LA, Wouters IM, Hobo MM, Eduard W, Doekes G, Heederik D.

Institute for Risk Assessment Sciences, Division of Environmental and
Occupational Health, Utrecht University, Utrecht, The Netherlands.
L.Smit@iras.uu.nl

AIMS: Episodes of serious work related health problems resembling organic dust
toxic syndrome (ODTS) in workers of a grass seed quality inspection laboratory
prompted the authors to study personal endotoxin exposure levels in this
facility and in the agricultural seed processing industry. In addition,
microbial and inflammatory characteristics of agricultural seeds were studied.
METHODS: The authors assessed inhalable dust and endotoxin levels in 101 samples
from 57 workers in grass, cereal, and vegetable seed plants who were handling
mainly grass seeds as bulk product, and horticulture seeds in smaller
quantities. Additionally, real-time dust exposure was measured using a DataRAM
monitor in 12 grass seed workers to obtain more information on exposure patterns
during specific tasks. Endotoxin concentrations in seed extracts were determined
by LAL assay and seed samples were analysed by scanning electron microscopy.
Release of inflammatory cytokines was measured in supernatants of whole blood
samples stimulated with lipopolysaccharide (LPS) or agricultural seed extracts
in a human whole blood assay (WBA). RESULTS: Endotoxin concentrations in
personal samples were high (geometric mean 1800 EU/m3), particularly in the
grass seed quality inspection lab where endotoxin levels up to 274 000 EU/m3
were measured. The recommended health based endotoxin exposure limit of 50 EU/m3
was amply exceeded in almost all personal samples. Job tasks dumping and mixing
were associated with highest dust and endotoxin exposures, which was confirmed
by real-time measurements. Microbial infestation was found in almost all seed
samples. WBA results showed that most seed extracts were capable of inducing a
pronounced dose dependent cytokine release. CONCLUSIONS: Workers handling grass,
cereal, or vegetable seeds are at risk of exposure to high levels of endotoxin
containing seed dust. Occupational exposure to inhalable agricultural seed dust
can induce inflammatory responses, and is a potential cause of ODTS.

PMID: 16361407 [PubMed - indexed for MEDLINE]


(A greater incidence of PD has been noted among men than among women for reasons unknown.)

10. LPS and gender differences in PD:

1: Curr Pharm Des. 2005;11(8):1017-30.

Estrogen and cytokines production - the possible cause of gender differences in
neurological diseases.

Czlonkowska A, Ciesielska A, Gromadzka G, Kurkowska-Jastrzebska I.

Second Department of Neurology, Institute of Psychiatry and Neurology,
Sobieskiego 9, 02-957 Warsaw, Poland. czlonkow@ipin.edu.pl

Naturally occurring sexual dimorphism has been implicated in the risk,
progression and recovery from numerous neurological disorders. These include
head injury, multiple sclerosis (MS), stroke, and neurodegenerative diseases
(Parkinson's disease (PD), Alzheimer's disease (AD) or amyotrophic lateral
sclerosis (ALS). Accumulating evidence suggests that observed differences
between men and women could result from estrogen's wide range of effects within
the mammalian central nervous system (CNS), with it's neuroprotective effect
being one of the most important. It seems possible that neuroprotective activity
of estrogen could be partially a result of it's anti-inflammatory action. It has
been well established that inflammation plays an important role in the
etiopathogenesis and manifestation of brain pathological changes. In this
regard, an important role has been suggested for pro-inflammatory cytokines
produced by activated glial cells, neurons and immune cells that invade brain
tissue. Within the CNS, cytokines stimulate inflammatory processes that may
impair blood-brain barrier permeability as well as promote apoptosis of neurons,
oligodendrocytes and induce myelin damage. Given that estrogen may modulate
cytokine expression, coupled with the fact that gender differences of cytokine
production are apparent in animal models of PD and MS, suggests an important
connection between hormonal-cytokine link in neurodegeneration. Indeed, while MS
patients and mice subjected to experimental autoimmune encephalomyelitis (EAE)
display gender specific alterations of IFN-gamma and IL-12, variations of TNF
and IL-6 were associated with PD. Also in case of more acute neurodegenerative
conditions, such as stroke, the effect of IL-6 gene G-174C polymorphism was
different in males and females. Given that our understanding of the role of
estrogen on cytokine production and accompanying CNS pathological conditions is
limited, the present reviews aims to present some of our recent findings in this
area and further evaluate the evidence that may be relevant to the design of new
hormonal anti-inflammatory treatment strategies for neurodegenerative diseases.

Publication Types:
Review

PMID: 15777251 [PubMed - indexed for MEDLINE]

(Sleep disturbances are common in PD for reasons unknown. Also, dopamine is produced and stored during REM sleep. Non-REM sleep may shorten the time available to complete this process each night.)

11. LPS inflammation and sleep:

1: Bull Exp Biol Med. 2003 Aug;136(2):110-3.

Activity of the hypothalamic-pituitary-adrenocortical system and sleep-wake
cycle in rats with acute systemic inflammation.

Eliava MI, Grinevich VV, Oganesyan GA.

I. M. Sechenov Institute of Evolutional Physiology and Biochemistry, Russian
Academy of Sciences, St. Petersburg. m_eliava@hotmail.com

Activity of the hypothalamic-pituitary-adrenocortical system and EEG
characteristics of the sleep-wake cycle were studied on adult male Wistar rats
with acute inflammation produced by bacterial lipopolysaccharide in a dose of
250 microg/100 g body weight. Blood concentrations of adrenocorticotropic
hormone and corticosterone increased by 6 and 10 times, respectively, 30 min
after lipopolysaccharide administration and peaked 2 hours after challenge. In
this period the sleep-wake cycle underwent the most pronounced changes that
could be attributed to the stupor-like state observed in clinical practice. It
was manifested in dissociation between locomotor activity of animals and EEG
characteristics, suppression of EEG components in slow-wave sleep, increase in
the number of beta-waves, and decrease in the number of delta-waves in EEG. In
the present work we consider possible mechanisms of temporal relationships
between activity of the hypothalamic-pituitary-adrenocortical system and
disorganization of the sleep-wake cycle during acute systemic inflammation.

PMID: 14631484 [PubMed - indexed for MEDLINE]



1: Am J Physiol Regul Integr Comp Physiol. 2000 Apr;278(4):R947-55.

Dose-dependent effects of endotoxin on human sleep.

Mullington J, Korth C, Hermann DM, Orth A, Galanos C, Holsboer F, Pollmacher T.

Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
mullingt@caregroup.harvard.edu

The role of the central nervous system in the host response to infection and
inflammation and modulation of these responses by the
hypothalamic-pituitary-adrenal system are well established. In animals,
activation of host defense mechanisms increases non-rapid eye movement (NREM)
sleep amount and intensity, which, in turn, are thought to support host defense,
or the body's ability to defend itself against challenges to its immune system.
In humans, the evidence is conflicting. Therefore, we investigated the effects
of three placebo-controlled doses of endotoxin on host response, including
nocturnal sleep in healthy volunteers. Administered before nocturnal sleep
onset, endotoxin dose dependently increased rectal temperature, heart rate, and
the plasma levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptors,
interleukin (IL)-1 receptor antagonist, IL-6, and cortisol. The lowest dose
reliably increased circulating levels of cytokines and soluble cytokine
receptors, but it did not affect rectal temperature, heart rate, or cortisol.
This subtle host defense activation increased deep NREM sleep amount, often
referred to as slow-wave sleep (stages 3 and 4), and intensity (delta power).
Conversely, the highest dose of endotoxin disrupted sleep. Whereas it is well
established that the endocrine and thermoregulatory systems are very sensitive
to endotoxin, this study shows that human sleep-wake behavior is even more
sensitive to activation of host defense mechanisms.

Publication Types:
Clinical Trial
Controlled Clinical Trial

PMID: 10749783 [PubMed - indexed for MEDLINE]