The brain born substances. Although largely protected by the

 

 

The Blood
Brain Barrier is an acutely selective, semipermeable membrane formed of
cerebral endothelial tight junctions, Astrocyte end-feet and Pericytes, evolved
to separate the circulating blood from the periphery, and Cerebral Spinal Fluid
(CSF) from the Central Nervous System. The segregation of circulating blood and
CSF is paramount due its partial Immuno-privileged status. Previously thought
to be entirely immunoprivileged , the brain does possess resident surveillance
immunological cells, such as Microglia, Oligodendrocytes and Astrocytes. These
cells are paramount for Neurogenesis and Synaptogenesis as well as the
integrity of the neural cavity. However, increased activity of glial cells,
which comprise nearly 50% of the neural cells, indicates gliosis and subsequent
neurodegeneration, such as that seen in Alzheimer’s disease and Multiple
Sclerosis.

 

The
evolutionary advantageous development of the Blood Brain Barrier (BBB) provides
three crucial behaviours; 1) Protection from blood milieu and pathogens 2) Selective
Transport and 3) the metabolism or modification of blood or brain born
substances.  

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Although
largely protected by the BBB, the brain does encompass regions with diminished
protection, where the endothelial Tight-Junctions are replaced by Fenestrated
Capillaries, increasing permeability ; such as the circumventricular Organs,
dura mater and choroid plexus. The secretion of neurochemicals required for peripheral
bodily functions, such as the production of ACTH by the Pituitary gland, and
its subsequent stimulation of the adrenal glands, requires increased vascular
permeability, and thus the reason behind the lack of the BBB. Although
necessary, these regions of diminished vascular security provide a metaphorical
Achilles heal, both to exogenous pathogens and endogenous inflammatory cytokines. 

 

Broadly
termed the “Inflammation Response System”, inflammation and the release of
pro-inflammatory Cyotkines are released in response to damaging, harmful
stimuli such as irritants, toxins, trauma and heat, as well as Infection. The
damage of host tissue from pathogens causes the release of chemical mediators,
depending on the branch of CD4+ T cell evoked (ie Th1, Th2 and Th17) and their
subsequent release of cytokines, such as interleukin-6, Tumour Necrosis
Factor-alpha (TNF-alpha) NF-KappaB and JAK-STAT. One of the fundamental
qualities of cytokines is their induction of vascular permeability, in order to
increase blood flow and increase the number of soluble cells of the immune
system at the site of infection (NK cells, Dendritic Cells, Antibodies and CD8
T Cells). However, by using the circulatory system as a mechanism for immunity,
every perfused tissue within the body is also exposed to the cytokines,
inducing systemic vascular permeability and endothelial damage, including that
of the BBB.

 

‘Sickness
Behaviours’ are a naturally occurring, coordinated set of adaptive behavioural
changes that occur during the course of an infection, brought about by the
release of Pro-Inflammatory Cytokines. Evolutionary selected for, Sickness
Behaviours have adaptively developed in order to conserve energy in order to
combat acute infection and inflammation whilst minimising damage to bodily and
neural tissues. Sickness behaviours include that of anhedonia, depression,
fatigue and malaise and sleep disorder as well cognitive impairment. Studies
carried out by Reichenberg et al, showed that even within healthy volunteers,
when exposed to Lipopolysaccharides, found on the CSM of bacteria, they
displayed depression and anxiety, diminished social interaction and physical
activity, as well as cognitive impairment.

 

Current
thought on systemic infection and inflammation and subsequent BBB interactions
suggests a dual effect, the first being the direct infliction of damage on the
BBB within a neurally healthy individual, and the second is that it accelerates
the rate of cognitive decline in individuals that have pre-existing neurodegenerative
diseases, for example in Alzheimer’s disease (AD) and Multiple Sclerosis. The
soluble mediators gain access to neural tissue, via the CNS, the
circumventricular organs and by causing a direct increase in permeability
through the BBB. The exposure of soluble cytokines and chemokines, once in the
cranial cavity, can interfere with the structure and function of neuronal
cells, such as glial cells, neurons and astrocytes, two of which are needed to
maintain the immunological integrity of the brain. The translocation of cytokines
and the subsequent damage of neural cells, leads to an imbalance in the
carefully regulated homeostatic systems and the manifestation of behavioural
and cognitive alterations and deficits, primarily designed to protect the body
and remove the infection. Although Sickness Behaviours are often acute and self
limiting, upon occasion of constant systemic inflammation these changes can
become a permanent fixture, as seen in survivors of Sepsis and patients with
Systemic Lupus Erythematosus, (SLE) (a chronic autoimmune disease).

 

SLE is
chronically relapsing and involves not only multiple organ, but also the CNS
and symptoms, including motor, cognitive, behavioural and sensory impairments,
are attributed to the deposition of Immunoglobulin complexes. Individuals with
deposits located within the CNS have an increase in psychiatric involvement
ranging up to 95%.(Ainiala et al). Evidence so far currently suggests the
decline in memory capabilities is attrivuted to ADCC (Antibody dependent cell
mediated cytotoxicity) of neuronal cell Receptors, for example glutamatergic
NMDA receptors in the hippocampus, as well as a significant increase in
hippocampal atrophy. (Appenzeller et al)

 

Current
research has identified one of the key pathways involved in regulation of
neuroimmunity, termed the Cholinergic Efferent Pathway (CAP), which uses
indirect stimulation of the release of Noradrenaline by splenic nerve via the
Vagal Nerve. The release of NAdr stimulates a class of splenic T Cells
(specifically CD4+CD44hiCD62L,) which in turn binds to Alpha7 Nicotinic
receptors on the Cell Surface Membrane of Macrophages. This innervation of
Macrophages causes subsequent regulation and modification of the release of TNF
alpha. A study in 2002 by Bernik et al, has proven the stimulation of the
neuronal reflex (CAP) can modify the inflammation and in turn, the survival of
patients with Sepsis, proving the close interconnection of the brain and immune
system.

 

The
induction of systemic inflammation is not solely down to infection. A study in
1991 by  Kiecolt-Glaser et al discovered
a significant link between the increase in incidence of illness and cognitive
decline in those who are caregiver to relatives with Alzheimer’s Disease –or
those exposed to chronic stress. A secondary study, was carried out by Epel et al
in 2004, which suggested the dysfunction in the immune system due to chronic
stress caused an increase in the destruction of telomerase and telomeres
respectively, leading to early onset immune senescence , leaving an individual susceptible
to further chronic inflammation and accelerated decline in cognitive function.

 

Unlike
acute, diffuse infections such as Sepsis, chronic illnesses that illicit
long-term inflammation post and prior to diagnosis, including that of hepatitis
B and C, HIV and Tuberculosis, have also been proven to show a positive
correlation with cognitive, behavioural and emotional impairments. With chronic
infections, the immune response is organised and focused and although often
unable to clear the infection, ie HCV, the immune response is significant
enough to elevate the risk and incidence of depression and malaise. Not only
this, but samples of metabolic brain activity from individuals with HCV are
significantly impeded as analysed by Hilsabeck and Forton et al. An extreme
case of this was seen in Clive Wearing, dubbed the man with 7 second memory,
with Herpes-Simplex Virus induced encephalitis and destruction of the
hippocampus.

 

From
laboratory and animal models, the suggestion of neurotoxicity mediated by NMDA
signalling contributes to brain impairment (Dawson et al).  Levels of NADPH oxidative activity and nitric
oxide synthase (iNOS) were sampled following infection and indicated a
significant rise in levels of metabolites associated with a negative neuronal
effect, which was further confirmed from post-mortem analysis of patients that
died from Sepsis (Sharshar et al).This discovery prompted a team headed by
Yokoo et al, to administer Endarvone prior to the development of sepsis, which
showed a reduction in neuronal damage and a decrease in BBB permeability.

Furthermore, but administration of antioxidants to combat the reactive oxygen
species produced by iNOS, such as Deferoxamine and N-Acetylcysteine after
sepsis, indicated a long term reduction in cognitive decline as well as
suggesting possible neuroprotective properties (Barichello et al.)

 

Pro-Inflammatory
cytokines released in response to systemic, peripheral infection mediate a
decline in cognitive and brain function. Sepsis stimulates the release of the
proinflammatory signal HMGB1 which primes monocytes, including those residing
in neural tissue to produce  inflammatory,
damaging cytokines (Valdes-Ferrer et al). This increase in HMGB1 is supported
by a decrease in CA1 dendritic spine density of NMDA Glutamate Receptors,
suggesting a possible imbalance in the ratio of excitatory to inhibitory
synapses, commonly seen in diseases such as Autism Spectrum Disorders. From
studies carried out by Ely et al, 81% of sepsis survivors develop SAD – or
Sepsis Associated Delirium, and SAD induced in elderly patients have been
proven to cause cognitive decline so severe that it impedes with quality of
life.( Iwashyna et al). MRI imaging has also identified regions of increased
white matter, which is emphasised in neonatal sepsis. Babies who experience
sepsis post gestation have an increase in white matter (increase of 66%) which
is directly correlated with a decline in psychomotor and neural development
(Shah et al) indicating that not only does sepsis and bacterial infection impact
on brain function but also on neural connectivity and structure. Further more,
post mortem brain histology carried out on the brains of Sepsis victims showed
a significant increase in white matter located within the cerebral cortex, and
within it the levels of amoeboid-shaped activated microglia and Major
Histocompatibility Complex Class II (MHC II) microglia, both of which indicate
the presence of infection and inflammation, as well as tissue degeneration
within the Brain (Lemstra et al).  

 

Animal
models can be particularly helpful in demonstrating complicated and ethically
turbulent disorders. In 2005, rats with forcibly induced Sepsis, even once
recovered and with negative, clean blood cultures, indicated persistent and
permanent cognitive dysfunction. Not only this but intricate studies looking at
the molecular and cellular disturbance of neural tissue induced by sepsis discovered
a below than average cell membrane recovery potential, as well as the BBB
within mice becoming ‘leaky’ under 20 hours after infection, subsequently
followed by an increase in neural degeneration.

 

GFAP or
Glial Fibrillary Acidic Protein is commonly used to measure the rate of neural
decline and progression of Alzheimer’s disease. When mice were exposed to
systemic LPS, 4 hours post administration, mRNA levels of GFAP as well as
Toll-Like Receptors 2,4 and  interleukin-1beta
and 6, ( all markers of inflammation) , were detected at a significantly
increased rate, suggesting that neuronal glial cells and inflammation of the
cortex occur simultaneously with the progression of  systemic infection.( Silverman et al). Mouse
models of LPS induced sepsis (10% mortality) showed indefinite neurological
defects, particularly that of astrogliosis within the dentate gyrus and
hippocampus, interfering with working memory and modification of excitatory
signalling (Fu et al).

 

Delirium
and Sickness Behaviours can be directly attributed to proinflammatory soluble
cytokines, including that of TNF alpha, HMGB1 and interleukin-1beta. Further
animal models suggested an increase in the number and activation of microglial
cells within the hippocampus and a decline in the proliferation of neural stem
cells, displayed behaviourally as a decrease in memory and social-spacial
tests. (Anderson et al). (1700)

 

Not only
does systemic infection induce cognitive impairments, but it can accelerate pre-existing
neurodegenerative diseases. Research being currently undertaken at the
University Of Southampton have identified a 6 fold increase in the rate of
cognitive decline not only in elderly AD patients with Urinary Tract
Infections, but also elderly AD patients following surgical trauma, such as
that of a hip replacement .In vivo studies have identified that trauma or
surgical exposure can stimulate the release endogenous proinflammatory
cytokines (DAMPs) – specifically that of interleukin 1 and tumour necrosis
factor (TNF) alpha (Terrando et al). Similarly a study carried out by Brugg et
al identified an increase in levels of beta-amyloid precursor peptides (APP)
nearly 24 hours post exposure to LPS, in transgenic mice with presustained AD.

As well as exhibiting a decline in motor coordination and cognitive
capabilities. Furthermore, rat models of toxin induced Parkinson’s disease (by
the precursor 5-hydroxydopamine) exposed to chemically induced systemic
infection by interleukin-1beta, showed a significant decline in neuronal number
and dopaminergic neurons as well as an increase in the number of Substantia
Nigra microglia cells, all correlated with a decline in cognitive, social and
behavioural performance.

 

Highlighted
throughout, its evident that the intricate cross-talk and interaction between
the immune system and nervous system is highly complicated, yet undoubtedly existent.

The stimulation of interleukin-1beta, TNFalpha and other proinflammatory
cytokines by systemic, peripheral inflammation and infections, underpin the
necessary yet if sustained, deleterious neuropsychiatric induction of sickness
behaviours. Indefinite systemic inflammation, common in not only autoimmune
diseases (SLE) but in previous septic patients, not only accelerates cognitive
decline in susceptible, primed brains (AD and Parkinsons) but can induce
destruction of neural tissue in multiple regions of the brain in previously
healthy individuals, affecting memory, behavioural and cognitive functions via
the increased vascular permeability of the Blood Brain Barrier.

 

 

 

 

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