Another good article re CFS?

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From: DSNurse@...

Sent: Tuesday, August 16, 2005 6:19 PM

CFS PHOENIX

A Laymen's Guide to Choline in Chronic Fatigue Syndrome

Part I: Choline on the Brain?

By Cort

This paper largely follows the outline of a paper by Chaudhuri and Behan that

examined magnetic resonance studies on CFS (Chaudhuri and Behan 2004).

Brain Metabolic Activity in CFS -. Three studies have examined metabolic

functioning in the brain using proton magnetic spectroscopy (MRS) (Chaudhuri et.

al. 2003, Tomoda et. al. 2000, Puri et. al. 2002). The levels of three

metabolites (N-acetyl aspartate (NAA), choline, creatine) in the brain are

examined using this technique.

Puri’s study found that CFS patients (a) have significantly higher levels of

choline in the occipital region of the brain than do controls and ( exhibit an

abnormal choline gradient between the motor and occipital cortex (Puri et. al.

2002). Chaudhuri’s study found increased choline levels in the basal ganglia

(Chaudhuri et. al. 2003). A very small study (n=3) examining adolescents with

CFS also found increased choline levels in the basal ganglia as well (Tomoda et.

al. 2001). Three studies then, all of them small, but most with highly

significant findings (p<.05, p<.001, p<.008) have found increased brain choline

levels mostly in the basal ganglia. Normal NAA levels in two studies indicated

neuronal mass was not disturbed.

The Basal Ganglia - The basal ganglia are large masses of gray matter at the

base of the cerebral hemisphere; i.e. they are near the base of the skull where

it meets the spinal column. They provide a nexus for interactions combining

limbic/motor activities with volition; i.e. they play a key role in internal

motivational states. How they function can effect our perception of effort.

The limbic system is a collective term that denotes an array of interconnected

brain structures (hippocampus, amygdale, fornicate gyrus) at or near the edge

(limbus) of the cerebral hemisphere that connect with the hypothalamus. By way

of these connections, the limbic system exerts an important influence upon the

endocrine and autonomic motor systems and appears to effect motivation and mood.

Basal ganglia dysfunction often causes problems with ‘tasking’. Sequential

task processing, for instance, an important process used in initiating and

following through complex tasks, is often impaired. The ‘reward’ system

which provides motivational impulses that in turn stimulate other parts of the

brain is also often disrupted. Since the brain has trouble carrying information

from one stage to the next then doing tasks, especially complex ones, can become

very labor intensive and highly effortful.

A disease called akinesia which is defined as " poverty and slowness in willful

movements " can also occur because of basal ganglia disease. It is believed to

result from the inability of the brain to respond to environmental cues such as

sight, sound and touch.

Choline - is found in three forms in humans; phosphatidycholine (lecithin),

acetylcholine and cytidine diphosphocholine. Most of the choline in the body is

found in specialized fat cells called phospholipids that are abundant in the

membranes of cells. Choline in used in the synthesis of three components in cell

membranes; phospholipids, phosphatidycholine (lecithin) and sphingomyelin.

Causes of increased brain choline production - Elevated brain choline levels are

usually associated with increased cell production (malignant tumors) and/or

increased cell membrane turnover due to inflammation or ischemia (Chaudhuri et.

al. 2003). Immune cell activation by macrophages and/or neuronal astrocytes has

been shown to produce choline peaks in AIDS patients. Accumulations of

neutrophils, lymphocytes and macrophages have also been associated with high

choline peaks in patients with non-malignant tumors of the brain (Cummings et

al. 2000).

Areas of inflammation and cell death are readily observed on MRI’s. Two MRI

studies, however, have found no indication that either are present in the basal

ganglia of CFS patients. Apparently whatever is causing the increased choline

levels is not activating the immune system. Nor have systematic metabolic

studies on lipid and peroxisomal function indicated systemic abnormalities in

phospholid metabolism. Given these findings the authors suggest the changes seen

are due to local changes in the lipid composition of the membranes of the nerves

that could be due to reparative gliosis or altered ‘intramembranal

signaling’ (Chaudhuri et. al. 2003).

Glial cells are non-neuronal components of the central nervous system that

closely interact with neurons. Consisting of astrocytes, oligodendroctyes and

microglia cells, they play an important role in neuroprotection. Through their

detoxification of glutamate they confer protection against glutamate toxicity.

Glial cells also secrete trophic factors that appear to protect against cerebral

ischemia. Through their ability to siphon off excess potassium from neurons they

regulate potassium levels.

Most glial cells are astrocytes that surround the ends of the synapses and

border endothelial cells in the capillaries. They help shuffle nutrients and

metabolites from the blood into the neurons and play an important role in

regulating the extracellular concentrations of ions, metabolites and

neurotransmitters and in supporting neuronal functioning. Olidgodendrocytes form

myelin, an substance involved in the propagation of the action potential

involved in nerve impulse transmission. Continual monitors of the

microenvironment, microglia rapidly react to pathological changes in their

microenviroment with cytokine and/or trophic factor production (Hansson and

Ronnback 2003).

Reparative gliosis or glial cell activation often occurs in response to tissue

injury in the brain. Activated glial cells such (as astrocytes and the microgla)

produce several cytokines (IL-1, S100B) that appear to ameliorate, at least at

first, neuronal damage. Chronic glial cell activation appears to cause a cascade

of events that eventuate in neurodegneration. Gial activation and cytokine

production have been implicated in the progression of Alzheimers disease, for

instance (Mrak and 1997). Some evidence suggests that glial activation

increases the risk of Alzheimer’s, as does interestingly, head trauma. While

transient glial activation occurs in many viral encephalopathies, chronic glial

cell activation occurs, for reasons that are not yet known, occurs in AIDS (Mrak

and 1997). Mrak and 's suggestion that neurodegeneration could

'persist or progress even following successful eradication of the virus' is

intriguing given the viral-like presentation of symptoms often initially seen in

CFS. Somewhat ominously they question whether chronic glial activation may place

one at risk for Alzheimer's (Mrak and 1997).

Levels of a substance produced by astrocytes, granulocyte/macrophage colony

stimulating factor (GM-CSF), were significantly lower in the spinal fluid of CFS

patients (Natelson et. al. 2005). Reduced levels of this factor, which plays a

role in granulocyte and macrophage development and the inflammatory process,

could signal a hole in the immune defenses through which bacteria, in

particular, could slip. It is intriguing that choline upregulation occurs in CFS

patients without evidence of inflammation. Some not well informed speculation

might question whether the lack of inflammatory response in the face of

reparative gliosis could be due to reduced levels of GM-CSF? (It is clear that

normal inflammatory processes do not occur always occur in the brain but I am

unclear if reparative gliosis often occurs without signs of inflammation (???);

i.e. is the situation in CFS of no inflammation but increased choline levels

unusual?).

Interestingly glial cells are the main source of a growth factor in the brain of

a cytokine, transforming growth factor beta, (TBG-, that is increased in the

PBMC’s or serum of CFS patients ( et. al. 1994, et. al. 2000,

Kennedy et. al. 2004). TBG-b activity in the brain appears to contribute to

further neurodegeneration (Borlongan et. al. 2000).

An ATP Connection? – Chaudhuri and Behan suggest there may be a connection

between the high brain choline levels and reduced ATP production. Evidence of

impaired ATP production in two subsets of CFS patients and in another fatigue

syndrome suggests reduced ATP production exists in at least some CFS patients.

A few small studies using magnetic resonance spectroscopy have found that at

least a subset of CFS patient’s exhibit significantly reduced skeletal muscle

exercise capacity that is accompanied by an early onset of intracellular

acidification. In the one larger study (n=46) twenty percent of CFS patients had

reduced phosphocreatine (PCr) /ATP ratios and higher levels of ADP upon

exercise.

When energy is released ATP is transformed into ADP. Since higher rates of ADP

imply higher ATP utilization – this study appears to indicate that CFS

patients are using up ATP faster than normal. The breakdown of PCr furnishes the

phosphate needed for the resynthesis of ATP from ADP. Thus low PCr ratios

indicate that less phosphate is available to resynthesize ATP. Thus not only are

some CFS patients using up ATP faster than normal they appear to be less able

than normal to resynthesize ATP.

Two other studies have found reduced ATP concentrations during exercise and

reduced PCr recovery during exercise in CFS. The common component to all these

studies appears to be reduced availability of ATP probably because of increased

breakdown of ATP; i. e. increased energy utilization in CFS patients.

Intriguingly, Chaudhuri and Behan have also reported significantly increased

resting energy expenditure (REE) levels in CFS patients.

CFS is not the only fatigue ‘syndrome’ that appears to be associated, at

least in part, with reduced ATP levels. Cardiac syndrome X (CSX) is

characterized by cardiac angina pain, a normal angiogram and in a significant

portion of long term patients fatigue, muscle pain and exercise intolerance. CSX

is believed caused by reduced ATP levels in the cardiac cells. Twenty percent of

CSX patients in a recent study exhibited PCr/ATP ratios in cardiac muscle

similar to those found in the skeletal muscles of CFS patients.

Intriguingly a thallium cardiac scan of CFS patients indicated that CFS patients

may display cardiac cell abnormalities similar to those found in CSX ( et.

al. 1997). High outflows of cellular potassium may be responsible for the

defects in thallium tracer distribution in the left ventricles of CFS patients

( et. al. 1997, Chaudhuri et. al. 2003). An interesting finding given Dr.

Cheney’s focus on energy production in the hearts of CFS patients.

Putting It All Together – CFS is a Disease of Increased Phospholipase (PLA)

Activity - Chaudhuri and Behan suggest increased choline levels contribute to

cognitive dysfunction (effortful task processing) and reduced ATP levels impair

aerobic metabolism and contribute to the exercise intolerance seen in CFS. What

might increased brain choline and decreased ATP production have in common?

Chaudhuri and Behan believe reduced muscle ATP levels and increased brain

choline levels are due to increased phospholipase (PLA) activity. This appears

to suggest they believe increased PLA activity occurs not just in the brain but

is systemwide. Since PLA is ubiquitous in the body increased PLA activity could

affect a wide variety of tissues.

Phospholipases (PLA’s) – are a superfamily of esterases that release

phospholipids ‘moieties’ (fractions) including choline when they hydrolyze

(break) the ester bonds in the lipids in membranes in an ATP driven process.

Phospholipids in the CNS cell membranes are high in polyunsaturated fatty acids

(PUFA’s) and PUFA metabolism is ‘stringently controlled’ by PLA2 (and

acetyltransferase). Normally when fatty acids are released by PLA2 they are

rapidly taken up by membrane phospholipids by an energy dependent mechanism

using CoA and ATP.

Phospholipase activity releases factors that exert widely varying effects in the

cell. Phospholipids play a key role in regulating the release of arachidonic

acid, the precursor of eicocanisoid synthesis. The eicocansoids (prostaglandins,

thromboxanes, leukotrienes) mediate (trigger) the inflammatory process. A marker

of cellular injury, the inflammatory process begins with the release of AA. AA

is broken up to produce pro-inflammatory mediators such as prostaglandins (COX

1, 2) and leukotrienes. Prostaglandins then combine with cellular receptors to

initiate signaling cascades which utilize G-proteins and cyclic CMP (cAMP) to

produce pro-inflammatory substances.

PLA2 activity has been implicated in the pathology of a number of

neurodegenerative diseases including Alzheimer’s and is thought to play a role

in neuronal plasticity (Sun et. al. 2004). The activation of the P2Y nucleotide

receptor on astrocytes triggers ‘reactive gliosis’, a process implicated in

these neurodegenerative diseases and which may be occurring in CFS.

Another type of phospholipase, PLD2, also liberates choline from cell membranes.

PLD2 is also known as choline phospholipase. Some of the choline released is

used to make acetylcholine, a key neurotransmitter. One form of PLD2 appears to

be localized in the caveolar domains of plasma membranes that viruses often use

to penetrate the cell.

TRIGGERING PHOSPHOLIPASE ACTIVITY - Why phospholipase activity would be

increased in CFS patients is unclear. CFS patients appear to be subject,

however, to several factors (infection, increased neurotransmitter/ cytokine

levels, oxidative stress, neurotoxins) that could trigger phospholipase

activity. Chaudhuri et. al. note that infection and/or neurotoxins can produce

prolonged changes in membrane functioning (Chaudhuri et. al. 2003). The authors

suggest the adaptation of the host cell to either a pathogen or its exotoxin

(neurotoxin) could result in a long term derangement of the membranes.

Viruses – Viruses can induce phospholipase activation and the release of

lipids including choline by effecting membrane permeability. Indeed, many

bacteria, viruses and parasites utilize lipid rich membrane domains as routes of

entry into the cell. Does the lack of immune activation (inflammation) in the

brains of CFS patients suggests either an ongoing pathogenic attack is not

involved or that it occurs without evoking an immune response (?). The

possibility that a neurogenic pathogen could trigger PLA activity immediately

brings up the question of two viruses, HHV6 and EBV, that have been historically

linked with CFS.

HHV6 – infects the very cells Chaudhuri and Behan suggest may be producing the

choline peaks in CFS. The HHV6 foundation suggests HHV6 activity in the glial

cells could cause fatigue by altering ion channel function. A very high

percentage of CFS patients test positive for ciguatoxin, a marker of ion channel

dysfunction (Hokama et. al. ).

HHV6 is ubiquitous in the human population; almost everyone has been exposed to

it by third year. The lack of an antigenic response to HHV6 in healthy controls

suggests it remains in its latent state most of the time. In vitro studies

indicate HHV6 is able to infect a number of nervous system cells including

neurons, astrocytes, oligodendrocytes, microglial cells). Astrocytes, in

particular, appear to function as latent reservoirs for the virus. Antigenic

responses to HHV6 in MS and a type of encephalitis indicates HHV6 reactivation

occurs in some neurological disorders. PCR analysis has indicated HHV6 is

present in encephalitis, meningitis, febrile seizure and encephalopathy. HHV6

reactivation occurs in two neurological diseases, multiple sclerosis (MS) and

Guillain-Barre syndrome, in which fatigue is a prominent symptom (Dewhurst

2004).

Two variants of HHV6 exist, HHV6A – which has not been clearly associated with

any disease, and HHV6-B – which is responsible for most of the symptomatic

infections in childhood. HHV6A appears to occur more commonly in central nervous

system (CNS) tissues than HHV6-B (Dewhurst 2004).

The history of HHV6 and CFS is decidedly mixed. Once thought to be a key factor

in CFS, after many studies HHV6 activation is generally now thought not to play

a major role in CFS. Questions regarding the efficacy of most HHV6 testing

procedures in establishing the presence of an active population have, however,

left a window open for HHV6’s possible re-emergence as a vital research topic

in CFS. The HHV6 foundation asserts that only early antigen testing of HHV6 is

effective in CFS.

Epstein-Barr Virus (EBV) – EBV has an even more tortured history with CFS than

does HHV6. Once thought possibly to be the cause of CFS EBV is now considered

only to be an opportunistic infection. Recent studies indicate that as with HHV6

late antigen testing for antigens found on the surface of EBV may miss

substantial numbers of CFS patients who contain a virus that is active but fails

to replicate. Although replication is never achieved the virus is nevertheless

able to produce enzymes that negatively affect the body (Glaser et. al. 2005).

Since the inability of the immune system to recognize these enzymes could result

in a pathogenic process unaccompanied by immune activation. Could this explain

the lack of inflammation in the brains of CFS patients?

Oxidative stress – Studies indicate increased free radical production occurs

in neurodegenerative disorders. Autopsies indicate the brains of people with

neurodegenerative diseases (Alzheimer’s, Parkinson’s, ALS, Huntington’s,

etc.) display signs of oxidative damage. Whether this damage is the causal in

nature or simply a common endpoint of a chronic disease process has been a

source of controversy (Klein and Ackerman 2003).

Melatonin, a free radical scavenger, has been an effective neuroprotector in

rodents exposed to oxidative stresses (Borlongan et. al. 2000). One theory

suggests increased levels of oxidants or (neuro)toxins can rearrange the

position of lipids in membranes so that their ester bonds are more accessible to

PLA attack.

Cytokines - Cytokines such as IL-1 and TNF-a and lipopolysaccharides (LPS) and

neuronal components such as NMDA, glutamate and muscarinic cholinergic enhancers

(agonists) can all trigger PLA2 release.

Others- Neurotransmitters and growth factors can also trigger PLA activity.

Treatment recommendation - Because oxidative stress can trigger phospholipase

activity the authors recommend the use of highly unsaturated fatty acids

(HUFA’s) in CFS.

Ongoing Research - The CFIDS Association of America (CAA) is currently funding

two studies that may help; one uses hydrogen magnetic resonance spectroscopy to

examine neurometabolites in the brains of CFS patients; the other examines the

levels of a cytokine, IL-6, known to activate the SNS. Eye On The CAA.

Summary – The researchers suggest increased choline levels seen in the brains

of CFS patients occur when pathogenic (or other) insults on the cell membranes

in the brain trigger phospholipase activity and choline release. Increased

choline levels in a part of the brain involved in task processing and motor

activities (movement) could account for the fatigue associated with mental

effort and movement found in CFS. Reduced ATP levels due to high phospholipase

activity in the muscles could also contribute to the exercise intolerance seen

in CFS. Several processes that appear to be upregulated in CFS (cytokine

production, oxidative stress) could trigger phospholipase activity.

The very small sample sizes in the studies noted automatically raises a red

flag; too many small apparently significant studies of CFS patients have failed

the test of replication. It is encouraging, however, when independent study

groups, no matter how small their sample sizes, find similar results in two

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