New Klimas Paper- NPY, Stress, HPA Axis and CFS

[shannah]

Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome.
Mary A Fletcher , Martin Rosenthal , Michael Antoni , Gail Ironson , Xiao R Zeng , Zachary Barnes , Jeanna M Harvey , Barry Hurwitz , Silvina Levis , Gordon Broderick and Nancy G Klimas

Behavioral and Brain Functions 2010, 6:76doi:10.1186/1744-9081-6-76


Published: 29 December 2010

Abstract (provisional)

Background
Chronic fatigue syndrome (CFS) is a complex, multi-symptom illness with a multisystem pathogenesis involving alterations in the nervous, endocrine and immune systems. Abnormalities in stress responses have been identified as potential triggers or mediators of CFS symptoms. This study focused on the stress mediator neuropeptide Y (NPY). We hypothesized that NPY would be a useful biomarker for CFS.

Methods
The CFS patients (n = 93) were from the Chronic Fatigue and Related Disorders Clinic at the University of Miami and met the 1994 case definition of Fukuda and colleagues. Healthy sedentary controls (n = 100)) were from NIH or VA funded studies. Another fatiguing, multi-symptom illness, Gulf War Illness (GWI), was also compared to CFS. We measured NPY in plasma using a radioimmunoassay (RIA). Psychometric measures, available for a subset of CFS patients included: Perceived Stress Scale, Profile of Mood States, ATQ Positive & Negative Self-Talk Scores, the COPE, the Beck Depression Inventory, Fatigue Symptom Inventory, Cognitive Capacity Screening Examination, Medical Outcomes Survey Short Form-36, and the Quality of Life Scale.

Results
Plasma NPY was elevated in CFS subjects, compared to controls (p=.000) and to GWI cases (p=.000). Receiver operating characteristics (ROC) curve analyses indicated that the predictive ability of plasma NPY to distinguish CFS patients from healthy controls and from GWI was significantly better than chance alone. In 42 patients with CFS, plasma NPY had significant correlations (<0.05) with perceived stress, depression, anger/hostility, confusion, negative thoughts, positive thoughts, general health, and cognitive status. In each case the correlation (+ or -) was in the anticipated direction.

Conclusions
This study is the first in the CFS literature to report that plasma NPY is elevated compared to healthy controls and to a fatigued comparison group, GWI patients. The significant correlations of NPY with stress, negative mood, general health, depression and cognitive function strongly suggest that this peptide be considered as a biomarker to distinguish subsets of CFS.

http://www.behavioralandbrainfunctions.com/content/6/1/76

 

[WillowJ]

subsets, nice!

 

[Angela Kennedy]

subsets, nice!

Yeah, subsets based on 'perceived stress' and negative thoughts.

Whoopee sh*t.

 

[WillowJ]

I was thinking that I was in favor of separating those that felt stress was important from those that felt it wasn't, but then I looked a little closer and changed my mind.

what on earth were Klimas and Fletcher thinking, signing this study? used Reeves criteria!

 

[leaves]

:Eeeh yeahh
Weird she puts her name on this one

 

[omerbasket]

It's not only that her name is on this one - it also says that she contributed equally to this study, along with the first author (which is also the corresponding author). So, it's not just her name - that study is very much done by her.

 

[WillowJ]

I wrote and asked for an explanation

 

[WillowJ]

Dr. Mary Ann Fletcher is normally a very sane person interested in biomedical stuff. This doesn't make sense for either of them. The background reads like something penned in collaboration with the CDC

 

[Angela Kennedy]

Why not CC defined patients? Why not separate out the CNS signs and symptoms, the cardiovascular problems, mitochondrial dysfunction? Where are THOSE patients?

Also - in what causative direction are they proposing those psychological correlations? Have they not heard of psychological impact of illness, any illness?

Are we sure they are using Reeves and not just Fukuda criteria?

This whole thing is preposterous.

 

[WillowJ]

"Chronic fatigue syndrome patients... were drawn from the University of Miami Miller School of Medicine CFS and Immunodeficiency Clinic after they were diagnosed with CFS, using the 1994 international [sic] research case definition [1], as modified according to Reeves, et al [2]."

So, using Reeves applied to Klimas' patients is a better set than Reeves on general population, but, Reeves inclusion criteria should not be condoned at all, cited, used, etc. This is a travesty.

 

[Jemal]

My stress hormone is acting up, because of this paper.

Anyway, the conclusion is important I think. It says the stress mediator neuropeptide Y (NPY) could also be induced by viral infections and that more research is needed. Maybe this is why Klimas got involved?

It might not all be in our heads

 

[Sam Carter]

...

Are we sure they are using Reeves and not just Fukuda criteria?

...

The definition they use isn't Reeves' Empirical Definition (2005) but one I haven't seen before:

Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.

Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; International Chronic Fatigue Syndrome Study Group.

BMC Health Serv Res. 2003 Dec 31;3(1):25.

 

[lansbergen]

Neuropeptide Y Has a Protective Role during Murine Retrovirus-Induced Neurological Di

http://jvi.asm.org/cgi/content/abst...+Y&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

Journal of Virology, November 2010, p. 11076-11088, Vol. 84, No. 21

Neuropeptide Y Has a Protective Role during Murine Retrovirus-Induced Neurological Disease

Min Du,1 Niranjan B. Butchi,1 Tyson Woods,1 Timothy W. Morgan,2 and Karin E. Peterson

Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, 903 S. 4th St., Hamilton, Montana 59840,1 Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr., Baton Rouge, Louisiana 708032

Viral infections in the central nervous system (CNS) can lead to neurological disease either directly by infection of neurons or indirectly through activation of glial cells and production of neurotoxic molecules. Understanding the effects of virus-mediated insults on neuronal responses and neurotrophic support is important in elucidating the underlying mechanisms of viral diseases of the CNS. In the current study, we examined the expression of neurotrophin- and neurotransmitter-related genes during infection of mice with neurovirulent polytropic retrovirus. In this model, virus-induced neuropathogenesis is indirect, as the virus predominantly infects macrophages and microglia and does not productively infect neurons or astrocytes. Virus infection is associated with glial cell activation and the production of proinflammatory cytokines in the CNS. In the current study, we identified increased expression of neuropeptide Y (NPY), a pleiotropic growth factor which can regulate both immune cells and neuronal cells, as a correlate with neurovirulent virus infection. Increased levels of Npy mRNA were consistently associated with neurological disease in multiple strains of mice and were induced only by neurovirulent, not avirulent, virus infection. NPY protein expression was primarily detected in neurons near areas of virus-infected cells. Interestingly, mice deficient in NPY developed neurological disease at a faster rate than wild-type mice, indicating a protective role for NPY. Analysis of NPY-deficient mice indicated that NPY may have multiple mechanisms by which it influences virus-induced neurological disease, including regulating the entry of virus-infected cells into the CNS.

 

[Snow Leopard]

The above Virology paper is certainly interesting.

Unfortunatley NPY itself has had a coloured research history. http://en.wikipedia.org/wiki/Neuropeptide_Y

In this study, we found that the stress hormone, NPY, was statistically elevated in plasma from CFS cases compared to healthy controls – and to a group of patients with another
fatiguing, multi-symptom illness, GWI. This later finding was unexpected. However, it might be explained by gender distribution, which was very different between CFS and GWI.

Hmm.

 

[WillowJ]

The definition they use isn't Reeves' Empirical Definition (2005) but one I haven't seen before:

Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.

Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; International Chronic Fatigue Syndrome Study Group.

BMC Health Serv Res. 2003 Dec 31;3(1):25.

that's the one where they discuss exclusion criteria (and I think they decided to allow past history of psychiatric-classified disorders if they were considered resolved or controlled, but I don't recall for sure)

 

[Cort]

Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome.
Mary A Fletcher , Martin Rosenthal , Michael Antoni , Gail Ironson , Xiao R Zeng , Zachary Barnes , Jeanna M Harvey , Barry Hurwitz , Silvina Levis , Gordon Broderick and Nancy G Klimas

Behavioral and Brain Functions 2010, 6:76doi:10.1186/1744-9081-6-76


Published: 29 December 2010

Abstract (provisional)

Background
Chronic fatigue syndrome (CFS) is a complex, multi-symptom illness with a multisystem pathogenesis involving alterations in the nervous, endocrine and immune systems. Abnormalities in stress responses have been identified as potential triggers or mediators of CFS symptoms. This study focused on the stress mediator neuropeptide Y (NPY). We hypothesized that NPY would be a useful biomarker for CFS.

Methods
The CFS patients (n = 93) were from the Chronic Fatigue and Related Disorders Clinic at the University of Miami and met the 1994 case definition of Fukuda and colleagues. Healthy sedentary controls (n = 100)) were from NIH or VA funded studies. Another fatiguing, multi-symptom illness, Gulf War Illness (GWI), was also compared to CFS. We measured NPY in plasma using a radioimmunoassay (RIA). Psychometric measures, available for a subset of CFS patients included: Perceived Stress Scale, Profile of Mood States, ATQ Positive & Negative Self-Talk Scores, the COPE, the Beck Depression Inventory, Fatigue Symptom Inventory, Cognitive Capacity Screening Examination, Medical Outcomes Survey Short Form-36, and the Quality of Life Scale.

Results
Plasma NPY was elevated in CFS subjects, compared to controls (p=.000) and to GWI cases (p=.000). Receiver operating characteristics (ROC) curve analyses indicated that the predictive ability of plasma NPY to distinguish CFS patients from healthy controls and from GWI was significantly better than chance alone. In 42 patients with CFS, plasma NPY had significant correlations (<0.05) with perceived stress, depression, anger/hostility, confusion, negative thoughts, positive thoughts, general health, and cognitive status. In each case the correlation (+ or -) was in the anticipated direction.

Conclusions
This study is the first in the CFS literature to report that plasma NPY is elevated compared to healthy controls and to a fatigued comparison group, GWI patients. The significant correlations of NPY with stress, negative mood, general health, depression and cognitive function strongly suggest that this peptide be considered as a biomarker to distinguish subsets of CFS.

http://www.behavioralandbrainfunctions.com/content/6/1/76

I don't have any problem with this...this fits me to a T and I'm very happy to have found a biological marker that may help with my 'system arousal', irritability, cognitive problems, etc. By the way guys - my understanding - if my memory is right and it could be wrong - is that she ties NPY upregulation to an immune defect.... (Either that or she ties them the other way around).

 

[Cort]

Viral infections in the central nervous system (CNS) can lead to neurological disease either directly by infection of neurons or indirectly through activation of glial cells and production of neurotoxic molecules. Understanding the effects of virus-mediated insults on neuronal responses and neurotrophic support is important in elucidating the underlying mechanisms of viral diseases of the CNS. In the current study, we examined the expression of neurotrophin- and neurotransmitter-related genes during infection of mice with neurovirulent polytropic retrovirus. In this model, virus-induced neuropathogenesis is indirect, as the virus predominantly infects macrophages and microglia and does not productively infect neurons or astrocytes. Virus infection is associated with glial cell activation and the production of proinflammatory cytokines in the CNS.

In the current study, we identified increased expression of neuropeptide Y (NPY), a pleiotropic growth factor which can regulate both immune cells and neuronal cells, as a correlate with neurovirulent virus infection. Increased levels of Npy mRNA were consistently associated with neurological disease in multiple strains of mice and were induced only by neurovirulent, not avirulent, virus infection. NPY protein expression was primarily detected in neurons near areas of virus-infected cells.

Interestingly, mice deficient in NPY developed neurological disease at a faster rate than wild-type mice, indicating a protective role for NPY. Analysis of NPY-deficient mice indicated that NPY may have multiple mechanisms by which it influences virus-induced neurological disease, including regulating the entry of virus-infected cells into the CNS.

The central nervous system viral infection/NPY connection - now that is nice Lansbergen.....LOVE IT!

 

[WillowJ]

ok, here's the text of the ambiguities study cited: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC317472/?tool=pubmed

This is what I was thinking of:

Permanent psychiatric exclusions include lifetime diagnoses of bipolar affective disorders, schizophrenia of any subtype, delusional disorders of any subtype, dementias of any subtype, organic brain disorders, and alcohol or substance abuse within 2 years before onset of the fatiguing illness. The 1994 case definition stated that any past or current diagnosis of major depressive disorder with psychotic or melancholic features, anorexia nervosa, or bulimia permanently excluded a subject from the classification of CFS. Because these illnesses may resolve with little or no likelihood of recurrence and only active disease or disease requiring prophylactic medication would contribute to confusion with evaluation of CFS symptoms, we now recommend that if these conditions have been resolved for more than 5 years before the onset of the current chronically fatiguing illness, they should not be considered exclusionary.

they also talked about assessing fatigue (which is criticized here) and accompanying symptoms (sleep disturbance, neurocognitive functioning, pain).

 

[WillowJ]

The central nervous system viral infection/NPY connection - now that is nice Lansbergen.....LOVE IT!

yes, that's good

 

[eric_s]

The central nervous system viral infection/NPY connection - now that is nice Lansbergen.....LOVE IT!

Also read the last 3 sentences before "Competing interests" on page 15 of the pdf. Unfortunately, i can't copy from that document, for whatever reason.