Chronic Stress, Hippocampus atrophy, HPA-axis dysregulation

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Chronic Stress, Hippocampus atrophy, HPA-axis dysregulation

Postby Anonymoose » Sat Jan 05, 2013 3:15 pm

Onset of MS often occurs 3-5 years after high chronic stress event. Chronic stress and resulting chronic cortisol surge cause hippocampus damage/atrophy. In healthy folks, the hippocampus works to keep the hpa-axis in balance by shutting down the release of cortisol by inhibiting the release of ACTH. In people with hippocampus atrophy, this doesn't work very well. Decreased hippocampal volume has been documented in CIS, RRMS, PPMS (and probably SPMS but I'm tired of chasing papers!). The fact that hippocampus atrophy is noted in CIS (VERY early MS...if it is MS, CIS in study below had o-bands), seems to indicate that hpa-axis dysregulation and hippocampus atrophy are possibly primary events in the development of MS.

http://www.jneurosci.org/content/19/12/5034.full
Prolonged exposure to elevated levels of glucocorticoids reduces hippocampal cell number (Sapolsky et al., 1985) and can induce cultured neurons to undergo apoptosis (Reagan and McEwen, 1997). This same effect has been shown in intact animals. Chronic stress or chronic administration of glucocorticoids to rodents (Watanabe et al., 1992) or nonhuman primates (Sapolsky et al., 1990) results in the degeneration of vulnerable hippocampal neurons, especially CA3 pyramidal cells. Animals exposed to high physiological levels of corticosterone (CORT) exhibited a persistent depletion of hippocampal CORT receptors and evidence of an impaired HPA axis (Sapolsky et al., 1983). Furthermore, a recent study (Lupien et al., 1998) has shown that in human aging, higher cortisol levels correlated longitudinally with greater hippocampal volume loss.


http://www.sciencedirect.com/science/ar ... 9307012061
The present findings are consistent with other evidence that the hippocampus, as reflected in volume, partially determines the efficacy of negative feedback in modulating cortisol levels.


http://onlinelibrary.wiley.com/doi/10.1 ... 0553.x/pdf
The glucocorticoid cascade hypothesis given the apparent deleterious effects of chronically elevated GCs on the hippocampus in experimental animals and man, a body of thought has developed, encapsulated in the ` glucocorticoid cascade hypothesis' (Sapolsky et al. 1986). This suggests that with `unsuccessful' ageing there develops a cascade of GC-induced deleterious events afflicting the hippocampus. Accumulated GC-induced damage of the hippocampus leads to progressive dysregulation of the HPA axis and then to further elevation of plasma GCs, amplifying the destructive process. Whether all individuals are susceptible to such deleterious GC effects as yet remains unclear. Indeed, a proportion of animals of the Brown Norway rat strain appears to show facilitated cognitive function with age when GC levels are higher in earlier life (De Kloet et al. 1998); this is however a particularly long-lived strain which perhaps selectively models ` successful' ageing, rather as the excessively GC-sensitive Fischer 344 strain may better model `unsuccessful' ageing of the hippocampus at least.


http://brain.oxfordjournals.org/content ... 1134.short
Regional hippocampal atrophy in multiple sclerosis
N. L. Sicotte1,2, K. C. Kern1, B. S. Giesser1, A. Arshanapalli1, A. Schultz1, M. Montag1, H. Wang3 and S. Y. Bookheimer4
+ Author Affiliations
1Department of Neurology, 2Division of Brain Mapping, 3Department of Biomathematics and 4UCLA Neuropsychiatric Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Correspondence to: Nancy L. Sicotte, MD, 710 Westwood Blvd. Rm 4-238, Los Angeles, CA 90095, USA E-mail: nsicotte@ucla.edu
Received October 18, 2007.
Revision received January 10, 2008.
Accepted February 11, 2008.
Summary

Gray matter brain structures, including deep nuclei and the cerebral cortex, are affected significantly and early in the course of multiple sclerosis and these changes may not be directly related to demyelinating white matter lesions. The hippocampus is an archicortical structure that is critical for memory functions and is especially sensitive to multiple insults including inflammation. We used high-resolution MR imaging at 3.0 T to measure hippocampal volumes in relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) patients and controls. We found that both groups of MS patients had hippocampal atrophy and that this volume loss was in excess of global brain atrophy. Subregional analysis revealed selective volume loss in the cornu ammonis (CA) 1 region of the hippocampus in RRMS with further worsening of CA1 loss and extension into other CA regions in SPMS. Hippocampal atrophy was not correlated with T2-lesion volumes, and right and left hippocampi were affected equally. Volume loss in the hippocampus and subregions was correlated with worsening performance on word-list learning, a task requiring memory encoding, but not with performance on the Paced Auditory Serial Addition Task (PASAT), a test of information processing speed. Our findings provide evidence for selective and progressive hippocampal atrophy in MS localized initially to the CA1 subregion that is associated with deficits in memory encoding and retrieval. The underlying histopathological substrate for this selective, symmetric and disproportionate regional hippocampal vulnerability remains speculative at this time. Further understanding of this process could provide targets for therapeutic interventions including neuroprotective treatments.


http://msj.sagepub.com/content/16/9/1083.abstract
Background: In multiple sclerosis (MS), demyelination and neuroaxonal damage are seen in the hippocampus, and MRI has revealed hippocampal atrophy.
Objectives: To investigate and compare hippocampal volume loss in patients with relapsing—remitting MS (RRMS) and primary progressive MS (PPMS) using manual volumetry, and explore its association with memory dysfunction.
Methods: Hippocampi were manually delineated on volumetric MRI of 34 patients with RRMS, 23 patients with PPMS and 18 controls. Patients underwent neuropsychological tests of verbal and visuospatial recall memory. Linear regression was used to compare hippocampal volumes between subject groups, and to assess the association with memory function.
Results: Hippocampal volumes were smaller in MS patients compared with controls, and were similar in patients with RRMS and PPMS. The mean decrease in hippocampal volume in MS patients was 317 mm3 (9.4%; 95% CI 86 to 549; p = 0.008) on the right and 284 mm3 (8.9%; 95% CI 61 to 508; p = 0.013) on the left. A borderline association of hippocampal volume with memory performance was observed only in patients with PPMS.
Conclusion: Hippocampal atrophy occurs in patients with RRMS and PPMS. Factors additional to hippocampal atrophy may impact on memory performance.


http://onlinelibrary.wiley.com/doi/10.1 ... 177.x/full
The hippocampus in MS exhibits significant atrophy
Comparison of the average hippocampal coronal cross-sectional area between MS cases (n = 13) and controls (n = 7), using brain weight as a covariate, revealed a 22.3% reduction in the MS blocks, which indicates a significant degree of atrophy in the MS hippocampus (ANCOVA, P = 0.004; Figure 5A). The average hippocampal cross-sectional area exhibited no significant correlation either with the level of HLA class II immunoreactivity or with the extent of demyelination seen in the MS hippocampal blocks. To further analyze the relationship between demyelination and hippocampal atrophy in the MS hippocampus, we examined whether hippocampal cross-sectional area differed among MS cases with demyelinated lesions, MS cases not affected by lesions and controls, using brain weight as a covariate. Cross-sectional area was decreased by 22.2% in MS hippocampal blocks with lesions (n = 9, LSD post-hoc test P = 0.007) and by 17.9% in MS blocks without lesions (n = 4, LSD post-hoc test P = 0.036), compared with controls (n = 7, ANCOVA, P = 0.021) (Figure 5B). The average cross-sectional area correlated with the total neuronal counts (rS = 0.58, P = 0.044) (Figure 5D) as well as with neurone size in CA1 (rS = 0.691, P = 0.009), suggesting that hippocampal atrophy is largely determined by neuronal atrophy and loss.
.....
It is highly likely that the majority of our cohort of patients were given high-dose glucocorticoid pulse therapy as treatment for MS exacerbations at some stage in their disease course. Recently, high-dose glucocorticoid treatment was reported to aggravate retinal ganglion cell apoptosis in MOG-EAE in the rat (19). Evidence suggests that prolonged exposure of hippocampal neurones to high levels of glucocorticoids leads to irreversible pathological changes including hippocampal atrophy and neurone loss in rodents and primates (55, 56, 68). The fields thought to be most susceptible to glucocorticoids are CA3 and CA2 (56). Despite the lack of direct evidence of hippocampal pathology secondary to exposure to supraphysiologic levels of glucocorticoids in humans, this possibility merits consideration.


http://www.ajnr.org/content/33/8/1573.full
RESULTS: Patients with early RRMS showed significantly lower SDGM but not cortical volumes compared with patients with CIS. The most apparent SDGM differences were evident in the caudate and thalamus (P < .0001), total SDGM (P = .0001), and globus pallidus (P = .01). Patients with CIS with a median T2 lesion volume >4.49 mL showed lower total SDGM, caudate, thalamus (P < .001), globus pallidus (P = .007), hippocampus (P = .004), and putamen (P = .01) volumes and higher lateral ventricle volume (P = .001) than those with a median T2 lesion volume <4.49 mL. Decreased thalamic volume showed the most consistent relationship with MR imaging outcomes (P < .0001) in patients with CIS.

CONCLUSIONS: Significant SDGM, but not cortical, atrophy develops during the first 4 years of the RRMS. GM atrophy is relevant for disease progression from the earliest clinical stages.

ABBREVIATIONS:

ASA Avonex-Steroid-Azathioprine CIS clinically isolated syndrome EDSS Expanded Disease Status Scale FSL FMRIB Software Library GM gray matter NBV normalized brain volume NCV normalized cortical volume NGMV normalized gray matter volume NLVV normalized lateral ventricle volume NWMV normalized white matter volume RRMS relapsing remitting MS SDGM subcortical deep gray matter SET Study of Early Interferon β 1a Treatment in High Risk Subjects after CIS
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Re:Magnesium, Chronic Stress, , HPA-axis dysregulation

Postby CaliReader » Wed Jan 09, 2013 3:03 pm

Interesting. Thanks.

I found this, which should be of special interest to Jimmylegs.

Magnesium deficiency induces anxiety and HPA axis dysregulation: Modulation by therapeutic drug treatment
Neuropharmacology. 2012 January; 62(1): 304–312
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198864/ full text

I don't think this causes MS, but since this goes wrong in MS, perhaps correcting could lead to better health for longer. Good luck with the new drug treatment.
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby Anonymoose » Wed Jan 09, 2013 3:23 pm

Which came first? The chicken? Or the egg?

http://ajcn.nutrition.org/content/34/11 ... l.pdf+html
Mineralocorticoids (aldosterone) increase renal
excretion of magnesium and glucocorticoids (cortisol)
decrease intestinal absorption.

Allegedly, excess cortisol also inhibits production of vitamin D production by monopolizing cholesterol which is needed for vitamin d synthesis. GC can also occupy vitamin d receptors, so even if vitamin d is there, it can't go to work. There are a bunch of sites online that explain this but I've not been able to find an actual credible scientific source.
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby jimmylegs » Thu Jan 10, 2013 9:18 am

the nutrients. take those away and see how the HPA axis gets on.
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby Anonymoose » Thu Jan 10, 2013 9:42 am

That's it. I'm bringing out the "viscous cycle" again! lol High cortisol, reduced nutrient absorption/production, higher cortisol, more reduced nutrient absorption/production.... It seems to be too much of a coincidence that most people with ms have a pretty standard set of nutritional deficiencies given all of our different lifestyles and diets. The high cortisol came first! :P

I think your mega supplementation of all of the nutrients that cortisol tends to mess with probably does work to reduce cortisol secretion though.

If I can get my doc to prescribe something to knock cortisol (and aldo) down, I'll ask him to test my zinc, d, magnesium, b12 (anything else?) at the beginning and 6 mos later. We'll see what happens to levels w/o supplements and hamburgers. They are going to go up and I'm going to neener neener at you (or eat some crow which should help my levels anyway so its a win-win for me either way). lol
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby jimmylegs » Thu Jan 10, 2013 11:57 am

i'll see your neener neener, and raise you a nuh-uh. the vicious cycle starts with physiological stress, and only one fraction of that originating stress comes from cortisol. go check out figure 6 in the article i posted in the vit d3 thread. malnutrition, exercise, trauma/inflammation, these all involve nutrient depletion and lead to cortisol production via the HPA axis. anxiety, another route to increased cortisol levels, can have nutritional roots too (magnesium). that really is a vicious cycle b/c the anxiety leads to magnesium excretion and so on, and so on..

as for coincidence, line up my pre-dx food and fluid diary next to your average joe ms patient's, and i can show you exactly how vastly different diets can lead to the same nutritional problems.

i agree, optimizing nutrition via whatever methods, can't help but reduce cortisol secretion, given the knowns about the nutritional underpinnings of physiological stress.

as for your experiment, i will start researching tasty crow recipes. re experimental methodology, in order to control for confounding factors, please include a food/fluid/symptom diary for 3 mo prior to introducing the pharma intervention, and during the entire 6 months of the intervention. either way, using a drug to improve nutrient status reminds me of actual real life research showing that beta interferon increases serum vitamin e levels (which by the way helps protect against zinc deficiency). why the heck wouldn't a person just make sure they had adequate vit e and zinc?? anyway. i look forward to seeing your results!
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby Anonymoose » Thu Jan 10, 2013 12:32 pm

Lol! It's on! Only problem is I've been supplementing a lot for 3 mos. That might skew my original baselines. Oh well. It will be interesting anyway.

I'll buy ya a case of zinc if you win. :D
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby jimmylegs » Thu Jan 10, 2013 5:21 pm

all right then methodology revision time - your new mission, should you choose to accept it (i wouldn't) is a 3 month total supplement washout with food/fluid/symptom diary, prior to taking this whatever drug to reduce cortisol! wouldn't want you giving this drug - whatever it is - the credit if it's actually due to the supplements, after all ;)
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby Anonymoose » Thu Jan 10, 2013 5:33 pm

If anything my baseline results will be skewed in your favor...making my miraculous increase in levels seem so much less impressive. LOL Six months is long enough for all of those supplements to wash out anyway, right?

I've been trudging through antibiotics for 3.5 months...you really think once I am back to normal (whatever that is) I am going to log my diet and symptoms? Pfft! I *will* occasionally update to let you know how bodaciously awesome I am doing though. :P I think my first update will be entitled "I can feel the zinc surging through my veins!"
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Re: Chronic Stress, Hippocampus atrophy, HPA-axis dysregulat

Postby jimmylegs » Fri Jan 11, 2013 7:38 am

all right i see your game, you go on the drug, implement the top secret nutrient dense power smoothie diet on the down low, and pretend your cortisol idea is the be all and end all, very sly, very sly ;)
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