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: firstname.lastname@example.org
Received October 18, 2007.
Revision received January 10, 2008.
Accepted February 11, 2008.
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.
Background: In multiple sclerosis (MS), demyelination and neuroaxonal damage are seen in the hippocampus, and MRI has revealed hippocampal atrophy.http://onlinelibrary.wiley.com/doi/10.1 ... 177.x/full
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.
The hippocampus in MS exhibits significant atrophyhttp://www.ajnr.org/content/33/8/1573.full
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.
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.
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