Nevrodegenerasjon

Nevrodegenerasjon er tap av celler i sentralnervesystemet (hjernen eller ryggmargen) eller perifere nerveceller. Tapet (degenerasjonen) kan omfatte hele nervecellen (nevronet), nervecellens utløper (aksonet) eller koblingen mellom to nevroner (synapsen).

Den kliniske markøren for nevrodegenerasjon er hjerneatrofi; globalt tap av vev og celler i hjernen. Hjerneatrofi visualiseres med forskjellige MRI-teknikker (magnetisk resonans imaging). Nevrodegenerasjon er involvert i flere sykdommer som demens, Parkinsons sykdom og Multippel Sklerose (MS).

Tidligere ble betennelse (inflammasjon) som førte til tap av aksonets isoleringslag (demyelinisering) sett på som den eneste mekanismen for utvikling av nevrologisk dysfunksjon (attakk) ved MS [1]. Dette klassiske synet er nå utfordret av nye MRI teknikker og patologiske studier som viser at nevrodegenerasjon i form av tidlig aksonal skade og tap av nevroner er en viktig mekanisme for utviklingen og progresjonen av MS. Denne nevrodegenerative fasen synes å være årsaken til at flesteparten av pasienter med relapsing-remitting MS (RRMS) utvikler en sekundær progressiv MS (SPMS) hvor det er en gradvis akkumulering av nevrologisk dysfunksjon uten symptombedring [2, 3].

Nevrodegenerasjon er en sammensatt prosess. Visse celler i immunsystemet (CD8+ T-lymfocytter og makrofager) kan feilaktig angripe myelinlaget rundt aksonene. Immuncellene aktiveres via pro-inflammatoriske faktorer kalt cytokiner. Andre immunceller, som Treg , som skal regulere og hindre at dette skjer kan også få forandret funksjon [4]. Tapet av myelin fører til at nervecellen får et økt energibehov samtidig som den delen av nervecellen som er ansvarlig for energiproduksjon har redusert funksjon hos 40-50 % MS pasienter [5]. Denne kombinasjonen fører til svekket cellefunksjon og celledød [6, 7].

Det finnes også mekanismer som fører til nevrodegenerasjon uavhengig av inflammasjon og demyelinisering. Nye studier viser at ved MS kan aksoner skades direkte uten å miste myelinlaget først, også tidlig i sykdomsutviklingen [8-11]. Mikroglia celler, som vanligvis er nødvendige for å regulere og beskytte nevroner, kan forandre funksjon ved MS. De kan da skade nevroner direkte ved å skille ut toksiske stoffer; reaktivt oksygen eller nitrogenoksid [12-14]. Mikroglia kan også skille ut proinflammatoriske cytokiner.

Nevrodegenerasjon – sammenheng med MS diagnose og sykdomsutvikling

Degenerasjonen av nevroner har viktige implikasjoner for diagnose og sykdomsutvikling ved MS. Allerede ved diagnosesetting spiller nevrodegenerasjon en viktig rolle. Konvensjonelle MRI metoder, som hyperintense lesjoner på T2-vektede bilder og gadolinium-økte lesjoner på T1-vektede bilder, brukes for visualisering av lesjoner i hjernen eller ryggmargen som et avgjørende kriterie for å sette diagnosen MS.

Ved visse tilfeller kan slike bilder feiltolkes som kroniske lesjoner på grunn av væskeansamling og remyelinisering og kan være en dårlig prognosemarkør for videre utvikling av sykdommen [15, 16]. Andre markører som nevrodegenerasjon har vist seg å være bedre indikator for utvikling av invaliditet [17, 18], kognitiv dysfunksjon [18, 19], og depresjon [20], enn konvensjonelle MRI bilder [19, 21-23].

Fremtidig fokus på nevrodegenerasjon vil trolig gi bedre innsikt i MS og mulighet for å hindre nevrodegenerasjon og beskytte nervecellen (nevroproteksjon).

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3. Lucchinetti, C., W. Bruck, and J. Noseworthy, Multiple sclerosis: recent developments in neuropathology, pathogenesis, magnetic resonance imaging studies and treatment. Curr Opin Neurol, 2001. 14(3): p. 259-69.

4. Bennett, J.L. and O. Stuve, Update on inflammation, neurodegeneration, and immunoregulation in multiple sclerosis: therapeutic implications. Clin Neuropharmacol, 2009. 32(3): p. 121-32.

5. Su, K.G., et al., Axonal degeneration in multiple sclerosis: the mitochondrial hypothesis. Curr Neurol Neurosci Rep, 2009. 9(5): p. 411-7.

6. Stys, P.K., et al., Role of extracellular calcium in anoxic injury of mammalian central white matter. Proc Natl Acad Sci U S A, 1990. 87(11): p. 4212-6.

7. Stys, P.K. and Q. Jiang, Calpain-dependent neurofilament breakdown in anoxic and ischemic rat central axons. Neurosci Lett, 2002. 328(2): p. 150-4.

8. Luessi, F., V. Siffrin, and F. Zipp, Neurodegeneration in multiple sclerosis: novel treatment strategies. Expert Rev Neurother, 2012. 12(9): p. 1061-76; quiz 1077.

9. Kuhlmann, T., et al., Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain, 2002. 125(Pt 10): p. 2202-12.

10. Bo, L., et al., Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler, 2003. 9(4): p. 323-31.

11. Bjartmar, C., et al., Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology, 2001. 57(7): p. 1248-52.

12. Ransohoff, R.M. and V.H. Perry, Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol, 2009. 27: p. 119-45.

13. Vogt, J., et al., Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann Neurol, 2009. 66(3): p. 310-22.

14. Hohlfeld, R., Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain, 1997. 120 ( Pt 5): p. 865-916.

15. Bitsch, A., et al., A longitudinal MRI study of histopathologically defined hypointense multiple sclerosis lesions. Ann Neurol, 2001. 49(6): p. 793-6.

16. Vigeveno, R.M., et al., Shifting imaging targets in multiple sclerosis: from inflammation to neurodegeneration. J Magn Reson Imaging, 2012. 36(1): p. 1-19.

17. Bakshi, R., et al., Regional brain atrophy is associated with physical disability in multiple sclerosis: semiquantitative magnetic resonance imaging and relationship to clinical findings. J Neuroimaging, 2001. 11(2): p. 129-36.

18. Zivadinov, R., et al., MRI techniques and cognitive impairment in the early phase of relapsing-remitting multiple sclerosis. Neuroradiology, 2001. 43(4): p. 272-8.

19. Benedict, R.H., et al., Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden. Arch Neurol, 2004. 61(2): p. 226-30.

20. Bakshi, R., et al., Brain MRI lesions and atrophy are related to depression in multiple sclerosis. Neuroreport, 2000. 11(6): p. 1153-8.

21. Fisher, E., et al., Eight-year follow-up study of brain atrophy in patients with MS. Neurology, 2002. 59(9): p. 1412-20.

22. Paolillo, A., et al., Brain atrophy in relapsing-remitting multiple sclerosis: relationship with 'black holes', disease duration and clinical disability. J Neurol Sci, 2000. 174(2): p. 85-91.

23. Bermel, R.A., et al., A semiautomated measure of whole-brain atrophy in multiple sclerosis. J Neurol Sci, 2003. 208(1-2): p. 57-65.


 

Novel MRI techniques expand the possibilities to monitor multiple sclerosis in patients and asses disability and treatment

Study design

Magnetic resonance imaging (MRI) techniques such as T2-weighted and gadolinium-enhanced T1-weighted sequences have been extensively used to diagnose multiple sclerosis (MS). Conventional MRI can detect lesion in the advanced stages of MS. Improvement in imaging has been necessary to distinguish minor metabolic, micro-structural and functional changes which are present early lesions. Initially, MS was characterized by focal demyelination of the white matter (WM) in the central nervous system. Advances in MRI techniques have shown a more widespread inflammatory and neurodegenerative disease process, also in the normal appearing white matter (NAWM) and grey matter (GM). These observations lead to the development of treatments targeting the neurodegenerative component of the disease. Advanced MRI-derived imaging techniques can aid in the understanding of the pathology of the disease and the identification of early markers. Based on literature on MS imaging published between 2010 and 2013 advanced in MRI imaging were discussed.

Demographics

Not applicable. Several studies were reviewed in this publication.

Main findings incl. graphics

NAWM- NAWM show abnormalities that were previously undetected with conventional MRI. MTR reduction is more pronounced in GM than in NAWM in patients with primary progressive MS (PPMS). However, the reduction in MTR in NAWM is more predictive of the clinical outcome, as NAWM abnormalities occur earlier in the course of the disease, before the onset of symptoms. Diffusion tensor imaging (DTI) show increased diffusivity in MRI visible lesions and NAWM in relapse-remitting MS (RRMS) and secondary progressive MS (SPMS). In SPMS patients DTI derived measures correlated with the clinical disability, showing the potential for monitoring in advanced stages. Proton magnetic resonance spectroscopy (1H-MRS) allows the quantification of metabolites such as N-acetyl aspirate (NAA), the marker for axonal integrity. Decreasing NAA/Cr ratio and increasing EDSS were more pronounced in patients with RRMS than in patients suffering from SPMS, suggesting axonal damage from earliest disease onwards. Treatments (IFNb, glatiramer acetate (GA) and natalizumab) partially reverse axonal injury in NAWM.

Spinal cord -Changes in cord cross-damage area (CSA) correlate better with clinical disability than changes in conventional T2 lesion burden. The active surface model of the cord surface gives reproducible measures of cord CSA from C2 to C5 and revealed correlations with clinical manifestations. SPMS patients have a widespread pattern of atrophy while patients with PPMS have localized clusters in the posterior cord.

Whole brain atrophy-The frequency of whole brain atrophy is only 0.5-1% of the total patient group. Consequently, highly reproducible and sensitive techniques are essential. GA, IFNb and natalizumab have been reported to reduce brain atrophy. The atrophy occurs very early in the onset of the disease, but does not always manifest in clinical disability. Due to thisheterogeneity among patients a predictive marker is necessary. Within subject registration based technique SIENA can estimate the percentage brain volume change better than segmentation based techniques. However,in the early phase of the treatment brain volume loss was observed, as a result of resolution of inflammation associated edema.This indicates that quantification of whole brain atrophy is not suitable during the first year of medication.

Grey matter atrophy -GM atrophy may have a different pathology, as there is no correlation with WM lesions or NAWM damage. GM atrophy is not affected by inflammation may provide a marker for neurodegeneration. Voxel/wise distributions of GM revealed correlations between fatigue severity and GM atrophy in the left precentral gyrus. Treatment with GA reduced GM atrophy to a great extent than IFNb treatment. This supports the potential of GA to reduce the progression of cognitive impairment.

Cortical lesions and reorganization -Cortical demyelination is common in early lesions but not detectable with conventional MS. More advanced techniques such as double inversion recovery can visualize the demyelination. Cortical lesions can explain locomotor disability and cognitive impairment observed in patients. Natalizumab decreases cortical lesion atrophy in severe RRMS. Cortical lesion detection can be enhanced by double inversion recovery combined with phase-sensitive inversion recovery and 3D magnetization-prepared rapid acquisition with gradient echo images. Functional MRI demonstrated subtle modifications in brain activation in MS patients and can be used to monitor the effects of cognitive rehabilation. The reorganization limits the functional impact of MS in the early phase. In later stages this capacity is exhausted, leading to disability and cognitive impairment.

Safety

Not applicable.

Discussion

Advanced MRI techniques show great potential to identify factors associated with the progression of locomotor disability and cognitive impairment in MS. These are affected by commonly prescribed treatments as GA, IFNb and natalizumab. In the future NAWM, spinal cord, whole brain atrophy, GM atrophy and/or cortical lesions and reorganization could serve as markers to select novel treatments. The reproducibility of these methods has not been challenged yet, as the number of studies is low. More and larger studies are necessary to elucidate the reproducibility, precision and accuracy of the techniques.

Link to full article at publishers web page

http://link.springer.com/article/10.1007%2Fs00415-014-7340-9


 

Illuminating gray matter atrophy in long-standing multiple sclerosis

Study design

Previous studies focused on grey matter (GM)atrophy during early phases of multiple sclerosis (MS). The neurodegenerative aspects of MS can be quantified in patients with longstanding disease, with more pronounced physical and pathologic decline. For that reason, Steenwijket al.focused on patients with longstanding MS. By using the T1-weighted and fluid-attenuated inversion-recovery MR images a lesion segmentation is obtained. Then the lesions in the original T1-weighted image are filled. Subsequently, SIENAX (part of FSL 5.0.2, http://www.fmrib.ox.ac.uk/fsl) is used to obtain GM, WM, and cerebrospinal fluid segmentations, and FSL FIRST is used to segment the deep GM structures (not shown). Then the FreeSurfer 5.1 pipeline is used to obtain mean cortical thickness. Finally, mean diffusion-weighted metrics, such as, fractional anisotropy (FA), are obtained in the normal-appearing WM and lesions.

Demographics

A total of 208 patients (67% women) with MS and 60 healthy controls (62% women) were included. Patients had average disease duration of 20 years. The group consisted of 130 relapse-remitting MS (RRMS), 53 secondary progressive MS (SPMS) and 25 primary progressive MS (PPMS) patients. Of the patients 10 used glatimer, 40 used beta-interferron and 9 used natalizumab. Patients with MS were older that the control group (53.70 ± 9.62% vs 50.33 ±7.06 %). Compared to patients with RRMS (3.0) the EDSS score is increased in SPMS patients and PPMS patients (both 6.0).

Main findings incl. graphics

In the model for NGMV the NMWV, NLV, age and sex explained 58% of the variance. In the model for cortical thickness the FANAWM, NLV, age and sex accounted for 32% of the variance. Especially when parallel coordinate plot illustrate the multivariate behavior if patients. When focusing on sex and age, the explanatory markers of GM atrophy (high NWMV, low NLV and high FANAWM) divide the patients in two groups. Patients with high NGMV and cortical thickness are mostly younger women (orange lines Figure 3A-J) with high NDGMV, high NWMV, low NLV and high FANAWM and have short disease duration and low EDSS. On the other hand older men (blue lines Figure 3 A-J) have low NDGMV, low NGMV and cortical thickness, high NLV. Interesting correlations were identified when the investigators focused on the specific patients groups. In patients with RRMS 59% of the variance was explained by the NGMV model. In patients with SPMS the model for NGMV explained only 44% of the variance, a reduction compared to 58 in the control group. Even though the number of patients was low, NGMV explained 72% of the variance in PPMS patients. On the other hand, the NDGMV model was less explanatory in PPMS patients (63%) compared to the total patient group (75%), RRMS (78%) and SPMS (74%) patients.


Figure 3: Parallel coordinate plots illustrate the multivariate behavior of all patients with MS, with the data on the vertical axes rank ordered. Curves represent single patients and show the values observed. Curves are colored by (A) sex, (B) age, (C) disease duration, (D) EDSS, (E) NGMV, (F) NWMV, (G) cortical thickness, (H) NLV, (I)NDGMV, (J)FANAWM and the three clinical subtypes (K) RRMS in bleu, (L) SPMS in red and (M) PPMS in green.

Safety

Not applicable.

Discussion

In line with earlier reports, MS patients showed extensive GM atrophy which correlated with the EDSS scores, especially in patients with SPMS.Analysis of the clinical subgroups demonstrated a weaker correlation between GM atrophy and WM abnormalities. In line with earlier reports, MS patients showed extensive GM atrophy which correlated with the EDSS scores, especially in patients with SPMS. Widespread damage was observed in NAWM, demonstrating that WM abnormalities were not restricted to focal lesions. Surprisingly, no increase in ADNAWM was observed, most likely because the mean value was calculated rather than the relative value compared the centers of the tracts. Earlier studies also found the sex to be a predictor for GM atrophy. This study did have some limitations. The average age was higher in the MS group compared to the healthy controls. Also, the PPMS and SPMS group were relatively small compared to the RRMS group. Furthermore, 28% of the patients with MS received disease modifying therapy, which could influence the results. Future studies with larger patient groups are necessary, to properly investigate the effect of therapy on the relationship between GM atrophy and WM abnormalities. In conclusion, the study demonstrated whole brain and deep GM atrophy were associated with WM atrophy and lesion volume.

Link to full article at publishers web page

http://pubs.rsna.org/doi/abs/10.1148/radiol.14132708

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