1. Alzheimer’s Disease and Myelin February 2012 Jason Su

2. Outline WM degeneration in AD – Connection between WM and GM New developments in WM/myelin imaging Myelin imaging in MS with mcDESPOT – Highly sensitive to early changes The myelin hypothesis in AD – How might we design a study to prove or disprove it?

3. WM Damage in AD and Its Relationship to GM Atrophy Agosta, Filippi, et. al. (Milan) AD is a disease that affects both GM and WM Some WM loss may precedes GM: there may be a mix of primary and secondary myelin degeneration involved in AD

4. Goals Use DTI to explore WM in probable AD patients and amnesic mild cognitive impairment (aMCI) – Correlate this with GM atrophy Previously, DTI has shown higher mean diffusivity (MD) and lower fractional anisotropy (FA) in AD – Temporal, parietal, and some frontal lobes – Are these changes primary or secondary to GM atrophy?

5. Study Design 23 probable AD 15 aMCI (criteria by Peterson and one biomarker) 15 controls MMSE and many other cognitive tests

6. Methods Acquisition: 1.5T – Dual-echo turbo spin-echo, 0.5x0.5x2.5mm 3 – T1w MPRAGE, 0.5x0.5x0.9mm 3 – DTI, 2x2x2.5mm 3, 12 directions, b = 1000 sec/mm 2 Analysis: FSL and SPM5 – Tract based spatial statistics to measure DTI parameters along WM tracts TBSS aligns FA maps between multiple subjects via nonlinear registration and an align-invariant tract/skeleton representation – Voxel based morphometry to measure GM atrophy

7. Methods Statistical: – Corrected for age and education – Compared group differences for MD, FA, axial diffusivity, and radial diffusivity via t-test – Compared GM differences via ANCOVA

8. Results – DTI Probable AD vs Control – MD: significant differences in all major WM tracts studied (limbic, cortico-cortical association, interhemispheric) Parahippocampal, inferior longitudinal fasciculus and splenium had most tract involvement – FA: no significant differences – Axial and radial: widespread differences, radial diffusivity changes in large portions of tract aMCI vs Control – MD: no differences – FA: no differences – Axial: some differences in various fasciluci and corpus callosum but less tract involvement than AD AD vs aMCI – No differences

9. Results – DTI TBSS color maps in patients with AD are overlaid on a mean FA skeleton (green) to show voxelwise differences between patients and control subjects.

10. Results – DTI TBSS color maps in patients with aMCI are overlaid on a mean FA skeleton (green) to show voxelwise differences in axial diffusivity between groups.

11. Results – VBM AD vs Control – Significant loss in temporal lobes, thalami, bilateral fontrol cortex, and left occipital cortex aMCI vs Control – Significant loss in left anterior hippocampus and fusiform gyrus – Some loss in hippocampus and parahippocampal gyrus AD vs aMCI – No differences

12. Results – VBM Regions of significant GM loss in patients Row C shows non- significant changes

13. Results – WM and GM AD: mean MD in splenium and parahippocampal tract correlated with hippocampus and parahippocampal gyrus volume aMCI: no correlation – Widespread increase in axial diffusivity but GM is relatively spared GM atrophy (cyan) and WM axial diffusivity changes (red).

14. Discussion Axial diffusivity is a potential early marker Correlation of WM and GM in parahippocampus consistent with secondary degeneration model However, several WM tracts not correlated with GM atrophy, especially in aMCI – May be indicative of primary WM degeneration – Perhaps some WM patterns are secondary, others primary – Worthy further study!

15. Discussion No significant differences between AD and aMCI probably indicative of large variance in patient population Limitations: – Sample size – No confirmation of aMCI as AD

16. Relaxation Based Myelin Imaging DTI is not an ideal measure of myelin (low resolution, crossing fibers problem) T2 (or R2) has been used in the past as a crude correlate of myelin – Myelination reduces water content in brain, lower T2 – T2w FLAIR is used in MS to highlight lesions – T2 mapping gives a more sensitive indicator

17. Myelin Water Fraction Recent methods have focused on a more specific measure: myelin water fraction (MWF) Multiecho qT2 – vary TE, decomposes the signal into a spectrum of T2 times (UBC, MacKay) – Well validated way to produce MWF maps that represent myelin – Few slices, long acquisition time mcDESPOT – vary flip angle, models SPGR and SSFP steady state signal – Also based on modeling relaxation and two pool exchange – Validation in progress – High resolution, whole brain, but long processing time (24 hours) Intra- and extra-cellular water, T2 ≈ 80ms Myelin water, T2 ≈ 20ms

18. FA vs MWF (UBC) FA map (3.0 T), myelin-water (MW) map (3.0 T), MD map

19. mcDESPOT Maps in Normal T1 single T1 fast MWF T2 single T2 slow T1 slow T2 fast Residence Time 0 – 0.234 0 – 137ms 0 – 555ms 0 – 9.26ms 0 – 1172ms 0 – 123ms 0 – 2345ms 0 – 328ms

20. MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE J.Su 1, H.H.Kitzler 2, M.Zeineh 1, S.C.Deoni 3, C.Harper-Little 2, A.Leung 2, M.Kremenchutzky 2, and B.K.Rutt 1 1 Stanford U, CA, USA, 2 TU Dresden, SN, Germany, 2 U of Western Ontario, ON, Canada, 3 Brown U, RI, USA ISMRM 2011 E-P OSTER #4643 Highly sensitive to early changes in pre-MS patients, well before global atrophy is evident

21. Background Conventional MRI measures such as lesion load have been criticized with adding little new information on top of clinical scores for multiple sclerosis (MS) patients Measures that quantify the hidden burden of disease in white matter are urgently needed MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

22. Purpose To apply mcDESPOT, a whole-brain, myelin- selective, multi-component relaxometric imaging method, in a pilot MS study Assess if the method can explain differences in disease course and severity by uncovering the burden of disease in normal-appearing white matter (NAWM) MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

23. Study Demographic Data Healthy Controls All Patients CISRRMSSPMSPPMS N26 10565 Mean age, yr (SD) 42 (13) 49 (12) 41 (12) 48 (12) 58 (7) 55 (7) Male/Female ratio10/167/193/70/50/64/1 Mean disease duration, yr (SD) — 14 (13) 2 (2) 15 (10) 28 (8) 20 (12) Mean EDSS score (SD) — 3.6 (2.4) 1.7 (0.9) 2.0 (1.7) 6.4 (1.1) 5.6 (1.1) MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

24. Scanning Methods 1.5T GE Signa HDx, 8-channel head RF coil mcDESPOT: 2mm 3 isotropic covering whole brain, about 15 min. – SPGR: TE/TR = 2.1/6.7ms, α = {3,4,5,6,7,8,11,13,18}° – bSSFP: TE/TR = 1.8/3.6ms, α = {11,14,20,24,28,34,41,51,67}° 2D T2 FLAIR: 0.86 mm 2 in-plane and 3mm slice resolution 3D T1 IR-SPGR: 1mm 3 resolution with pre/post Gd contrast MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

25. Processing Methods: Demyelination Non-linearly register mcDESPOT MWF maps to MNI152 standard space Combine normals together to form mean and standard deviation MWF volumes For each subject, calculate a z-score ([x – μ]/σ) at every voxel to determine if it is significantly demyelinated, i.e. MWF < -4σ below the mean Demyelinated Voxels MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

26. Processing Methods: WM Brain extract MPRAGE images Segment white and gray matter with SPM8 3 Filter tissue masks to reduce noise then manually edit by a trained neuroradiologist Calculate parenchymal volume fraction (PVF) as WM+GM divided by the brain mask volume FLAIRWM MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643 3 Statistical Parametric Mapping software package.

27. Processing Methods: Lesions & DAWM Non-linearly register T2-FLAIR images to MNI152 standard space Combine normals together to form mean and standard deviation volumes Segment lesions as those voxels with z-score > +4 and diffusely abnormal white matter > +2 Edit masks by a trained neurologist DAWMLesions MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

28. Processing Methods: NAWM & DVF Segment normal-appearing white matter (NAWM) as WM – DAWM – lesions Find demyelinated volume fraction (DVF) – Sum the volume of demyelinated voxels in each tissue compartment and normalize by the compartment’s volume – # demy. voxels in compartment * voxel volume / compartment volume Normal-Appearing White Matter MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

29. Segmentations and DV FLAIRNAWMDAWMLesions MWFDemyelinated Voxels WM DV in NAWMDV in DAWMDV in Lesions MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

30. Results: Mean MWF in Compartments Dotted line shows mean MWF in WM for normals. Rank sum testing was done for each bar against this Testing was also done for RRMS vs. SPMS and CIS vs. RRMS, any significant differences are shown with a connecting bracket Significance levels: * p < 0.05 ** p < 0.01 *** p < 0.001. MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

31. Results: DVF in Compartments Dotted line shows demyelinated volume fraction in WM for healthy controls With DVF, all patient subclasses were significantly different from healthy controls PVF, however, fails to distinguish CIS and RR patients from normals MC DESPOT-D ERIVED MWF I MPROVES EDSS P REDICTION IN MS P ATIENTS C OMPARED TO A TROPHY M EASURES A LONE ISMRM 2011 #4643

32. Characteristics of AD Afflicts >50% of people over 85 Age and ApoE4 allele are the primary risk factors for late-onset AD Deposition of extracellular Aβ plaques and intracellular tau tangles – Aβ is produced by two acts of cleavage of APP, first by β-site APP cleavage enzyme 1 (BACE1) then γ- secretase Treatment of amyloid plaques has shown little improvement of symptoms for Alzheimer’s patients

33. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown George Bartzokis (UCLA)

34. The Myelin Hypothesis Myelin enables higher level functions in brain, AD is a disease where these facilities are progressively degraded Disruption in the myelin repair mechanism leads to a cascade resulting in the “Alzheimerization” of the brain – Repair failure caused by age (oligodendrocyte vulnerability) or genetics (ApoE4) – Accumulation of plaques and tangles – Memory loss and language difficulty

35. Disrupted Myelin Repair

36. The Myelin Hypothesis: Myelin Breakdown Myelination in brain follows inverted-U shape, peaked at middle age Normal aging is strongly associated with myelin loss Oligodendrocytes are uniquely vulnerable to accumulation of toxins and free radicals with age because they consume 2-3x more energy than other brain cells Later myelinated temporal and frontal lobes are thinner: develop lesions first (recapitulation)

37. The Myelin Hypothesis: Failed Repair BACE1 accumulates, cleaves neuroregulin to signal oligodendrocytes to myelinate Repair of myelin depends on transport of cholesterol by ApoE, ApoE4 is poorer transporter than ApoE2/3 Aβ and tau deposition are a byproduct of myelin repair processes that are failing to keep up with the “Alzheimerization” of the brain

38. The Myelin Hypothesis: Treatment Offers a unifying theme why traditional therapies that reduce amyloid are ineffective Treatments should be “upstream” of Aβ and tau formation: maintain myelin health and resilience, do not entirely inhibit BACE1

39. Myelin Imaging and AD Many of the hypotheses derived from the myelin model need further assessment in prospective studies to help determine causality – Aβ and tau deposits, the development and breakdown of myelin, as well as important risk factors such as ferritin iron levels can be imaged with increasing specificity Questions we can explore with myelin imaging like mcDESPOT: – Can disease severity be linked to myelin (or MWF) loss, especially on a spatial level? Cross-sectional – How closely does myelin loss follow the pattern of recapitulation? Cross-sectional or longitudinal – How do existing treatments like BACE1 inhibitors affect myelin? Longitudinal

40. ADmcDESPOT Hypothesis: myelin loss is a precursor/predicts the development of Aβ plaques and tau tangles Longitudinal study, have to avoid CT or PET? Imaging methods: – MWF imaging via mcDESPOT – DTI – Amyloid PET? Aβ and tau concentrations in CSF as crude measures Questions – How active is plaque/tangle development in AD? How finely should we sample in time? – Besides MMSE, what are vital cognitive measures? – What are the normal diagnostic imaging tools for AD?

41. References Agosta F, Pievani M, Sala S, Geroldi C, Galluzzi S, Frisoni GB, Filippi M. “White matter damage in Alzheimer disease and its relationship to gray matter atrophy.” Radiology. 2011 Mar;258(3):853-63. Epub 2010 Dec 21. Bartzokis G, Cummings JL, Sultzer D, Henderson VW, Nuechterlein KH, Mintz J. “White matter structural integrity in healthy aging adults and patients with Alzheimer disease: a magnetic resonance imaging study.” Arch Neurol. 2003 Mar;60(3):393-8. Mädler B, Drabycz SA, Kolind SH, Whittall KP, MacKay AL. “Is diffusion anisotropy an accurate monitor of myelination? Correlation of multicomponent T2 relaxation and diffusion tensor anisotropy in human brain.” Magn Reson Imaging. 2008 Sep;26(7):874-88. Epub 2008 Jun 4. Kitzler HH, Su J, Zeineh M, Harper-Little C, Leung A, Kremenchutzky M, Deoni SC, Rutt BK. “Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi- component relaxation MRI.” Neuroimage. 2012 Feb 1;59(3):2670-7. Epub 2011 Sep 2. Bartzokis G. “Alzheimer's disease as homeostatic responses to age-related myelin breakdown.” Neurobiol Aging. 2011 Aug;32(8):1341-71. Epub 2009 Sep 22.