How good is MRI at elucidating evolving HIV neuropathogenesis? Research and clinical implications

Transcription

1 HIV Endgame I: Closing Gaps in the Care Cascade, October 26tth, 2016 Toronto, Canada OHTN/ISNV How good is MRI at elucidating evolving HIV neuropathogenesis? Research and clinical implications Lucette A. Cysique, Ph.D. Neuroscience Research Australia, Randwick, NSW, Australia UNSW Australia, Sydney, NSW Australia Peter Duncan Neuroscience Research Unit at the St. Vincent s Applied Medical Research Centre, Darlinghurst, NSW, Australia

2 Presenter Disclosure Presenter: Lucette Cysique Relationships with commercial interests Grants/Research support: Gilead Science Speakers Honoraria: none Consulting Fees: none Other: none

3 A New Context With the widespread use of combined antiretroviral treatment (cart) HIV-related neuropathology persists but it has fundamentally changed: Uncontrolled HIV replication is no longer a common cause HIV-related brain injury is now chronic Comorbid chronic conditions may play a role (aging; pathological aging; cardiovascular diseases) HIV-associated neurocognitive disorder (HAND) persists but mostly in a mild non-demented form HIV-associated dementia is relatively rare

4 Proposed model of HAND pathology mechanisms at population level in the cart era From Nightingale S, Winston A, Letendre S, et al. Controversies in HIV-associated neurocognitive disorders. Lancet Neurol 2014;13:

5 Proposed model of HAND pathology mechanisms at population level in the cart era From Nightingale S, Winston A, Letendre S, et al. Controversies in HIV-associated neurocognitive disorders. Lancet Neurol 2014;13:

6 Morphometric and volumetric MRI Magnetic Resonance Spectroscopy Diffusion Tensor Imaging Systematic review in the cart era criteria: To provide an overview of naturalistic studies and how they may inform the evolving HIV neuropathology Standard search with keywords: HIV, brain, cognition, HAND, and the MRI methods and included if: Written in a language other than English Peer reviewed original research article only At least 40% on cart Not a Randomized clinical trial on specific ART agent effect Only studies adults aged 18+ Excluded significant alcohol/drug use Presentation of studies is based on their primary aim: studies will have been optimally designed / powered for the 1 st aim

7 Morphometric and volumetric MRI: smri 25 studies were retrieved Conducted between 2007 and % of studies were conducted in the USA 1 longitudinal study

8 smri in HIV: samples overview Demographics Sample size Age*** % male Education % White Impairment Median HIV+ % (min-max) % %-58%^ Median HIV- % (min-max) 51** % ** HIV markers HIV duration years cart coverage cart duration months CSF VL <50 Plasma VL <50 Nadir CD4 Current CD4 Median % (min-max) % 48%-100% 79^^ ^^ * *Only 1study had a sample that was entirely virally supressed ** N=9 studies with an HIV- control group; N=7 for ethnicity in HIV- ***Some studies had large age differences between HIV-/HIV+ groups ^N=4; 11 studies did not state % of cognitive impairment but included neuropsychological test scores; 3 did not include neuropsychological testing. ^^ N=6 studies

9 smri: methodological overview Scanner 40% 1.5T 60% 3T Automated Segmentation Voxel/Deformation/Tensorbased Morphometry Custom 40% 28% 32% Standardized Yes No Anatomy Local specificity Whole brain Rationale Hypotheses-driven Exploratory and data-driven Processing choices Low impact on results High impact on results Freesurfer example Callaert et al Front. Aging Neurosci. 2014

10 smri: volume changes vs. controls Cohen s d ;.45;.36.79,.39;.99;.007;.12;.51.; ;.63;.54.45;.32;.53; ;.03;.58;.60.71;.60,.65.55;.99;.20; 30;.58;.40.88;.32;.48;.19 *>.32; *>.1;.*49.72;.78 (TWM=.75);.48) ; ; *>.32; *>.1;. *49.55 *>.32;.28; *>.1.68 *VBM/DBM

11 smri: volume changes vs. controls 54% (6/11) studies found no cortical differences *VBM/DBM tends to find cortical differences where ROIs analyses don t

12 smri: volume changes vs. controls Age effect was commonly observed HIV *age interaction effect was inconsistently observed Most studies detected correlations between atrophy and worse neurocognition, but not all The only 1 longitudinal study was small (N=12) & showed no reduction of atrophy after 9 months of stable cart Most robust risk factors for atrophy: Low nadir CD4, HIV duration, longer ART exposure Emerging/less robust risk factors for atrophy: Detectable/Residual CSF HIV RNA; Higher cholesterol, Diabetes; plasma HIV DNA; smoking; early life trauma Only 1 study assessed gender effect and found no difference between HIV+ men and women

13 smri: Take home message CLINICAL Acquisition protocol is fairly standard High resolution anatomical MRI is the procedure of choice to eliminate obvious non HIV brain conditions Analytic protocol includes some degree of standardization especially for regions of interest analyses RESEARCH Brain with severe changes (e.g., highly enlarged ventricles) remains a challenge for all platforms DBM, VBM and TBM remains research tools for now, but they have high potential longitudinally Longitudinal studies are needed Standardization would need to be based on large appropriate control samples to draw clinically useful conclusions

14 Proton Magnetic Resonance Spectroscopy ( 1 H MRS) 18 studies were retrieved Conducted between 2001 and % of studies were conducted in the USA 3 longitudinal studies

15 Main brain metabolites Metabolites NAA (N-Acetyl Asparte) Cho (Choline) Cr (Creatine) MI (Myo-Inositol) Glx (Glutamate Glutamine) Chemical Shift Normal concentration range 2.03 ppm 7.8 mm ( ) 3.2 ppm 1.3 mm ( ) 3.0 ppm 4.5 mm ( ) 3.56 ppm (short TE only) 3.8 mm ( ) ppm (short TE only) Glu ~10 mm / Gln ~ 5mM Physiological significance in HIV Neuronal integrity/density Axonal integrity/density Membrane turnover; acute neuroinflammation Cellular energetic marker Glial cell marker; chronic neuroinflammation AA neurotransmitter Glutamate excitatory AA neurotransmitter Glutamine inhibitory

16 MRS in HIV: samples overview Demographics Sample size Age % male Education Ethnicity Impairment Median HIV+ % (min-max) Median HIV- % (min-max) % % Mostly balanced between group Diverse 49% 22%-76%^ Mostly white - HIV markers HIV duration years cart coverage cart duration months CSF VL <50 Plasma VL <50 Nadir CD4 Current CD4 Median % (min-max) % % * Days ** * *Could not be summarized as too many studies did either not report the information or did not provide adequate data **N=6 ***N=7 ^72% studies included NP testing and impairment rate

17 MRS: methodological overview Scanners Scanner SV Long/Short TE PRESS Absolute/relative 1 study used MSRI 76% 1.5T 18% 3T 6% 4T 100% 94% short TE 85% 45% relative to Cr 15% relative to H 2 O 40% absolute Rae CD. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem Res 2014;39:1-36.

18 MRS: which brain regions do we study?

19 MRS & persistent HIV-injury on cart: HIV effects Most common findings -NAA +MI -NAA +MI Low nadir Detectable plasma VL HIV duration Less common findings +MI -Cr +Cho -Glu +Glu +Cho +Glx -Glu Detectable plasma VL; Low nadir

20 MRS & Persistent HIV-injury on cart: aging, CVD Most common findings HIV * Aging -NAA +MI -NAA +MI Less common findings -Cr +Cho -Glu +Glu +Cho +Glx +MI -Glu Aging Pathological aging; CVD

21 MRS & Persistent HIV-injury on cart: Brain functions Most common findings Subcortical & WM atrophy -NAA +MI -NAA +MI Less common findings +MI Cognitive impairment -Cr +Cho -Glu +Glu +Cho +Glx -Glu Subcortical atrophy

22 MRS & Persistent HIV-injury on cart: complexity Most common findings Subcortical & WM atrophy -NAA +MI -NAA +MI HIV * Aging Low nadir Detectable plasma VL BBB compromise; CSF neopterin; MCP-1 HIV duration Less common findings -Cr +Cho -Glu +GLx +Cho +Glx +MI -Glu Cognitive impairment Aging Detectable plasma VL; Low nadir Pathological aging; CVD Subcortical atrophy

23 MRS: Take home message CLINICAL MRS acquisition standardization is possible:. US HIV neuroimaging consortium. International consortium for PRESS MRS analytical standardization needs selection of a particular platform and comparisons to large appropriate control samples RESEARCH Longitudinal studies are needed Inclusion of more areas potentially important in HIV*aging, CVD, is challenging in terms of scan time

24 Diffusion Tensor Imaging (DTI) in HIV 27 studies were retrieved Conducted between 2006 and % of studies were conducted in the USA 2 longitudinal studies

25 Main DTI outcomes Outcomes Measurement Biological significance in HIV Fractional Anisotropy (FA) Mean Diffusivity (MD) Normalized measure of the fraction of the tensor s magnitude due to anisotropic diffusion, corresponding to the directionality of diffusion Ranges from 0 (isotropic diffusion) to 1 (anisotropic diffusion). High FA, high directionality Mean of the 3 eigenvalues; Corresponds to the molecular diffusion rate Lower values mean low diffusivity Degree of axonal structural integrity Possibly astrocytic structural integrity WM microstructure density (Degree of extracellular space between WM tracts)

26 1 st Author date 1. Pfefferbaum Hoare 2011 Samples 41 HIV+ 88 HIV- 44 HIV+ 10HIV- DTI Proof of concept Mean Age * Not clinically demented; ANI, MND and HAD used but % not provided % HAND CART / Suppressed?* 78% / 19.5% HIV duration HIV disease 8.5 years 27% Hx AIDS NR* NR NR Median CD4: directions, b=860 s/mm 2, quantitative fiber tracking directions, b=1000 s/mm 2, voxel-based analysis HIV effect only on longitudinal (λl) diffusivity (index of axonal injury) on EC, IC, Cingulum, RCC No effect on FA HIV (HAD/MND) effect on FA decrease in CC, SLF, Saggital Stratum, Cingulum No HIV effect on MD, but HAD effect on SLF, AC, IC, IFOF, CC, Cingulum,

27 DTI in virally suppressed HIV 1 st Author date Towgood 2012 Correa 2016 Longitudinal 26.6 months Su st Author date Towgood 2012 Correa 2016 Su 2016 Samples 40 HIV+ 42 HIV- Mean Age HIV % ANI 9% MND 0% HAD 100 HIV+ 70 HIV Scan type % HAND CART / Suppressed HIV duration HIV disease Low 100% / 100% 8-13 years Median CD % with MND, ANI? 100% / 100% 14 years Median CD % Hx AIDS 100%/100% 13.4 years Median CD % Hx AIDS Directions b value Processing Analysis 3T FSL, SPM, in house WM clusters 1.5T FSL TBSS 3T FSL TBSS

28 DTI in virally suppressed HIV: Results 1 st Author date Towgood 2012 Correa 2016 Su 2016 FA MD Other Comments No HIV effect No HIV effect Not tested High functioning men No time effect No time effect No time effect on volumes HIV effect (across the brain WM) HIV effect (across the brain WM) Past immune compromise duration CVD effect Site effect Small sample Alcohol + drug use in both HIV- and HIV+ Copyright 2016 Wolters Kluwer Health, Inc. Published by Lippincott Williams & Wilkins, Inc. Su et al AIDS. 30(2): , January DOI: 1Su0.1097/QAD

29 DTI in HIV: the question of ageing 1 st Author date Samples Mean Age % HAND CART / Suppressed HIV duration HIV disease Chang 2008 Longitudinal: 1y 39 HIV+ 32 HIV Some impairment (exact %?) 100% / 56% baseline, 62% Follow-up 13.6 years Baseline CD4=417 Nadir=168 Nir HIV+ 31 HIV Some impairment (exact %?) 89% / 95% 20 years Baseline CD4=520 Nadir=205 Seider HIV+ 49 HIV Impairment? 83% / 68% 12 years Baseline CD4=451 58% nadir <200 1 st Author date Chang 2008 Scan type Directions b value Processing Analysis 3T DTI-studio HIV pathology based ROIs Nir T FDT FSL minimal deformation template partial voluming correction Seider T FDT FSL - TBSS ROIs FA, MD, RD and AD maps ROIs

30 DTI: HIV * aging: Results 1 st Author date Chang 2008 Nir 2014 Seider 2016 FA MD Comments HIV effect (parietal WM) HIV effect (+CC, across the WM) Age effect HIV*age effect HIV effect (frontal WM) HIV *age effect (CC genu) HIV effect (across the WM) Also for AD and RD Trends for HIV*age effect in putamen but meaning of MD is different in non- WM No HIV*age effect WM changes correlated with age Lower cognition correlated with WM changes Older participants but restricted range - No HIV effect on FA HCV effect on FA Seider main results

31 DTI in HIV: question of cardiovascular disease 1 st Author date Nakamoto st Author date Nakamoto 2012 Samples 22HIV+ with and without CVD Mean Age % HAND CART / Suppressed 58 Some impairment (exact %?) HIV duration HIV disease 95% / 82% 17 years Nadir=210 Scan type Directions b value Processing Analysis 3T FSL FA & MD maps + Grey matter ROIs RESULTS 1 st Author date Nakamoto 2012 FA MD Comments CVD effect in Hippocampus and Caudate CVD effect in Hippocampus and Caudate Meaning of MD and FA is different in non-wm CVD effect = Impaired glucose metabolism

32 DTI in HIV: Take home message CLINICAL DTI may not be a method of choice to detect subtle HIV-related brain injury, but only useful for moderate to severe HIV-related brain injury Wide variability in acquisition protocol and processing software affect clinical utility potential RESEARCH Expected HIV effect size is probably small in virally suppressed cohort (<4-8 times less age effect) Anatomical specificity is needed (perhaps via quantitative fibretracking ) Improved diffusion protocol (HARDI, apparent fibre density ) as WM is complex by nature Tournier 2015

33 Where to from there? Or My 2 cents as an emerging researcher in this area An international HIV neuroimaging consortium to yield a greater research potential for new discoveries by defining most important research questions? Presence, severity, profile of HAND in cart treated cohort Predictive Monitoring Treatment response / ART toxicities Active versus inactive CNS disease Identify and quantify impact of comorbidities Latent HIV infection / Insight into new neuropathological mechanisms Large collaborative studies with appropriate controls and good sampling for age education and sex Guidelines for reporting key HIV disease; treatment cognitive impairment; & other key markers Guidelines on methods (pros and cons) Participation in clinical use implementation; standardisation

34 Large multidimensional datasets allow complex system analyses Torsten Hoefler's Network Topology Repository Chen & Sharp BMC Bioinformatics 2004 Expanded Perception and Interaction Centre (EPICentre) at UNSW Australia & NeuRA Topology and function in molecular chaperons Nat. Struct. Mol. Biol., DOI: /nsmb.1436 Note: Relevance for potential International NeuroHIV working group

35 Acknowledgements Prof. Bruce Brew Prof. Caroline Rae Students Michael Tobia Maddie Nichols James Soares Emma Hubner Lucie Swaffield Post-doc & other collaborators Lauriane Jugé Thomas Gates Ben Cassidy Roland Henry Acknowledgements and funding We would like to thank the participants for their time. The study was funding by the NHMRC project grant (APP568746; CIA/PI Cysique) and NHMRC Career Development Fellowship (APP ; CIA/PI Cysique), and the support of the Peter Duncan Neuroscience Unit at St. Vincent s Hospital Applied Medical Research Centre (Director: Prof. Brew)