Introduction • Higher rates of cognitive impairment have been reported in people living with HIV (PLWHIV), compared to HIV-negative people, despite being well-treated with combination antiretroviral therapy (cART). • Potentially, HIV and/or cART might exacerbate the effects of ageing on the brain, increasing the risk of cognitive decline. • Previously, ‘accentuated’ structural brain-ageing has been reported cross-sectionally in COBRA participants (Cole et al., 2017). • Here, we used a longitudinal design to assess evidence for an acceleration to known facets of brain ageing, using multiple neuroimaging modalities inthe COBRA participants.Methods - ParticipantsPLWHIV with plasma HIV RNA <50 copies/ml on antiretroviral therapy for >1 year and demographically comparable HIV-negative controls were recruited at the AMC Amsterdam and Imperial College London as part of the EU FP-7 funded COBRA collaboration.Methods - NeuroimagingParticipants were assessed at baseline and two years with multi-modal magnetic resonance imaging (MRI):

T1-weighted T2-FLAIRDiffusion-MRI Resting-state fMRIArterial Spin Labelling (ASL) MR Spectroscopy (MRS)

These were processed to generate global and regional summary metrics of brain structure and function.Methods - NeuropsychologyNeuropsychological assessments (reported as domain T- scores adjusted for age, sex, education) tested the cognitive domains of attention, executive function, language, memory, motor function and processing speed.Methods - StatisticsBetween-group comparisons of baseline values and change over time were assessed using linear and mixed-effects regression respectively, with models accounting for age, time between assessments and (for neuroimaging only) intracranial volume and scanner type.

Figure 1. Longitudinal rates of change in neuroimaging measures

James Cole1, Matthan Caan2, Jonathan Underwood3, Rosan van Zoest4, Davide de Francesco5, Alan Winston3, Caroline Sabin5, David Sharp1, Peter Reiss4,6

on behalf of the COBRA (CO-morBidity in Relation to AIDS) collaboration.

LONGITUDINAL ANALYSIS SHOWS NO EVIDENCE FOR ACCELERATED BRAIN AGEING IN TREATED HIV

CROI abstract 352LB

Acknowledgements COBRA is funded by an EU Framework 7 programme grant (GA# 305522). The authors would like to thank all the COBRA investigators for their work on the project.

1Computational, Cognitive & Clinical Neuroimaging Laboratory, Imperial College London, UK. 2Brain Imaging Centre, Academic Medical Center Amsterdam, Netherlands. 3Division of Infectious Diseases, Imperial College London, UK. 4Department of Global Health, Academic Medical Center Amsterdam, Netherlands. 5Department of Infection & Population Health, University College London, UK. 6Dutch HIV Monitoring Foundation, Amsterdam, Netherlands

Results • At baseline, PLWHIV had smaller grey matter volume, abnormal white matter microstructure and poorer cognitive function compared to HIV-negative controls. • Age-related declines in neuroimaging measures were evident in both groups, e.g., PLWHIV lost 0.82% of brain volume/year, HIV-negative controls lost 0.77%. • However, there were no group differences in the rates of brain volume loss or change in any neuroimaging measure (p>0.1, Table 2). • Cognitive function showed limited change, with no group differences in rates of change in cognition (p>0.1),except attention T-score, where the groups became more similar.

●

●

●

●

0.63

0.64

0.65

0.66

0.67

0.68

0.69

Baseline Follow−upVisit

Gre

y m

atte

r vol

ume

(mL)

Group●●

HIV−negativeHIV−positive

●●

●

●

1000

1500

2000

2500

3000

Baseline Follow−upVisit

Whi

te m

atte

r hyp

erin

tens

ity lo

ad

Group●●

HIV−negativeHIV−positive

Table 1. COBRA participant characteristics

Conclusions • PLWHIV with suppressed viraemia on cART had abnormalities in measures of brain structure and function at baseline. • There was no difference in the dynamics of these measures over time between PLWHIV and HIV-negative controls. • Cognitive performance did not decline over two years. • Although we previously found evidence for increased brain age in this cohort of PLWHIV, this analysis does not find evidence for brain ageing to be accelerated over time during continued suppressed viraemia on cART.

A) T1 - Grey matter volume

●

●

●

●

0.540

0.545

0.550

0.555

Baseline Follow−upVisit

Frac

tiona

l ani

sotr

opy

(who

le b

rain

ske

leto

n)

Group●●

HIV−negativeHIV−positive

●

●

●

●

52

56

60

64

Baseline Follow−upVisit

Cere

bral

Blo

od F

low

(gre

y m

atte

r)

Group●●

HIV−negativeHIV−positive

C) DTI - White Matter structure D) ASL - Cerebral blood flow

B) FLAIR - White Matter Hyperintensities

●

●

●●

1.30

1.35

1.40

1.45

1.50

Baseline Follow−upVisit

NA

A:c

reat

ine

ratio

(fro

ntal

whi

te m

atte

r)

Group●●

HIV−negativeHIV−positive

●

●

●

●

4.5

5.0

5.5

6.0

Baseline Follow−upVisit

Def

ault

Mod

e w

ithin

net

wor

k co

nnec

tivity

Group●●

HIV−negativeHIV−positive

E) MRS - Neural metabolites F) Resting state fMRI - Functional network connectivity

Table 2. Mean [SD] values of neuroimaging and neuropsychological measures at baseline and changes over two years

ReferenceCole JH, Underwood J, Caan MWA, De Francesco D, van Zoest RA, Leech R, Wit FWNM, Portegies P, Geurtsen GJ, Schmand BA, Schim van der Loeff MF, Franceschi C, Sabin CA, Majoie CBLM, Winston A, Reiss P, Sharp DJ on behalf of the COBRA collaboration (2017). Increased brain-predicted ageing in treated HIV disease, Neurology (in press).COBRA study group acknowledgementsAcademisch Medisch Centrum, Universiteit van Amsterdam - Department of Global Health and Amsterdam Institute for Global Health and Development (AIGHD): P. Reiss, J. Schouten, K.W. Kooij, R.A. van Zoest, E. Verheij, S.O. Verboeket, B.C. Elsenga, F.R. Janssen, W. Zikkenheiner. Division of Infectious Diseases: M. van der Valk. Department of Experimental Immunology: N.A. Kootstra, A.M. Harskamp-Holwerda, I. Maurer, M.M. Mangas Ruiz, A.F. Girigorie. Department of Medical Microbiology: J. Villaudy, E. Frankin, A. Pasternak, B. Berkhout, A. van der Kuyl. Department of Neurology: P. Portegies, B.A. Schmand, G.J. Geurtsen, Department of Radiology: C.B.L.M. Majoie, M.W.A. Caan, T. Su. Department of Cell Biology: K. Weijer, E. Siteur-Van Rijnstra. Division of Endocrinology and Metabolism: P.H.L.T. Bisschop. Department of Experimental neuroendocrinology: A. Kalsbeek. Department of Ophthalmology: F. Verbraak, N. Demirkaya, M. Wezel. Department of Psychiatry: I. Visser.Stichting HIV Monitoring - F.W.N.M. Wit, S. Zaheri, M.M.J. Hillebregt, Y.M.C. Ruijs, D.P. Benschop. Imperial College of Science, Technology and Medicine - Department of Medicine, Division of Infectious Diseases: A. Winston, J. Underwood, L. Tembo, L. McDonald, M. Stott, K. Legg, A. Lovell, O. Erlwein, N. Doyle, C. Kingsley, P. Norsworthy, Scott Mullaney. Department of Medicine, Division of Brain Sciences, The Computational, Cognitive & Clinical Neuroimaging Laboratory: D.J. Sharp, R. Leech, J.H. Cole. University College London - Research Department of Infection and Population Health: C. Sabin, D. De Francesco. GGD Amsterdam/Public Health Service Amsterdam - Cluster of Infectious Diseases, research department: M. Prins, M.F. Schim van der Loeff, J. Berkel, T. Kruijer, L. del Grande, C. Gambier, G.R. Visser, L. May. Stichting Katholieke Universiteit Nijmegen - D. Burger, M. de Graaff-Teulen. Erasmus Universitair Medisch Centrum Rotterdam - Department of Genetics: J. Hoeijmakers, J. Pothof. Vlaams Instituut voor Biotechnologie - Inflammation research center: C. Libert, S. Dewaele. Universität Konstanz - Department of Biology: A. Bürkle, T. Sindlinger, S. Oehlke. Alma Mater Studiorum Università di Bologna - Department of Experimental, Diagnostic and Specialty Medicine: C. Franceschi, P. Garagnani, C. Pirazzini, M. Capri, F. Dall’Olio, M. Chiricolo, S. Salvioli. Göteborgs Universitet - M. Gisslén, D. Fuchs, H. Zetterberg. Università degli studi di Modena e Reggio Emilia - Department of Medical and Surgical Sciences for Children & Adults: G. Guaraldi. German Institute of Human Nutrition - Department of Molecular Toxicology: D. Weber, T. Grune. National Institute of Public Health and the Environment - Laboratory for Health Protection Research: E.H.J.M. Jansen.

Baseline N

Assessment interval (years)

PLWHIV

134

CD4+ count (cells/µL)

1.93646.0 ± 213.6

79

Follow-up N 120 76

1.89-

Age at baseline (years)

Gender (male/female)

Site (Amsterdam/London)

125/975/59

57.4 ± 7.4

73/6

50/29

58.8 ± 7.8

HIV-negative controls

Nadir CD4+ count (cells/µL) 185.5 ± 144.0 -Values are presented as mean ± standard deviation or N (count)