Neuropsychological Profile / Neurocognitive dysfunction / Retrieval deficit
Slowness
Attention
Executive dysfunction
Focal cognitive impairment
Fluctuating and variable course / Saylor et al., Nature Reviews, 2016
Cohen et al., Alzheimers Res Ther, 2015
Heaton et al., J Neurovirol, 2011
Woods et al., Neuropsychol Rev, 2009
Robertson et al., AIDS, 2007 / Learning and consolidation deficit
Visuospatial deficit
Semantic memory
Global cognitive deficit
Progressive decline / Weintraub et al., Cold Spring Harb Perspect Med, 2012
McKhann et al., Alzheimers Dement, 2011
Salmon et al., Annu Rev Psychol, 2009
Motor component / Motor slowing
Loss of coordination
Gait imbalance
Sometimes initial manifestation
Most prominent in advanced stages / Saylor et al., Nature Reviews, 2016
Valcour et al., J Neurovirol, 2008
DeVaughn et al., Neuropsychol Rev, 2015 / Increased muscle tone
Myoclonus in severe cases
Gait disorders with risk for falls
Most prominent in advanced stages / Tarawneh et al., Cold Spring Harb Perspect Med, 2012
Romanelli et al., Arch Neurol, 1990
Behavioral manifestation / Apathy
Depression
Agitation
Anxiety / Do et al., PloS One, 2014
Milanini et al., AIDS Care, 2017
Paul et al., J Neuropsychiatry Clin Neurosci, 2009 / Depression
Apathy
Agitation
Delusion and hallucinations in advanced stage / Boublay et al., Eu J Neurol, 2016
Cummings, N Engl J Med, 2004
M FM et al., Curr Alzheimer Res 2016
Neuroimaging / DTI / Widespread WM aberrations
Initial frontal abnormalities
Abnormalities correlate with viral load
Frontal WM, parietal WM, caudate, splenium, genu, putamen, globus pallidus, thalamus / Nir et al. Hum Brain Mapp, 2015
Pomara et al., Psychiatry Res, 2001
Seider et al., J Neurovirol, 2016
Filippi et al., Am J Neuroradiol, 2001
Chang et al., J Neuroimmune Pharmacol, 2008
Holt et al., J NeuroVirol, 2012 / Early hippocampal changes
WM changes extensively described in the cingulum bundle, uncinated fasciculus, corpus callous, anterior commissure and superior longitudinal fasciculus
Increased MD in hippocampus, temporal lobe, posterior cingulum and more posterior regions / Sexton et al., Neurobiol Aging, 2011
Chua et al., Curr Opin Neurol, 2008
Hess, Magn Reson Imaging Clin N Am, 2009
Douaud et al., NeuroImage, 2011
Stebbins & Murphy, Behav Neurol, 2009
MRI / Smaller global cerebral volume
Early reductions in basal ganglia and frontal lobe volumes
WM loss primarily periventricular and frontal
Atrophy rates correlate with age and viral load / Pfefferbaum et al., Biol Psychiatry, 2012
Ances et al., J Acquir Immune Defic Syndr, 2012
Chang et al., Neuroimage, 2011
Becker etal., Neuroradiology, 2011
Cardenas et al., J NeuroVirol, 2009 / Increased rates of cerebral atrophy
Mesial temporal lobe atrophy
Pronounced hyppocampal atrophy
Early white matter changes / Frings et al., PloS One, 2014
Sachdev et al., Curr Opin Psychiatry, 2013
Du et al., J Neurol Neurosurg Psychiatry, 2001
FDG or PiB
PET / No PiB binding in cognitively unimpaired individuals with low CSF amyloid levels
No PiB binding in HAND patients compared to AD / Ances et al., Arch Neurol, 2012
Ances et al., Neurology, 2010 / Early changes in posterior association cortex
High uptake found in the prefrontal cortex, precuneus, and posterior cingulate cortex followed by lateral parietal, lateral temporal cortex and striatum
Correlate with ApoEε4 carrier status / Minoshima et al., J Nucl Med, 1995
Laforce & Rabinovici, Alzheimers Res Ther, 2011
Neuropathology / Aβ
Beta-amyloid / Decreased (especially in HAD or early infection) or normal levels
Diffuse extracellular plaques
Primarily intracellular
Primarily concentrated in frontal lobe and basal ganglia / Green et al., AIDS, 2005
Brew et al., J Neuroimmune Pharmacol, 2009
Achim et al., J Neuroimmune Pharmacol, 2009
Rempel & Pulliam, AIDS, 2005
Soontornniyomkij et al., Hum Pathol, 2013 / Decreased levels
Neuritic plaques
Initially concentrated in the entorhinal cortex and hippocampus
Primarily extracellular / Braak et al., Acta Neuropathol, 1991
Braak et al., Acta Neuropathol, 2006
Ubhi & Masliah, J Alzheimers Dis, 2013
Rosen et al., Mol Neurodegener, 2013
Tau
pathology / Normal or increased t-tau levels and normal p-tau
Accelerated deposition of p-tau in the hippocampus and entorhinal cortex / Anthony et al., Acta Neuropathol, 2006
Brown et al., Mol Neurodener, 2014
Peterson et al., Plos One, 2014 / Increased t-tau and p-tau levels
Early accumulation in entorhinal cortex, then spreading to the hippocampus and cerebral cortex / Gomez-Isla et al., J Neurosci, 1996
De Calignon et al.,Neuron, 2012
Liu et al., PloS One, 2012
APP / Decreased soluble forms of APP in HAD / Gisslen et al., BMC Neurology, 2009
Krut et al., Virulence, 2013 / Higher concentrations of soluble APPs in MCI-AD / Perneczky et al., Neurology, 2011
Krut et al., Virulence, 2013
NFL / Increased in HAD patients
Lack of increase in acute HIV
Positive association with plasma viral load
Negative association with CD4
Significantly associated with monocyte activation markers / Abdulle et al., J Neurol, 2007
Peluso et al., J Infect Dis, 2015
McGuire et al., J NeuroVirol, 2015 / Moderately elevated, especially light NF / Rosengren et al., Neurology, 1999
Zetterberg et al., JAMA Neurol, 2015
Neurotrophic Factors / BDNF/GDNF / Reduced BDNF levels
Decreased GDNF levels in HAD / Avdoshina et al., AIDS, 2011
Mocchetti et al., Curr Trends Neurol, 2014 / Decreased BDNF levels / Philips et al., Neuron, 1991
Genetics / ApoEε4 / Cognitive dysfunction
Reduced white matter integrity
Cerebral atrophy
Disease progression / Wendelken et al., JAIDS, 2016
Burt et al., Proc Natl Acad Sci U S A, 2008 / Higher risk for Aβ aggregation
Accelerated longitudinal memory decline
Risk factor for cardiovascular disease / Liu et al., Nat rev Neurol, 2013
Abbreviations: WM: white matter; MD: mean diffusivity; HAD: HIV-associated dementia.
Supplemental Table. Summary of key features differentiating HAND from Alzheimer’s disease