Valutazione dei disturbi neurocognitivi e invecchiamento: non solo HAND. Workshop Nazionale CISAI Lecco 20 Marzo 2015
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1 Valutazione dei disturbi neurocognitivi e invecchiamento: non solo HAND Workshop Nazionale CISAI Lecco 20 Marzo 2015 Paola Cinque Dipartimento di Malattie Infettive Istituto Scientifico San Raffaele, Milano
2 PC disclosures (past 12 months) AbbVie Biogen Idec Bristol-Myers Squibb Gilead Inhibikase Ther. Janssen Cilag Johnson & Johnson Merck Millenium Pharmaceuticals Pfizer Viiv Healthcare
3 Outline 1. Quick update of HIV in the CNS 2. Separate effects of aging and HIV on the CNS 3. Additive effects of aging and HIV on the CNS
4 HIV and CNS: What we see now CSF viral escape Unfrequent, often severe Caused by HIV!!! Neurocognitive impairment (NCI) Frequent, often mild Caused by HIV???
5 Prevalence of HAND - Rome, ANI: Asymptomatic Neurocognitive Impairment (NP test abnormalities only) MND: Mild Neurocognitve Disorder (NP test abn + mild functional problems) HAD: HIV-associated dementia 83% suppressed plasma VL Pennetta, Antinori et al. CROI 2015
6 Potential causes of cognitive impairment in HIV infection HIV (HIV-associated NCI) Previously established irreversible tissue damage by HIV or other causes (legacy effect) Psychiatric disorders Drugs, alcool Alzheimer s and other neurodegenerative diseases Metabolic problems and cerebro-vascular disease Drug toxicity (ART, other drugs) Aging
7 2. Separate effects of aging and HIV on the CNS
8 The aging brain: decrease of weight and volume Sullivan EV, Br J Radiol 2007
9 The brain with HIV:cortical thinning in the prefrontal and parietal cortex Total brain Total gray and white matter Regional gray matter HIV controls Thompson PM, PNAS 2005
10 The brain with HIV: microstructural white matter alterations by diffusion tensor imaging Apparent Diffusion Coefficient (ADC) HIV-neg HIV-POS Fractional Anisotropy (FA) FWM: frontal white matter; CC-G: corpus callosum, genu; CC-S: corpus callosum, splenium Ferretti F, 2014, unpublished
11 The aging brain: microglial deterioration Streit WJ, Trends Neurosci 2006
12 The aging brain: microglial degeneration and immuneactivation Dystrophy Spheroid swelling HLA-DR expression Segmentation Streit WJ, Progr. Neurobiol 1999 Streit WJ, Trends Neurosci 2006
13 The HIV brain: increased immuneactivation (asymptomatic ART-treated patients) HIV+ HIV- CD68 MHCII Smith J NeuroVirol 2014
14 The aging brain: altered functional activation Cabeza R, Neuroimage 2002, Andrews-Hanna, Neuron 2007, Bishop Nature 2010
15 The HIV brain: altered functional activation Asymptomatic, mostly ART-treated patients Activation Likelihood Estimation (ALE) meta-analysis: overlap of fmri differences between HIV+ and HIV-neg Higher activation in the left inferior frontal gyrus and caudate in HIV+ Du Plessis, AIDS 2014
16 The aging brain: increased proportion of people with increased CSF levels of markers of axonal damage (NFL) and Alzheimer disease (T-tau) 5,542 clinical samples ( ) obtained for diagnostic purposes (HIV-neg) Age Skillbäck et al. Alzheimer's Research & Therapy 2013
17 The HIV brain: increased level of CSF markers of axonal damage (NFL) and Alzheimer disease (T-tau) in severe NCI forms Peterson J et al., PlosOne 2014
18 3. CNS, HIV and aging
19 Is there an additive effect of age and HIV status on neurocognitive function? - Clinical studies - Biomarker studies
20 Neurologic disorders incidence in HIV+ vs HIV- men Multicenter AIDS Cohort Study, Mateen FJ, et al. Neurology, 2012
21 Apparent additive Effects of HIV Infection and Aging on Instrumental Activities of Daily Living (IADL) Young: <40 years Old: >50 years Older HIV+ had - longer duration of infection (18 vs. 5 ys) - lower CD4 nadir (148 vs. 247) Morgan EE et a., JAIDS 2012
22 Additive effect of age and HIV on verbal memory HVLT: Verbal Learning Test-Revised (HVLT-R) 54 HIV+ vs. 30 HIV- aged NP assessments one year apart Selder et al., J Clin Exper Neuropsychol 2014
23 Additive effect of aging and HIV on cerebral blood flow (CBF) Baseline CBF Functional CBF P< (age) P= (HIV) Age P=0.005 (age) P=0.013 (HIV) cart untreated + treated Ances B et al., CID 2009
24 Additive effect of age and HIV on CSF NFL HIV+, neuroasymptomatic, no ART > HIV-neg (18.5 years) HIV+, neuroasymptomatic, ART > HIV-neg (3.9 years) Krut JJ et al., PlosOne 2014
25 CNS, aging and HIV: conclusions Aging and HIV exert independent effects on the CNS: Structural and microstructural Biological Functional and clinical Both individually and likely also in concert
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