This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Neurocognitive Impairment in the Pre-ARV, Pre-HAART and HAART Eras
Grant 1987 HNRC-500 1995 CHARTER 2008
50%
75%
100%
rcen
t Im
pair
ed
0%
25%
HIV- CDC-A CDC-B CDC-C
Per
Frascati Classification of HIV‐Associated Neurocognitive Disorders (HAND)
• ANI = AsymptomaticANI = Asymptomatic neurocognitiveimpairment
• MND = Mild neurocognitivedisorderdisorder
• HAD = HIV‐1 associated dementia
4/12/2012
6
HIV Associated Neurocognitive Disorders (HAND): Frascati Criteria
Asymptomatic Neuropsychological
Impairmentabnormality in twoor more cognitive
Mild NeurocognitiveDisordercognitive
impairment with mild functional
HIV-associatedDementia
marked cognitive impairment with
marked functional
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
gabilitiesimpairmentimpairment
Antinori, et al., Neurology 2007
HIV Associated Neurocognitive Disorders (HAND): Frascati Criteria
Asymptomatic Neuropsychological
Impairmentabnormality in twoor more cognitive
Mild NeurocognitiveDisordercognitive
impairment with mild functional
HIV-associatedDementia
marked cognitive impairment with
marked functional
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
gabilitiesimpairmentimpairment
Antinori, et al., Neurology 2007
4/12/2012
7
Asymptomatic HIV-associated Neurocognitive Disorder (ANI) Increases Risk for Future Symptomatic Decline: A Risk for Future Symptomatic Decline: A
CHARTER Longitudinal Study
Robert Heaton, PhD1, Donald Franklin, BS1, Steven Woods, PsyD1, Christina Marra, MD2, David Clifford, MD3,
Benjamin Gelman, MD,PhD4, Justin McArthur, MBBS5, Susan Morgello MD6 Allen McCutchan MD1 and
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Susan Morgello, MD6, Allen McCutchan, MD1, and Igor Grant, MD1 for the CHARTER Group
1 University of California, San Diego; 2 University of Washington, Seattle; 3 Washington University, St. Louis;4 University of Texas Medical Branch, Galveston; 5 Johns Hopkins University, 6 Mount Sinai School of Medicine
DiagnosisCHARTER Neurocognitive Test Battery
Verbal Fluency Motor» Letter Fluency» Category Fluency
Speed of Information Proc.» WAIS-III Symbol Search» WAIS-III Digit Symbol» Trail Making Test Part A
Attention/Working Memory
» Grooved Pegboard
Abstraction/Executive» Wisconsin Card Sorting Test 64» Trail Making Test Part B
Learning and Memory» Hopkins Verbal Learning Test-R» Brief Visuospatial Memory Test R
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
» Paced Auditory Serial Addition Test -50
» WAIS-III Letter-Number Sequencing
» Brief Visuospatial Memory Test-R» Story Memory Test » Figure Memory Test
Everyday Functioning: Patient’s Assessment of Own Functioning InventoryActivities of Daily Living Scale
4/12/2012
8
Participants
347 longitudinal CHARTER participants with up to 90 months of follow-up (median 45.2 months)months of follow up (median 45.2 months)» 226 NML cases: No neurocognitve impairment and no self-
reported or observed declines in everyday functioning
» 121 ANI cases: Neurocognitvely impaired, but no self-reported or observed declines in everyday functioning
Participants completed neuromedical, laboratory,
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
neurocognitive, and both self-report and performance-based measures of everyday functioning approximately every 6 months
Self-Report Functional Impairment Measures
Patients Assessment of Own Functioning Inventory (PAOFI): Measures cognitive complaints over 5 domains (eg Measures cognitive complaints over 5 domains (eg., memory, language, cognition)» Symptomatic = 3 or more complaints
Activities of Daily Living (ADL): Measures increased dependence in completing basic activities of daily living (eg., housekeeping, cooking, managing finances)
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
( g , p g, g, g g )» Symptomatic = declines in 2 or more areas at least partially
attributed to cognitive problems
Self-report symptomatic HAND requires both PAOFI and ADL to be symptomatic
4/12/2012
9
Performance-based Functional Impairment Measures
Medication Management Test-Revised (MMT-R): Assesses ability to perform tasks related to medication management» Tasks include ability to correctly place pills in a pill organizer according
to prescription schedule and ability to infer answers from prescription labels
» Symptomatic = Score 1SD below the mean of cognitively normal sample
Valpar System 3000 Work Samples and Computerized Assessment: Assesses abilities considered important for
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Assessment: Assesses abilities considered important for performing work-related tasks» Symptomatic = Score 1SD below the mean of cognitively normal
sample
Baseline Comparison of ANI and NML:Background Characteristics
NML (n=226) ANI (n=121) P-value
A 43 0 (8 6) 44 8 (8 0)Age 43.0 (8.6) 44.8 (8.0)
Education 12.9 (2.4) 13.5 (2.2) .04
% Male 81.9% 81.8%
% Caucasian 45.6% 46.3%
% Lifetime Substance Dx 71.2% 69.4%
% with Comorbidity 22.6% 44.6% <.0001
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
4/12/2012
10
Baseline Comparison of ANI and NML:Disease Characteristics
NML (n=226) ANI (n=121) P-value
% AIDS 56.2% 62.8%
Current CD4 459 [290-669] 425 [286-578]
Nadir CD4 201 [61-370] 162 [38-273] .03
% on ART 66.2% 72.7%
Est. Duration HIV+ (months) 117.7 (75.0) 120.7 (81.6)
% HCV+ 20.4% 27.3
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
ANI Increases Risk for Symptomatic HAND: Based on Self-Report of Functional Impairment
p=.003
(Asy
mp
tom
atic
)
NML: n=226ANI: n=121
Relative Risk: 2.30CI: 1.38, 3.86
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Su
rviv
ing
(
4/12/2012
11
ANI Increases Risk for Symptomatic HAND: Performance-based Functional Impairment
NML: n=226
p<.0001
g (
As
ymp
tom
ati
c)
NML: n=226ANI: n=121
Relative Risk: 4.70CI: 2.93, 7.71
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Su
rviv
ing
ANI Increases Risk for Symptomatic HAND: Self-report or Performance-based
NML: n=226ANI: n=121
p< 0001g (
As
ymp
tom
ati
c)
Relative Risk: 3.02CI: 2.08, 4.42
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
p<.0001
Su
rviv
ing
4/12/2012
12
Asymptomatic Neurologic Impairment May Predict Functional Decline
Mechanism remains uncertain
Cannot “write off” this substantial portion of successfully treated HIV patients
Tracking change in this population is challenging
Measures of cognitive function that can be
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Measures of cognitive function that can be repeated and tracked might be of value
International HIV Dementia Scale
•International HIV Dementia Scale •Naming four objects•Fingertapping•“Luria” psychomotor learning task•Recall of names
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Sacktor et al. Neurology 2003 60;1:A186-187
4/12/2012
13
CogState
Executive Function
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Trail making A and B Robertson et al ALLRT Trail making A and B
Symbol digit test
Hopkins Verbal Learning test
Robertson, et al, ALLRT
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
Being assessed in comparison with tools currently used that
i li d
HIV NEUROBEHAVIORAL RESEARCH PROGRAM | UNIVERSITY OF CALIFORNIA, SAN DIEGOCNS HIV ANTI-RETROVIRAL THERAPY EFFECTS RESEARCH | UNIVERSITY OF CALIFORNIA, SAN DIEGO
require licenses, and norming
http://www.mocatest.org/
Cognitive Dysfunction in HIV
AIDS Dementia (now HAD)Pre‐HAART
HAND (ANI/MND)Post‐HAART
4/12/2012
15
Slide 29
To develop effective treatment we need to know causes HAND now…
• Evidence for direct• Evidence for direct viral mechanism poor
• Cytokines that formerly were most closely associated no longer provide reliablelonger provide reliable signal
…by the way, I’m from Missouri where famously you have to “Show me….”
• “Noninfectious pathologies and minimalNoninfectious pathologies and minimal changes correlated with HIV‐associated neurocognitive disorder, suggesting a shift in pathogenesis from florid HIV replication to other, diverse mechanisms”
• 88% of sample had HAND88% of sample had HAND
• 17.5 % has parenchymal HIV brain pathology which was associated to nadir CD4 and plasma viral load
4/12/2012
16
Slide 31
To develop effective treatment we need to know causes HAND now?
• Co-morbidities• Co-morbidities
• Virus
• Inflammation
• Drugs
• Perfusion/Vascular
Slide 32
Is this all due to non-HIV-associated co-morbidities?
• Contribution of other factors to cognitive performance– ?trauma
– ?drugs
– ?hepatitis
– ?CMV
– ?psychiatric dx/rx
4/12/2012
17
Slide 33
Neurocognitive Impairment by Co-Morbidity Status
30
40
50
60
70
80
impa
irm
ent
0
10
20
Total Minimal Moderate Severe
%
Slide 34
Co-morbidity
• Large effect of co morbid associated• Large effect of co-morbid associated impairment masks HIV associated findings
• Only in the “clean” group can one see impact of HIV viral load, CD4 nadir
• Co-morbidity may set up environment for C y y pongoing pathologic interaction with HIV and/or its consequences like inflammation
4/12/2012
18
Slide 35
To develop effective treatment we need to know causes HAND now?
• Co-morbidities• Co-morbidities
• Virus
• Inflammation
• Drugs
• Perfusion/Vascular
Slide 36
Viral Escape• CNS is functional
compartment• Untreated HIV
– CSF generally one log – Viral isolates may be
unique
– Cells infected in CNS are monocytes/macrophages with unique viral
lower VL than periphery
– During HAD CSF VL rises with autonomous CNS isolates
– Most often when requirements
– Rx may differperipheral virus controlled so is CSF
4/12/2012
19
Slide 37
Symptomatic Viral Escape
Peluso, Spudich et al, Poster 489
• Controlled plasma viral pload
• Subacute onset of new neurologic symptoms
• CSF demonstrated independent replicationp p
• Drug selection based on virus in CSF improved clinical condition
Implications of Viral Escape
• HIV therapy is not perfect
• Viral replication sometimes occurs in CNS and generates important resistance mutations
• Attention to virus in CNS remains critical
• Justify CSF analysis when new neurologic problems occur in HIV patient even with goodproblems occur in HIV patient, even with good control in plasma
• Rarity suggest it doesn’t explain common HAND
4/12/2012
20
Slide 39
Does viral subtype matter?
• Work in Uganda with dementia suggests• Work in Uganda with dementia suggests difference in risk between Subtype A and D
• Work in Ethiopia suggests Subtype C might have less neurovirulence
• Projects in Cape Town and in Brazil are j C paddressing potential differences, to date seems less likely to be important
HIV infection in the brain may not be fully reflected in blood studies and therapies not as effective in brain….
• Does HIV or its therapy accelerate aging?accelerate aging?
• Path evidence of premature p‐tau and amyloid
• Driving force could be chronic inflammatory or toxicor toxic
• Findings were subclinical but evident at post mortem
Anthony et al, Acta Neuropathol , 2006
• NNTC evaluation in HIV subjects 50‐76 yo
• Neuritic α‐synuclein in 12/73 HIV+ and not controls
• β‐amyloid deposits in 35/36 HIV brains
• Not found in association with HIV brain pathologypathology
• Suggest accelerated degenerative disease not directly HIV virus driven
4/12/2012
32
Potential Mechanisms
• Chronic inflammatoryinflammatory state may lead to amyloiddeposition
• TAT inhibition of neprilysnneprilysn
• Ubiquitin‐proteosomedysfunction
Neurology, Dec 2009
4/12/2012
33
CSF Amyloid β 1‐42 Is Low in Cognitively Impaired HIV+ Patients
CSF Tau Not Elevated
4/12/2012
34
Better Biomarkers: CSF Amyloid and PET PIB
• Biology of low CSF AB42• Biology of low CSF AB42 appears different in HIV and AD
• PIB binding correlates to low CSF AB42 in AD
• In HIV, low CSF AB42 is NOT i t d ith
A. HIV +, Low Aβ1‐42, cog NB. Community, Low Aβ 1‐42, cog NAnces and Clifford, Archives of Neurology,
2012
NOT associated with extracellular amyloiddeposits
Alzheimer’s Disease in HIV
• AD is common and will likely occur in HIV
• HAND may be distinguished by:likely occur in HIV
patients as they age
• Rx for AD advancing, and specific dx will be important
– Anticholinesterase rx
distinguished by:
– Lack of tau elevations in CSF
– Lack of PIB binding amyloid on PET scanning of brain
– Anticholinesterase rx
– NMDA antagonist (memantine)
• More data needed on biology of amyloid in HIV (as well as AD!)
4/12/2012
35
Slide 69
To develop effective treatment we need to know causes HAND now?
• Co-morbidities• Co-morbidities
• Virus
• Inflammation
• Drugs
• Perfusion/Vascular
Cardiovascular Risks Associated with Poor Cognitive Performance in SMART
Study• Traditional HIV associated risk factors
CROI 2010
associated risk factors were not associated with baseline NP performance
• CVD risk factors were associated with poorerassociated with poorer baseline performance
4/12/2012
36
Multicenter AIDS Cohort
Af i f d i• After accounting for education, depression and race
• Carotid intima‐media thickness (IMT) and GFR associated with psychomotor speed
• IMT associated with memory
• HIV serostatus not associated with poorer cognitive performance overall
• In HIV+, HIV detection in plasma associated with poorer memory
Slide 72
HIV Indirectly Contributes to Cognitive Impairment?
HIV Age
Carotid IntimaThickening
HIV gHBPDMLipids
Cognitive Normal
CognitiveImpaired
4/12/2012
37
Slide 73
Effects of HIV and Aging on rCBF
m/m
in)
ebra
l blo
od f
low
(m
l/10
0gm
Ances et al. , JID, Feb 2010
Cer
e
Age (years old)
Slide 74
Blood Flow May be Biomarker for Blood Flow May be Biomarker for HIV HIV SynaptodendriticSynaptodendritic Injury/InflammationInjury/Inflammation
HIV
DisruptionNormal
Synapto-dendriticDensity
Normal
Disruption or Loss of Synapto-dendriticcommunication
R d d
Masliah et al,Ann Neurol 1997
Masliah et al,Ann Neurol 1997
NormalCerebral
Blood Flow
ReducedCerebral
Blood Flow
HAART
4/12/2012
38
Slide 75
Modifiable Risk FactorsModifiable Risk Factors
SmokingSmokingSmokingSmoking
DietDiet•• GlucoseGlucose•• LipidsLipids
ExerciseExercisePh i lPh i l•• PhysicalPhysical
•• MentalMental
RestRest
Slide 76
Modifiable Risk FactorsModifiable Risk Factors
SmokingSmokingSmokingSmoking
DietDiet•• GlucoseGlucose•• LipidsLipids
ExerciseExercisePh i lPh i l•• PhysicalPhysical
•• MentalMental
RestRest
4/12/2012
39
Overall NC Impairment status at baseline and last visit: No major cohort worsening
NP Normal Mild NCI NP Normal
Baseline Last Visit
38%
8%
NP Normal Mild NCI
≥ Moderate NCI
29%
11%
Mild NCI
≥ Moderate NCI
54%38%
60%
29%
77
Slide 78
ConclusionsConclusions
Cognitive functions remain impaired Cognitive functions remain impaired in many optimally treated HIVin many optimally treated HIVin many optimally treated HIV in many optimally treated HIV patientspatients
Optimal therapy should avoid low Optimal therapy should avoid low nadir CD4, optimize HIV control, nadir CD4, optimize HIV control, minimize chronic immune activation,minimize chronic immune activation,minimize chronic immune activation, minimize chronic immune activation, and optimize cerebral perfusionand optimize cerebral perfusion
Healthy lifestyles as well as HIV Healthy lifestyles as well as HIV control should contribute to better control should contribute to better neurologic outcomesneurologic outcomes
4/12/2012
40
Thanks• Washington U
• Beau Ances• Turner Overton• ACTU and NARC staff
• NARC investigators• Ned Sacktor• Justin McArthur• David Simpson• Christina Marra• Giovanni Schifitto• Scott Evans
• CHARTER investigators• Ron Ellis• Ron Ellis• Scott Letendre• Igor Grant
• NIH: NINDS (NARC and CHARTER)• NIH: NIMH (CHARTER and CIT2)• NIH: NIAID (ACTU)• NIH: Fogarty (West Africa)