CSF Amyloid 42 Levels Link HIVAssociated Cognitive Disease and Alzheimers Disease

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CSF Amyloid ?42 Levels Link HIV-Associated
Cognitive Disease and Alzheimers Disease

• David B. Clifford, MD, John S.K. Kauwe, MS, Aarti
  R. Shah, MS, Michael L. Spinner, MA, John C.
  Morris, MD, David M. Holtzman MD, Anne M. Fagan,
  PhD

IAS Sydney Australia July 22-25, 2007
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Aging and AIDS

• Prof Gazzard emphasized aspects of aging
  associated with HIV
• Potential interaction of aging and the biology
  underlying cognitive impairment in HIV

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HIV Associated Cognitive Dysfunction Accelerated
by Aging

• Age has consistently been a risk factor for
  development of HIV associated cognitive
  impairment
• Consider possible interaction of Dementia
  of Alzheimer type (DAT) and HIV

Valcour, et al. AIDS, 2004
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Beta-amyloid deposition found in almost half of
AIDS brains, both in plaques and intraneuronal
Green, et al
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Potential Mechanisms

• Chronic inflammatory state may predispose to
  amyloid associated toxicity
• HAART therapy may predispose to amyloid
  deposition
• Facilitating aging
• Metabolic toxicity
• Ubiquitin-proteosome dysfunction
• TAT toxicity may be associated with amyloid
  deposition

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Rempel and Pulliam

• Neprilysin is a neuronal endopeptidase that
  degrades A?
• HIV-1 TAT inhibits neprilysin in vitro human
  brain aggregates by 80

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Rempel and Pulliam
A? immunostain
Bielschowsky silver stain
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Populations Studied

• Controls and pts with Dementia of the Alzheimer
  Type (DAT)
• Washington University Alzheimers Dx Research
  Center (ADRC) provided CSF samples carefully
  assessed volunteers
• Dx based
• Careful history
• Neurological examination
• Psychometric testing
• Scored with CDR scale where CDR 0 normal
• CDR 0.5/1.0 every mild or mild DAT

CDR Memory Orientation Judgment/ Problem
Solving Community Affairs Home/Hobbies Personal
Care
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HIV Patients National NeuroAIDS Tissue Consortium

• NIH funded research program to provide
  characterized HIV research samples
• Dx based on
• History
• Patient examination
• Neuropsychometric testing
• Algorithm for accurate dx of HIV associated
  neurological dx
• Samples were from patients diagnosed with minor
  cognitive motor disorder (MCMD) or with
  HIV-associated dementia (HAD)

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Methods

• CSF for control and DAT collected in fasting
  subjects at 730 am All CSF frozen quickly,
  thawed once for analysis.
• Commercial ELISA assay (Innotest) used for
  measuring total tau, ptau181, A?42
• A ?40 ELISA assay performed according to Fagan,
  et al Ann Neurol 2006 59512-519

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Statistical Methods

• Analyzed for association with dx status using
  ANCOVA after adjusting for age
• A?40, A?42, tau and ptau181 log transformed to
  approximate normal distributions
• Bonferroni correction for the number of tests (4
  conditions) makes estimate of significance
  P0.0125

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Population Studied
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A?42 Depressed in Patients with HIV Associated
Neurocognitive Disease

P-values derived by ANCOVA testing after
adjusting for age
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Low CSFA?42 Seen in Both MCMD and HIV-Associated
Dementia
P-values derived by ANCOVA testing after
adjusting for age
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CSF A?40 Not Depressed in HIV-Associated
Neurocognitive Disease
P-values derived by ANCOVA testing after
adjusting for age
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Unlike in DAT, CSF Total Tau and pTau Similar to
Controls in HIV-Associated Neurocognitive Disease
Tau
p181 Tau

P-values derived by ANCOVA testing after
adjusting for age
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CSF Aß42 is in equilibrium with plaques
plaque
ISF
intracellular
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Analysis of CSF Ab42 levels appears to be useful
as a screening tool to identify the presence of
PIB brain amyloid regardless of clinical status
0.15
1250
93 Specificity (54/58)
1000
(pg/ml)
750
42
b
500
443 pg/ml
CSF A
100 Sensitivity (13/13)
250
0
-0.25
0.00
0.25
0.50
0.75
1.00
1.25
mean cortical PIB binding
(amyloid binding potential)
Solid squares, CDR 1-2, mild-moderate DAT
Open triangle, CDR 0.5, very mild DAT Solid
triangles, CDR 0.5, non-AD dementia Open
circles, CDR 0, cognitively normal
Fagan et al. Ann. Neurol, 2006 Fagan et al. Arch.
Neurol, 2007
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Conclusion

• Low CSF A?42 levels with normal A?40 levels are
  found in patients with HIV cognitive impairment
• CSF A?42 levels found in HIV have correlated with
  pathologic amyloid brain deposition in
  Alzheimers disease patients
• HIV does not fully replicate the CSF parameters
  seen in DAT since CSF tau and ptau are not
  elevated as in DAT
• Further studies of amyloid metabolism in HIV may
  be important in understanding potential
  acceleration of cognitive impairment with aging

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Acknowledgements

• National NeuroAIDS Tissue Consortium
• E Singer, S Morgello, B Gelman, I Grant
• Funding NS32228 and NIMH22005(DBC), P50AG05681,
  P01AG0399, and P01AG026276 (JCM, DMH, AMF), NNTC
  NS38841(Singer), R24MH59724(Morgello),
  R24NS45491(Gelman), MH05745(Grant)

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