Visualization and Computational Modeling for Science

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Centers for Behavioral and Preventive Medicine
Neurocognitive consequences of clade C virus a
preliminary report
Tokugha Yepthomi, M.D. Rob Paul,
Ph.D./ABCN Timothy Flanigan, M.D. David Tate,
Ph.D.. N. Kumarasamy, M.D. Snigdha
Vallabhaneni, B.S. Suniti Solomon, M.D. David
Laidlaw, Ph.D.
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The importance of cognition in HIV
Centers for Behavioral and Preventive Medicine

• Cognitive performance predicts
• Financial management
• Driving skill
• Shopping
• Cooking
• Medication adherence
• Employment
• QOL

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Cognition in HIV
Centers for Behavioral and Preventive Medicine

• Most studies that have examined cognitive
  function in HIV
• have focused on clade B.
• Clade C is common in many
• developing countries, and it is
• unclear whether infection with
• clade C is harmful to CNS
• function.

Frequency of HAD

• Reports suggest that HAD is infrequent in
  clade C.

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Clade C Properties
Centers for Behavioral and Preventive Medicine

• Recent study (Ranga et al. 2005) identified a
  defective region of the Tat protein in clade C.
• Natural variation in C31S
• the dicysteine motif.
• Disruption in CS or SC
• (CC) resulted in lt
• monocyte migration
• in cell migration assays.

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Clade C Properties
Centers for Behavioral and Preventive Medicine

• Implications of previous studies
• Suggestion that clade C, via reduced monocyte
  migration, is less harmful to the CNS.
• However
• Cognition was not examined in Ranga study.
• Published studies have not examined cognition
  using
• structured objective testing
• locally-derived normative comparisons

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Brown-YRG Collaborative Study
Centers for Behavioral and Preventive Medicine

• Collaboration w/ YRG Care in Chennai, Southern
  India.
• Aim
• Determine whether cognition is intact among
  individuals with clade C virus.
• Specific goals
• Develop and implement a battery of cognitive
  tests for administration in Southern India.
• Collect normative data from demographically
  similar individuals residing in the same region
  of India.
• Collect cognitive data before and after beginning
  ART.

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Cross cultural cognitive studies in Chennai, India
Centers for Behavioral and Preventive Medicine

• Inclusion/Exclusion
• Age 18-55
• No Hx of psychiatric, neurologic disease, active
  ETOH or drug abuse, presence of neurological OI
• Participants
• 30 HIV patients (36.0 years of age 9 years of
  education)
• 30 controls (34.3 years of age 10.5 years of
  education)
• Patients naïve to ART median CD4 cell count
  104

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Cognitive Assessment in India
Centers for Behavioral and Preventive Medicine

• Cognitive measures
• Cognitive flexibility, inhibition, and motor
  speed, visual learning and memory, verbal
  learning and memory.
• Stroop test
• Color Trails
• Grooved Pegboard

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Centers for Behavioral and Preventive Medicine
Stroop Test (inhibition) Trail Making
(flexibility)
Red Green Blue XXX XXX XXX Red
Green Blue
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Centers for Behavioral and Preventive Medicine
Pegs
Visual Memory Test
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Centers for Behavioral and Preventive Medicine
Verbal Memory Test Modified
HVLT-R

• Modifications completed by a team including
• 2 US neuropsychologists (1 ABCN)
• 1 US medical student (born and raised in
  Chennai, India fluent in regional languages)
• 1 Indian neurologist
• ITC guidelines

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Centers for Behavioral and Preventive Medicine
Verbal Memory Test Modified
HVLT-R

• Primary modifications
• Standard test consists of 3 categories
• 1. Animals
• 2. Dwellings
• 3. Gemstones
• For present study, gemstones replaced with fruit
  (pineapple, grapes, mango, banana). For
  recognition trial, added jackfruit and
  sweetlime.
• Forward and backward translation and multiple
  beta administrations prior to study enrollment.

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Centers for Behavioral and Preventive Medicine
Results
Completion Rates 100 for most tests Color
Trails 93 (both groups) Stroop 73 -
patients 93 - controls Telegu compared to
Tamil No significant differences (Fs lt 2.0).
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HIV-positive vs. HIV-negative
Centers for Behavioral and Preventive Medicine
.05
.05
.05
.05
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HIV-positive vs. HIV-negative
Centers for Behavioral and Preventive Medicine
.05
.05
.05
.05
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Between-group contrasts on cognitive measures
Centers for Behavioral and Preventive Medicine
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Cognitive contrasts
Centers for Behavioral and Preventive Medicine
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Percentages of Impairment
Centers for Behavioral and Preventive Medicine

• Performances 1.5 SD below that of seronegative
  control subjects.
• Consistent with results presented by Drs. Das
  Gupta and Satishchandra.

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Cognitive Assessment in India
Centers for Behavioral and Preventive Medicine
No correlations between cognitive function and
CD4 count (r lt .25). limited range of CD4
count Strong correlations between education and
performance on Color Trails 1 and 2, and
correlations between age and performance on
grooved pegboard.
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Summary
Centers for Behavioral and Preventive Medicine

• HIV patients performed more poorly than controls
  on most tests.
• CNS may be vulnerable in the context of clade C.
• Considering studies by Drs. Das Gupta and
  Satishchandra-
• Notable percentage of patients with clade C
  exhibit cognitive difficulties regardless of
  lower (100) vs. higher (gt300) CD4 count.
• In clade C, HAD may be infrequent even in the
  context of low CD4 count, yet milder cognitive
  difficulties exist in early and more advanced
  disease.

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Where to go from here?
Centers for Behavioral and Preventive Medicine

• Develop a common battery to extend normative data
  and establish a robust system to assess cognitive
  difficulties.
• Assessment of ADLs.
• Collect post-tx therapy and examine natural
  history of cognition in clade C.
• Identify neuroimaging signatures
• DTI examines the diffusion of water molecules
  along fiber tracts. Allows for assessment of the
  integrity of white matter regions of interest.
• Fractional anisotropy (FA) mean diffusivity
  (MD)

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Centers for Behavioral and Preventive Medicine
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DTI Visualization
Centers for Behavioral and Preventive Medicine
All fibers
Tracts
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DTI Visualization and Scalar Metrics
Centers for Behavioral and Preventive Medicine
Standard DTI scalar metrics include regionally
defined FA and MD New methodology integrates
visualization and novel metrics ( of fibers,
fiber length)
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