# Presentation: 669703

## HIV, METH AND THE BRAIN: IMPLICATIONS FOR HIV RISK

**Igor Grant, M.D.**
**HIV Neurobehavioral Research Center **
**University of California, San Diego**
**http://www.hnrc.ucsd.edu/**

## Slide 2

## BEHAVIORAL 

**    **_**Primary**_
**      ****	****Asymptomatic ****	****   ****	****	****   Neurocognitive    ****	****	****   Impairment**
**       ****	****Mild Neurocognitive**
**	****    ****Disorder**
**       ****	****Dementia**
**    **
**    **_**Secondary**_
**	****Infection**
**	****Neoplasia**
**	****Cerebrovascular**
**	****Nutritional**
**	****Treatment Related**

**EMOTIONAL & OTHER**
**BEHAVIORAL**** **
**   **_**New Onset**_
**      ****	****Depression**
**       ****	****Anxiety**
**       ****	****Adjustment Disorders**
**       ****	****HIV Mania **
**       ****	****HIV Psychosis**
**   **
**   **_**Recurrent/Comorbid**_
**      ****	****Mood Disorders**
**       ****	****Substance Use Disorders**
**       ****	****Other Mental Disorders**

**HIV NEUROBEHAVIORAL DISTURBANCES**

**HIV NEUROBEHAVIORAL RESEARCH CENTER**

## Prevalence of Neurocognitive Disorders by Stage of HIV Disease

## Meaning of NP Impairment: Employment

**% Unemployed**

## Mean Number of Accidents on 

**City Driving Simulation**

**Number of Accidents**

## Adherence to Antiretrovirals Related to Neurocognitive Impairment 

**(N=19)**

**(N= 8)**

**(N=15)**

**(N= 8)**

**% That Followed Schedule ****“Most of the Time”**

**% That Followed Specific Instructions****Re Meds “Most of the Time”**

## Proportions of Persons Judged to have 

**Global NP Impairment that have **
**Specific Ability Deficit**

**Attention**

**Learning**

**Verbal**

**Motor**

**Memory**

**Psychomotor**

**Sensory**

**Abstraction**

**% Impaired**

## Percent of Various Cells at Autopsy Having HIV

- 							_**%**_
**Microglia****	****	****	****	****	****80**
**Astroglia****	****	****	****	****	****?**
**Endothelial****	****	****	****	****10**
**Neurons****	****	****	****	****	**** 0**

## HIV-Associated Brain Damage Involves

**Neuronal Pathology**
**Post-synaptic Injury is Prominent**

**HIV NEUROBEHAVIORAL RESEARCH CENTER**

## Synaptophysin & MAP-2 Immunostaining

**HIV-**

**HIV+**

**HIV NEUROBEHAVIORAL RESEARCH CENTER**

## Dendritic Complexity in Subjectswith Varying Levels of Cognitive Impairment

**HIV NEUROBEHAVIORAL RESEARCH CENTER**

## Possible Mechanisms of Neurotoxicity in HIV-1 Infection 

**Macrophage**

**Astrocyte**

**Neurone**

**Cytokines (e.g., TNF********, IL-6)**

**GP120**

**NMDA Receptor**

**Cytokines**

**Protective****Factors**

**HIV**

**QA**

**Ca****++**

**GP120**

**GP120**

**GP120**

**GP120**

**VIP****Receptor**

**Chemokine****Receptor**

**Possible Mechanisms of Neurotoxicity ****in HIV-1 Infection**

**GAL**
**C**

## Cofactors in HIV Associated Neurocognitive Complications

**Drug Abuse - example of methamphetamine**
**Coinfection with Hepatitis C [HCV]**
**Neurotoxic Treatments**

## MA and HIV

- ~60% of persons seeking MA tx are HIV infected (Peck et al., 2005)
- MA use associated with
- Loss of interneurons (Chana et al., 2007)
- Additive NP effects (Rippeth et al., 2004)
- - Immunocompromise (Carey et al., 2006)
- HIV drug resistance (Colfax et al., 2007)
- Problems in everyday functioning (Sadek et al., in press)
- - Poor ARV adherence (Reback et al., 2003)

## Slide 16

## % Having Global NP Impairment by Methamphetamine Abuse and HIV Status Accounting for Acute Intoxication on Day of NP Examination

**HIV-**

**HIV+**

**HIV-**

**HIV+**

**Non-Meth Abusing Group**

**Meth Abusing Group**

## Pattern of neuropsychological impairment according to risk factor

| Deficit | Meth | HIV | HCV |
| --- | --- | --- | --- |
| Learning | +++ | +++ | +++ |
| Retention | - | - | ? |
| Attention/Working Memory | + | ++ | + |
| Speed of Information Processing | ? | + | +++ |
| Visuospatial Functioning | ? | - | ? |
| Motor |  |  |  |
|    Disinhibition | ++ | - | ? |
|    Slowing | +++ | ++ | +++ |

## Pattern of neuropsychological impairment according to risk factor

| Deficit | Meth | HIV | HCV |
| --- | --- | --- | --- |
| Executive Functioning |  |  |  |
|    Problem-Solving/Planning | ++ | ++ | + |
|    Cognitive Disinhibition | ++ | - | ? |
|    Decision-making | +++ | + | ? |
| Frontal Systems Behavioral |  |  |  |
|    Disinhibition | ++ | - | ? |
|    Apathy | - | ++ | ? |
|    Executive | + | ++ | ? |

## Significant regional volume alterations related to METH and/or HIV 

- METH (increases)

- HIV (decreases)

- METH & HIV
- (opposing effects)

**Significant regional volume alterations related to METH and/or HIV**

**Notes:**
Same as ANOVA results before.  Occipital, temporal, frontal and thalamus DOWN in HIV.  Parietal lenticular and nucleus accumbens UP in METH and Caudate significant for both in opposing directions.  Not shown here is white matter is significantly down in HIV

## Association of Cortical Volumes with Impairment

**r =-.41, p<.05**

**r =.46, p<.05**

## Association of Cortical Volumes with Attention Deficits

- HIV+

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**0.40**

**0.45**

**0.50**

**0.55**

**0.60**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**0.40**

**0.45**

**0.50**

**0.55**

**0.60**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**0.40**

**0.45**

**0.50**

**0.55**

**0.60**

**CEREBRAL CORTEX VOLUME**

**CLINICAL RATING OF ATTENTION**

## Meth have larger Accumbens volume for age relative to controls

**Meth have larger Accumbens volume for age ****relative to controls**

**Notes:**
Same as previous slide except linear function with confidence intervals is shown rather than quadratic. Age effect in Meth group.  Note the significant finding is due to the younger participants. 

## MAP-2 in midfrontal cortex of HIV+ cases 

**MAP-2 in midfrontal cortex of HIV+ cases **
**with & without HIVE and with or without METH **

- Preserved neuronal and dendritic structure in HIV patient HIVE (-) METH (-).
- Moderate neuronal and dendritic damage in a HIVE (-) METH (+) patient.
- Moderate to severe neuronal damage in an HIVE (+) METH (-) patient.
- Severe neuronal and dendritic damage in an HIVE (+) METH (+) patient.
- Bar = 25 microns

## Degeneration of Interneurons in HIVE+METH Users

**Parvalbumin**

**Degeneration of Interneurons in ****HIVE+METH Users**

**Control                  HIVE(+)/METH(-)       HIVE(+)/METH(+)**

-  **No Alterations          Neuronal Damage          Severe Neuron Loss      **

**HIV- Meth-**

**HIV+ Meth-**

**HIV+ Meth+**

## Loss of calbindin interneurons is associated 

**with cognitive impairment and memory loss**

**HIV+ (control)                        HIVE+ METH-                    HIVE+ METH+**

## Mechanisms of neurodegeneration 

**mediated by HIV and METH**

**Oxidative stress**
**Excitotoxicity**
**Mitochondrial dysfunction**
**Alterations in calcium metabolism**
**Interference with signaling pathways of **
**	****trophic factors**
**6. Caspase mediated apoptosis**
**7. Cytokines, chemokines and other neuro-**
**    ****inflammatory factors**

## Possible Mechanisms of Neurotoxicity in HIV-1 Infection 

**Macrophage**

**Astrocyte**

**Neurone**

**Cytokines (e.g., TNF********, IL-6)**

**GP120**

**NMDA Receptor**

**Cytokines**

**Protective****Factors**

**HIV**

**QA**

**Ca****++**

**GP120**

**GP120**

**GP120**

**GP120**

**VIP****Receptor**

**Chemokine****Receptor**

**Possible Mechanisms of Neurotoxicity ****in HIV-1 Infection**

**GAL**
**C**

## METH and InflammationMore Inflammation in METH Users

**METH users had higher levels of 5 markers of macrophage activation* in plasma**
**3 were also higher in CSF **
**Similar to HIV RNA, levels varied with recency of METH use**
**HIV-METH- lowest **
**METH+Utox- intermediate **
**METH+Utox+ highest**

****MCP-1, sCD14, sTNFR-II, TNF-alpha, and MIP-1 beta***

## Chang, et al (2005)

## Predictors of Meth Relapse after 2 yrs

-  53% of a sample of HIV+ MA abusers    relapsed over a 2-year follow-up period
- Predictors of relapse in HIV included:
- Younger age
- Fewer years of education
- Earlier age at MA use onset
- Greater amounts of MA use
- Higher baseline HIV RNA in plasma
- No AIDS diagnosis
- ASPD, absence of depression
- Cognitive impairment

## Cognitive & Psychiatric Status Correlates of Meth Relapse

## Medication Adherence

- Prospective memory impairment predicts ARV nonadherence at 5 weeks in HIV+ substance abusers (*d *= -1.1)*** ***

## Relapse to METH Abuse or Dependence diagnosis during 12 month follow-up is associated with higher plasma HIV RNA (n=63)

## Antiretroviral Drug ResistanceMethamphetamine is Associated with DR

- Resistance mutations were determined in 63 subjects enrolled in NIDA-funded projects
- 45% had resistance mutations for at least one antiretroviral
- Among METH dependent individuals, DR was associated with shorter durations of METH abstinence

**Hightower et al, XIV International HIV Drug Resistance Workshop, Submitted**

## Acknowledgments

**Coordinating Core: JH Atkinson MD, JA McCutchan MD, RJ Ellis MD PhD, T Marcotte PhD**
**Neuromedical Core: RJ Ellis MD PhD, JA McCutchan MD, S Letendre MD, E Capparelli PharmD, R Schrier PhD**
**Neurobehavioral Core: RK Heaton PhD, JH Atkinson MD, SP Woods PsyD, M Cherner PhD**
**Neurobiology Core: E Masliah MD, I Everall MD PhD**
**Neuroimaging Core: T Jernigan PhD, JR Hesselink MD, S Archibald MA, J Annese PhD, MJ Taylor PhD, B Schweinsburg PhD, O Alhassoon PhD**
**Neurovirology Core: D Richman MD, D Smith MD**
**Developmental Core: I Everall MD PhD, SA Lipton MD PhD**
**International Core: JA McCutchan MD**
**Statistics: I Abramson PhD, D Lazzaretto MS, R Deutsch PhD, T Wolfson MA**

## Funding support provided by:

**NeuroAIDS: Effects of Methamphetamine and HCV, NIDA P01 DA12065**
**HIV Neurobehavioral Research Center (HNRC), NIMH P30 MH62512**
**CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER), NIMH N01 MH22005 **
**California NeuroAIDS Tissue Network (CNTN), NIMH R24 MH59745**

## HIV, METH AND THE BRAIN: IMPLICATIONS FOR HIV RISK

**Igor Grant, M.D.**
**HIV Neurobehavioral Research Center **
**University of California, San Diego**
**http://www.hnrc.ucsd.edu/**

## Rates of Global NP Impairment as determined by GDS cut-off scores

## Relation of Dendritic Damage to Neurocognitive Impairment

**% Area Occupied by Dendrites**

## HIVE-

**HIVE-**

**HIVE+**

- Abnormal White Matter

**Notes:**
Example section from a participant with HIV encephalitis and a participant with HIV but no encephalitis.  Coronal Proton Density and T2

## Example sections from morphometric analysis

**Example sections from morphometric analysis**

**Notes:**
Upper left is posterior and bottom right is most anterior

## Abnormal white matter volume predicts HIV encephalitis and dendritic loss at autopsy

**10**

**15**

**20**

**25**

**MAP2**

**0.00**

**0.01**

**0.02**

**0.03**

**0.04**

**0.05**

**HIVE+**

**HIVE-**

**10**

**15**

**20**

**25**

**MAP2**

**0.00**

**0.01**

**0.02**

**0.03**

**0.04**

**0.05**

**HIVE+**

**10**

**MAP2**

**0.00**

**0.01**

**0.02**

**0.03**

**0.04**

**0.05**

**HIVE+**

**0.06**

**Abnormal White Matter**

**Notes:**
From Archibald et al Archives of Neurology 2004