1. HIV Infection of the Nervous System
HIV Infection of the CNS
HIV Infection of the Nervous System
Neuropsychological Factors
Eric Miller - Epi April 2013 1

2. How Does HIV Affect the Nervous System?
HIV Infection of the CNS
How Does HIV Affect the Nervous System?
HIV easily crosses the blood-brain barrier
Dave R, Pomerantz RJ. (2005). HIV neuropathogenesis: persistent infection, persistent questions. Science & Medicine.
Eric Miller - Epi April 2013 2

3. How Does HIV Affect the Nervous System?
HIV Infection of the CNS
How Does HIV Affect the Nervous System?
General immunosuppression can lead to:
Opportunistic Infections
Fungal (Cryptococcal Meningitis)
Parasitic (Toxoplasmosis)
Viral (Progressive Multifocal Leukoencephalopathy)
HIV-Related Tumors
Eric Miller - Epi April 2013 3

4. How Does HIV Affect the Nervous System?
HIV Infection of the CNS
How Does HIV Affect the Nervous System?
Primary HIV Disease can lead to:
AIDS Dementia Complex (brain)
Vacuolar Myelopathy (spinal cord)
Peripheral Neuropathy (nerve)
Meningitis (acute and chronic)
Eric Miller - Epi April 2013 4

5. How Does HIV Affect the Nervous System?
HIV Infection of the CNS
How Does HIV Affect the Nervous System?
HIV indirectly destroys cells in the nervous system
Kaul, Garden & Lipton (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410,
Eric Miller - Epi April 2013 5

6. How Does HIV Affect the Nervous System?
HIV Infection of the CNS
How Does HIV Affect the Nervous System?
10-15% of AIDS patients present with neurologic symptoms only
35-50% of AIDS patients have neurologic symptoms during life1,2
75-90% have neuropathologic abnormalities at death3
1) Brouwman et al, Neurology ; 50:
2) McArthur J Neuroimmunol 2004; 157 : 3-10
3) Vago et al., AIDS. 2002;16:
Eric Miller - Epi April 2013 6

7. Progression of HIV Infection of the Nervous System
HIV Infection of the CNS
Progression of HIV Infection of the Nervous System
HIV neg
HIV positive, but
otherwise asymptomatic
Constitutional Symptoms & Severe
Immunosuppression, but no OIs
AIDS
Acute
Chronic Meningitis
Schematic diagram of HIV-related diseases that affect central nervous system (solid border) and peripheral nervous system (dotted border). Adapted from Johnson et al., 1988.
Eric Miller - Epi April 2013 7

8. Progression of HIV Infection of the Nervous System
HIV Infection of the CNS
Progression of HIV Infection of the Nervous System
HIV neg
HIV positive, but
otherwise asymptomatic
Constitutional Symptoms & Severe
Immunosuppression, but no OIs
AIDS
Acute
Chronic Meningitis
HIV-Associated Neurocognitive Disorders
Schematic diagram of HIV-related diseases that affect central nervous system (solid border) and peripheral nervous system (dotted border). Adapted from Johnson et al., 1988.
Eric Miller - Epi April 2013 8

9. HIV Infection of the CNS
HIV-associated Neurocognitive Disorders (HAND) (HIV-1-Associated Dementia) (HIV-associated Cognitive/Motor Complex) (HIV-associated Mild Neurocognitive Disorder) (Asymptomatic Neurocognitive Impairment) (HIV-Associated Mild Cognitive/Motor Disorder) (AIDS Dementia Complex)
“Patients with the AIDS dementia complex present with a variable, yet characteristic, constellation of abnormalities in cognitive, motor, and behavioral function. Perhaps the salient aspects of the disorder are the slowing and loss of precision in both mentation and motor control …. These patients often lose interest in their work as well as in their social and recreational activities.” (Price et al., 1988)
Eric Miller - Epi April 2013 9

10. HIV-Associated Neurocognitive Disorders (HAND)
HIV Infection of the CNS
HIV-Associated Neurocognitive Disorders (HAND)
HIV dementia is generally considered a subcortical dementia.
Eric Miller - Epi April 2013 10

11. HIV-Associated Neurocognitive Disorders (HAND)
HIV Infection of the CNS
HIV-Associated Neurocognitive Disorders (HAND)
HIV dementia is generally considered a subcortical dementia.
HIV dementia symptoms are more associated with motor slowing and loss of executive control than with language and memory disturbance.
Eric Miller - Epi April 2013 11

12. HIV-Associated Neurocognitive Disorders (HAND)
HIV Infection of the CNS
HIV-Associated Neurocognitive Disorders (HAND)
HIV dementia is generally considered a subcortical dementia.
HIV dementia symptoms are more associated with motor slowing and loss of executive control than with language and memory disturbance.
Later stage illness affects both cortical and subcortical regions and may affect memory.
Eric Miller - Epi April 2013 12

13. HIV-Associated Neurocognitive Disorders (HAND)
HIV Infection of the CNS
HIV-Associated Neurocognitive Disorders (HAND)
Neurocognitive Impairment (Neuropsychological Testing)
Functional Impairment
(Activities of Daily Living)
Asymptomatic Neurocognitive Impairment (ANI)
≥ Mild
None
Mild Neurocognitive Disorder (MND)
> Mild
HIV-Associated Dementia (HAD)
≥ Moderate
> Moderate
Woods, SP, et. al. Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. Journal of Clinical and Experimental Neuropsychology, 2004,26, p
Antinori A, et al. Neurology 2007; 69;
Eric Miller - Epi April 2013 13

14. HIV Infection of the CNS
Assessment of HAND
Behavioral Observations
Eric Miller - Epi April 2013 14

15. HIV Infection of the CNS
Assessment of HAND
Behavioral Observations
Acquired abnormality
Eric Miller - Epi April 2013 15

16. HIV Infection of the CNS
Assessment of HAND
Behavioral Observations
Acquired abnormality
Change in normal Activities of Daily Living
Eric Miller - Epi April 2013 16

17. HIV Infection of the CNS
Assessment of HAND
Behavioral Observations
Acquired abnormality
Change in normal Activities of Daily Living
Change in mood or normal social relationships
Eric Miller - Epi April 2013 17

18. HIV Infection of the CNS
Assessment of HAND
Behavioral Observations
Acquired abnormality
Change in normal Activities of Daily Living
Change in mood or normal social relationships
Rule out other medical conditions
Eric Miller - Epi April 2013 18

19. HIV Infection of the CNS
HIV-Associated Neuro-cognitive Disorder
Other medical conditions
HIV-Associated Neurocognitive Disorders may share symptoms with:
Mood disorders
Drug and alcohol abuse
Mania and psychosis
Other infections and neurologic problems
Oversedation with medications commonly given for sleep, mood problems and other disorders
Eric Miller - Epi April 2013 19

20. HIV Infection of the CNS
Assessment of HAND
Behavioral Observations
Acquired abnormality
Change in normal Activities of Daily Living
Change in mood or normal social relationships
Rule out other medical conditions
Neuropsychological (Cognitive) Tests
Eric Miller - Epi April 2013 20

21. Neuropsychological Tests
HIV Infection of the CNS
Neuropsychological Tests
Functional Domains
Attention and Concentration
Gross and Fine Motor Skills
Verbal and Nonverbal Memory
Language Skills
Visuoperceptual Skills
Executive Skills/Higher Order Reasoning
Eric Miller - Epi April 2013 21

22. Neuropsychological Tests
HIV Infection of the CNS
Neuropsychological Tests
Functional Domains Impaired in HIV
Attention and Concentration
Gross and Fine Motor Skills
Verbal and Nonverbal Memory
Language Skills
Visuoperceptual Skills
Executive Skills/Higher Order Reasoning
Eric Miller - Epi April 2013 22

23. Neuropsychological Tests
HIV Infection of the CNS
Neuropsychological Tests
Mini-mental status exam lacks sensitivity (no measures of psychomotor change)
Standard psychological measures (personality, aptitude, achievement) are helpful, but lack specificity
Eric Miller - Epi April 2013 23

24. Core Cognitive Impairments
HIV Infection of the CNS
Core Cognitive Impairments
Cognitive and motor slowing
Reaction time tests
Motor measures
Poor divided attention / executive skills
Trail Making test
Stroop Color Interference
Memory (usual in later stages)
Eric Miller - Epi April 2013 24

25. HIV Infection of the CNS
Trail-Making Part B
Eric Miller - Epi April 2013 25

26. Stroop Color Interference Test
HIV Infection of the CNS
Stroop Color Interference Test
Eric Miller - Epi April 2013 26

27. HIV Infection of the CNS
Grooved Pegboard
Eric Miller - Epi April 2013 27

28. Neuropsychological Assessment of HIV Dementia
HIV Infection of the CNS
Neuropsychological Assessment of HIV Dementia
Neuropsychological tests are used to:
Identify specific patterns of cognitive impairment that are associated with HIV dementia.
Potentially identify different subtypes of HIV dementia.
Track the progression of cognitive changes typically seen in HIV dementia.
Eric Miller - Epi April 2013 28

29. Progression of Untreated HIV Infection
HIV Infection of the CNS
Progression of Untreated HIV Infection
Simplified course of untreated HIV infection; there is considerable variability across individuals.
----  CD4+ T Lymphocyte count (cells/mm³)   HIV RNA copies per mL of plasma
Eric Miller - Epi April 2013

30. HIV Infection of the CNS
Changes in Performance on Trails B Before and After HIV-1 Seroconversion
Eric Miller - Epi April 2013 30

31. Changes in Performance on Trails B Before and After Diagnosis of AIDS
HIV Infection of the CNS
Changes in Performance on Trails B Before and After Diagnosis of AIDS
Eric Miller - Epi April 2013 31

32. Stage of HIV Disease and Neuropsychological Test Performance
HIV Infection of the CNS
Stage of HIV Disease and Neuropsychological Test Performance
Decline on neuropsychological testing is closely linked to general systemic illness.
In general, observable cognitive changes are not seen during early, medically asymptomatic, stages of HIV disease.
Data from HIV-positive subjects with known dates of seroconversion suggest that there is no relationship between duration of HIV seropositivity and neuropsychological decline.
Eric Miller - Epi April 2013 32

33. HIV Infection of the CNS
Incidence and Prevalence of HIV-Associated Neurocognitive Disorders (HAND)
Prior to HAART (before 1995)
After HAART (1996+)
New cases of dementia occurred at a rate of 7% per year
Incidence of all types of primary HIV neuropsychiatric disease have decreased dramatically
15-40% of individuals developed dementia prior to death
Incidence of cognitive impairment has been halved and dementia is rare
Median survival after dementia was 6 months
With proper treatment, HIV is considered a chronic disease
Eric Miller - Epi April 2013 33

34. Declines in Incidence of HIV-associated CNS Disease in the HAART Era
HIV Infection of the CNS
Declines in Incidence of HIV-associated CNS Disease in the HAART Era
Eric Miller - Epi April 2013 34

35. HIV Infection of the CNS
HAND in the Era of HAART
Although incidence of HIV dementia has decreased dramatically, milder forms of cognitive impairment have increased.
After over 25 years of research, the specific triggers for HAND remain unknown.
Improved survival means that more individuals with HAND must learn to cope with the disabling effects of impaired cognition.
Eric Miller - Epi April 2013 35

36. HIV Infection of the CNS
HAND in the Era of HAART
Effective treatments for HAND are not yet available.
Individuals who are treated with HAART shortly after the first symptoms of cognitive impairment appear may show dramatic improvement.
Individuals who have shown symptoms of cognitive impairment for a while do not seem responsive to treatment.
Eric Miller - Epi April 2013 36

37. HIV Neuropathogenesis
HIV Infection of the CNS
HIV Neuropathogenesis
Sustained CNS inflammation
Eric Miller - Epi April 2013 37

38. HIV Infection of the CNS
HIV indirectly destroys cells in the nervous system
Kaul, Garden & Lipton (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410,
Eric Miller - Epi April 2013 38

39. HIV Neuropathogenesis
HIV Infection of the CNS
HIV Neuropathogenesis
Sustained CNS inflammation
Accelerated vascular disease
Eric Miller - Epi April 2013 39

40. HIV Infection of the CNS
Thompson Neuroimaging Laboratory, UCLA (2005)
Eric Miller - Epi April 2013

41. HIV Neuropathogenesis
HIV Infection of the CNS
HIV Neuropathogenesis
Sustained CNS inflammation
Accelerated vascular disease
Amyloid deposition
Eric Miller - Epi April 2013 41

42. HIV Infection of the CNS
Brain deposition of beta-amyloid is a common feature in HIV+ patients (age years) (Green et al AIDS 2005)
Amyloid is increased in diffuse non-neuritic plaques in HIV+ brains
An increase in diffuse plaques suggest early aging with HIV infection and may be enough to cause cognitive impairment AD
HIV
HIV
HIV
Eric Miller - Epi April 2013 42

43. HIV Infection of the CNS
Risk Modifiers
Demographic Factors (age, education, etc.)
Substance Abuse
Genetic Factors
CNS responsiveness to HAART
Eric Miller - Epi April 2013 43

44. Demographic Risk Factors
HIV Infection of the CNS
Demographic Risk Factors
Individuals with less education are at greater risk
Brain reserve capacity
Socioeconomic status and access to health care
Early studies suggested that older individuals may be at greater risk
Eric Miller - Epi April 2013 44

45. HIV Infection of the CNS
HIV and Aging
In recent studies of HIV and aging, the best predictors of poorer cognitive functioning were markers of early cerebrovascular disease, not HIV serostatus.
In the post-HAART era, it appears that HIV infection may not be a particularly important predictor of cognitive functioning, at least among individuals with access to medical care and appropriate medications.
Primary risk factors for cognitive impairment in older HIV-infected individuals are the same medical conditions that are associated with normal aging.
(Becker, 2009; Sacktor, 2009)
Eric Miller - Epi April 2013 45

46. Genetic Susceptibility
HIV Infection of the CNS
Genetic Susceptibility
Several genetic loci have been tentatively associated with changes in cognitive functioning.
Genetic studies have been difficult to replicate.
Genetic factors associated with cognitive impairments may be similar across dementing disorders (HIV, Alzheimers, etc.).
Predictive power of genetic profiles has not been particularly strong.
Eric Miller - Epi April 2013 46

47. Medical Treatments for HIV Dementia
HIV Infection of the CNS
Medical Treatments for HIV Dementia
Does HAART penetrate the blood-brain-barrier?
Many types of HAART do not easily cross into the brain in laboratory studies
However, HIV-infected individuals may show increased permeability of the blood-brain-barrier
Eric Miller - Epi April 2013 47

48. Medical Treatments for HIV Dementia
HIV Infection of the CNS
Medical Treatments for HIV Dementia
High dose zidovudine (AZT) (ACTG 005)
Nimodipine (ACTG 162; Calcium channel antagonist)
Memantine (ACTG 301; NMDA antagonist)
Selegiline (ACTG A5090; antioxidant/cell repair)
Highly Active Antiretroviral Therapies (HAART)
Eric Miller - Epi April 2013 48

49. Medical Treatments for HIV Dementia
HIV Infection of the CNS
Medical Treatments for HIV Dementia
HAART usually reduces viral load both in the periphery and in the CNS.
Reduction of viral load in the CNS is associated with reduced cognitive symptoms. (Ellis et al., 2003)
Individuals with stable viral load do not show increased risk for cognitive decline, even after 5 years of monitoring. (Cole et al., 2007)
Eric Miller - Epi April 2013 49

50. What are the Practical Implications of These Research Findings?
HIV Infection of the CNS
What are the Practical Implications of These Research Findings?
Changes in brain metabolism may be present even during early stages of HIV infection.
When viral load is adequately controlled, these changes in brain metabolism do not affect day-to-day functioning, motor skills, or higher order reasoning even though very subtle changes may appear on cognitive testing.
Eric Miller - Epi April 2013 50

51. What are the Practical Implications of These Research Findings?
HIV Infection of the CNS
What are the Practical Implications of These Research Findings?
With heightened viral load and immunosuppression, HIV may cause a potentially reversible inflammation of brain tissue.
With sustained viral replication, HIV may cause permanent cell death.
Even with uncontrolled viral load and immunosuppression, many people do not develop HIV dementia.
Eric Miller - Epi April 2013 51

52. Goals of Current Research
HIV Infection of the CNS
Goals of Current Research
Identify risk factors for developing dementia
Identify biological mechanisms that lead to cell death and dementia
Establish effective screening tools to identify early stage dementia
Develop medical interventions that will reverse the symptoms of dementia before permanent damage occurs
Eric Miller - Epi April 2013 52

53. HIV Infection of the CNS
Eric Miller - Epi April 2013 53