HIV Infection of the Nervous System - Jonathan and Karin ... · How Does HIV Affect the Nervous System? Primary HIV Disease can lead to: AIDS Dementia Complex (brain) Vacuolar Myelopathy

HIV Infection of theHIV Infection of theNervous SystemNervous System

Neuropsychological FactorsNeuropsychological Factors

How Does HIV Affect the Nervous System?How Does HIV Affect the Nervous System?

HIV easily crosses the bloodHIV easily crosses the blood--brain barrierbrain barrier

Dave R, Pomerantz RJ. (2005). HIV neuropathogenesis: persistent infection, persistent questions. Science & Medicine.


General immunosuppression can lead to:General immunosuppression can lead to:

Opportunistic Infections Opportunistic Infections Fungal (Cryptococcal Meningitis)Fungal (Cryptococcal Meningitis) Parasitic (Toxoplasmosis)Parasitic (Toxoplasmosis) Viral (Progressive Multifocal Viral (Progressive Multifocal

Leukoencephalopathy)Leukoencephalopathy)

HIVHIV--Related TumorsRelated Tumors


Primary HIV Disease can lead to:Primary HIV Disease can lead to:

AIDS Dementia Complex (brain)AIDS Dementia Complex (brain) Vacuolar Myelopathy (spinal cord)Vacuolar Myelopathy (spinal cord) Peripheral Neuropathy (nerve)Peripheral Neuropathy (nerve) Meningitis (acute and chronic)Meningitis (acute and chronic)


HIV indirectly destroys cells in the nervous systemHIV indirectly destroys cells in the nervous system

Kaul, Garden & Lipton (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988-994.


1010--15% of AIDS patients present with 15% of AIDS patients present with neurologic symptoms neurologic symptoms onlyonly

3535--50% of AIDS patients have neurologic 50% of AIDS patients have neurologic symptoms during lifesymptoms during life1,21,2

7575--90% have neuropathologic abnormalities at 90% have neuropathologic abnormalities at deathdeath33

1) Brouwman et al, Neurology. 1998 ; 50:18141) Brouwman et al, Neurology. 1998 ; 50:1814--20. 20. 2) McArthur J Neuroimmunol 2004; 157 : 32) McArthur J Neuroimmunol 2004; 157 : 3--10103) Vago et al., 3) Vago et al., AIDS. 2002;16:1925AIDS. 2002;16:1925--8. 8.

Progression of HIV Infection of Progression of HIV Infection of the Nervous Systemthe 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.

Progression of HIV Infection of Progression of HIV Infection of the Nervous Systemthe 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.

HIVHIV--associated Neurocognitive Disorders (HAND)associated Neurocognitive Disorders (HAND)(HIV(HIV--11--Associated Dementia)Associated Dementia)

(HIV(HIV--associated Cognitive/Motor Complex)associated Cognitive/Motor Complex)(HIV(HIV--associated Mild Neurocognitive Disorder)associated Mild Neurocognitive Disorder)

(Asymptomatic Neurocognitive Impairment)(Asymptomatic Neurocognitive Impairment)(HIV(HIV--Associated Mild Cognitive/Motor Disorder)Associated Mild Cognitive/Motor Disorder)

(AIDS Dementia Complex)(AIDS Dementia Complex)

““Patients with the AIDS dementia complex present with a Patients with the AIDS dementia complex present with a variable, yet characteristic, constellation of abnormalities in variable, yet characteristic, constellation of abnormalities in cognitive, motor, and behavioral function. Perhaps the cognitive, motor, and behavioral function. Perhaps the salient aspects of the disorder are the slowing and loss of salient aspects of the disorder are the slowing and loss of precision in both mentation and motor control precision in both mentation and motor control ……. These . These patients often lose interest in their work as well as in their patients often lose interest in their work as well as in their social and recreational activities.social and recreational activities.”” (Price et al., 1988)(Price et al., 1988)

HIVHIV--Associated Neurocognitive Associated Neurocognitive Disorders (HAND)Disorders (HAND)

HIV dementia is generally considered a HIV dementia is generally considered a subcortical dementia.subcortical dementia.


HIV dementia is generally considered a HIV dementia is generally considered a subcortical dementia.subcortical dementia. HIV dementia symptoms are more associated HIV dementia symptoms are more associated

with motor slowing and loss of executive with motor slowing and loss of executive control than with language and memory control than with language and memory disturbance.disturbance.


HIV dementia is generally considered a HIV dementia is generally considered a subcortical dementia.subcortical dementia. HIV dementia symptoms are more associated HIV dementia symptoms are more associated

with motor slowing and loss of executive with motor slowing and loss of executive control than with language and memory control than with language and memory disturbance.disturbance.

Later stage illness affects both cortical and Later stage illness affects both cortical and subcortical regions and may affect memory.subcortical regions and may affect memory.

HIVHIV--Associated Neurocognitive Associated Neurocognitive Disorders (HANDDisorders (HAND))

Neurocognitive Impairment

(Neuropsychological Testing)

Functional Impairment

(Activities of Daily Living)

Asymptomatic Neurocognitive

Impairment (ANI)≥ Mild None

Mild Neurocognitive Disorder (MND) ≥ Mild > 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 759-778.

Antinori A, et al. Neurology 2007; 69;1789-1799

Assessment of HANDAssessment of HAND

Behavioral ObservationsBehavioral Observations


Behavioral ObservationsBehavioral Observations Acquired abnormalityAcquired abnormality


Behavioral ObservationsBehavioral Observations Acquired abnormalityAcquired abnormality Change in normal Activities of Daily LivingChange in normal Activities of Daily Living


Behavioral ObservationsBehavioral Observations Acquired abnormalityAcquired abnormality Change in normal Activities of Daily LivingChange in normal Activities of Daily Living Change in mood or normal social relationshipsChange in mood or normal social relationships



Rule out other medical conditionsRule out other medical conditions

HIVHIV--Associated Neurocognitive Disorders may share Associated Neurocognitive Disorders may share symptoms with:symptoms with: Mood disordersMood disorders Drug and alcohol abuseDrug and alcohol abuse Mania and psychosisMania and psychosis Other infections and neurologic problemsOther infections and neurologic problems Oversedation with medications commonly given for sleep, Oversedation with medications commonly given for sleep,

mood problems and other disordersmood problems and other disorders

HIV-Associated

Neuro-cognitive Disorder

Other medical

conditions



Rule out other medical conditionsRule out other medical conditions Neuropsychological (Cognitive) TestsNeuropsychological (Cognitive) Tests

Neuropsychological TestsNeuropsychological Tests

Functional DomainsFunctional Domains Attention and ConcentrationAttention and Concentration Gross and Fine Motor SkillsGross and Fine Motor Skills Verbal and Nonverbal MemoryVerbal and Nonverbal Memory Language SkillsLanguage Skills Visuoperceptual SkillsVisuoperceptual Skills Executive Skills/Higher Order ReasoningExecutive Skills/Higher Order Reasoning


Functional Domains Impaired in HIVFunctional Domains Impaired in HIV Attention and ConcentrationAttention and Concentration Gross and Fine Motor SkillsGross and Fine Motor Skills Verbal and Nonverbal MemoryVerbal and Nonverbal Memory Language SkillsLanguage Skills Visuoperceptual SkillsVisuoperceptual Skills Executive Skills/Higher Order ReasoningExecutive Skills/Higher Order Reasoning


MiniMini--mental status exam lacks sensitivity mental status exam lacks sensitivity (no measures of psychomotor change)(no measures of psychomotor change)

Standard psychological measures Standard psychological measures (personality, aptitude, achievement) are (personality, aptitude, achievement) are helpful, but lack specificityhelpful, but lack specificity

Core Cognitive ImpairmentsCore Cognitive Impairments

Cognitive and motor slowing Cognitive and motor slowing Reaction time testsReaction time tests Motor measuresMotor measures

Poor divided attention / executive skillsPoor divided attention / executive skills Trail Making testTrail Making test Stroop Color InterferenceStroop Color Interference

Memory (usual in later stages)Memory (usual in later stages)

TrailTrail--Making Part BMaking Part B

Stroop Color Interference TestStroop Color Interference Test

Grooved PegboardGrooved Pegboard

Neuropsychological Assessment of Neuropsychological Assessment of HIV DementiaHIV Dementia

Neuropsychological tests are used to:Neuropsychological tests are used to: Identify specific patterns of cognitive Identify specific patterns of cognitive

impairment that are associated with HIV impairment that are associated with HIV dementia.dementia.

Potentially identify different subtypes of HIV Potentially identify different subtypes of HIV dementia.dementia.

Track the progression of cognitive changes Track the progression of cognitive changes typically seen in HIV dementia.typically seen in HIV dementia.

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

Changes in Performance on Trails BChanges in Performance on Trails BBefore and After HIVBefore and After HIV--1 Seroconversion1 Seroconversion

Changes in Performance on Trails BChanges in Performance on Trails BBefore and After Diagnosis of AIDSBefore and After Diagnosis of AIDS

Stage of HIV Disease and Stage of HIV Disease and Neuropsychological Test PerformanceNeuropsychological Test Performance

Decline on neuropsychological testing is closely Decline on neuropsychological testing is closely linked to general systemic illness.linked to general systemic illness.

In general, observable cognitive changes are not In general, observable cognitive changes are not seen during early, medically asymptomatic, seen during early, medically asymptomatic, stages of HIV disease.stages of HIV disease.

Data from HIVData from HIV--positive subjects with known positive subjects with known dates of seroconversion suggest that there is no dates of seroconversion suggest that there is no relationship between duration of HIV relationship between duration of HIV seropositivity and neuropsychological decline.seropositivity and neuropsychological decline.

Incidence and Prevalence of HIVIncidence and Prevalence of HIV--Associated Associated Neurocognitive Disorders (HAND)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

Declines in Incidence of HIVDeclines in Incidence of HIV--associated associated CNS Disease in the HAART EraCNS Disease in the HAART Era

HAND in the Era of HAARTHAND in the Era of HAART

Although incidence of HIV dementia has Although incidence of HIV dementia has decreased dramatically, milder forms of decreased dramatically, milder forms of cognitive impairment have increased. cognitive impairment have increased.

After over 25 years of research, the specific After over 25 years of research, the specific triggers for HAND remain unknown.triggers for HAND remain unknown.

Improved survival means that more individuals Improved survival means that more individuals with HAND must learn to cope with the disabling with HAND must learn to cope with the disabling effects of impaired cognition.effects of impaired cognition.

HAND in the Era of HAARTHAND in the Era of HAART

Effective treatments for HAND are not yet Effective treatments for HAND are not yet available.available. Individuals who are treated with HAART Individuals who are treated with HAART

shortly after the first symptoms of cognitive shortly after the first symptoms of cognitive impairment appear may show dramatic impairment appear may show dramatic improvement.improvement.

Individuals who have shown symptoms of Individuals who have shown symptoms of cognitive impairment for a while do not seem cognitive impairment for a while do not seem responsive to treatment.responsive to treatment.

HIV NeuropathogenesisHIV Neuropathogenesis

Sustained CNS inflammationSustained CNS inflammation

HIV indirectly destroys cells in the nervous systemHIV indirectly destroys cells in the nervous system

Kaul, Garden & Lipton (2001). Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988-994.



Accelerated vascular diseaseAccelerated vascular disease

Thompson Neuroimaging Laboratory, UCLA (2005)



Accelerated vascular diseaseAccelerated vascular disease

Amyloid depositionAmyloid deposition

Brain deposition of betaBrain deposition of beta--amyloid is a common amyloid is a common feature in HIV+ patients (age 31feature in HIV+ patients (age 31--58 years) 58 years)

((Green et al AIDS 2005)Green et al AIDS 2005)

AD

HIV

HIV

HIV

•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

Risk ModifiersRisk Modifiers

Demographic Factors (age, education, Demographic Factors (age, education, etc.)etc.)

Substance AbuseSubstance Abuse Genetic FactorsGenetic Factors CNS responsiveness to HAARTCNS responsiveness to HAART

Demographic Risk FactorsDemographic Risk Factors

Individuals with less education are at Individuals with less education are at greater riskgreater risk Brain reserve capacityBrain reserve capacity Socioeconomic status and access to health Socioeconomic status and access to health

carecare

Early studies suggested that older Early studies suggested that older individuals may be at greater riskindividuals may be at greater risk

HIV and AgingHIV and Aging

In recent studies of HIV and aging, the best predictors of In recent studies of HIV and aging, the best predictors of poorer cognitive functioning were markers of early poorer cognitive functioning were markers of early cerebrovascular disease, cerebrovascular disease, notnot HIV serostatus. HIV serostatus.

In the postIn the post--HAART era, it appears that HIV infection may not HAART era, it appears that HIV infection may not be a particularly important predictor of cognitive functioning, be a particularly important predictor of cognitive functioning, at least among individuals with access to medical care and at least among individuals with access to medical care and appropriate medications. appropriate medications.

Primary risk factors for cognitive impairment in older HIVPrimary risk factors for cognitive impairment in older HIV--infected individuals are the same medical conditions that are infected individuals are the same medical conditions that are associated with normal aging.associated with normal aging.

(Becker, 2009; Sacktor, 2009)(Becker, 2009; Sacktor, 2009)

Genetic SusceptibilityGenetic Susceptibility

Several genetic loci have been tentatively Several genetic loci have been tentatively associated with changes in cognitive functioning. associated with changes in cognitive functioning. Genetic studies have been difficult to Genetic studies have been difficult to

replicate.replicate. Genetic factors associated with cognitive Genetic factors associated with cognitive

impairments may be similar across dementing impairments may be similar across dementing disorders (HIV, Alzheimers, etc.).disorders (HIV, Alzheimers, etc.).

Predictive power of genetic profiles has not Predictive power of genetic profiles has not been particularly strong.been particularly strong.

Medical Treatments for HIV Medical Treatments for HIV DementiaDementia

Does HAART penetrate the Does HAART penetrate the bloodblood--brainbrain--barrier?barrier? Many types of HAART do not Many types of HAART do not

easily cross into the brain in easily cross into the brain in laboratory studieslaboratory studies

However, HIVHowever, HIV--infected infected individuals may show individuals may show increased permeability of the increased permeability of the bloodblood--brainbrain--barrierbarrier


High dose zidovudine (AZTHigh dose zidovudine (AZT)) (ACTG 005)(ACTG 005)

NimodipineNimodipine (ACTG 162; Calcium channel (ACTG 162; Calcium channel antagonist)antagonist)

MemantineMemantine (ACTG 301; NMDA antagonist)(ACTG 301; NMDA antagonist)

SelegilineSelegiline (ACTG A5090; antioxidant/cell (ACTG A5090; antioxidant/cell repair)repair)

Highly Active Antiretroviral Therapies Highly Active Antiretroviral Therapies (HAART)(HAART)


HAART usually reduces viral load both in the HAART usually reduces viral load both in the periphery and in the CNS.periphery and in the CNS.

Reduction of viral load in the CNS is associated Reduction of viral load in the CNS is associated with reduced cognitive symptoms. with reduced cognitive symptoms. (Ellis et al., 2003)(Ellis et al., 2003)

Individuals with stable viral load do not show Individuals with stable viral load do not show increased risk for cognitive decline, even after 5 increased risk for cognitive decline, even after 5 years of monitoring. years of monitoring. (Cole et al., 2007)(Cole et al., 2007)

What are the Practical Implications of What are the Practical Implications of These Research Findings?These Research Findings?

Changes in brain metabolism may be present Changes in brain metabolism may be present even during early stages of HIV infection.even during early stages of HIV infection.

When viral load is adequately controlled, When viral load is adequately controlled, these changes in brain metabolism do not these changes in brain metabolism do not affect dayaffect day--toto--day functioning, motor skills, or day functioning, motor skills, or higher order reasoning even though very higher order reasoning even though very subtle changes may appear on cognitive subtle changes may appear on cognitive testing. testing.

What are the Practical Implications of What are the Practical Implications of These Research Findings?These Research Findings?

With heightened viral load and With heightened viral load and immunosuppression, HIV may cause a immunosuppression, HIV may cause a potentially reversible inflammation of potentially reversible inflammation of brain tissue.brain tissue.

With sustained viral replication, HIV With sustained viral replication, HIV may cause permanent cell death.may cause permanent cell death.

Even with uncontrolled viral load and Even with uncontrolled viral load and immunosuppression, many people do immunosuppression, many people do not develop HIV dementia.not develop HIV dementia.

Goals of Current ResearchGoals of Current Research

Identify risk factors for developing dementiaIdentify risk factors for developing dementia Identify biological mechanisms that lead to cell Identify biological mechanisms that lead to cell

death and dementiadeath and dementia Establish effective screening tools to identify Establish effective screening tools to identify

early stage dementiaearly stage dementia Develop medical interventions that will reverse Develop medical interventions that will reverse

the symptoms of dementia before permanent the symptoms of dementia before permanent damage occursdamage occurs

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HIV Infection of the Nervous System - Jonathan and Karin ... · How Does HIV Affect the Nervous System? Primary HIV Disease can lead to: AIDS Dementia Complex (brain) Vacuolar Myelopathy