HIV Infection of the Nervous System · Inflammatory Neuropathy Sensory Neuropathy Schematic diagram of HIV-related diseases that affect central nervous system (solid border) and peripheral

HIV Infection of theHIV Infection of theNervous SystemNervous System

Neuropsychological FactorsNeuropsychological Factors

HIV Infection of theHIV Infection of theNervous SystemNervous System

•• 1010--15% of AIDS patients present with 15% of AIDS patients present with neurologicneurologic symptoms symptoms onlyonly (5% with (5% with dementia).dementia).

•• 3030--50% of AIDS patients have 50% of AIDS patients have neurologicneurologicsymptoms during life (20symptoms during life (20--30% with 30% with dementia)dementia)

•• 7070--90% of AIDS patients have nervous 90% of AIDS patients have nervous system abnormalities present at autopsy.system abnormalities present at autopsy.

Nervous System Disease Nervous System Disease Associated with HIVAssociated with HIV•• Opportunistic Infections Opportunistic Infections (Fungal, Parasitic, (Fungal, Parasitic,

Viral)Viral)

•• HIVHIV--Related TumorsRelated Tumors•• Primary HIV DiseasePrimary HIV Disease

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

HIV and the BrainHIV and the Brain

•• HIV easily crosses the bloodHIV easily crosses the blood--brain barrierbrain barrier•• HIV is present in the brains of almost all HIV is present in the brains of almost all

infected individualsinfected individuals



infected individualsinfected individuals•• HIV directly or indirectly destroys cells in HIV directly or indirectly destroys cells in

the nervous systemthe nervous system

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.

Direct Injury: 1 Cell ModelDirect Injury: 1 Cell Model

Indirect Injury: 2 Cell ModelIndirect Injury: 2 Cell Model

Indirect Injury: 3+ Cell ModelIndirect Injury: 3+ Cell Model



infected individualsinfected individuals•• HIV directly or indirectly destroys cells in HIV directly or indirectly destroys cells in

the nervous systemthe nervous system•• HIV causes a dementia syndrome in some HIV causes a dementia syndrome in some

individualsindividuals

HIVHIV--Associated Cognitive/Motor ComplexAssociated Cognitive/Motor Complex(HIV(HIV--Associated Dementia)Associated Dementia)

(HIV(HIV--Associated Mild Cognitive/Motor Disorder)Associated Mild Cognitive/Motor Disorder)(HIV(HIV--Related Encephalopathy)Related Encephalopathy)

(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 variable, yet characteristic, constellation of abnormalities in cognitive, motor, and behavioral function. Perhaps the in 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 precision in both mentationmentation and motor control …. These and motor control …. 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.” (Price et al., 1988)social and recreational activities.” (Price et al., 1988)

Diagnostic Criteria for HIVDiagnostic Criteria for HIV--1 Dementia1 Dementia(American Academy of Neurology, 1991)(American Academy of Neurology, 1991)

•• Acquired abnormality in attention, Acquired abnormality in attention, speed of processing, abstraction, speed of processing, abstraction, memory, or verbal skillsmemory, or verbal skills

•• Acquired abnormality in motor function Acquired abnormality in motor function or decline in motivation or emotional or decline in motivation or emotional controlcontrol



Constitutional Symptoms & Severe Immunosuppression, but no OIs AIDS

Acute

Chronic Meningitis

HIV-Associated Cognitive/Motor Complex




Constitutional Symptoms, but no Opportunistic Infections AIDS

Acute

Chronic Meningitis

HIV-Associated Cognitive/Motor Complex

Myelopathies

Inflammatory Neuropathy

Sensory Neuropathy


Incidence and Prevalence of HIV Dementia Incidence and Prevalence of HIV Dementia in the MACS (Prior to HAART)in the MACS (Prior to HAART)

•• After a diagnosis of AIDS, new cases of After a diagnosis of AIDS, new cases of dementia occurred at a rate of 7% per dementia occurred at a rate of 7% per yearyear

•• 15% of the MACS cohort developed 15% of the MACS cohort developed dementia prior to deathdementia prior to death

•• Median survival after dementia was 6 Median survival after dementia was 6 monthsmonths

Number of Deaths

*Adjusted for reporting delays Quarter-Year of Death

Estimated AIDS Deaths*, of Adults/Adolescents,by Race/Ethnicity, 1985-1999, United States

1,000

2,000

3,000

4,000

5,000

6,000

7,000White, not HispanicBlack, not HispanicHispanic

01985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Asian/Pacific IslanderAmerican Indian/Alaska Native

Num

ber o

f Dea

ths

Incidence and Prevalence of HIV Dementia Incidence and Prevalence of HIV Dementia in the MACS (Since HAART)in the MACS (Since HAART)

•• Incidence of all types of primary HIV Incidence of all types of primary HIV neuropsychiatricneuropsychiatric disease have decreased disease have decreased dramatically.dramatically.

•• Incidence of dementia has been halved.Incidence of dementia has been halved.•• Survival time since diagnosis of dementia Survival time since diagnosis of dementia

has increased dramatically.has increased dramatically.

Changes in Incidence of Changes in Incidence of CryptococcalCryptococcal MeningitisMeningitis

00.5

11.5

22.5

33.5

44.5

5

1990-1992(monotherapy)

1993-1995 (dualtherapy)

1996-1998(HAART)

Incidence rates are number per 1000 person-years.(Sacktor et al., 2001)

Changes in Incidence of Changes in Incidence of ToxoplasmosisToxoplasmosis

0

1

2

3

4

5

6



1996-1998(HAART)

Incidence rates are number per 1000 person-years.(Sacktor et al., 2001)

Changes in Incidence of HIV Changes in Incidence of HIV DementiaDementia

0

5

10

15

20

25



1996-1998(HAART)

Incidence rates are number per 1000 person-years.

(Sacktor et al., 2001)

HIV Dementia in the Era of HAARTHIV Dementia in the Era of HAART

•• Although incidence of HIVAlthough incidence of HIV--dementia has dementia has decreased, it continues to be a problem for decreased, it continues to be a problem for many individuals.many individuals.

•• After 18 years of research, the specific triggers After 18 years of research, the specific triggers for HIV dementia remain unknown.for HIV dementia remain unknown.

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


•• Effective treatments for HIV dementia are Effective treatments for HIV dementia are not yet available.not yet available.–– Individuals who are treated with HAART Individuals who are treated with HAART

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

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


•• Before we can study dementia effectively, Before we can study dementia effectively, we need specific procedures and criteria we need specific procedures and criteria for defining what we mean by dementia.for defining what we mean by dementia.

•• HIV dementia is generally considered a HIV dementia is generally considered a subcorticalsubcortical dementia.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.

Assessment of HIV DementiaAssessment of HIV Dementia

•• 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 Change in mood or normal social

relationshipsrelationships


•• 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 Change in mood or normal social

relationshipsrelationships

•• Psychological TestsPsychological Tests

•• HIVHIV--Associated Cognitive Motor Disorder shares Associated Cognitive Motor Disorder shares many symptoms with:many symptoms with:•• DepressionDepression•• AnxietyAnxiety•• Drug and Alcohol AbuseDrug and Alcohol Abuse•• Other infections and Other infections and neurologicneurologic problemsproblems•• OversedationOversedation with medications commonly given for sleep, with medications commonly given for sleep,

mood problems and other disordersmood problems and other disorders

HIV-Associated Cognitive

Motor Disorder

Depression

Major DepressionMajor Depression

0

5

10

15

20

25

Major Depression (DSM-IIIR)

HIV Negative

Asymptomatic HIVPositiveSymptomatic HIVPositive


•• Behavioral ObservationsBehavioral ObservationsAcquired AbnormalityAcquired AbnormalityChange in normal Activities of Daily LivingChange in normal Activities of Daily LivingChange in mood or normal social Change in mood or normal social relationshipsrelationships

•• Psychological TestsPsychological Tests•• Neuropsychological (Cognitive) TestsNeuropsychological (Cognitive) Tests

Neuropsychological TestsNeuropsychological Tests

•• Functional DomainsFunctional DomainsAttention and ConcentrationAttention and ConcentrationGross and Fine Motor SkillsGross and Fine Motor SkillsVerbal and Nonverbal MemoryVerbal and Nonverbal MemoryLanguage SkillsLanguage SkillsVisuoperceptualVisuoperceptual SkillsSkillsExecutive Skills/Higher Order ReasoningExecutive Skills/Higher Order Reasoning

Neuropsychological TestsNeuropsychological Tests

•• Functional Domains Impaired in HIVFunctional Domains Impaired in HIVAttention and ConcentrationAttention and ConcentrationGross and Fine Motor SkillsGross and Fine Motor SkillsVerbal and Nonverbal MemoryVerbal and Nonverbal MemoryLanguage SkillsLanguage SkillsVisuoperceptualVisuoperceptual SkillsSkillsExecutive Skills/Higher Order ReasoningExecutive Skills/Higher Order Reasoning

TrailTrail--Making Part BMaking Part B

Grooved PegboardGrooved Pegboard

Symbol Digit ModalitiesSymbol Digit Modalities

StroopStroop Color Interference TestColor Interference Test

Neuropsychological Assessment of Neuropsychological Assessment of HIV DementiaHIV Dementia

•• Neuropsychological tests can be used to Neuropsychological tests can be 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.

•• Neuropsychological tests can be used to Neuropsychological tests can be used to track the progression of cognitive track the progression of cognitive changes typically seen in HIV dementia.changes typically seen in HIV dementia.

Models of HIVModels of HIV--Associated Associated DementiaDementia

•• Progressive cognitive decline starting at Progressive cognitive decline starting at time of initial infectiontime of initial infection

•• Latency period followed by gradual Latency period followed by gradual declinedecline

•• Latency period followed by rapid declineLatency period followed by rapid decline•• Multiple latent or dormant periods and Multiple latent or dormant periods and

declinesdeclines

CrossCross--Sectional vs. Longitudinal Sectional vs. Longitudinal AssessmentAssessment

•• Unless a patient is grossly demented, you Unless a patient is grossly demented, you cannot evaluate cannot evaluate declinedecline in cognitive functioning in cognitive functioning without serial assessments.without serial assessments.

•• Accurate diagnosis of HIVAccurate diagnosis of HIV--Associated Associated Cognitive/Motor Disorder Cognitive/Motor Disorder requiresrequires multiple multiple observations over at least a one month period.observations over at least a one month period.

•• Symptoms of depression (apathy, impaired Symptoms of depression (apathy, impaired attention, motor slowing) are often attention, motor slowing) are often misinterpreted both by patients and by health misinterpreted both by patients and by health care workers as early signs of dementia.care workers as early signs of dementia.

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 In general, observable cognitive changes are not seen during early, medically asymptomatic, not 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 dates of seroconversionseroconversion suggest that there is suggest that there is no relationship between duration of HIV no relationship between duration of HIV seropositivityseropositivity and neuropsychological decline.and neuropsychological decline.

MACS Neuropsychological StudyMACS Neuropsychological StudyLongitudinal FindingsLongitudinal Findings

•• Cognitive decline most often occurs Cognitive decline most often occurs around the time of severe around the time of severe immunosuppressionimmunosuppression or AIDSor AIDS

•• Clinically significant cognitive Clinically significant cognitive impairment is relatively infrequent impairment is relatively infrequent even among individuals with AIDSeven among individuals with AIDS

What is Going on Cognitively During Earlier What is Going on Cognitively During Earlier Stages of HIV Disease?Stages of HIV Disease?

•• Many patients continue to report changes in Many patients continue to report changes in memory and other cognitive skills even during memory and other cognitive skills even during the asymptomatic phase of the disease.the asymptomatic phase of the disease.

•• Very sensitive cognitive psychology measures Very sensitive cognitive psychology measures sometimes show subtle changes during sometimes show subtle changes during otherwise asymptomatic HIV disease.otherwise asymptomatic HIV disease.

•• Functional Functional neuroimagingneuroimaging suggests that some suggests that some changes in brain metabolism may occur at changes in brain metabolism may occur at relatively early stages of HIV disease.relatively early stages of HIV disease.

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

•• While these findings are of interest to While these findings are of interest to researchers and are suggestive of possible researchers and are suggestive of possible patterns of disease progression in the brain, patterns of disease progression in the brain, keep in mind that almost all research to date keep in mind that almost all research to date suggests that there is no impairment of daysuggests that there is no impairment of day--toto--day functioning, motor skills, or higher day functioning, motor skills, or higher order reasoning during otherwise order reasoning during otherwise asymptomatic HIV disease. asymptomatic HIV disease.

•• Also, even during symptomatic HIV disease, Also, even during symptomatic HIV disease, the prevalence of HIVthe prevalence of HIV--associated cognitive associated cognitive disorders is relatively low.disorders is relatively low.

Why do some patients insist that Why do some patients insist that they are experiencing cognitive they are experiencing cognitive problems, even when they are problems, even when they are otherwise relatively healthy?otherwise relatively healthy?

Cognitive Complaints in Cognitive Complaints in Asymptomatic HIV InfectionAsymptomatic HIV Infection

•• Studied 256 HIV negative and 233 Studied 256 HIV negative and 233 medically asymptomatic HIV positive medically asymptomatic HIV positive menmen

•• Study participants completed Study participants completed neuropsychological testing and selfneuropsychological testing and self--report measures of cognitive report measures of cognitive complaints (CFQ) and depression (CEScomplaints (CFQ) and depression (CES--D)D)

Cognitive Complaints in Cognitive Complaints in Asymptomatic HIV InfectionAsymptomatic HIV Infection

•• There was no association between There was no association between cognitive complaints and cognitive complaints and neuropsychological test performanceneuropsychological test performance

•• For both HIV positive and negative For both HIV positive and negative subjects, there was a significant subjects, there was a significant correlation between cognitive correlation between cognitive complaints and selfcomplaints and self--reported reported symptoms of depressionsymptoms of depression

Critical Issues to be AddressedCritical Issues to be Addressed

•• Potential Triggers/Risk FactorsPotential Triggers/Risk Factors: The : The specific triggers that lead some specific triggers that lead some individuals to develop dementia while individuals to develop dementia while others remain cognitively healthy need to others remain cognitively healthy need to be identified. be identified.

•• Medical TreatmentsMedical Treatments: Treatments still : Treatments still need to be developed to reverse or delay need to be developed to reverse or delay the progression of dementia.the progression of dementia.

Potential Triggers/Risk FactorsPotential Triggers/Risk Factors

•• Individuals with less education are at Individuals with less education are at greater riskgreater risk

•• Older individuals are at greater riskOlder individuals are at greater risk•• Individuals with lower hemoglobin before Individuals with lower hemoglobin before

the onset of AIDS are at greater riskthe onset of AIDS are at greater risk•• Individuals with lower body mass indices Individuals with lower body mass indices

before the onset of AIDS are at greater before the onset of AIDS are at greater riskrisk

Higher Frequency of Dementia in Older HIV+ Higher Frequency of Dementia in Older HIV+ Individuals (Hawaii Aging Cohort)Individuals (Hawaii Aging Cohort)

0

10

20

30

40

50

60

Nl NL MCMD MCMD HAD HAD

Younger Older Younger Older Younger Older

ProbablePossible

Greater Severity of HIV Dementia in Older HIV+ Greater Severity of HIV Dementia in Older HIV+ Individuals (Hawaii Aging Cohort)Individuals (Hawaii Aging Cohort)

0102030405060708090

0/0.5 1 2 3MSK Stage

Younger Older

Potential Triggers/Risk FactorsPotential Triggers/Risk Factors

•• Potential explanatory factorsPotential explanatory factors–– Brain reserve capacity?Brain reserve capacity?–– Genetic susceptibility?Genetic susceptibility?–– Greater CNS responsiveness to certain Greater CNS responsiveness to certain

medications?medications?

Mean Fasting Plasma Glucose with Confidence Intervals and Percent Comorbid Diabetes Mellitus by Diagnostic Catagory

87.093.6 95.2

25.8%

6.9%4.4%

60

85

110

No MC/MD or HAD HIV Associated MC/MD HIV Associated DementiaComplex

Diagnostic Category

Mea

n Fa

stin

g Pl

asm

a G

luco

se

(mg/

dl)

0%

50%

100%

Perc

ent

Com

orbi

d D

iabe

tes

Mel

litusFasting Glucose

Comorbid Diabetes

Is HIV Dementia Associated with an Is HIV Dementia Associated with an Increased Risk of Alzheimer’s Disease?Increased Risk of Alzheimer’s Disease?

•• Tat inhibits activity of beta Tat inhibits activity of beta amyloidamyloid degrading degrading enzyme, enzyme, neprilysinneprilysin ((RempelRempel et al, 2002)et al, 2002)

•• Tat and HIV dementiaTat and HIV dementia--associated neurotoxin, associated neurotoxin, quinolinicquinolinic acid, lead to increased beta acid, lead to increased beta amyloidamyloid

•• CSF CSF amyloidamyloid beta 1beta 1--42 levels decreased in HIV 42 levels decreased in HIV dementia, in same range as AD (Brew et al, 2004)dementia, in same range as AD (Brew et al, 2004)

•• AmyloidAmyloid plaques identified in brains at higher plaques identified in brains at higher frequency in older vs. younger AIDS patientsfrequency in older vs. younger AIDS patients

ApoApo E4 Increased in Older HIV Dementia E4 Increased in Older HIV Dementia Patients (Hawaii cohort)Patients (Hawaii cohort)

20.8%20.8%40.0%40.0%34.3%34.3%16.7%16.7%At least At least one one ApoApo E4 E4 alleleallele

79.2%79.2%60.0%60.0%65.8%65.8%83.3%83.3%No No ApoApo E4 E4 alleleallele

No No DementiaDementia

HIV HIV DementiaDementia

No No DementiaDementia

HIV HIV DementiaDementia

OlderOlderYoungerYounger

HIV Dementia and Aging: a ModelHIV Dementia and Aging: a Model

The Corpus The Corpus CallosumCallosum is abnormally thin in is abnormally thin in AIDS suggesting altered Cortical StructureAIDS suggesting altered Cortical Structure

Whole Corpus Collosum Volume

4800

5000

5200

5400

5600

5800

6000

6200

6400

6600

1

Group

Volu

me

(mm

^3)

CTLHIV

HIV infected cell

toxins

OH·

O:ONOO-

Free radicals

Stimulate HIV replication

Damage tocellular organelles

Apoptosis

Free radical scavangers:EstradiolPlant estrogensVitamin EThioetic acid

GSH GSSG

GSH Peroxidase

NitrosoglutathioneN-Acetyl Cysteine

Selenium

Estrogen

DNA

Increased transcription of anti-apoptotic genes

integrins

matrix proteins

α β γ

GSK-3A.A. PGE

Cox-1 and -2

Cox inhibitors including indomethacin

G protein-coupled receptors include:CXCR4 CCR5 PAF receptor EPs (prostaglandin

E receptors)

MMPs

(heterotrimeric G protein complex)

GSK-3 inhibitors including lithium and valproate

PAF and chemokinereceptor antagonists

Tat gp120TNF SDF PAF PGE

EAA receptors

Glutamate QuinolinateTat gp120

TNF

Calcium

NMDA receptor antagonists

MMP inhibitors

Mitochondrion

Intermembrane space

Cytosol

H+ H+

F0F1ATPasemolecule

Active site

Medical Treatments for HIV Medical Treatments for HIV DementiaDementia•• High dose High dose zidovudinezidovudine (AZT) (AZT) (ACTG 005)(ACTG 005)

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

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

•• Ritalin Ritalin ((psychostimulantpsychostimulant))

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

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

Assessment of Treatment Assessment of Treatment EffectsEffects•• Behavioral ObservationBehavioral Observation•• Psychological TestsPsychological Tests•• Neuropsychological Tests Neuropsychological Tests (current gold standard)(current gold standard)

•• Functional Functional NeuroimagingNeuroimaging–– Changes in Brain Metabolites secondary to Changes in Brain Metabolites secondary to

TreatmentTreatment–– Changes in Brain Function while engaged in Changes in Brain Function while engaged in

Cognitive TestsCognitive Tests

HAART and Changes in Cognitive HAART and Changes in Cognitive FunctioningFunctioning

•• Studied 51 men in the MACS with cognitive Studied 51 men in the MACS with cognitive impairment who were just initiating HAARTimpairment who were just initiating HAART

•• Men were classified as “responders” or Men were classified as “responders” or “non“non--responders”responders”–– Responders = undetectable viral load within Responders = undetectable viral load within

one year of starting HAART (n=30)one year of starting HAART (n=30)–– NonNon--responders = viral load still detectable responders = viral load still detectable

during first year of HAART (n=21)during first year of HAART (n=21)


•• Viral load responders were significantly Viral load responders were significantly more likely to show improvement on more likely to show improvement on cognitive measures (Trailcognitive measures (Trail--Making, Symbol Making, Symbol Digit) relative to nonDigit) relative to non--respondersresponders


00.10.20.30.40.50.60.70.8

Cha

nge

in z

-sco

Trail-Making Symbol Digit

Cognitive Changes Over One Year

Viral load Responder Non-Responder

Medical Treatments for HIV Medical Treatments for HIV DementiaDementia•• Method of action of HAART is not understoodMethod of action of HAART is not understood

Reduced systemic viral load?Reduced systemic viral load?Reduced brain viral load?Reduced brain viral load?Disruption of release of neurotoxins?Disruption of release of neurotoxins?

•• Does HAART penetrate the bloodDoes HAART penetrate the blood--brainbrain--barrier?barrier?Many types of HAART do not easily cross into the Many types of HAART do not easily cross into the brain in laboratory studiesbrain in laboratory studiesHowever, HIVHowever, HIV--infected individuals may show infected individuals may show increased permeability of the bloodincreased permeability of the blood--brainbrain--barrierbarrier

Medical Treatments for HIV Medical Treatments for HIV DementiaDementia•• Regardless of the mechanism, HAART usually Regardless of the mechanism, HAART usually

reduces viral load both in the periphery and in reduces viral load both in the periphery and in the CNSthe CNS

•• Reduction of viral load in the periphery is Reduction of viral load in the periphery is correlated with reduced cognitive symptoms, correlated with reduced cognitive symptoms, though this is probably because it also is though this is probably because it also is correlated with reduced viral load in the CNS.correlated with reduced viral load 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)..

Goals of Current ResearchGoals of Current Research

•• Need to identify risk factors for developing Need to identify risk factors for developing dementiadementia

•• Need to identify biological mechanisms that Need to identify biological mechanisms that lead to cell death and dementialead to cell death and dementia

•• Need to establish effective screening tools to Need to establish effective screening tools to identify early stage dementiaidentify early stage dementia

•• Need to find medical interventions that will Need to find medical interventions that will reverse the symptoms of dementia before reverse the symptoms of dementia before permanent damage occurspermanent damage occurs

Documents

HIV Infection of the Nervous System · Inflammatory Neuropathy Sensory Neuropathy Schematic diagram of HIV-related diseases that affect central nervous system (solid border) and peripheral