AIDSAIDSDementia Dementia ComplexComplex

(ADC)(ADC)

SynonymsSynonyms

HIV-associated DementiaHIV-associated Dementia HIV DementiaHIV Dementia HIV (or AIDS) EncephalopathyHIV (or AIDS) Encephalopathy HIV-1 Cognitive/Motor ComplexHIV-1 Cognitive/Motor Complex AIDS Subacute EncephalitisAIDS Subacute Encephalitis

Intro Intro

HIVHIV

Retrovirus that kills T4 cells (cells Retrovirus that kills T4 cells (cells that fight off microorganisms)that fight off microorganisms)

Manufactures its DNA in host cellsManufactures its DNA in host cells

AIDSAIDS

Diagnosed when patient Diagnosed when patient

- has HIV- has HIV

- has an opportunistic infection or - has an opportunistic infection or Kaposi’s sarcomaKaposi’s sarcoma

- has a low ratio of T4 (CD4+) to T8 - has a low ratio of T4 (CD4+) to T8 (CD8+) cells (CD8+) cells

AIDS surfaced in the US in 1981AIDS surfaced in the US in 1981 By 1985, HIV was found to be in By 1985, HIV was found to be in

brain tissue of AIDS patients brain tissue of AIDS patients suffering from cognitive impairment suffering from cognitive impairment and dementiaand dementia

HIV-infected macrophages contribute HIV-infected macrophages contribute to cell death and will not fight to cell death and will not fight infection if signaled by T4 cellsinfection if signaled by T4 cells

HIV is the most common cause of HIV is the most common cause of dementia in adults 40 years old or dementia in adults 40 years old or lessless

If ADC is left untreated, it worsens in If ADC is left untreated, it worsens in monthsmonths

A decade ago, 40%-70% of AIDS A decade ago, 40%-70% of AIDS patients suffered from ADC; now it is patients suffered from ADC; now it is about 20%about 20%

Symptoms and Stages Symptoms and Stages

Stages of dementia range from mind Stages of dementia range from mind to severeto severe

Motor and cognitive skills decline Motor and cognitive skills decline progressivelyprogressively

Become mentally slow, weak Become mentally slow, weak physically, clumsy, and may develop physically, clumsy, and may develop tremorstremors

In end stages may become In end stages may become hallucinatory and unawarehallucinatory and unaware

Sometimes may develop mania in Sometimes may develop mania in late stageslate stages

Stage 0 (normal)Stage 0 (normal)

Normal motor and mental function Normal motor and mental function

Stage 0.5 Stage 0.5 (Equivocal/Subclinical)(Equivocal/Subclinical)

Minimal symptoms of motor and Minimal symptoms of motor and cognitive dysfunction (e.g., slow cognitive dysfunction (e.g., slow movement of extremities) movement of extremities)

No work and daily life activity No work and daily life activity impairmentsimpairments

Stage 1 (mild) Stage 1 (mild)

Clear motor or intellectual Clear motor or intellectual impairment present (through testing)impairment present (through testing)

Work and daily life activity Work and daily life activity impairments only in more demanding impairments only in more demanding aspectsaspects

Able to walk without helpAble to walk without help

Stage 2 (moderate)Stage 2 (moderate)

Some patients unable to walk at all; Some patients unable to walk at all; some able to walk with assistancesome able to walk with assistance

Can maintain basic self-care, but not Can maintain basic self-care, but not more demanding aspects of daily life more demanding aspects of daily life

Stage 3 (severe)Stage 3 (severe)

Severe motor or intellectual disabilitySevere motor or intellectual disability Cannot think through complex Cannot think through complex

dialog; cannot follow events or news, dialog; cannot follow events or news, etc.etc.

Slowness of limbs and cannot walk Slowness of limbs and cannot walk unassistedunassisted

Stage 4 (end stage) Stage 4 (end stage)

Almost vegetativeAlmost vegetative Social and intellectual capacities are Social and intellectual capacities are

nearly non-functionalnearly non-functional Little or no ability to speakLittle or no ability to speak Doubly incontinentDoubly incontinent Paraplegic or parapareticParaplegic or paraparetic

Tests and ImagingTests and Imaging

Most tests and imaging are not Most tests and imaging are not diagnostic, but characteristic diagnostic, but characteristic

ADC patients may have abnormal ADC patients may have abnormal cerebral atrophy, abnormal white cerebral atrophy, abnormal white matter, as well as abnormal basal matter, as well as abnormal basal ganglia or thalamusganglia or thalamus

Children with ADC may have Children with ADC may have calcification of the basal ganglia with calcification of the basal ganglia with brain atrophybrain atrophy

Cerebrospinal fluid (CSF) in ADC patients, Cerebrospinal fluid (CSF) in ADC patients, as compared with normal AIDS patients as compared with normal AIDS patients who do not have dementia, may have who do not have dementia, may have higher levels of quinolinic acid, Interleukin-higher levels of quinolinic acid, Interleukin-6, prostaglandins, tumor necrosis factor-α, 6, prostaglandins, tumor necrosis factor-α, and interleukin-1β neopterin, and β2-and interleukin-1β neopterin, and β2-microglobulinmicroglobulin

These chemicals have cytokinetic These chemicals have cytokinetic pathways involved, suggesting CNS effects pathways involved, suggesting CNS effects may be based on this type of reactionmay be based on this type of reaction

Epidemiology Epidemiology

ADC develops in severe ADC develops in severe immunosuppressionimmunosuppression

67% of AIDS patients with ADC in 67% of AIDS patients with ADC in stage 2, 3, or 4 died within six months stage 2, 3, or 4 died within six months

Low hemoglobin levels in patients with Low hemoglobin levels in patients with ADCADC

Older ADC patients may have high Older ADC patients may have high levels of neopterin and β2-levels of neopterin and β2-microglobulinmicroglobulin

Neuropathy Neuropathy

Multi-nucleated cell encephalitisMulti-nucleated cell encephalitis White matter is paleWhite matter is pale Excess astrocytesExcess astrocytes Vacuolar myelopathyVacuolar myelopathy

▪ ▪ Death in the:Death in the:

- Basal ganglia- Basal ganglia

- Hypothalamus- Hypothalamus

- Thalamus- Thalamus

- White matter- White matter

- Brainstem- Brainstem Cortex is not usually affectedCortex is not usually affected

Etiology and Pathogenesis Etiology and Pathogenesis

HIV affects neurons by way of an HIV affects neurons by way of an indirect mechanism that is not indirect mechanism that is not completely understoodcompletely understood

Toxic cytokines, viral gene products, Toxic cytokines, viral gene products, and neurotoxic pathways are involved and neurotoxic pathways are involved in these indirect mechanismsin these indirect mechanisms

High proviral DNA levelsHigh proviral DNA levels Viral DNA/RNA and viral antigens are Viral DNA/RNA and viral antigens are

present in brain tissuepresent in brain tissue

Macrophage maintains infection in Macrophage maintains infection in the brain and stimulates cytokine the brain and stimulates cytokine pathwayspathways

HIV causes macrophages and HIV causes macrophages and microglia to fuse, creating multi-microglia to fuse, creating multi-nucleated cellsnucleated cells

Virus infects astrocytes and Virus infects astrocytes and microglia, among other types of cellsmicroglia, among other types of cells

Treatment Treatment

Antiretroviral drugs can treat ADC Antiretroviral drugs can treat ADC Highly active antiretroviral therapy Highly active antiretroviral therapy

(HAART)(HAART)

Nucleoside Reverse Nucleoside Reverse Transcriptase InhibitorsTranscriptase Inhibitors

Drug Drug Clinical Clinical

Efficacy Efficacy CSF CSF

Efficacy Efficacy CSF:serumCSF:serum

ratioratio

Zidovudine Positive Positive 0.6

Didanosine Didanosine (dideoxyinosin(dideoxyinosine) e)

Conflicting Conflicting No DataNo Data

Available Available 0.2 0.2

Zalcitabine Zalcitabine Positive Positive No DataNo Data

Available Available 0.2 0.2

Lamivudine Lamivudine No DataNo Data

Available Available No DataNo Data

Available Available 0.1 0.1

Stavudine Stavudine No DataNo Data

Available Available No DataNo Data

Available Available 0.3-0.4 0.3-0.4

Abacavir Abacavir No DataNo Data

Available Available No DataNo Data

Available Available 0.2 0.2

Protease Inhibitors Protease Inhibitors

Drug Drug Clinical Clinical

Efficacy Efficacy CSF CSF

Efficacy Efficacy CSF:serumCSF:serum

ratio ratio

Indinavir Indinavir No DataNo Data

Available Available No DataNo Data

Available Available 0.18 0.18

Nelfinavir Nelfinavir No DataNo Data

Available Available No DataNo Data

Available Available No DataNo Data

Available Available

Saqinavir Saqinavir No DataNo Data

Available Available No DataNo Data

Available Available No DataNo Data

Available Available

Ritonavir Ritonavir No DataNo Data

Available Available No DataNo Data

Available Available No DataNo Data

Available Available

VX-478 VX-478 No DataNo Data

Available Available No DataNo Data

Available Available No DataNo Data

Available Available

Non-nucleoside reverse Non-nucleoside reverse transcriptase inhibitors transcriptase inhibitors

Drug Drug Clinical Clinical

Efficacy Efficacy CSF CSF

Efficacy Efficacy CSF:serumCSF:serum

ratio ratio

Delaviricine Delaviricine mesylate mesylate

No DataNo Data

Available Available No DataNo Data

Available Available No DataNo Data

Available Available

Loviride Loviride No DataNo Data

Available Available No DataNo Data

Available Available No DataNo Data

Available Available

Nevirapine Nevirapine No DataNo Data

Available Available No DataNo Data

Available Available 0.45 0.45

Agents that protect the neurons may Agents that protect the neurons may also be effective (neuroprotectants) also be effective (neuroprotectants)

Nimodipine (a CaNimodipine (a Ca2+2+ channel blocker) channel blocker) Memantine (NMDA-glutamate Memantine (NMDA-glutamate

antagonist)antagonist)

Conclusion Conclusion

Macrophages and migroglia live long, Macrophages and migroglia live long, enabling the virus to inhabit those enabling the virus to inhabit those cells and remain inactive for years in cells and remain inactive for years in the brainthe brain

Before immunodeficiency begins, Before immunodeficiency begins, replication may be more controlled; replication may be more controlled; but, when patient becomes severely but, when patient becomes severely immunodeficient, virus replication immunodeficient, virus replication may become out of controlmay become out of control

Before HAART was introduced, Before HAART was introduced, children with ADC were often left children with ADC were often left severely mentally disabledseverely mentally disabled

Up to 50% of AIDS patients had some Up to 50% of AIDS patients had some kind of cognitive impairment at kind of cognitive impairment at death (some sources say as many as death (some sources say as many as 70%)70%)