Cognitive Disorders in HIV Marshall Forstein MD Associate

Cognitive Disorders in HIV Marshall Forstein, MD Associate Professor of Psychiatry Harvard Medical School Chair, Steering Committee on HIV Psychiatry American Psychiatric Association

Disclosures • Nothing to disclose

Overview • What do we mean by cognitive disorders? • What are the underlying causes for changes in mental functioning? • What should clinicians be looking for? • How is HIV-related cognitive impairment assessed and treated?

HIV Impacts Brain and Mind • Primary effects of HIV • Consequences of immunological compromise • Metabolic/endocrine dysfunction • Iatrogenic effects of treatment • Impact of disease on psychological state • Acute/chronic psychiatric disorders

CNS Dysfunction Due to Treatment • • • Antiretrovirals Antimicrobials Chemotherapies Herbal medicines Substances of abuse Psychoactive medications

HIV Cognitive Impairment

The CNS May Be an Independent Sanctuary Site for HIV Replication, Particularly in the Symptomatic Stages of HIV Illness

The Brain

Compartments CSF Brain CSF Blood Brain Barrier Organ Tissues Blood

Course of HIV Infection 1, 400 OD 4 Count 1, 200 1, 000 800 600 Acute “Spike” in VL: CNS Seeded Early in Infection CD 4 < 500: Constitution al Symptoms Develop Virologic Setpoint: Carries Prognostic Significance CD 4 VL (x 1000) CD 4 < 200: AIDS 400 Diagnosis, Development of OI’s 200 Including CNS Disorders 0 <---- Months----<-----Years--------------> --> Time Since Infection Primary HIV Infection OI = opportunistic infection; VL = viral load

Brain/ Mind function • Cognition • Psychomotor • Behavior

Cognitive Dysfunction in HIV/AIDS • HIV impact on brain function – Direct or indirect • Hepatitis C virus (HCV) in CNS – Evidence of cognitive dysfunction independent of liver function tests (LFTs) • Substances of abuse – Alcohol abuse – Methamphetamine X, K, G, etc.

HIV and Methamphetamine • The combined effects are consistent with an additive model, suggesting additional neuronal injury and glial activation due to the comorbid conditions 1 • Addictive drug increases HIV replication and mutation 2 • The combination increases subcortical brain cell injury and death 3 • Barrier to HIV medication adherence 4 1 Chang L (2005), Am J Psychiatry 162(2): 361 -369; 2 Ahmad K (2002), Lancet Infec Dis 2(8): 456; 3 Langford D et al. (2003), J of Acq Immune Def Synd 34(5): 467 -474; 4 Reback CJ et al. (2003), AIDS Care 15(6): 775 -785

Domains of Cognition • Attention • Orientation • Memory – New memory – Recall – Long term • Verbal fluency- language/ communication • Executive function- organization, decision making, judgment • Spatial orientation – Construction • Thinking / reasoning

Cognitive Domains • • mental flexibility concentration speed of mental processing memory Visuo-spatial constructional abilities fine motor functions

Classification System Asymptomatic Neurocognitive Impairment Mild Neurocognitive Impairment HIV-Associated Dementia 1 SD 2 Domains 2 SD 2 Domains No Functional Impairment Mild Functional Impairment Moderate to Severe Functional Impairment NIMH, NINDS Panel, June 2005

Cells of the CNS • Microglia: brain macrophages – Parenchymal: long-lived, fixed-cells of CNS – Perivascular: slow turnover with blood monocytes • Macroglial cells – Astrocytes: maintain optimal micro environment for neurons, maintain integrity of BBB – Oligodendrocytes: surround neuronal axons with myelin sheath; electrical insulator for proper conduction • Neurons: functional unit

HIV-1 neuroinvasion

Risk Factors for HIV Neurocognitive Impairment • • Serocoversion illness Early cognitive impairment, MCMD Anemia Vitamin deficiencies (B 6, B 12) Low CD 4 High CSF viral burden More physical limitations Depression

MRI in HIV Dementia MRI findings in a patient with HIV-associated dementia (right) in comparison to normal (left) at approximately The same level. T 2 -weighted images show diffuse, symmetrical, confluent hyperintensities throughout the hemispheric white matter with prominent atrophy (widened sulcal markings). There is no enhancement with gadolinium contrast (not shown) and there is no mass effect. This appearance is typical in HIV associated dementia but is neither sensitive (i. e. , some HIV associated dementia patients may not show this finding) nor pathognomonic (i. e. , other disease processes may yield a very similar MRI picture).

HIV and the CNS Relationship between concentration of HIV-1 RNA in CSF and cognitive impairment : unclear association Ellis RJ, Moore DJ, Childers ME, Letendre S, Mc. Cutchan JA, Wolfson T, et al. Progression to neuropsychological Impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human Immunodeficiency virus RNA. Arch Neurol 2002; 59: 923– 928 Mc. Arthur JC, Mc. Clernon DR, Cronin MF, Nance-Sproson TE, Saah AJ, St Clair M, Lanier ER. Relationship between Human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 1997; 42: 689– 698. Ellis RJ, Hsia K, Spector SA, Nelson JA, Heaton RK, Wallace MR, et al. Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. Ann Neurol 1997; 42: 679– 688. Conrad AJ, Schmid P, Syndulko K, Singer EJ, Nagra RM, Russell JJ, Tourtellotte WW. Quantifying HIV-1 RNA using the polymerase chain reaction on cerebrospinal fluid and serum of seropositive individuals with and without neurologic abnormalities. J Aquir Immune Defic Syndr Hum Retrovirol 1995; 10: 425– 435.

HIV and the CNS • AIDS patients with severe cognitive impairment found to have higher CSF VL than those cognitively intact or at only minor neurological signs • HIV positive patients without AIDS: no association reported between CSF VL and cognitive impairment

Important Questions • What is the relationship between plasma HIV RNA and CSF HIV RNA? • How does antiretroviral medication affect the long term outcome of central nervous system dysfunction due to HIV? • Does penetration of anti-retroviralsinto the CSF correlate with improvement of cognitive function?

Potential problems with HAART and cognitive function • Neurologically active antiretrovirals may: – Not penetrate equally all brain tissue – May include mitochondrial toxicity – May not sustain improvements over the long term • Other mechanisms for CNS impairment may be unaffected by HAART – Inflammatory response – Cytokine cascade

Impact of HAART on NP fx • HAART does not lead to uniform neurocognitive function – Psychomotor slowing improves with HAART • (at least initially) – Verbal memory and executive function may not improve with HAART • Despite lack of change in overall prevalence of NP impairment there are quantitative and qualitative changes in the patterns of cognitive impairment in post HAART

Prevalence and Pattern of Neuropsych Impairment in HIV/AIDS: pre and post HAART • Study: neuropsych deficits – Patients with overt Dementia excluded – -2 SD in 2 neuropsychological measures – Pre-HAART = 41. 1% Post HAART = 38. 8% • No significant reduction in patients with undetectable plasma VL • Pattern of impairment different pre/post HAART – Improvement in attention, verbal fluency, visuoconstruction deficits – Deterioration in learning efficiency and complex attention – Meaning? : deficits do not reflect “burnt out” damage but the presence of an active intra-cerebral process Cysique, Maruff, Brew 2004 Journal of Neuro. Virology 10: 350 -357, 2004

HIV, Age, and Cognitive Impairment • RISK FACTORS: – – Older age Depression Substance use Detectable VL in Cerebrospinal Fluid – References: • • Alcour VG at al. Cognitive impairment in older HIV-1 -seropositive individuals: prevalence and potential mechanisms. AIDS 18 (suppl. 1): S 79 - 86, 2004. Becker JT et al. Prevalence of cognitive disorders differs as a function of age in HIV virus infection. AIDS 18 (suppl. 1): S 11 ﾐ S 18, 2004. Cherner M et al. Effects of HIV-1 infection and aging on neurobehavioral functioning: preliminary findings AIDS 18 (suppl. 1): S 27 ﾐ S 34, 2004. Justice AC et al. Psychaitric and neurocognitive disorders among HIV-positive and negative veterans in care: Veterans Aging Cohort Five-Site Study. AIDS 18 (suppl. 1): 49 -59, 2004.

Treatment of HIV Cognitive Impairment

Pharmacotherapy of HIV Associated Cognitive-Motor Disorders • Primary Treatments – Antiretroviral medications • Secondary Treatments – Immunostimulants and inflammatory mediators • Palliative Treatments – Neurotransmitter manipulation • Stimulants (methylphenidate/Ritalin) • Neuroprotective agents (selegiline/L-Depryl)

Modafinil ( Provigil) • • Rabkin JG, et al : pilot study Open label, 4 weeks 30 pts all completed 4 weeks of treatment 24/30 (80%) rated as responders: – Improvement on measures of fatigue, depressive sxs and executive fx – Side effects: headache, irritability, “hyper” – Caution re: cognitive effects vs. affective/energy – [J of Clin Psyciatry, 2004, Dec, Vol 65(12) pges 1688 -95]

Psychostimulants • Methylphenidate – Dopamine agonist • 5 -10 mg daily • Move to tid dosing (7 am, 10 am, and 1 pm) • Usual dose range 30 -60 mg/daily • Beware of potential for abuse – Infrequently seen • Beware in patients with history of seizures – May exacerbate any disposition to seizures/movement disorders • Watch for appetite suppression

Assessment of HIV Cognitive impairment

Modified HIV Dementia Scale Max Score Pt. Score Task Memory-Registration Give four words to recall (dog, hat, green, peach) - 1 second to say each. Then ask the patient all 4 after you have said them. ) Psychomotor Speed Ask patient to write the alphabet in upper case letters horizontally across the page below and record time: ____ seconds. less than or equal to 21 sec = 6; 21. 1 - 24 sec = 5; 24. 1 - 27 sec = 4; 27. 1 - 30 sec = 3; 30. 1 - 33 sec = 2; 33. 1 - 36 sec = 1; > 36 sec = 0) 6 Memory - Recall Ask for 4 words from Registration above. Give 1 point for each correct. For words not recalled, prompt with a "semantic" clue, as follows: animal (dog); piece of clothing (hat), color (green), fruit (peach). Give 1/2 point for each correct after prompting 4 Construction Copy the cube below; record time: ____ seconds. (< 25 sec = 2; 25 - 35 sec = 1; > 35 sec = 0) 2 Total Score Max= 12 /12 < 7. 5 may indicate dementia and should be evaluated by full battery if possible

Modified HIV Dementia Scale Write Alphabet: Modified from the Johns Hopkins University Department of Neurology HIV Dementia Scale- Powers, et al.

International HIV Dementia Scale (IHDS)

1. Memory-Registration • Give four words to recall – (dog, hat, bean, red) – 1 second to say each. • Then ask the patient all four words after you have said them. Repeat words if the patient does not recall them all immediately. Tell the patient you will ask for recall of the words again a bit later.

2. Motor Speed Have the patient tap the first two fingers of the non-dominant hand as widely and as quickly as possible. 4 = 15 in 5 seconds 3 = 11 -14 in 5 seconds 2 = 7 -10 in 5 seconds 1 = 3 -6 in 5 seconds 0 = 0 -2 in 5 seconds _____

3. Psychomotor Speed Have the patient perform the following movements with the non-dominant hand as quickly as possible: – – 1) Clench hand in fist on flat surface. 2) Put hand flat on surface with palm down. 3) Put hand perpendicular to flat surface on the side of the 5 th digit. Demonstrate and have patient perform twice for practice. 4 = 4 sequences in 10 seconds 3 = 3 sequences in 10 seconds 2 = 2 sequences in 10 seconds 1 = 1 sequence in 10 seconds 0 = unable to perform _____

4. Memory-Recall • Ask the patient to recall the four words. For words not recalled, prompt with a semantic clue as follows: – animal (dog); piece of clothing (hat); vegetable (bean); color (red). • Give 1 point for each word spontaneously recalled. • Give 0. 5 points for each correct answer after prompting • Maximum – 4 points. _____

Total International HIV Dementia Scale Score This is the sum of the scores on items 2 -4. ____ The maximum possible score is 12 points. A patient with a score of 10 should be evaluated further for possible dementia. N. Sacktor, et. al. Department of Neurology Johns Hopkins University Baltimore, Maryland

Living with Cognitive Impairment • Adapting to the diagnosis • Accurate assessment of specific deficits – Self report is not accurate • Depression most commonly confused with cognitive slowing • Adherence to medications, appts.

Protecting the Brain • • • Reducing cardiovascular risk Preventing hypertension Mental and physical Exercise Diet Attitude

Living with Cognitive Impairment • • Will to live Spiritual issues Sexuality issues Use of complimentary/alternative Rx’s

Living with Cognitive Impairment • Diet • Exercise increases BDNF – Brain Derived Neurotropic Factor • Shown to increase neuron growth and increase synaptic transmission • Protein encoded by BNDF gene on Chromosome 11 • Meditation, relaxation training • Psychotherapy – Individual, group, self help, volunteerism