HIV and the Brain

ITS A BRAIN THING: THE QUIET IMPORTANCE

OF THE NATIONAL NEUROLOGICAL AIDS BANK

Karen Ocamb with support from H. Aaron Aronow, MD and Elyse J. Singer, MD.

It is an unwritten maxim that the worth of a life is measured by a persons contribution. While the rich and famous may leave their mark on history, most expect their legacy to be etched on the memories of family and friends. Many consent to the pink organ donor dot on their drivers license in the deep desire to help others after theyve gone. But by whatever means, all human beings wish to end their time with the belief that somehow their life mattered.

For many people with HIV/AIDS, taking the pink dot off their license was a gut-wrenching experience. After all, the decision to donate had been difficult in the first place, quieted only by the profound sense of being able to do some good after death. With an HIV diagnosis, the body suddenly became contaminated, an unsuitable gift to those in need. Losing that sense of legacy can be quietly traumatic for those already stressed with the burden of enduring a chronic illness.

But for the past two years, an immeasurably important longitudinal neurological study has been discreetly recruiting volunteers with full blown AIDS who contribute their time, medical, emotional, and psychological history, as well as their tissue, blood, and spinal fluids to help find a cure for HIV/AIDS. The National Neurological AIDS Bank is focused on discovering how HIV affects the brain, the nervous system, and the rest of the body.

"One of the reasons we dont have effective treatments for many AIDS-related diseases is because we dont have a complete picture of how the virus damages the body, particularly the brain," says Dr. Elyse J. Singer, Associate Professor of Neurology at UCLA School of Medicine and the Principal Investigator and Director of the National Neurological AIDS Bank (NNAB); Dr. Singer has been doing AIDS research for 13 years. "Theres still a lot to learn. Treatments are going to be affected greatly by what scientists discover over the next few years. The whole reason to perform this study is to get really high-quality neurological and psychological information and well-characterized, well-preserved tissue samples for scientists to use for AIDS research."

One of the problems in AIDS research, says Singer, is that there isnt a lot of good-quality research tissue around. Thats because, says Dr. Piotr Kozlowski (who coordinates the efforts of Singers NNAB study and three others like it), most tissue banks refuse to take AIDS or other infectious specimens, a fact he discovered in a study for the National Institutes of Health (NIH). Even then, much of the banked tissue was useless for research because it had either not been collected in a timely fashion or it had not been prepared appropriately, or because the donors medical history was not available.

Two years ago, Singer received a five-year grant from the NIHs National Institute of Neurological Disorders and Stroke to conduct an AIDS neurological study. Her Bank is part of the National Neuro-AIDS Tissue Consortium coordinated in Staten Island, New York by Dr. Kozlowski. The Consortium was the brainchild of the National Institutes of Mental Healths Dr. Diane Rausch, a program director with the federal Office of AIDS Research. "It was her vision," says Kozlowski. "She doggedly pushed this whole idea to have a good neurological AIDS research program." Right now, he says, the Consortium "is really doing great. People are really understanding the important nature of this program, and the number of requests from scientists for tissue and fluid specimens is growing."

In addition to the study in Los Angeles, three other studies for the National Neuro-AIDS Tissue Consortium are being conducted by Banks in New York City, San Diego, CA and Galveston, TX.

"In the two decades of the HIV/AIDS epidemic, there has not been adequate research into the neurological manifestations and complications of HIV/AIDS," says Dr. H. Aaron Aronow, Associate Professor of Neurology and Internal Medicine at USC School of Medicine, Research Neurologist at the AIDS Healthcare Foundation, and co-investigator in the NNAB study. "Neurology got pushed off to the side in the rush to keep people alive. Further, many physicians are frightened of neurological disease. They dont understand it. They have a notion that the nervous system is incredibly complicated. However, those of us who are experts at neurology look at this work as an absolute joy. Every time I see an interesting patient or a subject, I get to play Sherlock Holmes at the height of medical investigation. But Im also always mindful that Im doing this to help very, very sick people."

A good neurologist, says Aronow, a gay physician who has received numerous public service awards for his work on behalf of people with AIDS, "takes into account how people think, how they feel, how they move, how they behave. From the organic point of view, everything can be reduced to the function of the brain, the seat of the soul. Thats what really makes us individual human beings. And damage to any part of the nervous system harms our quality of life. If you cant think properly, if you are forgetful, miss appointments or drop things, or you cant move properly, then you cant function, work, or communicate with other people as you are used to."

Dr. Ernestina H. Saxton, an African American/Hispanic woman from Panama whos a co-investigator with Singer and Aronow on the NNAB study, notes, "A study is not the same as a doctor-patient relationship. Different rules apply." Saxton, who comes to neurology by way of a UCLA MD and a PhD in medical microbiology, immunology, and bacterial genetics, has just been approved for full professorship at UCLA. "One of the benefits of being in our study is that if we find a medical problem that the subject or the treating physician is not aware of, we can tell the subject and the primary physician about it. While we dont treat the subjects as a part of this study, we try to make sure they get the proper treatment." But for the most part, says Saxton, the study is "geared to getting knowledge for humankind. But our hearts wont let us look at people as just study subjects. Were patient advocates first, before were investigators."

The criteria for joining the National Neurological AIDS Bank study is that the person should be at least 18 years old, be HIV-positive, and have a CD4 count of less than 50; OR they should be HIV-positive and have some serious opportunistic infection, neurological disease, or a life-threatening illness such as wasting, heart disease, cancer, or kidney disease. A limited number of HIV-negative persons with other serious illnesses, such as cancer, organ transplants, and neurological diseases, are also recruited as controls. The study staff takes an in-depth history. Then every six months, the subject gets a general medical examination as well as a neurological and psychological exam to test functioning and to attempt to identify any problems in the brain, spinal cord, or nervous system. Subjects are also asked to donate samples of blood, urine, and spinal fluid, and information from their medical record.

"The goal of this is not only to study people with late-stage HIV and AIDS disease over time neurologically, but also to collect fluidsspecifically blood, spinal fluid, and urine during the course of their lifetime," says Aronow. "And if they are unlucky enough to pass away during the course of the study, they agree, because this is a banking study, to donate their brains, spinal cords, and other bodily tissues to a bank that preserves the tissues for future research. But in Los Angeles, AIDS doctors do a very good job of keeping people alive."

"Its very exciting working with such cutting-edge doctors," says Jennifer GrabotGomez, the head research nurse of the SingerAronowSaxton study and a former hospice nurse. "Its kind of special and unique because the doctors are very loving, caring people. They dont treat patients just like a number or a piece of tissue, but like wed want our family members treated."

Michael Sausser is one study subject who would follow Dr. Singer anywhere. Diagnosed with full-blown AIDS in November of 1994 after living with HIV for ten years, Sausser was "very far gone" with AIDS dementia complications when he met Singer. She had been asked to call Sausser by his primary care physician. Sausser, who had done graduate work in Urban Planning at UCLA and was a project planner with a small governmental relations consulting firm in Hollywood, had continued to work even as his dementia slowly stripped him of his ability to drive, then to dial a phone number correctly. Finally he missed a very important deadline that created a great deal of trouble for his client. "Thats when I got the diagnosis from a doctor that I had HIV encephalopathy and encephalitis. I was told I was only going to deteriorate, I would continue to lose body functionsand then I would die. I asked if I should get a second opinion. He said I could get one but he didnt think there was any real reason."

Sausser says his comprehension was so low, "I didnt have the brain capacity to really understand what it was he was saying." But he knew what the doctor said "wasnt true for me." When Singer called, "she said flat out, Im not going to let you die," Sausser recalls. Singer put him on an experimental drug trial and his dementia was reversed with high does of AZT. His relationship with Singer solidified, Sausser moved his medical care to UCLA, where Singer practices in the Care Clinic. "When this AIDS Bank trial came around, she talked to me about it, and I said I wanted to be involved. Ive been there for anything she has brought to me. But often its not so much about what a trial can do for me, but what I can give back to other people who are coming down the road. Ive gotten a lot out of society and I dont have a lot to give monetarily anymore. But I can give my body; I can give my blood; I can give my time; and I get to deal with really wonderful, caring, compassionate people." Even the spinal taps make him feel "really good and positive" and "centered with the world again."

Jenny Guembes concurs. Diagnosed with HIV since 1987, and with full blown AIDS since 1993, Guembes is a participant in the national Womens Interagency HIV Study as well as the National Neurological AIDS Bank study. She also works as a research assistant at AIDS Healthcare Foundation where Aronow conducts his research. Significantly, Guembes does not take any HIV/AIDS medication. "Aaron doesnt approve," she says, but neither does he judge.

"I asked a doctor how does AZT compare to aspirin and he said AZT is like chemotherapyso I just took a chance. Besides, its just a pain in the butt taking pills every day. So I see it in a very cold way. Im dying. I live one day at a time because I cant do anything about tomorrow."

Guembes, who gave birth to an HIV-negative son nine years ago, qualifies for the study because her T-cells are in the range of 4565. And while she hasnt had any serious opportunistic infections, she has had shingles twice and gets "a lot of yeast infections." Nonetheless, shes interested in the "real science" of the study, doing spinal fluidblood comparisons, and waiting "to see if I go crazy because of HIV or old age." She was also drawn by the studys offer of compensation for time spent during the exam and for the spinal taps, as well as child care, transportation, a meal, and cremation after donation. "Often at the end of life, if youve been chronically ill for a long time, you dont have the money to even pay for your own memorial. This program pays for your cremation, burial certificate, and an urn is provided to your family, loved ones, significant others.

Or we can donate towards their funeral if that would be more aesthetically acceptable," says 25-year veteran nurse Grabot Gomez, a mother of two. Gumbes, a Latina, is also representative of the gender, racial, and ethnic diversity among the volunteers of the National Neurological AIDS Bank Study. Although the HIV epidemic is increasingly affecting women and minorities, many researchers still seem to concentrate on recruiting middle-class, predominantly white subjects. However, by design, NNAB volunteers include over 50% racial and ethnic minorities, 15% women, and many persons who speak only Spanish. Singer attributes much of the NNABs success in recruiting donors from notoriously hard-to-reach groups to "the diversity of the NNAB staff, especially among the investigators. The NNAB investigators include many people from groups that are underrepresented among the academic community such as women, African Americans, Asians, Hispanics, and openly gay people," as well as white males. Three of the four study neurologists are fully bilingual in Spanish. "Our whole approach to recruitment is enhanced by our different backgrounds."

In addition, Singer says, "we have worked hard to establish study sites outside of UCLA. In addition to AIDS Healthcare Foundation, which is a community-based healthcare organization, NNAB has a study site at Olive View Medical Center in Sylmar CA, a small county hospital that serves a largely minority population. The site is run by co-investigator Dr. Glenn Mathisen, who is the Chief of their Division of Infectious Diseases. He and his staff really have a tremendous insight into their subjects problems and have earned their trust."

Ernesto Magdaleno is in charge of enrolling Hispanic subjects to maintain the Los Angeles studys commitment to minority participation. He graduated from Mexicos Universidad de Autónoma de Guadelajara as a "médico cirjuano e partero" or medical doctor.

"We try to help overcome language and cultural barriers," says Magdaleno, a father of two with a set of twins on the way. Different cultures have different beliefs about death and dying, as well as potential religious barriers, Magdaleno explains. "Many Hispanics are Catholics and there is resistance to cremation, one of the options offered to the subjects after the autopsy." (The Catholic Church no longer objects to cremation, however.) "I explain to them that this is something for future patients, to help our people."

Many in the African American community are still suspicious of medical research, says Saxton, because of the haunting memories of the Tuskegee experiments where doctors acting on behalf of the government allowed syphilis-infected subjects to go horribly untreated in the name of science. "Potential subjects need to feel vested in participating in the study. They are more likely to develop confidence in us, and to participate, if we bring the study to their community. Trust is key," she says.

Another barrier is the often off-putting notion of an autopsy. But the NNAB autopsies are nothing like neuropathologist and FBI Agent Dana Scullys "very inaccurate" portrayal, says Singer, an X Files fan. "Youd have to be out of your mind to perform an autopsy the way she does them on TV. Its not this dark, grim, horrible Frankenstein-ish stuff. Most autopsy rooms look more like a surgical suite."

The type of autopsy performed for the study, says Aronow, "is not a full autopsy and does not disfigure the body for the purposes of a viewing. Most of the visible portions of the body are preserved and can be viewed and made up for burial with an open casket. "In fact, the autopsy is critical to the NNAB study. "One of the positive aspects of this study is that were getting a better idea of what people with AIDS do die of now, during the era of aggressive treatment. A number of our subjects apparently died not from AIDS, but from other diseases such heart attacks and strokes," says Singer. Another potentially important observation is the high rate of hepatitis C virusassociated complications in the subjects. (See the special summer issue of Numedex) "Too often," she says, "physicians are overly confident that they know the cause of death in an AIDS patient. But physicians are still capable of overlooking an important cause of death. Autopsies provide a valuable form of education and feedback for the treating physician."

Additionally, the researchers are studying how HIV medications affect both the body and the brain. "Protease inhibitors are very large molecules and highly protein-bound, so they have difficulty penetrating the brain," says Aronow. "In shorthand," says Singer, "the bloodbrain barrier keeps out the drugs, but not the bugs. We want to know if people who are treated with drugs that have good penetration do better neurologically than people who do not take such drugs."

The researchers note the possibility that the brain could remain inadequately treated or be a reservoir for virus that can replicate or mutate in people whose systemic circulation shows very low level of virus.

"Its very important for us to look at this tissue reservoir and ask, Does this virus have different resistance patterns to drugs in the brain or spinal fluid than in the rest of the body? And are the drugs really effective in penetrating the brain and if so, which drugs are best? Are there some types of changes in therapies that need to be made in the future based on what we find? We dont know any of this," says Singer. "In some ways this study represents a pioneering approach to longitudinal medical research."

In addition to the area of study, the teams commitment to diversity, and the important information already gleaned in just two years, the NNAB study is also unique because the pre-mortem study and the autopsy are specifically interlinked so that an autopsy becomes a part of their postmortem care. There is some mention that this format might be replicated by the NIH in studying other diseases. Dr. Al Kerza, a program officer for National Institute of Neurological Disorders and Stroke, says that the Banks "serve as a model for other banks around the country."

"Because the subjects are asked to make plans to continue their participation in the longitudinal study, they also have the opportunity to address other issues related to death and dying, such as appointing a person with durable power of attorney for their health care," says Singer. "Another key and relatively new part of this study is that NNAB obtains the consent for tissue donation from the donor prior to death. In some parts of the United States, once you die, your body is no longer considered your property. Many people dont realize that. So if you want to donate your body to science in these states, your family could still stop the donation after you die. But in California, if youre legally competent and make a donation prior to death, then your family cant legally overrule your wishes. We try very hard to get the family on board and collaborating with the subject and the study. But a lot of these patients dont have a family or theyre in domestic partnership relationships which arent recognized by the legal authorities."

"There are so many neurological diseases that are wreaking havoc on our subjects and are causing them a lot of pain and a lot of disability, more than any other organ system disease," says Aronow. "Of course Im prejudiced because Im a neurologist, but I think the effects of AIDS on the nervous system is the most important thing we can study. And its why studies such as the NNAB are so critical. We not only examine people over time to look at the effects of medication on their nervous system while theyre alive, but we also have their tissue to try to figure why this disease process took place and see if theres anything unique that we didnt know before. With that information, researchers all over the world can develop new treatments for AIDS. This is the crux of this study."

"This study will give us an opportunity to determine whether or not the current treatment is lowering the incidence of AIDS neurologic disease," says Singer. "Im personally betting that we will see fewer cognitive problems and more neuropathy with the current treatments. But thats just my personal opinionthe point of being in science is to test your hypotheses in a fair and neutral way. This study is an admirable way to determine what is really going on with people with AIDS: what are the diseases they are dying of? What are the side effects of the drugs? Is there an interaction of IV drug abuse and AIDS? Another thing thats very important is that so much of AIDS research has been focused on white, middle-class gay and bisexual men. Weve made specific plans to address different segments of the HIV population, like women. I believe that what were doing here is going to eventually improve care for people with other neurological diseases as well. Likewise, we have been able to apply what is known about other neurologic diseases to Neuro-AIDS." But because all of the NIH projects are highly competitive and political, its not unusual to have funding decreased or pulled. Now starting its third year, Singer is already worried about continuing the study. Dr. Kozlowski, while noting that NNAB study may be creating a paradigm of the way doctors and scientists work together and share information, confirms Singers concern.

"Its conceivable [that] with a change in Administration, the governments priorities and funding may shift, and this study could become a causality," he says. But all the researchers "working together to standardize protocols, helping each other, and exchanging ideas" once every two months via teleconferencing, "is uncommonly good. This good resource will produce good research." But for study participants like Michael Sausser, the National Neurological AIDS Bank is an opportunity to confer a transcendent meaning to his life and create his own legacy. "This is the last thing I can give back. But a little bit of me will live on until, hopefully, theres a cure for this disease."

Karen Ocamb is an award-winning journalist who worked as an Associate Producer with CBS Network News and has freelanced for print publications ranging from the Los Angeles Times to The Advocate and POZ Magazine.

H. Aaron Aronow, MD, Associate Professor of Neurology and Internal Medicine USC School of Medicine and Co-Investigator National Neurological AIDS Bank

Elyse J Singer, MD, Associate Professor of Neurology UCLA School of Medicine and Principal Investigator National Neurological AIDS Bank.