The Long Goodbye

by Sue Pondrom

Bill Jacoby’s family began to notice that he was becoming angry and forgetful. His wife Agnes was worried even though his doctor shrugged off the 73-year-old San Diegan’s memory problems as part of normal aging.

“We were coming home from a car trip to Las Vegas when he started yelling that I was driving on the wrong road,” she says. “When we got home, he didn’t recognize our neighborhood street.”

A few weeks later, Bill drove his car to get cigarettes at the neighborhood store. When he didn’t return in 20 minutes, Agnes and a friend went to look for him then called the police. Nearly three hours later, Bill found his own way home. Scared and confused, he said he’d driven only a couple blocks and then couldn’t remember where he was or where he was going. It was another two years, however, before Bill saw a neurologist who diagnosed Alzheimer’s disease.

“Alzheimer’s disease is not exaggerated aging or an extension of the aging process,” says UCSD neuroscientist Eliezer Masliah, M.D. “It’s not normal. It’s a disease.”

UCSD geriatric specialist John W. Daly, M.D., concurs, adding that Alzheimer’s is a feared diagnosis for the aging population. Director of UCSD’s Seniors Only Care (SoCARE) program, Daly says the prospect of losing memories and forgetting loved family members is so frightening that many newly diagnosed patients seek second or third opinions before they accept the disturbing news.

The most common cause of dementia among people age 65 and older, Alzheimer’s affects approximately 4.5 million Americans. The risk doubles every five years after age 65. The other major risk factors are family history and the inheritance of a susceptibility gene. At this time, there is no cure.

A Senior Moment or Alzheimer’s?
While many older people experience occasional memory lapses, and even joke about their “senior moments,” these lapses are just part of normal aging, during which some brain cells are lost. On the other hand, patients with Alzheimer’s disease lose a larger number of nerve cells called neurons in parts of the brain that control memory, and affect behavior.
Specifically, the normal aging brain loses some neurons, as well as the connections between neurons, and brain chemicals called neurotransmitters. Changes also occur in axons, the long thread-like projections that enable the neuron to transmit signals rapidly over relatively long distances in the body. At the same time, the aging body undergoes sensory deficits in hearing and sight, which means that messages are not captured well enough to be transmitted to the brain.

In Alzheimer’s disease, however, the loss of connections in the brain is widespread and severe. It is accompanied by cell death in vulnerable areas of the brain. The disconnection and cell death are related to the characteristic markers of Alzheimer’s, called lesions, which include plaques and tangles. This results in dementia, a syndrome characterized by deterioration of intellectual function such as memory, abstract thinking and problem solving. Alzheimer’s disease accounts for two-thirds of dementia cases in persons over age 65. While Alzheimer’s begins gradually and irreversibly worsens over a period of years, other forms of dementia, such as those resulting from strokes or infections, can progress rapidly.

Mark Tuszynski, M.D., Ph.D., reviews the patient’s brain scan with the surgical team, during the first-ever gene therapy for Alzheimer’s patients. The patient’s genetically modified tissue was implanted in his own brain.

While there is still no simple test to diagnose Alzheimer’s disease, trained physicians are currently achieving a success rate of nearly 90 percent accuracy. Patients receive a comprehensive medical and psychiatric assessment as well as tests that evaluate their ability to do common daily activities such as managing finances and medications. As well as evaluations of thinking and memory, there are interviews with family members or caregivers.

Researchers at the UCSD Shiley-Marcos Alzheimer’s Disease Research Center (ADRC) developed several of the neuropsychological exams in use today. In one test, a patient is asked to draw a clock, put the hours on it, and set the hands to 3:30. (See illustration on page 21). In another test, the individual is asked to remember three unrelated items and then recall them later after they have answered several other questions. Additional tests include counting backwards from 100 by 7’s, reconstructing a simple design with blocks to match one shown by the test administrator, and recognizing and naming various objects.

Inevitable Progression
Storing a memory is not a simple process, comments UCSD neurologist Jody Corey-Bloom, M.D., Ph.D. Incoming sensations, sights, sound and other “stuff” are registered in the brain’s short-term memory holding zone, called the hippocampus, where memories are converted for storage into long-term memory in other brain areas. What moves memories from short-term to long-term retention remains unclear, but that is precisely the mechanism Alzheimer’s disease affects early on. As the disease progresses, long-term memory already stored also begins to deteriorate.

Neurosurgeon Hoi Sang U, MD, performs a surgery on a gene- therapy patient. The surgery was originated by Tuszynski.

By the time symptoms of Alzheimer’s appear, the disease may have already been destroying the brain over a 10- to 20-year period. Although the course of the disease varies from person to person, patients with Alzheimer’s live, on average, for 8 to 10 years following diagnosis.

Now 79 years old, Bill Jacoby has trouble remembering the day he was diagnosed, except to say “it took me a while
to understand. I had no idea what this
disease was. It was discouraging but also a relief to find out what was wrong with me.”

The diagnosis compelled Bill and Agnes to plan for future healthcare expenses by creating a reverse mortgage on their home in order to insure continuing income. They sought additional information about Alzheimer’s and emotional help from the UCSD Shiley-Marcos ADRC.

Diagnosis
A definitive diagnosis of Alzheimer’s disease is possible only through a brain autopsy, which allows pathologists to identify the hallmark plaques and tangles that appear to play a role in the destruction of brain cells. Plaques are thick, sticky deposits of a protein called beta amyloid, which includes abnormal fragments “snipped” from a normal larger protein called amyloid precursor protein (APP). Beta-amyloid fragments bind together to form plaques in the spaces between the brain’s nerve cells. Tangles, also called neurofibrillary tangles, are chemically changed, abnormal collections of twisted protein threads called tau, found inside nerve cells.

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