Alzheimers:

3-4 million Americans have the disease and expected to triple within 20 years. Have to rule out other causes of dementia.

Dementia: 2 parts of the brain (Substantia nigra and the cerebellum) believed to be involved in control of movement may; also be important for problem solving. Parkinsons disease=also signs of mental deterioration (Peter Strick in Syracuse).

a. injected herpes viruses to trace brain connections. Neurons in SN and cerebellum project to cerebral cortex.

b. supports view that people with schizophrenia have abnormal cerebellums.

1. plaques: clusters of abnormal cells surrounding masses of protein, plaques primarily on axon terminals

2. inject scopolamine (anticholinergic)=amnesia.

3. physostigmine=enhances memory ( reduces rate at which body breaks down ACh) Lecithin provides addition choline and physostigmine prevents breakdown of ACh.

4 agonists of ACh=facilitates memory.

Memory loss in Alzheimers=beta amyloid (a common protein in the brain) can make cell membranes leak choline and thus reduce the production of acetylcholine in cells). Choline is essential for acetylcholine.

Two hallmarks of Alzheimers disease are accumulation in the brain of beta amyloid and reduction of the concentration of ACh.

2.The brain cells that produce ACh are known to die. (published in Brain Research 1994?).

3. new tests to detect early stages of Alzheimers. A gene implicated in heart disease also appears to be involved in most "Alzheimer cases. (Reiman in Phoenix) began with a blood test for the suspect gene and coupled its results with PET scans (Published in New England JH. of Medicine in 96). The gene is known as apolipoprotein E or apo E. (3 varieties E-2, E-3, E-4) E-2 version protects people from getting Alzheimers, while E-4 makes it start at a younger age. The risk from E-3 (the most common apo E gene ) falls in between. Each person inherits two copies of every gene, everybody has one of 6 possible combinations of apo E and each confers a different risk of ‘Alzheimers. PET scans show 8 spots (4 per side) where brain cells are dead or less active. double E-4s =worst. It monitor can see if treatment is working without waiting years for symptoms to occur.

1. drugs used to combat inflammation may slow Alzheimers. In twin study; (50 sets) those who had used anti-inflammatory drugs for 1 year were four times more likely than control twins to remain healthy; or develop the disease later. (thought the study was too small to be conclusive).

2. skin test to detect Alzheimers. Brain cells in Alzheimers develop a channel through which flows a form of potassium. potassium channels are collapsed in tissue from Alzheimer patients. Perhaps then can use potassium channels in the skin for diagnosis.

Alkon applies a special dye that causes normal cells to glow when bathed in calcium. If closed potassium channel = no calcium flow and cells remain dark. if potassium channel works=a calcium flash.

3. Jones and Yakel , J. Physiology, 1997 = a nicotinic receptor (ACh) on interneurons in the hippocampus may be clue as to why nicotine sometimes helps the memories of people with Alzheimer’s disease. Alzheimers patients have fewer nicotinic receptors in their brains. Their symptoms are mitigated a bit by nicotine or nicotinic-type drugs.

A rare form of epilepsy know as autosomal dominant nocturnal frontal lobe epilepsy is know to result from a mutation in the gene for one part of this receptor—thus a link to epilepsy, smoking and Alzheimer’s! (Nicotine has been shown in several studies to enhance cognition).

Considerable research evidence strongly suggests that the deficiency of antioxidant nutrients may increase Alzheimer’s risk, but experts do not yet consider this well-established. As humans, we obviously need O2 to live, but O2 also has a down side. That is, in the body, some O2 molecules become so highly chemically reactive that they disrupt other body processes. These "troublemaker" molecules are called "free radicals," and many scientists believe that the damage they inflict (oxidative damage) is at the root of both cancer and heart disease. In addition, smoking and a high fat diet greatly increase the number of free radicals in the blood. Free radicals also contribute to the development of Alzheimer’s disease. Fortunately, certain nutrients (antioxidants) can prevent the oxidative damage free radicals cause. Antioxidants are vitamin A, vitamin C, vitamin E, the mineral selenium, and beta-carotene. Though only a few studies have been conducted, results have been promising.

A blood protein called apoE can slow the accumulation of amyloid in the brain, a process linked to the

development of Alzheimer’s disease A team led by Dr. David Holtzman, assistant professor of neurology and

molecular biology and pharmacology at Washington University School of Medicine in St. Louis, Missouri, studied the effects of the protein in mice. "This is the first experiment that clearly demonstrates that human apoE affects amyloid-beta metabolism (in an animal),"

ApoE3 is the most common of several forms of apoE found in lipid-protein complexes. Previous studies have suggested that people with the apoE4 version are more likely to develop Alzheimer’s disease at an earlier age than people with apoE3 or apoE2. Researchers have speculated that the disease process was somehow related to the interaction of apoE and amyloid-beta peptide, which forms the plaques found in the brains of Alzheimer patients.

In their study, Holtzman and colleagues from Washington University and Lilly Research Laboratories in Indianapolis, Indiana, bred mice unable to make their own apoE and then inserted the gene for human apoE into their cells. Some of these mice were bred to mice that made human amyloid-beta peptide.

developed plaques in their brains by the time they were 9-months old. But the mice that also made human apoE did not have any amyloid plaques in their brains at that age.

Holtzman speculates that human apoE may remove amyloid from plaques, similar to its role in taking cholesterol out of fatty plaques in arteries. "raising levels of apoE might slow the onset or progression of Alzheimer’s disease."

As for apoE4, he suspects that it may be a risk factor for Alzheimer’s disease because it does not work as well as apoE2 and apoE3 in clearing out the amyloid.

Jo Nalbantoglu of McGill University in Montreal and colleagues said their mouse had been genetically engineered to produce human amyloid precursor protein (APP), which is involved in Alzheimer’s.

The mice developed many of the symptoms of Alzheimer’s as they got older in mouse years, Nalbantoglu’s team reported in the science journal Nature.

They lost cells in the hippocampus, the part of the brain associated with learning and memory, showed degeneration of brain cells and they had the beta-amyloids that form the characteristic "plaques" in the brains of Alzheimer’s patients.

When tested in mazes, the genetically altered mice did not learn as quickly as normal mice.

Mark Mattson and Katsotoshi Furukawa of the University of Kentucky said this was one of the best attempts yet to genetically engineer a mouse that developed Alzheimer’s like a human does.

"Transgenic mouse models of AD (Alzheimer’s) will provide crucial in vivo (in a living animal) screening systems that may allow effective approaches towards the prevention and treatment of the human disorder to be identified," But none of the current mice "models" being worked on completely imitated human Alzheimer’s—notably they lacked the "neurofibrillary tangle" of proteins in the brain on a microscopic scale.

Studies have shown that mice genetically engineered to produce a protein associated with Alzheimer’s disease have severe learning problems that worsen with age.

Now a new study suggests that these mice demonstrate specific problems in nerve cell function. If the same is true in humans, potential treatments can be aimed at restoring proper function, rather than replacing dead brain cells, according to Dr. Karen K. Hsiao of the University of Minnesota Medical School in Minneapolis and colleagues.

The animals in the study were genetically engineered to produce the mutant version of the amyloid precursor protein (APP), which is found in plaques in the brains of human Alzheimer’s patients. As the mice age, they develop APP plaques in the brain, and begin to perform poorly in tests of learning and memory, such as running mazes.

However, it was difficult to demonstrate what exactly was going wrong in the brain. Unlike humans, the mice had no obvious death of nerve cells that might be related to the memory problems, according to the report in the March issue of Nature Neuroscience.

The researchers found that the mice had problems forming connections

between nerve cells in response to activation, a process known as

long-term potentiation, which is key to learning,

The findings suggest that the impairment in nerve function may underlie the learning and memory problems in the mice, and possibly in Alzheimer’s patients as well.

"Defining the relationships among amyloid precursor protein, amyloid beta, and mechanisms known to contribute to the induction of expression of long-term potentiation will therefore be critical to understanding the development of Alzheimer’s disease," the authors conclude.

NEW YORK, Jan 99 -- The onset of Alzheimer’s disease may be delayed in people with larger brain volumes.

"Brain volume is an important determinant of reserves against cognitive (intelligence-related) decline in Alzheimer’s disease," say Japanese researchers from the Hyogo Institute for Aging Brain and Cognitive Disorders in Himeji, Japan.

They measured the brain volume of 60 elderly patients suffering from Alzheimer’s disease, then tested each patient to measure the progress of the disease. Those with initially larger brain volumes seemed better protected against early onset of some disease symptoms.

Since Alzheimer’s disease is thought to be characterized by the death and disappearance of cells in the brain’s cerebral cortex over time, study authors surmise that the increased number of cells in those with larger brains may serve as a "buffer," delaying disease progression.

study is still inconclusive since it was performed on patients already experiencing symptoms of the disease. "Study needs to be done over a long period of time," "We need to be measuring intellectual status and all these things before these people become demented, then follow a group of people until some of them do get Alzheimer’s." Firmer conclusions could then be drawn by comparing brain volumes of the sick with those of the well Researchers found the decline of other brain functions—especially those connected with memory and language—seem unrelated to brain size location may be the key. Memory, "is rooted in the hippocampus, which is buried deep within the temporal lobe and doesn’t contribute as much to total brain volume to begin with." in this study... no significant correlation was shown between the (Alzheimer) test scores and level of education,"

Since men generally tend to have larger brains than women, study lead author Dr. Etsuro Mori believes this may be one reason why women are more often afflicted with Alzheimer’s than men. "Added to increased longevity in women, the difference of brain size might account for a part of this predominance," he explains. But he adds that "we should cautiously interpret our results in terms of sex, because there could also be unknown social or cultural biases."

Scientific American has a very interesting short piece in the June 1996 titled Senile Words. the work was more fully described in JAMA, Feb. 21, Vol. 275, No. 7, pp 528-532 in a paper titled Linguistic Ability in Early Life and Cognitive Function and Alzheimer’s Disease in Late Life, with Snowdon as the lead author.

This is part of a larger study which is following a group of nuns living in common quarters (hence controlling for quality of medical care, living conditions, and a host of other variables). Earlier reported findings included *The median age at death was 89.4 years for sisters with educational attainment of a bachelor’s degree or higher, 82.2 years for sisters with some high school or college education, and 82.0 years for sisters with only a grade school education.* (Education, survival, and independence in elderly Catholic sisters, 1936-1988, David A. Snowdon PhD, Sharon K. Ostwald PhD, Robert L. Kane MD , American Journal of Epidemiology 1989;130:999-1012). This was important because it showed an effect of education on longevity even when the usual suspects (medical care, living conditions) were controlled for.

It is fascinating that any test can predict a disease 50 years before death. I interpret the cognitive test as a measure of g, or intelligence. There are two at least plausible explanations for this finding. A popular one in the Alzheimer’s literature is a reserve capacity one. When this is depleted to a critical level, dementia is diagnosed (which is an absolute standard in this and most studies, independent of where the person begun). High IQ people have more capacity to start with and thus the date of diagnosis is delayed. For reasons discussed in the paper this is less likely.to be the whole story.

An alternative theory is that there is some common factor that produces both high IQ, and 50 years later, Alzheimer’s and senile plaques. This common factor is probably genetic. A plausible candidate would be genes for an antioxidant. The second abstract here reports a relationship between functional impairment and a plasma anti-oxidant, lycopren. In general, antioxidants are known to slow aging.

Interesting, Plomin et al (1995) found evidence that suggested that several alleles affected intelligence, one or more of which could be related to Alzheimers Even more interesting, Plomin et al. (1994) found evidence that the manganese superoxidase dismutase gene had an allele (SOD2(B)) that was more frequent (p<.03) in the highly intelligent than in the less intelligent. This gene is reported to produce an anti-oxidant enzyme that protects mitochondria from oxygen mediated free radical damage implicated in neurodengenerative diseases (p. 115 of Plomin et al., 1994).

Weiss (1995) has been arguing for an effect of erthrocyce glutathione perioxidase activity on intelligence which appears to be basically based on the observation of a correlation of .58 with IQ in 50 trisomy-21 patients, and a correlation in Downs patients of .73 between erthrocyce glutathione perioxidase activity and a short term memory score. A major function of glutathione is apparently to protect the mitochondria from oxidative damage (Meister, 1995).

there are reports that 5out of 6 Alzheimers patients have OXPHOS complex complex IV defects in platlet mitochondria (Wallace, 1992, citing Parker et al, and there is additional evidence in Wallace, 1995, p. 150,) and mitochondria differences have been reported for Parkinson’s and Huntingtons.

One problem in mitochondrial metabolism is the production of free radical and peroxidases from a small percentage of the oxgen handled which threatens destruction of the mitochondria. The mitochondria seem to have specialized mechanisms for reducing these. Wallace appears to be arguing that the efficiency of these decline with age.

The OXPHOS reactions decline with age (Wallace, 1993, p. 628) and this has the potential to explain the generalized slowing in reaction times etc. observed in aging and show by the work of Salthouse (1992a,b,1993a, b, c, Salthouse, & Babcock (1991), Salthouse, & Mitchell, 1990); Myerson, Hale, Wagstaff, Poon, & Smith, (1990), Myerson, Widaman, & Hale, (undated), Schaie, (1989), etc. Apparently also the efficiency of the cell in energy conversion does decline appreciably in cases of increasing numbers of oxidative mutations (different from those studied in IQ and Vo2 max) until a very high proportion of the mitochondria have been affected. This could explain the rapid decline in efficiency with old age in humans (relatively flat until fairly close to the age of death).

A gene that is thought to increase the risk for Alzheimer’s disease also appears to be associated with poor recovery from traumatic brain injury, say Israeli researchers.

Those who carry the gene, apolipoprotein E-4 (Apo E-4), are less likely to recover well from a brain injury than those without the gene, according to a report in the journal Neurology. Patients who had a single copy of Apo E-4 were more than 5 times as likely to spend 7 days or more unconscious compared with those without the gene, according to a study of 69 patients with severe brain injuries.

The study results "could be very important in tailoring the proper treatment to each patient and in identifying patients who need more intensive rehabilitation after an injury," said study author Dr. Zeev Groswasser of Tel Aviv University . There are 3 different types of apolipoprotein, E-2, E-3 and E-4, and people inherit two copies of the gene—one from each parent. Those with 1 or 2 copies of Apo E-4 have a substantially increased risk of Alzheimer’s disease, though some individuals with the gene never develop the disease.

Apolipoprotein E appears to play "a pivotal role in central nervous system response to injury," report the research team, led by Dr. G. Friedman of Hadassah Hebrew University Medical Center in Jerusalem. Apo E-4 in particular appears to delay the repair of nerve damage, they write.

When the researchers looked at the patients 6 months after brain injury, they found that 13 of 42 patients (31%) without the Apo E-4 gene were free of complications such as speech problems, behavioral abnormalities or difficulty in swallowing. In contrast, only 1 of 27 patients (4%) with the Apo E-4 gene had a good outcome.

Overall, after taking into account age and duration of unconsciousness, the patients with Apo E-4 had nearly 14 times the risk of having a less-than-optimal outcome after the head injury.

While the authors acknowledge that further studies are necessary to confirm their findings, they conclude that their results point to the existence of "a genetic susceptibility to the effect of brain injury."

November 30, 1998

By MARION ROACH

Twenty years ago, my mother’s mind went to battle with Alzheimer’s disease and lost. Last month scientists at New York University Medical Center, in a hunt for clues to the blight of her brain, spent three days looking at mine.

It is because I survived the enormous effect of this illness in my family that I was willing to undergo this investigation. Family members of patients think of ourselves as survivors: We saw the disease rage through our lives and turn children into parents, kill spouses from exhaustion and financially devastate us along the way.

But to science, we are also potential victims, statistically more at risk than others. In our brains may be a key to understanding the illness of our parents. But because of my mother, I dreaded a diagnosis: What if they found in my brain the premonitions of what happened to her?

Researchers at N.Y.U.’s Silberstein Aging and Dementia Research Laboratory have spent 20 years studying the spectrum of aging, from normal live brains and healthy behavior through dementia and on to autopsy. The lab’s clinical director, Dr. Barry Reisberg, developed the scales used worldwide to measure the ordinal losses of abilities in Alzheimer’s disease.

And so it was that this summer, while I was at the lab with a friend who was concerned about his own memory loss, that Dr. Mony de Leon, the lab’s research director and an acquaintance, said he wanted to give me some tests.

Even now, the moment appears like an image in a zoom lens—a minute before I was not really there, off in the distance, safely detached from being back in the place I had brought my mother and attended years of family support groups. Safely distanced from the present, as well, I walked past the freezers that limn the hallways, wondering which one held her autopsied brain. I was also detached because of the enormous fear that my dear friend might have what my mother had (he does not). But then I snapped into focusing on the fact that I was sweating and stammering something to Dr. de Leon about being busy, being a mother, living upstate.

A work-up at the N.Y.U. lab, he explained, requires psychiatric, neuropsychological and memory testing, as well as thorough neurological and physical examinations and an M.R.I. of the brain.

"I want to study children of early-onset patients, in particular," Dr. de Leon said, "but I really want to have a look at everybody I can."

My mother was 49 when she lost the ability to make change. Soon a daily search for her keys became a daily rage, and I would find her, purse contents strewn about, shrieking that she was losing her mind. She was. And for all that catastrophic behavior to be occurring then, Dr. de Leon believes that there must have been a good deal to show for it in her brain when she was 40. And 30. And maybe even 20. To get a sense of her younger brain, the doctor asked to have a look at mine.

I left without giving him an answer. These tests are about genetics, probability, and the organic changes in the brain that might precede the illness. I didn’t want to know if I had any of them.

Then I realized that if I didn’t agree to be tested, I had no right to expect anyone else would either. I called to sign on.

There are more than four million Alzheimer’s disease patients in America. It is well known what the brain of a patient looks like at death. Equally well documented are the losses of abilities that occur in a predictable way. What is not known is the mechanism that triggers the illness and when it starts.

"We know nothing about pre-Alzheimer’s," de Leon told me. "Five years ago, we realized that people in their 50’s were showing changes in the parts of the brain that are the gateway to all memory. What we didn’t know is those changes can be seen at 30. And we never realized, until now, that we could identify who is going to get memory change years before they do."

He explained that I would be tracked for the rest of my life. Every two years I would return to N.Y.U. for a psychiatric evaluation and a physical follow-up. Every four years would be the three-day review, including the magnetic resonance image. So this, like my first mammogram, was to be a baseline.

"I can now tell you the age of a living brain by looking at an M.R.I. as easily as I can tell your age from your face," de Leon said. "For years pathologists have been able to stage autopsied brains. I am staging the living."

He does so by measuring the M.R.I. images of those parts of the brain associated with memory. These days his focus is on the entorhinal cortex which he describes as "a memory processing center of the brain that funnels information to the hippocampus"—where the first lesions of Alzheimer’s disease appear.

I started at home, filling out a questionnaire about family history, psychiatric well-being, memory and health, sleeping patterns and alcohol and drug use. At the end of it I felt like a normal, somewhat bemused, reasonable 42-year-old woman who should never run for public office.

The tests, the standard for an Alzheimer’s work-up at N.Y.U., would take three days, which I chose to do consecutively. The first day started with a psychiatric workup, which took about 30 minutes. It can take Alzheimer’s patients nearly two hours. I was asked to remember three words—apple, book, chair—and to name childhood friends and teachers from grammar school. At the end of the interview, I was asked to recall the three words. I did.

I filled out an autopsy consent form and got a laminated wallet-sized card that reads "At the Time of Death" in boldface and gives instructions to call the funeral home affiliated with the study when I die, so my brain can be studied after death. The card is the same color as my American Express card, and it pleases me to know that someday, at least, one will cancel out the other.

On to the Red Screen memory test. I defined 40 words accurately. But when I was told 10 pairs of unrelated words, then asked to recall the pairings, I performed dreadfully, and managed to recall only 4. A researcher read a paragraph aloud, then asked me to recite it. I managed only the first couple of sentences, a phrase from the end, and not much in between. I felt a sense of panic.

I did finger-tapping exercises for speed and accuracy. Cognitively impaired people have poor motor control. Symbols on flash cards tested my spatial memory and digit symbol substitution required me to correctly choose symbols representing numbers one through nine over and over again on a long page. A test measured my ability to recognize angles of lines; another checked my category retrieval. (How many things could I name that are worn on feet? What male names begin with F?) Then the researcher asked again about those word pairs. I could remember only two. I was scared.

Fourteen tubes of blood were drawn from my arm at the beginning of the second day. The glucose metabolism mechanism is disturbed in Alzheimer’s disease and so my glucose will be checked. Among the blood tests will also be a screening for the ApoE, or apolipo protein, to see which type I carry. Type four is considered a susceptibility factor for the disease, although not either causative or predictive.

Next came the Wechsler Memory Scale test: counting backward, reciting the alphabet, multiplying figures and remembering drawings that looked like cubist paintings. My figurative memory seemed to get better with practice.

When the researcher announced that a word pairs test was next, I was ready. I aced it: all 10 right.

There were more exercises: numbers backward and forward, patterns to remember. And 40 minutes later, the word pairs returned. Aced it again. All 10.

Walking down the hall toward my neurological exam, I ran into de Leon. ‘I hear you’re doing great," he said. Maybe I was.

The neurological exam tested more than 200 items, including language, left-right orientation, sensory perception, gait, posture and reflexes. The neurologist was stroking my top lip with a plastic picnic knife. I asked him what he was looking for. "The sucking reflex," he said.

Alzheimer’s, he explained, is the reverse of normal human development. It begins with the loss of the ability to hold a job and handle simple finances—I remembered my mother’s inability to make change—and the regression continues, as patients lose the ability to dress, to control bowels and bladders, to speak five or six words, then one word, then even sit up, smile and hold up their heads. During this reversal, reflex responses return—such as sucking.

I suddenly remembered that early in her illness, my mother made sucking sounds, and puckered up if her face was touched. Now I knew why.

Next came a thorough physical exam, then, in the computer lab, tests that resemble computer games, then oral exams after that, checking my understanding of idiom and literal commands. I left the lab at 4:30 P.M. It had been a long day.

The third and final day began with Marnie, the tester who had seen me fail so miserably on the first day with word-pair association and paragraph recall. By computer and then orally, my recognition and memory were gauged. Marnie read me a list of 10 grocery items. I remembered 6. She read them again. I got 8. Then 10. More computer testing. Then the grocery items again. Got 8. Studied. Got 10. Could I alphabetize them in my head? I could. On the first try.

Finally came the M.R.I. That image, compared to my test results, will give us a complete picture of who I am. The researchers will know what my brain looked like at this age and how my memory exhibited itself.

The question is how I progress.

I called de Leon a week later. "Oh, I’m just sitting here looking at your brain," he said.

Silence.

"Ah, Doc," I said, hesitantly, "how does it look?"

"Looks great," he said. "See you in two years."

M.R.I.’s of the brains of 40- and 70-year-olds that show how the hippocampus shrinks as Alzheimer’s disease progresses.

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