The Tangled Neuron

Flurizan, Lipitor and Alzhemed: Negative Study Results

On Monday, Myriad Genetics Inc. announced the failure of Flurizan in Phase III trials.  This news follows the results from the LEADe study showing the cholesterol drug Lipitor did not benefit Alzheimer's patients, and the failure of Alzhemed in Phase III trials last year.

With all this disappointing news, it seems more important than ever for professionals, with input from patients and their families, to talk about new approaches to Alzheimer's research and care.  Maybe implementing some of the ideas discussed at the National Institute on Aging 2006 conference would help.  I'll be at ICAD (the International Conference on Alzheimer's disease) in late July - it will be interesting to see whether new approaches are widely discussed.

AAFP-ACP Guidelines for Drug Treatment of Dementia: What Do You Think Of The AAFP's Photo?

When my father was struggling with memory loss, his doctors prescribed both Aricept and Namenda. If they helped his memory and thinking, I couldn’t tell. For Dad, the side effects of these medicines didn’t seem to be worth any benefit.

Dad and my nephew Chris play the piano

But for other people with memory loss, these drugs seem to be very helpful, and the side effects are generally tolerable. This wide variety in benefits and side effects may be what the American Academy of Family Practitioners (AAFP) and the American College of Physicians (ACP) were trying to address when they published new guidelines about drug treatment of dementia last month.

Amyloid Inhibitors for Alzheimer's: Less Promising Than Thought?

Summary: Amyloid inhibitors, a type of Alzheimer’s drug under development, may not be as promising as once thought. A cheap and easy test early in the drug development process should help researchers focus on the most promising compounds. This finding does not apply to the vaccines being developed to clear amyloid.

If you’re one of the millions waiting for Alzheimer’s drugs now under development, you’ll want to know that researchers at the University of California, San Franciso (UCSF) have come to some interesting conclusions about one type of potential treatment. Which do you want first - the good news or the bad?

UCSF researchers Brian Shoichet, Ph. D. (left) and Robert Fletterick, Ph.D

Let’s start with the bad news. It looks like “amyloid inhibitors” may not be as promising as once thought. Some Alzheimer’s researchers are focused on developing these compounds to prevent beta amyloid proteins from clumping together to form the fibrils and plaques thought to be harmful to your brain. But as with other diseases, the trick is to find compounds that will affect only the beta amyloid “target,” without affecting other proteins your body and brain might need.

Research conducted in the lab of Brian Shoichet, a professor in the Department of Pharmaceutical Chemistry at UCSF, suggests that amyloid inhibitors often affect too many other proteins to be safe and effective Alzheimer’s treatments. The results of his work on this topic were published in late January in Nature Chemical Biology online.

Enbrel – an Alzheimer’s “Miracle” and Irresponsible Reporting

When I started blogging about Alzheimer’s and dementia, people began sending me links to information about miracle cures for memory loss. I’ve received entire books about “hidden discoveries” and Alzheimer’s conspiracies in the mail. So far, none of the information (including an analysis I received a few weeks ago explaining how oral sex causes Alzheimer’s!) has been backed up by careful research. So when I saw excerpts of a press release about a new “miracle” cure for Alzheimer’s early this month in the Alzheimer’s Daily News (“Alzheimer’s Treatment Shows Promise”), I didn’t pay much attention.

But it turns out other media outlets were repeating the words of the press release, and attaching sensational headlines. ScienceDaily’s headline read “Reversal of Alzheimer’s Symptoms Within Minutes In Human Study” and FOXNews.com said “Study: Arthritis Drug Shows Promise in Reversing Symptoms of Alzheimer’s.”

It’s no surprise that Alzheimer’s message boards are full of emails about this “study,” which is really a case report published in The Journal Of Neuroinflammation. The case report tells about a man with probable Alzheimer’s who appeared to show immediate improvement (“within minutes”) when the arthritis drug Enbrel was injected into his spine. This “study” is not a clinical trial, and involved only one patient. The journal also published a link to a video [look under Additional Material - requires Apple QuickTime to view] “depicting family’s description of change in patient.”

Articles about this report were published with little or no investigative journalism or analysis. Many appear to simply repeat, word for word, a press release from the University of Arkansas. [This was weird in and of itself - why would we rely on a University of Arkansas press release about research supposedly conducted at UCLA and USC?] Most of us still harbor hopes for a cure for memory loss, and we want to believe Alzheimer’s headlines. Irresponsible reporting may drive advertising revenues, but it doesn’t help us sort through what might be helpful and what’s simply hype.

Gabrielle Strobel has published a careful analysis of this case and the circumstances surrounding the report on the Alzheimer Research Forum site. I also like Dr. Peter Whitehouse’s comments during an ABC interview, published on his Beyond The Myth blog.

Cholesterol, Statins and Alzheimer’s, Part 2 of 3

Summary: In a small pilot trial, Lipitor (a statin), seemed to improve scores on neuropsychological tests, especially for patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation. The results of two large trials of statins for treatment of Alzheimer’s should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias.

In my last post, I wrote how recent research has dampened hopes that the cholesterol-lowering drugs called statins can reduce the risk of dementia. But what about people who’ve already been diagnosed with dementia?

Two large trials of statins to treat Alzheimer’s are underway. Dr. Larry Sparks, Head of the Ralph & Muriel Roberts Laboratory For Neurodegenerative Research at the Sun Health Research Institute in Arizona, is a lead investigator for one of these trials. He’s enthusiastic about exploring the connection between cholesterol and Alzheimer’s.

“Think about it,” Dr. Sparks says. “APOE4 [the genetic variation linked to increased risk of Alzheimer’s] leads to elevated cholesterol. I don’t think cholesterol causes Alzheimer’s, but I believe it negatively influences it, or causes it to progress faster. There’s definitely a vascular influence.”

Earlier in his career, Dr. Sparks was a Medical Examiner in Kentucky. While performing autopsies of non-demented people with coronary artery disease, he noticed they had amyloid plaques similar to those in people who had been diagnosed with Alzheimer’s. Later, working at the Sun Health Research Institute, he found that rabbits fed high cholesterol diets developed amyloid plaques in their brains. This plaque build-up was reversed when the cholesterol was removed from the rabbits’ diet.

Now, in a small pilot trial, Dr. Sparks and his colleagues have shown that a statin called Lipitor may actually improve scores on neuropsychological tests for some people with Alzheimer’s. In an article published last year, they wrote that Lipitor seemed to help the most in patients with mild Alzheimer’s, high cholesterol and the APOE4 genetic variation.

So reducing cholesterol to treat Alzheimer’s seems logical, right? Nothing is that simple with Alzheimer’s and dementia.

First, some scientists think statins might work by reducing inflammation in the brain, rather than by reducing cholesterol. Second, brain cells produce cholesterol because they need it to function. While bringing down cholesterol levels in the blood might prove helpful for Alzheimer’s, decreasing cholesterol in the brain may harm neurons. Three statins, Mevacor (Lovastatin), Zocor (Simvastatin) and Baycol (Cerivastatin – now off the market in the US) appear to work in the brain as well as in the blood. Two trials at the University of Pittsburgh testing the effects of Mevacor and Zocor on cognitive functioning in people with high cholesterol showed the drugs may have caused a small decrease in performance on some neuropsychological tests. While the effect of these statins on the brain is unknown, Dr. Sparks thinks a safer approach is to influence the brain indirectly by using statins that reduce cholesterol in the blood rather than in the brain.

Finally, a new study shows a late-life drop in cholesterol may actually be associated with an increased risk of Alzheimer’s. I’ll talk about that in my next post.

The results of the two large trials of statins for treatment of Alzheimer’s [CLASP (testing simvastatin or Zocor) and LEADe (testing atorvastatin or Lipitor)] should be published in 2008. Whether or not statins prove to be effective against Alzheimer’s, this research adds to the evidence of a connection between heart disease and some dementias. Dr. Sparks puts it this way: “if you’re sufficiently resilient that you don’t succumb to cardiovascular disease, then you’re looking down the barrel of dementia.”

Cholesterol, Statins and Alzheimer's: Part 1 of 3

Summary: Cholesterol is the Anna Nicole Smith of the Alzheimer’s world – it’s always in the news, and its relationships are hard to understand. High cholesterol in mid-life may be a risk factor for developing dementia. Studies on whether cholesterol-lowering drugs called statins can reduce that risk have had mixed results, with more recent research finding no effect. As with the men claiming to be the father of Ms. Smith’s baby, further tests will determine the role cholesterol-lowering drugs will play.

Going through my father’s medical records, I found a 2004 notation from his first neurologist: The recent total cholesterol (on Mevacor) was only 139 (LDL 81). Therefore, the Mevacor will be decreased to 10 mg. daily beginning today.

Mevacor is a statin, prescribed to lower cholesterol levels. But as far as I know, Dad’s cholesterol was always low – why was he taking Mevacor?

In the last few years, headlines on the use of statins to prevent dementia have swung from wild optimism to flat-out skepticism, and it seems Dad was dragged along for the ride.

In early 2000, when Dad started calling himself “stupid,” Loyola University researchers announced their analysis of hospital records showed patients taking statin drugs had a lower prevalence of probable Alzheimer’s. A paper by Boston University scientists that same year showed that British patients taking statins seemed to have a reduced risk of developing dementia. Dad probably saw the headlines: “Cholesterol drug may prevent Alzheimer’s” and “Statins Take On the Brain: Cholesterol-lowering drugs may also treat or prevent Alzheimer's disease.”

By 2001, he was combing through newsletters from Mayo Clinic and Harvard Medical School looking for ways to improve his memory. That year, Finnish researchers at the University of Kuopio published an article in BMJ that seemed to confirm the Alzheimer’s/cholesterol link. In their study of 1449 Finns followed over 21 years, high cholesterol levels at midlife were a risk factor for Alzheimer’s disease later in life. Shortly after that, studies in several labs showed a relationship between cholesterol and beta amyloid plaques and suggested that, at least in a test tube, high cholesterol leads to increased beta amyloid production. Surely the newsletters Dad subscribed to carried stories about these studies.

In 2003 or 2004, his family doctor must have prescribed Mevacor, but none of us know why. Maybe both Dad and his doctor had read about these studies, and agreed to give a statin a try.

By early 2005, Dad wasn’t reading much at all. But when I called to say hi one day, he was exasperated by a headline he’d seen in the local paper. “Did you see that?” he asked. “Now they say those drugs don’t help your brain.” The story was about a study by Johns Hopkins University researchers. After following approximately 5000 people over a period of five years, they found “no association between statin use and subsequent onset of dementia or AD”. Later that year, University of Washington scientists said that their analysis of statin use and dementia prevalence among 2798 participants in the Cardiovascular Health Study showed the use of statins was not associated with decreased risk of dementia. They wrote that the results of their investigation and similar studies depended on how they looked at the data, and that more research is needed.

After these negative results were published, the excitement about using statins to prevent Alzheimer’s had died down. Dad had stopped taking Mevacor anyway, and had definitely developed dementia.

Although statins may not prevent Alzheimer’s, studies are underway to see if they can be used to treat the disease after onset. I’ll write more about that in my next post.

Alzheimer's, Ulcerative Colitis and the Poetry of Donald Rumsfeld

My brother James called from his hospital bed in New Mexico to ask me to research cyclosporine, a potential treatment for his ulcerative colitis. He is weak and has lost more than thirty pounds. The beeping in the background means his IV system needs attention. I hold on while the nurses add steroids, morphine and the solution he gets his nourishment from.

James at Dripping Springs, Las Cruces, New Mexico

As with Alzheimer’s, no one is sure what triggers ulcerative colitis. And although medicines for ulcerative colitis are more effective than those for Alzheimer’s, there are not a lot of studies about treating an acute case like my brother’s. This is probably due to the fact that most people in the midst of painful, severe, life-threatening ulcerative colitis attacks don’t volunteer for clinical trials.

I pulled up the prescribing information for cyclosporine, and sorted through the few articles I could find. I looked up terms I didn’t understand (“parathesia” is a tingling or numbness, “renal insufficiency” is a fancy term for kidney failure). I checked the size of the studies on cyclosporine for ulcerative colitis (small, with around 50 participants). I marked some pages, and made some notes.

Then I called my brother back. “Did I wake you up?”

“That’s OK.”

“Cyclosporine is an immunosuppressant.” I was looking at Mayo Clinic’s site.

“Mmmmm,” he said. I think he already knew this.

“This potent drug is normally reserved for people who don't respond well to other medications or who face surgery because of severe ulcerative colitis,” I read to him. I flipped to a list of side effects I found in a study published in 2003. “Irreversible liver damage, kidney damage in 23% of patients, infections in 20%, seizures in 3%.”

“I don’t want that drug.” By then, he was wide awake. His doctor planned to start the cyclosporine within a couple of days if James didn’t get better.

The rush to research is a reflex action for me. But I don’t think all my compulsive research helped my father deal with his dementia, and I worry it won’t help my brother. I can only evaluate information from a layperson’s point of view. Am I influencing James and his wife Katya to refuse a treatment he needs? I’m getting an uncomfortable sense of déjà vu.

This is the way it goes when doctors and patients have to deal with a lot of unknowns. I was still thinking about this when the Alzheimer’s Research Forum posted a table called “What We Know, What We Don’t Know” for discussion and comment. Under the What We Know column, the editors listed research findings and achievements. There are 41 entries in the What We Know Column. But for every entry in the What We Know column, there is a corresponding entry in the What We Don’t Know column.

This makes me wonder if I should keep blogging about Alzheimer’s research, when there is so much “unknown.” But I think many of us want to understand what’s in the What We Know and What We Don’t Know columns when we’re weighing treatment options for various diseases. And who knows what we’ll find out about Alzheimer’s in the next few years? Maybe there will be a “breakthrough” discovery that really improves prevention or treatment.

Maybe this is what Donald Rumsfeld meant during a February 12, 2002 news briefing when he said:

As we know,
There are known knowns.
There are things we know we know.
We also know
There are known unknowns.
That is to say
We know there are some things
We do not know.
But there are also unknown unknowns,
The ones we don't know
We don't know.

I’ll update you on my brother’s progress. In the meantime, maybe we need to add a third column to our tables: What We Don’t Know We Don’t Know. It’s that Rumsfeld column that keeps me blogging about Alzheimer’s.

Diabetes and Alzheimer's

I was sorry to hear that Paula Martinac’s father died last month. As she writes in Dementia Blues, he had both diabetes and dementia. Gail Rae Hudson’s (The Mom and Me Journals) mom is a Type 2 diabetic, and has had what Gail refers to as “dementia-lite” since suffering a mini-stroke. “I think that her diabetes is definitely linked to her mental acuity,” Gail emailed me. “The better control we have of her blood glucose levels, the better her mental acuity.”

Bad for your memory?

These connections between insulin problems and dementia in real life are reflected in recent scientific theories and study results:

- Diabetes may increase the risk of Alzheimer’s

- Diet-induced insulin resistance [a condition in which the body fails to properly use insulin] increases beta amyloid production in mice, and is associated with increased memory problems and increased levels of plaque in the brains of these mice

- Alzheimer’s might be a “type 3 diabetes”

- Mutations in the IDE (insulin degrading enzyme) gene are associated with a higher risk of both diabetes and Alzheimer’s

- IDE degrades or decreases both insulin and beta amyloid [the protein thought to cause Alzheimer’s].

Diabetes and insulin resistance are clearly linked to dementia, but no one knows exactly how. Theories about the mechanism by which insulin problems may cause dementia include:

- Insulin affects glucose utilization in the brain [glucose provides the brain’s energy]

- Insulin modulates acetylcholine [a neurotransmitter involved in learning and memory] levels in the brain

- Insulin increases abnormal changes in tau, the protein that makes up the tangles found in neurons in Alzheimer’s brains

- Insulin makes cortisol [a stress hormone, chronically high levels of which are sometimes linked to cognitive impairment] more toxic to neurons

- Insulin increases inflammation in the brain, damaging cells and increasing production of beta-amyloid, which further increases inflammation

- Insulin problems may increase vascular disease, clogging blood vessels, and reducing blood flow to the brain

- Increased insulin uses more IDE, so less IDE is available to degrade the beta amyloid thought to cause Alzheimer’s.

Even before they can understand how insulin problems contribute to dementia, researchers are studying whether diabetes medicines can help treat or prevent Alzheimer’s and dementia. Scientists at the Veterans Affairs Puget Sound Health Care System and the University of Washington found that raising insulin levels in some patients [those without the APOE4 genetic mutation associated with Alzheimer’s] improved their memories. These researchers are also testing nasal insulin in people diagnosed with early Alzheimer’s or Mild Cognitive Impairment. In a small trial, “nasal insulin improved the ability to retain story details about 25 percent,” says Dr. Suzanne Craft, one of the researchers and Professor of Psychiatry and Behavioral Sciences at the University of Washington.

The idea of increasing insulin levels to improve memory seems counterintuitive, since high insulin levels may damage the brain. “In a healthy physiology, optimal levels of insulin that are secreted and cleared quickly are likely beneficial,” Dr. Craft explains. “But excessive or prolonged elevations are likely detrimental because of induction of insulin resistance and inflammation.” So we may need just the right level of insulin to keep our brains humming along.

Scientists are also studying drugs that increase sensitivity to insulin, instead of increasing insulin levels. “It’s too early to tell about the comparative benefits of the two approaches,” says Dr. Craft. Results of one study using this approach were disappointing. A twenty-four week trial of Rosaglitazone, a drug that increases sensitivity to insulin, in people diagnosed with mild to moderate Alzheimer’s disease showed no benefit over placebo. (Trial results did show that the drug may have helped participants who did not have the APOE gene mutation, but this needs further study.)

Even if it’s not clearly effective in treating Alzheimer’s, perhaps this approach will work to prevent mild memory problems from progressing to full-blown dementia. A preliminary study of Rosiglitazone in 30 people diagnosed with Mild Cognitive Impairment showed improvements in memory and attention. Researchers are now recruiting for a larger trial of the drug in people with Mild Cognitive Impairment. The study will measure the drug’s effects on attention and memory in 120 people 55 and older.

Whether or not diabetes drugs are useful in preventing or treating Alzheimer’s, this research shows how important it is to prevent insulin resistance and diabetes. “Our work strongly suggests that preventing insulin resistance by increasing physical activity, optimizing diet and preventing obesity will ameliorate the risk of Alzheimer’s disease, or at least delay onset,” Dr. Craft says.

Antipsychotic Medicines and Alzheimer's, continued

I wrote in an earlier post about a new study concluding that the side effects of antipsychotic medicines often outweigh the advantages for Alzheimer’s patients. In some situations, modifying the dementia patient’s environment may reduce agitation or other behavioral symptoms without medications. “In many treatment contexts (home, nursing home, group living situations), behavioral management techniques are probably under-utilized and medications are probably over-utilized,” says Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine.

Patty Doherty of The Unforgettable Fund commented on the problems her family had when her father became agitated by “that guy,” who was his own reflection in the mirror. The dose of Risperdal needed to stop her father’s hallucinations made him sleep day and night. Instead, Patty’s family simply covered all the reflective surfaces in her dad’s environment.

Several web sites offer high level descriptions of environmental changes and behavioral management techniques for agitation, aggression, hallucinations and delusions in Alzheimer’s patients:

- Alzheimer’s Foundation of America
- U.S. National Institute on Aging
- The Alzheimer’s Association.

When environmental changes and behavioral management techniques aren’t enough, and antipsychotics aren’t well tolerated or effective, doctors may try medications approved for other uses. Several clinical trials are underway to determine how effective these drugs already on the market are in reducing agitation in dementia patients. These medications include:

-Cholinesterase inhibitors such as donepezil (Aricept – currently used for treatment of Alzheimer’s disease)
-Memantine (currently used for treatment of Alzheimer’s disease)
-Anticonvulsants such as Valproate and Depakote
-Antidepressants such as Citalopram (Celexa).

Tegretol, another anticonvulsant, is also sometimes prescribed for agitation.

In the meantime, research is underway to find new antipsychotic medications with fewer side effects. One such effort at The Fisher Center for Alzheimer’s Research at the Rockefeller University focuses on Fisher Center scientists’ discovery that some of the adverse effects of the current antipsychotic medicines stem from the fact that they block dopamine receptors. Dopamine is a neurotransmitter, or chemical messenger in the brain, and too little of it has been associated with Parkinson’s disease and some of the Parkinson’s-like side effects of antipsychotic medicines.

“Much of this research deals with a protein called DARPP-32, which is located inside brain cells involved in dopamine signaling,” explains Dr. William Netzer, a researcher at The Fisher Center and scientific liaison to the Fisher Center for Alzheimer's Research Foundation and the Michel Stern Parkinson's Disease Research Foundation. “DARPP-32 is a master regulator protein, integrating numerous signals from its cellular environment and orchestrating the cell's responses. [Fisher Center Director] Dr. Greengard and colleagues found that DARPP-32 connects several major signaling systems in the brain. They are the dopamine, serotonin and glutamate systems, and each is involved at various levels in agitation and other behaviors. It may be possible to fine-tune the way DARPP-32 regulates these systems so that certain side effects of antipsychotic and anti-agitation drugs may be avoided, either by directly or indirectly affecting the functions of DARPP-32.”

I hope some of these existing drugs or new antipsychotic medicines will be prove to be more effective than current antipsychotics and environmental changes. In the meantime, Alzheimer’s patients, their caregivers and doctors are left with a trial and error process for managing psychiatric symptoms.

Antipsychotic Medications and Alzheimer's

Throughout his life, my father laughed away any worries. He never locked doors; he trusted everyone. When lightening struck a transformer ten feet from where he stood, he brushed it off. Nothing kept him awake at night.

But when I visited my parents for Dad’s 73rd birthday last year, he was confused and seemed to be hallucinating. “Where are the others?” he asked over and over. “They were here a little while ago – I’m sure I saw them.” I had flown up by myself, and no one was with us in the house.

Later that week, he told Mom he couldn’t sleep because he thought the vibrating box fan in the doorway of the bedroom was going to attack him. He was upset, and it was hard for my mother to reassure him.

Symptoms like Dad’s are common in Alzheimer’s patients, and add to caregivers’ burdens. According to the U.S. National Institute for Mental Health (NIMH), antipsychotic drugs are widely used to treat psychiatric symptoms in people with Alzheimer’s. More than 27% of patients in American nursing homes receive these drugs, which were initially developed for schizophrenia. But, at least in the U.S., these drugs carry “black-box” warnings that they are not approved for the treatment of patients with dementia-related psychosis.

Results of a five year study of antipsychotic medicines in Alzheimer’s patients were published earlier this month in the New England Journal of Medicine. The “Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer’s Disease” study tested three antipsychotic medications against a placebo in 421 Alzheimer’s patients living in their own homes, in family members’ homes, or in assisted living. The medications tested were:

- olanzapine (Zyprexa)
- quetiapine (Seroquel) and
- risperidone (Risperdal).

Input from caregivers was used to help with doctors’ assessments of any improvements or side effects. Although these drugs showed some benefit for some patients, the researchers concluded that “adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.”
Side effects seen in some patients included problems with coordination of movement, sedation, confusion and psychotic symptoms. Antipsychotic medicines have also been shown to increase the risk of developing diabetes and stroke.

Despite recent headlines about this research (“Little Benefit Seen in Antipsychotics Used in Alzheimer's,” etc.), it’s hard to say what the study results mean for each individual patient. Dr. Constantine Lyketsos, Chair of Psychiatry at Johns Hopkins Bayview and Vice Chair of Psychiatry at Johns Hopkins Medicine, co-authored the study. “Neither the CATIE study nor other studies suggest that these medicines shouldn’t be used,” he says. “If you look at the CATIE study, it’s not that the medicines weren’t effective, but the risk/benefit ratio has changed. For the sub-groups of trial participants for whom the medications weren’t discontinued because of side effects, they were more effective than placebo. If a patient’s symptoms are high-risk, then doctors can try antipsychotics with careful safety monitoring. If one of these drugs is well-tolerated, then I can tell you from clinical practice that it’s often effective.”

Constantine (Kostas) G. Lyketsos, M.D., MPH

“I think it would be unfortunate if everyone stopped prescribing any medication solely on the basis of one study,” agrees Dr. Ray Ownby, Professor of Psychiatry at the University of Miami Miller School of Medicine. “Contrary to what many people believe about the study results (and I'll agree that the presentation is confusing), I would not argue that it shows that antipsychotics don't work. It simply shows that antipsychotics aren't enormously effective and that they have lots of side effects. Physicians should prescribe what's appropriate for their individual patients while being aware of the risks and benefits of any given treatment.”

In a “Question and Answer” page on this study, the NIMH recommends caution in prescribing these drugs:

Although some patients may benefit greatly from these medications, the evidence from this study suggests these medications hold limited value for the majority of patients. These results further emphasize the challenge of managing behavioral problems in Alzheimer's patients. Prior to prescribing these medications, clinicians must ensure that agitation or aggression in their Alzheimer's patients are not related to medical, social, or environmental factors (e.g., fever from an infection, side effects from another medication) which might be mitigated without resorting to psychotropic medications.

In a future post, I’ll write about potential alternatives to these drugs, and efforts to develop antipsychotic medications with fewer side effects. But right now, there are no easy answers for doctors or for caregivers.

In the weeks after Dad’s birthday, things got better. Although he was still confused sometimes, he didn’t seem to be hallucinating, and wasn’t as agitated. His doctor thought maybe his symptoms were the result of heat exhaustion (he had mowed the lawn in the summer heat just before these incidents). I now wonder if he’d had a small hemorrhagic stroke that day. If my father had lived longer, he might have gone through more periods when he was anxious, agitated and confused. As the anniversary of his death approaches, we all miss him terribly. But I’m glad we didn’t have to agonize over whether antipsychotic medicines would help him or hurt him.

Calcium Channel Blockers and Alzheimer's

Every day, in Alzheimer’s labs and clinics around the world, researchers conduct target practice. One of their targets is beta amyloid, the sticky protein many scientists think causes Alzheimer’s. This target practice is somewhat of a trial and error process, involving educated guesses about which weapons might work against beta amyloid and other substances and conditions implicated in Alzheimer’s.

One such target practice is directed from the Roskamp Institute, only thirty miles south of where I live. Working with the Trinity College Institute of Neuroscience in Dublin, Ireland, Dr. Michael Mullan and his colleagues are conducting a clinical trial of the calcium channel blocker Nilvadipine to see whether it reduces beta amyloid and improves memory in Alzheimer’s patients.

Calcium channel blockers are drugs used to treat high blood pressure and other diseases. Some studies have shown that these medications might be useful in preventing or treating dementia. A follow-up to the Systolic Hypertension in Europe trial showed that for people with high blood pressure, long term use of a calcium channel blocker may cut the risk of developing dementia by 55%. This makes sense, because scientists have observed toxic levels of calcium in Alzheimer’s brains. “Calcium overload in cells is lethal, says Dr. Mullan, “and this is the final pathway by which cells may die in Alzheimer’s.”

It’s not clear whether calcium channel blockers as a group help preserve memory. Results from the Canadian Study of Health and Aging showed that people taking these drugs were more likely to suffer from cognitive decline. Another study concluded that patients taking blood pressure medicines, including calcium channel blockers, performed worse on cognitive tests than did those taking other drugs. The conflicting results of these studies might be because each drug in this class has different effects.

The fact that Nilvadipine is a calcium channel blocker may be irrelevant anyway. “Nilvadipine's anti-amyloid effects do not seem to be due to the calcium channel blocking of drugs,” says Dr. Mullan. It’s not clear how Nilvadipine might reduce amyloid in Alzheimer’s brains, but it may be related to increased blood flow.

“This drug increases cerebral blood flow in rodents and humans, and we wonder whether there is a link between the two,” Dr. Mullan says. “It could be that there is increased clearance of amyloid from the brain due to increased blood flow. If that is the case, we don't know what the mechanism would be. However, the most likely reason that we see reduced amyloid in the brains of mice is that Nilvadipine directly reduces amyloid production. We've seen this effect in a number of cell types.”

The trial of Nilvadipine in 150 people diagnosed with mild to moderate Alzheimer’s is being carried out in Ireland, where the drug is available by prescription [it’s not currently approved for use in the US]. Doctors will measure the level of amyloid in these patients’ blood. If the levels of amyloid are higher in the blood of patients taking Nilvadipine compared with those not taking the drug, this may mean that it is clearing amyloid from the brain. Doctors will also monitor any changes in blood flow in the brains of trial participants, as well as blood pressure and performance on cognitive tests.

In the US, the Roskamp Institute is also looking for volunteers who have been diagnosed with Alzheimer’s. These volunteers won’t receive any medication, but will give blood to provide data to be used in the trial.

When my father had mild dementia, I wondered whether increased blood flow to his brain would help his memory. I asked Dr. Mullan if Dad would have been eligible for this trial, given that his pulse rate and blood pressure were low, not high. “It's possible (although there are many alternative reasons why your father may have had his cardiovascular signs) that increasing cerebral blood flow would have been beneficial. However, the blood pressure lowering effect of Nilvadipine would probably have precluded him from the study,” he says.

Dad also had cerebral amyloid angiopathy (CAA), and it’s not clear how Nilvadipine and other drugs thought to reduce amyloid would affect CAA patients. In CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein deposits cause the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia as well as major hemorrhagic strokes like the one Dad had. “The vessel walls are weakened by amyloid and removing it (depending on how it is removed) might weaken them further,” says Dr. Mullan. “This is a very difficult area to predict, and clinically we will see when we have potent anti-amyloid drugs.”

Memory Pharmaceuticals is testing a similar drug called Mem 1003, and this trial is currently recruiting patients in the US. The company hasn’t responded to my request for information. [11/01/06 Note: Memory Pharmaceuticals says that Mem 1003 works by modulating the amount of calcium that enters neurons in the brain. This seems to be a different mechanism for treating dementia than the potential anti-amyloid action of Nilvadipine.]

It’s too late for my father, but I hope all this target practice means that multiple treatments for Alzheimer’s and dementia will be ready in time to help others who have dementia now. With its established safety record, Nilvadipine could be available fairly quickly. But first it must be proven effective in this study and in future trials.

Trial of Alzheimer's Drug Halted

The Raleigh (North Carolina) News & Observer is reporting that Voyager Pharmaceutical Corporation has put its trial of Memryte (leuprolide acetate) on hold because of “clinical and financial issues.” The trial was based on the hypothesis that midlife changes in reproductive hormones (in this case luteinizing hormone) are an underlying cause of Alzheimer’s. According to the article, the company hopes to find more funding and restart trials in eighteen months.

Looks like we’ll have to rely on other trials and studies to find out more about the relationship between reproductive hormones and Alzheimer’s…

The Dementia Resource Fair And Information Disconnect

When Dad was alive, much of the information I found about Alzheimer’s and dementia just didn’t add up. Sometimes it was downright odd. After a visit to a local Dementia Resource Fair, I’d say nothing has changed.

The fair was held this week at an assisted living complex near where I live. Just like the telecommunications conferences I’m used to, the event featured presentations and an exhibition floor. Exhibitors included:

• A non-profit providing adult daycare services
• The geriatric behavioral health unit at a local hospital (offering inpatient psychiatric services)
• The local Alzheimer’s Association chapter
• Pharmaceutical companies
• A home health care service
• Two memory disorders clinics
• A geriatric care management company
• The spa and fitness center located within the assisted living complex.

Dementia patients and their families could wander through these booths and get a pretty good idea of what services are available in the area. I got there around 11:30 in the morning, and I was the only person looking at the material in the booths. But upstairs, the presentation room was jammed. The main draw appeared to be the free lunch: sandwiches, macaroni salad, potato salad, brownies, cake and cookies. There were fewer than ten people who might be caregivers in the room – the rest were residents of the facility. They were talking and chewing so loudly I could barely hear the speakers.

Here’s some of the information I heard at the fair:

• You can Baker-act a dementia patient to protect him from scams
• Use blue and red dinnerware if your Alzheimer’s patient isn’t eating
• “Eating saturated fats is like putting arsenic on your brain with a paintbrush
• A pharmaceutical company has a medication in Phase II trials that will radically change Alzheimer’s treatments – but it’s a secret
• “It’s SO beneficial if you can diagnose them early and start medicating them”
• “With fish oil, you’ll make a superior product with the new cell you’ve created” [this same fish oil supplement has been “cleansed of over 28 toxins”]
• People have had one quarter to one half of their brains surgically removed and their brains have “adopted to all the things they need to do”

I left the fair thinking about the information disconnect in the world of Alzheimer’s. There seemed to be no connection between the lives of dementia patients and their caregivers and this collection of factoids. And there seemed to be only loose connections between the factoids and current scientific research.

But I don’t think anyone was listening anyway. If fair attendees had been paying close attention, they might have rejected the idea of Baker-acting a dementia patient, demanded more information about the “secret” drug, and stopped eating platefuls of dessert laden with saturated fat.

Maybe the Dementia Resource Fair just mirrors the larger world of Alzheimer’s and dementia. Until we start paying more attention, we’re stuck with information disconnect.

Stress, Depression and Alzheimer's, Part 2

In a previous post, I wrote about how a history of depression may increase your risk of developing dementia. This connection is not well understood, and is further complicated by the fact that many Alzheimer’s patients are depressed, even when they have no previous history of depressive episodes. If my father had lived long enough, he might have been dealing with depression as well as cerebral amyloid angiopathy and probable Alzheimer’s.

Dr. George Zubenko, Professor of Psychiatry at the University of Pittsburgh School of Medicine, spent some time last week helping me make sense of all this.

“The rate of depression in people 65 and over is quite low – a few percent,” Dr. Zubenko says. “But somewhere between 30 and 50% of Alzheimer’s patients suffer from depression. Some of that is probably due to the realization that they’re losing mental capacity – major depressive episodes often seem to be triggered by stressful life events. The much higher rates of major depression in AD [Alzheimer’s disease] patients suggest that the emergence of MDD [Major Depressive Disorder] in AD is often the result of the neurodegenerative disorder.

George S. Zubenko, M.D., Ph.D.

It’s obvious that major depression increases the suffering of dementia patients and their caregivers. Dr. Zubenko points out that it also exaggerates the patients’ disabilities, makes institutionalization more likely, and may hasten death. For these reasons, it’s important to diagnose depression in dementia patients. Diagnosis can be tricky, though - doctors don’t agree on the definition of "depression" in AD, and it’s often difficult for dementia patients to communicate their symptoms.

To help diagnose and characterize depression in Alzheimer’s patients, Dr. Zubenko and his coworkers developed a diagnostic interview called Clinical Assessment for Depression in Dementia (CADD). He believes that “major depressive disorder in Alzheimer’s disease” is not the same as major depression in non-demented patients. When the CADD was administered to 243 patients with probable Alzheimer’s disease and 151 non-demented control patients, the data showed that Alzheimer’s-related depression had somewhat different symptoms than “regular” depression. In this study, depressed Alzheimer’s patients were less likely to have sleep disturbances or feelings of worthlessness or excessive guilt than non-demented depression patients, but were more likely to have problems concentrating or making decisions.

The results of this same study confirmed other research showing that the prevalence of major depression did not increase with the severity of Alzheimer’s disease. This may mean that major depression in Alzheimer’s is not related to the overall degeneration of the brain, but rather to degeneration in specific areas. In fact, several studies have shown that major depression in Alzheimer’s disease patients is associated with the degeneration of the areas of the brain stem that produce mood-regulating chemicals such as serotonin, noradrenaline, and dopamine. It’s unclear whether this is relevant for other types of dementia.

Dr. Zubenko is one of a group of scientists proposing that the next update of the Diagnostic and Statistical Manual of Mental Disorders (a reference manual used by doctors in the U.S.) include more accurate characterizations of various psychiatric symptoms in dementia, including depression. Better diagnosis would be another step towards understanding the causes of and treatment for depression in Alzheimer’s.

In the meantime, can doctors help AD patients with depression? Most clinical trials of anti-depressants for depression in Alzheimer’s have been relatively small and short term. At first glance, results look mixed, with some trials showing anti-depressants were more effective than placebo, and some not. In one larger study of 511 patients, an anti-depressant significantly improved both depression and memory. Research currently underway may yield more information. Israeli researchers are conducting a trial of Escitalopram (Lexapro, Cipralex)) for depressive syndrome in various dementias, and there’s also a U.S.-based trial of Zoloft for depression in Alzheimer’s disease.

But the published trial results are really more positive than it first appears, because many show large improvements in the patients taking antidepressants AND in those taking placebos. For example, researchers from the Raul Carrea Institute of Neurological Research in Argentina published the results of a trial of anti-depressants in 41 depressed Alzheimer’s patients. The symptoms of depression went away in 47% of patients treated with the anti-depressant, and in 33% of those treated with placebo. The large placebo effect may be due to non-drug factors such as the attention paid to patients and caregivers during clinical trials, or to the fact that depression in Alzheimer’s patients seems to come and go. Even though it’s not well understood, Dr. Zubenko says this finding means doctors can provide some assistance for AD patients with depression.

“The goals of most controlled clinical trials are somewhat different from the goals of clinical care,” he explains. “Most controlled clinical trials are designed to evaluate whether a particular treatment is effective. To accomplish this, the only difference between the treatment and control groups is the specific treatment whose potential benefit is being evaluated. These controlled trials are important because they provide scientific information from which healthcare professionals and caregivers can decide what treatments work for a particular condition and which do not. Doctors recommend treatment plans for individual patients based on this information, but are not limited to one particular treatment approach. In such cases, we often recommend multiple interventions to maximize the likelihood of a beneficial response, hopefully in an organized way, so that we can also infer which interventions are benefiting the patient. This practical approach is especially important when time is of the essence--e.g the patient's condition is deteriorating in ways that place them in harm's way, they are dangerous to others, or when other practical realities limit the available duration of treatment (such as often occurs in inpatient settings).”

Medications are helpful, but “nonspecific clinical interventions can have valuable effects on optimizing function and minimizing disability,” Dr. Zubenko says. “Patients who are in physical pain or discomfort, or are impaired in other ways by medical problems or medication side effects, commonly have secondary disturbances of mood and cognition. Performing a complete medical evaluation and optimizing general health care can have significant positive effects on level of function and the quality of life. Supportive care is also important-- improving nutrition among malnourished patients, addressing personal hygiene, normalizing and structuring daily activities, providing a safe environment with activities and aids that facilitate memory and promote normal functioning , and reevaluating these plans periodically to ensure that they remain appropriate to the patient's needs. Based on my clinical experience, major depression in AD patients usually responds best to a multimodal treatment approach.

It's also important to remember that the ongoing care of a patient with AD is a challenging task for the caregiver. Over the intermediate and long term, it is necessary to provide support, education, assistance, and resources to the caregivers as well. Proper attention and support reduces the stress on caregivers and decreases or delays the need for institutionalization. Failure to do so results in poorer outcomes for both patients and caregivers alike.”

So, major depression and dementia are closely linked, and our understanding of causes and treatments for both of these diseases is still incomplete. For depression sufferers around the world, there’s an increased risk of AD. And for Alzheimer’s patients around the world, there’s a potential depressive ripple effect, for both patients and caregivers.

Careful medical attention for both the patient and the caregiver may help, but I wonder how many patients and caregivers can get this attention. In my family’s experience, it was difficult to coordinate Dad’s care between his family physician and his neurologist, let alone “optimize” all the factors Dr. Zubenko talks about. If my father had lived long enough to need intensive caregiving, only minimal assistance and resources would have been available to us.

It’s hard to find the silver lining in this research, but Dr. Zubenko put it in perspective for me. “We’re trying to treat a complicated behavioral syndrome in the context of degenerative brain disease – any progress is remarkable, and efforts to optimize treatment are well worth it for patients and their family members,” he says.

What the caregiver hears

“The good news is that Alzheimer’s is now a treatable disease.  That’s why it’s so important that you bring your loved one in for a diagnosis – we can help.”

This was the main message at a seminar for caregivers from a doctor who directs a university-based Alzheimer’s center.  I went to the seminar last year looking for information to help Dad, and to hear this expert’s opinion on the latest research.

In his presentation, he used graphics I’d seen on the Aricept web site.  They showed the results of a study where patients who took Aricept for longer periods stayed at home nearly two years more than those who took it for less time.   The Aricept web site notes that “…results may be caused by other factors.”

Neither the doctor nor the web site said where this data came from, but I think it is from an article published in 2003 in the Journal of the American Geriatrics Society. 

The seminar speaker didn’t mention another recent study, called AD2000 in which researchers said “No significant benefits were seen with donepezil compared with placebo in institutionalization.” 

Three of the five sponsors for this seminar were pharmaceutical companies that manufacture or market the medications discussed.  I’m sure that would have made it awkward for the speaker to mention that the results of recent studies have been mixed, and that the benefits of these drugs are hotly debated in the medical community.  But patients and their caregivers deserve to know.

Did Aricept help Dad?

At seven o’clock in the evening, Dad was already thinking about going to bed.  He took a yellow pill out of the basket near the fridge, and got a glass of water to wash it down.

“I don’t like taking pills, but they help my brain,” he told me.

Maybe because I was visiting, Dad stayed up a little longer to play the piano, and I wandered into the living room to sit with him.  I don’t know if he remembered the four hand arrangement of “Tea for Two” we used to play.  We would laugh when we got out of sync, and pretend to push each other off the piano bench. 

He picked out the melody of an Irving Berlin tune and added a few chords, all with his right hand.  He didn’t use his left hand much anymore. 

“How deep is the ocean, how high is the sky…” I sang along.   I still loved it when he played. 

“Do you think your son could read this?”   Dad gestured to the music.  I could tell he was confusing me with my sister, whose son is learning to play the piano.  I don’t have a son. 

“I think he could read the melody, Dad,” I told him, not knowing what else to say.  He headed off to bed.  I went back into the kitchen and looked at the medicines in the basket. 

“The neurologist gave your father something for his memory,” Mom had told me two years before.  That something was Aricept, the yellow pill Dad took every night.  At first, Mom had thought he might be improving.

“He seems a little happier,” she’d told me on the phone after he’d been taking the medicine a few weeks.  Maybe she was right, but I never heard any improvement when I talked with him.  Instead, I heard his increasing frustration as he groped for words. I don’t think Aricept helped Dad at all.