The Tangled Neuron

Alzheimer's Plaque-Buster?

For years, Dad had a night job. By day, he ran our family’s retail lumberyard. By night, he ran a mouse relocation program. Our house was full of mice. They scampered through the attic and ran down plumbing and electrical ducts, nabbing cotton balls and Kleenex to build their nests. They got into our food, and left droppings along the baseboard.

The situation came to a head when my mother went into the kitchen to get a plastic bag full of garbage she had left on the counter. “There was a mouse sitting inside the bag, stuffing his face,” she says. She called Dad into the kitchen. He carefully closed the bag, carried it outside, and let the mouse go.

That night, my father brought home a small Havahart trap, baited it with peanut butter, and set it in the laundry room. A quivering brown mouse was in the cage the next morning. On his way to work, Dad drove his passenger down a dirt road, and released him in the woods.

Dad reset the trap that night, and another mouse was there in the morning. This went on for months – almost every morning, another mouse. And almost every morning, Dad would head down the dirt road to his mouse drop-off spot.

“They’ve posted a sign,” he joked, “free peanut butter and a ride.” My parents kept a tally - after four months, Dad had transported 123 mice. They seemed to be multiplying faster than he could clear them out.

Breaking Down Beta Amyloid

Scientists think the same thing may be happening with beta amyloid, the protein that makes up the plaques found in Alzheimer’s. The protein is constantly produced by the body, then cleared from the brain. It may be that in people with Alzheimer’s, the beta amyloid is building up faster than it can be eliminated, and the excess protein is toxic to brain cells.

Researchers have found several enzymes that break down beta amyloid, including insulin degrading enzyme (IDE). Increasing the amount of these substances in the body could help speed up the elimination of excess beta amyloid.

Dr. Jin-Moo Lee, Assistant Professor of Neurology at Washington University School of Medicine in St. Louis has shown that another enzyme called matrix metalloprotease-9 (MMP-9) also degrades beta amyloid. Dr. Lee found that MMP-9 is able to break down the fibrils that make up the plaques found in Alzheimer’s. MMP-9 and other enzymes break down a free-floating kind of beta amyloid that hasn’t formed into plaques. But in Dr. Lee’s lab, the other enzymes didn’t seem to degrade fibrils the way MMP-9 did. These results suggest that MMP-9, already found in the body, may be helpful in clearing plaques from the brain.

Jin-Moo Lee, M.D., Ph.D.

There’s more evidence that the enzyme may help regulate beta amyloid levels. Dr. Lee and his colleagues found that turning off the gene for MMP-9 in mice increased the levels of beta amyloid in their brains.

MMP-9’s Role In Other Diseases

Harnessing MMP-9 to break down beta amyloid will be a delicate task. High levels of the enzyme are associated with cancer and arthritis. Even worse in terms of dementia, Dr. Lee has shown that high levels of MMP-9 near blood vessel walls in the brain are associated with cerebral amyloid angiopathy (CAA). In CAA, beta amyloid is deposited on blood vessel walls in the brain. The walls then thicken, harden and crack, allowing blood to leak out into the surrounding tissue. My father’s autopsy showed severe CAA, and it’s likely that the disease and resulting microbleeds caused his dementia. He died last year of a massive hemorrhagic stroke, probably due to CAA.

So MMP-9 may clear Alzheimer’s plaques, but may also be involved in CAA and brain hemorrhages. Is MMP-9 good or bad for the brain?

“MMP-9 is neither ‘good’ nor ‘bad,’ Dr. Lee says, “but may have different responses and activities in different cells and different locations. We have hypothesized that MMP-9 may play a role in weakening the vessel wall in CAA (though this is far from proven)…. We have shown that MMP-9 and -2 can degrade Abeta [beta amyloid] in the brain. These are two different locations and two different activities.”

The fact that increased levels of MMP-9 have been found in the brains of ischemic stroke patients provided a clue to MMP-9’s role in brain hemorrhages. “MMP-9 is upregulated after ischemic stroke,” Dr. Lee explains, “and likely plays a role in converting an ischemic stroke into a hemorrhagic stroke (by weakening the vessel wall). This is why it is so intriguing that MMP-9 is upregulated in CAA vessels, with the thought that CAA vessels may have increased MMP-9 which might eventually lead to weakened vessels.”

Dr. Lee is working to confirm the role of MMP-9 in CAA. He has a study underway to see if lowering MMP-9 levels in mice with CAA reduces the frequency of brain hemorrhages. “This data will be far more convincing,” he says.

More Research Needed

Adding to the uncertainty of MMP-9’s role in dementia, it’s not clear what effect breaking down the beta amyloid fibrils will have. “Again, this may be "good" or "bad," Dr. Lee explains. “Recent reports suggest that smaller aggregates of Abeta (oligomers) may be toxic or inhibit neurotransmission. It is possible that MMP-9 may break down fibrils into these smaller aggregates, which might be even more toxic than fibrils. On the other hand, it is possible that MMP-9 could degrade both fibrils and oligomers rendering them non-toxic. We are currently investigating this.”

It’s also not clear whether drugs designed to increase or decrease levels of MMP-9 could stop brain degeneration and dementia, or what any side effects would be. One possibility for therapy stems from the fact that MMP-9, like many other enzymes, requires the presence of zinc to work. So in theory, reducing the amount of zinc in the body via chelation therapy might inactivate MMP-9 and reduce damage to blood vessel walls. It’s unclear what this might do to the beta amyloid plaques in other areas of the brain, though, and there could be severe side effects. “Removing zinc would likely be detrimental to other systems,” says Dr. Lee.

The connection of MMP-9 to both Alzheimer’s and CAA is intriguing, but still murky. More research is needed before any treatments can be developed. “I think we are far from therapies at this point,” Dr. Lee says. “One must remember that at this level of research, we are trying to understand molecular mechanisms, and we are somewhat removed from therapies. However, our goal is to identify potential targets for the development of therapies. It’s too early to say whether MMP-9 will provide us with viable targets, but therapies to ameliorate disease are always on our minds.”

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.

Can Insulin-Degrading Enzyme Drain Beta Amyloid From Alzheimer's Brains?

Our roads flood all the time here in Tampa Bay. We’re close to sea level. When it rains, there’s just no place for the water to go, especially at high tide. Storm drains back up, the water level rises, cars stall and traffic stops. The problem isn’t just too much rain, it’s also too little drainage.

Some Alzheimer’s researchers think the same thing may be happening in the brains of people with dementia. According to this theory, the problem isn’t really just too much production of beta amyloid [the sticky protein that forms plaques and is thought to cause Alzheimer’s], it’s also too little “drainage” of that beta amyloid.

Most of the efforts to find a cure for Alzheimer’s have focused on preventing the over-production of beta amyloid. But over the last few years, some scientists have been exploring the idea that in Alzheimer’s brains, the balance between production and elimination of this protein has gone awry.

One of the researchers working to find treatments based on this “drainage” theory is Dr. Malcolm Leissring at The Scripps Research Institute. He is testing various proteases’ [enzymes that break down proteins] ability to destroy beta amyloid and unplug the drain. Much of his research is focused on one specific protease: Insulin-Degrading Enzyme (IDE).

Malcolm Leissring, Ph.D.

Insulin-Degrading Enzyme

“I am interested in all beta amyloid degrading proteases, but IDE is particularly attractive for a lot of reasons,” Dr. Leissring says. “It is one of the few to be linked genetically to Alzheimer’s disease. It appears to be the main protease involved in the degradation of (extracellular) beta amyloid in neurons, because when you delete IDE from cells, you also reduce the amount of beta amyloid degradation by over ninety percent. And there are a lot of tantalizing and unanswered questions about IDE, such as how it gets secreted from cells, which makes it very attractive for research.”

His research fits well with that of other scientists who have found that IDE levels are low in the hippocampus of the brains of people who have been diagnosed with Mild Cognitive Impairment, and even lower in those diagnosed with Alzheimer’s. Low levels of IDE are associated with high levels of beta amyloid.

Progress So Far

Dr. Leissring and his colleagues have shown that mice bred to have increased IDE (or another protease called neprilysin) have reduced levels of beta amyloid in their brains. The increased level of IDE appeared to slow plaque formation in the brains of these mice.

Focusing on the proteases that might increase beta amyloid drainage gives researchers a lot of new possible therapies to prevent dementia. “I don’t think we are anywhere near [human] trials involving IDE,” Dr. Leissring says, “ but there are some exciting results coming out.” One encouraging finding is that increasing the levels of IDE or other proteases (and thereby reducing beta amyloid levels in the brain) might be done via the bloodstream. This could be much safer than attempting to administer a therapy directly to the brain.

Raising levels of IDE will probably not involve adding the enzyme itself to the bloodstream or the brain. According to Dr. Leissring, logistical problems with purifying IDE make it more probable that potential treatments will take a slightly different approach. “All cells make IDE,” he says, “and we can engineer bacteria or other cells to produce it. So it’s easy to produce, but not so easy to purify. I don’t think it will ever be produced on a scale for use in humans. More likely, a drug will be found that affects IDE or influences its expression levels within cells.”

The Insulin Connection

The promise of IDE-related therapies seems to contradict studies that show increasing insulin levels may improve memory for some Alzheimer’s patients. IDE degrades insulin as well as beta amyloid, so increasing IDE levels would be expected to lower insulin levels.

While increasing insulin levels may help some patients in the short term, Dr. Leissring points out that “accumulating evidence suggests that chronically high levels of insulin are not good, neither for diabetes nor for AD. There is a growing body of evidence that suggests that chronically high levels of insulin cause the body to become desensitized to the hormone’s effects---which is exactly what Type 2 diabetes is.”

”Based on our understanding of the causes of Alzheimer’s disease, and the role of IDE in degrading beta amyloid,” he says, “increasing insulin levels would be predicted to increase beta amyloid levels. We actually know that this is true from human studies. But insulin is a potent hormone that has myriad effects on cells, and it just might work for some other reason.”

Some diabetes drugs work to increase insulin sensitivity, rather than raising insulin levels. Researchers at the University of Washington are studying whether these drugs can improve memory in patients diagnosed with Mild Cognitive Impairment.

So, Dr. Leissring thinks simply increasing insulin may not help Alzheimer’s patients. “The approach of using insulin enhancers, on the other hand, seems sound, and there is emerging evidence from animal studies that it might work,” he says.

The Cerebral Amyloid Angiopathy Challenge

Cerebral amyloid angiopathy (CAA) seems to have been the main cause of my father’s dementia and death. In people with CAA, beta amyloid similar to that in Alzheimer’s plaques is deposited on the walls of the blood vessels in the brain. The protein causes the vessel walls to crack, allowing blood to leak out. Every hemorrhage, large or small, damages brain cells and can cause dementia and major hemorrhagic strokes like the one Dad had.

Unfortunately, some therapies that decrease the beta amyloid in Alzheimer’s plaques seem to increase the beta amyloid deposits on blood vessels. In theory, Dr. Leissring says, increasing the elimination of beta amyloid would be predicted to prevent both Alzheimer’s and CAA. But in some studies, attempts to dissolve beta amyloid via vaccination have increased CAA and hemorrhages in animals.

A large percentage of Alzheimer’s patients also have CAA. For them, using drugs designed to dissolve amyloid may be risky. “I think we can definitely hope for a preventative treatment for CAA, but the chances of a cure are less certain and will require much more study,” he says.

The Funding Challenge

Dr. Leissring reports that his research is currently funded by “start-up” money from Scripps Florida, funds from the National Institute on Aging (NIA), and a grant from the Ellison Medical Foundation. But even with this funding, he says he’s only been able to start ten percent of his planned projects.

“We are living in an incredible age, where we can do things in a day that would have taken many months just a few short years ago,” he says. “But it really does simply boil down to money (and lab space, ultimately). The more money, the more scientists we can hire and the more experiments can get done.”

Other Alzheimer’s researchers are experiencing the same problems - government and large organization funding seems totally inadequate. It may be that the only way to fill the gap is with private donations. The McNally family, whose father Richard died of Alzheimer’s six weeks after my dad’s death, has started a non-profit fund to support the research of Dr. Leissring and his colleagues. If you’d like to help, please go to The Unforgettable Fund, read the McNally family’s blog, and click on How to Donate.

Beta Amyloid in Alzheimer's and CAA: Dr. Jekyll or Mr. Hyde?

Two weeks ago, I met with Dr. Craig Atwood at the University of Wisconsin to talk about the theory that mid-life hormonal changes trigger a chain of events leading to Alzheimer's and similar neurodegenerative diseases.  It turns out this isn't the only area in Alzheimer's research in which his thinking diverges from the mainstream.

During our discussion on reproductive hormones, I gave him Dad's autopsy report to read.

"Hmmm, severe CAA [cerebral amyloid angiopathy].  Well, I would suggest that the amyloid deposits were your dad's brain's attempt to protect itself by sealing off ruptures to prevent hemorrhage.  I don't think the amyloid caused his problems."  He opened a file cabinet and pulled out a copy of a review he wrote on this topic.  Published in Brain Research Reviews in 2003, the article lays out the logic behind the theory that amyloid [the protein found in Alzheimer's plaques and on the brain's blood vessel walls in CAA patients] could be protective, not destructive as most researchers believe.  The logic goes something like this:

• Normally, when damaged parts of the body start bleeding, the blood coagulates, or clots, and this seals off any "leakage," but can prevent blood flow through damaged vessels to neighboring tissue...
• If this happened to the blood vessel walls deep within the brain, the resulting clot would block the supply of glucose and oxygen carried by the blood to that part of the brain, depriving neurons of essential nutrients and leading to dysfunction...
• The brain has developed a different mechanism to stop bleeding:  amyloid aggregates around the blood vessel wall, sealing the lesion and preventing blood from clotting.  This allows continuous blood flow through the damaged vessel, in the way that repairing a corroded or cracked plumbing pipe would allow water to flow through the pipe...
• Amyloid has properties that make it a good sealant...
• The fact that amyloid deposits have been observed near injury sites in the brains of people who have had head trauma [see an early report, for example] can be seen as support for this theory...
• Therefore, amyloid could be a protective molecule that is formed when there is damage to the brain caused by injury, stroke, Alzheimer's or age-related changes to blood vessel walls.

Dr. Atwood is not alone in questioning whether beta amyloid is really the evil Mr. Hyde of Alzheimer's.  The Wall Street Journal summarized the larger controversy in articles published on April 9, 2004 and April 16, 2004.  But the idea that amyloid could be a vascular sealant is in direct opposition to the widely held belief that amyloid is toxic and causes Alzheimer's and brain hemorrhages like Dad's.

The theory that amyloid is a "good" protein is important in the context of researchers' and pharmaceutical companies' efforts to develop vaccines to clear amyloid from the brain.  The first clinical trial of such a vaccine in humans was halted in 2002 after some of the participants developed inflammation of the brain and spinal cord.  Despite the safety issues, the vaccine appeared to have slowed memory loss in twenty of the thirty patients followed after the trial was stopped.  Trials of vaccination against amyloid in mice have had similar results:  University of South Florida scientists report that vaccination clears amyloid plaque deposits and improves memory in mice, but increases amyloid on blood vessel walls and causes hemorrhages.

Researchers are developing new, hopefully safer, ways to vaccinate against amyloid, but Dr. Atwood remains unconvinced that these efforts will succeed.  "If you believe that amyloid is protective, then it's no surprise, that mice and humans develop problems when they are immunized," he says.

Of course, Dr. Jekyll and Mr. Hyde were one and the same.  The evil Mr. Hyde could only be suppressed if Dr. Jekyll continued to take the potion he'd developed in his lab.  Could the beta amyloid in Dad's brain have been somehow both helpful and harmful?  Maybe someday we'll have the magic potion we need to harness its good properties while suppressing the bad.

Cerebral Amyloid Angiopathy and Alzheimer's Disease: Evil Twins?

A couple of posts ago, I mentioned that my father had both cerebral amyloid angiopathy (CAA) and Alzheimer's disease.  This isn't unusual - one study estimates 25% of people with Alzheimer's have moderate to severe CAA.

It turns out that the protein in the deposits on CAA patients' blood vessel walls is closely related to the protein seen in the plaques associated with Alzheimer's.  Researchers don't understand why excess levels of these proteins build up in some people's brains, or exactly what the connection is between CAA and Alzheimer's.

One recent study shows that a kind of CAA concentrated in small capillaries, rather than in larger blood vessels, is linked to Alzheimer's disease.  But Dad's CAA was not concentrated in his capillaries.  In fact it seems his CAA and Alzheimer's were not really connected.  "The burden of CAA in the brain vastly exceeds that seen in even the most severe and advanced cases of AD [Alzheimer's disease], indicating that this is likely to have been an independent disease process," Dad's autopsy report says.

There's growing recognition that CAA can cause or contribute to dementia, as well as cause hemorrhagic strokes like the one my dad had.  The fact that cerebral microbleeds, which can be caused by CAA, were common in Dutch memory clinic patients in a recent study seems to support this.

Whether or not CAA and Alzheimer's disease are evil twins, they were double trouble for Dad.

Cerebral Amyloid Angiopathy and Alzheimer's Disease: Dad's Double Burden

     Five years after Dad first had memory problems, we're starting to understand what caused his dementia.  Seven months after he died, we know what caused his hemorrhagic stroke.  I'm both relieved and sad to have a diagnosis.

     Last week I got a report from the Neuropathology Lab at Massachusetts General Hospital, where we sent some of Dad's brain tissue.  The report says he had severe cerebral amyloid angiopathy, or CAA.  In people with CAA, a destructive protein is deposited on the walls of the blood vessels in the brain. The protein causes the vessel walls to crack, allowing blood to leak out.  Every hemorrhage, large or small, damages brain cells and can cause dementia, difficulty speaking, or even paralysis.  Some CAA patients, like Dad, die of these hemorrhagic strokes.

     In a way, it's a relief to know that researchers don't yet understand what causes CAA, or how to treat it.  As Dad's memory problems slid into full-blown dementia, I felt like there was an answer, but we just couldn't find it.  This diagnosis means no one - not me, not my family, not his doctors - could have done anything to help him, no matter how hard we tried.

     My father also had a "moderate number" of the plaques and tangles characteristic of Alzheimer's disease in some areas of his brain.  According to the neuropathology report, these "contributed to his neurologic difficulties."  It's sad to think about him entangled by both Alzheimer's and CAA.

     On my birthday last year, Dad stayed on the phone with me longer than usual.  It was hard for him to find words, but he wanted to talk.

        Dad, Beau and Mom

     "Things are different here now," he said.  "But when I nap, Beau [their dog] stays with me.  He climbs up on me so I feel better. And Mom and I still push on each other [give each other backrubs], so that's good."

     "You've got a lot of good things, Dad."

     "Yes.  Hi from me to you...happy birthday," he said.  "I'm still older than you are!"

     Struggling under the double burden of CAA and Alzheimer's, Dad kept both his gratitude and his sense of humor.

Microbleeds in memory clinic patients

     A new article on cerebral microbleeds in memory clinic patients was published in the May 9 issue of Neurology.  Microbleeds are the small hemorrhages that doctors could see signs of on the MRI of my father's brain.  Thes microbleeds happen when the blood vessel walls in the brain thicken, harden and then crack, allowing blood to seep into the brain.  This can be caused by high blood pressure or by deposits of a protein called amyloid on the vessel walls (cerebral amyloid angiopathy).

     The Neurology article describes how researchers from the Department of Neurology/Alzheimer Center at the Vrije Universiteit (VU) Medical Center in Amsterdam looked for cerebral microbleeds in 772 memory clinic patients.  They found microbleeds in 65% of vascular dementia patients (whose dementia is caused by problems with blood supply to the brain), 18% of Alzheimer's disease patients and 20% of patients diagnosed with mild cognitive impairment.  While these percentages are lower than those of hemorrhagic stroke patients (estimated at 68% in one study), they are higher than the percentages found in the general population.  For example, as part of the Framingham study in the US, researchers found microbleeds in 4.7% of 472 participants with a mean age of 64 years, only two years younger than the mean age of the Dutch memory clinic patients.

     The VU scientists' findings raise some questions about the relationship of microbleeds and vascular disease to Alzheimer's.  Currently, vascular dementia and Alzheimer's are viewed as separate conditions.  But some researchers wonder whether vascular disease causes or contributes directly to Alzheimer's.

    For an expert opinion on these issues, I checked in with Dr. Philip Scheltens, Professor of Cognitive Neurology, Director of the Alzheimer Center at the Vrije Universiteit Medical Center and co-author of the new study.  His study concludes that the relatively high proportion of microbleeds in Alzheimer's disease and mild cognitive patients "provides further evidence for the involvement of vascular factors in neurodegenerative disease such as Alzheimer disease."

Dr. Philip Scheltens

     I asked Professor Scheltens whether he thinks microbleeds might actually cause or contribute to Alzheimer's.  "I think they are yet another phenomenon that occurs alongside Alzheimer's," he says, "and certainly do not cause it but may precipitate the clinical picture."

     Could microbleeds cause dementia independent of Alzheimer's?  "That we don't know yet," Professor Scheltens says, noting that there are not enough large studies on this topic to come to a firm conclusion.  "My view is that AD is a clinical label to which many pathologies can contribute; there are pure cases and cases where degenerative and vascular pathology go together and one may influence the other."

     I'm waiting for an analysis of Dad's tissue that I hope will provide more clues as to what caused his dementia, and whether he had cerebral amyloid angiopathy and/or Alzheimer's.  In the meantime, studies like Professor Scheltens' are providing more clues about the relationships among these conditions and diseases.  That may help researchers better understand the causes of dementia and eventually lead to the development of more effective treatments.

The Eye Exam Every Dementia Patient Should Have?

After reading that problems with blood vessels in the eye might be a sign of similar problems in the brain, I asked Mom to get Dad’s eye exam records. 

A study published in the January issue of Stroke showed that for people with high blood pressure, abnormalities of the blood vessels in the eye are associated with small strokes that can be detected only with an MRI .  Patients and their families might not notice any one of these strokes, but the combined effect could cause dementia.

These same abnormalities may mean a patient has a higher than normal risk of having a stroke (see http://www.thelancet.com/journals/lancet/article/PIIS0140673601062535/abstract - this  requires free registration to The Lancet).

My father did not have high blood pressure, but because his autopsy results had tentatively shown “hypertensive arteriosclerosis” (thickening of the blood vessel walls associated with high blood pressure),  I thought it might be helpful to know if the blood vessels in his eye showed any problems.

Tien Wong, MD, PhD is co-author of the new study in Stroke and the two other studies I linked to above.  He sent me this photograph below as a sample of the retinal blood vessel disease an eye doctor might see.  The red spots are retinal hemorrhages and aneuryisms, he explained, while the yellow spot indicates a mini-stroke.

Retinal photograph courtesy of Tien Y Wong, MD, PhD, Centre for Eye Research Australia, University of Melbourne

It turns out that the blood vessels in Dad’s eyes were normal.  I’m not sure if that would lead his neurologist to suspect my father’s microbleeds were not caused by hypertensive arteriosclerosis.  Either way, I would think anyone with dementia would want to ask his eye doctor to check for signs of retinal blood vessel abnormalities, and report the results to his neurologist and other doctors.

The MRI every dementia patient should get?

At the neuroconference, Dr. Fleming put up a slide of images from Dad’s MRI.  He pointed to several small dark spots.

“When we look on the T2* GRE sequence, we can clearly see microbleeds.  But you have to do the correct MRI sequence to detect these bleeds!  The GRE or Gradient Refocused Echo takes only an extra 45-55 seconds.”

“I went to the American Society of Neurological Imaging meeting this weekend, and kind of had a bee in my bonnet about this.” He then went through several slides on technical aspects of MRIs.   “At every coffee break, I talked with my colleagues about it.  Turns out at some centers, every brain gets a GRE, but at many top centers, they don’t routinely do it.  When I asked why they don’t, people shrugged.  ‘Well, if we find them, what are we going to do,’ they asked.  I say, if we don’t find out what’s going on first, we can’t figure out what to do.”

“A sizeable part of the population will have these bleeds,” Dr. Fleming pointed out, bringing up a slide referring to studies showing an estimate 3-12% of various populations have microbleeds.  The older you get, the higher the risk, according to this research.

It seemed to me he made a good point about the importance of documenting the microbleeds, even if there’s no treatment yet. Maybe some patients with “probable Alzheimer’s” diagnoses have dementia caused by microbleeds.  And maybe there are certain prescription and over-the-counter medicines that should be avoided or used with caution for these patients.  I’ll try to find out whether there are any guidelines about this.

At the neuroconference

Today, Mom and I sat down with twenty doctors around a conference table at Pitt Memorial Hospital in Greenville, North Carolina.  They were neurologists, neurosurgeons and pathologists from East Carolina Neurology and from the Brody School of Medicine at EastCarolinaUniversity.  All of us were here for Dr. Frank Fleming’s presentation of my Dad’s case.

One of the doctors gave us the handouts for the presentation – 85 slides!  I felt really good that Dr. Fleming had taken my questions on Dad’s dementia and his autopsy report so seriously.  But this was the first time I’d been back to Greenville and the hospital where Dad died, and if it was painful for me, it must have been worse for my mother.  We agreed that if she got upset, she would step out of the room, and I would stay and take notes. 

“OK, let’s get started,” Dr. Fleming said.  “Today I’m going to talk about microbleeds and discuss the case of a 73 year old gentleman who unfortunately died of a hemorrhagic stroke in November. Something quite unusual for these Neuroconferences – we have the family here today…”

                                                                                                                                          

The first few slides were about Dad’s medical history.  He started having problems finding nouns about four years ago.  By March 2004, he was having “minor trouble with arithmetic” and had difficulty drawing a clock.  Shortly before he died in 2005, he struggled to find any words, and was increasingly confused.

Tests showed my father had normal or low blood pressure, no thyroid problems, no “clinical stroke event.” His cholesterol was low, the arteries in his neck weren’t blocked, and he didn’t have the APOE4 gene associated with a higher risk of Alzheimer’s.  In short, there weren’t a lot of clues about what might have caused Dad’s dementia.

“But now we look at these images from his MRI in October 2005,” the doctor said.  “You see a dark area on the right side, a spot in the cerebellum here – all these hyperintensities are old hemosiderin deposits.”  He was telling us Dad’s brain had been bleeding for a long time.

.

My grandmother had a stroke too...

Dr. Fleming asked me to investigate my grandmother’s medical history to see if she had the same type of hemorrhagic stroke Dad did.  Her name was Amalie and she came from a very wealthy family in New Britain, Connecticut. 

She fell in love with my grandfather in high school, and married him despite her family’s objections about his poverty.  They lived next door to us when I was young, and I have a lot of fond memories of time spent with them.

In her early 70’s, my grandmother was still working as a home health aide, and was very sharp.  But in her mid-70’s, she was sometimes confused, and then had a major stroke when I was away at college.  No one in the family seems to know what kind of stroke it was, so I’ve sent for a copy of her death certificate and will try to get a copy of her medical records from the hospital in Connecticut where she was treated for her stroke.

Dad's last gift

     "Let go of my hand, please," Dad said as the emergency room technicians worked to insert a needle in his vein.  He had had a massive hemorrhagic stroke, and those were his last words.  Typical Dad - kind and polite even in the worst of circumstances.

    
     He died quietly two nights later.  "It's Dad's last gift to us," my sister Ginger said.  We all knew it was better than years of struggling with dementia.

    
     Thinking back to the people who came to Dad's memorial service or sent letters of sympathy, I'm struck by how many of them mentioned their relatives' dementia or Alzheimer's.  Some of my parent's neighbors talked about their spouses, and the clerk at the local pharmacy said her aunt had Alzheimer's.  Two of my best friends from junior high have parents with dementia.

    
Here's some scary facts:

• In the U.S., 10% of people over 65 and almost half of those over 85 have Alzheimer's.
• An estimated 24 million people worldwide have dementia - that's about the number of people who live in the state of Texas, or the entire country of Saudi Arabia.

     Alzheimer's Disease is only one type of dementia, so the number of people affected is probably much larger. 
Thinking of all the families involved, I guess we're lucky Dad died while he still enjoyed life and was relatively independent.