We Are Our Brains (50 page)

FIGURE 31.
In the final stage of Alzheimer's, the patient lies curled up in bed in a fetal position. Courtesy of Professor E.J.A. Scherder of the Clinical Neuropsychology Department of VU University in Amsterdam.

Language and music are stored in a part of the memory that's
only affected at a late stage of Alzheimer's. The ability to speak only disappears in Stage 7. Musical skills can be retained for a very long time. A professional pianist with Alzheimer's could no longer comprehend anything that was said or written, including sheet music. Yet she could retain pieces of music that she heard for the first time and reproduce them with musical feeling. At a later stage she could still play the melodies with which she was familiar, a pastime that gave her great satisfaction. A case has also been described of a violinist with Alzheimer's who retained his musical skills. The inverse of the brain's retention of musical skills is true too; music is one of the earliest influences in an infant's development. Indeed, the effects of music on brain function can be seen very early on. Premature babies in incubators become calmer, have better oxygen values, and are able to leave incubators earlier if music is played to them. Newborn babies are much more interested when a mother sings than when she speaks, and they already have a sense of rhythm. So, rather like businesses undergoing reorganization, Alzheimer's functions along the lines of “last in, first out,” with the most senior members of staff being allowed to stay put. But of course the brain isn't being reorganized in Alzheimer's; it's being demolished.

Despite the marked shrinkage of the cerebral cortex in Alzheimer's (
fig. 32
), which can cause the brain in the skull to resemble a walnut in its shell, it retains all its neurons. In contrast to what's generally thought, brain cells don't die en masse as a result of Alzheimer's. Cell death is limited to regions like the entorhinal cortex, part of the hippocampus, and the locus coeruleus and only occurs at an advanced stage of the disease. Conversely, reduced activity, leading to neuronal shrinkage (
fig. 33
), affects the entire brain from an early stage. This also explains why symptoms can fluctuate so strongly at the beginning of the disease. Someone can show marked signs of senility one moment but be able to carry on an intelligent conversation the next. If the memory disorders in the early stages of Alzheimer's were indeed due to cell death, such fluctuations wouldn't occur, as cell death isn't reversible.

FIGURE 32.
A characteristic symptom of Alzheimer's is marked shrinkage (atrophy) of the entire cerebral cortex, which can cause the brain to look like a walnut (a normal brain is shown underneath). Courtesy of the Netherlands Brain Bank.

FIGURE 33.
Microscope slides showing atrophied neurons in the nucleus basalis of Meynert. A is a control sample taken from a healthy patient, showing the large neurons extending their nerve fibers into the cerebral cortex, where they release the neurotransmitter acetylcholine (see also
fig. 25
). B shows how Alzheimer's causes these cells to shrink (the arrow points to a group of three dramatically shrunken neurons). Courtesy of Dr. Ronald Verwer.

Activation Versus Alzheimer's

While patients are of course indifferent to whether their dementia is due to loss of neurons or reduced neural activity, the difference is crucial for developing therapeutic strategies. If neurons are still there, albeit atrophied and nonfunctioning, it should, in principle, be possible to reactivate these cells, which is a focus of our research.

Growing up bilingual, having a good education and a challenging job, and remaining active in old age reduce the likelihood of Alzheimer's. This suggests that maximizing brain activity has a preventive effect. There are, moreover, areas of the brain in which neurons aren't affected by the disease. We have found such areas to be extremely active, sometimes even becoming more active as aging progresses. In 1991, I paraphrased the hypothesis that activating neurons appeared to provide some protection against aging and Alzheimer's as “Use it or lose it.”

Studies also show that activation can reduce Alzheimer's pathology. Transgenic mice with considerable buildup in their brains of the toxic protein amyloid (a symptom of Alzheimer's) were placed in an enriched environment—a large cage in which they could play with one another and in which they were regularly treated to new toys. When mice remained in this environment, their amyloid levels decreased (and went down even further if they also got more exercise than usual). Sadly, the research team headed by Erik Scherder at the
VU University in Amsterdam couldn't link extra physical exercise to improved function in Alzheimer's patients. Yet he did find, in an earlier study, that general stimulation of the group's brains (through transcutaneous electrical nerve stimulation) had a beneficial effect on cognition and mood. The team headed by Mark Tuszynski in San Diego is using gene therapy to stimulate the nucleus basalis of Meynert (
fig. 25
), a brain structure that's important in memory, in Alzheimer's patients with promising results (see
chapter 11
).

Stimulating the Biological Clock with Light

To test the effectiveness of activating neurons affected by Alzheimer's, we opted to stimulate the circadian system. The study also had clinical importance, because nighttime restlessness is the main reason that people with dementia are institutionalized. It makes them putter around late at night, turning on the gas and doing other potentially dangerous things, or go out and wander the streets. Sooner or later their partner can no longer cope with the Herculean task of caring for them and keeping an eye on them day and night. The circadian system (from the Latin
circa
, meaning “around,” and
diem
, meaning “day”), which is responsible for all our day and night rhythms, is affected very early on in Alzheimer's. Patients no longer get their nightly peak of melatonin, the sleep hormone secreted by the pineal gland. We established that these early changes are caused by the biological clock, the suprachiasmatic nucleus, a structure that can easily be stimulated by means of light therapy. As expected, light therapy improved circadian rhythms and reduced restlessness in Alzheimer's patients. It didn't work in patients with impaired vision—a nice control demonstrating the effectiveness of light. A three-and-a-half-year follow-up study by Eus van Someren and his team showed that more light doesn't just stabilize rhythms but also improves mood and even slows the deterioration of memory. The combination of more light during the day and melatonin supplements before sleep proved even more effective in some respects.

FIGURE 34.
Thin slices of tissue removed from the brain of a patient with Alzheimer's within ten hours of death. At this stage, neurons can be cultured for many weeks. In this model, stem cells proved to secrete an unknown substance that improved the survival of the cultured neurons. After forty-eight days in normal culture conditions (A), only a few neurons are still active and intact (indicated by arrows). These are outnumbered by neurons with leaky membranes (triangles), evident from their colored nuclei. Many nuclei of dead cells can also be seen (small dots, some of which are marked with an asterisk by way of example). B shows how, after a slice of this kind is cultured with stem cells, there are many more active, intact neurons (arrows) and fewer leaky (triangles) and dead (asterisks) cells. Courtesy of Dr. Ronald Verwer.

The results of this simple intervention are fully equal to those of current anti-Alzheimer's drugs and do not have any of the side effects. Although stimulating the biological clock can improve the quality of life of Alzheimer's patients and their carers, it isn't, of course, a therapy for the disease itself. However, it does prove an important principle, namely that even if neurons are affected by Alzheimer's, their function can be restored through stimulation.

Current Research

The Netherlands Institute for Neuroscience (NIN) is currently looking at substances that can activate neurons in other areas of the brain. Ronald Verwer has devised a procedure that enables neurons in thin sections of brain tissue obtained within ten hours of death to be cultured for several weeks. This allows us to test the effects of potentially activating substances without inconveniencing patients. In this model, stem cells proved to secrete a substance that promoted the survival of the cultured neurons (
fig. 34
). But as yet we have absolutely no idea what the nature of this compound is.

A second line of research is based on the finding that, in the initial stages at least, the brain appears to resist Alzheimer's successfully. Our NIN team with Koen Bossers and Joost Verhaagen found this to be the case in the very earliest stage of the condition, before any memory impairment occurs. A number of brain areas appear to engage in compensatory increased activity, protecting memory for a time. Our team found that hundreds of genes are activated in the prefrontal cortex before typical Alzheimer's-type changes affect that region. The study's conclusion is that the prefrontal cortex (
fig. 15
) does its utmost to continue to function normally when Alzheimer's first strikes. However, this compensatory mechanism eventually fails, metabolism decreases, and memory impairment begins its relentless progress. We hope that by studying the brain's initial defense mechanisms against Alzheimer's we can develop new medication. It's just a pity that the pace of research is often so frustratingly slow.

Dementia is a humiliating condition that tends to go hand in hand with depression and, especially in its early stages, with fear. It's a reason why many of us decide that we don't want to undergo this process. A committee of the Dutch Association for Voluntary Euthanasia (NVVE) on which I sat concluded that the current euthanasia legislation provides scope for people with dementia to opt for euthanasia, providing that they do so in time (see later in this chapter). The suffering associated with dementia can indeed be considerable, and it isn't just caused by the fear of deterioration. Neuropsychologist Erik Scherder is one of the few to have pointed out that the very brain disorder that underlies dementia also makes it much harder to diagnose and treat pain. Inadequate pain treatment for patients with dementia is a common, extremely worrying problem that increases with the severity of dementia. Sometimes, as in the case of vascular dementia, the disease generates its own “central” pain. In addition, many elderly people suffer chronic pain already, for instance because of arthritis, and since dementia is an aging disorder, it stands to reason that many elderly patients with the condition suffer from chronic pain as well. Yet if you look at painkiller use, a strange picture emerges. A patient with dementia who, say, breaks their hip, is prescribed fewer painkillers than a patient without dementia. This isn't because people with dementia don't suffer pain. Inadequate pain treatment has more to do with the difficulty that doctors experience in estimating the degree of pain suffered by this category of patients. People whose brains are intact can tell you how much pain they are experiencing. Their blood pressure and heart rate also go up in response to pain—an automatic reaction of the nervous system. In Alzheimer's, however, this system is impaired. As a result, moderate pain doesn't affect patients' blood pressure and heart rate; by the time an increase is perceptible, they are in severe pain. But there are methods for estimating pain levels, not just for patients in the early
stages of dementia, who can still communicate, but also for patients with severe dementia who have lost all power of communication. For patients in the early stages of dementia, pain scales to indicate pain intensity have been devised. For patients with severe dementia, pain assessment has to be done on an observational basis, just as in the case of very young children.