Circadian Rhythms Hold Key to New Alzheimer Symptom

Discovery could lead to Treatments for Devastating Sleep Disturbances

April 12, 2001 -- Belmont, MA -- Tracking the daily, or circadian, rhythms of patients with advanced dementia may provide a tool for distinguishing whether they suffer from Alzheimer's disease or other forms of dementia, according to a new report by McLean Hospital researchers. The method could lead to more effective ways of treating the sleep disturbances that accompany all forms of dementia— disturbances so overwhelming they often lead to institutionalization of patients.

David Harper, PhD, research fellow in the Department of Geriatric Psychiatry at McLean Hospital, and his colleagues monitored two key features of the circadian system—the rise and fall of core body temperature and the waxing and waning of spontaneous motor activity—in 38 dementia patients with Alzheimer's disease or another form of dementia, fronto-temporal degeneration.

They found that body temperature reached its peak much later in the 24-hour day in the Alzheimer patients than it did in controls. People with fronto-temporal degeneration exhibited a much different pattern. Their activity levels reached a peak earlier in the day than in controls while their body temperature rhythm appeared normal. The findings appear in the April Archives of General Psychiatry .

Intriguingly, fronto-temporal dementia patients were able to attain a stage of quiescence, or subdued activity, though it did not necessarily happen at night as it does in controls. This more restful state eluded Alzheimer's patients.

"Alzheimer patients never really get to a state of normal quiescence," said Harper.

Alzheimer's effects on memory and cognition are notorious but the accompanying sleep disturbances are among the most devastating aspects of Alzheimer's disease and other forms of dementia, including fronto-temporal degeneration.

"In dementias you have the cognitive disturbances which are horrific, but you also have the non-cognitive disturbances—sleep problems, hallucinations, and delusions," said Harper. "Sleep disturbances are actually more disturbing to caregivers than the cognitive symptoms. They are often cited as the primary factor behind the decision to institutionalize."

Once moved to an unfamiliar institutional setting, Alzheimer patients often experience a rapid decline.

Clinicians have tried to treat these sleep disorders by resetting the circadian clock—for example by exposing patients to bright light early in the morning or by giving them melatonin, a hormone that helps to regulate sleep-wake cycles, at bedtime—with mixed results. The problem is that doctors have not identified the type of dementia their patients suffer from, said Harper. Based on their study, Harper believes that such chronobiological approaches may be more helpful to Alzheimer patients than those with fronto-temporal degeneration.

"Taking a one-size-fits-all approach to progressive dementia may be doing these individuals a disservice," Harper said.

In addition to refining existing treatments, the discovery could lead to new therapies.

"Once we understand what's causing the disturbances—the specific circadian defects—in the different dementias, then we may be able to devise new and effective treatments," he said.

Harper and his colleagues first began tracking the body temperature and motor activity of the 38 advanced dementia patients—all classified as Alzheimer patients—six years ago. Because these patients often fall asleep early in the evening, by 6 or 7 pm, the researchers expected the patients' circadian systems, which synchronize the body's wake-sleep signals with the light-dark patterns in the environment, to be advanced—that is, that they would signal the body to fall asleep earlier than they do in controls. But the circadian signals appeared to come later, on average, in the patients.

After the patients died, Harper and his colleagues examined the autopsied brains and found that 20 percent of the so-called Alzheimer patients lacked the telltale plaques of the disease and, instead, had suffered from various forms of fronto-temporal degeneration. Scrutinizing the circadian activity patterns of all of the patients, the researchers found that in the fronto-temporal patients, the activity cycle was advanced—a decidedly different pattern from the delayed phase of the Alzheimer patients.

"We were very surprised to find that the phase delay in core body temperature and activity appears to be a distinctive hallmark of Alzheimer's disease," Harper said.

He believes that this delay could explain why chronobiological methods such as light exposure have not worked consistently in Alzheimer patients. In such therapy, patients are exposed to bright light in the morning, often around 9 am. Yet in some patients, the circadian phase delay may be so great as to push the beginning of the circadian cycle, which usually occurs between 4 and 5 am, to past 9 am. In such extreme cases, the effect of light therapy would be to delay the cycle even more rather than to advance it to a more normal position.

"This timing for therapy could make things worse for many patients," Harper said.

He and his colleagues observed that though the circadian rhythm was delayed in all Alzheimer patients, it was delayed by different amounts in different patients—a finding that clinicians could use to tailor more effective chronobiological treatments for their patients.

"When giving light or melatonin treatment, the most important thing to remember is that these patients have a subjective internal time," Harper said. "You need to measure the actual circadian rhythm of the patient before you administer light treatment."