MIAMI BEACH — Neuroimaging studies of patients with Down syndrome are pointing the way to the early detection of Alzheimer disease (AD), before symptoms of dementia appear.
In the first longitudinal brain imaging study of adults with Down syndrome, PET scans revealed that patients with Down syndrome experience a spike in the glucose metabolic rate (GMR) in the temporal cortex prior to the onset of dementia, said Ira T. Lott, MD, Professor of Pediatrics and Neurology at the University of California College of Medicine-Irvine.
Earlier identification of these patients may allow early intervention, he said. “With new therapeutic agents evolving all the time, we want to apply them as soon as possible.”
The findings, which Dr. Lott reported here last fall at the Annual Meeting of the Child Neurology Society, also appear in the December 23rd issue of Neurology (2003;61:1673–1679).
Middle-aged people with Down syndrome provide a unique opportunity to study pre-symptomatic brain patterns that may predict the onset of dementia, Dr. Lott said.
Amyloid plaques are deposited in the Down syndrome brain during the first decade and accumulate over the years, he said; at autopsy, nearly all people with Down syndrome show the neurofibrillary tangles and amyloid plaques associated with AD, even when dementia is not apparent. “This is the only disease I know of in which you see this similarity,” he said.
While 50 to 75 percent of people with Down syndrome develop AD by middle age, it is not known whether the neuropathology of dementia is the same in the two disorders, Dr. Lott said.
To determine whether the same disease processes are at work, the researchers used PET to study brain activity. In earlier PET studies, the GMR was increased in mentally retarded patients, Dr. Lott said. “Now we focused on the temporal lobe – where the action is in Alzheimer disease. We asked the question, does the glucose metabolic rate topography parallel the anatomic degeneration over time?”
The researchers studied 17 nondemented patients with Down syndrome, whose mean age was 41.4 years; 10 patients with moderate Alzheimer disease, with a mean age of 76 years; and 12 age- and sex-matched controls for each group.
PET with a F-18 fluorodeoxyglucose tracer was used to measure the GMR while each participant was performing a continuous performance test. The test required the subject to watch single digits in random order and press a button whenever they see a zero, Dr. Lott said. On a separate day, each subject also had a structural MRI for coregistration with the PET image – that is, to ensure they were in the right anatomical region.
Conjunctional analysis – which allows the identification of commonalties in GMR activations or deactivations between groups – showed that in general, the GMR is lower in patients with both Down syndrome and AD than in controls.
But there were areas of discordance, Dr. Lott said, with the most significant difference occurring in multiple areas of the inferior temporal cortex, mainly in the entorhinal cortex.
“What we found,” he said, “is that in Down syndrome patients, the glucose metabolic rate was higher in the entorhinal cortex than in controls and in people with AD. But in AD, the glucose metabolic rate is lower in this cortex than in controls. The glucose metabolic rate is going down in the AD group just when it is going up in the Down syndrome group.”
A COMPENSATORY RESPONSE?
According to Dr. Lott, “This finding in the entorhinal cortex suggests that a compensatory response is occurring prior to the onset of Alzheimer disease.” Since the Down syndrome patients were not clinically demented, entorhinal cortex hypermetabolism may signify a compensatory response early in disease progression and prior to the onset of dementia, he explained.
The increased metabolic rate may reflect a compensatory response in neurons associated with the progressive age-dependent accumulation of both senile plaques and neurofibrillary tangles, Dr. Lott said. “But when neuronal damage in the temporal cortex region reaches the point where increased metabolism can no longer compensate, the metabolic rate will decrease, as was observed in the Alzheimer-diseased brains scanned for the study.
“This suggests that people with Down syndrome and the highest glucose metabolic rate in parts of the entorhinal cortex will develop dementia, but only after a sharp drop in the glucose metabolic rate,” he said. “And we think this process will be an early marker [for the disease].”
Seeking a neuro-anatomic correlate, the researchers then went to Down syndrome tissue bank and got cuts of same area from four brains, Dr. Lott said.
In the entorhinal cortex, they found three markers: the anti-tau antibody AT8, a marker of pathological tau, and growth associated protein (GAP) 43 and microtubule-associated protein (MAP) 2, both neuronal growth markers.
“Looking at the four Down syndrome brains, what we are seeing is a concentration of tau in the 37-year-old brain and then an activation of the neuronal growth markers in the 47- to 54-years-old Down brains,” Dr. Lott said.
“So we have anatomical evidence of a sprouting response in the hippocampus, particularly regions receiving projections from the entorhinal cortex – that is, approximately the same area of the brain in which PET showed activation,” Dr. Lott said.
“That is what makes our finding so robust,” he said. “We have essentially the same finding by both anatomical imaging and functional imaging.”
NEXT RESEARCH PHASE
The study suggests that “functional brain imaging may be able to identify the Alzheimer disease process at an earlier age epoch in Down syndrome and ultimately determine whether preventive and therapeutic interventions are needed,” Dr. Lott said. Neuroimaging may also help to monitor response to treatment, he said.
The next step, Dr. Lott said, is to perform PET studies on younger people with Down syndrome to see if the changes predictive of Alzheimer disease can be detected even earlier.
He said that in a separate study, his team is looking at whether high-potency antioxidant supplements can help slow the development of the Alzheimer disease in people with Down syndrome and dementia. Studies have shown these patients have an intrinsic oxidative defect, he said.
Edward J. Novotny, MD, Associate Professor of Pediatrics and Neurology at Yale University in New Haven, CT, and moderator of the session, said the study was important, showing that “state-of-the-art PET techniques can be used for prevention.
“We know that children with Down syndrome develop Alzheimer disease 20 to 30 years earlier, on average, than other people who get Alzheimer disease. So studying these children is extremely important, as it will permit earlier diagnosis and treatment,” he said.
PET is more sensitive than MRI, he said. While MRI gives a picture of the structure of the brain, PET also offers a snapshot of brain function. “Early imaging changes on PET can identify the disease at a very early time point,” Dr. Novotny said. “This would allow for early intervention.”
Would the non-Down syndrome patient show this pattern? “We don't know,” he said. “I would hypothesize yes, but those studies still need to be done.”
ARTICLE IN BRIEF
✓ In the first longitudinal brain imaging study of adults with Down syndrome, PET scans revealed that patients with Down syndrome experience a spike in the glucose metabolic rate in the temporal cortex prior to the onset of dementia.