Picturing Alzheimer's

Picturing Alzheimer's

Although there is no definitive diagnostic test or treatment for those with Alzheimer's, a group of researchers is studying high-resolution brain scans for clues
January 26, 2011
The Siemens High Resolution Research Tomograph
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The Siemens High Resolution Research Tomograph (HRRT) Scanner is the most sophisticated brain scanner in the world. Researchers hope it will help in the early diagnosis of Alzheimer Disease.
Positron Emission Tomography Imaging at UBC

The numbers tell a startling story.

According to a 2009 study by the Alzheimer Society of Canada, 500,000 Canadians are living with Alzheimer’s disease or a related dementia. Of those, more than 71,000 are under 65, and approximately 50,000 are under 60. And 72 percent are women. An estimated 1.3 million Canadians could be afflicted by 2038.

And the estimated costs of managing dementia are staggering: pegged at $15 billion in 2008, they are predicted to rise to $158 billion in 30 years. Similar predictions are equally bleak worldwide.

Researchers are crossing borders and disciplines to use every research tool available — blood tests, brain- and spinal-fluid measurements, cognitive-ability scores and high-tech brain scans — to find effective diagnostic tests and treatments.

While Alzheimer’s can be identified with some reliability through cognitive and other tests, a definitive diagnosis is possible only when certain proteins are found in excess in and around nerve cells in the brain, usually during an autopsy. The hope is that high-tech neuroimaging of living patients will help unravel the mysteries of the disease and lead to predictive tests and effective treatments.

The University of British Columbia (UBC) and the TRIUMF Positron Emission Tomography (PET) Centre are one example. The centre is one of five Canadian and more than 50 American sites contributing PET-scan information to the Alzheimer’s Disease Neuroimaging Initiative (ADNI), one of the largest studies funded by the U.S. National Institutes of Health.

PET scans are slowly opening new doors to understanding Alzheimer’s through 3-dimensional images of the brain’s chemical activity in living subjects.

Launched in 2004, ADNI is exploring how PET imaging can be used to uncover whether drugs or behavioural changes are helping 700 subjects with mild cognitive impairment (MCI) and Alzheimer’s. Specifically, the PET scans look for beta-amyloid (A-beta) plaques, proteins found outside the brain’s nerve cells that, when present in large amounts, have been identified as a key characteristic of Alzheimer’s. Researchers also test blood and cerebrospinal-fluid biomarkers.

All the PET-image data collected as part of ADNI are archived at the Laboratory of Neuro Imaging at the University of California, Los Angeles. The database is being used by researchers worldwide and is starting to produce results. Researchers at the University of Pennsylvania, for example, recently used the database to compare the cerebrospinal-fluid biomarkers of more than 100 people diagnosed with Alzheimer’s, 200 with MCI and over 100 cognitively normal subjects.

In December, they announced that two biomarkers — reduced levels of a specific A-beta and increased levels of a phosphorylated tau protein — form a distinct signature in 90 percent of Alzheimer’s patients, 72 percent of MCI patients and 36 percent of cognitively normal volunteers. The researchers believe this protein signature suggests Alzheimer’s could be active and detectable earlier than expected, which opens the door to the possibility of testing healthy people to determine those at risk for the disease.

The TRIUMF-UBC group uses a High Resolution Research Tomograph (HRRT), the most sophisticated brain scanner in the world, on its ADNI subjects, along with those involved in studies on Parkinson’s disease and psychiatric conditions, such as schizophrenia and bipolar disorders.

While the HRRT provides extra detail that is removed for the ADNI database, researchers will have a use for that data.

“The data will undergo secondary analyses where the high resolution provided by the HRRT will be able to detect smaller functional abnormalities and thus, hopefully, become an aid to earlier detection of the disease,” says Vesna Sossi, a professor in the physics and astronomy department at UBC and director of UBC’s PET group.  

Two new ADNI sub-studies, run through UBC Hospital’s Clinic for Alzheimer Disease and Related Disorders, will include a new radioactive dye that reveals increased detail in order to more clearly differentiate Alzheimer’s from other types of dementia. Previous dyes showed promise as Alzheimer’s biomarkers at the earliest stages, but were either difficult to access or less sensitive when it came to following disease changes or progression, says cognitive neurologist Robin Hsiung, who leads the project.

Hsiung hopes the ADNI study will help find clear biomarkers of the disease and lead to predictive tests and drug treatments within a few years.

“Successful drug developments must parallel the advances in early diagnosis,” says Hsiung. “If we wait until the disease progresses to the point of clinical dementia, treatment is too late; we will not be able to preserve any remaining brain function. The ideal timing of treatment is before clinical dementia sets in.”

The current method of memory tests every six months as a marker for Alzheimer’s, he adds, makes it hard to track treatment efficacy, since memory decline is so slow.

“Development of biomarkers that can track presymptomatic Alzheimer pathology, either by PET scans, MRI scans or blood or cerebrospinal-fluid tests, will be needed,” he says. “The ADNI studies will help identify patients at risk for worsening at a much earlier stage, and hopefully, the treatment will be much more effective.”

Some Alzheimer facts

 History: In 1906, German neurologist and psychiatrist Dr. Alois Alzheimer noted changes in the brain tissue of a woman who died after suffering memory loss, language problems and unpredictable behaviour. He found abnormal clumps in her brain and tangled fibre bundles (now called amyloid plaques and neurofibrillary tangles). These are two main features of what is now called Alzheimer’s disease. A third is the loss of connections between brain nerve cells (neurons).

 

Research focus: Dr. Jack Diamond, scientific director of the Alzheimer Society of Canada, notes that much of today’s Alzheimer’s research is focused on drugs and behavioural strategies to decrease A-beta levels, a brain protein that is found in excess in Alzheimer patients. The amyloid protein that deposits to form the plaques is what Dr. Alzheimer first described. Why excessive levels develop is a mystery. Genetics play a role but only slightly increase a person’s risk. Age is a key factor, but researchers suggest lifestyle choices can significantly slow the progression of Alzheimer’s.

 

Identifying the disease: There are as yet no conclusive screening tests to identify the disease before death. Along with psychoses, depression, agitation, apathy and aggression, Alzheimer sufferers can also have seizures, strokes, diabetes and obesity. Memory loss is often a first symptom.

 

Lifespan: On average, a person will live 7 to 10 years after being diagnosed with Alzheimer’s.

Some recent research developments:

  • In mice experiments, Dr. Serge Rivest, a researcher at Centre hospitalier de l’Université Laval in Québec, showed that injecting microglia — octopus-like immune cells that protect the central nervous system — can reduce the amyloid load, such as that found in Alzheimer’s patients. The findings are being used to develop a therapeutic approach to transform stem cells into amyloid-fighting “super soldiers” during the early stages of Alzheimer’s.
  • Dr. Andrea LeBlanc and a team of researchers at the Jewish General Hospital in Montréal announced in October 2010 that they had isolated an enzyme they believe is the real cause of Alzheimer’s. LeBlanc’s theory is that an enzyme called Caspase-6, and not A-beta, triggers the onset of Alzheimer’s. LeBlanc discovered extremely high levels of activated Caspase-6 in the brains of people who died of the disease but none in older subjects without the disease or in anyone under the age of 45. LeBlanc also found elevated levels in older people with memory impairment other than Alzheimer’s. LeBlanc, who is also a professor of neurology and neurosurgery at McGill University, surmises that neurodegeneration may be reversible.
  • In August 2010, Eli Lilly and Company halted two long-term clinical trials of a drug targeting A-beta brain levels. While the drug reduced A-beta production in 2,600 mild to moderate Alzheimer’s subjects, cognitive decline in those on the drug was “significantly” worse than for those on placebo. The results raise questions about the leading theory on the causes of Alzheimer’s and how to treat it.
  • In December 2010, a U.S. researcher announced that in a study of 1,130 white, black and Hispanic residents of New York City over 65, those with the highest levels of high-density lipoprotein (HDL), often called “good cholesterol,” were 60 percent less likely to develop Alzheimer’s over four years than those with the lowest HDL levels. Dr. Christiane Reitz of Columbia University’s Taub Institute, in New York City, suggests that raising HDL could lower the frequency of Alzheimer’s disease.