Time’s Strain on the Brain

A team of HMS researchers hopes to decipher Alzheimer’s disease by first understanding how brain systems function in normal aging.

Courtesy Jessica R. Andrews-Hanna

Brain drain. Separate brain regions show correlated activity in young adults (background image). But in advanced aging, coordinated activity among brain regions decreases and accompanies cognitive decline (foreground).

Senior author Randy Buckner, Howard Hughes investigator and HMS lecturer in radiology at Massachusetts General Hospital, lead author Jessica Andrews-Hanna, a graduate student in Buckner’s lab, and colleagues began from the hypothesis that cognitive decline occurs when cerebral regions are disconnected by deteriorating white matter tracts. Their study, published in the Dec. 6 Neuron, tested 93 adults aged 18 to 93 and found that older subjects experienced a cognitive, functional, and structural decline similar to patients with Alzheimer’s, but with milder effects.

“What we found was that networks of brain regions that are correlated in young adults become less integrated with advanced aging, even in individuals who showed no signs of early Alzheimer’s disease,” said Buckner.

Nine randomly selected older individuals tested negative for signs of Alzheimer’s disease in a PET exam to uncover amyloid buildup.

The researchers took an “activity snapshot” of participants’ brains to examine neural crosstalk. Volunteers inside an fMRI scanner were asked to determine whether words represented living or nonliving objects. Buckner and colleagues calculated functional activity correlations from the scans, which showed how different areas of the brain communicated with one another. This may be the first time researchers have used such activity correlations across widely distributed brain regions to study normal aging.

“When we think, we don’t just use one brain region at a time. We use brain regions that are connected to one another and need to interact to communicate with each other to perform the task,” said Andrews-Hanna.

Older patients experienced a marked decline in the brain’s default system, which specializes in internal cognition and is thought to be connected by white matter tracts from the front to the back of the brain.

In addition to the fMRI, 40 older participants completed a variety of cognitive tests that measured executive function, memory, and processing speed. Individuals exhibiting the lowest functional correlations also exhibited the poorest cognitive tests. In spite of this link, depleted neurotransmitters or gray matter atrophy might also contribute to cognitive decline, the researchers said. A longitudinal study will be needed to uncover the causes.

“If we can come up with an understanding of how neural eavesdropping can be predictive of cognitive decline, it might help us understand the changes that occur in normal aging,” said Andrews-Hanna. “And it might help us better predict Alzheimer’s disease.”

—Laura Geggel

Technique Pilots Bone-forming Cells to the Bone Marrow

The estimated 44 million Americans who suffer from osteoporosis might benefit if scientists could direct adult mesenchymal stem cells (MSCs) from the bloodstream to the bone marrow, where they are able to develop into osteoblasts producing healthy, new bone.

For the past eight years, Robert Sackstein, a bone marrow transplant physician and HMS associate professor of dermatology at Brigham and Women’s Hospital, has been searching for ways to accomplish this by modifying the surface of MSCs so they dock on a receptor found on blood vessels within the marrow.

“Twenty years ago, we had no clue how stem cells migrated into the marrow; we now know a great deal,” Sackstein said.

In a mouse study appearing online Jan. 13 in Nature Medicine and in the February print issue, lead author Sackstein and colleagues describe the chemical engineering of human MSCs ex vivo. The researchers injected the cells intravenously into the animals, where they migrated to the bone marrow and formed bone cells.

Sackstein began this research investigating hematopoietic stem cell–homing molecules—proteins that function like GPS devices to direct cell migration. His work identified a novel glycoform of CD44 called hematopoietic cell E-selectin/L-selectin ligand (HCELL) that is found on the surface of human hematopoietic stem cells. HCELL avidly binds to E-selectin, a molecule found on the lining of blood vessels at sites of tissue injury. Simultaneously, other labs found that E-selectin is continuously expressed on specialized vessels within the bone marrow and is responsible for attracting stem cells.

Since E-selectin acts as a beacon for recruitment of cells to the bone marrow, Sackstein searched for a molecule on human MSCs that could bind to it. It turned out that MSCs express a modified version of CD44 that is one sugar, a fucose, short of being HCELL. Sackstein realized that if he fucosylated the surface CD44 on MSCs into HCELL, he might be able to direct MSCs to the marrow and achieve bone growth.

“It’s remarkable that you can take one single sugar, put it on a protein, and change the entire capacity of that cell to home,” Sackstein said.

He then found a way to selectively catalyze fucosylation of CD44 without causing toxicity to the cells. He decorated CD44 with the missing fucose, injected the human MSCs into mice, and watched as the cells migrated to E-selectin in the bone marrow within one hour. HCELL expression remained stable for 24 hours, but declined within 96 hours, presumably due to turnover of surface protein.

Patches of bone appeared in the mice within weeks. “This is the first time a human mesenchymal stem cell has migrated in blood flow to a bone tissue in an animal model and actually made bone,” Sackstein said.

—Laura Geggel

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