Leukoaraiosis: 'Harmless' condition shown to alter brain function in elderly

Researchers at the Mayo Clinic say a common condition called leukoaraiosis, made up of tiny areas in the brain that have been deprived of oxygen.

They appear as bright white dots on MRI scans, is not a harmless part of the aging process, but rather a disease that alters brain function in the elderly.

Results of their study are published online in the journal Radiology. "There has been a lot of controversy over these commonly identified abnormalities on MRI scans and their clinical impact," said Kirk M. Welker, M.D., assistant professor of radiology in the College of Medicine at Mayo Clinic in Rochester, Minn.

"In the past, leukoaraiosis has been considered a benign part of the aging process, like gray hair and wrinkles."

 Leukoaraiosis, also called small vessel ischemia and often referred to as unidentified bright objects or "UBOs" on brain scans, is a condition in which diseased blood vessels lead to small areas of damage in the white matter of the brain.

The lesions are common in the brains of people over the age of 60, although the amount of disease varies among individuals.

"We know that aging is a risk factor for leukoaraiosis, and we suspect that high blood pressure may also play a role," Dr. Welker said.

Dr. Welker's team performed functional MRI (fMRI) scans on cognitively normal elderly participants recruited from the Mayo Clinic Study of Aging between 2006 and 2010.

In 18 participants, the amount of leukoaraiosis was a moderate 25 milliliters, and in 18 age-matched control participants, the amount of disease was less than five milliliters.

The patients were imaged in an MRI scanner as they performed a semantic decision task by identifying word pairs and a visual perception task that involved differentiating straight from diagonal lines.

fMRI is a special type of magnetic resonance imaging that measures metabolic changes in an active part of the brain.

Although both groups performed the tasks with similar success, the fMRI scans revealed different brain activation patterns between the two groups.

Compared to members of the control group, patients with moderate levels of leukoaraiosis had atypical activation patterns, including decreased activation in areas of the brain involved in language processing during the semantic decision task and increased activation in the visual-spatial areas of the brain during the visual perception task.

"Different systems of the brain respond differently to disease," Dr. Welker explained. "White matter damage affects connections within the brain's language network, which leads to an overall reduction in network activity."

He pointed out that identifying leukoaraiosis in the brain is important, both for individual patients undergoing brain mapping for surgery or other treatments and for research studies.

 For improved neurological health, Dr. Welker said efforts should be taken to prevent leukoaraiosis from occurring.

"Our results add to a growing body of evidence that this is a disease we need to pay attention to," he said.

"Leukoaraiosis is not a benign manifestation of aging but an important pathologic condition that alters brain function."

Motor Neurone Disease: New Insight about how it works

When we imagine how research results can change society or help us make new bounds in medical science we think of proving a hypothesis or cracking a code, but sometimes research that refutes a theory can be just as beneficial, as scientists can eliminate a hypothesis from the mix and save years of wasted-time investigating dead ends and a team of German researchers has just done exactly that.

Writing in the journal Proceedings of the National Academy of Sciences (PNAS), the team refute a widely accepted hypothesis about a causative step in neuro-degenerative conditions.

These results deal specifically with animal models of human amyotrophic lateral sclerosis (ALS), more commonly known as Motor Neurone Disease, but the findings also have implications for other neuro-degenerative diseases such as Alzheimer's or Huntington's disease.

One of the ways neuro-degenerative diseases manifest themselves is in the loss of axons - essentially, the transmission lines for electrical signals in individual nerve cells - and synapses, the key sites for communication between them.

In the past, such damage has been attributed to deficits in the bi-directional transport of organelles, such as the intracellular power plants called mitochondria, along the axons of nerve cells.

The team, from the Technische Universitaet Muenchen (TUM) and Ludwig-Maximilians-Universitaet Muenchen (LMU), put these previously-held assumptions to the test in one of the most thorough tests carried out to date.

They used novel imaging techniques, with high resolution in both space and time, to observe changes in both axon morphology and organelle transport in several different animal models of ALS.

Their results show that transport deficits and axon degeneration can develop independently of each other, throwing into question the theory that one is a direct cause of the other.

They observed axonal organelle transport in living tissue in real time, and in a way that enabled them to track the movement of individual mitochondria, using a novel imaging approach that involves transgenic labelling.

They were also able to observe transport of another kind of organelle, endosome-derived vesicles. Several different animal models of ALS were investigated, all of which are based on human mutations associated with the disease.

One of the study authors, Professor Thomas Misgeld from the Institute of Neuroscience at the Technische Universitaet Muenchen, comments on their findings: 'We do think these insights have implications for other studies of ALS, or even studies of other neuro-degenerative diseases.

What our experiments really say is that it is not easy to develop faithful models of neuro-degenerative diseases.

So it might be worth spending more effort to get better animal models, as this is the only way forward for mechanistic studies, while always checking them against human pathology or human-derived cellular models.

In the meantime, it is probably prudent to work with several of the available models in parallel. Moreover, in more general biological terms, our results also speak to the relationship between axonal transport disruptions and degeneration - which might not be as tight as we assumed. Here we have a lot more to understand.'

The iPSoALS project brings together researchers from France, Germany, Israel and Sweden with the aim of better understanding ALS disease mechanisms.

For more information, please visit: Technische Universitaet Muenchen (TUM)

Study finds child abuse and stunted brain development connection

A small team of researchers has found that various forms of child abuse can lead to stunted development in certain regions of the brain. The research carried out by Martin Teicher, Carl Anderson and Ann Polcari, all working in the Boston area, relied on questionnaires.

MRI brain scans were used to determine that certain parts of the hippocampus, all known to be sensitive to stress, were up to six percent smaller in adults who as children had been sexually, verbally or physically abused. The team has published their results in the Proceedings of the National Academy of Sciences.

The three areas affected: the cornu ammonis, the dentate gyrus and the subiculum, all located in the hippocampus, are known to be vulnerable to stress which leads to less cell development than would normally occur in the absence of abuse.

To test the relationship between brain development and childhood abuse, the research team enlisted a group of otherwise healthy adult volunteers: 73 men and 120 women, all between the ages of 18 and 25.

All were given questionnaires that delved into their childhood, specifically addressing issues of verbal, mental and physical abuse and other types of stresses such as the death of someone close to them or problems between parents.

All were also given brain scans using an MRI machine. The team then compared the answers given on the questionnaires to the possibly impacted areas in the hippocampus of each volunteer. In so doing, they found that the brain regions under study were 5.8 to 6.5 percent smaller than average for those that reported such childhood stresses.

The researchers suggest that smaller brain regions due to childhood stress may help explain the abnormally high levels of mental illness (depression, bi-polarism, anxiety, etc.) seen in adults who have endured abuse as children and why so many wind up with drug dependency problems.

They also noted that one of the regions impacted, the subiculum, serves as a relay, moving information in and out of the hippocampus, which can have a direct impact on dopamine production. Those with reduced volume have been found to have problems with drug addiction and in some cases develop schizophrenia.

The researchers believe that increased stress leads to higher levels of the hormone cortisol, which in turn can slow or even stop the growth of new neurons in the brain which can result in permanently stunting certain brain regions.

The researchers are hoping their results will further highlight the damage that is done when children are subjected to adverse living conditions, leading perhaps to earlier interventions and possibly a means for developing treatments that may aid in preventing the stunting of brain regions, thus helping to pave the way for a better quality of life for those that have been abused as children.

More information: Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum, PNAS, Published online before print February 13, 2012, doi: 10.1073/pnas.1115396109

Abstract
Childhood maltreatment or abuse is a major risk factor for mood, anxiety, substance abuse, psychotic, and personality disorders, and it is associated with reduced adult hippocampal volume, particularly on the left side.

Translational studies show that the key consequences of stress exposure on the hippocampus are suppression of neurogenesis in the dentate gyrus (DG) and dendritic remodeling in the cornu ammonis (CA), particularly the CA3 subfield.

The hypothesis that maltreatment is associated with volume reductions in 3-T MRI subfields containing the DG and CA3 was assessed and made practical by newly released automatic segmentation routines for FreeSurfer.

The sample consisted of 193 unmedicated right-handed subjects (38% male, 21.9 ± 2.1 y of age) selected from the community.

Maltreatment was quantified using the Adverse Childhood Experience study and Childhood Trauma Questionnaire scores.

The strongest associations between maltreatment and volume were observed in the left CA2-CA3 and CA4-DG subfields, and were not mediated by histories of major depression or posttraumatic stress disorder.

Comparing subjects with high vs. low scores on the Childhood Trauma Questionnaire and Adverse Childhood Experience study showed an average volume reduction of 6.3% and 6.1% in the left CA2-CA3 and CA4-DG, respectively.

Volume reductions in the CA1 and fimbria were 44% and 60% smaller than in the CA2-CA3. Interestingly, maltreatment was associated with 4.2% and 4.3% reductions in the left presubiculum and subiculum, respectively.

These findings support the hypothesis that exposure to early stress in humans, as in other animals, affects hippocampal subfield development.

"Chemo Brain" - Brain Scan Study Finds Evidence

Women who survive breast cancer after undergoing chemotherapy may also have to contend with impairments in attention, memory and planning skills, U.S. researchers said Monday.

They said women who had undergone chemotherapy for breast cancer had significantly less activity in parts of the brain responsible for executive functioning tasks compared with breast cancer patients who were not treated with chemotherapy.

Among those treated with chemotherapy, the study also found a strong correlation between women who complained they were having trouble with memory and thinking skills and actual deficits in these regions of the brain.

The study may help explain why many breast cancer patients complain of "chemo brain" -- a term used to describe foggy thinking and memory lapses following treatment with chemotherapy.

"This is a huge validation for these women who are telling their doctors 'something is wrong with me'," said Shelli Kesler of Stanford University School of Medicine in California, whose study appears in the Archives of Neurology.

Kesler said the conventional thinking is that chemotherapy drugs cannot cross a protective membrane called the blood-brain barrier that protects the brain from toxins.

And doctors have dismissed women's complaints of brain deficits after chemotherapy, chalking them up to exaggeration and stress related to the cancer.

"This shows that when a patient reports she's struggling with these types of problems, there's a good chance there has been a brain change," Kesler said.

Her study involved 25 breast cancer patients who had been treated with chemotherapy, 19 breast cancer patients who had surgery and other treatments, and 18 healthy women.

All were asked to perform a card-sorting task that involves problem-solving skills while their brain activity was monitored through functional magnetic resonance imaging or fMRI.

The women also completed questionnaires to assess their own cognitive abilities.

As in prior studies of cancer patients, the team saw significant reductions in activity in two parts of the prefrontal cortex, including one used for working memory, cognitive control and monitoring.

But they also found significantly reduced activation of an additional region of the prefrontal cortex linked with executive function -- the area of the brain needed for planning.

Women in the chemotherapy group were also found to make more errors on the card-sorting task and take longer to complete it than healthy women and cancer patients who were not treated with chemotherapy.

While a finding in 25 women seems small, Kesler said it is large for a brain scan study and points to a need to start identifying which women who undergo chemotherapy are most vulnerable to these types of deficits.

She said future studies should be done in which women are tested before they undergo chemotherapy to determine the impact of treatment on brain function.

Women are increasingly surviving their breast cancer, with breast cancer survivors comprising 22 percent of the nearly 12 million cancer survivors in the United States, according to the Centers for Disease Control and Prevention.

Breakthrough, nerve connections are regenerated after spinal cord injury

Researchers for the first time have induced robust regeneration of nerve connections that control voluntary movement after spinal cord injury, showing the potential for new therapeutic approaches to paralysis and other motor function impairments.

In a study on rodents, the UC Irvine, UC San Diego and Harvard University team achieved this breakthrough by turning back the developmental clock in a molecular pathway critical for the growth of corticospinal tract nerve connections.

They did this by deleting an enzyme called PTEN (a phosphatase and tensin homolog), which controls a molecular pathway called mTOR that is a key regulator of cell growth. PTEN activity is low early during development, allowing cell proliferation. PTEN then turns on when growth is completed, inhibiting mTOR and precluding any ability to regenerate.

Trying to find a way to restore early-developmental-stage cell growth in injured tissue, Zhigang He, a senior neurology researcher at Children’s Hospital Boston and Harvard Medical School, first showed in a 2008 study that blocking PTEN in mice enabled the regeneration of connections from the eye to the brain after optic nerve damage.

He then partnered with Oswald Steward of UCI and Binhai Zheng of UCSD to see if the same approach could promote nerve regeneration in injured spinal cord sites. Results of their study appear online in Nature Neuroscience.

“Until now, such robust nerve regeneration has been impossible in the spinal cord,” said Steward, anatomy & neurobiology professor and director of the Reeve-Irvine Research Center at UCI. “Paralysis and loss of function from spinal cord injury has been considered untreatable, but our discovery points the way toward a potential therapy to induce regeneration of nerve connections following spinal cord injury in people.”