Scientists have wrestled to understand why Huntington’s disease, which is caused by a single gene mutation, can produce such variable symptoms. An authoritative review by a group of leading experts summarises the progress relating cell loss in the striatum and cerebral cortex to symptom profile in Huntington’s disease, suggesting a possible direction for developing targeted therapies
Huntington’s disease (HD) is an inherited progressive neurological disorder for which there is presently no cure. It is caused by a dominant mutation in the HD gene leading to expression of mutant huntingtin (HTT) protein. Expression of mutant HTT causes subtle changes in cellular functions, which ultimately results in jerking, uncontrollable movements, progressive psychiatric difficulties, and loss of mental abilities.
Although it is caused by a single gene, there are major variations in the symptoms of HD. The pattern of symptoms shown by each individual during the course of the disease can differ considerably and present as varying degrees of movement disturbances, cognitive decline, and mood and behavioural changes. Disease duration is typically between ten and twenty years.
Recent investigations have focused on what the presence of the defective gene does to various structures in the brain and understanding the relationship between changes in the brain and the variability in symptom profiles in Huntington’s disease.
Analyses of post-mortem human HD tissue suggest that the variation in clinical symptoms in HD is strongly associated with the variable pattern of neurodegeneration in two major regions of the brain, the striatum and the cerebral cortex. The neurodegeneration of the striatum generally follows an ordered and topographical distribution, but comparison of post-mortem human HD tissue and in vivo neuro-imaging techniques reveal that the disease produces a striking bilateral atrophy of the striatum, which in these recent studies has been found to be highly variable.
‘What is especially interesting is that recent findings suggest that the pattern of striatal cell death shows regional differences between cases in the functionally and neurochemically distinct striosomal and matrix compartments of the striatum which correspond with symptom variation,’ says author Richard L.M. Faull, MB, ChB, PhD, DSc, Director of the Centre for Brain Research, University of Auckland, New Zealand.
‘Our own recent detailed quantitative study using stereological cell counting in the post-mortem human HD cortex has complemented and expanded the neuroimaging studies by providing a cortical cellular basis of symptom heterogeneity in HD,’ continues Dr Faull. ‘In particular, HD cases which were dominated by motor dysfunction showed a major total cell loss (28% loss) in the primary motor cortex but no cell loss in the limbic cingulate cortex, whereas cases where mood symptoms predominated showed a total of 54% neuronal loss in the limbic cingulate cortex but no cell loss in the motor cortex. This suggests that the variable neuronal loss and alterations in the circuitry of the primary motor cortex and anterior cingulate cortex associated with the variable compartmental pattern of cell degeneration in the striatum contribute to the differential impairments of motor and mood functions in HD.’
The authors note that there are still questions to be answered in the field of HD pathology, such as, how and when pathological neuronal loss occurs; whether the progressive loss of neurons in the striatum is the primary process or is consequential to cortical cell dysfunction; and how these changes relate to symptom profiles.
‘What is clear however is that the diverse symptoms of HD patients appear to relate to the heterogeneity of cell loss in both the striatum and cerebral cortex,’ the authors conclude. ‘While there is currently no cure, this contemporary evidence suggests that possible genetic therapies aimed at HD gene silencing should be directed towards intervention at both the cerebral cortex and the striatum in the human brain. This poses challenging problems requiring the application of gene silencing therapies to quite widespread regions of the forebrain which may be assisted via CSF delivery systems using gene suppression agents that cross the CSF/brain barrier.’ EurekAlert

Women who go into early menopause are twice as likely to suffer from coronary heart disease and stroke, new Johns Hopkins-led research suggests. The association holds true in patients from a variety of different ethnic backgrounds, the study found, and is independent of traditional cardiovascular disease risk factors, the scientists say.
‘If physicians know a patient has entered menopause before her 46th birthday, they can be extra vigilant in making recommendations and providing treatments to help prevent heart attacks and stroke,’ says Dhananjay Vaidya, Ph.D., an assistant professor in the Division of General Internal Medicine at the Johns Hopkins University School of Medicine, and leader of the study.
‘Our results suggest it is also important to avoid early menopause if at all possible.’
For example, he says, research has shown that smokers reach menopause, on average, two years earlier than non-smokers do, so quitting smoking may delay it.
Notably, the researchers said, their findings about the negative impact of early menopause were similar whether the women reached it naturally or surgically, via removal of reproductive organs, he says, though more research is needed. Often, Vaidya says, women who undergo hysterectomies have their ovaries removed, which precipitates rapid menopause. ‘Perhaps ovary removal can be avoided in more instances,’ he says, which might protect patients from heart disease and stroke by delaying the onset of menopause.
Cardiovascular disease is the number one killer of women in the United States, according to the Centers for Disease Control and Prevention.
Previous studies, Vaidya says, have shown a link between early menopause and heart disease and stroke among white women, but similar associations had not been demonstrated in more diverse populations. Hispanic and African-American women, he says, tend, on average, to go through menopause somewhat earlier than women of European descent.
Vaidya and his colleagues examined data from 2,509 women involved in the Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of men and women aged 45 to 84 years, all enrolled between 2000 and 2002 and followed until 2008. Of the women, 28 percent reported early menopause, or menopause that occurs before the age of 46. Vaidya emphasizes that although the risk of heart attack and stroke was doubled in these groups, the actual number of cardiac and stroke events recorded among study participants was small. Only 50 women in the study suffered heart events, while 37 had strokes.
Menopause is a process during which a woman’s reproductive and hormonal cycles slow, her periods (menstruation) eventually stop, ovaries stop releasing eggs for fertilization and produce less estrogen and progesterone, and the possibility of pregnancy ends. A natural event that takes place in most women between the ages of 45 and 55, menopausal onsets and rates are influenced by a combination of factors including heredity, smoking, diet and exercise.
Vaidya says some women are treated with hormone replacement therapy (HRT) to control menopause symptoms such as profuse sweating and hot flashes, but its widespread long-term use has been limited after large clinical trials showed that it increased the risk of heart attacks in some women. In Vaidya’s study, no role was detected for HRT in potentially modifying the impact of early menopause.
‘Cardiovascular disease processes and risks start very early in life, even though the heart attacks and strokes happen later in life,’ he says. ‘Unfortunately, young women are often not targeted for prevention, because cardiovascular disease is thought to be only attacking women in old age. What our study reaffirms is that managing risk factors when women are young will likely prevent or postpone heart attacks and strokes when they age.’ Johns Hopkins

The brains of teenage girls with behavioural disorders are different to those of their peers, UK researchers have found. The study of 40 girls revealed differences in the structure of areas linked to empathy and emotions. Previous work has found similar results in boys.
Experts suggest it may be possible to use scans to spot problems early, then offer social or psychological help. An estimated five in every 100 teenagers in the UK are classed as having a conduct disorder.
It is a psychiatric condition which leads people to behave in aggressive and anti-social ways, and which can increase the risk of mental and physical health problems in adulthood. Rates have risen significantly among adolescent girls in recent years, while levels in males have remained about the same.
In this study, funded by the Wellcome Trust and Medical Research Council, UK and Italian researchers conducted brain scans of 22 teenage girls who had conduct disorder and compared them with scans of 20 who did not.
They also checked the scans against others previously taken of teenage boys with conduct disorder. The team found part of the brain called the amygdala was smaller in the brains of male and female teenagers with conduct disorder than in their peers.
The amygdala is involved in picking up whether or not others feel afraid – and plays a role in people feeling fear themselves. Girls with conduct disorder also had less grey matter in an area of the brain called the insula – linked to emotion and understanding your own emotions.
However the same area was larger in boys with conduct disorder than healthy peers, and researchers are not yet sure why that is the case. The brains of those with the worst behaviour were most different from the norm.
Dr Andy Calder, from the MRC cognition and brain sciences unit, who worked on the study, said: ‘The origins of these changes could be due to being born with a particular brain dysfunction or it could be due to exposure to adverse environments such as a distressing experience early in life that could have an impact on the way the brain develops.’
Dr Graeme Fairchild, of the University of Cambridge who also worked on the study, said there were potential uses for the finding.
‘In the US, people are already using brain scans to argue diminished responsibility. I think we’re too early in our understanding to really do that, but it is happening.
‘It would also be possible to use scans where a person is at high risk of offending in the future.
‘More help could be given to the family and, in the same way that someone with language impairment receives extra help, help could be given to teach a person to understand emotions – and the emotions of others – better.’ BBC

Reduced production of myelin, a type of protective nerve fibre that is lost in diseases like multiple sclerosis, may also play a role in the development of mental illness, according to researchers at the Graduate School of Biomedical Sciences at Mount Sinai School of Medicine.
Myelin is an insulating material that wraps around the axon, the threadlike part of a nerve cell through which the cell sends impulses to other nerve cells. New myelin is produced by nerve cells called oligodendrocytes both during development and in adulthood to repair damage in the brain of people with diseases such as multiple sclerosis (MS).
A new study led by Patrizia Casaccia, MD, PhD, Professor of Neuroscience, Genetics and Genomics; and Neurology at Mount Sinai, determined that depriving mice of social contact reduced myelin production, demonstrating that the formation of new oligodendrocytes is affected by environmental changes. This research provides further support to earlier evidence of abnormal myelin in a wide range of psychiatric disorders, including autism, anxiety, schizophrenia and depression.
‘We knew that a lack of social interaction early in life impacted myelination in young animals but were unsure if these changes would persist in adulthood,’ said Dr. Casaccia, who is also Chief of the Center of Excellence for Myelin Repair at the Friedman Brain Institute at Mount Sinai School of Medicine. ‘Social isolation of adult mice causes behavioural and structural changes in neurons, but this is the first study to show that it causes myelin dysfunction as well.’
Dr. Casaccia’s team isolated adult mice to determine whether new myelin formation was compromised. After eight weeks, they found that the isolated mice showed signs of social withdrawal. Subsequent brain tissue analyses indicated that the socially isolated mice had lower-than-normal levels of myelin-forming oligodendrocytes in the prefrontal cortex, but not in other areas of the brain. The prefrontal cortex controls complex emotional and cognitive behaviour.
The researchers also found changes in chromatin, the packing material for DNA. As a result, the DNA from the new oligodendrocytes was unavailable for gene expression.
After observing the reduction in myelin production in socially-isolated mice, Dr. Casaccia’s team then re-introduced these mice into a social group. After four weeks, the social withdrawal symptoms and the gene expression changes were reversed.
‘Our study demonstrates that oligodendrocytes generate new myelin as a way to respond to environmental stimuli, and that myelin production is significantly reduced in social isolation,’ said Dr. Casaccia. ‘Abnormalities occur in people with psychiatric conditions characterised by social withdrawal. Other disorders characterised by myelin loss, such as MS, often are associated with depression. Our research emphasises the importance of maintaining a socially stimulating environment in these instances.’
At Mount Sinai, Dr. Casaccia’s laboratory is studying oligodendrocyte formation to identify therapeutic targets for myelin repair. They are screening newly-developed pharmacological compounds in brain cells from rodents and humans for their ability to form new myelin. EurekAlert

Researchers from Boston University School of Medicine (BUSM) and Veterans Affairs (VA) Boston Healthcare System have demonstrated that the effects on white matter brain volume from long-term alcohol abuse are different for men and women. The study also suggests that with abstinence, women recover their white matter brain volume more quickly than men.
The study was led by Susan Mosher Ruiz, PhD, postdoctoral research scientist in the Laboratory for Neuropsychology at BUSM and research scientist at the VA Boston Healthcare System, and Marlene Oscar Berman, PhD, professor of psychiatry, neurology and anatomy and neurobiology at BUSM and research career scientist at the VA Boston Healthcare System.
In previous research, alcoholism has been associated with white matter pathology. White matter forms the connections between neurons, allowing communication between different areas of the brain. While previous neuroimaging studies have shown an association between alcoholism and white matter reduction, this study furthered the understanding of this effect by examining gender differences and utilising a novel region-of-interest approach.
The research team employed structural magnetic resonance imaging (MRI) to determine the effects of drinking history and gender on white matter volume. They examined brain images from 42 abstinent alcoholic men and women who drank heavily for more than five years and 42 non-alcoholic control men and women. Looking at the correlation between years of alcohol abuse and white matter volume, the researchers found that a greater number of years of alcohol abuse was associated with smaller white matter volumes in the abstinent alcoholic men and women. In the men, the decrease was observed in the corpus callosum while in women, this effect was observed in cortical white matter regions.
‘We believe that many of the cognitive and emotional deficits observed in people with chronic alcoholism, including memory problems and flat affect, are related to disconnections that result from a loss of white matter,’ said Mosher Ruiz.
The researchers also examined if the average number of drinks consumed per day was associated with reduced white matter volume. They found that the number of daily drinks did have a strong impact on alcoholic women, and the volume loss was one and a half to two percent for each additional daily drink. Additionally, there was an eight to 10 percent increase in the size of the brain ventricles, which are areas filled with cerebrospinal fluid (CSF) that play a protective role in the brain. When white matter dies, CSF produced in the ventricles fills the ventricular space.
Recovery of white matter brain volume also was examined. They found that, in men, the corpus callosum recovered at a rate of one percent per year for each additional year of abstinence. For people who abstained less than a year, the researchers found evidence of increased white matter volume and decreased ventricular volume in women, but not at all in men. However, for people in recovery for more than a year, those signs of recovery disappeared in women and became apparent in men.
‘These findings preliminarily suggest that restoration and recovery of the brain’s white matter among alcoholics occurs later in abstinence for men than for women,’ said Mosher Ruiz. ‘We hope that additional research in this area can help lead to improved treatment methods that include educating both alcoholic men and women about the harmful effects of excessive drinking and the potential for recovery with sustained abstinence.’ Boston University Medical Center