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

A fast, accurate diagnosis is essential for efficient treatment, especially in patients with complications. The Rapid Influenza Diagnostic Tests (RIDTs) for influenza detection have been developed to subtype the influenza virus, but rapid testing is no good unless it is accompanied by high levels of selectivity, specificity and accuracy. Over the course of a year, this study obtained over 1,000 nasal aspirate samples from patients with symptoms of influenza-like illness and evaluated by 2 types of RIDTs, Standard Diagnosis (SD) and QuickVue (QV) Rapid tests followed by real-time RT-PCR. The results showed that the SD rapid test appeared to be more sensitive than the QV test during high season activity, whereas the QV test was more sensitive during the period of low influenza virus activity. The conclusion was that due to persistent genetic drift of the influenza virus, the available RIDTs should be re-evaluated each year.

^{Makkoch J. et al. Clin. Lab. 2012; 58(9-10): 905-910. DOI: 10.7754/Clin.Lab.2011.111003}

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Originally, the label "borderline personality disorder" was applied to patients who were thought to represent a middle ground between patients with neurotic and psychotic disorders. Increasingly, though, this area of research has focused on the heightened emotional reactivity observed in patients carrying this diagnosis, as well as the high rates with which they also meet diagnostic criteria for posttraumatic stress disorder and mood disorders.

New research by Dr. Anthony Ruocco at the University of Toronto and his colleagues paints perhaps the sharpest picture we have so far of the patterns of brain activity which may underlie the intense and unstable emotional experiences associated with this diagnosis.

In their report, the investigators describe two critical brain underpinnings of emotion dysregulation in borderline personality disorder: heightened activity in brain circuits involved in the experience of negative emotions and reduced activation of brain circuits that normally suppress negative emotion once it is generated.

To accomplish this, they undertook a meta-analysis of previously published neuroimaging studies to examine dysfunctions underlying negative emotion processing in borderline personality disorder. A thorough literature search identified 11 relevant studies from which they pooled the results to further analyse, providing data on 154 patients with borderline personality disorder and 150 healthy control subjects.

Ruocco commented, "We found compelling evidence pointing to two interconnected neural systems which may subserve symptoms of emotion dysregulation in this disorder: the first, centred on specific limbic structures, which may reflect a heightened subjective perception of the intensity of negative emotions, and the second, comprised primarily of frontal brain regions, which may be inadequately recruited to appropriately regulate emotions."

Importantly, reduced activity in a frontal area of the brain, called the subgenual anterior cingulate, may be unique to borderline personality disorder and could serve to differentiate it from other related conditions, such as recurrent major depression.

"This new report adds to the impression that people with borderline personality disorder are ‘set-up’ by their brains to have stormy emotional lives, although not necessarily unhappy or unproductive lives," commented Dr. John Krystal, Editor of Biological Psychiatry.

"Given that many of the most effective psychotherapies for borderline personality disorder work to improve emotion regulation skills, these findings could suggest that dysfunctions in critical frontal ‘control’ centres might be normalised after successful treatment," concluded Ruocco.EurekAlert

A protein known as Sp2 is key to the proper creation of neurons from stem cells, according to researchers at North Carolina State University. Understanding how this protein works could enable scientists to “program” stem cells for regeneration, which has implications for neural therapies.

Troy Ghashghaei and Jon Horowitz, both faculty in NC State’s Department of Molecular Biomedical Sciences and researchers in the Center for Comparative Medicine and Translational Research, wanted to know more about the function of Sp2, a cell cycle regulator that helps control how cells divide. Previous research from Horowitz had shown that too much Sp2 in skin-producing stem cells resulted in tumours in experimental mice. Excessive amounts of Sp2 prevented the stem cells from creating normal cell “offspring,” or skin cells. Instead, the stem cells just kept producing more stem cells, which led to tumour formation.

“We believe that Sp2 must play a fundamental role in the lives of normal stem cells,” Horowitz says. “Trouble ensues when the mechanisms that regulate its activity are overwhelmed due to its excess abundance.”

Ghashghaei and his team – led by doctoral candidate Huixuan Liang – took the opposite approach. Using genetic tools, they got rid of Sp2 in certain neural stem cells in mice, specifically those that produce the major neurons of the brain’s cerebral cortex. They found that a lack of Sp2 disrupted normal cell formation in these stem cells, and one important result was similar to Horowitz’s: the abnormal stem cells were unable to produce normal cell “offspring,” or neurons. Instead, the abnormal stem cells just created copies of themselves, which were also abnormal.

“It’s interesting that both an overabundance of this protein and a total lack of it result in similar disruptions in how stem cells divide,” Ghashghaei says. “So while this work confirms that Sp2 is absolutely necessary for stem cell function, a lot of questions still remain about what exactly it is regulating, and whether it is present in all stem cells or just a few. We also need to find out if Sp2 deletion or overabundance can produce brain tumours in our mice as in the skin.

“Finally, we are very interested in understanding how Sp2 regulates a very important decision a stem cell has to make: whether to produce more of itself or to produce offspring that can become neurons or skin cells,” Ghashghaei adds. “We hope to address those questions in our future research, because these cellular mechanisms have implications for cancer research, neurodevelopmental diseases and regenerative medicine.”North Carolina State University