Message Board

Structural MRI detects progressive regional brain atrophy and neuroprotective effects in N171-82Q Huntington's disease mouse model


'Studies suggest that clinical trial of a putative neuroprotective agent could begin as early as 15 years prior to estimated motor diagnosis in a cohort of persons at risk for, but not meeting clinical motor diagnostic criteria for HD, and that neuroimaging might be among the best predictors of early diagnosis'

1. What is Sertraline, and what was it?s role in the study?

2. Where did they find the most significant changes in brain volume? Does this make sense, given the typical symptoms of HD? Please explain.

3. The figures presented do a good job of visualizing the changes detected throughout the study ? which was the most striking for you?

4. The study also detected a loss of white matter volume early on in the disease progression; several theories on this pathology exist, but further testing is needed. Offer some ideas for an experiment to further explore this aspect of HD (Ex. imaging tools, histology, behavioral, neurotransmitter levels ect.)

Sertraline (Brand name: Zoloft) is a popular antidepressant often prescribed to people experiencing depression and anxiety disorders. Aside from being an SSRI, they have been shown to have neuroprotective effects by stimulating BDNF that extend the lifespan of dying neurons. The latter was the main role that sertraline played in the experiment. The researchers wanted to see if the administration of sertraline could attenuate nerve degeneration and prolong the motor function as well as lifespan of the N171-82Q mice model. On a side-note, I kind of question why they only used sertraline as their source of generating BDNF. SSRIs are known for impacting the serotonergic neurons, which may inadvertently affect the progression of HD in pathways other than NGF of striatal DA neurons. I know that a lot of previous research have used sertraline as a standard, but maybe it would have been more convincing if they used other types of neuroprotective agents such as tocotrienol or berberine in congruence with sertraline and compared the results.

The researchers mentioned that the most significant changes in brain volumes are regions of the hippocampus, striatum, neocortex, and the whole brain. This mostly make sense because the striatum connects the cortex to the basal ganglia and it?s atrophy is known to cause Huntington?s disease and it?s symptoms of choreas. However, I?m not really sure how the hippocampus plays into this. This could perhaps be associated with cognitive dysfunctions we see in later stages of HD.

The figures were presented clearly, and it?s surprising to see the drastic amount of decrease in the brain regions. I find that the amount of recovery due to treatment with sertraline very shocking. It makes me wonder if a more effective nerve growth factor could be more effective in preventing the death of neurons in those regions of the brain. At the same time, I wonder why the researchers didn?t do the same experiments on the R6/2 model of mice, we know that this model is popularly used because it phenotypically mimics the HD disease, however, having more evidence is always good since the pathophysiology of HD in mice and humans will invariably be slightly different.

To measure white matter differences, an effective method would be to use diffusion weighted MRI, which uses the proton behavior of water in a magnetic field to generate an image of soft tissue such as white matter. This method is in use for stroke patients to see the damage to their white matter after an attack, this should also be useful to detect the neuronal degeneration we see in HD model mice.

Sertraline is a selective serotonin reuptake inhibitor (SSRI) sold under the brand name Zoloft that is used to treat depression, anxiety disorders, OCD, and other mood and behavior disorders. Aside from these functions, it has also been shown (by the same group of researchers) to act as a neuroprotective agent by promoting production of brain-derived neurotrophic factor (BDNF), increasing neurogenesis, and slowing down continued brain atrophy. For these reasons, sertraline was used in this study to examine whether brain degeneration due to Huntington?s Disease (HD) in mouse models could be attenuated and, subsequently, their motor function preserved and their lives lengthened. Nick makes a good point here, though, about how serotonin could affect systems in the brain other than the one being studied that could contribute to the results being observed by the researchers. I feel like simply using BDNF itself could have avoided this potential problem since it?s effects in the brain are fairly well known and could be accounted for, but Nick?s suggestion of other neuroprotective agents is also a good one.
The most significant changes in brain volume were observed in the neocortex and the striatum, though volume loss was also observed in the hippocampus, the thalamus, the hypothalamus, and across the entire brain in general. There was also white matter lost in the corpus callosum, an interesting observation and one that I would like to see more research on. As far as whether volume loss in these areas makes sense when typical HD symptomology is considered, Nick makes the good point that the basal ganglia are closely interconnected with the striatum and that atrophy here is associated with motor deficits such as those observed in Huntington?s. My major sticking point, though, is that there were never any significant changes in volume associated with the cerebellum in any of the mice studied, and the cerebellum is involved in planning and coordination of voluntary movements, so I would have expected this to have shown some degeneration in the HD mice.
The most striking image for me is Fig.1a on page 3. It shows the differences in severity of degeneration between mice with HD and wildtype healthy mice. The areas shown in dark blue show the greatest severity of atrophy in HD mice as compared to wildtype mice of the same age, and I think these images really highlight the widespread degeneration seen in HD and give a pretty clear idea of just how all-encompassing the disease process truly is. As it continues, it just gets worse and worse, more and more neurons atrophying and dying, creating the symptoms we associate with HD.
To further investigate the white matter loss seen in these mouse models of HD, I would like to see MRI imaging done showing the degree of connection still existing between the two hemispheres via the corpus callosum (eg. employ a view/technique that would enable the researcher to see the extent to which connection has been lost). I also think it would be interesting to use human research subjects with HD to examine how communication between the hemispheres is altered in HD. Tests such as those famously used on split-brain patients could be employed, possibly enabling researchers to track disease progress by tracking whether patients can still report the identity of a word or image seen only in their left visual field. If they were to have a more difficult time reporting the identity of the word over the course of observation, it may indicate progressive white matter loss in the corpus callosum.

I think the study presented a very good case for the use of structural MRI as a means of assessing a treatments efficacy in treating the Huntington?s disease model mice. The treatment they chose to use was Sertraline, a commonly prescribed medication for a number of disorders such as depression and various anxiety disorders due to its action as an SSRI. In addition to its role as an SSRI, Sertraline has been shown to have neuroprotective effects via promotion of the neurotrophin BDNF. In fact, there is some speculation that it is Sertraline?s neuroprotective effect that underlies its efficacy of treatment, particular in the neurogenesis it can encourage in the hippocampus. I also think Nick made an excellent point in that the Sertraline could have been exerting other effects aside from just promoting BDNF, particularly in the serotonergic pathway (though despite being an SSRI, Sertraline is not entirely selective, inhibiting some dopamine reuptake as well as acting as an agonist or antagonist on several different receptors).

HD eventually causes widespread neural degeneration in various structures like the striatum, cerebral cortex, and hippocampus, with the striatum typically showing both the earliest and most severe degeneration. This is consistent with HD?s symptoms, given that it is primarily characterized by uncontrolled, jerky movements which would be normally controlled via the striatum and the rest of the basal ganglia. As the neural degeneration becomes more widespread, so to do the symptoms, with various additional motor and cognitive deficits occurring as the damage progresses. The researchers found the most drastic changes in brain volume in the striatum, neocortex, and hippocampus, which seems to accurately model the structural changes observed in HD. I found figure 1 to most clearly present this data, and it was astonishing just how different the amount of atrophy was in the wild type versus the HD model mouse.

The paper offered two existing theories as to the white matter loss observed in HD. The first theory presented is that the huntingtin protein?s role in myelination ultimately leads to the neurons to be over stimulated to the point of excitotoxcicity. One way that this could potentially be examined would be measuring levels of excitatory neurotransmitters (e.g. glutamate) in the regions where white matter loss was observed in order to see if excitotoxicity is playing a role. The other theory mentioned was that the lost white matter may be due to differences in development rather than active neural degeneration. The researchers in the study found that the white matter loss is less progressive than the gray, lending some credence to this theory. This second theory could be more thoroughly explored by using the imaging described in this study, as well as other chemical markers like various trophic factors at earlier times in the mouse?s development to determine when exactly this white matter loss occurs or if it is a result of abnormal development.

Sertraline is a selective serotonin reuptake inhibitor (SSRI) commonly used to treat depression. In previous studies Sertraline has proved to increase neurogenesis and increase neurotrophic factors in Huntington?s patients, lessening observed neural atrophy. Notably, the serotonin reuptake of the striatum can be decreased 80-90% following four weeks of treatment with this drug (Meyer et al., Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses. American Journal of Psychiatry, 2004). Hence, Sertraline?s strong effect on the striatum, an area known to undergo atrophy in association with Huntington?s Disease, is another reason why Cheng et al. honed in on this particular neuroprotective drug.

In the treatment of depression and other anxiety disorders the effects of SSRIs are not immediate, implying that it is not the mere presence of serotonin that prompts improvement, but rather the neural response/adaptation to continued serotonin exposure that incites improvement (as discussed in class). Naturally, this leads me to question if the same holds true with this study?s use of Sertraline as a pre-symptomatic Huntington?s treatment. Fig. 3 indicates that at week ten both the sertraline-treated HD mice and no-treated HD mice experienced statistically the same amount of atrophy in the hippocampus, and neocortex still. Indicating that the SSRI treatment may once again be causing improvement based on neural adaptation to the serotonin. If this is in fact the case, frankly, we should really increase our efforts to figure out the exact mechanism of actions being use.

Cheng et al. found the most significant changes in brain volume in the neocortex, striatum, hippocampus, hypothalamus, thalamus, and amygdala. The striatum is highly involved in initiating voluntary movements, and the neocortex plans out these movements. Hence it makes sense that their declining volume would result in jerky, involuntary muscle contractions. Dementia, and decline of cognitive abilities associated with Huntington?s could similarly be traced back to the neocortex?s atrophy. The hippocampal decline could account for the memory decits of Huntington?s. Moreover, the mood alterations such as irritability, anxiety, depression, and apathy seen with this disease may be a product of the decreased functionality of the smaller hypothalamus, amygdala, and hippocampus. The thalamus, major relay center of all information in the brain could have a negative effect on any of these systems in response to HD.

I actually loved all of the line graphs in this piece, particularly those in Fig 1 and 3. They were incredibly simple yet showed you all the relationship information you wanted (wild type vs N171-82Q, wild type vs sertraline-treated HD mice vs non-treated HD mice). Trends were unbelievably easily to see and significance (p<.05) was clearly marked (*). Honestly, that?s all I want out of a figure, to be able glance at it and immediately know the main outcome of the experiment. Simplicity isn?t always a sign of laziness; here it?s a clear sign of just being efficient. The additional structural MRIs were also great to visualize exactly where brain volume was declining and by how much. It left nothing the imagination.

The white matter loss detected by Cheng et al. is believed to ultimately be either a result of abnormalities in white matter production or a result of mutant huntintin causing functioning myelinated neurons to undergo demylination leading to the overstimulation of the neuron via feedback. To determine which of these is the case, we ?merely? need to determine whether white matter is being produced in the first place. Thus I propose a study in which immunocytochemistry is used on N171-82Q mice and wild type mice to measure markers of the myelination process in the known areas of HD atrophy-- the striatum, neocortex, hippocampus, hypothalamus, etc. These myelination markers could be known transcription factors, proteins, and even transcripts of the neuregulin gene itself (the neuregulin gene stimulates myelination). By comparing the immunocytochemistry of the wild type and the HD mice at several different ages, we should be able to tell if the amount of the myelination process is lowered in Huntington?s patients, i.e. we should be able to tell if the white matter is being made and then destroyed or merely made in smaller amounts.

As stated, Sertraline is an SSRI used to treat depression and anxiety disorders. It also has the effect of promoting Brain Derived Neurotrophic Factor. BDNF helps to support neuron survival and encourages the growth of new neurons and synapses. This was its primary goal in the study, to promote neuron survival in a disease related cell death. By increasing cell life, the researchers hoped to preserve motor function in the test subjects. Though, one factor that they could not examine in the mice would be cognitive decline associated with HD. Would BDNF increases help protect against cognitive loss and dementia? I would assume so, as the researches took full MRI scans for comparison. This also exalts the merit of the MRI as a diagnostic tool.

Significant loss was observed in the hippocampus, neocortex and striatum; though significant volume loss was observed all over. This makes perfect sense since the Striatum is involved in planning and modulation of movement pathways. As nick stated, it integrates the basil ganglia and the cortex. Degradation in the neocortex is indicative loss of motor control and spatial reasoning among other things. I also agree with Nick that the Hippocampal degradation is indicative of dementia and cognitive decline. As a major structure of memory, degradation in this region would impair memory and spatial navigation.

I find figure 4 to be very interesting. Specifically, section A shows that untreated mice have a steady decline, indicating that the disease progresses differently in each untreated mouse. The mice that received the treatment lived longer, but all seem to drop off around the same week. This suggests that the disease will overtake treatment quickly. After all, the genetic flaws are being promoted; there is just a chemical present that helps keep the cells alive. When the cells die naturally, they all seem to go down. Secondly, the dispersion of data points in D and the lack there of in C makes me wonder. Decline in the striatum is almost linear, while the neocortex declines are all over the place. This fits with HD as the NC formulates the movement while other brain regions initiate and fine tune. The decline in the striatum seems to be what interrupts function.

Regarding an experiment to look further into the decline of white matter in HD patients, perhaps looking at the glia that produces the myelin would be informative, namely oligodendrocytes. We see neuronal volume decline all over, but neurons are not the whole brain. Are the Glia also seeing defective/dying cells? Likewise, is there something that is inhibiting them from producing more myelin for the excitotoxic cells? To observe this, perhaps flag a chemical that is used in the cellular metabolism of the oligodendrocytes and use an MRI to observe the travel of the tag.

Sertraline is a SSRI (selective serotonin reuptake inhibitor) that is typically used to treat depression. In this experiment, sertraline was used as a positive drug to determine the sensitivity of structural MRI measures. This SSRI was said to have neuroprotective properties that increased BDNF and neurogenesis and slowed the degeneration of neurons in patients with Huntington's Disease.

The most significant changes in the brain, as demonstrated in the experiment are "progressive brain atrophy in the striatum and neocortex as well as in whole brain;" The striatum and neocortex are related in motor coordination. These areas contribute to the symptom of "abnormal involuntary writhing movements" (Wikipedia) called chorea. Since the overall brain shows atrophy, it also makes sense that HD patients experience cognitive decline and dementia. Since neurons in these areas are dying, there is memory loss and the symptoms of Huntington's Disease are then displayed.

The graphs and visual features in the paper are very helpful in making the results clear. I particularly found figure 3 the most helpful in demonstrating these results. It showed that sertraline really did make a difference in slowing down the degeneration of neurons throughout the brain as time progressed. In chart E of figure 3, describing the full brain volume changes, it is clear that the whole brain is affected by these SSRIs and that they may truly be useful as a drug in the future.

As Drew said, this paper states that differences in white matter may be a developmental issue as opposed to the degeneration of neurons throughout the brain. This can be looked into by looking at the amount of white matter in developing mice, some that end up developing HD and others that don't. Then they can also determine the progression of degeneration of white matter in these mice before symptoms of HD develop. This would first show the amount of development in the brain pre-Huntington's disease. And again, they could also measure the trophic factors between mice that would develop HD. The different levels of trophic factors will help determine if white matter is lost because of neuronal factors of if it truly is a developmental problem

Sertraline is an antidepressant drug that acts as a selective serotonin reuptake inhibitor. the reason it was used in this experiment is because it had been shown to increase BDNF, a neurotrophic factor that promotes neuron survival and promotes new synapse formation. Sertaline had been also shown to attenuate atrophy in HD mice. this was used as a positive drug to see if the drug had any possible beneficial effects on the huntington model neurodegeneration in rats. I also think Nick brought up a good point about using other neuroprotective agents besides sertraline in an effort to see if the alteration of serotonin is having a positive or negative effect. Is it possible to inject BDNF directly into the brain, or would that have horrible side effects?

the three areas of degeneration were the neocortex, the hippocampus and the striatum. This , as other people have said seems to be consistent with the symptoms of huntington?s disease. What I found interesting was that the neocortex seemed to decrease in volume to a higher extent that the striatum and hippocampus. The cortex lossed over 25% of volume while the striatum and hippocampus lossed less than 20% based on figure 1. I would assume that this is mainly made up of corticostriatal connections, but could provide insight into the subtle psychological and behavioural changes that are present but rarely identified in people developing huntington?s. Figure 1 is the most striking because it shows not only a numerical extent in terms of volume loss, but an astounding cross-region image of volume loss through the MRI. It was also really cool how the image shows the progression of neurodegeneration over the course of the experiment.

In terms of further studies, the use of DTI to identify white matter abnormalities and disease progression should be implemented. Also, it would be interesting to see if the SSRI/other neuroprotective agents acts solely on white matter or also on grey matter. I think conditional knockout of huntington, or conditional promoting of de-myelinating factors would be a good avenue for research into whether or not demyelination causes excitotoxicity. Also, relating back to the article we talked about for the BBB breakdown, we know that glutamate excitotoxictity may be involved in schizophrenia, perhaps observing glutamate levels in the developing HD brain white matter could provide answers.