TSC Research Article Summaries: Autism Spectrum Disorder/Behavior/Mental Health
Everolimus improves memory and learning while worsening depressive- and anxiety-like behavior in an animal model of depression
Author(s): Russo E, Leo A, Crupi R, Aiello R, Lippiello P, Spiga R, Chimirri S, Citraro R, Cuzzocrea S, Constanti A, De Sarro G.
Journal of Psychiatric Research
DOI: 10.1016/j.jpsychires.2016.03.008
What is the topic?
This article reports on a study of some of the mental impacts of the drug everolimus (also known by the brand name Afinitor). The researchers specifically looked at depression, anxiety, and cognitive ability (thinking, learning, remembering) in mice.
What did the researchers hope to learn?
They wanted to understand how the mTOR pathway could impact depression and other mental issues.
The mTOR pathway helps control cell growth in mammals. It is known to be affected by TSC, and drugs like everolimus (mTOR inhibitors) are given to TSC patients to try to reverse cell growth and shrink tumors. Some studies have shown that taking everolimus can also improve cognitive ability and have other neurological (mental) effects.
Scientists have questioned whether increased mTOR activity might help depression. One way to study this question was to test whether inhibiting (lowering) mTOR with everolimus might actually cause or worsen depression or anxiety. So these researchers set up a study to see how everolimus affected mice to try to understand how mTOR might affect cognitive abilities, anxiety, and depression.
Who was studied?
This study was performed on mice that did not have TSC, but were given a drug to cause chronic stress so that they would model depression and cognitive decline.
How was the study conducted?
Groups of mice were given different combinations of everolimus and the drug to cause stress/depression, then put through a series of tests to compare results. There were several behavioral and learning observations such as mazes and feeding tests, as well as chemical testing on brain tissue.
What did the researchers find?
They found that giving everolimus to mice on a long-term basis seemed to increase depression and anxiety. They also supported previous studies that found everolimus improved cognitive performance (such as thinking, learning, remembering). These researchers feel the testing provides evidence that changes to the mTOR pathway could impact depression and anxiety.
What were the limitations of the study?
The study was performed on mice, which do not have the same biology as humans and can’t be tested in the same way for depression, anxiety, learning, etc. The mice did not have TSC, so the results might not be the same for animals or humans who have TSC. The study can suggest further avenues of study to understand the causes of depression and anxiety (both with TSC and without) and how everolimus might affect those. But these data are not enough evidence to suggest any changes to the current treatment of humans with everolimus or other mTOR inhibitors (like rapamycin, sirolimus/Rapamune).
What do the results mean for you?
The results suggest that patients taking an mTOR inhibitor like everolimus on a long-term basis should be monitored for changes to their psychiatric health (such as depression and anxiety) and other neurological changes (such as differences in cognitive abilities). The authors feel this is especially important when the medications are given to younger patients whose brain is still developing.
This summary was written by Cristy Wade, MS, parent of child with TSC, clinical research coordinator, and peer reviewer for the Tuberous Sclerosis Complex Research Program (April 2016)
Early developmental trajectories associated with ASD in infants with tuberous sclerosis complex
Authors: Shafali Spurling Jeste, MD, Joyce Y. Wu, MD, Damla Senturk, PhD, Kandice Varcin, PhD, Jordan Ko, Brigid McCarthy, Christina Shimizu, Kira Dies, ScM, CGC, Vanessa Vogel-Farley, Mustafa Sahin, MD, PhD and Charles A. Nelson III, PhD
Neurology July 8, 2014 vol. 83 no. 2 160-168
DOI: 10.1212/WNL.0000000000000568
What is the topic?
Children with tuberous sclerosis complex (TSC) are at high risk of developing autism spectrum disorder (ASD). Research estimates that 25% to 60% of people with TSC will have ASD, compared to 1% to 2% of the general population. In this study, researchers collected medical information and gave developmental tests to babies with TSC to look for early signs of ASD. The authors hope that the information will help identify infants with early signs of ASD. This information could lead to earlier therapies for the special needs of babies with TSC and ASD.
What did the researchers hope to learn?
The researchers wanted to learn if there are early predictors of ASD in infants, by finding the specific types of delays that are first seen in babies who are later diagnosed with ASD. They collected clinical data about seizures, medications, operations, and other medical issues to see if any of this information could help predict ASD. They also wanted to find out if there are features of ASD unique to children who have both TSC/ASD, and they wanted to gather more information on the developmental path of TSC infants.
The researchers wanted to learn if there are early predictors of ASD in infants, by finding the specific types of delays that are first seen in babies who are later diagnosed with ASD. They collected clinical data about seizures, medications, operations, and other medical issues to see if any of this information could help predict ASD. They also wanted to find out if there are features of ASD unique to children who have both TSC/ASD, and they wanted to gather more information on the developmental path of TSC infants.
Who was studied?
The study enrolled 40 infants with TSC, as young as 3 months old. They were followed until 36 months of age. Typical (non-TSC) children of the same ages were also studied as controls.
How was the study conducted?
The babies were seen at 3, 6, 9, 12, 18, 24, and 36 months of age. Clinical data about seizures, medications, operations, and other medical information were collected. They were given developmental testing, social-communication assessments, and at 18 and 36 months they were evaluated for ASD. Examples of areas tested: gross motor, visual reception, fine motor, receptive language, expressive language, visual tracking, disengagement of attention, orients to name, anticipatory responses, social babbling, and eye contact.
What did the researchers find?
All but 4 of the TSC children had seizures, and these 4 did not have ASD. The children with ASD had more severe epilepsy (seizures started earlier, more medication needed). The authors did not find evidence that clinical findings alone could predict ASD, however epilepsy severity did seem to impair development.
On average, infants with TSC had developmental delays in all age groups, compared to infants in the control group. No TSC infants were recruited early enough for 3-month assessments, but at 6 months the TSC infants showed delays in nonverbal IQ (development not associated with language), particularly related to visual abilities. By 9 months, infants with TSC tested as delayed in most developmental areas.
Over half of the infants with TSC were diagnosed with ASD (22 of 40). Many of the TSC children who were not diagnosed with ASD still had some social communication deficits. By 12 months of age, the babies with ASD showed significantly greater cognitive (mental) delays than the non-ASD babies. From 12 to 36 months the children with ASD showed a significant decline in nonverbal IQ. Decline does not mean regression or loss of skills, but rather that the rate that they gain skills falls farther and farther behind non-ASD children of the same age.
Reduced nonverbal ability, first seen as delayed fine motor and visual reception at 6 months of age, may represent a TSC-specific pathway to ASD. In other words, young babies who have impaired ability to process things they see (tracking things with their eyes, eye contact, shifting attention, etc) may then have trouble learning nonverbal social communication. This type of ASD development may be unique to children with TSC.
What were the limitations of the study?
The study did not contain a large number of subjects, so it is difficult to draw firm conclusions without more data. Children up to 24 months of age could join the study, so not all of the children had testing done as infants. There were no 3-month-old infants with TSC in the study, and few 6 month olds. More data are needed from these younger infants when looking for the earliest signs of ASD. Since children came in at different ages, not all of them could have their development tracked throughout the study and compared at each age. Data were not collected on which of the children had already had therapy interventions. Such interventions could have had a slight effect on the results.
What do the results mean for you?
Studies such as this one could lead to earlier screening of infants with TSC, particularly those with epilepsy, so that deficits can be identified and interventions offered as soon as possible. The specific delays found in this study might help direct which tests to use, and identify the most effective therapies for TSC babies (such as targeting nonverbal communication). The authors say that analyzing the rate of progress in infant development with a series of screenings at different ages might serve as an early predictor of ASD in infants with TSC. They stress the need for research that studies early intervention for these high-risk infants
The Stress-Induced Atf3-Gelsolin Cascade Underlies Dendritic Spine Deficits in Neuronal Models of Tuberous Sclerosis Complex
Author(s): Nie D, Chen Z, Ebrahimi-Fakhari D, Di Nardo A, Julich K, Robson VK, Cheng YC, Woolf CJ, Heiman M, Sahin M
DOI: 10.1523/JNEUROSCI.4796-14.2015.
What is the topic?
Tuberous sclerosis complex (TSC) is caused by deficits in genes TSC1 and /or TSC2. These genes act together and inhibit the activation of an enzyme called mTOR. A deficit in one of the genes causes loss of regulation of mTOR leading to enlarged cells seen in TSC and neurobiological abnormalities like epilepsy and autism. The focus of this study was to find out specific genes involved when there is a deficit of TSC1 and/ or TSC2 since not a lot is known about this.
What did the researchers hope to learn?
By learning what gene are regulated when there is a dysregulation of mTOR, the researchers hoped to eventually be able to find novel therapy for TSC.
Who was studied?
The scientists used experimental mice for this study. Neuronal cultures from the hippocampus from normal mice and those that were deficient in TSC2 were compared in their genetic profile.
How was the study conducted?
Instead of using conventional gene profiling, the scientists used a procedure known as Translating Ribosomal Affinity Purification (TRAP) – this method provides a clearer resolution than gene profiling.
What did the researchers find?
By using the TRAP technology in cultures of mice that were deficient in TSC2, the researchers found several important genes that were increased and others were decreased in neurons that were deficient in TSC2 gene. They also found a novel signaling pathway called Atf3-gelsolin cascade that was abnormal, and linked this to the deficits seen in TSC in dendritic spines. These spines are the area on the neuron where neurotransmission takes place.
What were the limitations of the study?
The study was done in cell cultures and is outstanding work to start teasing apart genetic profiles in TSC. However, more work in whole rodents and in human tissue would be necessary in the future.
What do the results mean for you?
This study puts forward a novel signaling pathway to the deficits in dendritic spines and gives a possible explanation for autism and epilepsy observed in TSC. With the help of more research, targeted therapies that reverse these deficits could be found.
This summary was written by Sloka Iyengar, PhD, epilepsy researcher and science writer (February 2016).