ARTICLE IN BRIEF
Lithium seemed to improve memory and cognition in an animal model of Down syndrome. But several commentators noted that although the results are encouraging, safety concerns with lithium need to be addressed before applying to human trials of Down syndrome.
Lithium, a compound used for decades to treat bipolar disorder, restored neurogenesis in the hippocampus of a mouse model of Down syndrome, and produced improvements in measures of contextual learning, spatial memory, and object discrimination, according to a Jan. 2 paper in the Journal of Clinical Investigation.
After one month of treatment, the Ts65Dn mice that received lithium had approximately 3,500 cells in the hippocampus expressing doublecortin (DCX), which is present on the surface of newly formed neurons, while untreated mice had about 1,500. (Ts65Dn mice have a mutation on chromosome 16 similar to the human mutation on chromosome 21 that causes Down syndrome.)
The researchers contend that lithium increases the number of new neurons in mice by activating the beta-catenin/Wnt signaling pathway that has been implicated in neuronal development. Lithium increased the activation of this signaling pathway by 50 percent.
“We're very excited by this,” said lead author Laura Gasparini, PhD, team leader in the department of neuroscience and brain technologies of the Italian Institute of Technology in Genoa, Italy. “It's known that neurogenesis is sensitive to environmental stimuli and chemicals. So we thought, if neurogenesis is impaired in Down syndrome, can we find a way to stimulate neurogenesis, and would that improve cognition? The answer is yes.”
The authors note that impaired neurogenesis has been found in a variety of models relevant to neuropsychiatric diseases, including major depression, schizophrenia, and Alzheimer's, and in neurodevelopmental disorders including fragile X syndrome as well as Down syndrome. They believe that stimulating neurogenesis may represent a form of treatment especially for neurodevelopmental disorders caused by genetic mutations, such as Down syndrome.
Lithium, however, may not be the ideal treatment. “In principle, it's feasible, but we need to be careful with it,” Dr. Gasparini said. “Lithium is well tolerated in mice, but in humans it can have side effects. Still, it might be useful in proof-of-concept studies.”
EFFECTS OF LITHIUM
Declan G. Murphy, MD, MBBS, professor of psychiatry and brain maturation, and head of department of forensic and neurodevelopmental sciences at King's College in London, agreed that the animal study results were encouraging, but also concurred that that lithium could be problematic for use in humans.
[Dr. Murphy is currently analyzing data from a trial just completed in England to determine whether lithium can reverse the brain increase of a chemical called myo-inositol, which is elevated in the Down syndrome brain and related to the degree of intellectual disability.]
“You'd need a very significant benefit to outweigh lithium's side effects,” Dr. Murphy said, noting that lithium has been shown to have a negative effect on the heart, the thyroid, and white blood cells. This is troubling, he said, because people with Down syndrome are prone to cardiac abnormalities, hypothyroidism, and aberrations in their immune responses. Some evidence suggests that lithium can affect cognitive function in some people, causing confusion, and difficulties with attention and concentration, at least in the short term. Also, prolonged use of lithium has been linked to kidney damage.
More likely, the mechanism driving the effectiveness of lithium will point the way to better treatments with fewer side effects, Dr. Murphy said.
DR. LAURA GASPARINI ...Image Tools
Ira T. Lott, MD, professor emeritus of child neurology at University of California, Irvine, agrees that safety concerns would be an issue in human trials, but offered this caveat: “My thought is that if lithium is further validated for human clinical trials, individuals with Down syndrome would not automatically be excluded; but endocrine, renal, and other potential side effects would need to be studied through safety and tolerability protocols,” he said. Dr. Lott recently received a five-year, $2.4 million National Institutes of Health grant to seek ways of preventing or delaying the onset of dementia in people with Down syndrome.
Huntington Potter, PhD, who, in 1991, became the first to propose that Down syndrome and Alzheimer's are essentially the same disease, praised the paper by Dr. Gasparini and her colleagues for revealing mechanisms implicated in both diseases.
“Breakthrough is an overused term, but this is a result that will lead us in a new direction,” said Dr. Potter, director of the Alzheimer's Disease Program and a member of the Linda Crnic Institute for Down Syndrome at the University of Colorado School of Medicine. “This paper brings together beautifully many aspects of Alzheimer's disease and Down syndrome, which we now believe are two sides of same coin. I think it's a potentially very important paper because we don't have much in the way of treatment for cognitive problems in Down syndrome or Alzheimer's disease, so the fact that a very well tolerated and well understood drug like lithium can have benefits in a mouse model is very encouraging.”
Dr. Potter was particularly excited about the implications for Alzheimer's disease.
“The amyloid-beta [Abeta] peptide, which is overexpressed in Down syndrome as well as in Alzheimer's, inhibits the cell cycle by preventing cells from distributing their chromosomes correctly,” he said. “When they divide the daughter cells develop the wrong number of chromosomes including the very common development of trisomy 21 cells. This is true for every cell we have looked at, including neuronal precursor cells. The end result of that is that if you look at the brains and tissues of people with Alzheimer's disease, you find many cells, including neurons, that are aneuploid — especially trisomy 21. Just as people with Down syndrome develop Alzheimer's disease later in life, people with Alzheimer's disease develop Down syndrome-like cells with trisomy 21 over the course of their life. These accumulate and probably contribute to their cognitive problems.”
In a paper published in Cell Cycle in 2011, Dr. Potter and colleagues showed that toxic Abeta in both Down syndrome and Alzheimer's disease clogs the microtubule transportation mechanism within neurons responsible for moving proteins and for segregating the chromosomes when cells divide. If the segregation fails, chromosomes in the new cells may reassemble with an abnormal number of chromosomes — a result known as aneuploidy. Down syndrome occurs when this process takes place in utero on chromosome 21.
People with Down syndrome as well as people with advanced Alzheimer's have fewer neurons than normal in certain parts of the brain, presumably because of defective neurogenesis, especially in the dentate gyrus. When Abeta disrupts mitosis, resulting in aneuploidy, new cells are likely to die. A group at the University of Leipzig led by Thomas Arendt, MD, DSc, recently found that 89 percent of the cell death found at autopsy in the brains of Alzheimer's patients involved loss of aneuploid cells.
“You could conclude that chromosome aneuploidy underlies the neurodegeneration of Alzheimer's,” Dr. Potter said. “First you generate the aneuploidy, and then those cells are prone to degeneration.”
If lithium can stimulate neurogenesis in humans, it could open up the first effective treatment for Down syndrome, which has increased by about 30 percent in the United States over the past 30 years, presumably due to women bearing children later in life.
Still, Dr. Potter would discourage doctors from prescribing lithium off-label to such patients in hopes of promoting neurogenesis.
“We don't know what the toxicity might be in this vulnerable population,” he said. “That should be tested first before anyone tries it.”
FOR FURTHER READING:
• Contestabile A, Greco B, Gasparini L, et al. Lithium rescues synaptic plasticity and memory in Down syndrome mice. J Clin Invest
• Zhang X, Heng X, Le W, et al. Long-term treatment with lithium alleviates memory deficits and reduces amyloid-β production in an aged Alzheimer's disease transgenic mouse model. J Alzheimers Dis 2011;24:739–749.
• Forlenza OV, Diniz BS, Gattaz WF, et al. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry
• Borysov SI, Granic A, Potter H, et al. Alzheimer Aβ disrupts the mitotic spindle and directly inhibits mitotic microtubule motors. Cell Cycle 2011;10(9):1397–1410.