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Showing posts with label disease. Show all posts
Showing posts with label disease. Show all posts

Friday, August 21, 2009

Constantin von Economo's Spindle Cells & The Mind


Today we celebrate the birthday of Constantin von Economo. He was born in 1876. A comprehensive biography of his life entitled "Baron Constantin von Economo His Life and Work"can still be found as a used book. He was known as an avid aviator and a superb physician scientist. Elaborating on Korbinian Brodmann's ground-breaking maps of cerebral cortex, he meticulously charted his own divisions based on the composition of nerve cells seen in histological preparations. In this process, he identified a rare and special type of nerve cell that has intrigued neuroscientists to this day.

The cerebral cortex constitutes our brain's most prominent feature. It consists of a large convoluted sheet of nervous tissue separated at the mid-line into two hemispheres. Its gray matter can be divided into layers of nerve cells of varying shape and density with characteristic in- and output. Pyramidal cells are the predominant type of nerve cell providing output to nerve cells in other layers of the same area, other cortical areas as well as to nerve cells in subcortical structures and to the motor neurons in the spinal cord that innervate the musculature. The roughly triangular cell bodies of the majority of pyramidal cells are located in the deep layers of cortex near the white matter, that Ramon y Cajal defined as layers 5 and 6.

Pyramidal cells feature a distinct distribution of dendrites, that is the processes on which inputs from other nerve cells terminate. The apical dendrite points straight up. It traverses all cortical layers and ramifies in layer 1 under the cortical surface. In addition, a set of dendrites, known as basal dendrites, spreads out radially from the cell body, collecting input from the layer in which the cell body resides. The axon, that is the process conveying the nerve cell's output, emerges from the underside of the cell body. The axons of pyramidal cells are wrapped in sheaths of a fatty substance, known as myelin, for insulation and form the cortical white matter.

Clustered among the ubiquitous pyramidal cells, nerve cells of peculiar, strikingly different shape caught Constantin von Economo's eye. They were unique to only a select few areas in anterior cingulate and insular cortex. The cells possessed conspicuous large cell bodies. Like pyramidal cells, they featured a prominent straight dendrite spanning the cortical thickness and an axon projecting to distant brain structures,  but lacked basal dendrites, resulting in a distinctly bipolar appearance. Von Economo named them "Spindelzellen" or spindle cells in English.

In the past, spindle cells had only been found in humans and other great apes (Nimchinsky and others, 1999). The exclusivity has been taken to suggest that this type of nerve cell may be associated with the complex higher cognitive and affective mental functions that seem to distinguish us from the rest of animaldom, e.g. language, decision making and empathy. Spindle cells are known to be particularly prone to degenerate in people with Alzheimer's disease (Nimchinsky and others, 2004). Recently however, the cells have also been discovered in cetaceans (Marino and others, 2007) and pachyderms (Hakeem and others, 2009).

Little is known about the function of spindle cells. The distribution of their dendrites suggests that they collect input from other nerve cells along narrow radial columns across the cortical thickness, supporting the idea that the cerebral cortex is a functionally organized in discrete modules rather than in broad layers. Their long-distance projections suggest a role in a distributed neural network, processing information across sensory modalities. However, more research clearly needs to be carried out to examine their responsiveness to stimulation and the influences they exert on other nerve cells before any specific role can be assigned with certainty to Constantin von Economo's Spindelzellen.




Sunday, May 17, 2009

Amyotrophic Lateral Sclerosis & Iplex

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease in the U.S., is a devastating degenerative disease of the central nervous system, in which motor neurons die. Motor neurons are the nerve cells that innervate peripheral muscles and control our movements. Like most other nerve cells, motor neurons are not known to retain the potential to divide and replenish in the mature brain. They may die because of high oxidative stress and programmed cell death known as apoptosis. High oxidative stress results from an increase in free radicals. Free radicals are highly-reactive oxidative chemicals that can fatally damage the cell. On the other hand, apoptosis is a self-destruction mechanism of the cell that is triggered when the concentration of the excitatory neurotransmitter glutamate reaches abnormally high levels in the extracellular space. Therefore, therapies that lower free radicals and block the action of glutamate may offer benefits in the treatment of ALS.

Still we do not understand why the oxidative stress increases for motor neurons in ALS and why the extracellular glutamate reaches apoptotic levels. The motor neurons constitute the only nerve cells that reside inside the central nervous system, but make direct contact with cells outside. Perhaps, their endings pick up extrinsic molecules that increase their vulnerability in conjunction with a genetic predisposition.

Patient advocacy groups have recently petitioned the U.S. Food and Drug Agency to allow the compassionate use of Iplex developed by INSMED Inc. in terminally ill ALS patients. Amy Harmon reports the story of one family involved in her post for The New York Times published May 16, 2009. Iplex (mecasermin rinfabate) is a product of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) and has been used in th past to stimulate disrupted body growth in children. IGF-1 is known to promote proliferation and stifle apoptosis in cancer cells (Yu and Rohan, 2000). IGFBP-3 regulates IGF-1 action. Notably, it counteracts the growth factor's suppression of apoptosis. The protein may also inhibit tumor growth and stimulate apoptosis independent from IGF-1. Recent experience in Italy suggests that Iplex improves the condition of patients with ALS. How the drug interacts with motor neuron cell death is unclear at this point. Perhaps, the sum of its opposing effects slows the death of motor neurons. A lot more research needs to be done.

It is difficult to judge the wisdom of opting for such treatment, when the cause of the disease is entirely unknown. Faced with profound uncertainty, we are only left with hope.

Addenda

  • According to Esha Dey's post on Reuters dated Jun. 25, 2009, phase II clinical trials showed that Iplex failed to significantly improve the condition of patients with myotonic muscular dystrophy (MMD). An Insmed press release specifies that 69 patients were treated over 6 months in a randomized, double-blind, placebo-controlled study. MMD is recognized as a genetic disorder. In contrast to ALS, the modified genes affect muscle cell function (07/24/09).
  • Learn about ALS from people who live with it. The acounts were recorded for The New York Times series "Patient Voices: A.L.S.", produced by Karen Barrow and published Oct. 19 (10/10/23).
  • A recent study of Kaspar and others (2005) supports the contention above that IGF-1 may facilitate nerve cell survival in ALS. The researchers showed in a transgenic mouse model for ALS that physical exercise or delivery to the central nervous system of the gene for IGF-1 slowed the progression of the disease. Both treatments combined had a synergistic effect on function and survival (10/25/09).
  • As of Jul. 29, 2009, Insmed has put clinical trials with Iplex on hold. The drug has been unavailable to new patients since then. The company ascertains that current supplies will suffice to maintain the treatment of patients who were already enrolled in ongoing trials for another two years. No new decisions have been announced to date (12/22/09).
  • The route of administration may be crucial to the effectiveness of Iplex in the treatment of ALS. A recent study with 330 ALS patients showed that subcutaneous injection of IGF-1, the main component of Iplex, did not statistically significantly improve the condition of the participants (Sorensen and others, 2008) compared with participants administered a placebo. A compound must cross the blood-brain barrier to affect motor nerve cells. Perhaps, too little IGF-1 reached the motor nerve cells to initiate a detectable effect. However, other routes of drug delivery may be more efficacious than subcutaneous injections. For example, rabies viruses are neurotropic. That is, the virus is taken up by the endings of motor nerve cells, transported into their cell bodies and further retrogradely into the nerve cells innervating the motor nerve cells. In the process of the disease, the virus multiplies in the nerve cell bodies, causing severe encephalitis and, ultimately, death. Because of its retrograde transport, rabies virus is used in animals to examine nerve cell circuitry (Taber and others, 2005). It is conceivable that deactivated forms of the virus can be used as vehicle to shuttle drugs like Iplex into the central nervous system. Herpes simplex viruses possess similar neurotropic properties and may constitute another option (03/19/10).
  • Yesterday, NPR's Talk of the Nation (Science Friday) broadcast a segment on recent advances in stem cell research entitled "Stem Cell Research Update".  New studies are discussed that provide evidence that glia cells derived from human stem cells implanted into rats after spinal cord injury help functional recovery (Sharp and others, 2010). The senior investigator of the study believes that one day in the near future stem cells can be used to replace nerve cells lost in neurodegenerative diseases. The therapy may be promising with diseases in which the causes are well understood. By contrast, the cause for motor neuron cell death in ALS is completely unknown. Hence, replacing them with new ones derived from stem cells may be short-lived (05/22/10).
  • If you are considering stem cell therapy, you may find the information on the International Society for Stem Cell Research site helpful (07/26/10).
References
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Wednesday, April 8, 2009

Recent Advances in Parkinson's Disease

Two days ago, National Public Radio's  All Things Considered broadcast a segment in its series This I believe with Mohammed Ali's contribution entitled "I Am Still The Greatest". The great boxing champion is suffering from Parkinson's disease. But that did not stop him to deliver his testimonial. Despite his condition, Muhammad Ali has risen to even greater championship after his boxing career ended, becoming a relentless ambassador for humanitarian causes and for more research in better treatments for this horribly destructive disease.

Parkinson's Disease is a degenerative disease of the central nervous system, resulting in severe tremor of limbs, motor arrest, and disruption of speech. Its cause is unknown, though a subset of people with the disease are known to carry an inherited genetic mutation that may predispose degeneration.

Nerve cells located in the basal ganglia, a group of forebrain structures situated nose-ward under the cerebral cortex, control our fine movements. They provide feedback to the nerve cells in the motor areas of the cerebral cortex that connect with nerve cells in the ventral horn of the spinal cord. The spinal nerve cells, known as motor neurons, innervate muscle fibers and control limb movement.

Basal ganglia functionality depends on a set of nerve cells located in a structure behind the basal ganglia, known as substantia nigra. In Parkinson's disease, the substantia nigra cells degenerate over decades and eventually die. The loss of their input to the basal ganglia perturbs motor control.

The nerve cells in the substantia nigra use the neurotransmitter dopamine to communicate with the nerve cells in the basal ganglia. Replacing the lost dopamine with the systemic administration of the drug levodopa ameliorates the symptoms. However, over time the brain develops increasing tolerance to the drug, and even high doses cannot control tremors anymore. Efforts pioneered by A. Björklund at the University of Lund in Sweden at grafting into the brain undifferentiated cells induced to produce dopamine showed promising results in animal studies, but grafts with fetal ventral mesencephalic tissue, rich in dopaminergic neuroblasts, have not proved unequivocally successful in humans (Kefalopoulou and others, 2014).

When medication eventually fails, surgically removing specific parts of the basal ganglia or inter-brain structures also involved in fine motor control may improve the condition (Çoban and others, 2009). In the last decade, however, deep brain stimulation has gained popularity. The method is less invasive and has produced superb outcome. It entails electrical stimulation of nerve cells in the basal ganglia or the inter-brain using thin implanted micro-electrode wires. The electrical impulses are thought to disrupt the persistent nerve cell activity causing the tremors. As a potential further improvement of this procedure, a research study published recently in the journal Science showed that the electrical stimulation of spinal cord nerve fibers with micro-electrodes, threaded between the vertebrae to touch the outer spinal cord where bundles of nerve fibers run that convey sensory information to the brain, may suffice to subdue tremors in Parkinsonian mice (Fuentes and others, 2009). The promising findings were reported on Mar. 19, 2009, in Julie Steenhuysen's post entitled "Spinal cord device helped mice with Parkinson's" on Reuters and Sandra Blakeslee's article entitled "Spinal Shocks Ease Parkinson’s in Mice" in The New York Times. If this procedure proved successful in people, brain surgery would be rendered unnecessary.

If Parkinson's disease runs in your family, you may be interested in gene chip tests for a predisposition available from 23andMe.

Addenda

  • Some patients with Parkinson's Disease benefitted from having fetal midbrain tissue rich in dopamine-producing nerve cells grafted into the dopamine-depleted basal ganglion known as striatum. However, dyskinesias, that is severe bouts of involuntary movements, hampered recovery despite major improvements in motor control. Using radioactively labeled markers and Positron Emission Tomography, Politis and others (2010) recently showed that the grafts produce extraordinary amounts of the neurotransmitter serotonin, suggesting that excessive serotonergic innervation of the striatum causes the dyskinesias. Hence, medication with long-lasting serotonin antagonists may subdue the undesired effect in grafted patients, and the use of grafts that lack great amounts of serotonergic nerve cells in future surgery may improve outcome in implantation therapy (07/03/10).
  • If you are considering stem cell therapy, you may find the information on the International Society for Stem Cell Research site helpful (07/26/10).
  • Today, Diane Rehm interviewed Miguel Nicolelis on her show with the title "Miguel Nicolelis: 'Beyond Boundaries'". Dr. Nicolelis is a lead investigator in this research and discusses his fascinating insights (03/16/11).
  • Kefalopoulou and others (2014) report that 2 of the 18 patients who volunteered for the University of Lund trial implanting grafts of fetal ventral mesencephalic tissue 15 and 18 years ago showed significant, persistent behavioral improvements (04/09/2014).
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