Scientists at the University of Sussex have identified a potential pattern within blood which signals the presence of motor neuron disease; a discovery which could significantly improve diagnosis.
Currently, it can take up to a year for a patient to be diagnosed with amyotrophic lateral sclerosis (ALS), more commonly known as motor neuron disease (MND).
But after comparing blood samples from patients with ALS, those with other motor-related neurological diseases, and healthy patients, researchers were able to identify specific biomarkers which act as a diagnostic signature for the disease.
Researchers hope that their findings, published in the journal Brain Communications, and funded by the Motor Neurone Disease Association (MNDA), could lead to the development of a blood test which will identify the unique biomarker, significantly simplifying and speeding up diagnosis.
With patients living, on average, just 2-5 years after diagnosis, this time could be crucial.
Professor Majid Hafezparast, a professor of Molecular Neuroscience at the University of Sussex, led the research in collaboration with Professors Nigel Leigh and Sarah Newbury from the Brighton and Sussex Medical School, Martin Turner from the University of Oxford, Andrea Malaspina from Queen Mary, University of London, and Albert Ludolph from the University of Ulm.
He said: “In order to effectively diagnose and treat ALS, we are in urgent need of biomarkers as a tool for early diagnosis and for monitoring the efficacy of therapeutic interventions in clinical trials.
“Biomarkers can indicate the disease is present and help us to predict its progression rate.
“In our study, we compared serum samples taken from the blood of 245 patients and controls, analyzing their patterns of non-coding ribonucleic acids (ncRNA).
“We found a biomarker signature for motor neurone disease that is made up of a combination of seven ncRNAs. When these ncRNA are expressed in a particular pattern, we are able to classify whether our samples come from ALS patients or controls.”
Dr. Greig Joilin, the research fellow who undertook this work in Professor Hafezparast’s team said: “We hope that, with further work to validate these biomarkers, a blood test could be developed to help improve diagnosis of motor neuron disease.
“We are now looking to see whether they can predict prognosis to give patients and their families some insight as they begin to understand the disease. Our work could also help other scientists to measure the effectiveness of potential drug treatments against the ncRNA levels. Further, it provides new insight into the cellular and molecular events that contribute to the disease.”
ALS is a group of conditions which affects the nerves in the brain and spinal cord leading to weakness in the muscles and rapid deterioration.
Doctors still don’t know why this happens and there is currently no cure, although existing drug treatments can help patients with daily life and extend life expectancy – but only by two to four months on average.
Stephen Hawking is perhaps one of the most famous cases of motor neuron disease, but more recently Geoff Whaley and his wife Ann brought to light the troubling situation of patients in the UK who wish to end their life before the final phase of the disease takes hold.
Professor Hafezparast hopes that his team’s discovery will improve the outlook for patients by improving diagnosis and giving other researchers a valuable tool to test potential treatments.
The researchers are now looking to validate this biomarker signature in a larger cohort of patients and begin to understand why these ncRNAs change in ALS patients.
While the term “motor neuron” evokes the idea that there is only one type of neuron that conducts movement, this is far from the truth. In fact, within the classification of a “motor neuron,” there lies both upper and lower motor neurons, which are entirely different in terms of their origins, synapse points, pathways, neurotransmitters, and lesion characteristics.
Overall, motor neurons (or motoneurons) comprise various tightly controlled, complex circuits throughout the body that allows for both voluntary and involuntary movements through the innervation of effector muscles and glands.
The upper and lower motor neurons form a two-neuron circuit. The upper motor neurons originate in the cerebral cortex and travel down to the brain stem or spinal cord, while the lower motor neurons begin in the spinal cord and go on to innervate muscles and glands throughout the body.
Understanding the difference between upper and lower motor neurons, as well as the pathway that they take, is crucial to being able to not only diagnose these neuronal injuries but also localize the lesions efficiently.
Structure and Function
The upper and lower motor neurons together comprise a two-neuron pathway that is responsible for movement. Upper and lower motor neurons utilize different neurotransmitters to relay their signals. Upper motor neurons use glutamate, while lower motor neurons use acetylcholine.[1]
To perform a movement, a signal must begin in the primary motor cortex of the brain, which is in the precentral gyrus. In the primary motor cortex are the cell bodies of the upper motor neurons, referred to as Betz cells.[2]
Specifically, these cells are located in layer 5 of the motor cortex and have long apical dendrites that branch up into layer 1.[3] The upper motor neuron is responsible for integrating all of the excitatory and inhibitory signals from the cortex and translating it into a signal that will initiate or inhibit voluntary movement.
Thalamocortical neurons and callosal projection neurons regulate upper motor neurons. While the mechanism of regulation by these entities is not completely understood, it is thought that the majority of the excitatory input to these neurons comes from neurons located in layers 2, 3, and 5 of the motor cortex.
The axons of the upper motor neuron travel down through the posterior limb of the internal capsule. From there, they continue through the cerebral peduncles in the midbrain, longitudinal pontine fibers, and eventually the medullary pyramids.
It is at this location that the majority (approximately 90%) of the fibers will decussate and continue down the spinal cord on the contralateral side of the body as the lateral corticospinal tract. The lateral corticospinal tract is the largest descending pathway and is located in the lateral funiculus.
This tract will synapse directly onto the lower motor neuron in the anterior horn of the spinal cord. The pyramidal tract fibers that did not decussate at the medulla comprise the anterior corticospinal tract, which is much smaller than the lateral corticospinal tract.
This tract is located near the anterior median fissure and is responsible for axial and proximal limb movement and control, which helps with posture. Although it does not decussate at in the medulla, this tract does decussate at the spinal level being innervated.[4][5][6]
The lower motor neuron is responsible for transmitting the signal from the upper motor neuron to the effector muscle to perform a movement. There are three broad types of lower motor neurons: somatic motor neurons, special visceral efferent (branchial) motor neurons, and general visceral motor neurons.[1]
Somatic motor neurons are in the brainstem and further divide into three categories: alpha, beta, and gamma. Alpha motor neurons innervate extrafusal muscle fibers and are the primary means of skeletal muscle contraction.
The large alpha motor neuron cell body can be either in the brainstem or spinal cord. In the spinal cord, the cell bodies are found in the anterior horn and thus are called anterior horn cells. From the anterior horn cell, a single axon goes on to innervate many muscle fibers within a single muscle.
The properties of these muscle fibers are nearly identical, allowing for controlled, synchronous movement of the motor unit upon depolarization of the lower motor neuron.
Beta motor neurons are poorly characterized, but it has been established that they innervate both extrafusal and intrafusal fibers. Gamma motor neurons innervate muscle spindles and dictate their sensitivity.
These neurons primarily respond to stretch of the muscle spindle. Despite being named a “motor neuron,” these neurons do not directly cause any motor function. It is thought that they get activated along with alpha motor neurons and fine-tune the muscle contraction (alpha-gamma coactivation). A disruption in either alpha or gamma motor neurons will result in a disruption of muscle tone.[7][1]
Lower motor neurons also play a role in the somatic reflex arc. When muscle spindles detect a sudden stretch, a signal travels down the afferent nerve fibers. These nerve fibers synapse either directly onto the alpha motor neuron (monosynaptic reflex arc), or onto interneurons, which then synapse onto the alpha motor neuron (polysynaptic reflex arc).
The lower motor neuron innervates the effector muscle, allowing for a quick muscle response. A reflex arc allows for interpretation of and reaction on the stimulus immediately through the spinal cord, bypassing the brain, resulting in a faster effector response.[1][8]
Branchial motor neurons innervate the muscles of the head and neck that derive from the branchial arches. They are in the brainstem. The branchial motor neurons and sensory neurons together form the nuclei of cranial nerves V, VII, IX, X, and XI.[1]
Visceral motor neurons contribute to both the sympathetic and parasympathetic functions of the autonomic nervous system. In the sympathetic nervous system, central motor neurons are present in the spinal cord from T1-L2.
They appear in the intermediolateral (IML) nucleus. Motor neurons from this nucleus have three different pathways. The first two pathways are to the prevertebral and paravertebral ganglia, from which peripheral neurons go on to innervate the heart, colon, intestines, kidneys, and lungs.
The third possible pathway in this system is to the catecholamine-producing chromaffin cells of the adrenal medulla. By targeting these three pathways, the visceral motor neurons in the sympathetic division contribute to the “fight-or-flight” response.
On the other hand, in the parasympathetic system, the visceral motor neurons help give rise to cranial nerves III, VII, IX, and X. Besides in the brainstem, these visceral motor neurons contribute to the parasympathetic system in the spinal cord at levels S2-S4. Similarly to the sympathetic division, these motor neurons directly innervate ganglia in the heart, pancreas, lungs, and kidneys.
Thus, in both divisions of the autonomic system, these lower motor neurons take on a different role than somatic motor neurons in that they do not directly innervate an effector muscle, and instead innervate ganglia.[1]
References
1.Stifani N. Motor neurons and the generation of spinal motor neuron diversity. Front Cell Neurosci. 2014;8:293. [PMC free article] [PubMed]
2.Genc B, Gozutok O, Ozdinler PH. Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons. Int J Mol Sci. 2019 Aug 07;20(16) [PMC free article] [PubMed]
3.Jara JH, Genç B, Klessner JL, Ozdinler PH. Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease. Front Neuroanat. 2014;8:16. [PMC free article] [PubMed]
4.Diaz E, Morales H. Spinal Cord Anatomy and Clinical Syndromes. Semin. Ultrasound CT MR. 2016 Oct;37(5):360-71. [PubMed]
5.Emos MC, Agarwal S. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Dec 28, 2018. Neuroanatomy, Upper Motor Neuron Lesion. [PubMed]
6.Emos MC, Rosner J. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 9, 2019. Neuroanatomy, Upper Motor Nerve Signs. [PubMed]
7.de Carvalho M, Swash M. Lower motor neuron dysfunction in ALS. Clin Neurophysiol. 2016 Jul;127(7):2670-81. [PubMed]
8.Héroux ME. Tap, tap, who’s there? It’s localized muscle activity elicited by the human stretch reflex. J. Physiol. (Lond.). 2017 Jul 15;595(14):4575. [PMC free article] [PubMed]
More information: ‘Identification of a potential non-coding RNA biomarker signature for amyotrophic lateral sclerosis’ Brain Communications, 2020.
