Introduction:

ALS
Amyotrophic Lateral Sclerosis is a fatal degenerative disease that affects the motor neurons, it can also be referred to as Lou Gehrig’s disease. It is characterized by a gradual progression of the degeneration of both upper and lower motor neurons. Causing rapid muscular atrophy, paralysis and eventually results in respiratory failure and death [1]. ALS was first recognized in the United States when professional baseball player Lou Gehrig was diagnosed in 1939 [2]. Currently there are two known categories of ALS one is called Sporadic ALS, and the other is Familial or genetic ALS [2]. Sporadic ALS means that the disease seems to develop randomly with no clear associated risk factors and no family history of the disease this type occurs in 90-95% of cases. Familial or genetic ALS occurs in 5-10% of ALS cases, meaning they have inherited the disease from a parent. “There are several gene mutations said to have caused this type of ALS. About 25 to 40% of all familial cases and a small percentage of sporadic cases are caused by a defect in a gene known as chromosome 9 open reading frame 72, or C9ORF72. Another 12 to 20 percent of familial cases result from mutations in the gene that provides instructions for the production of the enzyme copper-zinc superoxide dismutase 1 (SOD1)” [3].

ALS is typically affects those within the ages of 50 and 60 but it has been seen at earlier ages. It is found to be more common in men, by a factor of about 1.5. The median survival rate after receiving the ALS diagnosis is about 23 to 52 months. Unfortunately, there is no cure yet for this dreadful disease [1]

Interesting Facts:
  1. 1. Approximately 6,000 people in the U.S. are diagnosed with ALS each year. The incidence of ALS is two per 100,000 people, and it is estimated there are more than 20,000 Americans may be living with ALS at any given time.
  2. ALS occurs throughout the world with no racial, ethnic or socioeconomic boundaries and can affect anyone.
  3. Military veterans are approximately twice as likely to develop ALS [4]
  4. The extraocular muscles tend to not be affected, in some cases progression can be so severe that eye movements are the only form of communication possible [1]
Functional Anatomical Review:

The Neuron:
Every second of every day there is a continuous stream of information being processed by sensory receptors of the human body that are then processed by the complex system of our body known as the brain. This stream of information will eventually lead to specific actions like movement of the hand or eye. This is all made possible by the neuron, a nerve cell [5]. Nerve cells are the basic unit of the brain. There are hundreds of thousands of these cells making deliberate connections with one another, they are the main signaling units of the nervous system. There are four distinct parts of the neuron; the cell body, dendrites, the axon, and pre synaptic terminals. The cell body which is also referred to as the soma, it contains the nucleus of the cells as well as other organelles. The cell body gives rise to two other sections of the cell, the dendrites and the axons. The dendrites are shorter portions of the cell, they branch out from the cell body and are the main receptor of information from surrounding nerve cells. The axon is typically a long extension, tube like, that is the primary conductor unit carrying signals from the cell body to other neurons. The distance they are able to send their signals varies depending on the size, length, and degree of myelination the axon has. Electrical signals are sent down the axon, these are called action potentials, they are transmitted when a receptor of the body like a muscle spindle or photoreceptor of the eye is stimulated. That receptor stimulation triggers a response, whether it be chemical or mechanical, there is a change in the membrane potential of the receptor which triggers an action potential to be sent. At the end of the axon is the presynaptic terminal. Here synaptic vesicles are stored, which will eventually be released to cause a response. In the case of a motor neuron, when the neurotransmitter acetylcholine is released at the neuromuscular junction this leads to a contraction of the muscle fiber, and a movement takes place. (class notes) There are three major categories of neurons, sensory neurons, motor neurons, and interneurons. Motor neurons are most important for the topic of ALS [5].

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Typical structure of a motor neuron (Figure 1)

Upper Motor Neurons:
An upper motor neuron is a neuron that projects from the primary motor cortex down into the spinal cord or brain stem. In a healthy functioning individual, these neurons send signals from the brain to lower motor neurons which connect to muscle fibers [1].


Primary Motor Cortex:

The primary motor cortex is the highest level of motor control. It is located in the precentral gyrus of Broadmans area 4 [5].The primary motor cortex controls movement on the opposite side of the body [1].The primary motor cortex is arranged somatotopically meaning there is an orderly arrangement along the gyrus of specific areas of control for the face, digits, hand, arm, trunk, leg, and foot. These areas are not all represented equally, their representation varies, it is determined by the precision each area requires [5].



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Functional areas of the brain (Figure 2) Primary motor cortex representation (Figure 3)

Premotor Areas:

Premotor areas are involved in coordinating and planning complex sequences of movement. They receive input from the posterior parietal association areas. These Premotor areas have output that they send to impact the primary motor cortex as well as the spinal cord [5].

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Areas of the brain, premotor area is represented by the coral color (Figure 4)

Brain Stem:

The brain stem contains two different systems, the medial and lateral. They receive input from the cerebral cortex as well as the subcortical nuclei. They project their information to the spinal cord [5].

Medial descending system- contributes to the control of posture by integrating vestibular, visual, and somatosensory information- medial and lateral vestibulospinal, and tectospinal [5]
Lateral descending system – controls more distal limb muscles that are important for goal oriented movements especially of the arm and hand –rubrospinal tract [5]


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Brain stem pathways(Figure 5)

Spinal Cord- Descending Motor Pathways:

Descending motor pathways play an important role, their main function is to send input from higher brain motor areas to muscle fibers in order to produce muscle contractions, and thus movement. There are two descending cortical pathways. These run together and are called the corticospinal tract. The two fiber tracts are called the corticobulbar fibers, and corticospinal fibers. These fibers will stem from either the right side of the brain, and innervate the left side muscles of the body, or they will stem from the left side of the brain and innervate right side muscles of the body. The cortex influences the spinal motor activity on descending brain stem pathways both directly and indirectly. One third of the corticospinal tact fibers originate in the precentral gyrus of the frontal lobe, another third is from Brodmann’s area 6, and the last are from areas 3, 2, and 1 of the somatosensory cortex. Corticospinal and Corticobulbar fibers run together through the posterior limb of the internal capsule, they will eventually reach the ventral portion of the midbrain. At the pons, these fibers separate into small bundles of fibers that travel between the pontine nuclei and then regroup at the medulla (primary place of decussation). Here they form the medullary pyramid. Corticobulbar fibers control muscles of the head and face musculature. There terminate in motor and sensory nuclei in the brain stem. They form monosynaptic connections with motor neurons in the trigeminal, facial, and hypoglossal nuclei. It is interesting to note in regard to ALS movement of the eyes are not affected if problem here because they are controlled by a different system of the brain. Three quarters of the fibers decussate here at the medulla spinal cord junction, these fibers descend into the dorsal part of the lateral columns and are called the lateral corticospinal tract. The fibers that did not decussate descent to the ventral columns and are called the ventral corticospinal tract. The lateral corticospinal tract project to motor nuclei in the lateral portion of the ventral horn, and interneurons in the intermediate zone. The ventral corticospinal tract projects bilaterally to the ventromedial cell column joining portions of the intermediate zone which contain motor neurons that innervate axial muscles. Each level involved in motor control, meaning the primary motor cortex, premotor areas, parietal areas, prefrontal areas each project parallel sensory input to sensory nuclei as well as other structures including the thalamus and the cerebellum [5].
Corticobulbar fibers – control nuclei un the brain stem that move facial muscles
Corticospinal fibers – control spinal motor neurons that innervate the trunk and limb movements

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Descending motor pathways (Figure 6)

Lower Motor Neuron:
The lower motor neuron is the location at which the upper motor neuron synapses. These neurons are located in the anterior horns of the central grey matter of the spinal cord. The axons of lower motor neurons project out of the spinal cord via anterior spinal roots, or cranial nerves and eventually reach muscle cells in the periphery. [1]. These neurons are what actually trigger the muscle to contract leading to movement.

Input Pathways to The Motor Cortex:

The primary motor cortex receives input from the parietal, prefrontal, and temporal association areas. The thalamus also project to the motor areas and conveys information from the basal ganglia and the cerebellum. Each level of motor control receives input from peripheral sensory systems. This is important because they can use that information to modify output as well as motor behavior at that level [5]. This sensory information that is coming from the receptors of the body which have axonal connections to the spinal cord through the dorsal root ganglions of the spinal cord. The pathways associated with proprioception, vibration, and crude touch are important to the motor cortex. These receptors information travels on the dorsal column pathway. They will travel from the receptor and enter into the dorsal root ganglion, to the white matter of the dorsal column, they will then ascend all the way up to the dorsal column nuclei in the medulla. Here they make a synapse onto second order neurons, they decussate here and ascend to the thalamus, from there they continue to the primary somatosensory cortex. The thalamic information project to the primary motor cortex [1].
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Input to cerebral cortex (Figure 7)

Thalamus:

The thalamus is a very important structure, every cortical structure receives input that has first synapsed in the thalamus. It also has output to all of these cortical areas most importantly in the case of ALS the motor cortex [1].

The Cerebellum and Basal Ganglia:

The cerebellum and basal ganglia are responsible for refining the output information from the motor systems. They both receive most of their input from the motor context. They then modifying that information from corticospinal and other descending tracts and project it back to the motor cortex by way of the thalamus [1].
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Basal Ganglia and Cerebellum (Figure 8)

Clinical Features:

Amyotrophic Lateral Sclerosis is a fatal degenerative disease that affects the motor neurons it is characterized by a gradual progression of the degeneration of both upper and lower motor neurons [1]. Due to the rapid loss of lower motor neurons patients face cramps, muscle atrophy, marked weakness, and fasciculation’s. Upper motor neuron damage is said to produce spasticity, hyperreflexia, as well as modest weakness. Rapid weight loss is also a sign of this disease. Progression is somewhat variable case to case however ALS usually begins in the limbs and arms for most patients, often unilateral. Doctors report seeing foot drop, difficulty walking, hand dexterity issues. In bulbar ALS specifically there are reports of head drop and kyphosis. Depression is also seen in some patients with ALS, due to the prognosis patients can feel hopeless, leading to lack of sleep and appetite. Repertory symptoms are also found in patients. Diagnosis is often confirmed by using electromyography, which would confirm the widespread lower motor disease. MRI’s have been used to confirm bilateral changes within the corticospinal tracts typical of ALS [6] .

Pathophysiology:

It is found that 5-10% of cases are said to be genetic. In these cases, genetic mutations are found. “Gene mutations cause motor neuron death through different pathways: SOD1 mutations lead to oxidative stress; TARDBP, FUS and c9ORF72 induce disturbances in RNA machinery; VAPB affects endosomal vesicle trafficking; and UBQLN2 contributes to ubiquitination” The c9ORF72 gene is thought to be the most frequent cause of ALS, with the mutation it produces protein accumulation in the brain [6]. Pathophysiological mechanisms are also proven to contribute to ALS that lead to cell death like mitochondrial dysfunction, protein aggregation, as well as the generation of free radicals. There are very few leads on how sporadic ALS occurs.

Treatment:

Unfortunately there is no cure for this disease yet. Most try to maintain their best quality of life as long as possible.

Conclusion:

ALS is a fatal disease of the upper and motor neurons, characterized by neuronal death. Thus, leading to muscle weakness, paralysis and eventually death due to repertory failure. Right now there seems to be no cure for this tragic disease however future research needs to be done to find the cause of sALS, this type of ALS makes up the majority of cases but it seems to spontaneously occur. Because protein folding’s seems to take place in diseased neurons hopefully this can be a drive for therapy intervention, leading to a cure for ALS as well as other neurodegenerative diseases [6].

Glossary of Terms:
  • ALS – Amyotrophic lateral sclerosis is a fatal neurodegenerative disease of both upper and lower motor neurons
  • Amyotrophic – no muscle nourishment
  • Sclerosis – hardening and scaring of a structure
  • Upper motor neuron – A neuron that projects from the primary motor cortex into the spinal cord
  • Corticobulbar – cortical fibers pertaining to the face
  • Fasciculation – an involuntary muscle twitch that can be visible under the skin
  • Kyphosis – rounding of the spine

Quiz:

1. What is the predominant age range of those affected by ALS?
a. 20-30
b. 100-105
c. 15-20
d. 50-60

2. What gender does ALS affect at a higher rate?
a. Male
b. Female

3. Are the eye muscles affected in this disease?
a. Yes
b. No

4. Is there a cure for sporadic ALS?
a. Yes
b. No

5. Who was the first known case of ALS in the United States?
a. Lou Gehrig
b. Michael Jordan
c. Abe Lincoln
6. Is there any leading cause of genetic ALS?

7. Does ALS affect the anterolateral somatosensory pathway?

Video:





References:

[1] Blumenfeld, H. (2002). Neuroanatomy through clinical cases. Sunderland, MA: Sinauer Associates, Inc.

[2] Zarei, S., Carr, K., Reiley, L., Diaz, K., Guerra, O., Altamirano, P. F., . . . Chinea, A. (2015, November 16). A comprehensive review of amyotrophic lateral sclerosis. Retrieved December 08, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653353/

[3] Amyotrophic Lateral Sclerosis (ALS) Fact Sheet. (n.d.). Retrieved December 08, 2017, from https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet

[4] What is ALS? (n.d.). Retrieved December 08, 2017, from http://www.alsa.org/about-als/what-is-als.html

[5] Kandel, E. R., Schwartz, J. H., & Jessell, T. M. (2000). Principles of Neural Science. New York: McGraw-Hill Companies.

[6] Gordon, P. (2013). Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials. Aging and Disease, 04(05), 295-310. doi:10.14336/ad.2013.0400295

Picture URL’s:

Figure 1 https://commons.wikimedia.org/wiki/File:1206_The_Neuron.jpg

Figure 2 http://neurones.co.uk/Neurosciences/Chapters/Chapter%203/P.3.1%20Cortical%20Functions.html

Figures 3 & 4 http://antranik.org/functional-areas-of-the-cerebral-cortex/

Figure 5 http://www.utdallas.edu/~tres/integ/mot2/display2_12.html

Figure 6 http://higheredbcs.wiley.com/legacy/college/tortora/0470565101/hearthis_ill/pap13e_ch16_illustr_audio_mp3_am/simulations/hear/corticospinal.html

Figure 7 https://www.dreamstime.com/stock-illustration-sensory-motor-nerve-pathways-stimulus-to-cortex-back-to-muscle-mechanism-avoiding-noxious-image58608673

Figure 8https://atlasofscience.org/a-systems-level-view-of-cerebellar-function-the-interplay-between-cerebellum-basal-ganglia-and-cortex/


Quiz Answers:
  1. 1. 50-60
  2. 2. Males
  3. 3. No
  4. 4. No
  5. 5. Lou Gehrig
  6. 6. Yes it is said to be caused by a gene nutation in the c9ORF72 gene.
  7. 7. No ALS is a disease specifically involving the motor systems. So its effects are only seen to involve the corticospinal tracts.