Chapter 27
Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
Questions
1.
Which of the following proposed pathogenic mechanisms in ALS are considered mutually exclusive
(present in isolation) of other proposed mechanisms of disease?
a. glutamate excitotoxicity
b. generation of free radicals
c. disrupted axoplasmic flow
d. altered calcium homeostasis
e. all of the above
f. none of the above
2.
Which statement best describes the meaning of ‘non-cell autonomy’ when referring to the pathogenesis of
ALS?
a. The risk of developing ALS is independent of cellular factors, and is more dependent on environmental
exposures.
b. The progression of disease in ALS is dependent upon therapeutic intervention and early detection
c. Motor neuron injury is independent of interaction with other cell populations within the CNS
d. Motor neuron injury is dependent on interaction with other affected cell populations within the CNS
3.
Which line(s) of evidence from human studies support that the immune inflammatory response in ALS
has a role in amplifying disease progression?
a. Increased expression of myeloid dendritic cells mRNA transcripts in ALS spinal cord that correlates with a
faster rate of progression
b. Increased mRNA expressions of the chemokine MCP-1, and the cytokine macrophage-colony stimulating
factor (M-CSF) in ALS spinal cord, which attracts and induces differentiation of monocytes and myeloid
dendritic cells, respectively.
c. Both a and b
d. Neither a or b
4.
Which line(s) of evidence from animal and in vitro studies support that the immune inflammatory
response has a role in motoneuron injury?
a. Studies from mSOD transgenic chimeric mice showing that mSOD expressing neurons that are surrounded
by wild-type glial cells remain intact
b. Motoneuron injury by activated microglia mediated by glutamate and peroxynitrite
c. Both a and b
d. Neither a or b
5.
The failure of immunosuppressive therapy in ALS is sufficient evidence that immune mediated
mechanisms are not relevant to disease pathogenesis
True/False
6.
The higher incidence of autoimmune diseases and paraproteinemias in ALS patients confirms that
sporadic motor neuron disease is autoimmune in nature
True/False
7.
Association between viral infection and motor neuron disease is based upon cases of motor neuron
disease due to retroviral infection (HIV, HTLV-1) and the presence of serum antibodies directed toward
endogenous retroviral gene sequences in ALS patients.
True/False
27. Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
2
8.
In CNS injury, the neuroprotective response of activated T cells is dependent upon early activation and
differentiation of microglia into antigen presenting cells which release neurotrophic growth factors.
True/False
9.
Although human and animal studies support a role for immune responses in ALS pathogenesis, which
statement(s) are reasonable explanations for why immunosuppressive therapy has failed in treating ALS?
1. Immune suppressive therapy is initiated beyond the point when motor neuron recovery and clinical
improvement are possible.
2. Inadequate access to or suppression of immune inflammatory cells in the CNS
3. Suppression of both cytotoxic and protective immune mechanisms
4. Immune inflammation does not contribute to ALS disease pathogenesis
a.
b.
c.
d.
e.
1, 2, 3
1, 3
2, 4
4 only
All of the above
10. Which of the following patient variables are associated with a poor prognosis?
1. Older age of onset
2. Female gender
3. Bulbar onset
4. Sporadic form
a.
b.
c.
d.
1, 2,3
1, 3
2, 4
4 only
11. Slurred speech, excessive salivation, and hoarseness may be the presenting feature in what percentage of
ALS patients?
a. 15%
b. 25%
c. 35%
d. 45%
12. Cognitive dysfunction is not a typical feature of ALS.
True/False
13. A clinical diagnosis of ALS requires the demonstration of lower motor neuron involvement in which
three areas?
a. upper extremity limb, eye muscles, and paraspinous muscles
b. lower extremity limb, eye muscles, and tongue
c. upper extremity limb, tongue, paraspinous muscles
d. lower extremity limb, upper extremity, eye muscles
14. Studies of which disease have provided an increased understanding of the interactions between neurology
and immunology?
a. Mollaret’s Meningitis
b. Guillan Barre Syndrome
c. poliomyelitis
d. multiple sclerosis
27. Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
3
15. The presence of an increased number of dendritic cells in ALS tissues provides evidence for activation of
an innate immune response.
True/False
16. The following molecules enhance the entry of leukocytes from the periphery into areas of injury and have
been observed in ALS tissues.
a. MCP-1, LFA-1, ICAM-1, AND MMP-9
b. COX-2, GFAP, ICAM-1 MMP-9
c. M-CSF, MCP-1, COX-2, MMP-9
d. COX-2, M-CSF, ICAM-1, MCP-1
17. MCP-1 is a chemokine which attracts monocytes and myeloid dendritic cells to sites of injury or
inflammation.
True/False
18. In vitro, motor neuron injury is induced by exposure to activated microglia. Which microglial
constituents initiate such injury?
1. kainite and IgG
2. mSOD1 and peroxynitrite
3. glutamate and IgG
4. peroxynitrite and glutamate
a.
b.
c.
d.
1, 2,3
1, 3
2, 4
4 only
19. The failure of immunosuppression to ameliorate type-1diabetes or chronic progressive multiple sclerosis,
predominantly immune mediated diseases, invalidates the role of immune mechanisms in initiating these
disorders
True/False
20. Prostaglandins have a dual role in either promoting neuronal survival or apoptotic death. What factors
may determine which role predominates in CNS injury or degeneration?
1. Target cell and tissue environment, degree of cellular response to the inflammatory mediators, and profile of
specific prostaglandin(s)
2. Exposure to prostaglandin and cox-2 inhibitors, target cell and tissue environment, and profile of specific
prostaglandins(s)
a.
b.
c.
d.
both 1 and 2
neither 1 or 2
1
2
27. Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
4
Answers
1.
Which of the following proposed pathogenic mechanisms in ALS are considered mutually exclusive
(present in isolation) of other proposed mechanisms of disease?
a. glutamate excitotoxicity
b. generation of free radicals
c. disrupted axoplasmic flow
d. altered calcium homeostasis
e. all of the above
f. none of the above
None of these explanations are mutually exclusive, since altered calcium homeostasis, free radical stress,
glutamate excitotoxicity and changes in axoplasmic flow may all participate in the cell injury cascade leading to
motor neuron death. In fact, alterations in one parameter can lead to alterations in other parameters, and each
can enhance and propagate the injury cascade.
2.
Which statement best describes the meaning of ‘non-cell autonomy’ when referring to the pathogenesis of
ALS?
a. The risk of developing ALS is independent of cellular factors, and is more dependent on environmental
exposures.
b. The progression of disease in ALS is dependent upon therapeutic intervention and early detection
c. Motor neuron injury is independent of interaction with other cell populations within the CNS
d. Motor neuron injury is dependent on interaction with other affected cell populations within the CNS
Neuronal injury and cell death do not occur in isolation, but may require the participation of non-neuronal cells
such as miroglia and astrocytes, as well as other immune cells.
3.
Which line(s) of evidence from human studies support that the immune inflammatory response in ALS
has a role in amplifying disease progression?
a. Increased expression of myeloid dendritic cells mRNA transcripts in ALS spinal cord that correlates
with a faster rate of progression
b. Increased mRNA expressions of the chemokine MCP-1, and the cytokine macrophage-colony stimulating
factor (M-CSF) in ALS spinal cord, which attracts and induces differentiation of monocytes and myeloid
dendritic cells, respectively.
c. Both a and b
d. Neither a or b
Those patients who progressed most rapidly expressed significantly more dendritic transcripts than patients who
progressed more slowly. These results support the involvement of an adaptive immune/inflammatory response
that is associated in amplifying motor neuron degeneration in ALS.
4.
Which line(s) of evidence from animal and in vitro studies support that the immune inflammatory
response has a role in motoneuron injury?
a. Studies from mSOD transgenic chimeric mice showing that mSOD expressing neurons that are surrounded
by wild-type glial cells remain intact
b. Motoneuron injury by activated microglia mediated by glutamate and peroxynitrite
c. Both a and b
d. Neither a or b
In vitro data clearly document that immune/inflammatory consitutents can mediate cytotoxicity. In vivo data
from animal models also provide evidence that glial cells, such as microglia, and infiltrating immune cells can
mediate cytotoxicity.
27. Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
5
5.
The failure of immunosuppressive therapy in ALS is sufficient evidence that immune mediated
mechanisms are not relevant to disease pathogenesis
False
6.
The higher incidence of autoimmune diseases and paraproteinemias in ALS patients confirms that
sporadic motor neuron disease is autoimmune in nature
False
Although, the higher incidence of autoimmune diseases and paraproteinemias in ALS patients continues to
suggest a link between dysimmunity or paraimmunity and motor neuron disease (Haverkamp et al, 1995;
Gardner et al, 1997), the evidence that ALS is a primary, autoimmune disease remains circumstantial.
7.
Association between viral infection and motor neuron disease is based upon cases of motor neuron
disease due to retroviral infection (HIV, HTLV-1) and the presence of serum antibodies directed toward
endogenous retroviral gene sequences in ALS patients.
True
Antibodies against HTLV-1 viral proteins have been reported in some ALS patients, as well as increased
reverse transcriptase activity in ALS sera (Ferrante et al, 1995; Andrews et al, 2000). Fifty –six percent of
sporadic ALS patients had IgG antibodies reactive to a protein encoded by the endogenous retroviral sequence,
HML-2/Herv-K, and that this immune response was identified in ALS patients more than five times as
frequently as in Alzheimer’s disease or healthy controls (Hadlock et al, 2004).
8.
In CNS injury, the neuroprotective response of activated T cells is dependent upon early activation and
differentiation of microglia into antigen presenting cells which release neurotrophic growth factors.
True/False
9.
Although human and animal studies support a role for immune responses in ALS pathogenesis, which
statement(s) are reasonable explanations for why immunosuppressive therapy has failed in treating ALS?
1. Immune suppressive therapy is initiated beyond the point when motor neuron recovery and clinical
improvement are possible.
2. Inadequate access to or suppression of immune inflammatory cells in the CNS
3. Suppression of both cytotoxic and protective immune mechanisms
4. Immune inflammation does not contribute to ALS disease pathogenesis
a.
b.
c.
d.
e.
1, 2, 3
1, 3
2, 4
4 only
All of the above
Some may argue that E is the correct answer. However, if answers are based on this chapter alone, then A is
correct
12. Which of the following patient variables are associated with a poor prognosis?
1. Older age of onset
2. Female gender
3. Bulbar onset
4. Sporadic form
a.
b.
c.
d.
1, 2,3
1, 3
2, 4
4 only
27. Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
6
13. Slurred speech, excessive salivation, and hoarseness may be the presenting feature in what percentage of
ALS patients?
a. 15%
b. 25%
c. 35%
d. 45%
Bulbar involvement includes hoarseness, slurred speech and drooling and often precedes pharyngeal muscle
involvement. These symptoms in association with tongue atrophy and fibrillations may be the presenting feature
in 20-25% of patients, for whom the majority are women over the age of 60 (Haverkamp et al 1995).
12. Cognitive dysfunction is not a typical feature of ALS.
False
Cognitive dysfunction due to fronto-temporal lobe involvement is a frequent associated feature in ALS patients
and ranges from mild frontal dysexecutive impairment in the majority to fronto-temporal dementia (Ringholz et
al, 2005).
15. A clinical diagnosis of ALS requires the demonstration of lower motor neuron involvement in which
three areas?
a. upper extremity limb, eye muscles, and paraspinous muscles
b. lower extremity limb, eye muscles, and tongue
c. upper extremity limb, tongue, paraspinous muscles
d. lower extremity limb, upper extremity, eye muscles
The history and neurological examination provide the foundation for the diagnosis of ALS and should
demonstrate a combination of lower motor neuron (LMN) involvement with weakness and atrophy in at least
three areas (upper extremity limb, lower extremity limb, tongue, or paraspinous muscles of the back),
Extraocular muscles and muscles of the external anal sphincter and urethra are relatively spared.
16. Studies of which disease have provided an increased understanding of the interactions between neurology
and immunology?
a. Mollaret’s Meningitis
b. Guillan Barre Syndrome
c. poliomyelitis
d. multiple sclerosis
The interrelationships between neurology and immunology have been studied extensively in multiple sclerosis,
the prototypical CNS autoimmune disease.
15. The presence of an increased number of dendritic cells in ALS tissues provides evidence for activation of
an innate immune response.
False
Dendritic cells are potent antigen-presenting cells that initiate and amplify lymphocytic adaptive immune
responses (Reichmann et al, 2002). They can be derived from the peripheral immune system or from resting
CNS microglia. The increased presence of myeloid dendritic cells in ALS tissues support the involvement of an
adaptive immune/inflammatory response.
27. Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
7
16. The following molecules enhance the entry of leukocytes from the periphery into areas of injury and have
been observed in ALS tissues.
a. MCP-1, LFA-1, ICAM-1, AND MMP-9
b. COX-2, GFAP, ICAM-1 MMP-9
c. M-CSF, MCP-1, COX-2, MMP-9
d. COX-2, M-CSF, ICAM-1, MCP-1
MCP-1 is well known to enhance the entry of monocytes and dendritic cells into tissues based on interaction
with the cognate receptor CCR2 on invading cells. Leukocytes that are observed in the postcapillary venules
also express leukocyte function antigen 1 (LFA-1), a surface molecule which gives activated leukocytes the
ability to adhere to endothelial cells and migrate into CNS tissue. This binding involves a specific interaction
between LFA-1 and intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule that is upregulated on
endothelial cells in areas of inflammation (McGeer et al, 2003). Another molecule that is upregulated in ALS
tissue is matrix metalloproteinase-9 (MMP-9) (Lim et al, 1996). MMP-9 is a proteolytic enzyme that is released
by leukocytes and reactive astrocytes to degrade proteins of the extracellular matrix and enhance the entry of
leukocytes into areas of inflammation.
17. MCP-1 is a chemokine which attracts monocytes and myeloid dendritic cells to sites of injury or
inflammation.
True
MCP-1 is a well-known chemoattractant involved in the recruitment of monocytes and dendritic cells into
tissues based on interaction with the cognate receptor CCR2 on invading cells.
18. In vitro, motor neuron injury is induced by exposure to activated microglia. Which microglial
constituents initiate such injury?
1. kainite and IgG
2. mSOD1 and peroxynitrite
3. glutamate and IgG
4. peroxynitrite and glutamate
a.
b.
c.
d.
1, 2,3
1, 3
2, 4
4 only
Using primary MN cultures to investigate the effects of microglia activated by lipopolysaccharide or IgG
immune complexes from patients with amyotrophic lateral sclerosis (Zhao et al, 2004), activated microglia
induced MN injury, by a synergistic effect of glutamate and peroxynitrite.
19. The failure of immunosuppression to ameliorate type-1diabetes or chronic progressive multiple sclerosis,
predominantly immune mediated diseases, invalidates the role of immune mechanisms in initiating these
disorders
False
The fact that immunosuppressant therapy has not been proven to halt progression has been cited as evidence
against an immune-mediated mechanism of motor neuron injury. However, several potential explanations for
this lack of efficacy could exist, including that what initiates the disease may be different from what propagates
the disease or administers the final cellular coup de grace. Finally, if both cytotoxic and neuroprotective
mechanisms are being mediated by the immune system, then suppression of such immunity may suppress
protective as well as toxic mechanisms.
27. Amyotrophic Lateral Sclerosis
Ericka P. Simpson, Albert A. Yen and Stanley H. Appel
8
20. Prostaglandins have a dual role in either promoting neuronal survival or apoptotic death. What factors
may determine which role predominates in CNS injury or degeneration?
1. Target cell and tissue environment, degree of cellular response to the inflammatory mediators, and profile of
specific prostaglandin(s)
2. Exposure to prostaglandin and cox-2 inhibitors, target cell and tissue environment, and profile of specific
prostaglandins(s)
a.
b.
c.
d.
both 1 and 2
neither 1 or 2
1
2
However, neuroinflammation is composed of multiple processes, working in series and parallel, which
cumulatively can limit cellular injury and promote regeneration, or cause tissue damage and cell loss. An
example of this is the dual role of prostaglandins, products of the COX-2 enzyme, in promoting either neuronal
survival or apoptotic death. Determining factors may include the target cell and tissue environment, profile of
specific prostaglandin(s), and the dose-dependent cellular response to the inflammatory mediators (Consilvio et
al, 2004).