Neuroinfectious Diseases Exam 2 Flashcards
1
Q
what does MNS stand for
A
mental, neurological, and substance abuse disorders
2
Q
what are the heterogenous range of diseases and disorders of MNS
A
Mental: schizophrenia, depression, autism
Neurological: dementias, ALS, Huntington
Substance-abuse: alcohol, illicit drugs, pain killers, sleep aids
3
Q
Symptoms and measurable impairments of MNS disorders are in part due to…?
A
some degree of brain dysfunction
4
Q
What 4 factors affect MNS disorders
A
- genetic
- biological
- psychological
- social
5
Q
Why are MNS disorders hard to study
A
bc of the high number of variables due to the brain being the most complex organ
6
Q
What are some examples of the genetic factors of MNS disorders?
A
- mutated SOD1 gene-> ALS
- Mutated MECP2 gene -> Rett syndrome
- Trisomy 21 -> Down Syndrome
- Loss of FMR1 -> Fragile X Syndrome
7
Q
Biological factors of MNS disorders
A
Age and gender (not necessarily sex)
8
Q
Psychological factors of MNS disorders
A
- mood disorders
- education/religion -> psychological strength
- depression (not sadness or unhappiness)
9
Q
what types of diseases are not very well understood?
A
biology of psychological diseases
10
Q
Social factors of MNS disorders
A
- socioeconomic status
- neighborhood factors
- environmental events
- large or sudden social changes (gentrification)
11
Q
what is the cyclical pattern in MNS disorders
A
social adversities increase risk for MNS disorders -> promotes poverty -> increase risk for MNS disorders
12
Q
What does YLLs stand for
A
Years of life lost
13
Q
What does YLDs stand for
A
Years lived with disability
14
Q
what does DALYs stand for and how do you calculate it?
A
Disability adjusted life years
YLL+YLD=DALYs
15
Q
In terms of medical burden, why are MNS disorders hard to measure?
A
MNS disorders increase the risk of premature death without being the actual cause
16
Q
By how much have MNS disorders increased from 1990 to 2010?
A
Increased by 41%
17
Q
Why have mns disorders increased from 1990s?
A
- Aging
- social factors (drug dealers targeting young people)
- population growth
- lifestyle factors (poor nutrition, excessive work hours)
18
Q
What are the substantial social and economic consequences of MNS disorders?
A
- maternal mental -> transmission to children
- correlation of substance use disorders and criminal behavior -> incarceration, lost of productivity
19
Q
what are the effects of mns disorders on family members engaged in caregiving
A
immigration and pop displacement due to conflict or climate change -> increased burden on healthcare system -> effects on equality of service
20
Q
what is the economic output lost to mns disorders globally in 2010?
A
$8.5 trillion
21
Q
what are the nonphysiological interventions?
A
- behavioral therapy
- life-skills education (adulting)
- psychosocial stimulation (for infants and kids)
- population based interventions (i.e. targeting risk factors affecting communities)
- promote healthier diet
- excise taxes
22
Q
what are the most effective mns disorder interventions
A
- use platforms: schools, hospitals
1. population - legislative and regulatory measures
2. community - workplace rules, teacher training
3. healthcare - detection and management of mns disorders - erase stigma of MNS disorders
23
Q
what are 2 problems that prevent effective intervention delivery for mns disorders?
A
- lack of evidence that it confers wider economic and social benefits (households-> society -> country)
- very cost effective but lower and middle income countries cannot afford it
24
Q
what MNS disorders is the lifestyle disorder diabetes mellitus associated with
A
diabetes mellitus ->cognitive disorders
25
what common lifestyle disorders (4) are associated with all mns disorders?
- atherosclerosis
- heart disease
- stroke
- obesity
26
what do all lifestyle disorders that are associated with mns disorders cause?
they all weaken the immune system ->infections ->medical and economic burden
27
what two aspects of healthcare are essential for treating mns disorders?
quantity (ease of access) and quality (effectiveness of treatment)
28
what are the three main non-infectious neurodiseases/disorders
1. progressive neurodegenerative diseases
2. neuropsychiatric disorders
3. addictive disorders
29
what are the 4 main examples of progressive neurodegenerative diseases?
1. Alzheimer's
2. Parkinson's
3. Guillain-Barre Syndrome
4. Multiple Sclerosis
30
what lifestyle disorders is alzheimer's associated with
amyloidosis and tauopathy
31
what lifestyle disorder is Parkinson's associated with
Synucleinopathy
32
what two diseases discussed in class autoimmune?
Guillian-Barre syndrome and Multiple Sclerosis
33
what are the two examples of neuropsychiatric disorders?
depression and schizophrenia
34
what are mental illnesses examples
neuropsychiatric and addictive disorders
35
What is a disorder
it effects your mood, thinking and behavior
36
what are some examples of disorders (5)?
- depression
- schizophrenia
- anxiety disorders
- addictive behaviors
37
what are severe caes of disorders called
psychosis
38
what percent of us population has schizophrenia?
less than 1%
39
what percent of us population experience psychosis
3.5-5%
40
What are three factors that cause changes in brain leading to mental illnesses?
genetics- higher risks if close relative have mental illnesses
environment - poverty, addiction, violence, military struggles
experiences - death of loved one, diseases, stressful situations
41
what type of chronic imbalances in neurotransmission occur that lead to mental illnesses
nerve circuits involved in rewards and emotions
42
Example of nerve circuits involved in rewards and emotions that lead to mental illnesses and where it occurs?
1. abnormally high amounts of dopamine and low amounts of glutamate
2. unbalance can happen in diff parts of brain
43
Structural changes are visible in mental illnesses but...?
inconclusive and nonspecific (see twin MRI images in lecture 24)
44
what is the commonality bw all the MNS disorders?
a. all exhibit symptoms and measurable impairments attributable to brain dysfunction
b. all are consequence of uncontrolled inflammation
c. all have plaques, or proteinaceous aggregates
d. all are transmissible from person-to-person
a. all exhibit symptoms and measurable impairments attributable to brain dysfunction
45
which of the following are clinical therapeutic interventions for mns disorders?
a. increased presence of behaviora therapists at schools
b. use of antipsychotic drugs for schizophrenia or antidepressants for mood disorders
c. policies and legislations to reduce access to the means of suicide
d. better training of teachers and nurses to recognize and identify MNS disorder symptoms
b. use of antipsychotic drugs for schizophrenia or antidepressants for mood disorders
46
there are various ways to treate mns disorders. These are?
a. targeting vectors, or vehicles of mns disorders
b. by enacting legislation that protects children from sources of mental or physical sickness
c. through use of antipsychotics
d. by a combination of therapeutic, psychological, and social interventions
d. by a combination of therapeutic, psychological, and social interventions
47
to implement and maintain an effect mns disorder intervention, lawmakers and funding agencies need ...?
a. to be able to recover the costs incurred
b. evidence of a positive effect on health and their costs and cost-effectiveness
c. to familiarize themselves with the problem by hiring affected individuals to lead the efforts
d. to familiarize themselves with the problem by infecting communities to see the outcome
b. evidence of a positive effect on health and their costs and cost-effectiveness
48
the mortality of mns disorders is difficult to measure or estimate because...?
a. mns disorders result in stillbirths
b. mns disorders increase the risk of premature deaths without being the actual cause of death
c. mns disorders are chronic diseases that do not result in death
d. mns disorders are overrepresented in certain populations but absent in others
b. mns disorders increase the risk of premature death without being the actual cause of death
49
mns disorders are complex because they can be affected and modulated by?
a. age, genetics, religion, and socioeconomic status of the patient
b. month of birth, weight, height, and horoscope
c. all of the above
d. a and b only
a. age, genetics, religion, and socioeconomic status of the patient
50
Which of the following attributes of health systems must be considered when analyzing possible interventions for MNS disorders
Inclusiveness of MNS disorders in health care packages or insurance schemes
51
which of the following is the best definition for mns disorders?
a heterogenous group of clinical manifestations that are affected, and caused, by a complex array of genetic, biological, psychological, and social factors
52
which of the following states is true for mns disorders
they are grouped together because they all owe their symptoms to a brain disfunction
53
what is the monoamine hypothesis referring to mental illnesses?
it is a disbalance of proteins in the brain resulting in neurodegeneration
54
what are the three vehicles or means to deliver interventions against mns disorders
population, community, and healthcare
55
under the healthcare platform, there are various levels at which interventions can take place. These are:
self management and care, primary healthcare, and hospital care
56
hree factors that have contributed to the steady increase in mns disorders in recent times are:
population growth, lifestyle changes, and aging
57
mns disorders manifest broadly and differently because they can be modulated by several factors including:
social, biological, and psychological factors
58
T or F: mns disorders are a catchall term for diseases and disorders that are usually treated equally
F; although mns disorders apply to broad spectrum of diseases, they are not always treated equally
59
T or F: interventions to reduce or prevent mns disorders have benefits for society (i.e. less injuries due to alcohol or drug use)
True
60
T or F: if we want to make a positive change on how we manage and prevent mns disorders, political will and commitment from development agencies to allocate the necessary resources and provide technical leadership is essential
True
61
T or F: Crude mortality numbers are used to estimate the medical burden of mns disorders because they are the direct cause of substantial deaths
False; mns disorders are hard to estimate because they can increase the risk of premature death without being the direct cause of death
62
what are the four main mneurotransmitters in the monoamine hypothesis that can lead to an imbalance in the brain
1. serotonin
2. dopamine
3. norepinephrine
4. epinephrine
63
what is dementia
loss of intellectual and cognitive abilities
64
what are the main three characteristics of dementia in alzheimers?
1. acquired
2. progressive/chronic
3. broad clinical picture, but dominated by personality, mental and motor changes
65
all patients exhibiting dementia deserve a thorough diagnostic evaluation because...
a treatable cause may be discovered
66
the progressive neurodegenerative diseases cause progressive destruction of what and what does it lead to?
progressive destruction of nerve cells lead to death
67
what age group is most likely to have a progressive neurodegenerative disease?
most often present in older people
68
what is senile dementia
decreases in mental abilities experienced by some people in old age
69
why is studying progressive neurodegenerative diseases important
because as population ages, the field becomes more imp as it affects more people
70
what is the most common form of dementia
alzheimer's
71
there is evidence that many progressive neurodegenerative diseases are a type of what?
prion disease
72
what evidence is there that progressive neurodegnerative diseases being a type of prion disease
1. accumulation of protein plaques
2. nerve cell necrosis
3. gliosis
73
what is nerve cell necrosis
Nerve cell necrosis, also known as neuronal necrosis, is a type of cell death that occurs in response to an unplanned injury to a neuron
74
what is gliosis
Gliosis is a nonneoplastic reaction that occurs when the body produces more or larger glial cells, which support nerve cells. This process can cause scars in the brain that impact how the body functions
75
what is amyloidosis and what disease is this seen in?
Amyloidosis is a rare disease that occurs when amyloid proteins build up in the body, causing abnormal protein build-up in tissues and eventually leading to organ dysfunction and death
- seen in alzheimer's
76
what is tauopathy and what disease is this associated with?
Tauopathies are a group of neurodegenerative disorders that cause abnormal tau protein to accumulate in the brain. These deposits can be found in neurons, glial cells, and the extracellular space. The misfolded tau proteins stabilize microtubules in cells, but eventually accumulate and form neurofibrillary tangles (NFTs). These NFTs can lead to neuronal toxicity and degeneration.
- seen in alzheimer's
77
when was alzheimer's disease (AD) first described and by who
first described in 1906 by Alois Alzheimer
78
who was the first patient that was used to describe AD and what evidence supported this
- a 51 yo suffering from severe dementia
1. described the symptoms and the pathological manifestations
2. extracellular deposits of a "peculiar substance"
3. intracellular fibrillary bundles
79
what were the peculiar substance and intracellular fibrillary bundles described by Alois Alzheimer
the peculiar substance was amyloids and the bundles were tau tangles
80
what year was AD accepted to be the cause of most senile dementias
1976
81
what rare mutation confirmed the hypothesis of AD causing senile dementia
a rare mutation discovered in chromosome 21, this also helped to explain incidence of dementia in down syndrome
82
how many APP mutations have been linked to AD since its discovery
more than 50
83
what percent of adults over 65 have AD
5%
84
what percent of adults over 85 have AD
30 to 40%
85
out of the top 10 global causes of deaths in 2016, what place was AD?
5th leading cause
86
out of the top 10 causes of deaths in high income countries in 2016, what place was AD?
3rd place
87
what is imp to note about the top 10 causes of deaths in high vs low income countries in terms of AD?
It is very prevalent in high income countries but not in the low income countries (not part of the top 10)
88
AD is disproportionally prevalent in the developed world, including in these two regions
USA and EU
89
women are ( ) more likely to get AD
2 times, according to Framingham study since 1948 (a still ongoing study)
90
African women are ( ) more likely to get AD
5 times, possibly due to diabetes
91
what is a risk factor for AD
diabetes
92
what type of possible factors are correlated with AD
environmental factors, but nothing conclusive
93
what seems to be protective for AD
education, maybe due to brain activity or just socioeconomic status
94
what percent of AD patients start with memory problems
75%
95
what type of function goes last with AD
motor function
96
what changes are seen in AD (6)
1. language becomes less fluid
2. comprehension declines
3. mood changes common (mild depression and social withdrawal)
4. memory loss more pervasive, involving older memories (capgras)
5. sever interference with normal activities like driving
6. motor skill problems
97
what is capgras syndrome
people replaced by identical impostors, symptom of AD
98
what are examples of motor skill problems associated with AD
problems walking, eating, taking care of themselves
99
how does motor skill loss of AD burden caregivers
not being able to take care of themselves places an economic and psychological burden on caregivers
100
what is the onset of death for AD
8 to 10 years
101
what are the two main types of dementia
cortical and subcortical
102
AD is a classic example of what type of dementia
cortical because of loss of the cerebral cortex
103
the senile plaques found in AD are made up of ?
amyloid Beta
104
what role does cell necrosis play in AD?
Necroptosis is a type of programmed cell death that can contribute to the development of Alzheimer's disease (AD). It can cause cell death and neuroinflammation, and may also contribute to other AD pathological events such as: Aβ aggregation, Axonal degeneration, Mitochondrial dysfunction, and Granulovacuolar degeneration.
105
AD tangles are?
hyperphosphorylated tau protein
106
the immune system reaction to the plaques in AD are?
inflammation that causes damages
107
the inflammation of AD inhibits what brain function
inflammation impairs clearance of waste from brain
108
in AD, what is the neuronal transport system interrupted by
its interrupted by the tau tangles
109
what is the effect of the tau tangles interrupting the neuronal transport system in AD
causes less neurotransmitters, and other components, to be delivered to synapses
110
what acts as catalysts that lead to dissemination and spread of AD
Plaques
111
what kind of response do plaques elicit in AD
elicit inflammatory response
112
the inflammatory response caused by plaques lead to what in AD
lead to neuron killing
113
how many fda approved drugs are there to treat AD
4`
114
is there a cure for AD
no
115
how do the 3 inhbitor medications for AD function
they are inhibitors of cholinesterase which causes increase of neurotransmitter availability
116
how does the NMDA receptor antagonist used to treat AD work?
the NMDA is involved in learning and allows for glutamate import which leads to glutamate toxicity
117
what is key to help treating AD
early diagnosis which is difficult to find volunteers at early stages of disease
118
do AD drugs combine both inhibitors and NMDA receptor antagonists?
yes, some treatments combine both classes
119
current research is targeting the clearance of ?
plaques, has been found to be promising and was based on learning about prion research
120
Parkinson's (PD) is the ( ) most common form of dementia?
2nd most common
121
when was PD first described
1817
122
PD is also known as
Shaking palsy
123
what was the main description of PD
described by tremors
124
what are the 3 classical symptoms of PD
tremors, abnormal posture and gait, and reduced muscle strength
125
what type of dementia is PD and what are of brain is being affected
it is a subcortical dementia that causes the degeneration of the substantia nigra in which neurons produce a black pigment
126
what percent of dopamine neurons are lost by the time of death for PD patients
70%
127
what are the main factors associated with PD
genetic and environmental factors
128
what percent of PD patients have a relative that was affected by PD as well
up to 25%
129
Is pd more common in men or women?
more common in men
130
what ethnicity is more likely to have PD?
caucasians are 3 times more likely to get PD
131
what age is the typical onset for PD
greater than 65 yo
132
are there early onset cases of PD?
yes, it is very rare, and due to genetic cases
133
how many genes are believed to be associated with PD?
7
134
What are the earliest symptoms of PD
tremors which are autorecognized
135
what are the 6 main symptoms seen in PD?
1. tremors
2. slowness of motion
3. overall rigidity and stiffness
4. loss of olfaction
5. mood changes
6. dementia
136
slowness of motion in PD affects movement how?
impairs initiation of movement
137
overall rigidity and stiffness in PD leads to
walking instability which leads to frequent falls
138
what symptom is a telltale sign of PD
loss of olfaction
139
what mood changes are seen in PD
depression and behavioral problems
140
dementia in PD affects what?
mostly daily function but WITHOUT memory loss
141
what disease is very well studied, aka is the oldest movement disorders identified and is also seen in lots of celebrities
PD
142
what neurotransmitter is associated with the mood disorders seen in PD
dopamine which play a role in the rewards system
143
how does dementia occur in PD
lewy bodies cause aggregates of alpha synuclein and in later stages of PD causes dementia due to build up
144
What are Lewy bodies?
Lewy bodies (LBs) are abnormal protein clumps that build up in the brain in people with Parkinson's disease. These deposits are found in areas of the brain responsible for thinking, visual perception, and muscle movement. The formation of LBs has been considered to be a marker for neuronal degeneration, because neuronal loss is found in the predilection sites for LBs
145
Lewy bodies role in PD
it is unclear but seem to be involved in the propagation/spread over the brain
146
what is the normal role of lewy bodies
not known
147
how do lewy bodies cause aggregates in PD
lewy bodies bind to the outside of vesicles (mostly alpha helical) causing the misfolds to form into beta sheets which promote aggregation
148
what is a possible marker for PD diagnosis
Lewy bodies
149
Prion like hypothesis
The prion-like hypothesis suggests that Lewy bodies and other pathological α-synuclein aggregates spread in a prion-like manner throughout Parkinson's disease (PD). This spreading can happen through a process of secretion and uptake, and some pathological forms of α-syn can seed healthy cells, which promotes a self-sustained cycle of inclusion formation, amplification, and spreading. This cycle ultimately underlies the progression of the disease.
150
what is the main causative pathology in PD
death of dopaminergic neurons
151
what kills neurons in PD and why are those the only neurons targeted?
mitochondrial function and ROS generation
152
how does mitochondrial function and ROS generation play a role in PD
Mitochondrial dysfunction is a major factor in the development of Parkinson's disease (PD). Mitochondria are the cell's powerhouse, performing important reactions such as energy production, calcium metabolism, and cell death regulation. They also produce free radicals that can lead to oxidative stress (OS), which can damage intracellular components and cause cell death
- ROS modification of alpha synuclein promotes aggregation
153
what sign presents early onset of PD
carriers of alpha synuclein mutations present early onset of PD leading to an increased level of alpha synuclein
154
What are the three main treatments for PD
1. dopamine and dopamine replacement therapy
2. deep brain stimulation
3. neuroprotection - nonmotor symptoms treatment
155
how does dopamine and dopamine replacement therapy for PD work?
it targets the motor problems only, and will wear off after some years before it can actually start to cause motor years
156
how does deep brain stimulation to treat PD work?
it is a surgical procedure that is given to patients who do not respond to medication, and it works by blocking electrical signals that cause the motor symptoms
157
how does neuroprotection, nonmotor symptoms treatment to treat PD work?
this is cholinesterase inhibitors, antidepressants, caffeine and nicotine supplements
158
study the lecture 25 graph on how the BBB is disrupted in AD
lecture 25
159
There are various causes for dementia, many treatable. Which of the following is treatable?
Certain dementias as a result of stroke
160
the molecular composition of the Alzheimer's plaques and fibers are?
amyloid-Beta and tau protein, respectively
161
what may explain the relatively common occurrence of dementia in young adults with down syndrome?
increased levels of amyloid-beta due to extra copy of the APP gene
162
which of the following are correct comparisons between prion disease and dementia syndromes
both exhibit pathologically clear proteinaceous aggregates
163
which of the following describes PD
a motor disorder, that is an excess or deficiency of movement impulse, movement automaticity, and/or muscle tone
164
Inflammation negatively affects AD and PD pathology because?
it removes the protein aggregates but, as collateral damage, kills the neurons
165
why inhibitors of cholinesterase alleviate AD and PD early symptoms
they increase the neurotransmitter availability which is affected in these diseases
166
Senile plaques, kuru plaques, lewy bodies, are all examples of ?
abnormal cellular debris
167
which of the following are common hallmarks of neurological diseases (infectious and noninfectious)?
neuronal death, gliosis, and inflammation
168
which of the following are main symptoms of PD
tremors, abnormal posture and gait
169
T or F: Most cases of what was previously called "senile dementia: we know now were cases of AD
True
170
T or F: The epidemiology of both AD and PD are similar
False; AD affects more people in high income countries and PD is more common in men than women
171
T or F: Lewy bodies disease is just one of many synucleinopathies, like Alzheimers
False, like PD not AD
172
T or F: All of the neurodegenerative diseases mentioned in class are pathologically defined by intracellular or extracellular protein aggregates
True
173
T or F: In PD, tau tangles disrupts the cellular transport machinery while amyloid plaques are involved in dissemination/spread of disease
False, Amyloid plaques and tau tangles lead to AD not PD
174
The mainstay Parkinson's treatment that can also be used as a diagnostic is...?
dopamine replacement therapy
175
All dementias can be classified into two broad types:
1. cortical
2. subcortical
176
Specific anatomical part of brain affected in PD
substantia nigra
177
Oligmers and plaques of ___________ drive the inflammation in AD
Oligmers and plaques of ___________ drive the inflammation in AD
178
what are the two classical examples of neuromuscular diseases/disorders
GBS and MS
179
what do diseases of motor neurons and neuromuscular junctions (NMJ) affect)?
They affect the signaling from the brain to the muscles aka the motor system
180
what areas of the motor system are affected by motor neuron and NMJ diseases?
1. motor neurons themselves
2. their axons
3. presynaptic terminal
4. postsynaptic terminal
181
what part does NMJ affect in progressive neurodegenerative diseases?
pre and post synaptic terminals
182
what area of the motor system does the GBS affect?
the motor axon, from the spinal cord to the muscles
183
what area of the motor system is affected in MS?
the corticospinal tract from the primary motor cortex all the way down to the caudate medulla
184
what is the most common acute paralytic neuropathy
Guillain Barre Syndrome aka GBS
185
how many cases of GBS are there a year
more than 100000
186
Why is GBS a syndrome and not a disease?
because there are various subtypes
187
what are the two subtypes of GBS and what is their difference
1. targeting myelin membrane - acute inflammatory demyelinating polyneuropathy, antibody injures myelin membranes
2. targeting axonal membrane - acute motor axonal neuropathy or acute motor and sensory axonal neuropathy, antibody injures axonal membranes
188
How long does it take for GBS to develop?
Develops days/weeks after infection or vaccination
189
How does molecular mimicry play a role in GBS?
Molecular mimicry occurs when the antigenic structures of pathogens and humans are similar enough to cause an autoreactive response of T or B lymphocytes after infection, which contributes to disease pathogenesis. In GBS, microbial carbohydrate epitopes induce IgM, IgA, and IgG subclasses, which challenges the classic concept of thymus-dependent (TD) versus thymus-independent (TI) antibody responses
190
How long does it take people to recover from GBS
most pp recover spontaneously in 3 to 4 wks
191
what percent of GBS people recover completely
70%
192
what percent of GBS patients retain residual weakness
30%
193
20 to 30% of people with GBS develop...?
into severe cases that can lead to complete paralysis, including respiratory muscles
194
in severe cases of GBS, how long does rapid progression occur after onset
in 3 to 4 days
195
there is strong evidence of GBS related with?
C. jejuni infection
196
what viruses is GBS associated with
flu, zika, CMV, and epstein barr
197
how is GBS related to C. jejuni infection?
Lipooligosaccharides (LOS) are glycolipids that are expressed on the outer membrane of mucosal Gram-negative bacteria. The LOS core of Campylobacter jejuni can mimic human antigens like gangliosides, and some strains of C. jejuni can trigger Guillain-Barré syndrome (GBS) by mimicking LOS.
198
Lipooligosaccharides (LOS) are glycolipids that are expressed on the outer membrane of mucosal Gram-negative bacteria. The LOS core of Campylobacter jejuni can mimic human antigens like gangliosides, and some strains of C. jejuni can trigger Guillain-Barré syndrome (GBS) by mimicking LOS.
Antibody production
199
immunopathology of GBS is mostly driven by?
mostly a humoral driven pathogenesis (antibody mediated)
200
How is immunopathology of GBS antibody mediated in each GBS subtype?
1. humoral driven pathogenesis against gangliosides in axonal membranes (exposed at nodes of Ranvier)
2. humoral driven pathogenesis against broad range of myelin sheet proteins (moesin was suggested)
201
what GBS subtype is most severe
Axonal subtype
202
what are humoral effects of GBS
Antibody deposits, complement activation of the immune system, macrophage recruitment
203
when is diagnosis for GBS best
early diagnosis correlates to better recovery
204
how is GBS syndrome treated (3 ways)
1. Intravenous Ig infusion
2. Plasma exchange
3. physical therapy for sever cases
205
how does IV Ig infusion treat GBS?
The addition of normal antibodies overcomes effect of autoreactive antibodies (lots of mechs, but most end up reducing inflammation)
206
how does plasma exchange treat GBS?
removal of autoreactive antibodies and other damaging humoral factors
207
why are treatments for GBS not as effective in lower income countries
because treatments are very expensive and often unavailable, so new therapeutics are needed
208
what percent of patients with GBS die and why?
10 to 15% of patients die due to lack of treatment and medical support
209
What is the most common autoimmune mediated disease of the CNS?
Multiple Sclerosis (MS)
210
MS is also known as
Disseminated Encephalomyelitis
211
How many MS cases are there in the US and worldwide?
350000 in US and 2.5 to 3 million worldwide
212
what is the most common age period to get MS
can occur at any age, but most commonly occurs at 20 to 40 yo
213
what are the clinical telltale signs of MS (5 signs)
1. sudden onset of muscle weakness
2. loss of sensation
3. numbness
4. pain
5. vision problems
214
what is protective against MS
pregnancy
215
are women or men more likely to get MS
women are 3x more likely
216
what are the four major types of MS
1. relapsing remitting MS
2. primary progressive MS
3. secondary progressive MS
4. progressive relapsing MS
217
after how long of of relapsing remitting MS does it turn into Secondary progressive MS
15 to 25 years
218
relapsing manifestation of MS is associated with?
autoimmune inflammation
219
progressive manifestation of MS is associated with?
neurodegeneration
220
Why is history of patient important for MS diagnosis?
the recurrence of isolated neurological symptoms is important to identify MS
221
what is the best way to see lesions of MS
MRI which shows aggregation of immune cells
222
the presence of lesions predicts MS development with what percent of accuracy?
more than 80% accuracy
223
T or F: size and number of lesions correlate with severity of MS
False
224
what is most critical when it comes to MS lesions
location is most critical, but steady increase is correlated with severity as well
225
how does MRI show lesions due to MS
the contrast enhancing media shows the BBB breaches due to inflammation
226
MS is due to?
chronic inflammation
227
In MS, does inflammation affect white or grey matter first?
white matter early on then spreads to grey matter
228
How does inflammation occur in MS?
1. autoreactive microglia and astrocytes signal for immune recruitment
2. activated T cells enter and bind their targets exposed by microglia and astrocytes
3. T cells now are programmed to bind and destroy myelin, oligodendrocytes, or axons
4. B cells are activated to generate autoantibodies
5. T cells release cytokines that activates astrocytes and microglia causing uncontrolled inflammation
229
Why is MS such a chronic disease with months of no symptoms between attacks?
When myelin is destroyed, the axon redistributes the ion channels and switches to continuous signaling rather than saltatory signaling
- there is also remyelination in which Oligodendrocyte progenitor cells (OPCs) are responsible for remyelination in the central nervous system (CNS) in health and disease.
BUT as MS progresses, remission periods are shorter and fewer
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What occurs as MS progresses and remission periods are shorter?
1. correlates with decline in remyelination
2. with less remyelination, axon dies
3. OPCs ability to differentiate declines with age
4. once axonal death starts, progression into advanced MS is inevitable
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Is there a cure for MS?
no
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What is one of the leading causes of death in MS?
Suicide
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What are the supportive treatments available for MS
1. amelioration of acute attack symptoms
2. anti-inflammatory agents
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what is the problem with MS treatments
1. very expensive with single dose averaging about $60000
2. can make you immunosuppressed aka susceptible to infections
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Ms is is an example of what in regards to neurodegenerative diseases?
MS is example that not all neurodegenerative diseases involve prion like component
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current disease modifying drugs for MS target what?
target the immune reaction not the actual causative pathology (axonal destruction)
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what is the 2 hits theory
The two-hit hypothesis, also known as the Knudson hypothesis, is a cancer genetics theory that states that most tumor suppressor genes (TSGs) require both alleles to be inactivated to cause a change in phenotype. This can happen through mutations or epigenetic silencing. The first hit can be promoter hypermethylation, and the second hit can be a nonsense or frameshift mutation, or loss of heterozygosity (LOH). The two-hit hypothesis provides a model for understanding cancer that occurs in individuals who carry a susceptibility gene and cancers that develop because of randomly induced mutations in otherwise normal genes.
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What are the 2 types of GBS
axonal and demyelinating
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Which of the following would be the most accurate definition of molecular mimicry in disease?
Similarities between the antigens and microbe and a host
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What can be affected in diseases of motor neurons?
neuromuscular junctions
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In MS, the pathology is driven by an humoral and cellular response towards
oligodendrocytes
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In MS, there are ______________ as well as _________________ epidemiological oddities
geographical; dietary
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T or F: in developed countries, MS is the most common peripheral nervous system disease that arises in young adults and causes permanent disability
False; MS is most common CNS disease
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T or F: The pathology in GBS is driven by a cellular response towards motor neuron axons
False; driven by humoral response
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T or F: GBS occurs when the autoreactive antibodies bind to the myelin sheath on the CNS nerves
False, it affects the peripheral nerves
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T or F: MS can strike at any age, but most cases are in people over 40
False; ms affects pp bw 20 and 40 yo
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T or F: a temporary remission from GBS symptoms occurs when women are pregnant
False, it is in MS where recovery of symptoms occurs
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Compare and contrast the two effective treatments for GBS
One form of treatment for GBS is IV Ig infusion which causes macrophage receptors to be blocked by Igs and makes macrophages unable to bind to motor neurons (basically adds normal antibodies to overcome effect of autoreactive antibodies) while plasma exchange removes the autoreactive antibodies along with other damaging humoral factors. The more severe cases are treated with IV ig infusions and patients averse to immunoglobulin therapy are recommended to use plasma exchange
249
IN class we discussed leading theories explaining the development of autoimmune reactions in GBS and MS. State them and briefly discuss why one is temporary (GBS) while the other is permanent (MS)
In GBS, there is a molecular mimicry in which C. jejuni infection results in gangliosides in PNS axons. In MS, the reaction is due to chronic inflammation where autoreactive microglia signal for immune recruitment causing T and B cells to activate and result in uncontrolled inflammation. GBS is temporary in that the symptoms can eventually ease up and patient can recover while MS causes permanent damage to nerve fibers
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Do microbes directly influence the brain?
there are clear examples of alter brain function by infections
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3 examples of how infections alter brain function
1. rabies ->vampirism or werewolf myth because of altered behavior
2. Toxoplasma and "cat ladies" (or taking away fear of cats in rodents)
3. Herpes virus infection linked to increased risk to develop MS
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What are some other infections linked to nervous disorders (2 examples)?
1. C. jejuni infection as driver of GBS
2. AD can be result of brain infection -> AB plaques are a defensive mech in overdrive against infection
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what is the gut brain axis?
The bidirectional link between the CNS and the GI track, mediated by endocrine, immune, and neural signaling
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What are the 5 main gut brain axis players?
1. microbiota
2. gut-immune link
3. vagus nerve
4. bacterial mediators
5. hypothalamic-pituitary-adrenal (HPA) circuit
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what is the microbiota
Individual microbial species in a biome - bacteria, fungi, archaea and viruses; all microorganisms living in stable association with their host
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what does disruption to the microbiota lead to
allergies and metabolic disorders
257
what is the Gut-immune link
acquisition of microbiota during birth essential to train immune intolerance, the microbial signature of a baby
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what is the vagus nerve
it is the 10th cranial nerve, the longest nerve in the ANS connecting the GI tract to the brain stem
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What are bacterial mediators
precursors to, or actual, neurotransmitters (Serotonin)
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what is the HPA circuit
the brain's stress response system
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ow does the gut brain axis work?
1. bacterial metabolites act upon the different interfaces in the gut: the epithelial, the immune and neural
2. SCFAs: short chain fatty acids
3. Balance of pro and anti inflammatory cytokines
4. response of the HPA to neuroactive metabolites
5. reaction of the gut and immune cells to HPA response
6. Counter reaction of microbiota to gut and immune cells response
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Balanced vs unbalanced gut brain axis
Balanced State: the epithelial and immune cells are trained in tolerance to correct microbiota AND microbiota is adapted to host's biochemical normal response
Unbalanced state: small change in either microbiota composition or host's biochemical response can lead to uncontrolled dysregulation (butterfly effect, leading to pathology)
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What are four ways the gut brain axis is seen in disease?
four ways the gut brain axis is seen in disease?
1. autoimmune diseases (hygiene hypothesis)
2. autism
3. depression and anxiety
4. obesity
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how does the gut brain axis and autoimmune disease correlate?
When the immune system training is disrupted and leads to aberrant immune reactions such as asthma, allergies, and MS
265
How are autism and the gut brain axis correlated?
The correlation between autism and dysbiosis of the gut. Picky eating habits, genetics, or environmental factors (this is not always clear)
266
what is the correlation between the gut brain axis and depression and anxiety?
high correlation between intestinal disorders and mental illness
267
what is the correlation between the gut brain axis and obesity
correlation between gut microbiota and misregulation in the CNS control of food intake
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what are 5 ways the gut brain axis can affect health/disease?
1. gut microbiota dysbiosis
2. inflammation ->leaky gut
3. leaky gut -> LPS exposure ->inflammation
4. chronic stress -> high cortisol levels
5. high cortisol -> go back to 1 and 2
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Study of AD, a faulty defense or dysbiosis of the brain? What are the main findings?
- response to infection where AB plaques are a defense strategy
- correlation bw brain herpes infection and risk to develop AD
- animal studies suggest plaque are a response to infection and are protective
270
What is the first brain? or fist two brains
the actual brain in skull
- brain stem and limbic system (oldest, emotional brain)
- neocortex (youngest, higher processing brain)
271
what is the third brain?
your enteric nervous system aka gut brain
- influenced by microbiota
272
what is the fourth brain?
brain microbiota
- same way gut microbiota influences our brain, but without the intermediary
273
what is the significance of the UAB med school findings?
they studied brain slices from healthy and schizophrenia patients and found rod shaped objects in EM images that were consistent with bacteria but did not know how they got there. it could represent a previously unknown mechanism by which the immune system activity within brain is regulated
274
what is fuel for the brain
neurotransmitters
275
what produces the same type of brain fuel
microbes
276
what is the chicken egg problem in the gut brain axis
what affects gut/brain also affects the gut/brain
277
what highlights the connection between mental and physical health
MS
278
Which of the following is not a player in the Gut brain axis
the stomach
279
mental illnesses can be classified into the following categories
mood disorders, cognition disorders, and behavioral disorders
280
which of the following statements best describe the gut brain axis
a bidirectional link between the gut and the brain mediated by several signals
281
which of the following is an example of a microbe influencing behavior
rabies infection turning the infected aggressive
282
how is the hygiene hypothesis related to the gut microiota
- the human microbiota is necessary to train immune system, and this period of immune training is disrupted by extremely clean household environments
- the lack of exposure to microbes early in life increases risk for autoimmune diseases like asthma
- constant, low grade exposure to antibiotics or hormones (like diary or cattle industry) changes ratio of bad and good gut microbes, which throws off the immune system, promoting aberrant reactions
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T or F: mental illnesses are considered disorders rather than diseases because the causative agent is unknown
True
284
T or F: there are 3 mediators between the gut and the brain: hormones, cytokines, and neuroreactive compounds
True
285
T or F: a small changes in the gut microbiota can affect the brain, but small changes in the brain does not affect the microbiota
False, the gut brain link is bidirectional meaning changes in brain also affect microbiota
286
T or F: the monoamine hypothesis states that a disbalance in levels of serotonin, norepinephrine (or epinephrine), and dopamine is behind mental illnesses
true
287
The 3 types of bacterial metabolites that can affect brain function
SCFAs, neurotransmitters, and immune modulatory metabolites
288
the 3 mental disease/disorders where there is a clear correlation with gut dysbiosis
autism, depression, and anxiety
289
4 ways by which the gut brain axis can affect health and disease
1. gut microbiota dysbiosis
2. inflammation leading to leaky gut
3. leaky gut leading to LPS exposure/inflammation
4. chronic stress causing high cortisol
290
what is essential to train and promote immune intolerance
gut immune link
291
collection of microorganisms living in stable association with their host
microbiota
292
part of our brain that coordinates the response to external stresses like hunger
HPA circuit
293
one of the cranial nerves that serve as a link between the gut and the CNS
vagus nerve
294
compounds produced by bacteria that can have an effect on the gut brain axis
bacterial mediators
