Trigger 8 - Alzheimer’s disease and amyloid targeting therapies Flashcards
1
Q
Define Dementia
A
Dementia is the loss of cognitive functioning (e.g., thinking, remembering, and reasoning) to such an extent that it interferes with daily life and activities.
2
Q
True or False: Dementia is a normal part of aging.
A
False. Dementia is not a normal part of aging.
3
Q
Fill in the Gap: Dementia prevalence increases with advancing _________.
A
Age.
4
Q
What is the most common form of dementia?
a) Vascular dementia
b) Frontotemporal dementia
c) Alzheimer’s disease
d) Lewy body dementia
A
c) Alzheimer’s disease
5
Q
Describe Early Onset Alzheimer’s Disease (EOAD):
A
EOAD occurs in individuals under 65 years of age and often has a significant genetic component.
6
Q
Describe Late Onset Alzheimer’s Disease (LOAD):
A
LOAD occurs in individuals over 65 years of age and is generally sporadic in nature.
7
Q
True or False: Alzheimer’s disease is characterized by short-term memory loss as its first symptom.
A
True
8
Q
Fill in the Gap: Alzheimer’s disease develops to more severe memory problems, confusion, disorientation, personality changes, and problems with ________ and _________.
A
Language and speech.
9
Q
Which of the following is NOT a sign or symptom of Alzheimer’s disease?
a) Misplacing items
b) Difficulty in decision making
c) Heightened ability to understand visual images
d) Social withdrawal
A
c) Heightened ability to understand visual images
10
Q
Define Alzheimer’s Disease
A
Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline, leading to interference with daily functioning and activities.
11
Q
True or False: Alzheimer’s disease is more prevalent in men than in women.
A
False. More women have Alzheimer’s disease than men.
12
Q
Fill in the Gap: Globally, over ______ million people have some form of dementia.
A
55 million.
13
Q
Which of the following is a common early symptom of Alzheimer’s disease?
a) Difficulty in problem solving
b) Reduced ability to understand visual images
c) Mood swings
d) Misplacing items
A
d) Misplacing items
14
Q
Describe Dementia Prevalence in the UK
A
In the UK, over 1 million people are currently affected by dementia, which accounts for approximately 1 in 11 individuals over the age of 65.
15
Q
True or False: Dementia prevalence is expected to decrease by 2050.
A
False. Dementia prevalence is expected to increase, with cases in the UK projected to reach at least 1.6 million by 2050.
16
Q
Fill in the Gap: Age is the biggest risk factor for _________.
A
Dementia
17
Q
Which form of Alzheimer’s disease has a larger genetic component?
a) Early onset
b) Late onset
c) Both have equal genetic components
d) Neither has a genetic component
A
a) Early onset
18
Q
Define Neuropathology
A
Neuropathology refers to the study of diseases of the nervous system, including the structural and biochemical changes that occur in the brain and nervous tissue.
19
Q
True or False: Alzheimer’s disease primarily affects the peripheral nervous system.
A
False. Alzheimer’s disease primarily affects the central nervous system, particularly the brain.
20
Q
Fill in the Gap: One of the signs of Alzheimer’s disease is confusion with ______ and ______.
A
Time and place.
21
Q
True or False: Memory loss is a common sign of Alzheimer’s disease.
A
True
22
Q
Fill in the Gap: Alzheimer’s patients may have difficulty in ________ items.
A
Misplacing
23
Q
Which of the following is a symptom of Alzheimer’s disease?
a) Enhanced ability in problem solving
b) Increased ability to complete complex tasks
c) Mood swings
d) Improved understanding of visual images
A
c) Mood swings
24
Q
Define: Repetitive Speech and Writing Issues
A
Repetitive speech and writing issues refer to the tendency of individuals with Alzheimer’s disease to repeat the same words, phrases, or sentences and to have difficulties with written communication.
25
True or False: Social withdrawal is not associated with Alzheimer's disease.
False. Social withdrawal is a common symptom of Alzheimer's disease.
26
Which of the following is NOT a symptom of Alzheimer's disease?
a) Difficulty in decision making
b) Enhanced ability to complete complex tasks
c) Inability to complete complex tasks
d) Reduced ability to understand visual images
b) Enhanced ability to complete complex tasks
27
Define: Inability to Complete Complex Tasks
Inability to complete complex tasks refers to the difficulty individuals with Alzheimer's disease may have in carrying out tasks that require multiple steps or intricate problem-solving skills.
28
True or False: Alzheimer's disease does not affect judgment and decision-making abilities.
False. Alzheimer's disease can impair judgment and decision-making abilities.
29
Define Mild Cognitive Impairment (MCI)
Mild cognitive impairment refers to cognitive decline that is abnormal for age and education but does not interfere with function and activities.
30
True or False: MCI is considered a precursor to degenerative dementia
True
31
Fill in the Gap: When memory loss predominates in MCI, it is termed ________ MCI.
Amnestic
32
Describe the Cause of Dementia
Dementia is caused by pathological changes in the brain that lead to loss of synaptic function and neurodegeneration, resulting in progressive impairment of brain circuitry and loss of function.
33
True or False: The pathological hallmarks of Alzheimer's disease include extracellular senile plaques and intracellular neurofibrillary tangles.
True
34
Fill in the Gap: The main component of senile plaques is ________ aggregates/oligomers.
Ab (beta-amyloid).
35
Which brain region largely spares the development of neurofibrillary tangles in Alzheimer's disease?
a) Neocortex
b) Cerebellum
c) Hippocampus
d) Entorhinal cortex
b) Cerebellum
36
Describe Neurofibrillary Tangles (NFTs)
NFTs develop from pre-tangles to mature tangles and are primarily composed of tau aggregates as paired-helical filaments (PHF), with "ghost tangles" remaining after neuron death.
37
True or False: The spread of plaques and tangles across the brain is associated with functional deficits, synapse loss, and neuron loss.
True
38
Fill in the Gap: Plaques originate in the ________ and spread through most other cortical areas and then most of the rest of the brain.
Neocortex
39
Define Prion-like Spread:
Prion-like spread refers to the process in which a native (soluble) protein is "converted" into a misfolded "seed" by a pathological protein that acts as a template.
40
True or False: Tau and Abeta spread along axon tracts and trans-synaptically to connected brain regions.
True
41
Fill in the Gap: The pathological protein propagates by ________ nucleation, recruiting endogenous protein into aggregates.
Seeded
42
What is the term for the process by which tau and Abeta spread along axon tracts and trans-synaptically to connected brain regions?
a) Seeded propagation
b) Prion replication
c) Axonal transmission
d) Trans-synaptic spread
d) Trans-synaptic spread
43
Describe the Prion-like Spread Mechanism
The prion-like spread mechanism involves the conversion of native soluble proteins into misfolded seeds by pathological proteins, which then propagate through seeded nucleation, recruiting endogenous proteins into aggregates and spreading along axon tracts and across synapses to connected brain regions.
44
Describe CERAD Staging
CERAD staging assesses plaque abundance in the neocortex as a method to score disease severity in Alzheimer's disease.
45
True or False: CERAD staging primarily focuses on tangle location in the brain
False. CERAD staging focuses on plaque abundance in the neocortex.
46
Fill in the Gap: Braak staging primarily focuses on the location of _________.
Tangles
47
Which staging system assesses tangle location in Alzheimer's disease?
a) CERAD staging
b) Braak staging
c) Amyloid imaging staging
d) CSF biomarker staging
b) Braak staging
48
Describe the Diagnosis of Alzheimer's Disease
Even with advances in biomarkers such as imaging, blood tests, and cerebrospinal fluid (CSF) analysis, Alzheimer's disease is usually diagnosed at an advanced stage. Genetic testing, particularly in those with mild cognitive impairment (MCI), along with biomarkers, may allow earlier diagnosis
49
True or False: AD blood tests are typically based on the levels of phospho-tau and/or Abeta species in the blood.
True
50
l in the Gap: A blood test for Alzheimer's disease may not be able to rule in or out the disease 100% of the time, but it might be a cheap and easy way to help doctors spot which patients have hidden physical signs of the disease, years before ________
Telltale
51
What does CERAD staging assess in Alzheimer's disease?
a) Tangle location
b) Amyloid plaque abundance
c) Synaptic dysfunction
d) Neuronal loss
b) Amyloid plaque abundance
52
Describe Amyloidogenic Pathway
In the amyloidogenic pathway, Ab is generated following cleavage of amyloid precursor protein (APP) by β and γ secretases.
53
Define Non-amyloidogenic Pathway
In the non-amyloidogenic pathway, cleavage of APP by α and γ secretases precludes Ab production.
54
Fill in the Gap: Gamma secretase first cleaves the APP-C99 substrate into either Aβ48 or Aβ49 peptides via ______-cleavage.
ε-cleavage.
55
Which Aβ peptides does the field generally focus on in Alzheimer's disease?
a) Aβ36 and Aβ38
b) Aβ40 and Aβ42
c) Aβ44 and Aβ46
d) Aβ50 and Aβ52
b) Aβ40 and Aβ42
56
Describe Ab42
Ab42 is pro-aggregatory and is generally believed to be damaging in Alzheimer's disease.
57
Ab42 is pro-aggregatory and is generally believed to be damaging in Alzheimer's disease.
True
58
l in the Gap: Oligomeric Ab forms a "halo" around plaques, with ______ at the core.
Fibrils.
59
Where is synapse loss greatest in relation to Ab oligomers?
a) At the center of plaques
b) Away from plaques
c) At the periphery of plaques
d) At the highest concentrations of Ab oligomers
d) At the highest concentrations of Ab oligomers
60
Tue or False: The tau protein is encoded by the MAPT gene located on chromosome 17.
True
61
Fill in the Gap: There are ______ main isoforms of tau in the adult human CNS, as a result of alternative splicing of Exons 2, 3, and 10.
Six
62
What is the ratio of 3R:4R tau isoforms in the healthy brain?
a) 2:1
b) 1:1
c) 1:2
d) 3:1
b) 1:1
63
Describe Tau Modifications in AD
In Alzheimer's disease, tau undergoes phosphorylation, C-terminal cleavage, further phosphorylation in the mid-region/C-term end, misfolding after changes in charge, and additional modifications such as acetylation and ubiquitination. These modifications lead to the stacking of tau into fibrils with the microtubule binding domain at the core.
64
True or False: Tau changes in Alzheimer's disease are unrelated to synapse loss and clinical features of the disease.
False
65
Fill in the Gap: Familial forms of AD, which are almost always early-onset, are caused by rare autosomal dominant mutations in 1 of 3 genes, including ______, ______, and ______.
APP, PSEN1, and PSEN2.
66
Which gene encodes the amyloid precursor protein (APP)?
a) PSEN1
b) PSEN2
c) APP
d) MAPT
c) APP
67
Describe the Role of PSEN1 and PSEN2 in AD
Presenilin 1 and 2 are part of the gamma secretase complex that cleaves Ab. Mutations in PSEN1 and PSEN2 largely favor the production of the most aggregation-prone forms of Ab.
68
True or False: Age is the greatest risk factor for Alzheimer's disease.
True
69
Fill in the Gap: Highly penetrant mutations in APP, PSEN1, and PSEN2 that segregate with autosomal dominant AD are _______ and have large effect sizes.
Extremely rare
70
Which of the following genetic variants increase the risk of Alzheimer's disease, particularly in pathways related to the immune system/inflammation, lipid processing, endosomal pathways, and synapses?
a) APOE ε4
b) APOE ε2
c) Variants discovered by genome-wide associations
d) Mutations in APP, PSEN1, and PSEN2
d) Mutations in APP, PSEN1, and PSEN2
71
Describe APOE ε2
APOE ε2 may provide some protection against Alzheimer's disease. If Alzheimer's occurs in a person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene.
72
True or False: APOE ε3 is believed to have a neutral effect on the risk of Alzheimer's disease.
True
73
Fill in the Gap: APOE ε4 increases the risk for Alzheimer's and is associated with an earlier age of disease onset in certain populations. About ______ of people have this allele.
15% to 25%
74
Which allele of APOE increases the risk of Alzheimer's disease?
a) APOE ε2
b) APOE ε3
c) APOE ε4
d) APOE ε6
c) APOE ε4
75
Describe the Role of Genetics in Alzheimer's Disease Risk
Genetics play a major role in the risk of Alzheimer's disease onset, with certain genes elevating a person's risk and others decreasing it. These genetic risk factors can be split depending on the form of AD, with APOE being a risk gene for late-onset AD and mutations in APP, PSEN1, and PSEN2 impacting early-onset AD.
76
ue or False: Environmental factors such as a healthy diet and exercise have no impact on the risk of Alzheimer's disease.
False
77
True or False: The number of patients with Alzheimer's disease doubles every 5 years after the age of 65.
True
78
Fill in the Gap: Genetics play a major role in the risk of Alzheimer's disease onset, with certain genes elevating a person's risk and others decreasing it. These genetic risk factors can also be split depending on the form of AD, including ______-onset and ______-onset.
Late; early.
79
Which chromosome is the APOE gene located on?
a) Chromosome 17
b) Chromosome 19
c) Chromosome 21
d) Chromosome 14
b) Chromosome 19
80
Describe the Role of Presenilin 1 and 2 in AD
Presenilin 1 and 2 are part of the gamma secretase complex that cleaves Ab. Mutations in PSEN1 and PSEN2 largely favor the production of the most aggregation-prone forms of Ab, contributing to the pathogenesis of Alzheimer's disease.
81
True or False: Inheriting two copies of the APOE ε4 allele is associated with a higher risk of Alzheimer's disease than inheriting one copy.
True
82
Fill in the Gap: Variants discovered by genome-wide associations are mostly ______ to ______ with small effect sizes.
Common; low-frequency.
83
What is the main form of pathogenesis in Alzheimer's disease?
a) Tau aggregate formation
b) Synapse loss
c) Neuroinflammation
d) Abeta plaque accumulation
d) Abeta plaque accumulation
84
Describe the Role of Age in Alzheimer's Disease Risk
Advancing age is the most influential risk factor for Alzheimer's disease. This is due to age-related co-morbidities such as atrophy of key brain areas, inflammation, vascular damage, production of free radicals, and breakdown of cell energy production.
85
True or False: APOE ε2 is associated with an increased risk of Alzheimer's disease
False. APOE ε2 may provide some protection against the disease.
86
Fill in the Gap: Each person inherits two APOE alleles, one from each biological parent, meaning people can have one of ______ possible combinations.
Six
87
Describe Pre-tangles
Pre-tangles represent the initial stage of neurofibrillary tangles and are characterized by the perinuclear accumulation of tau protein within neurons.
88
True or False: Granulovacuolar degeneration is a well-understood process in Alzheimer's disease.
False
89
Fill in the Gap: Eosinophilic Rodlike Inclusions are characterized by the presence of interweaving parallel fibers composed of actin, tropomyosin, and ________.
Viculin
90
Which component primarily constitutes the central core of senile plaques?
- a) Tau protein
- b) Amyloid beta protein
- c) Ubiquitin
- d) Cholinesterase
b) Amyloid beta protein
91
Describe Synaptic Loss in Alzheimer's Disease:
Synaptic loss refers to a substantial reduction in synaptic profiles, which correlates strongly with the severity of functional impairment in Alzheimer's disease.
92
True or False: Neurofibrillary tangles are primarily composed of amyloid beta protein
False
93
Fill in the Gap: Senile plaques originate in the neocortex and then spread to other cortical areas and ________.
The rest of the brain.
94
Which region of the brain is most commonly affected by granulovacuolar degeneration?
- a) Cerebellum
- b) Hippocampus
- c) Basal ganglia
- d) Neocortex
b) Hippocampus.
95
Describe Ghost Tangles
Ghost tangles are composed of loosely arranged bundles of fibers with no associated nucleus, indicating neuronal death in Alzheimer's disease progression.
96
True or False: Vascular amyloid deposition is a common feature in Alzheimer's disease that primarily affects the white matter of the brain.
False
97
Excitotoxicity Theory
The excitotoxicity theory suggests that prolonged elevation of calcium ions (Ca2+) leads to suppressed synaptic function, synaptotoxicity, atrophy, and loss of learning and memory functions in Alzheimer's disease. This theory is supported by the observation that NMDA receptor antagonists slow AD progression.
98
Fill in the Gap: Excitotoxicity theory proposes that prolonged elevation of _______ ions leads to suppressed synaptic function in Alzheimer's disease.
Calcium (Ca2+).
99
Which receptors mediate synaptic plasticity required for memory and learning in Alzheimer's disease?
- a) AMPA receptors
- b) GABA receptors
- c) NMDA receptors
- d) Dopamine receptors
c) NMDA receptors
100
Describe Tau Protein Dysfunction:
Tau protein dysfunction in Alzheimer's disease involves hyperphosphorylation, leading to the dissociation of the protein from microtubules. This results in inefficient transport, starvation of neurons, and ultimately, cell death.
101
True or False: Tau protein mediates the transfer of Fyn to the dendritic compartment, where it phosphorylates NMDA receptors.
True
102
Fill in the Gap: In Alzheimer's disease, Aβ accumulation leads to the formation of amyloid plaques through the _______ pathway.
Amyloidogenic
103
Which peptide is released as a result of the amyloidogenic pathway in Alzheimer's disease?
- a) Tau
- b) Amyloid beta (Aβ)
- c) Synaptophysin
- d) Neurofilament
b) Amyloid beta (Aβ)
104
Describe Mitochondrial Dysfunction and ROS Generation
Mitochondrial dysfunction in Alzheimer's disease results in the aggregation of Aβ peptides within mitochondria, leading to disrupted mitochondrial conformation, decreased ATP release, and increased generation of reactive oxygen species (ROS). This oxidative stress contributes to neuronal damage and apoptosis.
105
True or False: Oxidative stress occurs later in Alzheimer's disease progression.
False
106
Fill in the Gap: Aβ-peptides contribute to mitochondrial dysfunction by increasing the release of _______ and apoptosis-inducing factor.
Cytochrome C.
107
Which theory suggests that accumulation of oligomeric Aβ leads to neuroinflammation, neurofibrillary tangles, vascular injury, and cognitive deficits in Alzheimer's disease?
- a) Excitotoxicity theory
- b) Tau protein dysfunction theory
- c) Aβ hypothesis
- d) Mitochondrial dysfunction theory
c) Aβ hypothesis
108
Describe the Amyloid Cascade Hypothesis
The amyloid cascade hypothesis proposes that the accumulation of amyloid-beta (Aβ) peptides, resulting from mutations in APP, PSEN1, and PSEN2 genes, is the primary event leading to neurodegeneration in Alzheimer's disease.
109
True or False: Synapse loss is evenly distributed across all brain regions in Alzheimer's disease.
False
110
Fill in the Gap: Modified tau loses important physiological functions and gains ______ properties.
Toxic
111
Which of the following pathways are implicated in Alzheimer's disease, based on genetic and experimental data?
- a) Tau production
- b) Neuroinflammation
- c) Axonal transport deficits
- d) All of the above
- d) All of the above
112
Describe Tau Tangles in Alzheimer's Disease
Tau tangles are present in brain stem nuclei and the entorhinal cortex of many cognitively normal aged individuals. In Alzheimer's disease, the presence of cortical plaques correlates with neuronal tau propagation from the entorhinal cortex into neocortical areas.
113
True or False: The mechanisms underlying neurodegeneration in Alzheimer's disease are fully understood.
False
114
Fill in the Gap: The lack of certainty about which mechanism is the most important for disease pathogenesis is reflected in the various ______ being explored in current clinical trials.
Targets
115
What is the primary event proposed by the amyloid cascade hypothesis that leads to neurodegeneration in Alzheimer's disease?
- a) Accumulation of tau tangles
- b) Accumulation of amyloid-beta peptides
- c) Synapse loss
- d) Neuroinflammation
b) Accumulation of amyloid-beta peptides.
116
Describe Approved AD Treatments in the UK
Approved treatments in the UK for Alzheimer's disease address some symptoms but do not modify the disease course. These include anticholinesterase inhibitors (rivastigmine, galantamine, donepezil) to treat cognitive symptoms and memantine, an NMDA antagonist, to offset glutamatergic neuron toxicity.
117
True or False: Aducanumab was approved by the European Medicines Agency (EMA) for the treatment of Alzheimer's disease.
False
118
Lecanemab targets amyloid protofibrils and binds to them with high ______.
Affinity
119
What is the primary target of donanemab in Alzheimer's disease?
- a) Tau protein
- b) Glutamate receptors
- c) Amyloid protofibrils
- d) NMDA receptors
c) Amyloid protofibrils
120
Describe Aducanumab
Aducanumab is a drug that targets aggregated amyloid in Alzheimer's disease. Despite initially halted trials, subsequent analyses showed promising results, leading to FDA approval in the United States in June 2021. However, there have been conflicting opinions on its efficacy and safety.
121
True or False: Lecanemab has shown significant improvement in cognitive decline in a Phase 3 trial.
True
122
Fill in the Gap: Donanemab slowed the clinical progression of Alzheimer's disease by ______ weeks.
76
123
What is the primary mechanism of action of the approved AD drugs, Aducanumab, Lecanemab, and Donanemab?
- a) Inhibition of tau hyperphosphorylation
- b) Enhancement of cholinergic neuron function
- c) Targeting aggregated amyloid
- d) Modulation of glutamatergic neurotransmission
c) Targeting aggregated amyloid
124
Describe the Mechanism of Anticholinesterase Inhibitors in AD Treatment:
Anticholinesterase inhibitors, such as rivastigmine, galantamine, and donepezil, offset the effects of cholinergic neuron loss in Alzheimer's disease by inhibiting the breakdown of acetylcholine, thereby improving cognitive symptoms.
125
True or False: Memantine is a first-line treatment for Alzheimer's disease in the UK.
True
126
Fill in the Gap: Aducanumab targets aggregated amyloid in Alzheimer's disease and was approved by the ______ in June 2021.
U.S. Food and Drug Administration (FDA).
127
What is the primary target of Lecanemab in Alzheimer's disease?
- a) Tau protein
- b) Glutamate receptors
- c) Amyloid protofibrils
- d) NMDA receptors
c) Amyloid protofibrils
128
Describe the Trial Design of Donanemab
Donanemab underwent an 18-month Phase 3 double-blind multicenter randomized controlled trial (RCT) to assess its efficacy in early symptomatic Alzheimer's disease. Participants received intravenous doses of the drug every 4 weeks.
129
True or False: Aducanumab was initially removed from further trials due to its lack of efficacy.
True
130
What was the primary outcome of the Phase 3 trial for Donanemab?
- a) Reduction in tau pathology
- b) Improvement in cognitive decline
- c) Clearance of amyloid plaques
- d) Slowed clinical progression of the disease
d) Slowed clinical progression of the disease.
131
Describe the Safety Concerns Associated with Lecanemab
Despite its efficacy in improving cognitive decline, Lecanemab raised safety concerns, including adverse events such as amyloid-related imaging abnormalities (ARIA).
132
True or False: Donanemab was associated with more treatment-related deaths compared to the control group in its Phase 3 trial.
True
133
Define Active Vaccinations
Active vaccinations involve exposing an individual to an antigen to stimulate an adaptive immune response, resulting in the production of antibodies to combat the antigen.
134
Define Passive Vaccinations
Passive vaccinations entail administering antibodies against specific target proteins, bypassing the need for the individual's immune system to generate an immune response.
135
Passive vaccinations entail administering antibodies against specific target proteins, bypassing the need for the individual's immune system to generate an immune response.
Ab (amyloid-β).
136
Proposed Mechanisms of Anti-Aβ Antibodies
Anti-Aβ antibodies may directly target Aβ assemblies to neutralize their toxicity, activate microglia for phagocytosis via Fc-receptor (FcR) mediation, or create a concentration gradient between the brain and blood, facilitating Aβ removal via a peripheral sink mechanism.
137
Describe Astrocytes and Microglia:
Astrocytes and microglia are two types of neuronal cells with various physiological functions in the brain. Astrocytes provide metabolic support, regulate blood flow, and maintain synaptic health, while microglia, known as the "primary immune cells of the brain," engage in synaptic pruning and debris phagocytosis. In neurodegenerative diseases, both cells become activated, leading to altered functions, including driving neuroinflammation, which contributes to the disease pathology.
138
True or False: GFAP is commonly used as a marker of microglia reactivity and neuroinflammation in the brain.
False. GFAP is typically used as a marker of astrocyte reactivity and neuroinflammation in the brain.
139
Fill in the Gap: Microglia are implicated in antibody-mediated ______ clearance.
Ab (amyloid-β).
140
Which of the following is NOT a proposed mechanism of anti-Aβ antibodies?
- a) Direct targeting of Aβ assemblies
- b) Activation of astrocytes
- c) Fc-receptor-mediated phagocytosis
- d) Peripheral sink mechanism
b) Activation of astrocytes
141
Describe the Elan AN-1792 Vaccine Trial
The Elan AN-1792 vaccine trial was a double-blind, placebo-controlled phase 2a clinical trial utilizing an active vaccination approach with human amyloid-β (Aβ) 1-42 peptide. However, the trial was discontinued due to reports of serious side effects, specifically meningoencephalitis.
142
True or False: Antibody responders in the Elan AN-1792 trial showed improvements in cognition and reduced CSF tau levels.
True
143
Fill in the Gap: Antibody responders in the Elan AN-1792 trial showed decreased whole brain volume and increased ______ volume.
Ventricular
144
What was observed in the 4.5-year follow-up of the Elan AN-1792 trial responders?
- a) Increased MMSE scores
- b) Reduced brain volume loss
- c) Less decline on Disability Assessment for Dementia and Dependence scales
- d) Higher levels of CSF tau
c) Less decline on Disability Assessment for Dementia and Dependence scales.
145
Describe the Findings of the 15-Year Postmortem Follow-Up of the Elan AN-1792 Trial
Despite considerable plaque removal in antibody responders, most patients had progressed to severe dementia, suggesting that extensive tau pathology remained, potentially contributing to disease progression.
146
True or False: The Elan AN-1792 vaccine trial resulted in significant improvements in cognitive decline and brain volume loss compared to the placebo group.
False
147
Fill in the Gap: The Elan AN-1792 trial utilized an active vaccination approach using human amyloid-β (Aβ) _____ peptide.
1-42.
148
What was the primary reason for discontinuing the Elan AN-1792 trial?
- a) Lack of efficacy
- b) Serious side effects, including meningoencephalitis
- c) High cost of treatment
- d) Regulatory issues
- b) Serious side effects, including meningoencephalitis
149
Describe the Aducanumab Trials
Aducanumab trials consisted of two randomized, global, double-blind, placebo-controlled phase 3 clinical trials. It utilized passive immunotherapy with an antibody against human Aβ oligomers.
150
True or False: The Aducanumab trials were halted due to reports of significant improvement in cognitive functions.
False
151
Fill in the Gap: A re-analysis of the Aducanumab trials showed some improvement at the highest dose in one trial (EMERGE) and ______ in the other (ENGAGE).
Decline
152
What measure of cognition showed the most significant improvement in participants on the highest dose of Aducanumab in the ENGAGE trial?
- a) CDR-SB
- b) MMSE
- c) ADAS-Cog
- d) PET
- c) ADAS-Cog
153
Describe the Relationship Between Aducanumab Treatment and Plasma pTau
Aducanumab treatment resulted in reduced plasma pTau levels in both EMERGE and ENGAGE trials, and this reduction correlated with improvements in cognition.
154
True or False: Aducanumab treatment in the EMERGE and ENGAGE trials was associated with a decrease in ventricular volume as observed in structural MRI scans.
False
155
Fill in the Gap: ARIA occurred in ______% of participants treated with Aducanumab, with a higher incidence observed in ApoE4 carriers.
26% (low dose) - 36% (high dose).
156
What was the outcome of the FDA approval for Aducanumab?
- a) Full approval
- b) Conditional approval
- c) Withdrawn approval
- d) Approval pending
c) Withdrawn approval
157
Describe the Lecanemab Trial
Lecanemab trial was a multicenter (US) double-blind placebo-controlled phase 3 clinical trial. It utilized passive immunotherapy with an antibody against human soluble Aβ protofibrils for a duration of 18 months.
158
Fill in the Gap: Out of 5967 screened participants, ______ were selected for the Lecanemab trial.
1795
159
True or False: The completion rates for the Lecanemab trial were higher in the placebo group compared to the lecanemab group.
False
160
What was the primary endpoint measure used in the Lecanemab trial?
- a) ADAS-Cog
- b) ADCOMS
- c) MMSE
- d) CDR-SB
d) CDR-SB
161
Describe the Relative Improvement in Cognitive Decline Observed in Participants Treated with Lecanemab
Participants treated with lecanemab showed a significant decline in CDR-SB score relative to placebo, with a difference of 0.45 points on an 18-point scale, equivalent to approximately 12% overall improvement.
162
Fill in the Gap: Lecanemab treatment resulted in approximately ______% reduction in brain amyloid burden relative to controls as measured by PET scans.
50%
163
True or False: Lecanemab treatment in the trial was associated with an increase in adverse events leading to discontinuation compared to the placebo group, most of which were ARIA-related.
False
164
What was the outcome of the FDA approval for Lecanemab?
- a) Full approval
- b) Conditional approval
- c) Withdrawn approval
- d) Approval pending
b) Conditional approval
165
Describe the Donanemab Trial
The Donanemab trial was a randomized, global, double-blind, placebo-controlled phase 3 clinical trial. It utilized passive immunotherapy with an antibody against human Aβ aggregates (N-term, insoluble) for a duration of 18 months.
166
Fill in the Gap: Out of 1736 participants, ______ were allocated to the donanemab group in the trial.
860
167
True or False: The completion rates for the Donanemab trial were higher in the placebo group compared to the donanemab group.
False
168
What was the primary endpoint measure used in the Donanemab trial?
- a) ADAS-Cog13
- b) CDR-SB
- c) ADCS-iADL
- d) iADRS
d) iADRS.
169
Describe the Relative Improvement in Cognitive Decline Observed in Participants Treated with Donanemab
Participants treated with Donanemab showed a significant improvement in cognitive decline, with a 35% improvement in the low-medium tau group and a 21% improvement in the combined group, as measured by iADRS.
170
Fill in the Gap: Donanemab treatment resulted in approximately ______% reductions in cognitive decline on other scales relative to placebo.
20-30%
171
True or False: Both low-medium tau and combined groups in the Donanemab trial showed decreased brain volume and increased ventricular volume compared to placebo.
True
172
What was the outcome of the FDA approval for Donanemab?
- a) Full approval
- b) Conditional approval
- c) Withdrawn approval
- d) Approval pending
b) Conditional approval.
173
What is ADAS-Cog
ADAS-Cog, or the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, is a rating scale developed to assess the severity of cognitive dysfunction in Alzheimer’s disease.
174
What is the primary purpose of ADAS-Cog
ADAS-Cog is the gold standard for assessing the efficacy of antidementia treatments. It is specifically designed to measure cognitive impairment in Alzheimer's disease.
175
How is ADAS-Cog scored?
ADAS-Cog is scored from 0 to 150 by summing the number of errors made on each task. Higher scores indicate worse performance.
176
What are the two subscales of ADAS?
The two subscales of ADAS are ADAS-Noncog (non-cognitive subscale) and ADAS-Cog (cognitive subscale).
177
Describe the tasks included in ADAS-Cog.
ADAS-Cog includes tasks such as word recall, naming objects and fingers, following commands, constructional praxis, orientation, and word recognition.
178
What is iADRS and how is it calculated?
iADRS, or Integrated Alzheimer’s Disease Rating Scale, combines scores from ADAS-Cog and ADCS-iADL. It is calculated by summing the transformed ADAS-Cog14 score and the ADCS-iADL score
179
What is the purpose of iADRS in clinical trials?
iADRS allows detection of disease progression across a broad range of the symptomatic disease spectrum. It serves as a primary endpoint in clinical trials evaluating potential treatments for Alzheimer's disease.
180
How is iADRS scored and what does it indicate?
The iADRS score ranges from 0 to 146, with lower scores indicating worse performance. It captures changes in both cognitive and functional domains, enhancing sensitivity to treatment effects.
181
What is ARIA?
ARIA stands for amyloid-related imaging abnormalities, which are brain abnormalities detected by MRI findings in patients participating in Ab vaccination/immunotherapy trials.
182
What are the different types of ARIA?
ARIA-E (edema/sulcal effusion)
ARIA-H (haemosiderin deposits in brain parenchyma - microhaemorrhage)
ARIA-H (haemosiderin deposits on pial surface – superficial siderosis)
183
How is ARIA severity classified?
ARIA severity is classified based on the number and size of abnormalities detected by MRI.
184
Define: Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog)
The ADAS-Cog is a widely used test to assess cognitive dysfunction in Alzheimer's disease. It evaluates various cognitive domains such as memory, language, and praxis through a series of tasks.
185
The ADAS-Cog score is calculated by summing the number of errors made on each task, with higher scores indicating ______________.
greater cognitive impairment
186
What is the primary endpoint used in the evaluation of lecanemab in clinical trials?
a) MMSE
b) CDR-SB
c) ADCS-iADL
d) ADAS-Cog
b) CDR-SB
187
Define: Amyloid-related imaging abnormalities (ARIA)
ARIA refers to brain abnormalities detected by MRI findings in patients participating in AD vaccination/immunotherapy trials, including ARIA-E (edema), ARIA-H (microhaemorrhage), and ARIA-S (superficial siderosis).
188
What is the primary function of microglia in the brain?
a) Metabolic support
b) Blood flow regulation
c) Synaptic pruning
d) Neuronal signaling
c) Synaptic pruning
189
Describe: Aducanumab
Aducanumab is a passive immunotherapy that targets aggregated amyloid-beta (Aβ) oligomers. It was evaluated in global phase 3 clinical trials for the treatment of Alzheimer's disease.
190
The iADRS score ranges from 0 to __________, with lower scores indicating worse performance.
146
191
What is the main purpose of the integrated Alzheimer's Disease Rating Scale (iADRS)?
a) Assessing amyloid-beta levels
b) Evaluating functional independence
c) Measuring neuroinflammation
d) Detecting disease progression in Alzheimer's disease
d) Detecting disease progression in Alzheimer's disease
192
Define: Clinical Dementia Rating–Sum of Boxes (CDR-SB)
The Clinical Dementia Rating–Sum of Boxes (CDR-SB) is a scale used to measure the severity of cognitive impairment in patients with dementia. Scores range from 0 to 18, with higher scores indicating greater impairment.
193
Describe: Lecanemab
Lecanemab is a passive immunotherapy evaluated in clinical trials for the treatment of Alzheimer's disease. Its primary endpoint was the change from baseline to 18 months in the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score, with minimal clinically relevant changes estimated to be 1 to 2 points.
194
At 18 months, the CDR-SB score had increased from baseline by __________ points with lecanemab and by 1.66 points with placebo.
1.21
195
What is one criticism raised about the results of the lecanemab trial?
a) Significant improvement in cognitive decline
b) Meaningful change in outcome measures for women
c) Minimal reduction in amyloid PET signal
d) Lack of correlation between ARIA incidence and cognitive outcomes
c) Minimal reduction in amyloid PET signal
196
The minimal clinically relevant change in the CDR-SB score has been estimated to be __________ points.
1 to 2
197
Describe: General criticisms raised about statistical analysis of trial data
One criticism is the potential unblinding of participants when amyloid-related imaging abnormalities (ARIA) are detected, as well as the subjectivity of some scores (e.g., caregiver-based assessments) and the additional stress caused by MRI surveillance in some cases.
198
Benefit/risk analysis questions the ________ improvement over time and the sustained long-term ________ after treatments.
Continued; loss of brain volume
199
What is a concern regarding the lack of diversity in trials for anti-amyloid immunotherapies?
a) Lack of correlation between ARIA incidence and cognitive outcomes
b) Continued improvement over time
c) Significant loss of brain volume after treatments
d) Limited population eligibility, particularly among women and ApoE4 carriers
d) Limited population eligibility, particularly among women and ApoE4 carriers
200
Define: Anti-amyloid immunotherapies
Anti-amyloid immunotherapies are treatments designed to target and reduce amyloid-beta protein levels in the brain, with the goal of slowing or halting the progression of Alzheimer's disease. These therapies typically involve the use of antibodies or vaccines to target amyloid-beta aggregates.
