Alzheimer's Disease Flashcards
(81 cards)
1
Q
What is the current ranking of dementia as a cause of death? How many people globally live with dementia?
A
- Dementia is the 7th leading cause of death.
- Over 55 million people live with dementia worldwide.
2
Q
What percentage of people with dementia live in low- and middle-income countries?
A
More than 60% of people with dementia live in low- and middle-income countries.
3
Q
What is Alzheimer’s Disease (AD) and what percentage of dementia cases does it account for?
A
Alzheimer’s Disease is a chronic and irreversible neurodegenerative disorder, and it accounts for 60-70% of dementia cases.
4
Q
What are some other types of neurodegenerative diseases that cause dementia?
A
- Dementia with Lewy bodies
- Parkinson’s disease
- Huntington’s disease
- Frontotemporal dementia.
5
Q
When does Alzheimer’s Disease usually start, and what is the trend in its prevalence?
A
Alzheimer’s Disease usually starts in middle age, and its prevalence is increasing as the population ages.
6
Q
Do cognitively healthy older adults experience any cognitive changes?
A
Yes, cognitively healthy older adults may experience some declines in cognitive functioning.
7
Q
What is preclinical dementia and what does it involve?
A
Preclinical dementia involves subjective cognitive decline (SCD), where individuals experience cognitive changes that are noticeable but not yet severe.
8
Q
What is mild cognitive impairment (MCI) and how does it differ from normal aging?
A
Mild cognitive impairment (MCI) involves cognitive declines more severe than what is expected based on age and education.
9
Q
When is an individual diagnosed with dementia?
A
An individual is diagnosed with dementia once cognitive declines begin to impair daily functioning.
10
Q
What are some mild symptoms of dementia?
A
- memory loss
- language problems
- mood swings
- personality changes
- diminished judgment
11
Q
What are some moderate symptoms of dementia?
A
- behavioural and personality changes
- inability to learn or recall new information
- confusion
- wandering
- agitation
- aggression
- needing assistance with activities of daily living
12
Q
What are some severe symptoms of dementia?
A
- gait and motor disturbances
- inability to perform activities of daily living
- requiring long-term care placement.
13
Q
What are the key details about the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE)?
A
- MoCA
- Designed to detect mild cognitive impairment (MCI).
- Scored out of 30.
- A score of <26 typically indicates MCI.
- A score of <18 might indicate dementia.
- Sample questions include naming pictures of animals, remembering five words, and recalling date and location. - MMSE
-Also scored out of 30.
- A score of <24 typically indicates MCI.
- A score of <20 might indicate dementia.
14
Q
What is the Clinical Dementia Rating (CDR) and how is it used?
A
- The Clinical Dementia Rating (CDR) is a semi-structured interview of the patient and an informant.
- Assesses 6 domains:
Memory
Orientation
Judgment & problem solving
Community affairs
Home & hobbies
Personal care - Each domain yields a score between 0 (no impairment) and 3 (severe impairment).
15
Q
What are modifiable risk factors for dementia and how do they affect its development?
A
- Modifiable risk factors are factors that can be changed to help reduce the risk of developing dementia.
- While dementia may not be curable, reducing lifetime exposure to these risk factors may delay or even prevent dementia from occurring in many individuals.
16
Q
What are non-modifiable risk factors for dementia?
A
- Age: increased age associated with cell loss & neurodegeneration occurring over time.
- Vascular health: Reduced blood flow and vascular health impact brain function.
- Immune System.
- Genetics:
-> APO4 gene - most well-established genetic risk factor for sporadic late-onset Alzheimer’s Disease (after age 65).
-> PSEN1, PSEN2, and APP genes are associated with familial Alzheimer’s Disease (early-onset, typically before age 65). - Sex
17
Q
How do the rates of Alzheimer’s Disease (AD) diagnoses differ between females and males?
A
Females outnumber males in AD diagnoses at a rate of approximately two to one.
18
Q
What factor contributes to the higher prevalence of AD in females compared to males?
A
The difference in life expectancy contributes to the higher prevalence, as females live longer than males. In Canada, females live 4 years longer than males (83.9 years vs. 79.8 years).
19
Q
What are other potential contributing factors to the difference in AD prevalence between sexes?
A
Other contributing factors include biological differences and differences in engagement with social, political, and socioeconomic determinants of health.
20
Q
How do the progression and diagnosis of AD differ between females and males?
A
Women tend to progress faster or get diagnosed later than men.
21
Q
How does the APOE e4 genetic risk factor affect females compared to males?
A
The APOE e4 genetic risk factor confers a greater risk of Alzheimer’s Disease in females.
22
Q
What mental health condition is more common in females, and how does it relate to dementia risk?
A
Depression is more common in females and may be linked to an increased risk of dementia.
23
Q
What physical condition is more commonly reported in females that might contribute to dementia risk?
A
Frailty is reported at higher levels in females, which can be a risk factor for dementia.
24
Q
How do cardiometabolic risk factors differ between males and females?
A
Females experience a greater prevalence of cardiometabolic risk factors, which may increase dementia risk.
25
What are some female-specific risk factors for dementia?
1. High blood pressure during pregnancy (preeclampsia)
2. Menopause
3. Bilateral oophorectomy (removal of both ovaries and fallopian tubes) before age 48 without hormone replacement.
26
What is a male-specific risk factor for dementia?
Cumulative androgen deprivation therapy for prostate cancer is a male-specific risk factor.
27
What are some of the biological sex differences that influence dementia risk?
Stress response
Brain structure
Inflammation and metabolism
Pregnancy
Menopause
Frailty
Genetics and epigenetics
Prostate cancer
Obstructive sleep apnea
Hormones
28
What are some gender differences that affect dementia risk?
Experiences of stress
Education
Occupation
Diet and physical activity
Smoking
Alcohol use
Social isolation
Gender-based discrimination
Traumatic brain injury
29
How is the prevalence of dementia expected to change among different ethnic groups in the US by 2060?
1. Hispanics: Prevalence is expected to increase by 423%.
2. Blacks: Prevalence is expected to increase by 192%.
3. Whites: Prevalence is expected to increase by 63%.
30
What is the typical pattern of brain atrophy in Alzheimer’s Disease (AD)?
The typical pattern of brain atrophy in AD starts in the hippocampus and entorhinal cortex, then extends to the temporal and parietal lobes as the disease progresses. In later stages, it expands to the frontal lobes. There is widespread global atrophy and ventricular expansion in advanced stages.
31
What are the macroscopic features observed in the brain of an AD patient?
- Marked atrophy, especially in the hippocampus.
- Thinning of the gyri and deepening of the sulci.
- Widening of the inferior horn of the second ventricle.
- At autopsy, the brain does not show grossly apparent alterations that are diagnostic.
32
What are the major contributors to the neuropathology of Alzheimer’s Disease?
1. Extracellular amyloid β (Aβ) plaques.
2. Intracellular tau tangles.
33
How do amyloid β and tau contribute to Alzheimer's Disease?
- Amyloid β and tau are naturally occurring protein aggregates.
- They become pathogenic when they become structurally abnormal, a process known as misfolding.
34
What is Amyloid Precursor Protein (APP) and its role in the brain?
- APP is a cell membrane molecule.
- It helps neurons with growth and repair following injury.
- Over time, APP is used, broken down, and recycled.
35
What happens to APP in normal conditions and in Alzheimer’s Disease (AD)?
- Normal (non-AD): APP is cleaved by α and γ secretase, turning it into a soluble form.
- AD: APP is cleaved by β and γ secretase, producing an insoluble fragment that creates Aβ monomers.
- These Aβ monomers stick together outside neurons and form Aβ plaques.
36
What is the role of APOE in the genetics of Alzheimer’s Disease?
- APOE helps to break down Aβ.
- The ε4 allele is less effective than ε2 or ε3.
- Having ε4 instead of ε2 or ε3 increases the likelihood of developing Aβ plaques.
37
What are the key genes involved in Familial Alzheimer’s Disease (AD)?
- PSEN1 and PSEN2 are the key genes involved.
- These genes encode for presenilin 1 & 2, protein subunits of γ secretase.
- Mutations in PSEN1 and PSEN2 alter where γ secretase cleaves APP, creating Aβ molecules that are more likely to form plaques.
38
How do Aβ plaques contribute to Alzheimer's Disease?
- Aβ plaques disrupt neuron-to-neuron signaling, impairing cognitive functions.
- They also trigger inflammatory immune responses, which may damage the surrounding neurons.
39
What is Cerebral Amyloid Angiopathy (CAA) and its impact on the brain?
- CAA occurs when Aβ plaques deposit around blood vessels.
- This leads to the weakening of blood vessel walls, increasing the risk of hemorrhage.
40
What are diffuse Aβ plaques in Alzheimer's Disease?
- Diffuse plaques are loosely arranged, amorphous deposits of Aβ.
- They lack a dense core and do not have associated dystrophic neurites (degenerating axons and dendrites containing abnormal tau).
Pathological significance:
-> They are thought to represent an early or less toxic stage of Aβ deposition.
->Found in both healthy aging individuals and AD patients.
-> May eventually develop into neuritic plaques over time.
41
What are neuritic plaques in Alzheimer's Disease?
- Neuritic plaques are extracellular deposits composed primarily of Aβ peptides, especially Aβ42, which is more prone to aggregation.
- Aβ peptides aggregate to form dense core structures.
- These plaques are surrounded by dystrophic neurites, which are damaged axons and dendrites.
42
What is the role of tau protein in normal neurons?
- Tau is a protein that binds to microtubules, stabilizing them.
- It helps facilitate the movement of essential molecules along axons, ensuring proper communication between neurons.
43
How does tau become hyperphosphorylated in Alzheimer's Disease?
- In AD, kinases (enzymes that add phosphate groups) become overactive.
- They add too many phosphate groups to the tau protein, leading to hyperphosphorylation.
- When tau becomes hyperphosphorylated, it detaches from microtubules.
44
What happens when tau becomes hyperphosphorylated in Alzheimer's Disease?
- Hyperphosphorylated tau forms paired helical filaments (PHFs), which have twisted or helical shapes.
- PHFs and straight filaments aggregate into neurofibrillary tangles (NFTs).
- This destabilizes microtubules, impairs neuronal signaling, and eventually leads to neuronal dysfunction and death.
45
What happens to the brain as tau and Aβ plaques progress in Alzheimer's Disease?
- As neurons die, the brain atrophies.
- The ventricles and sulci enlarge as the brain tissue shrinks.
46
How are Aβ plaques and neurofibrillary tangles used in diagnosing Alzheimer's Disease?
- Extracellular Aβ plaques and intracellular neurofibrillary tangles (NFTs) are essential for the neuropathological diagnosis of AD.
- These lesions result in the loss of synapses and neurons, leading to brain atrophy and the clinical symptoms of AD.
- Histological examination can establish a definitive diagnosis.
- Semi-quantitative assessment of the density of these lesions and their topographical distribution helps in diagnosis.
47
Where are neurofibrillary tangles (NFTs) commonly found in Alzheimer's Disease?
In AD, high amounts of neurofibrillary tangles are seen in the hippocampus.
48
What is Cerebral Amyloid Angiopathy (CAA)?
- CAA is the deposition of Aβ peptides in the vessel walls.
- The Aβ-40 peptide is the major constituent in CAA, as it is more soluble.
- 85-90% of confirmed Alzheimer's Disease (AD) cases have some degree of CAA.
49
How does Aβ deposition affect blood vessels in Cerebral Amyloid Angiopathy (CAA)?
- Aβ deposition in the vessel walls causes them to shrink, which reduces blood flow.
- This results in a decrease in energy supply to the brain due to the reduced blood flow.
50
What can Cerebral Amyloid Angiopathy (CAA) cause in the brain?
- CAA can cause small infarcts (areas of dead tissue) in the cortex.
- Severe CAA can lead to hemorrhages (bleeding) in the frontal and occipital lobes.
- It can also cause diffuse white matter lesions in the brain.
51
How is disease severity in Alzheimer's Disease determined postmortem?
Disease stage can be determined postmortem by a semi-quantitative rating of the density and spread of Aβ plaques and neurofibrillary tangles (NFTs).
52
What are the stages of Thal Aβ Staging for Alzheimer's Disease (AD)?
0. Phase 0: No plaque (A0) → No AD or non-AD dementia
1. Phase 1: Sparse, small groups of diffuse neocortical plaque (A1) → Pre-AD or non-AD dementia
2. Phase 2: + Allocortex, hippocampus, and entorhinal cortex (A1) → Pre-AD or non-AD dementia
3. Phase 3: + Striatum, subpial, post-cingulate gyrus (A2) → Pre-AD or non-AD dementia
4. Phase 4: + Midbrain (substantia nigra), medulla oblongata (A3) → Symptomatic AD
5. Phase 5: + Cerebellum, reticular formation of the pons (A3) → Symptomatic AD
53
What are the six anatomic regions designated for histologic examination in CERAD staging?
1. Middle frontal gyrus
2. Superior and middle temporal gyri
3. Anterior cingulate gyrus
4. Inferior parietal lobule
5. Hippocampus and entorhinal cortex
6. Midbrain (including substantia nigra)
54
What is CERAD staging used to evaluate?
Neuritic plaque density in AD.
55
What does increased neuritic plaque density indicate in CERAD staging?
Greater severity and progression of AD.
56
What are the stages of Braak Tau Staging and their associated brain regions?
1. Stage I: Transentorhinal region and entorhinal cortex
2. Stage II: CA1 region of the hippocampus (preclinical phase, up to 20 years)
3. Stage III: Limbic structures (e.g., subiculum of hippocampal formation)
4. Stage IV: Amygdala, thalamus, and claustrum
5. Stage V: Isocortical areas (association areas affected first and more severely)
6. Stage VI: Primary sensory, motor, and visual areas
57
Which stages of Braak Tau Staging are correlated with mild cognitive impairment (MCI)?
Stages III and IV.
58
Which stage of Braak Tau Staging is typically associated with overt dementia?
Stage VI.
59
What does PET stand for in AD diagnostic tools?
Positron Emission Tomography.
60
What does Fluorodeoxyglucose (FDG) PET assess in AD diagnosis?
Glucose metabolism — reduced uptake indicates neuronal dysfunction.
61
What does Amyloid PET detect?
Aβ (Amyloid-beta) plaques
62
What are two key advantages of PET imaging for AD diagnosis?
1. Shows spatial distribution of Aβ and Tau
2. Assesses severity of pathology
63
What are three key challenges of using PET for AD diagnosis?
1. Limited availability (45 sites in Canada — 24 in Quebec, 12 in Ontario)
2. Expensive
3. Use of radioactive tracers
64
What are the limitations of PET in terms of diagnostic accuracy?
Sensitivity and specificity can vary depending on the tracer and disease stage.
65
What are the two advantages of using CSF and plasma biomarkers for AD diagnosis?
1. Cheaper
2. more widely available.
66
What are two disadvantages of using CSF and plasma biomarkers for AD diagnosis?
1. lack of spatial information.
2. lower sensitivity/specificity than PET.
67
What does MTA stand for in the context of MRI for AD diagnosis? What type of MRI image is used to assess MTA? What is considered an abnormal MTA-score in patients over 75 years old? What is the sensitivity and specificity of MTA-scoring for AD diagnosis?
1. Medial Temporal Lobe Atrophy
2. Coronal T1-weighted (T1w) image through the hippocampus at the level of the anterior pons
3. MTA-score ≥ 3 (A score of 2 can still be normal at this age)
4. ~85% sensitivity and specificity
68
What additional information can MRI provide in AD diagnosis?
MRI can detect progression of atrophy with high resolution.
69
What is the sequence of biomarker changes in Alzheimer's disease (AD)
Amyloid PET -> MTL tau -> Neocortical tau -> N (neuronal injury or dysfunction)-> C (cognitive decline)
- coexisting pathologies shift biomarker changes to appear earlier.
- Biomarkers must exceed the detection threshold to be measurable
- Co-existing pathologies cause earlier onset and faster progression of biomarkers
70
What are examples of discordance in AD diagnosis? (when tau and AB biomarkers do not match the expected pattern)
- Tau positive but Aβ negative → Other disease processes?
- Aβ and tau positive but in other brain locations → Atypical AD or other disorders?
- Aβ and tau positive but cognitively normal → Earlier stages?
71
How does cerebrovascular disease affect AD progression?
Increases the probability of dementia.
72
How common is "pure AD" without co-pathology in older indivdiuals?
- Rare, especially in older individuals.
73
What types of drugs for AD are approved by Health Canada?
1. Cholinesterase inhibitors
2. Memantine
74
What is the effect of cholinesterase inhibitors on AD symptoms? What are the common side effects of cholinesterase inhibitors?
1.
- May slow cognitive decline
- Temporarily improve memory, attention, and daily function
- Can help with aggression, apathy, and depression
2.
- Nausea, vomiting, diarrhea
- Loss of appetite
- Dizziness, muscle cramps
Some patients respond well, while others show minimal improvement.
75
How does memantine help AD patients? What are the common side effects of memantine?
1.
- May slow cognitive decline
- May improve memory, attention, and daily function
- Can reduce agitation, aggression, and irritability
2.
- Dizziness, headache, confusion
- Constipation
- Works well in combination with cholinesterase inhibitors
76
Do cholinesterase inhibitors and memantine affect Aβ and tau accumulation?
No
77
What monoclonal antibodies target Aβ in AD?
Donanemab.
Lecanemab
They reduce the rate of cognitive and functional decline compared with placebo.
Intended for patients with early AD (MCI or mild demnentia)
78
What are common adverse effects of monoclonal antibody therapy?
- Infusion reactions
- Amyloid-related imaging abnormalities (ARIA)
79
What are the two types of ARIA and their causes?
1. ARIA-E → Edema in sulcal space (detected by MRI)
2. ARIA-H → Hemosiderin deposits, including microbleeds and macrohemorrhages (detected by MRI)
can cause:
Headache
Confusion
Seizure
Hemorrhagic stroke
80
What increases the risk of ARIA?
Presence of cerebral amyloid angiopathy (CAA)
Having one or two copies of APOE ε4 allele
81
In which groups might monoclonal antibodies be less effective?
Females
APOE ε4 carriers
