Lecture 3 Flashcards
1
Q
progressive loss of neurons with associated secondary changes in white matter tracts
A
neurodegenerative disorder
2
Q
How are neurodegenerative disorders selective?
A
- affecting one or more groups of neurons while leaving others intact
- sometimes neurons next to degenerating ones are completely normal
3
Q
What is one pathology that is common with neurodegenerative disorders?
A
- finding common to many are protein aggregates that are resistant to degradation through the ubiquitin-proteasome system - form inclusions within neurons
4
Q
What are common neurodegenerative disorders?
A
Parkinson disease, Alzheimer disease
5
Q
T/F: Early dementia is a major neurocognitive disorder
A
False, minor
6
Q
T/F: Late dementia is a minor neurocognitive disorder
A
False, major
7
Q
What are characteristics of a major neurocognitive disorder (late dementia)?
A
- generalized, progressive impairment of cognitive function, accompanied by impairment in ADLs
- not impaired level of consciousness
- executive function, memory, attention can all be affected
8
Q
Things you do every day to take care of yourself and your home. They are one way to measure how well you can live on your own
A
Instrumental activities of daily living (IADLs)
9
Q
T/F: While activities of daily living (ADLs) are basic self-care tasks like bathing,IADLsrequire more complex planning and thinking.
A
True
10
Q
What are examples of activities of daily living?
A
- feeding
- continence
- transferring
- toileting
- dressing
- bathing
11
Q
What are examples of instrumental activities of daily living?
A
- using telephone
- shopping
- preparing food
- housekeeping
- doing laundry
- using transportation
- handling medications
- handling finances
12
Q
What type of activities are usually the first ones that become affected by dementia?
A
IADLs
13
Q
What are characteristics of mild neurocognitive disorders?
A
- ADLs not significantly impaired
- Reduction in function of one (or more) major cognitive domain noted - complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition
- Often patient is aware of (and frustrated by) deficit
14
Q
Which neurocognitive disorder causes patients to be aware of their deficit?
A
mild
15
Q
What are characteristics of major neurocognitive disorders?
A
- ADLs and iADLs are affected - iADLs often impaired first - shopping, food preparation, finances, medication management
- Larger impairment of one or more major cognitive domains
- Often patient is relatively unaware of deterioration
16
Q
What is the most common cause of dementia in elderly?
A
Alzheimer disease
Most common cause of dementia in elderly
prevalence of 1 in 8 in older populations, 40% in those in the 80-90 year old group
6th leading cause of death
17
Q
What are general pathological findings of Alzheimer disease?
A
- neurofibrillary tangles
- beta-amyloid plaques
- cerebral atrophy
- often loss of widely-distributed cholinergic neurons in the nucleus basalis of Meynert
18
Q
What do neuritic plaques (beta-amyloid) look like?
A
focal, spherical collections of dilated, tortuous, neuritic processes (dystrophic neurites)
19
Q
often around a central amyloid core, which may be surrounded by clear halo is a characteristics of what?
A
neuritic plaques
20
Q
What proteins does the amyloid core contain?
A
- Aβ, a peptide derived through specific processing events from a larger molecule, amyloid precursor protein (APP)
- Other proteins are present in plaques in lesser abundance, including components of the complement cascade and pro-inflammatory cytokines
21
Q
What is the size of neuritic plaques?
A
- 20-200 um in diameter
22
Q
Which cells are reactive in the periphery with reference to neuritic plaques?
A
microglial cells & reactive astrocytes
23
Q
What are neuritic plaques often found?
A
- Plaques are found in the hippocampus, amygdala, and neocortex
- primary motor and sensory cortices tend to be spared
24
Q
What are neurofibrillary tangles?
A
bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus
- basophilic (H&E staining)
25
Where are neurofibrillary tangles usually found?
- commonly found in cortical neurons
- especially in the entorhinal cortex, pyramidal cells of hippocampus, amygdala, basal forebrain
26
How are neurofibrillary tangles insoluble and resistant to clearance in vivo?
- major component of many “tangled filaments” is abnormally hyperphosphorylated forms of the protein tau
- Other components include MAP2 (another microtubule-associated protein) and ubiquitin
27
axonal microtubule-associated protein that enhances microtubule assembly
tau
28
What happens when you have neurons die?
cerebral atrophy
29
What is the amyloid precursor protein?
- membrane-associated protein that is thought to be a receptor for an as yet unidentified ligand
- is cloven as part of normal breakdown of cellular proteins
- Aggregates of beta-amyloid are directly neurotoxic and also activate microglia and astrocytes, resulting in chronic inflammatory injury to neurons
30
T/F: amyloid precursor protein can be soluble OR insoluble
True
31
What starts the neurodegenerative cascade?
cleaving amyloid precursor protein in the wrong way --> insoluble forms accumulate in the extracellular space and are thought to be important in the pathogenesis of Alzheimer disease
32
What is thought to be the responsible for neurofibrillary tangles within neurons?
accumulation of beta-amyloid
33
What are genetic risk factors for AD?
- Presenilin 1 and presenilin 2
- Apolipoprotein E4
34
Which genetic factor is related to sever early-onset AD?
Presenilin 1 and presenilin 2
35
What are Presenilin 1 and presenilin 2 involved in?
- protein is very important in regulating neuronal intracellular calcium levels in association with LTP (long-term potentiation)
- same protein is also involved in cleaving APP (performs similar function as secretase)
36
What is Apolipoprotein E4 involved in?
- help transport cholesterol throughout the CNS
37
What happens if someone has the heterozygous mutation for E4?
approximately double the risk of late-onset AD (LOAD) (about 25% of Caucasian population)
38
What happens if someone is homozygous for E4?
have a 16X increased risk of LOAD
39
T/F: Apo E4 positivity is not as strongly “causative” of AD as presenilin mutations that increase risk of AD
True
40
APP may be a primitive component of the innate immune system, therefore?
Seems to cause death of bacteria and viruses
41
What viruses are getting into the brain?
- Likely herpes family – HSV-1, HHV-6 and HHV-7
- HHV 6 and 7 are viruses that cause benign skin infections in kids, however the virus seems to be able to migrate into the CNS and remain dormant
42
What is the infectious theory of AD?
In some Alzheimer patients, the amyloid accumulation (APP) may lead to chronic inflammation instead of performing a virus-fighting role
43
the most common disorder of glucose metabolism
Type II diabetes
44
What are consequences of type II diabetes?
- Due to genetic and lifestyle factors, the diabetic patient develops resistance to insulin
- Fewer receptors
- Downregulation of intracellular signaling linked to the insulin receptor
- increase transport of glucose from bloodstream into liver & muscle
45
What does type II diabetes have long-term increased blood levels of?
- glucose
- free fatty acids
46
T/F: AD is much more common in those with type 2 diabetes mellitus than in those without
True
47
Why is type II diabetes a causative factor in AD?
- Insulin resistance likely reduces synaptogenesis
- Insulin seems to have a role in normal neuronal physiology and synaptic plasticity
- As resistance to insulin builds due to long-term hyperglycemia, then the intracellular signaling cascades are down-regulated --> decreased plasticity
- Insulin resistance increases the levels of circulating pro-inflammatory cytokines
- May lead to glial activation --> neuronal damage
- long-term hyperglycemia: As blood glucose increases, it becomes non-enzymatically linked to the basement membrane of brain capillaries --> a “leaky” blood-brain barrier --> Systemic pro-inflammatory cytokines can then leak through into the brain --> maladaptive glial activation and neuronal damage
- linked to elevated levels of free fatty acids (FFAs) in the blood --> Decreased insulin activity --> increased triglyceride breakdown --> increased circulating FFAs
High levels of FFAs can cause microglial activation --> neuronal damage
48
An extracellular protein whose function is altered by high levels of glucose binding to it
AGE (advanced glycation end-product)
49
What are DAMPs?
DAMPs = damage-associated molecular patterns.
- When they’re activated they can activate macrophages (i.e. microglial cells). When glucose becomes non-enzymatically bound to an extracellular protein it’s known as an advanced glycation end-product (AGE). Often the “sugared” protein has impaired function. There are receptors for AGEs (known as rAGEs) that often activate pro-inflammatory pathways.
50
What are clinical features of AD?
- short-term memory and executive functions (planning, logic) impaired relatively early - personality changes and loss of normal inhibitions can follow some time after
- language deficits and loss of learned motor skills tend to result from more advanced disease
- incontinence and impaired ambulation result from severe disease - impaired mobility related to development of pneumonia and sepsis
- 4 "A"'s & one "D"
- Anterograde amnesia + at least one of the other criteria are used to help make the diagnosis
51
What are the 4 "A"'s & one "D" of AD? (clinical features)
- anterograde amnesia
- aphasia
- Apraxia – difficulty with motor planning to perform tasks or movements
- Agnosia – difficulty recognizing/identifying objects, persons, or sounds although sensation is intact
- disturbance in executive function
52
What is mutated with reference to dementia with leqy bodies? What does this result in?
tau protein - results in aggregation of tau protein, or alteration of how tau interacts with microtubules
53
T/F: Dementia with Lewy bodies is a genetically-determined disorder?
True
54
Which lobes show marked atrophy is dementia w/ Lewy bodies?
frontal & temporal
55
How does dementia with Lewy bodies present?
- Parkinson-like movement disorder - tremor, rigidity, bradykinesia
56
T/F: dementia w/ Lewy bodies is usually the dementia that pre-dates diagnosis of Parkinson's
true
57
What does the presence of Lewy bodies cause?
likely aggregates of misfolded alpha-synuclein
58
What is the epidemiology of dementia w/ Lewy bodies?
0.1 – 5% of general elderly population
59
What are clinical features of dementia w/ Lewy bodies?
- Fluctuations in cognitive function with varying levels of alertness and attention - AD tends to be more constant
- Visual hallucinations that are vivid - other hallucinations may be present, AD rarely involves hallucinations
- Parkinsonian motor features (usually later or close to the same time as the onset of dementia)
- Anterograde memory loss: usually less prominent than that found in AD
- More prominent executive function deficits
60
“impairment in reality testing” – characterized by delusions and hallucinations
psychosis
61
beliefs that are not compatible with reality and are not normal beliefs for a culture
delusions
62
perception of a stimulus that isn’t there
hallucinations
63
What does audible and visual hallucination mean?
- Audible – hearing voices that do not exist (common)
- Visual – seeing things that aren’t there (a less common type of hallucination)
64
Very complex set of cognitive functions that seem to be orchestrated by the prefrontal cortex
executive functions
65
What are activities that include executive functions?
- Shifting effectively between tasks
- Inhibiting unwanted or inappropriate behaviours or responses
- Selecting and paying attention to information that applies to a particular task
- Using working memory to accomplish tasks
- Planning tasks
66
T/F: Executive functions often rely on memory and verbal fluency, but can be lost even when memory and verbal fluency are not that impaired
True
67
T/F: Executive functions are your brain’s “taskmaster” to keep you doing things effectively and appropriately, either in a social or job or school context
True
68
Patients with long-standing PD without cognitive impairment who slowly develop a dementia
Parkinson's disease dementia
69
What is associated with Parkinson's disease dementia?
associated with visual hallucinations and fluctuating alertness
70
T/F: Lewy bodies are not present in Parkinson's disease dementia
False, they are
71
What are frontotemporal dementias characterized by?
Characterized by deficits in executive function
- poor mental flexibility, abstract reasoning
- response inhibition, planning/organization, and increased distractibility
72
What are behavioural variants of frontotemporal dementias?
- behavioural disinhibition (socially inappropriate behaviour, impulsive, careless)
- apathy or inertia
- loss of sympathy or empathy
- Perseverative, stereotyped, or compulsive/ritualistic behaviour
- hyperorality and dietary changes
73
T/F: FTD has more prominent memory deficits than AD
False
74
On top of behavioural symptoms of FTD, what can also present?
often language and atypical motor symptoms can be present as well
75
Does FTD have a more constant, non-fluctuating course with often rapid decline, faster than Lewy body dementia and AD?
Yes
76
Who is FTD more common in?
More common in younger patients
77
As patient population ages, what becomes less common and what becomes more common?
- less = FTD
- more = AD
78
Multiple small infarcts (often affecting gray matter of the cortices) or hypertension (often affecting white matter) can present with dementia
vascular dementia
79
What causes vascular dementia?
- small vessel changes characteristic of hypertension (arteriolosclerosis) and multiple emboli are typical of small vessel disease
- many vascular disorders can be involved (multiple diseases)
80
The clinical presentation of vascular dementia varies based on pattern of injury, what are some of the presentations?
- Can present very similar to Alzheimer disease, but unlike Alzheimer disease, depression and psychosis can be prominent features --> psychosis will frequently include delusions and hallucinations; agitation can be dangerous to both the patient and the caregiver - lack of motivation is common
- gait abnormalities are common (gait apraxia), and lateralizing signs (increased tone/reflexes) often present
- often progresses in a step-wise fashion, corresponding to discrete vascular insults
81
What does MMSE assess?
- Orientation
- Short, recent, remote, remote memory
- Sustained concentration
- Executive functions: Recognition, Registration, Sequencing and organization, Comprehension, Perceptual - motor skills
82
