Neuropathy Common Neurocognitive Disorders Flashcards
What are disorders called with progressive loss of neurons with associated secondary changes in white matter tracts
Neurodegenerative disorders
Are neurodegenerative disorders selective as to which groups of neurons they choose?
Yes
What common finding are resistant to degradation through the ubiquitin-proteasome system? What do they form? Give 2 common examples
protein aggregates, inclusions with neurons, Parkinson disease, Alzheimer disease
What are the 2 different types of dementia and severity?
early – mild neurocognitive disorder
late – major neurocognitive disorder
What is generalized, progressive impairment of cognitive function, accompanied by impairment in ADLS?
dementia
Does dementia have impaired level of consciousness?
No
With dementia, are executive function, memory, and attention all affected?
Yes
Which requires more complex planning and thinking? ADLs or iADLs?
IADLs
IADLs: things you do to take care of self and home-telephone, shopping, cooking, housekeeping, laundry, transportation, finances, medications
ADLs: basic self-care tasks- bathing, dressing, toileting, transferring, continence, feeding
Are ADLs significantly impaired with MILD neurocognitive disorder? How many cognitive domains are reduced in function? Is the patient generally aware of deficit?
NO
1 or more (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition)
YES
Are ADLs and/or iADLS significantly impaired with MAJOR neurocognitive disorder? How many cognitive domains are reduced in function? Is the patient generally aware of deficit?
ADLs and iADLs are affected. iADLS often first!
Larger impairment of 1 or more major cognitive domains
NO
What is the most common cause of dementia in elderly? Prevalence?
Alzheimer disease, 1 in 8 in older populations, 40% in 80-90 group, 6th leading cause of death
What are some general pathological findings in Alzheimer disease?
1.) neurofibrillary tangles
2.) beta-amyloid plaques
3.) cerebral atrophy
4.) often loss of widely-distributed cholinergic neurons in the nucleus basalis of Meynert
What are focal, spherical collections of dilated, tortuous, neuritic processes (dystrophic neurites)?
Neuritic plaques (beta-amyloid)
Where are neuritic plaques often found? What might they be surrounded by?
Found around a central amyloid core. In the hippocampus, amygdala, and neocortex
May be surrounded by clear halo
Amyloid core in neuritic plaques contains several abnormal _____________. Examples?
PROTEINS
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
What is the range of size for a neuritic plaque?
20-200 um diameter
What is present at the periphery of NPs?
microglial cells and reactive astrocytes
Which 2 areas tend to be spared by plaques?
primary motor and sensory cortices
What are bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus?
neurofibrillary tangles
What type of neurons are neurofibrillary tangles typically found? Are they basophilic or acidophilic? What type of staining?
cortical neurons (especially in the entorhinal cortex, pyramidal cells of hippocamps, amygdala, basal forebrain), basophilic, H & E staining
What is a major component of many “tangled filaments”? Other components?
Abnormally hyperphosphorylated forms of protein TAU.
Tau= axonal microtubule-associated protein that enhances microtubule assembly
MAP2 (microtubule-associated protein)
Ubiquitin
What is APP?
Amyloid precursor protein
membrane-associated protein that is thought to be a receptor for an unidentified ligand
What form of APP is thought to be important in the pathogenesis of Alzheimer disease?
the insoluble form accumulated in the extracellular space
(APP is cleaved as a part of normal breakdown of cellular proteins. Depending on where it is cut, determines its solubility)
What results in chronic inflammatory injury to neurons? Accumulation of what is responsible for neurofibrillary tangles within neurons?
aggregates of beta-amyloid are directly neurotoxic and activate microglia and astrocytes = chronic inflammatory injury.
accumulation of beta-amyloid
REVIEW SLIDE 14 protein aggregation pathway in Alzheimer disease
Which cleavage produces Aβ peptides, which form pathogenic aggregates that contribute to the characteristic plaques and tangles of Alzheimer disease?
A.) β-amyloid-converting enzyme (BACE) and γ-secretase
B.) α-secretase and γ-secretase
C.) β-amyloid-converting enzyme (BACE) and α-secretase
D.) Presenilin 1 and α-secretase
A.) β-amyloid-converting enzyme (BACE) and γ-secretase
Which 2 proteins are associated with severe early-onset of AD? What do they regulate? What else are they involved in?
presenilin 1 and presenilin 2
regulate calcium levels associated with LTP (long-term potentiation)
Cleaving APP (similar function as secretase)
People that are heterozygous or homozygous for which protein have increased risk of AD? Which has more risk?
Apolipoprotein E4 - helps transport cholesterol throughout CNS
Heter- 2x risk (LOAD)
Homo- 16x risk (LOAD)
Which is more positively causative? Presenilin or Apo E4?
presenilin
How does diabetes II (increased blood glucose and FFAs) affect risk of AD?
Insulin resistance likely reduces synaptogenesis
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
What is the relationship between an increase in blood glucose and leaky BBB?
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
When glucose becomes non-enzymatically bound to an extracellular protein it’s known as what?
AGE (advanced glycation end-product)
What kind of pathways do rAGEs often activate?
Pro-inflammatory pathways
Which cognitive impairment happens relatively early in AD?
short-term memory and executive functions (planning, logic) impaired
personality changes and loss of normal inhibitions can follow some time after
Which cognitive impairment happens in more advanced AD?
language deficits and loss of learned motor skills
Which cognitive impairment happens in severe AD?
incontinence and impaired ambulation
impaired mobility related to development of pneumonia and sepsis
Clinical features of AD? (the 4 A’s and 1 D)
1.) anterograde amnesia
2.) aphasia
3.) Apraxia – difficulty with motor planning to perform tasks or movements
4.) Agnosia – difficulty recognizing/identifying objects, persons, or sounds although sensation is intact
4.) disturbance in executive function
Which one of the A’s is used to make the diagnosis?
Anterograde amnesia PLUS at least 1 other
What protein is mutated in dementia with Lewy bodies? What does this result in?
tau proteins
aggregation of tau protein, or alteration of how tau interacts with microtubules
Which lobes of the brain show more marked atrophy in Dementia with Lewy bodies?
frontal and temporal lobes
Which type of dementia has Parkinsons-like movements? What movements are these? Are these movements before or after the dementia?
Dementia with Lewy bodies
tremor, rigidity, bradykinesia
after
Dementia with Lewy Bodies usually predates or follows the diagnoses of Parkinson’s?
predates
Presence of Lewy bodies in neurons – likely aggregates of misfolded what?
alpha-synuclein
What percent of general elderly population have dementia with Lewy Bodies?
0.1-5%
AD or Lewy?
1.) Fluctuations in cognitive function with varying levels of alertness and attention
2.) Visual hallucinations that are vivid
3.) incontinence
4.) Prominent anterograde memory loss
5.) Executive function deficits
1.) Lewy
2.) Lewy
3.) AD
4.) AD
5.) Lewy
What is an impairment in reality testing, characterized by delusions and hallucinations
psychosis
What are beliefs that are not compatible with reality and are not normal beliefs for a culture?
delusions
What is the perception of a stimulus that isn’t there?
hallucination (can be audible or visual)
Which type of hallucination is more common in dementia? Audible or visual?
audible
Where are executive functions orchestrated from?
prefrontal cortex
True or False.
Executive functions often rely on memory and verbal fluency and therefore are always lost along with memory and verbal fluency.
FALSE.
Executive functions often rely on memory and verbal fluency, but can be lost even when memory and verbal fluency are not that impaired
What is your brain’s “taskmaster” to keep you doing things effectively and appropriately, either in a social or job or school context?
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
These are all examples of what?
executive functions
Patients with long-standing PD without cognitive impairment who slowly develop a dementia have what?
PD dementia
Which kind of dementia is associated with visual hallucinations and fluctuating alertness?
PD dementia
True or False. Lewy bodies are only found in Dementia with Lewy bodies.
FALSE. They are also found in PD dementia
Which type of dementia is a large group with diverse nomenclature and characterized by deficits in executive function, poor mental flexibility and abstract reasoning, response inhibition, planning/organization, and increased distractibility?
frontotemporal dementias
What are the most common behavioral variants in 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
FTD OR AD?
1.) more prominent memory deficits
2.) progressive inability to form words or use language
3) rapid decline
4.) common in older patients
1.) AD
2.) FTD
3.) FTD
4.) AD
What is 2nd most common cause of dementia after AD, with multiple small infarcts (often affecting gray matter of the cortices) or hypertension (often affecting white matter)?
vascular dementia
Depression and psychosis can be common in which type of dementia?
vascular
Which type of dementia has psychosis will frequently include delusions and hallucinations; agitation can be dangerous to both the patient and the caregiver?
vascular
True or False. Gait abnormalities are common (gait apraxia), and lateralizing signs (increased tone/reflexes) often present in VD?
True.
Which type of dementia progresses in a step-wise fashion?
VD
