Sheet 5 Flashcards
What are the classic features of neurodegenerative diseases?
1) Progressive and slow loss of neurons
2) Typically affects groups of neurons with functional interconnections
3) Different diseases involve different neural systems = different symptoms
4) The histologic hallmark for ALL diseases is the accumulation of protein aggregates
5) Same protein may aggregate in different diseases, but at different distributions
6) Proteins resist degradation, accumulate within the cells, elicit inflammatory response, and are toxic to neurons = neurons will die while proteins will stay and spread from one cell to another
What are the causes of protein accumulation?
1) Mutations that alter protein conformation as the protein is misfolded and resistant to cleavage
2) Mutations disrupting the processing and clearance of proteins
3) Subtle imbalance between protein synthesis and clearance (genetic or environmental factors)
What happens if the neurodegenerative disease involves the cortex?
Causes dementia, which is a collection of cognitive abnormalities (memory, behaviour and language).
What are examples of neurodegenerative diseases involving the cortex?
1) Alzheimer disease (AD)
2) Frontotemporal dementia (FTD)
3) Pick disease (subtype of FTD)
What happens if the neurodegenerative disease involves the basal ganglia?
Causes movement disorders
What are examples of neurodegenerative diseases involving the basal ganglia?
1) Parkinson disease: causes hypokinesia
2) Huntington disease: causes hyperkinesia
Parkinson disease causes __(hyperkinesia/hypokinesia), while Huntington disease causes __ (hyperkinesia/hypokinesia).
Hypokinesia; hyperkinesia
What happens if the neurodegenerative disease involves the cerebellum?
Causes ataxia because cerebellum is the coordinator of balance
What are examples of neurodegenerative diseases involving the cerebellum?
Spinocerebellar ataxia
What happens if the neurodegenerative disease involves the motor system?
Causes difficulty swallowing and respiration with muscle weakness
What are examples of neurodegenerative diseases involving the motor system?
Amyotrophic lateral sclerosis
Can neurodegenerative diseases be communicable?
No, there is no evidence of person-to-person transmission
What are the common features of neurodegenerative diseases?
1) Protein aggregates can seed the development of more aggregates
2) Protein aggregates can spread from one neuron to another in Prion-like pattern
3) Activation of the innate immune system
What is dementia?
The development of memory impairment and other cognitive deficits severe enough to decrease the person’s capacity to function at his previous level despite normal level of consciousness.
What is the difference between dementia and mild cognitive impairment?
The cognitive deficit must affect the person’s performance in his daily life activities to be called dementia
What are the cognitive changes of dementia?
1) Memory loss, which is usually noticed by someone else
2) Difficulty communicating or finding words
3) Difficulty reasoning or problem-solving (solving math problem for example)
4) Difficulty handling complex tasks (Many tasks at the same time)
5) Difficulty with planning and organizing
6) Difficulty with coordination and motor functions later (can’t wear his boots)
7) Confusion and disorientation
What are the psychological changes of dementia?
1) Personality changes
2) Depression
3) Anxiety
4) Inappropriate behavior
5) Paranoia
6) Agitation
7) Hallucinations
What are the complications of dementia?
1) Inadequate nutrition
2) Pneumonia
3) Inability to perform self-care tasks
4) Personal safety challenges
5) Death due to infections from aspiration of food (pneumonia)
What is the most common cause of dementia in older adults?
Alzheimer disease (AD)
Describe the incidence of Alzheimer disease (AD).
Increases with age (47% in those over 84 years).
What are some characteristics of Alzheimer disease (AD)?
1) Most cases are sporadic
2) 5-10% are familial (onset before 50)
3) Gradual onset
4) Impaired higher intellectual functions as recognition is weak, memory
impairment and altered mood and behavior.
5) Severe cortical dysfunction occurs late in this disease (disorientation, aphasia, profound disability, mute, and immobile)
6) Death usually due to infections (pneumonia)
What are the phases of Alzheimer disease (AD)?
1) Asymptomatic phase: Proteins start to aggregate
but the patient doesn’t show
2) Predementia phase: Early symptoms related to memory starts to appear, cognitive domains in the brain are not affected that much
3) Dementia phase: Decline in at least one cognitive skill that impairs daily functioning and independence.
What is the most commonly recognized symptom of Alzheimer Disease (AD)?
Inability to acquire new memories and difficulty in recalling recently observed facts.
What are the symptoms of advancing Alzheimer Disease (AD)?
1) Confusion
2) Irritability and aggression
3) Mood swings
4) Language breakdown
5) Long term memory loss
6) A gradual loss of bodily functions
7) Death
How does Alzheimer Disease (AD) occur?
Accumulation of two proteins: αβ amyloid and Tau in the form of plaques outside the cell and neurofibrillary tangles inside the cell = neuronal dysfunction, death, and inflammation.
Plaques deposit in the __, while tangles develop intracellularly
Neuropil
What is the critical initiating event for the development of Alzheimer Disease (AD)?
αβ generation
What elevates the risk of Alzheimer Disease (AD)?
Mutations of the gene encoding the precursor protein for αβ
What does NOT increase the risk of Alzheimer Disease (AD)?
Mutations of Tau gene
What is the final role of αβ amyloid in Alzheimer Disease (AD)?
Atrophy of the brain.
αβ amyloid is formed from:
Amyloid precursor protein (APP) which is a transmembrane protein
Amyloid precursor protein (APP) is formed by:
Many subunits, including α, β, and γ
Normally, amyloid precursor protein (APP) is cleaved by:
1) α-secretase
2) γ-secretase
They liberate a non-pathogenic peptide.
What happens to amyloid precursor protein (APP) in Alzheimer Disease (AD)?
It is cleaved by:
1) β-secretase converting enzyme (BACE)
2) γ-secretase
= αβ amyloid
What leads to familial Alzheimer Disease (AD)?
1) Mutations in amyloid precursor protein (APP)
OR
2) Mutations in components of γ-secretase
Where is the APP gene located?
On chromosome 21 = increased risk of down syndrome
What is the pathway of αβ amyloid?
Aggregation = plaques formation = decreased # of synapses and alters their function = memory disruption
What is Tau and where is it found?
A microtubule-associated protein; in axons in association with the microtubular network
What happens to Tau if αβ amyloid forms?
A kinase enzyme is activated = Tau is hyperphospholerated
What happens if Tau is hyperphosphorylated?
1) Microtubule disassembly = damages the pathway of vesicles as they are carried on microtubules to the synaptic knobs for transmitting of action
potential (loss of microtubule stability = neuronal toxicity and death).
2) Formation of Neurofibrillary tangles
What causes the spread of lesions in AD?
Tau aggregates passing across synapses from one neuron to the next
What does the innate immune system respond to?
1) αβ amyloid
2) Tau
Deposits of αβ amyloid start an inflammatory response from:
1) Microglia
2) Astrocytes
What causes neuronal injury overtime in AD?
1) Clearance of the aggregated peptide
2) Secretion of mediators
When do deposits of αβ amyloids and tangles appear in AD?
Before cognitive impairment
When do deposits of αβ amyloids and tangles appear in familial AD?
Before cognitive impairment by 15-20 years (usually occurs in 50 year olds)
Large burdens of plaques and tangles is:
Strongly associated with severe cognitive dysfunction
What correlates better with the degree of dementia: The number of neuritic plaques or the number of neurofibrillary tangles?
The number of neurofibrillary tangles
How do we diagnose AD?
Clinically by symptoms and excluding other reasons of the same manifestations.
What is the morphology of AD?
1) Cortical atrophy
2) Widening of the cerebral sulci & Compensatory ventricular enlargement
(hydrocephalus ex vacuo).
3) Most pronounced in the frontal, temporal, and parietal lobes.
Alzheimer disease neuropathologic changes include 2 things:
1) Neuritic plaques (Extracellular)
2) Neurofibrillary tangles (intracellular)
What is a neuritic plaque?
Central amyloid core surrounded by collections of dilated, tortuous, processes of dystrophic neurites
(surrounded by gliosis).
Where do neuritic plaques appear?
1) Hippocampus
2) Amygdala
3) Neocortex
(relative sparing of primary motor and sensory cortices until late).
What does the amyloid core of the neuritic plaques contain?
αβ
What are neurofibrillary tangles?
Basophilic fibrillary structures in the cytoplasm of neurons, displace or encircle the nucleus; persist after neurons die, becoming extracellular.
Where are neurofibrillary tangles found?
1) Cortical neurons
2) Pyramidal cells of hippocampus
3) Amygdala
4) Basal forebrain
5) Raphe nuclei.
What are neurofibrillary tangles made up of?
Hyperphosphorylated tau
What does Frontotemporal Lobar Degeneration (FTLD) cause?
1) Progressive deterioration of language and changes in personality
2) Clinically, frontotemporal dementias
Which symptoms manifest first in Frontotemporal Lobar Degeneration (FTLD)?
Behavioural and language problems before memory
disturbances (Opposite of AD)
When does the onset of symptoms start for Frontotemporal Lobar Degeneration (FTLD)?
Younger ages than in AD
What do Frontotemporal Lobar Degeneration (FTLD) neuronal inclusions contain?
Tau or TDP43
What is Pick disease (subtype of FTLD-tau) associated with?
Pick bodies: Smooth, round inclusions
What are the differences between AD and FTLD?
1) In AD there is sparing of the frontal lobe in the beginning = behavioral changes are a late manifestation
2) In FTLD, frontal lobe is affected from the beginning = behavioral changes manifest early
What is the morphology of FTLD?
1) Atrophy of frontal and temporal lobes
2) Neuronal loss and gliosis (In FTLD-tau, the characteristic neurofibrillary
tangles, similar to AD)
3) Rounded Pick bodies in pick disease
