Neurodegenerative Disease

Question 1

What is dementia?

Answer 1

general non-specific term to describe the cognitive, memory and communication impairment associated with neurodegenerative diseases
-focus, reasoning, judgement, control of emotions and motor
skills can also become impaired
-vascular conditions may contribute
-mixed dementias can also occur

Question 2

True or false: dementia is a normal part of aging

Answer 2

false

Question 3

How are dementias diagnosed?

Answer 3

tests of memory, language skills, math ability and mental functioning
lab tests to rule out infection, vitamin deficiency or hormonal issues
brain scans to identify if the problem is a stroke or tumor
-PET scan, MRI, CT
psychiatric evaluation to rule out depression and other disorders
genetic testing for disorders like Huntingtons

Question 4

What are examples of neurodegenerative diseases?

Answer 4

Alzheimers
Parkinsons
Amyotrophic lateral sclerosis
Picks
the features are characteristic because specific brain structures are affecfed

Question 5

What is Alzheimers disease?

Answer 5

degenerative brain disorder that develops in mid-to-late adulthood
results in progressive and irreversible decline in memory and deterioration of various other cognitive abilities

Question 6

True or false: Alzheimers rarely involves an inherited gene defect

Answer 6

true

Question 7

What are etiological factors for Alzheimers disease?

Answer 7

cardiovascular disease (HTN, head trauma, diabetes)
metals (arsenic, lead, copper, mercury)
environment (tobacco, smoke, pesticides)
aging (free radical generation)
genetics (mutation in APP, PSEN1, PSEN2, polymorphism of APOE)
ALTHOUGH THE ETIOLOGY IS UNCLEAR

Question 8

Atrophy to which part of the brain is a risk factor for Alzheimers?

Answer 8

cortical parts of the frontal and temporal regions of the brain

Question 9

Which age group is most affected by Alzheimers?

Answer 9

older people (>65yrs)
early onset is rare

Question 10

What are risk factors for Alzheimers?

Answer 10

modifiable:
-social engagement
-physical activity
-educational level
-mental activity
nonmodifiable:
-family history
-genetics: Apo E2 gene may confer risk in some but it is not absolute

Question 11

What is the pathology of Alzheimers?

Answer 11

development of neurofibrially tangles containing amyloid protein
this abnormal material is toxic, compressing, and destroying normal brain tissue near its threadlike or plaque-like accumulations
amyloid plaques are also present but do not seem to be the direct cause of neuronal dysfunction

Question 12

What are the areas of the brain particularly affected in Alzheimers?

Answer 12

hippocampus (affects new memories)
frontal lobe (affects behavior, cognition, judgement)
parietal lobe (affects language)

Question 13

What is the composition of neurofibrially tangles?

Answer 13

cytoskeletal intermediate filaments

Question 14

What are the stages of Alzheimers disease?

Answer 14

mild/early: 2-4 yrs
moderate/middle: 2-10yrs
severe/late:1-3+yrs

Question 15

What kind of drugs are used for Alzheimer’s?

Answer 15

cholinesterase drugs
-block the breakdown of ACh at the nerve synapse making it more available for activating post-synaptic muscarinic receptors

Question 16

What are the two classes of drugs approved to treat Alzheimer’s?

Answer 16

cholinesterase inhibitors
-donepezil
-rivastigmine
-galantamine
N-methyl-D-aspartate receptor antagonists
-memantine

Question 17

What is the signal-to-noise ratio hypothesis of Alzheimer’s?

Answer 17

there is is continual over activation of NMDA receptors by soluble B-amyloid oligmers and Mg cannot effectively modulate it
the “noise” increases making it more difficult to to detect a proper synaptic signal
neurons die due to excitotoxicity
glial cells can’t reuptake glutamate due to excess amyloid

Question 18

What are some adjunct drug therapies for AD under investigation to help with behavioural and sleep problems associated with the disease?

Answer 18

escitalopram and mirtazapine
carbamazepine and levetiracetam
lithium
methylphenidate

Question 19

What is the etiology of Picks disease?

Answer 19

several genes identified; can be familial
rare disease starting at age 40-60

Question 20

What is the pathogenesis of Picks disease?

Answer 20

abnormal accumulation of tau protein in swollen neurons (Pick bodies)
loss of cortical neurons, atrophy, gliosis, particularly in the frontal lobe with progressive loss of function

Question 21

Which lobes are highly affected in Picks disease?

Answer 21

Frontal and temporal
-speech, behaviour, personality

Question 22

What is Lewy body disease?

Answer 22

Dementia with Lewy bodies
-clumps of alpha-synuclein and ubiquitin protein
A type of dementia closely allied to both Alzheimer’s, and Parkinson’s

Question 23

What is the significance of alpha-synuclein when it is clumped?

Answer 23

Normal alpha-synuclein is active at neural synapses the clumped version impairs communication and causes neuronal cell death

Question 24

Which brain regions are affected by Lewy body disease?

Answer 24

Cerebral cortex (info processing, processing, thoughts, language)
Limbic cortex (emotions and behaviours)
Hippocampus (new emotions)
Midbrain and basal ganglia (movement)
Brain stem (sleep patterns and alertness)
olfactory pathways (smell)

Question 25

Differentiate between Alzheimer’s and Lewy body disease.

Answer 25

Alzheimer’s:
-women>men
-survival age ~84.6
-caused by amyloid plaques and neurofibrially tangles
Lewy body disease:
-men>women
-survival age ~79
-second most common form of dementia
-buildup of Lewy bodies

Question 26

What are the clinical manifestations of dementia with Lewy bodies?

Answer 26

Balance and motor control issues (early symptom)
Intermittent issues with memory
Flat face (emotionless)
Hallucinations
May physically act out what they are dreaming about (REM sleep disorder)
ANS dysregulated (hypotension, dizziness, falls)
Don’t give antipsychotics

Question 27

What is the treatment of dementia with Lewy Bodies?

Answer 27

no direct treatment
treat for symptoms:
-cognitive: cholinesterase inhibitors, NMDA antagonists
-motor: carbidopa/levodopa
-behavioral: antidepressants, atypical antipsychotics
-sleep: melatonin, clonazepam
-autonomic: fludrocortisone, midodrine

Question 28

Describe the epidemiology of Parkinsons disease.

Answer 28

appears in the ages of 50-70 at onset
affects about 1-2% of NA population, no notable changes in past 50yrs
men>women

Question 29

What is the etiology of Parkinsons disease?

Answer 29

usually sporadic cases, rare cases of inherited defects in the alpha synuclein gene resulting in early onset disease
fibrillogenesis is implicated
oxidative stress produced during melanin production in substantia nigra injures neurons by promoting misfolding of alpha synuclein and formation of filamentous inclusion

Question 30

True or false: Parkinsons is the only neurodegenerative disease with the accumulation of filamentous alpha synuclein inclusions

Answer 30

false
several neurodegenerative diseases where theres accumulation of filamentous alpha synuclein

Question 31

What is the tissue pathology of Parkinsons?

Answer 31

loss of neurons, particularly in the substantia nigra resulting in depigmentation of this area
accumulation of Lewy bodies made of filamentous aggregates of alpha synuclein including in other brain areas but to a lesser extent than in the substantia nigra
loss of dopaminergic neurons

Question 32

Response to which pharmacologic agent helps confirm the diagnosis of Parkinsons?

Answer 32

levodopa

Question 33

What are the clinical features of Parkinsons?

Answer 33

tremors at rest
cogwheel rigidity
expressionless face
postural instability
shuffling gait
small writing
soft voice
cognitive impairment
pain (musculoskeletal, neuropathic or central)
hallucinations/delusions in advanced disease

Question 34

What is the treatment of Parkinsons?

Answer 34

levadopa/carbidopa
-levadopa is a prodrug of dopamine that crosses BBB
-carbidopa reduces systemic metabolism of levadopa

Question 35

Which symptoms of Parkinsons are reduced when using levadopa?

Answer 35

bradykinesia type symptoms
-slowness of movements and difficulty initiating movements

Question 36

What are ALL the drug options for Parkinsons?

Answer 36

blocking peripheral metabolism of levadopa
-carbidopa, entacapone
blocking breakdown of dopamine at the neuron
-tolcapone, MAO-B inhibitors, selegiline, rasagiline
reducing reuptake of dopamine
-amandatine
direct dopamine agonists
-ergot alkali drugs (bromocriptine) and non-ergot
(pramipexole) and ropinirole

Question 37

What do the monoclonal antibodies used in Alzheimer’s target?

Answer 37

beta amyloid
-antibody-induced cell-mediated phagocytosis=dissociation of amyloid
-aducanumab, lecanumab