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M202 > W20 Neurodegeneration: Parkinsons Disease and Alzheimers > Flashcards

W20 Neurodegeneration: Parkinsons Disease and Alzheimers Flashcards

1
Q

What is Parkinson’s disease?

A
  • Disease linked with aging
  • Typical onset in 60’s (median age)
  • Incidence in the UK of 1 in 500, 10 000 diagnosed each year, 1 in 20 will be under 40 (early onset)
  • Parkinson’s was first described by Dr James Parkinson in 1817
  • He noted
    ** ‘Involuntary tremulous motion’
  • ‘A propensity to bend forwards’
  • ‘The senses and intellect are intact’**
  • In the 1860s Charcot named the condition Parkinson’s disease
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2
Q

What are the Parkinson’s cardinal symptoms for diagnosis? (4)
Classic symptoms?

A
  • Begins with tremor
  • Develops into bradykinesia (slowness of movement)
  • Rigidity
  • Postural instability
    3/4 cardinal symptoms for diagnosis

Classic symptoms
* Micrographia-handwriting gets smaller
* Altered posture
* Shuffling gait- dragging feet

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3
Q

What are the other symptoms of Parkinsons?

A
  • Sensory Phenomena (Pain, Dysthesia)
    Mental Changes (Dementia, Depression, Apathy)
  • Sleep disturbances
  • Motor (Postural instability, Freezing of gait, * Speech abnormalities, Dysphagia)
  • Autonomic nervous system dysfunction (Constipation, Sexual dysfunction, Urinary problems, Sweating)
  • Sleep disturbances (Sleep fragmentation, Sleep apnea, REM behavioural disordered, Restless leg syndrome)
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4
Q

Pathology of Parkinsons Disease: (for info)

A
  • 1960, Hornykiewicz:
    – PD brains had <10% of normal Dopamine
    (DA) levels in Substantia Nigra and Corpus
    Striatum
  • Corresponding neuronal loss of the dopaminergic nigrostriatal pathway
  • Lewy bodies
    – Present in CNS and PNS
    – Cytoplasmic protein inclusions that mostly
    contained alpha-synuclein (αS)
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5
Q

What are Lewy Bodies?
Where are they present?

A
  • Present in CNS and PNS
  • Intracellular cytoplasmic protein aggregates
  • Aggregates of alpha-synuclein
    -αS140 amino acid protein
    -Misfolded proteins
  • Leading pathogenic hallmarks in brain biopsies
    -May indicate problems with protein processing in the cell

Suggested..
* Parkinson’s disease symptoms: due to dopamine deficiency in the brain
* Now believed that the misfolding and subsequent aggregation of αS is a primary cause of dopaminergic degradation and cell (neuronal) death in PD

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6
Q

What is the ‘Braak hypothesis’?
What happens in the stages?

A
  • Spread of Lewy bodies sequential as disease progresses
  • Braak staging
  • Stage 1 and 2:
    Pathology is** confined to certain structures in the brain stem**, not yet the substantia nigra
  • Stage 3 and 4:
    Pathology spreads to the mid-brain and basal ganglia
  • Stage 5 and 6:
    Changes spread to the cortex
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7
Q

What is dopamine and where is it produced?
What is the role of Dopamine in Parkinsons?

A
  • Dopamine (DA) is a neurotransmitter produced in neurons of the Substantia Nigra (part of the basal ganglia)
  • Dopaminergic fibers radiate via striatum to
    cortical areas
  • The nigro-striatal pathway is the main pathway damaged in Parkinson’s disease
    -due to loss of DA producing neurones in the SN
  • Nuclei in basal ganglia crucial for the control of movement
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8
Q

What comprises the Basal Ganglia? (5)
What is their function?

A

A group of 5 bilateral nuclei lateral to the thalamus:
* caudate
* putamen
* globus pallidus (interna and externa)
* subthalamic nucleus
* substantia nigra (SN)

Substantia Nigra-excitatory

  • Initiate movement
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9
Q

Direct and indirect pathways through the basal ganglia:
What are the 2 main pathways?

A
  1. Indirect- slightly longer
    -Inhibits movement
  2. Direct- activated and sends messages to the cortex
    -Dopamine is set off from the SN and stimulates movement
    -Excitatory
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10
Q

Direct and indirect pathways through the basal ganglia:

A

Direct
* Cortex excites CP
* CP inhibits GPi
* inhibition of thalamus is reduced
* excitatory input to cortex increased
Indirect
* Cortex excites CP
* CP inhibits GPe
* GPe inhibition of STN is reduced
* STN excitation of Gpi increases
* GPi inhibition of thalamus is increased
* excitatory input to cortex decreased
Modulation by SNc
* Nigro-striatal dopamine pathway
* Activates direct pathway via D1
* Inhibits indirect via D2
* Balances the pathways

SN = substantia nigra
(c - compacta, r- reticulata)
STN = subthalamic nucleus
GP = globus pallidus
(e - external, i- internal)
D1 and D2 are dopamine receptors

  • Loss of DA neurones - imbalance in
    direct and indirect pathways
  • Indirect: increased
  • Direct: decreased
  • Increase in activity of GPI - Increases inhibition of thalamus
  • Switches off thalamo-cortical pathways
  • Loss of cortico-spinal output
  • Decreased movement, rigidity
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11
Q

Symptomatic Therapies - What are some different dopaminergic strategies? (4)

(how to inc/maintain dopamine levels?)

A
  • Replace the dopamine (L Dopa)
  • Increase the availability of dopamine to brain
    -Peripheral AADC inhibitors
  • – Decrease the breakdown of dopamine (in periphery)
    -MAO-B inhibitors
    -COMT inhibitors (limited – not shown)
  • Replace the post-synaptic dopamine
    stimulation
    -D2 agonists
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12
Q

Treatment of Parkinson’s:
first line?

A
  • First-line treatment
  • 1.3.5 Offer levodopa to people in the early stages of Parkinson’s disease whose motor symptoms impact on their quality of life. [2017]
  • 1.3.6 Consider a choice of dopamine agonists, levodopa or monoamine oxidase B (MAO-B) inhibitors for people in the early stages of Parkinson’s disease whose motor symptoms do not impact on their quality of life. [2017]
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13
Q

Symptomatic therapies - Non-dopaminergic strategies of treatment? (3)

A
  • Antiglutamatergics - Amantadine
  • The only available therapy for L-dopa induced dyskinesia (tremor)
  • Short duration of effect - 8 months
  • Anticholinergics
    – Tremor
    – profile of side effects
  • lack of dopamine means inc of acetylcholine so these are used

Benztropine= mACh antagonist for tremor

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14
Q

What are the 5 types of dementia?
Most to least common:

A

Alzheimer’s (62%)
Vascular Dementia (17%)
Mixed Dementia
Dementia with Lewy’s body
Frontotemporal Dementia

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15
Q

What is Dementia? (definition)

A
  • Umbrella term to define a syndrome
  • Defined - the loss of mental processing ability, communication, abstract thinking, judgment and physical abilities, such that it interferes with daily living
  • Chronic, progressive disorder
    Affects multiple parts of the brain:
  • Higher cognitive functions
    -Memory, thinking, comprehension, learning capacity, language
  • Daily living activities / Emotional behaviour (non-cognitive symptoms)
    -BPSD (Behavioural and psychological symptoms of dementia – agitation, apathy, depression, anxiety, delusions, hallucinations, irritability, wandering)
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16
Q

Alzheimer’s disease: Background

A
  • Often present with ‘memory lapses’
  • Physical abilities may be affected late stage
  • 3-20 year duration (7-10 more common)
  • Incidence of dementia (AD) increases with age
  • Age 65 - 1/14 have dementia
  • Age 80 - 1/6 have dementia
  • Female > Male
  • Current treatments relatively poor – symptomatic
  • Everyone experiences some decline in mental function with age – not dementia
17
Q

Broad clinical characteristics of AD?

A

Symptoms
* Memory lapses of increasing frequency and extent (often presenting symptom)
* Language deficits - word finding - comprehension - paraphasia
* Disturbed/repetitive behaviour
* Visuo-spatial deficits
* Impaired judgment and executive functions - risk assessment
Effects on social function
* Confusion, disorientation
* Lack of memory affects organisational skills
* Mood swings-depression, anger, paranoia
* Loss of confidence, withdrawal
* Loss of life skills and independence

18
Q

Alzheimer’s - gross pathology:
What essentially occurs to brain?
Which regions are particularly affected? (2)

A

AD: Lose nerve cells (die)
* Brain appears to shrink

  • Frontal cortex
  • Temporal lobe (hippocampus, amygdala)
19
Q

Microscopic Pathology of Alzheimer’s (2)
What are the 2 components?

A
  1. Extracellular (plaques)
    * Amyloid plaques
    * Contain Amyloid beta (Ab)
  2. Intracellular (protein deposits)
    * Neurofibrillary tangles (NFTs)
    * Contain tau (hyperphosphorylated)
20
Q

What is the Amyloid Hypothesis?

A
  • Build up of Ab (beta-amyloid) is crucial event (Amyloid Hypothesis – Ab drives AD)
    -Normally monomeric and soluble
    -Oligomerises (soluble) – toxic form ?
    =(oligomerisation depends on concentration)
  • Oligomers become insoluble (b-sheets)-> fibrils ->plaques
  • Ab cleaved from Amyloid Precursor Protein (APP)

=the accumulation and deposition of oligomeric or fibrillar amyloid β (Aβ) peptide is the primary cause of Alzheimer’s disease (AD)

21
Q

The amyloid hypothesis: APP processing to generate Abeta
Which enzymes cleave APP to produce Abeta? (2)
The build up of Abeta is thought to lead to..?

A
  • Beta secretase (BACE1)
  • Gamma secretase
    -Group of enzymes including one called presenillin

Build up of Abeta thought to lead to development of NFT (Neurofibrillary tangles)

22
Q

What are Neurofibrillary tangles
(NFT)?
What happens to them in AD?
What does this contribute to?

A
  • Made of Tau protein
  • Naturally occurring axonal protein
    -Cross-bridges with microtubules, promotes tubulin polymerization
  • -> microtubule stability
    Abnormally phosphorylated in AD
  • Inhibits tau-tau and tau-tubulin
  • Produces cytoskeletal disruption
  • Altered protein transport from and to dendrites
  • NFT contribute to neuronal cell death
  • Good correlation between the severity of dementia and NFT
    -higher no. of NFTs correlates with cognitive impairment
  • But much we don’t understand about how these changes lead to neuronal cell death
23
Q

Alzheimer’s disease:“Typical” progression
3 phases:
AD early phase symptoms?
Middle phase symptoms?
Late phase symptoms?

A

Mild Cognitive Impairment ( may or may not develop)

  • AD early phase.
    Forgetfulness, Anxiety/agitation, Paranoia, Disorientation
  • Middle phase.
    Withdrawal, loss of insight, Difficulty with speech (Aphasia);
  • Late phase
    Aphasia, affected comprehension. Disorientation in time and space. Psychiatric symptoms.
    Need for care for all daily activities
24
Q

Disease Progression of Alzheimers:
What happens to areas of brain?

A
  • Pathology appears sequentially (Cell death)
  • Early shrinkage - temporal lobes (contains hippocampus and amygdala), then frontal cortex
    -Memory (hippocampus) and speech defects
  • Progressive spread to whole cortex and subcortical structures
    -Higher order thinking (Executive function) affected
  • Variations – eg Posterior Cortical Atrophy
25
Q

Causes of Alzheimer’s Disease - Genetics
(dont try to remember details-for info)

A
  • Two presentations
    1. Early onset / Familial – strong genetic component (as early as 40)
    2. Late onset – sporadic (>65)
  • Genetics implicated in familial disease
    -Rare, Autosomal dominant
  • Mutations in APP
    -copy number (Down’s Syndrome)
    -Other - clustered around cleavage sites
    -Alter APP processing?
  • Mutations in presenilins (g-secretase components)

ignore
* Genetics implicated in sporadic disease Apolipoprotein E (ApoE4)
-Modifies age of onset
-Molecular mechanism uncertain
-May contribute to tau and Ab pathology
Multiple other susceptibility genes –
-genes of small effect

26
Q

What are some environmental causes of AD? (11)

A
  • Age
  • Lancet: 12 potentially modifiable risk factors (40%) including,
  • Hearing Loss
  • Head injury
  • Hypertension
  • Alcohol consumption
  • Smoking
  • Depression
  • Social isolation
  • Physical inactivity
  • Air pollution
  • Diabetes
  • Obesity and less education
27
Q

Alzheimer’s Treatments? (2)

A
  • All symptomatic
  • Do not affect underlying disease process (ie no effect on Aβ in case of AD)
  • Treat cognitive symptoms
    1. Acetyl cholinesterase inhibitors
    2. NMDA receptor antagonists
  • Non-cognitive symptoms
  • Behavioural and psychological symptoms of dementia (BPSD) – see lecture with Dr Guiguis
28
Q

Acetylcholinesterase inhibitors
examples?

A
  • Loss of cholinergic neurones
  • Substantial contribution to cognitive and non-cognitive symptoms
  • Counteract cholinergic deficits by inhibiting the b/d of acetylcholine
  • Donepezil (Aricept)
    -Selective AChE inhibition
  • Galantamine (Reminyl)
    -Selective AChE inhibition
  • Rivastigmine (Exelon)
    -AChE/BuChE inhibition
  • Some improvement in daily living BUT large placebo effect
  • Side effects: reflect peripheral parasympathomimetic and somatic
    neuromuscular stimulatory properties
  • No delay in disease progression
  • No change in Aβ!
29
Q

Excitotoxicity – NMDA receptor
antagonists

A
  • Excessive glutamate release
    -activates NMDA receptors.
  • Calcium influx results
  • Leads to the formation of reactive oxygen species and mitochondrial damage
  • This oxidative stress and the activation of proteases and endonucleases break down cells proteins and nucleic acids and contribute to neuronal death
  • NMDA receptor antagonists
  • Memantine (Ebixa) - uncompetitive antagonist, appears not to affect normal NMDA receptor activity
  • Moderate to advanced AD
  • No/little delay in disease progression /
  • No change in Ab
30
Q

New Drugs? to treat Alzheimer’s

A
  • Aducanumab (Aduhelm™)
  • Lecanemab (Leqembi™) - Early
    -Received accelerated approval as a treatment for Alzheimer’s disease from
    the U.S. Food and Drug Administration (FDA)
  • Monoclonal antibody – targets and aims to reduce Abeta
  • First new class of drugs approved for approx. 20 years
  • Availability?
  • Not in the UK (yet)!
31
Q

Dementia with Lewy bodies (not assessed)

A
  • Alpha synucleinopathy (as is PD)
  • Lewy bodies – round inclusion bodies in the cytoplasm of neurons
  • Substantia nigra and cortex
    -Lewy bodies contain alpha-synuclein
    -May see amyloid-beta deposits as well (not in Lewy bodies)
  • Loss of dopamine and acetyl choline (more so than in AD)
  • Symptoms
  • Fluctuating cognitive functions
    -Hallucinations
    -Features of parkinsonism – rigidity and slowness of movement
  • May respond better to cholinesterase inhibitors than AD (rivastigmine)
  • Movement disorders treated in similar way to PD
    -levodopa for rigidity and loss of spontaneous movement
  • Severe neuroleptic sensitivity
  • Neuroleptic (antipsychotic) sensitivity could worsen the motor symptoms
32
Q

Frontotemporal dementia (FTD) (not assessed)

A
  • Younger onset (50s)
  • Frontal/temporal lobe affected
  • Behavioural variant
    -Early decline in social interpersonal and personal conduct
    -Disinhibitions and executive functioning
  • Semantic (speech) variant
    -Gradual and progressive loss of words and comprehension
  • Recent memory typically preserved
  • Pathology
  • Pick cells/bodies – swollen neurons
    Protein inclusions
    -Tau / TDP-43
    -No Abeta
    -Little benefit of cholinesterase inhibitors (relative sparing of cholinergic neurons)

M202 (72 decks)

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