W20 Neurodegeneration: Parkinsons Disease and Alzheimers Flashcards
What is Parkinson’s disease?
- 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
What are the Parkinson’s cardinal symptoms for diagnosis? (4)
Classic symptoms?
- 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
What are the other symptoms of Parkinsons?
- 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)
Pathology of Parkinsons Disease: (for info)
- 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)
What are Lewy Bodies?
Where are they present?
- 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
What is the ‘Braak hypothesis’?
What happens in the stages?
- 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
What is dopamine and where is it produced?
What is the role of Dopamine in Parkinsons?
- 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
What comprises the Basal Ganglia? (5)
What is their function?
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
Direct and indirect pathways through the basal ganglia:
What are the 2 main pathways?
- Indirect- slightly longer
-Inhibits movement - Direct- activated and sends messages to the cortex
-Dopamine is set off from the SN and stimulates movement
-Excitatory
Direct and indirect pathways through the basal ganglia:
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
Symptomatic Therapies - What are some different dopaminergic strategies? (4)
(how to inc/maintain dopamine levels?)
- 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
Treatment of Parkinson’s:
first line?
- 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]
Symptomatic therapies - Non-dopaminergic strategies of treatment? (3)
- 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
What are the 5 types of dementia?
Most to least common:
Alzheimer’s (62%)
Vascular Dementia (17%)
Mixed Dementia
Dementia with Lewy’s body
Frontotemporal Dementia
What is Dementia? (definition)
- 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)
Alzheimer’s disease: Background
- 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
Broad clinical characteristics of AD?
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
Alzheimer’s - gross pathology:
What essentially occurs to brain?
Which regions are particularly affected? (2)
AD: Lose nerve cells (die)
* Brain appears to shrink
- Frontal cortex
- Temporal lobe (hippocampus, amygdala)
Microscopic Pathology of Alzheimer’s (2)
What are the 2 components?
-
Extracellular (plaques)
* Amyloid plaques
* Contain Amyloid beta (Ab) -
Intracellular (protein deposits)
* Neurofibrillary tangles (NFTs)
* Contain tau (hyperphosphorylated)
What is the Amyloid Hypothesis?
- 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)
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..?
- 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)
What are Neurofibrillary tangles
(NFT)?
What happens to them in AD?
What does this contribute to?
- 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
Alzheimer’s disease:“Typical” progression
3 phases:
AD early phase symptoms?
Middle phase symptoms?
Late phase symptoms?
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
Disease Progression of Alzheimers:
What happens to areas of brain?
- 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
Causes of Alzheimer’s Disease - Genetics
(dont try to remember details-for info)
- 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
What are some environmental causes of AD? (11)
- 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
Alzheimer’s Treatments? (2)
- 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
Acetylcholinesterase inhibitors
examples?
- 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!
Excitotoxicity – NMDA receptor
antagonists
- 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
New Drugs? to treat Alzheimer’s
- 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)!
Dementia with Lewy bodies (not assessed)
- 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
Frontotemporal dementia (FTD) (not assessed)
- 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)
