Lecture 25 - Neurodegenerative Disease 1 Flashcards
What are some potential causes of chronic disease?
- Repetitive tissue injury
- Continual environmental exposure
- Genetic modifications
- Inflammation
- Viral exposure
- Deposits of insoluble protein aggregates
Which cells in the CNS are predominantly affected by chronic diseases?
- Astrocytes
- Microglia
- Neurons
What is the most common chronic disease of the CNS?
Give some features
Dementia related disease
• Each one tends to affect different parts of the brain
• Over 100 diseases, similar, but not identical
What are the most common types of dementia?
- Alzheimer’s disease
- Tauopathies
- Transmissible spongiform encephalopathies
- PD
- Huntington disease
Describe the features of AIDS related dementia
• Pathogenesis
ADC: AIDS dementia complex
• Develops in some people with HIV disease
Pathogenesis:
- Immune cells (microglia, macrophages) present in the brain act as HIV reservoirs
- They produce neurotoxic cytokines
- Neuronal damage
Describe the features of alcohol related dementia
What is thought to be the pathogenesis?
What treatment options are available?
- Dementia related to excessive drinking of alcohol
- Effects memory, learning, personality changes, social skills
Pathogenesis:
• Heavy use of alcohol often accompanied by nutritional problems
• Key parts of the brain suffer vitamin deficiencies (thiamine)
Treatment:
• Abstinance from alcohol
• Thiamine replacement
Describe TBI
Which people can it affect?
What is it a strong risk factor for?
(Traumatic brain injury)
- External force may produce altered states of consciousness
- Impaired cognitive abilities
“Chronic traumatic encephalopathy”:
• Similar features as in AD
Focal damage:
• localised area
• damage to brain tissues and vessels
Diffuse damage:
• Widespread throughout the brain
Affects:
• All ages: children, sportspeople, combat veterans, seniors
Strong risk factor for AD
Describe how TBI is a strong risk factor for AD
- Activated microglia
- Abberant APP processing
- Increased gamma secretase
- Increased BACE
What is the main pathological feature of AD?
Amyloid plaques
Neurofibrillary tangles
How is AD diagnosed?
PET scanning using radioactively labelled carbon
PIB as a marker of the plaques
The chemical agents are not very specific; detect many different amyloid structures
What is the most common form of AD?
Sporadic
What is sporadic AD?
- Unknown aetiology
- Onset usually after 65 years
- Most common form of diagnosed AD
What is familial AD?
• Early onset • Genetic predisposition - APP - Presenilin 1 - Presenilin 2
Describe the Amyloidocentric Pathways in AD
Environmental risk factors affecting: • APP • Aβ Pathogenic mutations of: • APP Genetic risk factors affecting: • Aβ
APP and Aβ dysfunction lead to:
→ Accumulation of plaques
→ NFTs
Leading ultimately to:
→ Alzheimer’s disease
Describe what happens in the brain in AD, and how this relates to symptoms
- Deposition of plaques
• Free radical formation
• Synaptic dysfunction
• Inflammation - NFT formation in neurons
• Neuronal dysfunction
Gross atrophy of brain
Symptoms:
• Cognitive deficits
• Memory loss
(due to decrease neuronal function and connections)
How may AD be treated?
- No cure
* Cholinergic drugs slow progression by a few months
What is the link between Down syndrome and AD?
• APP encoded on chromosome 21
Down syndrome:
• Triplication of chromosome 21
• Almost of 100% people with Down syndrome at age 40 will get AD
• They make 1.5 as much APP that other people
• Excess tendency for abnormal amyloid breakdown
What is Fronto temporal lobar degeneration?
List some types
Dementia when there is degeneration in one of both of frontal lobe
Types:
• FTD: Fronto temporal dementia
• Pick’s disease
Compare acute and chronic diseases
Acute:
• Short lived
• Quick onset
Chronic:
• Long lasting
• Slow onset
Describe in CTE:
• Symptoms
• Pathological features
(Chronic traumatic encephalopathy)
Symptoms:
• Mood, personality, cognitive and behavioural changes
• Motor deficits
Pathological features: • Astrocytic tangles • Inflammation • Amyloid deposition • Tau deposits
Breifly describe Fronto Temporal Lobar degeneration (FTLD)
Degeneration in one or both of the frontal or temporal lobes of the brain
What is the aetiology of FTLD?
50% Genetic predisposition:
• Tau protein gene mutations
Describe the pathogenesis of FTLD
What normally causes death?
Tau protein abnormalities
→ Neurodegeneration
Death usually due to infection
What is the treatment for FTLD?
No treatment
What pathological features are seen in FTLD?
- Pick bodies
- Neuritic plaques
- NFTs
- Tau pathology
- Tufted astrocytes
What is vascular dementia?
List some
Dementia associated with problems with circulation in brain
There are a number of different types
Examples:
• Multi-infarct dementia
• Binswanger’s disease
What is the treatment for vascular dementia?
Various medications to control BP and prevent strokes
Describe the pathogenesis of multi-infarct dementia
What are the clinical signs?
Most common form of vascular dementia
Pathogenesis
• Number of small strokes (mini-strokes)
• Damage to cortex of the brain (important for memory, language and learning)
Clinical signs: • Reflects the areas affected Abnormalities in: • Memory • Language • Learning
What is ACA and CAA?
- Amyloid congophilic angiopathy
- Cerebral amyloid angiopathy
Different name for the same disease
What is the role of Tau in cells?
Associated with microtubules
Involved with intracellular transport
What happens to tau in disease?
Hyper phosphorylation
Aggregates into NFT intracellularly
→ Neuronal cell death
Which regions of the brain predominantly have NFTs?
Hippocampus and cortex
What is the prevalence of PD in the population?
Over 65 years of age: 1-2%
Are Lewy bodies intra- or extracellular?
Intracellular
Describe the pathology of PD
- Lewy body accumulation throughout brain inducing neuronal death
- Loss of dopaminergic neurons in the substantial nigra
Which has a quicker progression to death: AD or PD?
PD has a quicker progression: around 7 years
AD: up to 15 years
What are the treatments for PD?
L-DOPA
This helps movement, but does not reverse the loss of the neurons in the SN
What are the symptoms of PD?
Motor deficit
Sensory dysfunction
Autonomic abnormalities
Cognitive abnormalities
What are the risk factors for PD?
Metals
Pesticides
Rural residence
Male gender
What is Multiple system atrophy?
Rare neurological disorder
Combination of parkinsonism, cerebellar and pyramidal signs, as well as autonomic dysfunction
Which brain regions are affected in MSA?
(Multiple system atrophy)
• Basal ganglia
• Cerebellum
• Certain brainstem nuclei
Why don’t rabbits get CJD?
(Creuzfeld Jakob disease)
They do not have the prion protein in their brain
Describe Prion disease
- Acquired through contact with prion infectious material
- Rapidly progressive
- Causes deterioration of the brain
- Dementia
Examples:
• CJD
• Kuru
Describe CJD
• Symptoms
• Diagnosis
• Treatment
*
Conversion of healthy PrP to mutant form with contact to the mutant form
What is Amyotrophic lateral sclerosis? • Symptoms • Pathogenesis • Aetiology • Age of onset
(Lou Gehrig’s disease)
Pathogenesis:
• Degeneration of neurons in anterior horn of spinal cord
Symptoms:
• Muscle atrophy
Age of onset:
• After age of 50
Aetiology
• 5-10% hereditary
• SOD1 gene important
• Autosomal dominant
Describe spinal muscular atrophy
• Pathological features
• Age of onset
Pathological features:
• Affected lower motor neurons
• Atrophy of anterior horn cells
• Atrophy of anterior spinal roots
Age of onset:
• Children
Describe Bulbospinal atrophy (Kennedy syndrome)
• Clinical manifestations
• Aetiology
• Age of onset
Clinical manifestations:
• Distal limb amyotrophy
• Atrophy of tongue
• Dysphagia
Aetiology:
• Expansion of CAG repeat in androgen receptor gene
• Degeneration of lower motor neurons in spinal cord and brainstem
Age of onset:
Adolescence → middle adult life
Describe Huntington disease
• Symptoms
• Aetiology
Aetiology: • CAG repeats in the genome • Less than 28 repeats: normal • 28-35: intermediate, no disease • 35-40: reduced penetrance • more than 40 repeats: full penetrance
Pathological features:
• Brain atrophy
• Range of clinical manifestations
Describe Spinocerebellar ataxias (SCA)
• Aetiology
• Pathology
• Symptoms
Aetiology:
• Hereditary
• SCA gene
Pathology:
• Atrophy of the cerebellum
Symptoms:
• Motor deficits
• Gets worse with time
Describe how ageing contributes to chronic disease development
What is ageing?
- Changes that render humans more likely to die, i.e. increased susceptibility to death
- Associated with a wide range of physiological changes
- Limitation of normal functions
- More susceptible to a number of diseases
Which genes influence brain ageing?
Apolipoprotein E (ApoE):
• Thought to be protective
• Increased levels in centenarians
PRNP: prion protein gene
• Antioxidant ?
What is the key protein in the following diseases? • Prion diseases • AD • Tauopathies • PD • Multiple system atrophy • Huntington disease • Spinocerebellar ataxias
Prion diseases: PrP AD: Aβ Tauopathies: tau PD: alpha-synuclein Multiple system atrophy: alpha-synuclein Huntington disease: Huntington Spinocerebellar ataxias: ataxins
What is the location of aggregates (intra / extracellular) in the following diseases? • Prion diseases • AD • Tauopathies • PD • Multiple system atrophy • Huntington disease • Spinocerebellar ataxias
Prion diseases: Extracellular AD: extracellular Tauopathies: cytoplasmic PD: cytoplasmic Multiple system atrophy: cytoplasmic Huntington disease: nuclear Spinocerebellar ataxias: nuclear
What are some beneficial environmental factors for brain function in old age?
- Low caloric intake
- Physical exercise
- Education
- Cognitive stimulation
- B vitamins
- Statins
What are some factors that decrease longevity?
- Raised BP
- Raised cholesterol
- High caloric intake
Describe the effects of caloric restriction
- Decreased ROS
- Increased neurogenesis
- Increased repair of cellular damage
What is the function of the frontal lobes?
When is this area affected?
- Mood
- Behaviour
- Judgement
- Self-control
Affected in Fronto Temporal lobar degeneration (FTLD)
What are the functions associated with the temporal lobes?
- Organisation of sensory input: vision
- Auditory sensation
- Difficultly with categorisation
Describe the pathogenesis Binswanger’s disease
Which region of the brain is affected?
(a form of vascular dementia)
Region of brain:
• White matter
Aetiology:
• High BP
• Thickening of arteries
• Ischemia in brain
Pathogenesis:
• One single large stroke
• Damage to white matter of brain
