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PATH30001 - Mechanisms of Disease > Lecture 25 - Neurodegenerative Disease 1 > Flashcards

Lecture 25 - Neurodegenerative Disease 1 Flashcards

1
Q

What are some potential causes of chronic disease?

A
  • Repetitive tissue injury
  • Continual environmental exposure
  • Genetic modifications
  • Inflammation
  • Viral exposure
  • Deposits of insoluble protein aggregates
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2
Q

Which cells in the CNS are predominantly affected by chronic diseases?

A
  • Astrocytes
  • Microglia
  • Neurons
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3
Q

What is the most common chronic disease of the CNS?

Give some features

A

Dementia related disease
• Each one tends to affect different parts of the brain
• Over 100 diseases, similar, but not identical

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4
Q

What are the most common types of dementia?

A
  • Alzheimer’s disease
  • Tauopathies
  • Transmissible spongiform encephalopathies
  • PD
  • Huntington disease
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5
Q

Describe the features of AIDS related dementia

• Pathogenesis

A

ADC: AIDS dementia complex

• Develops in some people with HIV disease

Pathogenesis:

  1. Immune cells (microglia, macrophages) present in the brain act as HIV reservoirs
  2. They produce neurotoxic cytokines
  3. Neuronal damage
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6
Q

Describe the features of alcohol related dementia
What is thought to be the pathogenesis?

What treatment options are available?

A
  • 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

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7
Q

Describe TBI
Which people can it affect?

What is it a strong risk factor for?

A

(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

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8
Q

Describe how TBI is a strong risk factor for AD

A
  • Activated microglia
  • Abberant APP processing
  • Increased gamma secretase
  • Increased BACE
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9
Q

What is the main pathological feature of AD?

A

Amyloid plaques

Neurofibrillary tangles

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10
Q

How is AD diagnosed?

A

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

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11
Q

What is the most common form of AD?

A

Sporadic

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12
Q

What is sporadic AD?

A
  • Unknown aetiology
  • Onset usually after 65 years
  • Most common form of diagnosed AD
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13
Q

What is familial AD?

A 
• Early onset
 • Genetic predisposition
- APP
- Presenilin 1
- Presenilin 2
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14
Q

Describe the Amyloidocentric Pathways in AD

A 
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

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15
Q

Describe what happens in the brain in AD, and how this relates to symptoms

A
  1. Deposition of plaques
    • Free radical formation
    • Synaptic dysfunction
    • Inflammation
  2. NFT formation in neurons
    • Neuronal dysfunction

Gross atrophy of brain

Symptoms:
• Cognitive deficits
• Memory loss
(due to decrease neuronal function and connections)

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16
Q

How may AD be treated?

A
  • No cure

* Cholinergic drugs slow progression by a few months

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17
Q

What is the link between Down syndrome and AD?

A

• 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

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18
Q

What is Fronto temporal lobar degeneration?

List some types

A

Dementia when there is degeneration in one of both of frontal lobe

Types:
• FTD: Fronto temporal dementia
• Pick’s disease

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19
Q

Compare acute and chronic diseases

A

Acute:
• Short lived
• Quick onset

Chronic:
• Long lasting
• Slow onset

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20
Q

Describe in CTE:
• Symptoms
• Pathological features

A

(Chronic traumatic encephalopathy)

Symptoms:
• Mood, personality, cognitive and behavioural changes
• Motor deficits

Pathological features:
 • Astrocytic tangles
 • Inflammation
 • Amyloid deposition
 • Tau deposits
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21
Q

Breifly describe Fronto Temporal Lobar degeneration (FTLD)

A

Degeneration in one or both of the frontal or temporal lobes of the brain

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22
Q

What is the aetiology of FTLD?

A

50% Genetic predisposition:

• Tau protein gene mutations

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23
Q

Describe the pathogenesis of FTLD

What normally causes death?

A

Tau protein abnormalities
→ Neurodegeneration
Death usually due to infection

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24
Q

What is the treatment for FTLD?

A

No treatment

25
Q

What pathological features are seen in FTLD?

A
  • Pick bodies
  • Neuritic plaques
  • NFTs
  • Tau pathology
  • Tufted astrocytes
26
Q

What is vascular dementia?

List some

A

Dementia associated with problems with circulation in brain

There are a number of different types
Examples:
• Multi-infarct dementia
• Binswanger’s disease

27
Q

What is the treatment for vascular dementia?

A

Various medications to control BP and prevent strokes

28
Q

Describe the pathogenesis of multi-infarct dementia

What are the clinical signs?

A

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
29
Q

What is ACA and CAA?

A
  • Amyloid congophilic angiopathy
  • Cerebral amyloid angiopathy

Different name for the same disease

30
Q

What is the role of Tau in cells?

A

Associated with microtubules

Involved with intracellular transport

31
Q

What happens to tau in disease?

A

Hyper phosphorylation
Aggregates into NFT intracellularly
→ Neuronal cell death

32
Q

Which regions of the brain predominantly have NFTs?

A

Hippocampus and cortex

33
Q

What is the prevalence of PD in the population?

A

Over 65 years of age: 1-2%

34
Q

Are Lewy bodies intra- or extracellular?

A

Intracellular

35
Q

Describe the pathology of PD

A
  • Lewy body accumulation throughout brain inducing neuronal death
  • Loss of dopaminergic neurons in the substantial nigra
36
Q

Which has a quicker progression to death: AD or PD?

A

PD has a quicker progression: around 7 years

AD: up to 15 years

37
Q

What are the treatments for PD?

A

L-DOPA

This helps movement, but does not reverse the loss of the neurons in the SN

38
Q

What are the symptoms of PD?

A

Motor deficit
Sensory dysfunction
Autonomic abnormalities
Cognitive abnormalities

39
Q

What are the risk factors for PD?

A

Metals
Pesticides
Rural residence
Male gender

40
Q

What is Multiple system atrophy?

A

Rare neurological disorder

Combination of parkinsonism, cerebellar and pyramidal signs, as well as autonomic dysfunction

41
Q

Which brain regions are affected in MSA?

A

(Multiple system atrophy)
• Basal ganglia
• Cerebellum
• Certain brainstem nuclei

42
Q

Why don’t rabbits get CJD?

A

(Creuzfeld Jakob disease)

They do not have the prion protein in their brain

43
Q

Describe Prion disease

A
  • Acquired through contact with prion infectious material
  • Rapidly progressive
  • Causes deterioration of the brain
  • Dementia

Examples:
• CJD
• Kuru

44
Q

Describe CJD
• Symptoms
• Diagnosis
• Treatment

A

*

Conversion of healthy PrP to mutant form with contact to the mutant form

45
Q 
What is Amyotrophic lateral sclerosis?
 • Symptoms
 • Pathogenesis
 • Aetiology
 • Age of onset
A

(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

46
Q

Describe spinal muscular atrophy
• Pathological features
• Age of onset

A

Pathological features:
• Affected lower motor neurons
• Atrophy of anterior horn cells
• Atrophy of anterior spinal roots

Age of onset:
• Children

47
Q

Describe Bulbospinal atrophy (Kennedy syndrome)
• Clinical manifestations
• Aetiology
• Age of onset

A

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

48
Q

Describe Huntington disease
• Symptoms
• Aetiology

A 
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

49
Q

Describe Spinocerebellar ataxias (SCA)
• Aetiology
• Pathology
• Symptoms

A

Aetiology:
• Hereditary
• SCA gene

Pathology:
• Atrophy of the cerebellum

Symptoms:
• Motor deficits
• Gets worse with time

50
Q

Describe how ageing contributes to chronic disease development

What is ageing?

A
  • 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
51
Q

Which genes influence brain ageing?

A

Apolipoprotein E (ApoE):
• Thought to be protective
• Increased levels in centenarians

PRNP: prion protein gene
• Antioxidant ?

52
Q 
What is the key protein in the following diseases?
 • Prion diseases
 • AD
 • Tauopathies
 • PD
 • Multiple system atrophy
 • Huntington disease
 • Spinocerebellar ataxias
A 
Prion diseases: PrP
AD: Aβ
Tauopathies: tau
PD: alpha-synuclein
Multiple system atrophy: alpha-synuclein
Huntington disease: Huntington
Spinocerebellar ataxias: ataxins
53
Q 
What is the location of aggregates (intra / extracellular) in the following diseases?
 • Prion diseases
 • AD
 • Tauopathies
 • PD
 • Multiple system atrophy
 • Huntington disease
 • Spinocerebellar ataxias
A 
Prion diseases: Extracellular
AD: extracellular
Tauopathies: cytoplasmic
PD: cytoplasmic
Multiple system atrophy: cytoplasmic
Huntington disease: nuclear
Spinocerebellar ataxias: nuclear
54
Q

What are some beneficial environmental factors for brain function in old age?

A
  • Low caloric intake
  • Physical exercise
  • Education
  • Cognitive stimulation
  • B vitamins
  • Statins
55
Q

What are some factors that decrease longevity?

A
  • Raised BP
  • Raised cholesterol
  • High caloric intake
56
Q

Describe the effects of caloric restriction

A
  • Decreased ROS
  • Increased neurogenesis
  • Increased repair of cellular damage
57
Q

What is the function of the frontal lobes?

When is this area affected?

A
  • Mood
  • Behaviour
  • Judgement
  • Self-control

Affected in Fronto Temporal lobar degeneration (FTLD)

58
Q

What are the functions associated with the temporal lobes?

A
  • Organisation of sensory input: vision
  • Auditory sensation
  • Difficultly with categorisation
59
Q

Describe the pathogenesis Binswanger’s disease

Which region of the brain is affected?

A

(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

PATH30001 - Mechanisms of Disease (34 decks)

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