Unknown aetiology Onset usually after 65 years Most common form of diagnosed AD

Lecture 25 - Neurodegenerative Disease 1 Flashcards by Eleanor Nicklason

What are some potential causes of chronic disease?

Repetitive tissue injury
Continual environmental exposure
Genetic modifications
Inflammation
Viral exposure
Deposits of insoluble protein aggregates

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

Astrocytes
Microglia
Neurons

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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

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What are the most common types of dementia?

Alzheimer’s disease
Tauopathies
Transmissible spongiform encephalopathies
PD
Huntington disease

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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

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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

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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

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Describe how TBI is a strong risk factor for AD

Activated microglia
Abberant APP processing
Increased gamma secretase
Increased BACE

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What is the main pathological feature of AD?

Amyloid plaques

Neurofibrillary tangles

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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

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What is the most common form of AD?

Sporadic

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What is sporadic AD?

Unknown aetiology
Onset usually after 65 years
Most common form of diagnosed AD

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What is familial AD?

• Early onset
 • Genetic predisposition
- APP
- Presenilin 1
- Presenilin 2

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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

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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)

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How may AD be treated?

No cure

* Cholinergic drugs slow progression by a few months

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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

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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

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Compare acute and chronic diseases

Acute:
• Short lived
• Quick onset

Chronic:
• Long lasting
• Slow onset

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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

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Breifly describe Fronto Temporal Lobar degeneration (FTLD)

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

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What is the aetiology of FTLD?

50% Genetic predisposition:

• Tau protein gene mutations

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Describe the pathogenesis of FTLD

What normally causes death?

Tau protein abnormalities
→ Neurodegeneration
Death usually due to infection

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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