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Flashcards in lecture 25 Deck (62):
1

What are chronic diseases?

- they are diseases of long duration and generally of slow progression
- i.e. can take up to 10 to 30 years to develop

2

What are acute diseases?

- these diseases typically last only a short period of time e.g. days to weeks
e.g. heart attack

3

What are potential causes of chronic disease?

- repetitive tissue injury e.g. tbis
- environmental exposure
- genetic modifications
- inflammation
- viral exposure
- deposits of insoluble protein aggregates (common in a lot of ngds)

4

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

astrocytes
neurons
microglia
breakdown of communication between these cells can lead to cell death

5

What is the most common chronic disease of CNS?

- dementia related disease
- the effects of the different types of dementia are similar but not identical
- each one tends to affect different parts of the brain
- over 100 diseases can cause dementia

6

What do the most common types of dementia include?

- alzheimer's disease
- tauopathies
- transmissible spongiform encephalopathies
- fronto temporal disorder
- parkinson's disease
- multiple system atrophy
- amyotropic lateral sclerosis
- spinal muscular atrophy
- huntington disease
- spinocerebellar ataxias

7

What is AIDS related dementia?

- AIDS related dementia or as AIDS dementia complex (ADC)
- ADC is a complicated syndrome made up of different nervous systems and mental symptoms that can develop in some people with HIV disease
- only a small proportion of HIV/AIDS sufferers will develop ADC
- the incidence of ADC occurs predominantly in people with advanced disease status and in people not taking anti-HIV drugs
- while it has been shown that HIC does not directly infect nerve cells, it is thought that it can somehow infect them indirectly
- immune cells that are present in brain act as HIV reservoirs and are the primary source of indirect damage to nerve cells
- if an early diagnosis of ADC is made, appropriate treatment and management can be started
- the rate of progression varies from person to person
- however the disease can lead to complete dependence and death

8

What is the cause of alcohol related dementia?

- nutritional problems, which often accompany consistent or episodic heavy use of alcohol, are thought to be contributing factors
- key parts of the brain may suffer damage through vitamin deficiencies, particularly marked levels of thiamine deficiency and the direct effect that alcohol has on the absorption and use of thiamine

- depriving brain of required vitmins

9

What is alcohol related dementia?

- it is a form of dementia related to the excessive drinking of alcohol
- it affects memory, learning, personality changes, social skills
- korsakoff's syndrome and Wernicke/Korsakoff syndrome are particular forms of alcohol related brain injury which may be related to alcohol related dementia

10

Is there are treatment available for alcohol related dementia?

- abstaining from alcohol
- thiamine is important to limit some of the toxic effects alcohol
- affected by mostly men ages 45 to 65 with long history of alcohol abuse

11

What is traumatic brain injury?

- an insult to the brain caused by an external force that may produce diminished or altered states of consciousness, which results in impaired cognitive abilities or physical functioning

12

What is focal damage (tbi)?

occurs in localised area and causes damage to the underlying brain tissues and vessels

13

What is diffuse damage (tbi)?

- not restricted but widespread throughout the brain

14

Who does tbi affect?

all ages: children, sportspeople, combat veterans, aged people

15

What do multiple TBIs develop?

develop chronic traumatic encephalopathy

16

What is a strong epigenetic risk factor for Alzheimer's disease?

TBI
e.g. activated brain microglia, aberrant APP processing, increased gamma-secretase, BACE1

17

What is chronic traumatic encephalopathy?

- suffer from mood, personality, cognitive and behavioural changes (e.g. suicidality), and motor symptoms (e.g. abnormal gait, tremor)
- astrocyte tangles, neurites, diffuse axonal injury, white matter abnormalities, inflammation, and immune proinflammatory cytokine responses
- amyloid deposition (diffuse plaques) in approx 40% of cases
- PET image of Tau deposits in brain from retired NFL players
- higher levels in players compared with controls in all subcortical regions and the amygdala

18

What is trying to be determined Re: inflammation and neurodegeneration?

- is inflammation a cause or a consequence

19

What is the history of Alzheimer's disease discovery?

- the disease is named after the german physician, Alois Alzheimer
- in 1901, a patient named Mrs Auhuste Deter had short-term memory loss
- she died in 1906
- he used new staining techniques to identify amyloid plaques and NFT in brain biopsies
- in 1960s electron microscopy was used to identify plaques in AD brains at the nanometer level
- mid 1980s: purification of Beta amyloid peptide from AD brains (Masters (unimelb) and Beyreuther, Glenner and Wong)
- 1992: Hardy and Higgins conceptualised the 'amyloid cascade hypothesis'
- 1999: McClean first reported the correlation of soluble oligomeric Abeta species in AD brain with increasing severity of the disease

20

What is the the beta amyloid peptide?

4 kDa protein
42 amino acids is major form (ranging from 38 to 46 aas)

21

What are the amyloidocentric pathways in alzheimer's disease?

APP cleaved -> A-beta
aggregates into amyloid structures
intracellular NFTs
plaques are extracellular

ABCA7 identified to be a genetic risk factor
ApoE = genetic risk factor

pathogenic mutations: PS1,2

22

What are the two main classes of Alzheimer's disease?

- sporadic (unknown origin) and familial (genetic)

23

What is sporadic Alzheimer's disease?

- the disease can affect adults at any age, but usually occurs after age 65
- this is the most common form of diagnosed Alzheimer's disease
- it affects people who may or may not have a family history of the disease
- >90% of AD diagnosed
- caused onset is unknown

24

What is familiar or early onset alzheimer's disease?

- the disease runs in a few families and is very rare
- if a parent has a mutated gene, each child has a 50% chance of inheriting it
- age of onset is early - usually in their 40s or 50s (before 65)
- about 50% of early onset AD are familial AD where a genetic predisposition leads to the disease
- represent < PS1, PS2)

25

What happens to the brain in Alzheimer's disease?

- it attacks the brain resulting in impaired memory, thinking and behaviour
- as brain cells die, the substance of the brain shrinks
- abnormal material builds up as "tangles" in the centre of the brain cells and "plaques" outside the brain cells, disrupting messages within the brain, damaging connections between brain cells
- memory of recent events is the first to be affected, but as the disease progresses, long term memory is also lost
- the disease also affects many of the brain's other functions and consequently, many other aspects of behaviour are disturbed

26

How is AD diagnosed?

- postmortem histology
- PET imaging?
- blood or CSF assays?
- what is the early stage of people developing alzheimer's disease

27

What is the treatment for AD?

- no cure
- cholinergic drugs slow the progression down by a few months only
- PBT2, BACE1 inhibitors, vaccination, ?

28

What is the link between Down syndrome and AD?

- down syndrome is a genetic disorder
- sufferers have 3 copies of chromosome 21 in every cell body instead of the usual pair, upsetting the gene balance
- studies show that by age of 40, almost 100% of people with Down syndrome who die have the changes in the brain associated with AD
- APP is coded for on chromosome 21
- therefore, down syndrome make 1.5 times more APP
- this results in a tendency to produce the more amyloid breakdown products which cause toxic oligomers to form and kill off brain cells

29

What is fronto temporal lobar degeneration?

this is the name given to dementia when there is degeneration in one or both of the frontal or temporal lobes of the brain

frontal lobes
- the right and left frontal loves govern mood, behaviour, judgement and self-control
- damage leads to alterations in personality and behaviour, changes in the way a person feels and expresses emotion and loss of judgement

temporal lobes
- the right and left temporal lobes are involved in the organisation of sensory input such as what you hear or see
- damage may lead to difficulty placing words or picutres into categories
- there is considerable difference in FTLD symptoms depending on which parts of the frontal/temporal lobes are affected
- the three main subtypes or variants are:
- fronto temporal dementia (FTD) is the most common subtype or frontal variant
- it is mainly a disorder of behaviour
- people with FTD may be disinhibited or apathetic (e.g. find it extremely different to contribute to/enjoy a conversation)

30

What is pick's disease?

- pick's disease is a type of fronto temporal lobar degeneration
- named after the german neurologist who first described it in 1892
- Pick's disease affects the frontal lobes, but in some cases can affect the temporal lobe of the brain
- if the temporal lobe is damaged, memory is more likely to be affected

31

What causes fronto temporal lobar degeneration?

- about 50% of people with FTLD had a family history of the disease
- those who inherit it seem to have a mutation in the tau protein gene on chromosome 17, leading to abnormal tau protein being produced
- other risk factors are less well known

32

How does FTLD progress?

- the course of FTLD is one of inevitable progressive deterioration
- from the onset of the disease, life expectancy is two to fifteen years, with a average of six to twelve years
- death usually comes from another illness such as infection

33

Is there treatment available?

- there is not yet a cure for FTLD, nor is there currently any treatment

34

What are pathological features in FTLD-tau?

- atrophy of the frontal and temporal lobes
- pick bodies
- a globose tangle
- neuritic plaque
- neuronal and glial tau pathology in the frontal cortex
- tufted astrocyte

35

What is vascular dementia?

- dementia associated with problems of circulation of blood to the brain
- there are a number of different types of vascular dementia

multi-infarct dementia
- this is probably the most common form of vascular dementia
- it is caused by a number of small strokes, calle dmini-strokes or Transient Ischaemic Attacks (TIA)
- the strokes cause damage to the cortex of the brain, the area associated with learning, memory and language

36

What is Binswanger's disease?

- also known as subcortical vascular dementia
- it is the white matter deep within the brain that is affected
- it is caused by high blood pressure, thickening of the arteries and inadequate blood flow
- one single large stroke can sometimes cause vascular dementia depending on the size and location of the stroke

37

What is the treatment for vascular dementia?

- medications that can help prevent strokes and control high blood pressure

38

What is amyloid congophilic angiopathy (ACA)/cerebral amyloid angiopathy (CAA)?

- amyloid deposits form in walls of blood vessels of the CNS
- risk factors include stroke, hypertension, cerebral haemorrhage
- increased incidence in familial forms such as Icelandic and British type

39

What is tauopathy or NFTs?

- tau is a microtubule associated protein
- normal ageing results in the phosphorylation of Tau resulting in the formation of NFT
- these NFT structures destabilise cell integrity leading to enhanced cell loss
- predominantly found in hippocampus and cortex
- increase of soluble tau in CSF with ageing

40

What is parkinson's disease?

- 1-2% of the general population over the age of 65yo

pathology
- lewy bodies and lewy neurites particularly in the substantia nigra pars compacta dopaminergic neurons projecting to the striatum
- DA levels severely reduced in the striatum
- not limited to SN only, also found in the locus coeruleus basalis of Meynert, the cerebral cortex, the olfactory bulb and the autonomic nervous system
- confined largely to neurons; glial cells only rarely affected

symptoms
- resting tremor, bradykinesia, muscle rigidity

potential treatment
- levodopa and other dopaminergic drugs
- no treatment which would prevent the continuous degeneration of nerve cells in the substantia nigra and resulting striatal DA loss
- no disease-specific biological marker

41

What is dementia with lewy bodies?

- it is caused by the degeneration and death of nerve cells in the brain
- the presence of abnormal spherical structures, called Lewy bodies, develop inside nerve cells
- it is thought that these may contribute to the death of brain cells
- sometimes referred to as diffuse lewy body disease

42

What is the cause of dementia with lewy bodies?

- at present there is no known cause of dementia with lewy bodies and no known risk factors have been identified
- there is no evidence that dementia with lewy bodies is an inherited disease

43

How does dementia with lewy bodies progress?

- dementia with lewy bodies differs from alzheimer's disease in that the progression of the disease is usually more rapid
- the average lifespan after the onset of symptoms is about seven years

44

What are risk factors Parkinson's disease?

Age is the most important risk factor

- positive family history
- male gender
- environmental exposure; herbicide and pesticide exposure, metals (manganese, iron), well water, farming, rural residence, wood pulp mills; and steel alloy industries
- race
- life experiences (trauma, emotional stress, personality traits such as shyness and depressiveness)?

45

What is multiple system atrophy?

definition: a rare neurological disorder characterised by a combination of parkinsonism, cerebellar and pyramidal signs, and autonomic dysfunction

brain regions affected include:
- basal ganglia
- cerebellum
- and certain brainstem nuclei

the age range for onset - 33.3 to 75.6 years
- mean age of onset - 52.5 years
- survival range from onset 5 - 9 years

46

What is CJD?

- can be acquired via contact with prion infectious material
- a rapidly progressive disease
- causes deterioration of the brain and dementia
- it is one of a group of rare diseases that affects humans and animals (e.g. sheep, cows, deer)
- there is no cure for CJD
- death usually results within two years (typically 6 months)

the human TSEs or prion diseases include:
- sporadic CJD, which causes 85 to 90 percent of cases
- genetic or familial CJD, which causes 10 to 15 percent of cases
- kuru (highlands of new guinea)
- variant CJD (BSE)
- medically acquired CJD

symptoms
- may include memory loss
- mental status changes
- impaired coordination and visual disturbances
- later stages include pronounced mental decline, involuntary movements, profound weakness and ultimately coma

diagnosis
- brain electrical activity
- CSF
- brain biopsy or autopsy (after death)

treatment
none

PrPc --> PrPtse

47

What is ALS?

- amyotrophic lateral sclerosis (lou gehrig's disease)
- caused by the degeneration of neurons located in the ventral horn of the spinal cord and the cortical neurons that provide their afferent input
- characterised by muscle atrophy
- 5-10% are familial
- 90% autosomal dominant inheritance
- genetic locus mapped to Cu/Zn superoxide dismutase gene (SOD1)
- manifests in fifth decade or later

48

What is spinal muscular atrophy?

- affects lower motor neurons
- loss of anterior horn cells
- atrophy of anterior spinal roots
- onset occurs in children

49

What is Bulbospinal Atrophy?

- kennedy syndrome
- distal limb amyotrophy
- atrophy/fasciculations of tongue and dysphagia
- degeneration of lower motor neurons in the spinal cord, brainstem
- caused by expansion of CAF repeat in the first exon of the androgen receptor gene
- ages of onset vary from adolescence to old age, most commonly in middle adult life

50

What is huntington disease?

- huntingtin gene has a CAG trinucleotide repeat encoding a polyglutamine region of the protein
- more repeats is associated with increasing age onset of AD

brain atrophy
- striatum
- globus pallidus
- subthalamus
- cerebral cortex
- 25-30% of brain matter lost

< 28 repeats = normal

28-35 = intermediate (unaffected)

36-40 reduced penetrance

>40 full penetrance

51

What is spinocerebellar ataxias (SCA)?

major symptom
- atrophy of the cerebellum

a genetic disease
- SCA gene up to 30 identified to date
- each gene is associated with different age of onset and duration

52

What is the definition of a progressive disease?

gets worse with time

53

Can aging contribute to chronic disease development?

- ageing refers to the biological process of growing older in a deleterious sense (i.e. senescence)
- the collection of changes that render human beings progressively more likely to die
- a marker of ageing in humans is an age-related increase in mortality rates
- human ageing is associated with a wider range of physiological changes that not only make us more susceptible to death, but that limit our normal functions and render us more susceptible to a number of diseases

54

What are potential causes of chronic disease?

- genes that influence brain ageing
- the ability to up-regulate genes that repair damage is good

ApoE
- ApoE2 is protective

PRNP

55

What are environmental causes of chronic diseases?

beneficial influences on brain function in old age
- low calorie consumption
- physical exercise
- extended year of education
- cognitive stimulation
- high intake of polyunsaturated fatty acids
- taking B vitamins and statins
- consumption of curcumin, ginkobaloa, chocolate and wine

caloric restriction increases longevity
- decreased reproduction
- decreased ROS
- increased neurogenesis
- increased repair of cellular damage
- increase BDNF
- decreased energy usage switched to maintenance of the soma

factors decreasing longevity
- increased blood pressure
- increased cholesterol
- increased blood homocysteine
- increased caloric intake

56

What is the protein, normal structure, aggregate/inclusion and location associated with transmissible spongiform encephalopathies?

- PrP
- a-helix/random coil
- beta-pleated sheet/proteinase K-resistant
- extracellular?

57

What is the protein, normal structure, aggregate/inclusion and location associated with AD?

APP
a-helix/random coil
b-pleated sheet/amyloid
extracellular

58

What is the protein, normal structure, aggregate/inclusion and location associated with tauopathies?

tau
3 and 4 repeat isoforms
hyperphosphorylated aggregated protein
intracellular/cytoplasmic

59

What is the protein, normal structure, aggregate/inclusion and location associated with PD?

a-syn
random coil, repeats
aggregated/lewy bodies
cytoplasmic

60

What is the protein, normal structure, aggregate/inclusion and location associated with multiple system atrophy?

a-syn
random coil, repeats
aggregated, glial cytoplasmic inclusions
cytoplasmic

61

What is the protein, normal structure, aggregate/inclusion and location associated with huntington disease?

huntingtin
trinucleotide repeats
insoluble aggregates
nuclear

62

What is the protein, normal structure, aggregate/inclusion and location associated with spinocerebellar ataxias?

ataxins
trinucleotide repeats
insoluble aggregates
nuclear