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MD4001 Pathology > Neurodegenerative Disease > Flashcards

Neurodegenerative Disease Flashcards

1
Q

What is the major risk factor for most neurodegenerative diseases?

A

Old age

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2
Q

What is the biggest growing demographic group in the UK?

A

> 80 years

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3
Q

How many people have dementia?

A
  • 50 m (world)
  • Will rise to 140m by 2050
  • Around 900,000 in UK
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4
Q

How many people have Parkinsons disease in the UK?

A

130,000

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5
Q

What is the average life expectancy for someone with motor neuron disease?

A

3 years

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6
Q

What percentage of Dementia is Alzheimer’s?

A

70%

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7
Q

What is the prevelance of AD in different age groups?

A
  • 1% at 65
  • 40% at 90
    (Doubles every 5 years)
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8
Q

Is AD more common in men or women?

A

Women

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9
Q

What percetage of ADs are familial?

A

~ 10%

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10
Q

What are the signature proteins (aggreagates) of AD?

A
  • Extracellular amyloid plaques (largely composed of AB peptides)
  • Intracellular fibrils (neurofibrilary tangles) (predominantly composed of tau) (MT stabilising protein)
  • Tau in tangles is hyperphosphorylated + forms paired helical filaments
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11
Q

What is the AB peptide made from?

A

Amyloid Precursor Peptide being cleaved by secretases abnormally

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12
Q

What are some genes which cause autosomal dominant familial Alzheimer’s?

A
  • Amyloid precursor protein gene (downs, mutations, duplications)
  • Presenilin-1 gene
  • Presenilin-2 gene
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13
Q

What is the most common gene disorder which causes familial Alzheimer’s?

A

Presenilin-1 (80% of early onset cases)

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14
Q

What are major risk genes associated with Alzheimer’s?

A
  • ApoE4 (lipoprotein affects SORL1 trafficking)
  • TREM2 (binds ApoE, functions in recycling)
  • SORL1 (endocytic sorting in retromer)
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15
Q

What is at the heart of generating the Alzheimer phenotype?

A
  • Membrane trafficking and dysfunctional retromeres
  • Endosome enlargement occurs earlier than Tau or Amyloid
  • Aberrant trafficking results in mixing of Beta-secretase and APP
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16
Q

Key components of retromer are depressed in what area in AD patients?

A

Hippocampus

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17
Q

What is seen on CT/MRI in Alzheimer’s?

A

Grey matter shrinkage (e.g medial temporal lobe, posterior cingulate and precuneus)
- Not specific to AD

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18
Q

What will perfusion SPECT show in AD?

A

VAriations in regional cerebral blood flow - noticable early in AD

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19
Q

WHat can FDG-PET show in AD?

A

Uptake of FDG proportional to cerebral glucose metabolism, reflects cerebral metabolism better than amylois PET for assessing function in AD

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20
Q

WHat does Amyloid PET scan show in AD?

A

C-PiB crosses blood-brain barrier, binds to ABeta quantitative imaging. More recent probe is 18F-flutemetamol binds to amyloid deposits in AD

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21
Q

What does a Tau PET show in AD?

A

18F-flortaucipir binds to neurofibrillary tangles in AD

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22
Q

WHat are the main CSF biomarkers in AD?

A
  • Amyloid-B42
  • total tau
  • Phosphorylated tau (p-tau)
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23
Q

What can pTau 181 assay (peripheral bllod flow) detect in established AD?

A
  • Established AD correlates with tangles/plaques distinguished from other dementias
  • Increases the risk of developing AD by 11fold
24
Q

What did old/ineffective AD therpies focus on?

A
  • ANtibodies to toxic aggregates amyloid beta and tau
  • Phosphorylation -countering and Microtubule-modifying drugs
  • Often caused inflammatory changes in brain
25
Q

What is the new approach to treating AD?

A

Focus on developing molecular chaperones to improve retromer functions and remove trafficking defect (TPT-172; in development no human trials yet)

26
Q

What chemicals are specifically reduced in AD?

A
  • Ach, related to neuronal loss from nucleus basalis of Meynert
  • Loss of GABA from cortex to secondary neuronal loss
  • Serotonin (5HT) input from dorsal raphe nuclei reduced
  • NA input from locus coeruleus reduced
27
Q

Loss of what neurons is thought to be mostly responsible for memory and learning defects?

A

Ach

28
Q

What drugs affect Ach turnover and are used to treat AD?

A
  • Galantamine
  • Donepezil
  • Rivastigmine
29
Q

What is excitotoxicity?

A

NEuronal death caused by the overactivation of excitatory amino acid receptors - happens in AD - glutamte causes extrasynaptic activity which promotes cell death

30
Q

What drug to treat AD is associated with reducing excitotoxity?

A

Memantine (moderate to severe AD)

31
Q

Parkinon’s disease is primarily due to to the accumulation of what aggregate?

A

Alpha-synuclein create Lewy bodies

32
Q

What area of the brain does PD primarily affect?

A

Substantia nigra

33
Q

How are Lewy body dementia and PDs linked to each other?

A
  • PD starts with movement disorder then progresses to dementia (70% of the time)
  • Lewy Body dementia starts as dementia but can progress to a movement disorder
  • Both have Lewy bodies which contain alpha-synuclein present in cell bodies
34
Q

What percentage of dementia’s are Lewy Bodies?

A

5% of new cases (15% of all dementia)

35
Q

What kind of genes are associated with PD?

A
  • Genes associated with endosomes e.g VPS35 retromer component
  • Links to alpha-synuclein aggregation
36
Q

What are some different types of Motorneuron diseases?

A
  • Amyotrophic Lateral Sclerosis (UMN and LMN)
  • Progressive Muscular Atrophy (LMN)
  • Primary Lateral Sclerosis (UMN)
  • Spinal Muscular Atrophy
  • Lou Gehrig’s disease
37
Q

What is by farthe most common for of MND?

A

Amylotrophic lateral Sclerosis (ALS)

38
Q

What is associated with Amylotrophic lateral Sclerosis?

A
  • Affects UMNs and LMNs
  • Most patients die within 3-5 years
  • Fasiculations
  • Muscle cramps
  • Tight and stiff muscles
  • Muscle weakness affecting an arm, a leg, neck or diaphragm
  • Slurred and nasal speech
  • Difficulty chewing or swallowing
39
Q

What is Superoxide Dismutase 1?

A
  • Amylotrophic Lateral Sclerosis - type of MND

- Familial type (5-10% of ALS diseases)

40
Q

What are the different proteins responsible for ALS?

A
  • Superoxide Dismutase 1
  • TAR DNA Binding Protein (TDP-43)
  • Fused in sarcoma (FUS)
  • C9orf72 (most common also in FTD)
41
Q

What drug can be used to treat ALS?

A

Riluzole

42
Q

How does Riluzole thought to work?

A
  • Reduces Glutamate release (calcium block)
  • Increases astrocyte glutamate uptake
  • Decreases glutamate levels
  • Inhibits TDP43 metabolism via CK1delta (casein kinase) inhibition
43
Q

What are the Neuropsychological deficits associated with dementia?

A
  • Amnesia
  • Aphasia
  • Agnosia
  • Apraxia
44
Q

What are the frontal lobes associated with?

A

Sequencing and fluency

45
Q

What are the temporal lobes associated with?

A

Memory speech (L)

46
Q

WHat are the parietal lobes associated with?

A

Spatial awareness (R), Laungauage (L)

47
Q

How does one test frontal lobe function?

A
  • Luria hand sequencing task

- Verbal fluency 1 minute words F,A,S, animals

48
Q

How does one test temporal lobe function?

A
  • Address test
  • Object recall
  • Serial 7s
49
Q

How does one test parietal lobe function?

A
  • Clock face
  • Naming objects
  • Drawing cube, interlocking infinity
  • Agnosia
50
Q

What tests can be used to diagnose dementia?

A
  • Mini-mental state Examination (MMSE)

- ACE (mobile) (100% specific; 84% sensitive)

51
Q

What is MCI (Mild Cognitive Impairment)?

A

Subjective impairment and cognitive impairment but does not meet dementia diagnostic criteria - able to complete activities of daily living (ADL)
- May progress to dementia

52
Q

What is the aim of demntia detecting treatment effects?

A

reliably, reproducibly and sensitively detect and monitor cognitive state/dementia

53
Q

What would be the optimal features of a dementia detecting treatment?

A
  • Test to test reproducible
  • Tester to tester reproducible
  • Invariant or adjustable to gender and age difference
  • Detectiong of predementia/MCI
  • Sensitive scale with no ceiling effects
54
Q

What was the problem with ADAS-cog?

A

Does not produce linear scale - ceiling effects, need to be pretty demented to register change

55
Q

What are some of the difficulties associated with doing trials on neurodegenerative diseases?

A
  • Sensitivity, subjectivity and inherent bias can limit the usefulness of many traditional methods
  • Diseases difficult to detect
  • Measurement is problematic - how to measure precisely, reproducibly without bias the states of function and importantly how rto measure and be sensitive to changes in function
  • Precision of data will be impaired by variability and poor measurement scales

MD4001 Pathology (18 decks)

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