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302 SBM: Neurobiology > Neurodegeneration & cognitive disorders > Flashcards

Neurodegeneration & cognitive disorders Flashcards

1
Q

What is a neurodegenerative disorder?

Give three examples

A

A progressive CNS disease (but not all progressive diseases are NDD)

e.g. Alzheimer’s, Parkinson’s, Dementia with Lewy bodies, MND

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2
Q

What do the following conditions have in common?

  • Batten’s
  • Niemann-Pick
  • Tay-Sachs
A
  • very rare
  • recessive
  • result: mutant protein
  • occur in childhood
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3
Q

What do the following conditions have in common?

  • Huntington’s
  • Myotonic dystrophy
A
  • fairly rare
  • dominant (repeats)
  • results: mutant protein
  • any age
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4
Q

What do the following conditions have in common?

  • Alzheimer’s
  • Parkinsons
  • MLD
A
  • common
  • polygenic
  • result: misfolded protein
  • middle age onset
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5
Q

Which protein goes wrong in the following diseases?

  • Alzheimer’s
  • Parkinsons
  • MLD
A

Alzheimers: tau (+ amyloid)

Parkinsons: aSyn

MLD: TDP-43

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6
Q

What happens before neurones die in NDD?

Give an example of this pathognomonic finding

A

Before neurones die the proteins within them aggregate forming what is known as an inclusion body
- these can be seen on microscopy

e.g. neurofibrillary tangles in Alzheimers

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7
Q

What happens in rapid neuronal loss?

Give an example of a condition where this happens?

A

Spongiosis: fluid-filled holes

e.g. in CJD, FTLD

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8
Q

Outline the central dogma of NDD

A

Native protein becomes misfolded
(this is usually corrected by chaperone proteins, but this failed in NDD, protein degradation also occurs)

Misfolded protein undergoes oligomerization which results in oligers, protofibrils and other intermediates
(these can damage the cells and cause a loss of function as less native protein)

These undergo fibril formation –> fibrils

The issue is in there tertiary structure which causes misfolding and/- hyperphosphorylation

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9
Q

Using the region-cell-type-pathology structure, describe two NDDs

A

PARKINSONS DISEASE
Region: substantia nigra
Cell type: dopaminergic nigrostriatal neurones
Pathology: lewy bodies, neuronal loss

MND
Region: Primary motor cortex
Cell type: layer 5 pyramidal neurones
Pathology: neuronal loss, TDP-43 inclusions

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10
Q

State the cognitive functional domains

For each give an example of what it controls

A

MEMORY
- recent events, facts, encoding vs retrieval

LANGUAGE
- syntax, word-finding/naming, meaning

SOCIAL-BEHAVIOURAL
- disinhibition, apathy, loss of empathy

PSYCHIATRIC
- depression, hallucination, paranoia

VISUOSPATIAL
- wayfinding, arranging objects, copying a drawing

EXECUTIVE FUNCTION
- working memory, structured tasks

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11
Q

Give an example of a cognitive syndrome that can cause a deficit in the following cognitive domains:

a) memory
b) language
c) social-behavioral
d) visuospatial

A

a) Alzheimer’s
b) Primary progressive dysphasia
c) Frontal-temporal dementia (+ executive function loss)
d) Posterior cortical atrophy, Alzheimer’s

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12
Q

Give 3 examples of motor negative syndromes/symptoms

A
  • UMN lesions
  • LMN lesions
  • Parkinsonism
  • Apraxia
  • Ataxia
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13
Q

Give 3 examples of motor positive syndromes/symptoms

A
  • Tremor
  • Dystonia
  • Myoclonus
  • Chorea
  • Seizures
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14
Q

Give 3 examples of sleep syndromes/symptoms

A
  • insomnia
  • Decreased REM sleep
  • REM sleep behavioral disinhibition
  • periodic limb movements
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15
Q

Give 3 examples of autonomic syndromes/symptoms

A
  • sialorrhoea
  • constipation
  • postural HTN
  • Erectile dysfunction
  • Detrusor-sphincter dyssnergia
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16
Q

Give 3 examples of sensory syndromes/symptoms

A
  • insensitivity to pain
  • agraphasthesia
  • astereognosis
17
Q

Give 5 symptoms of Parkinsons

A
  • Parkinsonism
  • Apathy
  • Memory impairment
  • Dystonia (cog-wheel)
  • Resting tremor
  • Sleep dysfunctions
  • Autonomic dysfunctions
  • Psychiatric dysfunctions
  • Visuospatial dysfunction
  • Executive function
18
Q

How does MND present?

A

MND= UMN + LMN (corticospinal tract) damage

  • Language, executive, social, depression, paranoia, behavioral dysfunctions, sialorrhoea
19
Q

What information can imaging give us about NDD?

A
  • The cortex is small (due to neuronal loss)
  • However symptoms will start when neurones start to work less well: this may be before neurones die and so imaging wont always coincide –> less sensitive

This is why Alzheimers cannot be ruled out by MRI in the context of cognitive impairment

20
Q

What information can a PET scan give us in NDD?

A

In NDD, there is neuronal loss. This means the cellular demand for glucose decreases as neurones stop working. This will proceed any MRI changes

A PET scan uses radio-labelled glucose injected into peripheral NS and its uptake in the brain is monitored

  • in cancer this appears as hot spots
  • in NDD this appears as cold spots
21
Q

What might the PET scan of a patient with Alzheimers look like?

A

Cold spots affecting parietal and occipital lobes with frontal lobe sparing

22
Q

What information can a DAT scan give us in NDD?

A

Uses radioactive tracer to visualise dopamine transporter levels

Used as diagnostic tool for Parkinsons

23
Q

Describe the progression of NDD and symptoms onset

Think about specific diseases such as AD and PD

A

When pathology begins its asymptomatic

During the prodromal phase there is a large increase in the severity of the pathology

Once there is severe pathology this is usually when symptoms begin (in Alzheimer’s this is 10-15 years after onset)
- coupled with time between symptom onset and presentation to doctor, patients are usually late into disease by time of diagnosis

In PD, 80% of neuronal loss in substantial nigra before symptoms

24
Q

What is the gene mutation responsible for Tau-related NDDs?

A

MAPT

25
Q

What is the gene mutation responsible for TDP-43-related NDDs?

A

C9ORF72 (commonest single gene mutation that causes NDD)

GRN

26
Q

What proteins are incorrectly aggregated in Alzheimers?

A

B- Amyloid

Tau

27
Q

Describe how B-amyloid aggregation contributes to disease in patients with AD

A
  1. Aggregates outside cells forming amylod plaques
    - this precedes Tau dysfunction
    - it doesn’t cause any issues in itself
  2. Amyloid angiopathy: aggregates in blood vessel walls
    - not in all AD patients
    - makes blood vessels more fragile and increases the likelihood of small vessel ischemic disease and intracerebral haemorrhage
28
Q

An 85-year old patient undergoes MRI imaging for a suspected NDD following a progressive decline in cognitive functions
On imaging you see lots of microhaemorrhages

What diagnosis should you consider?

A

Alzhemiers disease with amyloid angiopathy

29
Q

Outline the central dogma of AD

A

A-Beta amyloid aggregation

Tau dysfunction and aggregation

Loss of function and neuronal cells

30
Q

Using the following parameters, how might AD present

Cognition:
Psychiatric:
Behaviour:
Motor:
Sleep:
A 
Cognition: memory deficits, language problems, visuospatial problems
Psychiatric: depression*, hallucinations
Behaviour: apathy 
Motor: (+) myoclonus (-) apraxia
Sleep: insomnia, reduced REM sleep
31
Q

Describe five atypical presentations of AD

A
  1. Primary progressive aphasia
    - language deficits preced memory problems
  2. Posterior cortical atrophy
    - visuospatial presentation
  3. “Frontal” Alzheimers
    - behavioral presentation: apathy, disinhibition, eating, stereotype
  4. (Depression: not diagnosed as AD from this)
  5. Corticobasal syndrome: negative motor symptoms e.g. apraxia
32
Q

Outline the progression of AD

A
  • Memory loss correlated with the visible progression of the disease
  • Initial pathology confined to the medial-temporal lobe (hippocampus)
  • Progression is predictable
33
Q

Is there any overlap in pathology between AD and other diseases?

A

Yes, it can happen be chance

  1. Association between Alzheimers and Lewy body disease
    - which either caused Dementia with Lewey bodies, or PD
  2. Small vessel cerebral vascular disease + AD
    - Alzheimers can cause cerebrovascular disease not though atherosclerosis (which is the usual cause) by due to cerebral amyloid angiopathy
34
Q

Is there hereditability in NDD?

A

There are RARE autosomal dominant monogenic causes

e.g.
APP (amyloid precursor protein)
PSEN 1
PSEN 2
APOE (Apolipoprotein E)
- has three polymorphisms (e2,e3,e4)
- e4 carries a substantial risk of developing AD
- unique to AD
35
Q

What treatments are used in AD?

A

AChE inihibitors
- to increase cholinergeric input from insula to cortex which provides a “wake up” signal (damages in AD)

  • e.g. Domapezil, Neurostigmine

Can elevate cognitive symptoms slightly

36
Q

In what way do NDDs differ in pathology?

A
  • The protein that aggregates differs
    (Tau- in AD, aSyn- Parkinsons, TDP-43- MND)
  • The type of tissue pathology (cellular level histological difference) e.g. spongiosis vs inclusion bodies
37
Q

How is AD similar and different to other NDD?

A

SIMILAR

  • misfolding proteins + aggregation in disease
  • wide range of clinical features in various domains

DIFFERENCES

  • Its much more common than others
  • Predictable progression
  • Double protein pathology (tau+ amyloid)
  • APOE genetic cause unique to AD

302 SBM: Neurobiology (1 decks)

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