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Block 3 > Degenerative Diseases & Dementia > Flashcards

Degenerative Diseases & Dementia Flashcards

1
Q

What diseases are caused by central degeneration?

A 
Dementia spectrum e.g. AD
MS
PD
HD
Encephalopathies
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2
Q

What diseases are caused by peripheral degeneration?

A

Diabetic neuropathy
MN disease (e.g. ALS)
Friedreich’s ataxia
Guillain Barre syndrome

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3
Q

What are the 3 different types of neurodegeneration?

A
  1. Wallerian: distal degeneration of axon and myelin (trauma induced mostly)
  2. Axonal: dying back of axon proximal to cell body (some regeneration possible)
  3. Demyelination: loss of oligodendroglial/Schwann cells affecting conduction velocity (e.g. MS + Guillain-Barre)
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4
Q

What are the common causes of Wallerian degeneration?

A 
Head trauma (e.g. diffuse axonal injury, shaken baby syndrome)
Nerve compression
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5
Q

What are the 3 Seddon’s classifications of Wallerian degeneration?

A
  1. Neuropraxia: least severe, quick recovery, no actual damage to fibres or sheathing, often stretching trauma
  2. Axonotmesis: moderate, axons damaged but sheathing intact
  3. Neurotmesis: most severe, partial or complete severance of axon + sheathing with likelihood of recovery dependent on type of cut (clean better than twisted/ripped)
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6
Q

Is regeneration possible in Wallerian degeneration?

A

Regeneration sometimes possible but this is dependent on environment as Schwann cells are better than oligodendroglial at releasing GFs so better in periphery than CNS

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7
Q

What other type degeneration may occur in Wallerian degeneration?

A

Transneural down to the ‘use it or lose it’ principle - if a neuron is not used, it is not needed

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8
Q

What would you see in a brain scan with Wallerian degeneration?

A

Multiple lesions generally at the grey-white matter border (fragile as myelin starts and cell body ends)

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9
Q

What would you see in an elderly person’s brains can?

A

More space around brain with wider sulci and thinner gyri with some ex-vacuo dilatation (compensatory mechanism)

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10
Q

What type of pain does Wallerian degeneration present with?

A

Neuropathic

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11
Q

What are amyloid plaques?

A

Extracellular aggregation of misfolded/fragmented proteins caused by changes in phosphorylation and protein folding leading to increased β-sheet formation

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12
Q

What are the different types of amyloid plaques?

A
  1. β-amyloid in AD amyloid precursor protein fragments
  2. α-synuclein in PD (mostly form fibrils)
  3. Prion proteins in CJD
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13
Q

What are neurofibrillary tangles (NFTs)?

A

Micro-tubule associated protein Tau functions in the structural composition of microtubules (transport in neuron) - hyperphosphorylation leads to misfolding which causes breakdown of tubules, β-sheet and fibril formation - fibrils then aggregate to form extracellular tangles

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14
Q

What are inclusions?

A

IC protein aggregations formed from misfolded and ubiquitinated proteins (α-synuclein but inc. ubiquitin, crystallin + neurofilament) generally including Lewy bodies and Pick cells characteristically having a dense core and halo of surrounding filaments

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15
Q

What is diabetic neuropathy?

A

Axonal degeneration which can be peripheral (often symmetrical - glove + stocking appearance), autonomic or central presenting with pain (nociceptive AND neuropathic), ulcers or if pain is absent, tingling and poor balance caused by a mixture of microvascular disease and glycolated end products, activated PKC and polyols (2ndary-high glucose)

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16
Q

What is Motor Neuron Disease (MND)?

A

Degeneration of motor pathways affecting outflow from anterior horn cells (aetiology unknown) presenting with UMN and LMN features, bulbar/pseudobulbar features, muscle weakness and atrophy but no sensory signs, bladder involvement or ocular involvement

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17
Q

How is Motor Neuron Disease (MND) grouped?

A

According to level of involvement:

  • Motor cortex
  • Corticobulbar pathways (pseudobulbar palsy)
  • CN nuclei (progressive bulbar palsy)
  • CST (primary lateral sclerosis)
  • Anterior horn cell (progressive muscular atrophy)
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18
Q

What are the statistics surrounding Motor Neuron Disease (MND)?

A

Male > female

Mean survival ~ 3 years

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19
Q

What is Amylotrophic Lateral Sclerosis (ALS)/Lou Gehrig’s disease?

A

Loss of motor neurons predominantly at the level of the CST losing Betz and anterior horn cells and there is thinning of anterior roots and fibre pathways caused by changes in SOD1 gene leading to protein misfolding and reduced ROS removal characterised by gliosis, astrocytosis, lateral column degeneration and muscle atrophy

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20
Q

How does Amylotrophic Lateral Sclerosis (ALS)/Lou Gehrig’s disease typically present?

A

Tonic atrophy where muscles are wasted and fasciculating with brisk reflexes (life expectancy post diagnosis = 2-6yrs)

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21
Q

What is Superoxide Dismutase (SOD)?

A

An enzyme that breaks down free radicals e.g. toxic superoxides into the more manageable peroxide (H2O2) and O2

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22
Q

What is Friedreich’s ataxia?

A

Most common inherited ataxia (but still rare) that presents at 10-15 years (average death ~38yrs) caused by an autosomal recessive disorder where GAA triplet repeats in Frataxian (FXN) gene lead to problems with iron metabolism caused by:

  • Loss of large myelinated fibres
  • SCT
  • Dorsal root ganglia
  • Posterior column
  • Later loss of cerebellar mass and CSTs
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23
Q

What are the key features of Friedreich’s ataxia?

A 
Progressive limb and gait ataxia
Dysmetria
Dysarthria
Poor balance (sensory ataxia)
Loss of joint position and vibration senses
Absent tendon reflexes in lower limb (extensor plantar)
Muscle weakness
Cardiomyopathy
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24
Q

What is Guillain-Barre syndrome?

A

Demyelinating disorder with unknown causes but autoimmune reaction may be triggered by preceding viral/bacterial infection (separates it from MS) causing rapid onset weakness and tingling that spreads through body normally starting in feet/legs spreading upwards, peak symptoms occur ~2-4wks after onset and it can lead to paralysis

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25
Q

What are the different forms of Guillain-Barre syndrome?

A
  1. Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)
  2. Miller Fisher syndrome (MFS) - ocular form
  3. Acute motor axonal neuropathy (AMAN) or Chinese paralytic syndrome which is aggressive but non-demyelinating
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26
Q

How is Guillain-Barre syndrome treated?

A

IV Igs
Plasmapheresis

= good prognosis

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27
Q

What are the signs and symptoms of Guillain-Barre syndrome?

A

Prickling ‘pins + needles’ in fingers, toes, ankles or wrists
Weakness in legs spreading to upper body
Unsteady walking or inability to walk/climb stairs
Difficulty with eye or facial movements e.g. speaking, chewing or swallowing
Severe pain that may feel achy/cramp-like (worst at night)
Difficulty with bladder control or bowel function
Rapid HR
Low/high BP
Difficulty breathing

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28
Q

What is Multiple Sclerosis (MS)?

A

Primary inflammatory autoimmune disease causing CNS demyelination presenting with neuropathy (usually single feature initially) e.g. blindness, weakness or numbness like a mini-stroke with a relapsing/remitting course most likely

29
Q

How do you diagnose Multiple Sclerosis (MS)?

A
  1. Based on demonstration of multiple levels of CNS involvement in symptoms (presents ~20-30yrs)
  2. CSF sample from lumbar puncture looking for oligoclonal (Ig) bands (present in ~70% patients so not fully diagnostic)
30
Q

What would you see in a brain scan of a Multiple Sclerosis (MS) patient?

A

‘Plaques’ are inflammation by-products accumulating in demyelinated areas so these are seen as flares in white matter regions of the CNS but grey matter is not affected

31
Q

There are at least 8 forms of Multiple Sclerosis (MS), describe 4 of these.

A
  1. Benign: change in neurological state that goes back to normal
  2. Relapsing-remitting: patients get an episode but each episode progresses disease more giving them more disabilities and problems
  3. 1mary progressive: fastest progression
  4. 2ndary progressive: looks like no. 2 then rapidly progresses
32
Q

What is the histology of Parkinson’s disease (PD)?

A

Loss of DA neurons in SN (~60% loss at presentation) with presence of Lewy bodies and raised α-synuclein/parkin levels but generally you would see loss of pigmented cells in the SN

33
Q

What is the key feature about diagnosing most of these conditions?

A

Diagnosis cannot be confirmed until a post-mortem has been done after death looking at the brain

34
Q

What is the difference between Parkinson’s disease (PD) and Lewy Body Dementia (LBD)?

A

In PD, Lewy bodies are present in the SN whereas in LBD, Lewy bodies are present in the neocortex, basal ganglia and diencephalon

35
Q

What are the characteristics of Huntington’s Disease (HD)?

A 
Choreiform movements
Character alteration
Psychotic behaviour
Presentation between 20-50yrs
Men > women
Time course ~15yrs
36
Q

What are the causes of Huntington’s Disease (HD)?

A 
Genetic (autosomal dominant)
Loss of GABA neurons
Loss of cholinergic function
Astrocytosis (causes increase immune/inflammatory response)
Loss of substance P
37
Q

What is the gross pathology of Huntington’s Disease (HD)?

A

Shrunken caudate head

Ex-vacuo dilatation (makes it look similar to hydrocephalus)

38
Q

What is ex-vacuo dilatation?

A

When the brain atrophies, more CSF has to be produced to support the brain so ventricles enlarge as well as the space around the brain

39
Q

What are the causes of spongiform encephalopathies?

A

Prion protein alteration from PrPc to PrPsc
Genetic
Transmissable

40
Q

What are the different forms of spongiform encephalopathies?

A
  1. Sporadic e.g. CJD (most common although still rare)
  2. Inherited/familial e.g. Gerstmann-Straussler-Scheinker (GSS) disease
  3. Iatrogenic/surgical e.g. Kuru
  4. Variant e.g. vCJD (cases increasing)
41
Q

What EEG finding would you see in spongiform encephalopathies?

A

Sharp wave complexes characteristic on slow background rhythms

42
Q

What are prion proteins? How can they go wrong?

A

Proteinaceous infectious particles that function in presynaptic transport and cell signalling (like α-synuclein) where conformation changes lead to formation of β-sheets and fibrils (like AD) - visible amyloid plaques and vacuolisation giving spongiform holey appearance

43
Q

Why is Variant Creutzfeld Jakob Disease (vCJD)/Mad Cow Disease different to other CJD forms?

A

X-species transmission from cows to humans due to eating meat with additional signs/symptoms:

  • Cerebellar presentation + spongiform
  • Plaques in cerebral + cerebellar regions
  • Psychiatric symptoms
  • PrP in GI tract
  • Broader age range with younger onset(average onset ~26yrs) but with variable presentation times
44
Q

Who must you notify Variant Creutzfeld Jakob Disease (vCJD)/Mad Cow Disease diagnosis too?

A

Local teams: Health Protection Teams (HPTs)/Consultant in Communicable Disease Control (CCDC)

National CJD Surveillance Unit (NCJDSU) and National Prion Clinic

45
Q

What is dementia?

A

Symptom complex rather than specific disease with multiple aetiologies where there is progressive global deterioration in cognition (memory, orientation, concentration + speech), behaviour
and personality sufficient to affect work, social function or relationships for a diagnosis

46
Q

Give some examples of causes of dementia.

A
  1. Neurodegenerative: AD, HD or PD
  2. Cerebrovascular: multi-infarct or Binswanger’s disease
  3. Infection: CJD or viral encephalitis
  4. Nutritional: Wernicke-Korsakoff (thiamine deficiency) or B12/folate deficiency
  5. Metabolic: hepatic, thyroid or Addison’s disease
  6. Chronic inflammatory: MS or neurosyphilis
  7. Trauma: head injury or dementia pugilistica (punch-drunk encephalopathy)
  8. Tumour: often frontal lobe/ventricular/callosal origin
  9. Normal pressure hydrocephalus
47
Q

How can dementias be classified according to clinical course?

A
  1. Acute (weeks): infective (e.g. encephalitis), delirium or paraneoplastic
  2. Subacute (months): Wernicke’s-Korsakoff, CJD (vCJD quicker) or inflammatory (e.g. vasculitis/sarcoidosis)
  3. Chronic (years): AD, HD, Pick’s disease or multi-infarct
48
Q

How can you test for dementia?

A
  1. History from patient and family/friend/carer
  2. Cognitive tests
  3. Bloods: FBC, ESR, CRP, B12, LFT, Ca2+, TFT, VDRL/TPHA (syphilis) + others (e.g. vasculitis screen)
  4. Neuroimaging: CT/MRI/fMRI
  5. Rapidly progressing dementia may need CSF lumbar puncture
49
Q

What do cognitive tests assess?

A

Orientation to time, place and person to ensure grossly intact but must refer to neuropsychology for more thorough assessment of cognition if required and specialised assessments by SALT or psychology etc.

50
Q

What are the pros and cons of cognitive tests?

A

Pros: standardised, validated and transferable

Cons: don’t cover all areas fully

51
Q

What are examples and features of subcortical dementia?

A

E.G. normal pressure hydrocephalus (ventricles expanding hitting subcortical areas), PD or HD affecting limbic system, basal ganglia and hippocampus etc. with symptoms:

  • Apathetic
  • Forgetful and slow
  • Impaired visuospatial abilities
  • Depression of mood
52
Q

What are examples and features of cortical dementia?

A

E.G. frontotemporal, CJD or AD with symptoms:

  • Higher cortical abnormalities
  • Dysphasia
  • Agnosia
  • Apraxia
53
Q

What are examples and features of sub-cortical and cortical (mixed) dementia?

A

E.G. multi-infarct or cortical Lewy body disease with symptoms of both SUBCORTICAL AND CORTICAL dementia

54
Q

What are the stages of Alzheimer’s dementia (AD)?

A
  1. Mild cognitive impairment: episodic memory issues + anterograde memory loss
  2. Mild-moderate: poor short-term + longer-term memory, poor semantic memory with poor naming ability, loss of general knowledge, visuo-spatial deficits, apathy, irritability + low mood
  3. Advanced: global intellectual loss with aphasia, amnesia + apraxia, disintegration of personality with myoclonus/extrapyramidal motor signs
55
Q

When does Alzheimer’s Dementia (AD) present?

A

Commonest cause (65%) rarely occurring under 45yrs although occasionally it is familial

56
Q

What may be seen if Alzheimer’s Dementia (AD) patients are imaged?

A

Early imaging normal but later may see neocortical/hippocampal atrophy and medial temporal lobe atrophy

Functional imaging shows hypometabolism in posterior cingulate and bilateral parieto-temporal regions

57
Q

What are the possible causes of Alzheimer’s Dementia (AD)?

A

Genetic
Environmental
Loss of cholinergic neurons

58
Q

How is Alzheimer’s Dementia (AD) diagnosis confirmed?

A

Cause of death is usually pneumonia and then post-mortem would show:

  • Plaques/NFTs
  • Cerebral atrophy (hippocampal/ temporal/cortical) with ex-vacuo dilatation
59
Q

What is vascular dementia?

A

2nd most common form (17%) which can be caused by stroke where there is step-wise deterioration due to multiple successive events (e.g. TIAs) causing multi-infarct or single-infarct dementia OR small-vessel (Binswanger’s disease) where pyramidal signs are common

60
Q

What is the 3rd most common cause of dementia?

A

Mixed e.g. AD/DLB (~10% of patients)

61
Q

What is Dementia with Lewy Bodies (DLB)?

A

Linked to AD/PD with characteristic Lewy bodies (α-synuclein protein deposits) and DA/ACh neurons lost with characteristics such as parkinsonism, visual hallucinations and fluctuations in cognition making up 4% of dementias

62
Q

How does a DAT scan show the difference between Dementia with Lewy Bodies (DLB), Parkinson’s Disease (PD) and Alzheimer’s Dementia (AD)?

A

DLB: reduced striatal binding
PD: reduced basal ganglia binding
AD: show neither of these

63
Q

What is fronto-temporal dementia?

A

Focal trophy of frontal or temporal lobes but more common in younger patients (<65yrs) with +ve family history of dementia, PD or MND (~30% patients) and a subgroup is genetic - current debate over existence but inc. Pick’s disease

64
Q

What is the different pathologies of fronto-temporal dementia?

A
  1. Tau +ve, Pick cells (ballooned cells) and neuronal inclusions (Pick bodies)
  2. Ubiquitin +ve cases
  3. Tau -ve and ubiquitin -ve cases
65
Q

What is normal pressure hydrocephalus?

A

Characterised by ventriculomegaly on imaging (idiopathic/preceding cause) but with no papilloedema or change in pressure as shown in lumbar puncture with 3 cardinal features:

  • Gait disturbance
  • Cognitive decline (subcortical pattern)
  • Urinary incontinence (frontal micturition centre impacted by swollen ventricles)
  • Ocular signs
66
Q

What treatments are used for dementia?

A
  1. Cholinesterase inhibitors (e.g. Donepezil, Galantamine + Rivastigmine) in mild-moderate dementia: prevent breakdown of ACh which is most affected in AD
  2. NMDA antagonist (e.g. Memantine) in moderate-severe dementia: interferes with glutamate mediated cell death by preventing Ca2+ entry (neuroprotective effect) with modest effect on disease progression
67
Q

What other diseases are glutamate receptor (NMDA) antagonists used for?

A
  1. PD: Amantadine + Talampanel

2. In trials for DLB

68
Q

What treatment is used for vascular dementia?

A

Drugs are ineffective but focus should be on improving QoL and background problems such as cholesterol or BP

69
Q

How do you treat normal pressure hydrocephalus?

A
  1. CSF shunt inserted (ventriculoperitoneal)
  2. 3rd ventriculostomy
  3. Perhaps Acetazolamide which can reduce CSF production in patients with increased ICP

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