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NMH BSc > Module 2: Neurological and Psychiatric Disorders of the Central Nervous System > Flashcards

Module 2: Neurological and Psychiatric Disorders of the Central Nervous System Flashcards

1
Q

What are the different categories of acute stroke?

A
  • TIA
  • Cerebral ischaemic stroke (CI) roughly 80%
  • Primary intracranial cerebral haemorrhage (ICH)
  • Sub-arachnoid haemorrhage (SAH)
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2
Q

Wha are current treatments for CI to improve blood flow?

A
  • tPA
  • mechanical thrombectomy
  • aspirin
  • anti-platelet drugs
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3
Q

What are some examples of prophylaxis for acute stroke?

A
  • Statins
  • ACE Inhibitors
  • Anti-platelets
  • Anti-hypertensives
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4
Q

What is the penumbra?

A
  • An area where tissue viability may be sustained
  • A realistic target for treatment
  • Penumbra represents tissue at risk of infarction where perfusion is adequate to maintain cell viability but not adequate for normal neuronal function
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5
Q

What is the blood flow in Cerebral Ischaemia?

A
  • Normal: >50ml/100g/min
  • Olighaemia: 22 - 50ml/100g/min
    (Hypoperfusion but likely to survive due to factors such as collateral blood vessels)
  • Ischaemic penumbra: < 22ml/100g/min
    (Misery perfusion likely to progress to infarction)
  • Rapid cell death: <10ml/100g/min
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6
Q

What is the therapeutic window for stroke?

A

3 hours

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7
Q

Describe energy failure in stroke

A
  • Reduced blood flow
  • ATP reduced (20% of total O2 consumption used by the brain which is ~ 2% body weight)
  • Ion gradients, Na+ pump fails and hence membrane potential NOT maintained
  • Extracellular glutamate (GLU) elevated
  • Energy dependent GLU transporters inactivated
  • Acidosis
  • Na+ and Cli- entry accompanied by H20 (passive) leads to oedema
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8
Q

Describe the mechanisms of calcium overload in stroke

A
  • Caused by NMDA receptor activated calcium entry and depolarisation
  • Leads to activation of:
    • Proteolytic enzymes (actin degradation)
    • Phospholipase A2 and Cyclo-oxygenase (free radical generation)
    • Nitric oxide synthase (NO generation)
  • Calcium causes mitochondrial swelling, reduced oxidative phosphorylation (loss of mitochondrial trans-membrane potential-proton motive force), cytochrome c loss (mitochondrial transition pore) —> APOPTOSIS
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9
Q

What are the different types of nitric oxide synthase?

A
  • nNOS: retrograde messenger
  • eNOS: vasodilator
  • iNOS: immune mediator
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10
Q

What does each NOS do?

A
  • nNOS: Causes toxic levels of NO free radicals- neuronal lesion
  • eNOS: improves cerebral blood flow
  • iNOS: Enhances toxic effects in ischaemia
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11
Q

What are some examples of exogenous antioxidants and free radical scavengers?

A
  • Superoxide dismutase
  • Catalase
  • Alpha-tocopherol
  • Glutathione peroxidase
  • Ascorbic acid
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12
Q

Describe severe insult due to NMDA receptor mediated neurotoxicity

A
  • Ca2+ entry
  • Ca2+ uptake into the mitochondria
  • Free radical generation
  • Severe ATP depletion
  • Mitochondrial swelling

—> NECROSIS

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13
Q

Describe mild insult due to NMDA receptor mediated neurotoxicity

A
  • Transient depolarisation
  • ATP levels reduced
  • Ca2+ loaded mitochondria
  • Cytochrome c release from mitochondria

—> APOPTOSIS

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14
Q

What is the experimental evidence that NMDA receptors mediate tissue damage?

A

NMDA Receptors:

  • NR2A KO decreases infarct size (focal ischaemia)
  • Interruption of signalling using a 2B subunit antibody affecting PSD95 interaction reduces ischaemic damage
  • NR1 antibody given at 4h after MCAO reduces infarct size from 25% to 15% (+/- tPA) (Macrez et al)
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15
Q

What is the experimental evidence that AMPA receptors mediate tissue damage?

A
  • GluR2 antisense knockdown increases injury (global)- AMPA receptor more Ca2+ permeable.
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16
Q

What are limitations of NMDA and AMPA antagonists?

A
  • HIGHLY effective up to ~2h after insult BUT have psychotomimetic (NMDA) and respiratory depressive properties
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17
Q

What is the ischaemic cascade?

A
  • A cascade of reactions which are self-perpetuating and no longer subject to physiological regulation (‘vicious cycle’) leading to cell death initially necrotic and later apoptotic
  • In parellel, neuroprotective mechanisms are activated and balance between the two mechanisms determines the fate of the new cell
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18
Q

What example of early response genes does glutamate activate?

A
  • Inducible transcription factors (IEGs) which activate/repress other genes
  • Enzymes such as COX-2 which underlie developmental and behavioural responses
  • Neuroprotective mechanisms e.g. HSPs which counter damaging effects
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19
Q

How does glutamate activate transcription?

A
  • NMDA Receptor Ca2+ entry —> Ca2+-calmodulin kinase IV pathway (CAMKIV) —> Phosphorylation of cAMP-response element binding protein —> CREB/CREB binding protein complex activates transcription (transcription factors and neurotrophic factors)
  • This pathway mediates an injury response that can contribute to cell survival or cell death
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20
Q

What are the penumbra/peri-infarct effects of glutamate?

A
  • Elevated extracellular K+ and glutamate depolarisation in penumbra
  • Upregulation in injury response genes (e.g. c-jun, ATF3 and HSPs)
  • Extends area of infarct
  • Sensitive to glutamate antagonists
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21
Q

Is chronic treatment with COX2 selective inhibitors a viable treatment for Stroke?

A
  • No
  • COX2 selective inhibitors, whilst lacking gastric toxicity, decrease prostacyclin (vasdilator) and lack COX1 anti-thrombotic properties which potentiates cardiovascular events
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22
Q

What are heat shock proteins?

A
  • Act as protein chaperones facilitating the transfer of proteins between subcellular compartments
  • Following a noxious stimulus (heat, ischaemia) HSPs are induced which target abnormal proteins for degradation
  • HSPs are also anti-apoptotic and antioxidant (HSP27)
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23
Q

What does Sulindac do? (Stroke)

A

It’s an NSAID which increase HSP27 and decreases infarct size

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24
Q

What is ischaemic pre-conditioning (IPC)?

A
  • IPC is a process in which brief exposure to ischaemia provides robust protection/tolerance to subsequent prolonged ischaemia (~TIA)
  • HSP involvement in IPC has been demonstrated in cardiac and cerebral ischaemia (Sun et al 2010) mediated through the NF-kB pathway(Tranter et al 2010).
  • Ischaemic preconditioning reduces infarct size in mouse
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25
Q

How does inflammation play a part in stroke?

A
  • Neutrophils enter the brain parenchyma (30 min) and later, lymphocytes and macrophages (5-7 days) (iNOS elevated).
  • Enabled by the disruption in the Blood brain barrier
  • Production of mediators of inflammation:
    • TNF alpha
    • Platelet activating factor
    • Interleukin 1 beta
    • Adhesion molecules on endothelial cell surface (ICAM-1, p and E-selectins)
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26
Q

Describe the cellular inflammatory response of stroke in more detail

A
  • Neutrophils accumulate within 30 minutes on vascular endothelial cells
  • Cell adhesion molecules (Selectins, Integrins, Immunoglobulins) promote adherence leading to infiltration of cells into the brain parenchyma.
  • Neutrophils cause tissue damage by releasing O2 free radicals & proteolytic enzymes
  • Other cells entering the tissue e.g. lymphocytes promote tissue damage (24h)
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27
Q

Describe the role of cytokines and chemokines in stroke

A
  • Produced by a range of activated cell types (endothelial cells, microglia, neurones, astrocytes, platelets, leukocytes, fibroblast) within the first few
    hours after ischaemia
  • IL-1 and TNF upregulate adhesion molecules promoting neutrophil migration
  • CSF levels of IL-1, IL-6 and TNF at 24h correlate
    with infarct size
  • Chemokines (e.g. CINC and MCP-1) detected in
    the brain between 6 and 24h attract neutrophils &
    infiltration
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28
Q

What are some neuroprotective examples against cytokines?

A
  • IL-1b receptor antagonists
  • TNF-alpha neutralising antibodies and antisense nucleotides
  • TGF b and IL-10 produced by lymphocytes limit
    leukocyte invasion and reduce immune responses
  • Complex protective/harmful effects are seen due
    to multiple sites of action.
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29
Q

Is neutrophil infiltration correlated with infarct size?

A
  • Preliminary studies supported this concept
  • However, Phase III anti-neutrophil drugs
    failed to improve stroke outcome and antiICAM
    (n=625) increased mortality(Becker et
    al 2002). [Thought to be due to neutrophil activation by
    the mouse antibody (complement)].
  • Neutrophils may have both proinflammatory or anti-inflammatory phenotypes (Easton 2013)
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30
Q

How does apoptosis occur in stroke?

A
  • Delayed cell death occurring in the penumbra
  • Triggered by free radicals, death receptor, DNA
    damage, protease action, ion imbalance
  • Release of cytochrome c from mitochondria
    activates the formation of an apoptosome complex
    (APAF1 + procaspase 9) and caspase 3 activation
    (detected at ~8h) leading to DNA fragmentation
  • Caspase 3 selective inhibitors (zDEVD.FMK) are
    effective up to 9h after reversible ischaemia.
  • Broad specificity caspase inhibitors (zVAD)/
    caspase 1 deletion protects against ischaemia.
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31
Q

Describe late stage repair? (Stroke)

A
  • Growth factors are secreted by neurones, astrocytes, microglia, macrophages,vascular and peripheral cells e.g. IGF1, erythropoietin
  • Glutamate-mediated synaptic activity increases BDNF transcription and secretion
  • Neuronal sprouting occurs in an attempt to form contacts
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32
Q

What is the limitation of intravenous tPA (IVT)?

A
  • IVT can salvage penumbra if given early but the recanalization rate is low (30% within 4.5h)
  • Poor outcome is linked to the fact that the infarct is already large at the time of recanalization and hence
    the need to slow infarct growth
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33
Q

What is the limitation of endovascular thrombectomy (EVT)?

A
  • EVT increases the likelihood of penumbral salvage (60%), however, half the patients who undergo successful canalisation do not achieve functional independence
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34
Q

What are the different types of ischaemic stroke?

A

Artery:

  • Acute Ischaemic Stroke (AIS)
  • Lacunar

Venous:
- Cerebral Venous Sinus Thrombosis (CVST)

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35
Q

What are the different types of haemorrhagic stroke?

A

Artery:

  • Aneurysm
  • AVM
  • Primary Intracerebral Haemorrhage (PICH)
  • Extradural haemorrhage

Venous:

  • Subdural haemorrhage
  • Cerebral Venous Sinus Thrombosis (CVST)
  • Cavernoma
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36
Q

What are specific causes of thrombosis?

A

AADDVISE (Arterial)
OOORR (Venous)
HEPARINISE (Venous/Arterial)

Atherosclerosis
Arteriosclerosis- hypertension
Dissection
Dysplasia, fibromuscular
Vasculitis
- Autoimmune, sarcoid, infection
Injury
- Iatrogenic: radiation, catheter
Spasm: migraine
Extra: embolism, compression

Operation esp. orthopaedic, obstetric
Obesity
Overland flights (e.g. long-haul flights)
Reduced circulating volume (e.g. hypovolaemia)
Right-sided heart failure

Hereditary: factor V Leiden, prothrombin mutations
Endocrine: oestrogen (OCP, HRT), testosterone, diabetic hyperosmolar non-ketotic coma
Polycythaemia and other haemotological disorders
Autoimmune: antiphospholipid syndrome, Behcet’s syndrome
Renal: nephrotic syndrome, volume depletion
Infection: systemic- TB, chlamydia, any other cause of raised CRP, local- otitis media or mastoiditis
Neoplasm: AML, adenocarcinoma
Injury: fracture, sympathetic stress response
Smoking:
Exogenous: chemotherapy, COX-2 inhibitors

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37
Q

Underline stroke pathophysiology

A
  • Thromboembolism
  • Hypoperfusion
  • Lacunar infarction
    (Causes include aging, diabetes, hypertension)
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38
Q

What are the features of lacunar infarction?

A

Acute Syndromes:

  • Pure motor
  • Pure sensory
  • Ataxia-hemiparesis
  • Dysarthria- clumsy hand
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39
Q

What are the features of small-vessel ischaemia?

A

Chronic Syndromes:

  • Executive cognitive impairment, bradyphrenia
  • Lower body parkinsonism, gait apraxia
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40
Q

What are the main clinical syndromes of stroke?

A

MCA, ACA, PCA and brainstem infarction

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41
Q

What are different types of MCA stroke?

A
  • Blockage of main branch (horizontal M1 —> wedge infarction)
  • Blockage of Lenticulostriate arteries (end-arteries)
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42
Q

What does an ACA stroke do?

A
  • Affects medial Brain —> contralateral leg weakness
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43
Q

What does a PCA stroke do?

A
  • Affects Occipital cortex —-> Homonymous hemianopia, Neglect
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44
Q

What does a brainstem infarction do?

A
  • E.g. PICA infarct —> Contralateral limb symptoms, Ipsilateral Cranial Nerve symptoms
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45
Q

How does a stroke lead to respiratory depression?

A
  • Stroke —> Increased ICP —> Midline shift —> Coning —> Respiratory depression
  • Tx: Hemi-craniectomy —> relieve pressure —> 50% survive
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46
Q

What are the main investigations requested in stroke?

A
  • CT Scan (Ischaemia: dark, oedema/Haemorrhage: bright, blood)
  • Further: Where is blood clot coming from? —> Carotid doppler
  • MR Angiogram
  • ECG (AF)
  • Echocardiogram (Vegetations)
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47
Q

What are the causes of death in Stroke patients?

A
  • Herniation —> Respiratory depression
  • Pneumonia (inability to swallow/cough)
  • PE (bedbound/VT)
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48
Q

What is MS?

A
  • Chronic inflammatory, multi-focal demyelinating condition of the CNS with an unknown cause characterised by loss of myelin and oligodendroglial and axonal pathology
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49
Q

What is the epidemiology of MS?

A
  • Affects 2.5 million people worldwide

- Female > Male (2:1)

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50
Q

What are the factors affecting MS incidence?

A
  • Latitude Effect
  • Time of exposure
  • Viral hypothesis
  • Genetic factors
  • Role of hormones
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51
Q

How does the latitude effect affect MS incidence?

A
  • Higher prevalence in Northern Countries (esp. UK vs World, Scot > Eng)
  • Role of Vit D: Decreased 25(OH)D —> Increased risk of MS (Simpson, 2010)
  • Correlation between low UWB intensity (low sun exposure) and risk of MS —> Prescribe Vit D to MS
  • However Black people are more likely to be Vit D deficient BUT decreased risk of MS
  • Norway North-South gradient risk inverted due to more time spent in outdoor activities during summer
  • Higher fish consumption and use of cod-liver oil supplement
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52
Q

How does time of exposure affect MS incidence?

A
  • Migration studies - migration age >15 retain original risk
    Age < 15 have risk of new area - Dean 1971
  • Month of birth effect: Increased risk of MS for May birth (Decreased Vit D in Winter)
  • Season variable of MS activity: ­Increased MS disease activity in spring (Decreased Vit D in winter)
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53
Q

What is the MS viral hypothesis?

A
  • Hypothesised MS is triggered by a virus (e.g. EBV) - Kurztke
  • EBV sero +ve —> Increased risk of MS
    EBV sero -ve —> 0 risk
    Increased anti-EBNA IgG titre —> Increased MS
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54
Q

How do genetic factors influence MS incidence?

A
  • First degree relatives have 10-25 times greater risk of MS
  • 25-30% monozygotic twins
  • 2-3% dizygotic twins
  • 1.9% non-twin siblings
  • HLA-class ΙΙ genes exert the strongest effect, accounting for 20-60% of the genetic risk, with a predominant role played by the HLA-DRB1*15
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55
Q

How do the role of hormones influence MS incidence?

A
  • During pregnancy —> Decreased MS relapses
  • Post-partum —> Increased MS relapses

PRIMS study

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56
Q

What are relapses?

A
  • Acute neurological deficit lasting more than 24 hours followed by complete or partial recovery (= demyelinating attack)
  • Inflammation —> Demyelination (Seen on MRI T2 as demyelinating plaque = pathological Hallmark of MS)
  • Followed by spontaneous recovery
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57
Q

Describe MS progression.

A
  • Insidious onset of irreversible accumulation of neurological deficit >1yr (Retrospective Dx)
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58
Q

What is RR MS?

A
  • Relapsing-remitting MS (80% of MS)
  • Acute demyelinating attacks followed by partial/complete recovery
  • Asymptomatic between relapses
  • With time, frequency of relapses decreases (Decrease of 17% in Annualised Relapse Rate every 5 years)
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59
Q

What is SP MS?

A
  • Secondary progressive MS
  • Shift RR MS (inflammation) —> SP MS (degeneration)
  • 10 years from disease onset
  • Increased irreversible disability
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60
Q

What is PP MS?

A
  • Primary progressive MS (20% of MS)
  • Disease starts with progression
  • Progressive paraparesis
  • 40% have superimposed paralysis
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61
Q

What is Clinically isolated syndrome?

A
  • 1st MS-like attack

- No DIT for clinically definite MS

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62
Q

What is the disease course of MS?

A
  • Age of Onset ~ 30 years (RRMS)
  • ~ 40 years (SP MS, PP MS)
  • Lasts 40 - 50 years
  • Patient unlikely to die from MS but from decreased QoL
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63
Q

What are the presenting symptoms of MS?

A
  • Relapses: Symptoms are highly variable – based on AMOUNT and LOCATION
  • Specific location of inflammation determines specific symptoms
  • E.g. optic neuritis, motor weakness, sensory disturbances
  • In later stage, mainly motor symptoms (Increased disability)
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64
Q

What is the key diagnostic criteria for MS?

A
  • Exclude DDx + appropriate presentation
  • Dissemination in Time (DIT): demyelination/inflammation on at least 2 separate occasions
  • Dissemination in Space (DIS): demyelination/inflammation in at least 2 different areas of CNS
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65
Q

What are the imaging features of MS?

A
  • MRI T2: round demyelinated plaque (white) | 5-10x ­ MRI lesions > Clinical attacks (clinically silent, less important area)
  • Typical locations: Perivascular, Corpus callosum, Cerebellum, Brainstem
  • Over time, they appear (demyelination, inflammation) and disappear (remyelination)
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66
Q

What are the clinical and laboratory tests for MS?

A
  • History: DIS & DIT (H&E sufficient for majority of cases, can use MRI to assess DIS if necessary)
  • MRI: DIS & DIT (new lesion compared to old or presence of GAD-enhancing and non-enhancing lesions)
    GAD enhances NEW lesions <6 weeks and not old lesions >6 weeks
  • CSF: Oligoclonal Band in CSF only (-ve in Serum) – inflammation limited to CNS – suggests MS
  • VEP: DIT asymptomatic + delayed nerve conduction indicates previous attack
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67
Q

What are potential DDx for MS?

A
  • ADEM (Acute disseminated encephalomyelitis)

- NMO (Neuromyelitis optica

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68
Q

What is ADEM?

A
  • Acute inflammatory demyelination of CNS
  • Prodromal infection (respiratory or intestinal)
  • Single attack
  • Very young age < 10
  • Larger inflammation lesions on MRI than MS
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69
Q

What is NMO?

A
  • Severe CNS myelination with optic neuritis and acute myelitis
  • Mainly Spinal cord involvement
  • MRI shoes Cord lesion >3 vertebrae
  • Auto-Ab to AQP4 channel
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70
Q

Describe the variability of disease course severity.

A
  • High variability: Spectrum from Benign MS (slow deterioration) to Malignant MS (rapid deterioration)
  • Expanded Disability Status Scale (EDSS) rates disability in MS patients (EDSS 6 = walking assistance)
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71
Q

What are the clinical and radiological factors affecting MS prognosis?

A

Poor prognostic factors:

  • Older age of onset
  • PP MS
  • Early relapses
  • MRI lesion load
  • Male
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72
Q

What are the basic pathophysiological mechanisms that lead to brain injury following trauma?

A
  • Focal: Fractures | Contusions | Haemorrhage —> CT/MRI

- Diffuse: Diffuse Axonal Injury | Diffuse Vascular Injury —> “Advanced MRI”

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73
Q

What is CT?

A
  • 3D reconstruction based on differential attenuation of X-ray beams passed through an object from multiple directions
  • Tailor CT to specific degree of attenuation (alter the window)
  • Water = 0, Bone > 1000
  • Hounsfield units
  • Nobel 1979
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74
Q

What are the advantages of CT?

A
  • Fast
  • Cheap
  • Better than MRI for bony abnormalities
  • Useful for imaging Acute bleeds and fractures
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75
Q

What are the disadvantages of CT?

A
  • Poor resolution

- Can’t see subtle changes in brain structure

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76
Q

What is an MRI?

A
  • Large magnet aligns all protons, 2nd RF misaligns protons which relax to original position releasing energy which is detected
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77
Q

Describe T1-weighted MRI scan

A
  • Good tissue discrimination
  • Dark CSF
  • Bright fat dark lesions
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78
Q

Describe T2-weighted MRI scan

A
  • Sensitive to water (oedema)
  • Bright CSF
  • Dark fat bright lesions
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79
Q

Describe FLAIR

A
  • Sensitive to water (oedema)
  • Dark CSF
  • Dark fat bright lesions
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80
Q

Describe echo imaging / MRI SWI (Susceptibility Weigh Imaging)

A
  • Useful for subtle injuries/microbleeds —> Any bleed will leave some haemosiderin (containing Iron) leftover
  • Microbleeds have a Parafalcine distribution (suggests axonal injury)
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81
Q

Describe Diffusion Tensor Imaging

A
  • Useful to look at specific tracts (white matter tracts)
  • Diffusion of water molecules is constrained by property of the tissue
  • In axons, normally diffuse along length
  • Diffusion Tensor Imaging measures how anisotrophic (e.g. the direction, scale 0-1) the water diffusion is
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82
Q

What are some features of Prion diseases?

A
  • Transmissible Spongiform Encephalopathies
  • A series of diseases with a common molecular pathway
  • Spongiform = vacuoles
  • Transmissable factor
  • No DNA or RNA involved
  • Prion (PRoteinacious Infectious ONly)
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83
Q

What are the human forms of Prion disease?

A
  • Creutzfeldt-Jacob Disease
  • Gerstmann-Straussler-Sheinker Syndrome
  • Fatal familial insomnia
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84
Q

What are the animal forms of Prion disease?

A
  • Scrapie
  • Bovine Spongiform Encephalopathy
  • Feline Spongiform Encephalopathy
  • Chronic Wasting Disease
  • Transmissible Mink Encephalopathy
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85
Q

What is the epidemiology of Prion disease?

A
  • 1-2 cases per million population
  • M = F
  • 10 - 15% familial
  • Age onset average 55-75
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86
Q

What is the neuropathology of prion disease characterised by?

A
  • Spongiform change: microscopic vacuoles, found in cerebral cortex and cerebellum —> ataxia
  • Neuronal loss + Synapatic loss: general atrophy (widening sulci, shrinking gyri, enlarged ventricles)
  • Astrogliosis: Activated astrocytes (GFAP marker) react to vacuolar change and prion desposition
  • Accumulation of PrP
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87
Q

What are some features of sporadic CJD?

A
  • Progressive dementia
  • Ataxia
  • EEG changes
  • Death within one year
  • Biopsy/Autopsy for Dx
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88
Q

What are some features of iatrogenic CJD?

A

Can be caused by

  • GH (extracted from cadaveric pituitatries)
  • Dural transplant
  • Neurosurgery
  • Slow incubation period
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89
Q

What are some features of GSS?

A

(Genetic version of CJD)

  • Autosomal dominant
  • Progressive dementia
  • Mild phenotype (4-5 years)
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90
Q

What are some features of fatal familial insomnia?

A
  • Autosomal dominant
  • Sleep disturbances
  • Neuropsychiatric presentation (tiredness, psychoses)
  • Late dementia
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91
Q

What are some features of a prion protein?

A
  • Normal cellular protein , PrPc
  • Expressed in neurons and glia
  • Chromosome 20
  • Membrane associated
  • Unknown function
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92
Q

What are some genetic features of prion proteins?

A
  • Many different types of mutations
    Valine or Methionine
  • Varying level of penetrance
  • Codon 129 (VV, MM, VM)
  • VV/MM are at a higher risk than VM
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93
Q

What is PrPp?

A
  • Abnormal protein
  • Accumulates within cells and in amyloid deposits
  • Resistant to degradation by proteinase K
  • Detectable by ICC
  • No amino acid difference betwen PrPc and PrPp
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94
Q

How does PrPc become PrPp?

A
  • Energy unfolds PrPc from alpha-helical structure to beta-pleated sheet (=Amyloid) - Equilibrium influenced by genetic susceptibility
  • Beta-pleated sheet structure converts other host proteins into beta-pleated sheet structure (Autocatalytical conversion)
  • Irreversible propagation —> Amyloid fibrils deposited in the brain

Nat Rev Neurosci, 6, 23-34 (2005)

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95
Q

What are the mechanisms that convert PrPc into PrPp?

A

1) Post-translational modification alters conformation
2) Mutation in Prion gene predisposes to PrPp conformation

PrP knockout mice are immune to PrP infection (from other sources)

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96
Q

Describe disease strains

A
  • Same protein can lead to different strains
  • Multiple passages of infection of Scrape in mice lines
  • –> different disease strains
  • Number of polysaccharide chains, either 1 (=A) or 2 (=B), attached to Prion protein can modulate clinical phenotype
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97
Q

Described glycosylated patterns

A
  • Type 1 = 20kDa band predominant
  • Type 2 = 19kDa band predominant
  • A = A band (monoglycosylated 25kDa) predominant
  • B = B band (19kDa band predominant)
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98
Q

What is the species barrier with regards to the emergence of new variant CJD (vCJD)?

A
  • Scott, 1989: Hamster PrPp (hPrPp) can only lead to Scrapie in Hamsters and transgenic mice expressing hPrPp
  • Species-specific infection
  • Inoculation of wild-type mice with hPrPp does not cause Scrapie
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99
Q

What are features of vCJD?

A
  • Sporadic neuropsychiatric disorder
  • Patients <45 years old
  • Cerebellar ataxia
  • Dementia
  • Longer duration than CJD
  • Linked to BSE
  • Diagnosed at autopsy since 1990
  • All 129 MM homozygotes

Will RG et al (1996):

  • Widespread vacoulation
  • Florid plaques (PrPp deposits)
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100
Q

What are the mechanisms of spread literature?

A

1) & 2) Beekes et al., FEBS, 2007, 274; 588-605

3) Frost B & Diamond MI (2010) Nat Rev Neurosci 11 155-159

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101
Q

Describe CJD diagnosis

A
  • Genetic CJD: genetic sig/PRNP seq
  • vCJD: PrP deposits in peripheral lymphoid tissue
  • Sporadic CJD (Brain biopsy)
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102
Q

What is the treatment for vCJD?

A
  • Symptomatic relief
  • Pentosan polysulphate
    • Post-exposure prophylaxis to prevent peripheral replication and neuroinvasion
  • Ablation of FDCs
  • Beta-sheet breaker peptides
  • Vaccination
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103
Q

What is the epidemiology of CNS Trauma?

A
  • Single largest cause of death in people under 45
  • 9 deaths from head injury per 100,000
  • Account for 25% of all trauma deaths
  • High morbidity:
    19% vegetative or severely disabled
    31% good recovery
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104
Q

What are the different types of head trauma?

A
  • Non-missile
  • Missile
  • Focal or Diffuse
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105
Q

What are features of non-missile head trauma?

A
  • Acceleration/deceleration
  • Rotation force (midline structures vulnerable)
  • RTA, falls, assaults
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106
Q

What are features of non-missile traumatic brain injury?

A
  • Acceleration/deceleration
  • Rotation forces (midline structures vulnerable)
  • RTA, Falls, Assaults
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107
Q

What is a feature of missile TBI?

A
  • Conflict-related
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108
Q

What are features of focal TBI?

A
  • Fractures
  • Contusions
  • Haemorrhage —> CT/MRI
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109
Q

What are features of diffuse TBI?

A
  • Diffuse Axonal Injury

- Diffuse Vascular Injury —> Advanced MRI

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110
Q

What is primary trauma damage?

A
  • Damage that has occurred, cannot be changed

- Depends on cause, type, location, age, drugs, pre-existing disease, genetics

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111
Q

What are the different types of primary trauma damage?

A
  • Scalp lactation
  • Skull fractures
  • Cerebral contusion
  • Intracranial haemorrhage
  • Diffuse axonal injury
  • All fatal non-missile head injury cases will have surface contusion and diffuse axonal injury
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112
Q

What are features of skull fractures?

A
  • Base of skull fracture —> CSF leakage —> Otorrhea/Rhinorrhoea, Battle’s sign/Racoon’s eyes
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113
Q

What are features of a cerebral contusion?

A

High risk areas:

  • Orbitofrontal cortex
  • Temporal lobe
  • Occipital lobe
  • Inferior surface of the brain
  • Coup-contrecoup damage associated with acceleration/deceleration injury
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114
Q

What are features of intracranial haemorrhage?

A
  • Extradural
  • Subdural/Burst lobe
  • Subarachnoid
  • Intracerebral
  • Tx: Surgical evacuation (drill 3 bore holes, remove bone flap, tie off vessel and reseal)
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115
Q

What are some features of diffuse axonal injury?

A
  • Due to shear & tensile forces on axons —> Retraction balls (marker of axonal damage)
  • Grade 1 (Parasagittal Frontal, Internal Capsule), Grade 2 (+ Corpus Callosum), Grade 3 (+ Dorsal Brainstem)
  • DAI is present in nearly all head injuries and is always present in fatal head injuries
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116
Q

Describe primary axotomy

A
  • Tear of axolemma —> Ca2+ influx —> activate proteases —> cytoskeletal dysfunction —> disconnect
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117
Q

Describe secondary axotomy

A
  • Rupture —> membrane sealing (imperfect stabilisation) —> highly susceptible to secondary insult (rugby)
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118
Q

What are the general mechanisms of diffuse axonal injury?

A
  • Shearing forces —> Axotomy —> Stops normal axonal transport —> Build-up of toxic proteins within the Axon
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119
Q

How can DAI be detected?

A
  • Immunostaining for APP (undergoes axonal transporter, marker of axonal damage) or Silver staining
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120
Q

What are different types of secondary trauma damage?

A
  • Ischaemia/Hypoxia
  • Cerebral swelling
  • Infection (if open head injury)
  • Seizure (Glutamate excitotoxicity)
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121
Q

How does cerebral swelling cause secondary damage?

A
  • Increased ICP —> Midline shift + herniation (most common secondary cause of death)
  • ICP measured using a Bolt monitor
  • MOA unknown: ?Vasodilation (to aid perfusion), ?BBB breakdown —> vasogenic oedema
  • Tx: Diuretics, Craniotomy
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122
Q

What are the different types of herniation?

A
  • Subfalcine herniation (under falx cerebri)
  • Tentorial herniation (under tentorium cerebelli)
  • Tonsillar herniation (cerebella tonsils under foramen magnum)
  • Coning (brainstem into foramen magnum)
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123
Q

What are the molecular and cellular pathways that have been implicated in TBI?

A

(Similar to ischaemic damage in Stroke Lectures)

  • Neurodegeneration: acute head injury may initiate protective response, if chronic, may cause neurodegeneration
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124
Q

What characterises Alzheimer’s disease pathology?

A
  • A-beta plaques and Tau neurofibrillary tangles (APP is a marker of traumatic axonal injury)
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125
Q

What does the literature on CTE say about boxing?

A
  • Boxing is associated with cognitive issues and molecular changes similar to AD (but boxers much earlier onset)
  • Key features in Boxers: Tear in midline structures - Earlier cognitive changes - Tau tangles (Corsellis) - A beta plaques (Roberts)
  • 50% of Boxers with Dementia were found to have CTE (Astrocytic Tau Pathology) - the other 50% did not have Tau pathology
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126
Q

What does the Glasgow group say about CTE?

A
  • 152 patients who died with 30 days of head injuries
  • 30% have A beta pathology - De novo AD pathology is linked to acute trauma? Is this age related (e.g. present regardless)?
  • If they survived, would they get AD pathology? or would A beta be cleared?
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127
Q

What is the proposed mechanism of CTE?

A
  • Inflammation is thought to be initially protective and persistence (cytokine cycle - IL-1, ApoE) —> neurodegeneration
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128
Q

What does McKee AC, 2009 say about CTE?

A
  • Newly described Tau pathology
  • Cause and effect is not known - Don’t know if clinical picture is same as pathology
  • Tau pathology in CTE is within Astrocytes (Astrocyte Tau Tangles) & found at base of sulci (where impact force concentrate)
    • AD Tau in Neurons - Astrocytic neurofibrillary Tau tangles found at bases of sulci, sub-pial, peri-vascular + cortex
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129
Q

What does McKee AC, 2012 say?

A
  • n = 85 athletes/military personnel with repetitive mild TBI (McKee AC, 2012)
  • 80% of repetitive mild TBI had CTE pathology
  • However some had concomitant AD/PD/FTLD
  • Therefore difficult to assess cause and effect of Tau and clinical phenotype
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130
Q

What does Tau PET ligand (11C-PBB3) do?

A
  • Visualises Tau pathology in vivo (useful for CTE and AD)

- A beta is less relevant for CTE

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131
Q

What does Goldstein, 2012 show?

A
  • Blast neurotrauma mouse model (blast head injury) shows Tau-related changes
  • But head injury in rodents if different in humans
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132
Q

What is ARTAG?

A
  • Age-related Tau-Astrogliopathy
  • ARTAG has no clinical phenotype
  • Age-related Tau pathology in Astrocytes
  • ARTAG confounds CTE
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133
Q

What are the future implications of CTE?

A
  • Need longitudinal studies to follow progression of retired sportsman to assess cognitive capacity and imaging changes
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134
Q

What are treatments for CTE?

A
  • Neuroprotection
  • Anti-inflammatories (but thought to initially be protective)
  • Protease inhibitors (decreased Ca2+ activated proteases)
  • Hypothermia/Hyperbaric treatment
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135
Q

What are the main categories of MS treatment?

A
  • Education and counselling
  • Management of acute attacks
  • Prevention of disease activity (disease modifying treatments)
  • Symptomatic therapy
  • Physical therapy
  • Treatment of complications
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136
Q

What is the management of acute MS attacks?

A
  • High-dose IV methylprednisolone

- Decide on necessity for treatment as Sx tend to be self-resolving (treat disabiling Sx e.g. double vision)

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137
Q

What is symptomatic therapy for MS?

A
  • Spasticity: stretching, physical therapy, Baclofen, Botulinum toxin
  • Paroxysmal pain: Gabapentin, Carbamazepine - no treatment for neuropathic pain
  • Chronic dysaesthetic pain: Amitroptyline
  • Fatigue: “Energy-savings”, Amantadeine
  • Depression: Antidepressants
  • Immobility (most concerning to pt): Encourage activity from start, Physiotherapy, Aids
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138
Q

What is the aim of disease modifying treatments?

A
  • Decrease inflammation/demyelination —> Decrease axonal damage —> Prevent disability
  • Many DMTs for RRMS (hard to test if they delay progression)
  • Limited progression for Progressive MS
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139
Q

What are different types of Injectable DMTs?

A
  • IFN-beta

- Glatiramer acetate

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140
Q

What’s the MOA of IFN-beta?

A
  • Decreased T-cell activation
    (Decreased MHC Class II, Decreased co-stimulation)
  • Decreased pro-inflammatory cytokines release
  • Decreased transmigration
    (Decreased VLA4, Decreased MMP, VCAM decoys)
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141
Q

What are the results of IFN-beta on MS?

A

ADVANCE trial

  • RRMS: 30% Decrease in ARR
    ? delay progression
  • CIS: delay 2nd episode
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142
Q

Is IFN-beta safe?

A
  • yes
  • Injection site infection
  • Flu-like Sx
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143
Q

What are further details about IFN-beta?

A
  • 1st line active MS

- 1st DMT available for RRMS

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144
Q

What is the MOA of Glatiramer acetate?

A
  • Decoy effect

Resembles MBP

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145
Q

What are the results of Glatiramer acetate on MS?

A
  • RRMS: 30% Decrease in ARR
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146
Q

Is Glatiramer acetate safe?

A

Yes

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147
Q

Further details on Glatiramer acetate?

A
  • 1st line active MS

- Only DMT for emergency

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148
Q

What are the different types of oral DMT?

A
  • Fingolimod

- Dimethyl fumerate

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149
Q

What is the MOA of Fingolimod?

A
  • Prevents T cells leaving lymph nodes
    (Decreased T cell sensitivity to chemotactic cues)

(S1P1 receptor agonist —> S1P1 receptor internalisation)

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150
Q

What are the results with Fingolimod?

A

TRANSFORM trial

  • 50% decrease in ARR vs IFN-beta

FREEDOM trial

  • 50% decrease in ARR vs placebo
  • Decreased disability progression
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151
Q

What are the side effects of Fingolimod?

A
  • Increased infections
  • Lymphopaenia
  • Bradycardia
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152
Q

What are further details of Fingolimod?

A
  • For highly active MS

- 1st oral DMT for RRMS

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153
Q

What is the MOA of dimethyl fumarate?

A
  • Decreasd pro-inflammatory cytokine production
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154
Q

What are the results of dimethyl fumarate?

A

DEFINE

  • 50% decrease in ARR vs placebo
  • Decreased disability progression
  • Decreased MRI lesions
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155
Q

Is dimethyl fumarate safe?

A
  • Safer than Fingolimod

S/E

  • Flushing
  • GI S/E
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156
Q

Further details on dimethyl fumarate?

A
  • 1st line active MS

- 1st oral drug offered as 1st line (choice)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
157
Q

What are the different types of Monoclonal Ab DMT?

A
  • Natalizumab
  • Alemtuzumab
  • Ocrelizumab
158
Q

What is the MOA for Natalizumab?

A
  • Decreased transmigration

block VLA-4 & VCAM-1 interaction

159
Q

What are results for Natalizumab?

A

AFFIRM

  • 70% decrease in ARR vs placebo
  • Decreased disease progression
  • Decreased MRI lesions (90%)
160
Q

What are the side effects of Natalizumab?

A

Rare S/E

  • Herpes
  • PML (4 in 1000)
    • 20% mortality
    • rapid decreased cognition
161
Q

What are further details on Natalizumab?

A
  • For highly active MS
162
Q

What is the MOA of Alemutzumab?

A
  • Depletes T and B cells

- Immune population rebuilds

163
Q

What are the results for Alemutzumab?

A

CARE MS I

  • 55% Decrease in ARR vs IFN-beta (similar to Natalizumab)
    no diff in disease progression
  • Decreased MRI lesions
  • No evidence of disease activity (NEDA)
164
Q

What are the side effects of Alemutzumab?

A
  • Opportunistic infections

- Autoimmunity (50% Graves’ in 5 years)

165
Q

What are further details on Alemutzumab?

A
  • 1st line active MS

- 2x injections

166
Q

What is the MOA of Ocrelizumab?

A
  • Targets CD20+ B cells
167
Q

What are the results of Ocrelizumab?

A

OPERA

  • 50% decrease in ARR vs IFN-beta
  • PPMS: 25% decrease in disability progression vs Placebo
168
Q

What are further details on Ocrelizumab?

A
  • 1st line active MS

- PPMS: 1st DMT for PPMS

169
Q

Describe autologous haematopoietic stem cell transplant (AHSCT)

A
  • Harvest stem cells
  • Immunosuppression
  • Repopulate with stem cells
  • Atkins, 2006: n = 24 had no further disease
170
Q

What is relapse-remitting MS?

A
  • Unpredictable attacks which may or may not leave permanent deficits followed by remission
171
Q

What is primary-progressing MS?

A
  • Steady increase in disability without attacks
172
Q

What is secondary progressive MS?

A
  • Initial relapse-remitting MS that suddenly begins to decline without periods of remission
173
Q

What is progressive-relapsing mutliple sclerosis?

A
  • Steady decline since onset with super-imposed attacks
174
Q

What are the clinico-pathological correlations of MS?

A
  • Inflammatory foci without demyelination = acute relapses
  • Primary demyelination = acute & chronic
  • Grey matter demyelination = progressive
  • Axonal loss in lesions = progressive symptoms
  • Grey matter neuronal axonal loss = Progressive motor, sensory and cognitive
  • Diffuse white matter changes = Fatigue?
  • Diffuse grey matter changes = motor, sensory and cognitive symptoms
  • Fatigue?
175
Q

What are some histological features seen in MS?

A
  • Brain atrophy
  • Vesicular enlargement
  • White Matter Lesions
    • Periventricular
    • Perivascular
    • Disseminated
  • Grey Matter Lesions
    • Sub-meningeal
  • Remyelinating areas
  • Lesions anywhere on the CNS
176
Q

What cells are involved in the perivascular immune cell infiltration of MS?

A
  • CD4 and CD8 T-Cells

- CD20 B-Cells

177
Q

What are the different lesion stages of MS?

A
  • Acute active: Macrophages throughout the lesions with synchronous myelin destruction
  • Chronic active: Numerous macrophages at expanding plaque edge; centre contains few cells
  • Chronic inactive: Hypocellular plaques with no macrophages and no ongoing demyelination
  • Shadow plaque: Represent remyelinated axons with thin myelin sheaths
  • Destructive plaques: Destruction of axons, oligodendrocytes, astrocytes and myelin loss - Marburg type MS and Devic’s disease
178
Q

What are the inflammatory mechanisms of neuronal damage in MS?

A
  • By-stander effect

- Autoimmune-mediated degradation of myelin sheath and oligodendrocytes

179
Q

What is the Bystander effect? (Neuronal damage)

A
  • Release of free radicals by peripheral immune cells and activated microglia
    • Nitric Oxide (NO), peroxynitrite (OON-), hydroxyl radicals (OH-)
  • Glutamate release by activated microglia results in excitotoxicity to oligodendrocytes (which express NMDA and AMPA receptors)
  • Hypoxia-like events
  • Mitochondrial dysfunction
  • Cytotoxic cytokine release by immune cells and microglia
    • TNF, lymphotoxin, IL-1beta, interferon-Y
180
Q

Describe autoimmune-mediated degradation of myelin sheath and oligodendrocytes

A
  • Macrophage-mediated
  • Presence of anti-myelin antibodies against multiple antigens (MOG, MBP…)
  • Epitope spreading —> oligoclonal bands
  • Complement activatio
181
Q

How does demyelination cause chronic symptoms?

A
  • Bystander effect: Inflammatory immune cells release antibodies and cytotoxic mediators that damage myelin
  • Without myelin, electrical signals leak out and fade away, making axons more vulnerable to damage
  • Leads to axonal loss, neuronal damage and neurodegeneration
182
Q

How does Na+/Ca2+ imbalance cause degeneration of chronically demyelinated axons?

A
  • In addition to normal Na+ channels at the nodes of myelinated axons, there are Na+/Ca2+ exchangers which allows sodium in and removes calcium
  • Na+ entry is also balanced by internodal Na+/K+ ATPase which uses ATP to pump K+ in and Na+ out
  • Na+ channels are diffusely distributed along demyelinated axons —> increased Na+ influx during AP transmission and increased ATP demand for operating Na+/K+ ATPase
  • Alterations in ATP production reduce Na+/K+ exchange capacity and increase axonal accumulation of Na+
  • Increased axonal Na+ reverses Na+/Ca2+ exchanger resulting in increased axonal Ca2+
  • Increased Ca2+ activates proteolytic enzymes, leading to damage of axoplasmic contents and axonal death
183
Q

Is axon loss responsible for clinical progression of MS?

A
  • Roughly 40% loss of corticospinal tract axons in cervical cord of SPMS
  • Axon loss is greatest during early inflammatory attacks and continues but decreases throughout course of MS
  • Identified by accumulation of APP and end bulbs
  • Only axon loss correlates with increasing chronic clinical disability in relapsing-remitting MOG-EAE
184
Q

How does neurodegeneration lead to chronic progression?

A
  • Inflammation can be resolved, remyelination can be repaired but axon and neuronal loss is irreversible
  • Irreversible but there is spare capacity
185
Q

What is the correlation between disease progression and WM/GM lesions?

A
  • Poor correlation between disease progression and inflammation/demyelination
    • Inflammation and demyelination in the white matter are key features of MS visible on MRI
    • MRI lesion load and rate of appearance of new lesions correlates poorly with clinical progression
    • Immunomodulatory therapies reduce relapse rate but fail to prevent long term progression of disability
  • Good correlation between disease progression and grey matter atrophy
186
Q

What are features of the lymphoid-like structures in MS?

A
  • A feature of meningeal inflammation
  • CD20+ cells
  • Ki67+ B-cells
  • Ig plasma cells (parafollicular)
  • CD35+ FDCs (reticular network)
  • CXCL13+ FDCs
  • CD4+ and CD8+ T-cells
  • Majority of B-cells appear to be CD27+ antigens
187
Q

What’s the relationship between meningeal inflammation and GM demyelination?

A
  • Positive correlation
188
Q

Does remyelination occur in MS?

A
  • Yes
  • Indicated by presence of thinly remyelinated sheaths
  • Remyelination is a frequent finding at the edge zones of inactive plaques
  • Suggested to be extensive in early stages but fails later on —> death of oligodendrocytes/increased damage
  • Complete remyelination of lesions can occur
  • Schwann cell remyelination is found in spinal cord
189
Q

What are glial progenitor cells’ role in remyelination?

A
  • Glial progenitors in the adult CNS are cycling
  • When isolated into culture, they differentiate into oligodendrocytes
  • Glial progenitors are thought to be responsible for oligodendrocyte replacement following demyelination
190
Q

What are possible mechanisms of repair failure?

A
  • Hostile environment/Inflammation/Axonal damage
  • No migration to lesion
  • No differentiation into oligodendrocytes
  • Differentiation but not maturation/effector function (no myelin formation)
  • Axons not reactive to myelin (no sheath formation)
191
Q

What is the definition of epilepsy?

A
  • The tendency to have recurrent (>1), unprovoked seizures
  • Need to have at least 2 seizures
  • Seizure must be unprovoked - anyone can have a seizure under appropriate stimulus
192
Q

What is the definition of a seizure?

A
  • Abnormal synchronised discharge of neurones
193
Q

What is the 10/20 convention?

A
  • Distance between electrodes within 10-20% of AP and lateral dimensions of skull
194
Q

How does an EEG work?

A
  • Synchronised discharge of set of cerebral neurons —> Na+ influx —> Sudden depletion in Na+ ions —> EEG -ve deflection
195
Q

What are the issues with EEGs?

A
  • Many layers of scalp diminish signal
  • Bell’s reflex (blinking artefact)
  • Scalp muscles give artefact
196
Q

What does epilepsy show on an EEG?

A
  • Spike and slow wave

- Normal variation: sharp transient (commonly misdiagnosed as epilepsy)

197
Q

What is the epidemiology of epilepsy?

A
  • Bimodal peak in age-specific incidence: Childhood (genetics) and later life (neurodegenerative disease or acquired CNS injury)
  • Increased risk —> increased risk of developing epilepsy
  • Prevalence = 0.5%
198
Q

How do epilepsy-related deaths occur?

A

1000 deaths per year in UK due to
- SUDEP

  • Status epilepticus (seizures fail to self-resolve —> can’t breathe —> hypoxia)
  • LOC —> Drowning
199
Q

What are the two main aetiologies in epilepsy?

A
  • Genetic disposition (normal brain with no obvious cause e.g. idiopathic)
  • Secondary to Brain Injury
200
Q

Describe the genetic disposition of epilepsy

A

Mendelian inheritance: 2% risk

Complex inheritance: 47% risk
- GWAS found 3 loci (2014): SCN1a (voltage-gated Na+ channel), PCDH7, FANCL

  • Trio studies look for de novo protein-truncating new mutations in affected children with healthy parents
    • Everyone has 1-4 de novo mutations - Healthy people: fall in tolerance genes or no change in aa sequence
    • Disease: fall in intolerant gene (synaptogenesis, synaptic transmission)
201
Q

Describe the “secondary to brain injury” mechanism

A

Environmentally acquired: Head injury, Tumour, Stroke, Infection

  • Innate immunity: Maroso (2010) induced status epilepticus using Pilocarpine in mouse model
    • Found increased HMGB1 —> activate TLR-4 on Neurons, Microglia, Astrocyte
    • –> release of pro-inflammatory cytokines —> modification of NMDA receptors —> Hyperexcitability —> Chronic seizures/Epilepsy is pro-inflammatory —> Vicious cycle
  • Adaptive immunity: Auto-antibodies against voltage-gated K+ channel, NMDA, AMPA, GABA-A R, GAD..etc

Inherited brain injury: Malformation of Cortical Development (MCD)

202
Q

What are the different types of seizures in generalised epilepsy?

A
  • Symptoms depend on location

Generalised epilepsy = Extensive, synchronised discharge in both cerebral hemispheres + LOC, EEG: global ictal discharge

  • Absence (brief LOC)
  • Tonic (contract)
  • Tonic-clonic (tense, jerk, repeat)
  • Myoclonic (fasciculation)
  • Atonic (no tone)
203
Q

What are the different types of seizures in focal epilepsy?

A

Focal epilepsy = Localised, synchronised discharge on part of the brain

  • Simple Partial (no LOC)
  • Complex Partial (with LOC)
  • Secondary Generalised (Partial —> Generalised)
204
Q

What are the decisions to treat epilepsy?

A
  • Benefits (seizure suppression) vs Harms (stigma)
  • Number of seizures at presentation (single seizure with normal MRI/EEG has 50% risk of 2nd seizure - Increased seizures —> Increased risk)
  • Seizure type, seizure severity, cause of seizure
205
Q

What are the MOA of AEDs?

A
  • Increased GABA inhibition
  • Decreased Glutamate mediation
  • Decreased voltage-gated Na+ channel activity
  • Decreased voltage-gated Ca2+ channel activity
206
Q

How does increased GABA inhibition work?

A
  • Benzodiazepine: allosteric modulation of GABA receptor —> Increased GABA influx
  • Barbiturates: allosteraic modulation of GABA receptor —> Increased GABA influx
  • Vitabatrin: inhibits GABA transaminase —> Decreased GABA degradation —> Increased synaptic GABA (not used, S/E 1 in 3 causes blindness
  • Tiagabine: inhibits GATI —> Decreased re-uptake —> Increased synaptic GABA
207
Q

How does decreased glutamate mediation work?

A
  • Presynaptic: Levetiracetam binds to presynaptic vesicle protein SV2A —> Decreased exocytosis
  • Postsynaptic: Parampanel: AMPA receptor antagonist, Felbamate: NMDA receptor antagonist
208
Q

What drugs block the voltage-gated Na+ channel?

A
  • Phenytoin, Carbamazepine, Valproate

- Use-dependent blockage (only blocks during seizures, minimises S/E)

209
Q

How does Gabapentin decrease Ca2+ channel activity?

A
  • Inhibits alpha2-beta subunit of Ca2+ channel —> decreased Ca2+ influx —> Decreased exocytosis
210
Q

What is classical Parkinsonism?

A
  • Bradykinesia
  • Rigidity
  • Rest tremor
  • Response to L-dopa
211
Q

What are the causes of Parkinsonism?

A
  • Idiopathic PD
  • Drug-induced PD
  • MSA
  • PSP
  • CBD
  • FTLD
212
Q

What are the different types of MSA?

A
  • Parkinsonism-type (MSA-P)

- Cerebellar type (MSA-C)

213
Q

What is the macroscopic pathology of MSA?

A
  • Cortical atrophy
  • Cerebellar atrophy
  • Pallor of locus coerulus
  • Pallor of SN
214
Q

What is the microscopic pathology of MSA?

A
  • Mixed neuronal and glia alpha-synuclein pathology

- Papp-Lantos bodies (Olig inclusions of alpha-syn)

215
Q

What are the symptoms of MSA?

A
  • Cerebellar signs, PD Sx
216
Q

What are features of CBD?

A
  • Alien limb phenomenon
  • Taupathy
  • PD Sx
217
Q

What is the microscopic pathology of CBD?

A
  • Fronto-parietal atrophy
  • Deep cerebellar nuclei affected
  • SN affected
218
Q

What is the microscopic pathology of CBD?

A
  • Mixed neuronal and glial pathology
  • Astrocytic plaques (tau in astrocytes)
  • Balloon Neurons (enlarged neurons with tau)
219
Q

What are features of PSP?

A
  • Tauopathy

- Supranuclear gaze palsy (lack of vertical eye movement)

220
Q

What is the macroscopic pathology of PSP?

A
  • Atrophy of basal ganglia, subthalamic nucleus and brainstem
  • Neuronal loss
  • Reactive gliosis
221
Q

What are microscopic features of PSP?

A
  • Neuronal and glial Tau +ve inclusion
  • Tufted astrocytes (many processes)
  • Coiled bodies (Oligoinclusions of Tau)
222
Q

What are some features of Tau?

A
  • Coded by MAPT gene on Chromosome 17
  • Tau stabilises microtubules
  • MAPT KO has no phenotype (other MAPs compensate)
  • Alternative splicing gives 6 isoforms: 3R-/4R- (MT-binding domain, depends on Exon 10) , 0N/1N/2N (Depends on additional inserts)
223
Q

Describe Tau phosphorylation

A
  • Tau phosphorylation —> Decreased MT Binding
  • Tau kinases: GSK-3beta and CDK5 (potential therapeutic targets)

Hyperphosphorylated Tau neurofibrillary tangles have a good clinicopathological correlation with Alzheimer’s disease

224
Q

Western Blot of Tau

A

Do card

225
Q

How can Parkinson’s plus disorder be distinguished clinicallly while patient is alive?

A
  • Biomarkers

- Imaging

226
Q

What biomarkers are seen in Parkinson’s plus disorders?

A
  • MSA has increased alpha-synclein in CSF IN PM (distinguishes it from other alpha-syncleinopathies)
  • CSF neurofilament levels may show signs of CNS damage
  • However a signal protein will not define a disease —> need an algorithm to assess many different proteins
227
Q

What does imaging do for Parkinson’s plus disorders?

A

PET imaging can distinguish PSP from CBD, MSA-P and PD

228
Q

What is it widely believed that MS is initiated by?

A
  • Autoreactive T and B cells reacting to an unknown antigen
229
Q

What happens during the early stages of MS?

A
  • Perivascular infiltrates
  • Axonal damage
  • Neurodegeneration
230
Q

Where do the early stages of disease occur?

A
  • Perivascular cuffs
  • Parenchyma (Intra-parenchyma infiltrates)
  • Meninges (Meningeal inflammation- B cells)
  • Lesions (Macrophages)
231
Q

Where are the B cells seen in MS?

A
  • Perivascular and meningeal locations

- Isolate B cells in parenchyma (active) or perivascular (chronic)

232
Q

What are the possible events leading to immune inactivation in MS?

A
  • Bystander mechanism (TCR dependent mechanism)
  • Role of EBV - infects B cells (persistent latent infection)
    • Sero +ve —> Increased risk of MS
    • Increased anti-EBNA —-> Increased risk of MS
233
Q

What is the rough immunological outline in MS?

A

1) Lymph node: APC (DC) presents autoreactive antigen to activate naive CD4 T cell —> T cell differentiates
2) Activated T cell extravasates into parenchyma
3) B cells migrate into the parenchyma and differentiate into plasma cells —> Immunoglobins —> Inflammatory

Macrophages produce ROS
Macrophages primed to M1 (pro-inflammaory) or M2 (anti-inflammatory)

4) Neuronal death —> neurodegeneration

Overall: Believed MS initiated by CD4 cells, amplified by CD8 cells infiltrating CNS, propagated by T/B cells, Macrophages

234
Q

What are possible antigens in MS?

A
  • Myelin basic protein (MBP)
  • Proteolipid protein (PLP)
  • MOG
235
Q

What are the pro-inflammatory T cells in MS?

A
  • CD4 Th1

- CD4 Th17

236
Q

How does CD4 Th1 exhibit its effects?

A

BOTH PRO-INFLAMMATORY CELLS:
Extravasation of autoreactive cells —> induces M1 microglia —> Neurotoxic mediators —> Neuronal death —> Protein debris —> DC captures antigens and go to lymph nodes —> vicious cycle

  • Th1 produces IFN-lambda, require IL-12 for differentiation
  • Increased MS activity correlates with IFN-lambda and IL-12 expression
  • IFN-lambda administration exacerbates MS
  • Transfer of Th1 —> EAE (mouse model of MS)
237
Q

How does CD4 Th12 exhibit its effects

A

BOTH PRO-INFLAMMATORY CELLS:
Extravasation of autoreactive cells —> induces M1 microglia —> Neurotoxic mediators —> Neuronal death —> Protein debris —> DC captures antigens and go to lymph nodes —> vicious cycle

  • Th17 produces IL-17. require IL-23 for differentiation
  • Increased IL-17 producing cells found in MS lesions
  • IL-23 deficiency —> resistance of EAE (greater role in initiating MS than Th1)
238
Q

What are the anti-inflammatory cells involved in MS?

A
  • CD4 Th2

- CD4 Treg

239
Q

How does CD4 Th2 exhibit its effects?

A

BOTH ANTI-INFLAMMATORY CELLS:
Induces M2 microglia —> Maintain tolerance in the CNS

  • Th2 secretes anti-inflammatory cytokines (IL-4, IL-5, IL-13)
240
Q

How does CD4 Treg exhibit its effects?

A

BOTH ANTI-INFLAMMATORY CELLS:
Induces M2 microglia —> Maintain tolerance in the CNS

  • Treg produces anti-inflammatory cytokines
  • MS: Decreased Treg activity and decreased removal of autoreactive T cells
  • CD25 is a MS susceptibility gene (GWAS) - essential for Treg development
241
Q

What other T cells are involved in MS?

A
  • CD8 cytotoxic T cells: Found at edge of inflammatory lesions and perivascular areas (clonal expression)
  • CD8 MAIT cells: Gut lymphocyte found in post-mortem MS brain tissue
  • Reg CD8 T cell subsets: AHSCT —> Increased CD8+ CD57+ cells (maintain tolerance once repopulated post-transplant
242
Q

What happens once activated T-cells extravasate into blood parenchyma?

A
  • Local DC activates more pro-inflammatory T cells —> Increased damage
  • Entry into CNS via BBB or Blood-CSF barrier (Choroid plexus —> SAD —> Pia —> Brain) - believed initiating mechanism
  • Lymphocyte require activation to enter CNS tissue
243
Q

Describe B Cell migration in MS

A
  • B cells migrate into the parenchyma and differentiate into plasma cells —> Immunoglobins —> Inflammatory
  • B cells locations: Intrameningeal + within White Matter | Demyelination located near Follicles – relationship?
  • IgG oligoclonal bands| APC |Clonal expansion in lesion | Ectopic B cell follicles in meninges & brain parenchyma
244
Q

What are macrophages and microglia’s role in MS?

A
  • Macrophages produce ROS —> axonal damage

- Microglia primedto M1 (pro-inflammatory) or M2 (anti-inflammatory)

245
Q

What are features of M1 microglia?

A
  • Pro-inflammatory phenotype
  • Injured neurons release inflammatory mediators —> M1 phenotype (and expanded by pro-inflammatory CD4
  • M1 Microglia —-> Phagocytosis + Cytokine release —> Neuronal death (MS lesion)
246
Q

What are features of M2 microglia?

A
  • Anti-inflammatory phenotype
  • Sustained by Th2/Treg
  • Th2 releases IL-4 —> M2 microglia release neurotrophic factors —> Increased neuronal survival
247
Q

How does neuronal death lead to neurodegeneration?

A
  • Inflammation —> Immune cells infiltrate —> Pro-inflammatory/Cytokine damage —> Axonal/Neuronal damage
  • Inflammation-dependent mechanisms: Loss of synapses | Retrograde and Anterograde Wallerian degeneration —> Axonal + Neuronal damage/loss
248
Q

What genes are strongly associated with MS?

A
  • HLA Class II genes - strongest, IL-7R, IL-2Ralpha, CD58
  • Many T helper cell differentiation pathway associated with MS risk
  • Different HLAs combinations modulate risk

No significant difference found between genome and epigenome of MS and non-MS twin–Baranzini, 2010

249
Q

How does the gut influence autoimmunity/MS?

A
  • Transfer of gut microbiome from MS —> mice model

- Dietary fatty acids influence GI T cell differentiation (long-chain FA —> Th1 and Th17 | short-chain FA —> Treg

250
Q

What are the CSF immunological abnormalities in MS?

A
  • CSF oligoclonal bands in >90% MS cases | Increased leukocytes, ­Increased CSF protein
251
Q

What is the overall alteration in T cell function in MS?

A
  • Increased freq of T cells responding to myelin antigens | Decreased Treg activity (to autoreactive T cells)
252
Q

Describe MS Comorbidity

A
  • MS is associated with increased ­incidence of other autoimmune conditions (esp Thyroiditis) and asymptomatic auto-Ab
253
Q

What is treatment for MS?

A
  • Only immune-modulatory | No regenerative or neuroprotective therapies | Limited Tx for Progressive MS
  • Acute relapse —> High-dose corticosteroids
  • Immunomodulatory treatment (1st line) - Injectables —> IFN-b, GA | Orals —> Dimethyl Fumarate, Teriflunomide
  • Block immune cell entry: to CNS - Natalizumab (remain in circ) | in periphery —> Gylenia (remain in LN)
    Modulating / Neutralising immune cells —> Daclizumab
  • Immunosuppressing / Depleting —> Alemtuzumab
  • Only for RRMS —> Autologous haematopoietic cell transplant (AHSCT) —> Decreased relapses, stabilises disease
254
Q

What are some symptoms of Parkinson’s disease?

A
  • Bradykinesia
  • Tremor
  • Postural instability
  • Rigidity
255
Q

What is Parkinson’s disease?

A
  • Progressive neurological disorder charactersied by bradykinesia, tremor, rigidity and postural instability (at least two)
  • Commonly associated features: autonomic dysfunction, cognitive disturbance, depression, dysphagia
256
Q

What is parkinsonism?

A
  • Clinical syndrome with some or all of these clinical features:
  • Bradykinesia
  • Tremor
  • Postural instability
  • Rigidity
257
Q

What are Parkinsonian disorders?

A
  • Disorders in which Parkinsonism is a prominent feature = akinetic-rigid disorders
258
Q

What did Ehringer & Hornkiewicz find about PD patients in 1960?

A
  • In the caudate/putamen of PD patients dopamine concentrations were only 10% of those found in controls
259
Q

How does Parkinson’s cause impaired mobility?

A
  • Loss of dopamine release in the striatum causes the acetycholine producers there to overstimulate their target neurons, thereby triggering a chain reaction of abnormal signalling leading to impaired mobility
  • Necessary to lose 80-85% of dopaminergic neurons and deplete dopamine levels by 70% before clinical symptoms of PD appear
260
Q

Why is MPTP used to model PD in animals?

A
  • MPTP=1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Prodrug to the neurotoxin MPP+
  • May be accidentally produced during the manufacture of the opioid drug desmethylprodine (MPPP)
  • Intoxication causes parkinsonism associated with degeneration of dopaminergic neurons
261
Q

What is the main site of PD and its clinical correlate?

A
  • SN

- Akinetic-rigid syndrome

262
Q

What is the main site(s) of Parkinson’s with dementia (PDD) and its clinical correlate?

A
  • SN, cerebral cortex

- Dementia more than one year after PD Dx

263
Q

What is the main site(s) of DLB and its clinical correlate?

A
  • SN, cerebral cortex

- Dementia less than one year after akinetic-rigid syndrome

264
Q

What is the main site(s) of autonomic failure and its clinical correlate?

A
  • Sympathetic neurons in the spinal cord

- Autonomic failure

265
Q

What is the main site(s) of LB dysphagia and its clinical correlate?

A
  • Dorsal vagal nucleus

- Dysphagia

266
Q

What is the pathological correlate of PD?

A
  • Neuronal inclusions composed of alpha-synuclein (Lewy bodies)
  • Neuronal loss in the substantia nigra (ventrolateral) with dopaminergic denervation of the striatum is the pathology correlate of main symptoms.
267
Q

Describe the differential regional and cellular vulnerability concept in PD?

A
  • Distinctive physiological phenotype of adult SNc DA neurons
  • Pacemaker-like properties of these cells, leading to frequent intracellular calcium transients
  • Pacemaking is necessary to maintain a basal DA tone in target structures, like the striatum; without it, movement ceases
  • Ventral tegmental area (VTA) DA neurons (also slow
    pacemakers)
    • No Calcium transients
    • Less Ca2+ channel density
    • Express high levels of the Ca2+-buffering protein calbindin
268
Q

What is α-synuclein?

A
  • α-synuclein is a member of the human synuclein family along with β-synuclein and γ-synuclein
  • It is abundant in the brain
  • It has an unknown physiological function but may be involved in the regulation of synaptic plasticity and neurotransmitter release (due to its presynaptic
    location)
  • Natively unfolded protein enriched in presynaptic terminals
  • “Amyloid-like” aggregation, pathologic post-translational modifications (including phosphorylation), truncation and oxidative damage
269
Q

What is the diagnostic gold standard for PD?

A
  • Now α-synuclein immunostaining is considered as the diagnostic gold standard
  • •Spillantini reported that Lewy bodies and Lewy neurites are immunoreactive for α-synuclein
270
Q

Where does Parkinson’s arise from the brain?

A
  • Begins in dorsal motor nucleus of the vagus nerve and anterior olfactory nucleus
  • Proceeds in rostral direction toward neocortex
  • Many cases also have Alzheimer-type plaques and tangles.
  • Conversely, a substantial number of individuals with Alzheimer disease develop Lewy pathology, especially in the amygdala
  • There may be involvement in the substantia nigra without obvious involvement
    of dorsal motor nucleus of the vagus
271
Q

Where outside the brain is Lewy Body pathology also observed?

A
  • Peripheral ganglia
    • Epicardial nerve vesicles
    • Paravertebral sympathetic ganglia
  • GI tract
    • Intermediolateral nucleus with affected preganglionic sympathetic neurons
    • Coeliac ganglion (postganglionic sympathetic neurons)
    • Auerbach’s plexus in the stomach
    • Enteric nervous system
272
Q

What are special types of PD?

A
  • Heterozygous GBA mutation carriers
    • 9–12% risk of PD, compared with 2.6% in the general population
    • Earlier age of onset and more-severe nonmotor symptoms
    • Lewy bodies and Lewy neurites contain glucocerebrosidase
    • Link between lysosomal dysfunction, α-synuclein aggregation and
      PD.
  • Heterozygous mutations in leucine-rich repeat kinase 2 (LRRK2)
    • 1% of idiopathic PD cases and 4% of familial PD cases
    • Typical LB pathology (majority)
    • Tau inclusions
    • No inclusions
  • Recessive forms of juvenile-onset parkinsonism
    • Parkin (an E3 ubiquitin ligase): majority no LBs
    • PINK1 (a mitochondrial protein kinase): LBs
273
Q

What can be used to visual early PD pathological lesions?

A
  • alpha-synuclein proximity ligation assay
274
Q

What is ALS?

A
  • chronic neurodegenerative condition causing
    muscle wasting, paralysis and death usually
    within 3-5 years due to respiratory failure
275
Q

What is ALS’ incidence?

A
  • New cases per annum: roughly 2/100,00 per year

- M > F

276
Q

What is ALS’ prevalence?

A
  • 5/8 per 100,000
277
Q

What is the lifetime risk of people with ALS in the UK?

A
  • M: 1 in 350

- F: 1 in 472

278
Q

What components are affected in ALS? (Neurons)

A
  • Upper motor neurons
  • Lower motor neurons
  • Two distinct and connected systems that are essential components in ALS
  • Both have long axons (length/cell diameter roughly 10,000)
  • Very active
  • High energy demands
279
Q

What are clinical signs of ALS?

A
  • Muscle atrophy and spasticity
  • Progressive denervation and secondary muscle weakness of limbs, trunk, tongue and respiratory (intercostal) muscles. Onset usually occurs in distal muscles of a single limb or may be bulbar, followed by widespread progression
  • Impaired swallowing and speech (‘bulbar signs’)
  • Spastic weakness and paralysis affect all skeletal muscle
  • Respiratory failure
  • No impairment of bladder, bowel or sexual function
  • Occulomotor, sensory and autonomic function spared
  • Cognitive function may be affected in a minority of cases
280
Q

What is the onset of ALS?

A
  • Starts focally and spreads
  • First signs usually occur in limb extremities or tongue
  • Wasting of thenar hand muscles
  • Wasting of the tongue muscle (‘bulbar onset’)
281
Q

What are early diagnostic tests of ALS?

A
  • Muscle biopsy

- Electromyogram (nerve conduction test)

282
Q

What are LMN signs in ALS?

A
  • muscle weakness
  • wasting
  • fasciculations
  • cramps
283
Q

What are UMN signs in ALS?

A
  • stiffness and slowness of movement
  • slow and clumsy speech
  • Babinski signs are often present
284
Q

What are features of primary lateral sclerosis?

A
  • Effects on UMNs predominate, spasticity, hyperreflexia, surivial is 20 years
285
Q

Describe treatment for ALS

A
  • Speech and swallowing: speech therapist
  • Mobility around home: occupational therapist
  • Swallowing and feeding: NG or PEG tube
  • Breathing: Oxygen, assisted ventilation (face mask)
  • Symptomatic treatments: cramps/muscle spasm
  • Slowing disease progression: Riluzole extends survial by roughly 3 months
286
Q

What is ALS characterised by?

A
  • Motor neuron loss in spinal cord, brain stem, motor cortex
  • Corticospinal tract degeneration
  • Ubiquitinated inclusions in neuronal cell bodies and proximal axons
287
Q

What is an ubiquitinated protein?

A
  • Post-translational modification by a small 76 aa regulatory protein, ubiquitin
  • Ubiquitinated inclusions are characteristic of ALS (sporadic ALS and familial ALS) and a subset of cases of frontotemporal dementia
  • TDP-43 identified as a major component of ubiquitinated inclusions in SALS, FALS and FTLD*
288
Q

What % of ALS and FTD cases are characterised by TDP-43+ve ubiquitinated inclusions

A
  • ~97% ALS cases (Familial ALS and Sporadic ALS)

- ~50% FTD (familial and sporadic, FTLD-TDP)

289
Q

What are the mutations that cause Familial ALS (FALS)?

A
  • SOD1
  • TARDBP
  • FUS
  • c9ORF72
  • Abnormalities in RNA binding proteins, proteostasis, cytoskeletal proteins
290
Q

What is TARDBP?

A
  • TAR DNA binding protein
  • TARDBP encodes TDP-43, binds TAR DNA sequences in DNA/RNA acting as a transcriptional repressor, inhibits splicing and regulates mRNA transport/ local translation
291
Q

What is the effect of TDP-43 mutations?

A
  • TDP-43 is cleaved, locates to cytoplasm
  • Hyperphosphorylated, ubiquitinated aggregates in cytoplasm, MNs, glia, neurites
  • Animal models: Neurodegeneration (cortical and spinal
    neurons) BUT without consistent formation of inclusions
  • Both wild-type (8) and mutant (4) TDP-43 rodent
    transgenics produce neurodegeneration and paralysis
    (threshold for toxicity may vary).
292
Q

How does TARDBP regulated RNA processing?

A
  • Repressor
  • Exon skipping
    Binds to CFTR pre mRNA
    UG intronic tract
293
Q

How does FUS regulate RNA processing?

A
  • ACTIVATOR nuclear hormone receptors, NFkB. (RNA polymerase complex)
  • Part of spliceosome machinery
294
Q

What are further actions of TDP-43?

A
  • 30% TDP-43 is cytoplasmic
  • Activity and cell stress stimulate nuclear efflux of both TDP-43 and FUS to the cytoplasm where they are found in RNA transport granules (stress granules and processing bodies).
  • TDP-43 also regulates local protein synthesis in dendrites (as occurs in LTP) and loss of TDP-43 reduces dendritic branching/ synapse formation and FUS knockout reduces spine formation
295
Q

What causes TDP-43 mislocalisation?

A
  • Inhibition of FUS nuclear transport protein
    (transportin) causes FUS accumulation in cytoplasm.
  • Similar inhibition of the TDP-43 nuclear transport protein (Importin) causes accumulation of soluble TDP-43 in cytoplasm.
  • Transgenic mice with a defective Nuclear Localisation Signal (NLS) show accumulation of insoluble, phosphorylated TDP-43 in brain and spinal cord, loss of endogenous nuclear
    mouse TDP-43, brain atrophy, muscle denervation, dramatic motor neuron loss and progressive motor impairments leading to death. (Mihevc et al 2016)
296
Q

How do stress granules form in the cytoplasm in ALS?

A
  • Effects on nuclear transport proteins are relevant to
    SALS, as these proteins decrease in abundance with
    age and could lead to increased cytoplasmic TDP-43.

—>

  • Cell stress, oxidative stress, heat shock, ER stress

—>

  • Formation of stress granules in the cytoplasm
    containing housekeeping mRNAs that do not require
    translation during stress also contain FUS and TDP-43
297
Q

What is the common pathway for ALS neurodegeneration?

A
  • Nuclear proteins (TDP-43 and FUS) that mislocalise to the cytosol
    TARDBP, FUS, ageing

—>

  • TDP-43+ve/FUS+ve - Ubiquitinated protein aggregates

—>

  • Neurodegeneration
298
Q

What chromosome locus is ALS and FTD linked to?

A
  • Chromosome 9p locus
299
Q

What genes are in the 9p21 ALS/FTD locus?

A
  • Chromosome 9 open reading frame 72 (C9ORF72)
  • Expanded repeats in intron 1 of C9ORF72 in FTD and ALS
  • TDP-43 +ve inclusions in cytoplasm
  • C9ORF72 containing 3 GGGGCC repeats arose in primate evolution: present in human, chimpanzee
    and gorilla but no other species
300
Q

What are some features of C9ORF72?

A
  • Unknown function likely to be a member of the DENN protein group involved in membrane fusion
  • Reduced mRNA levels
  • RNA foci accumulate in ALS (spinal cord, animal models and iPSCs) BUT overexpression of the repeat not associated with neurodegeneration
  • RAN peptides: Bi-direction transcription and translation of expanded repeat containing sequences
  • C9ORF72-specific pathology includes p62+ve cytoplasmic and nuclear inclusions in hippocampus and cerebellum that are TDP-43-ve
  • DENN = Differentially expressed in normal and neoplastic cells (Guanine nucleotide
    exchange factors for small GTPases like Rab)
301
Q

What is the putative mechanism of C9orf 72 pathogenesis?

A
  • Bi-direction transcription of expanded repeat containing sequences followed by translation of repeat associated non-AUG initiated (RAN) translation of aggregation-prone dipeptide repeat peptides (DPRs) (Cruts et al 2013).
  • Generates 5 DPRs: Poly GA, GP, GR, PR, PA
  • Poly GA is the most highly aggregatable and interferes most with proteostasis (Yamakawa et al 2014)
302
Q

Is the anatomical distribution of DPR species
related to neurodegeneration or clinical
phenotype (e.g. motor neurons and ALS)?

A
  • Inconsistent results from biological studies and
    low sample number/ restricted number of
    anatomical regions/ limited antibody use
303
Q

What did Mackenzie et al (2015) and Davidson et al (2016) find out?

A
  • Confirmed the presence of 5 DPR species (sense being most abundant) in unaffected regions: granule cells of hippocampus and cerebellum
  • BUT showed a lack of association between DPR and
    neurodegeneration and clinical features e.g. VERY
    RARE in ALS lower motor neurons
  • Degeneration and loss of anterior horn cells occurs
    in the absence DPR
304
Q

What is clinical characteristics of C9ORF72 FALS

cases compared to other FALS cases?

A
  • Age of onset
    C9ORF72+ve: 56
    All others: 61
  • Co-morbidity with FTD (%)
    C9ORF72+ve: 50
    All others: 12
  • Survival (months)
    C9ORF72+ve: 20
    All others: 26
305
Q

What factors can affect TDP-43+ve and FUS+ve ubiquitinated protein aggregates?

A
  • Activation of cell stress responses and protein degradation pathways impaired/overloaded
  • Trigger factors, cell stress, excitotoxicity, risk factors, ageing, variable penetrance
306
Q

How are FALS genes important in protein regulation?

A
  • Unfolded protein response (UPR): protective pathway increases levels of protein chaperones to facilitate folding
  • Protein degradation via the proteasome and autophagy via the lysosome (aggrephagy)
307
Q

What is VAP B?

A
  • Vesicle associated protein B
  • A VAPB mutation was first described in a Brazilian
    family linked to 20q13 (Nishimura et al 2004)
  • A second UK FALS-associated mutation was found (Chen et al 2010)
  • VAPB is localised in motor neurons and is significantly decreased in sporadic ALS spinal cord
308
Q

What is P4HB?

A
  • an ER foldase, that is induced in ER stress
    and SALS, that is a disease modifier (“risk factor”)
  • Disease onset or duration may vary substantially even
    within a family harbouring the same mutation (e.g. 0.5 to
    20 years duration). Risk factors are thought to contribute to this variable penetrance and modify disease onset/progression
309
Q

How does the waste disposal system work in ALS?

A
  • SOD1: ALS1, binds to Derlin 1
  • VCP: ALS14 and IBMPFD, ER protein export to the proteasome
  • Ubiquilin 2: X-linked FALS and SALS, binds to poly-ubi chains and components of the proteasome
310
Q

What is autophagy?

A
  • Aggrephagy of misfolded or aggregated proteins
    is activated by the failure of proteasomal degradation and molecular chaperones to resolve aggregate build-up.
  • Involves P62 (Ubiquitin binding protein Sequestosome and 1 SQSTM1) and OPTN ALS12 slow
    progressing AR/AD
311
Q

What is a novel ALS gene by Cirulli et al 2015?

A
  • TANK-binding Kinase 1 (TBK1)
312
Q

What does TBK1 do?

A
  • Phosphorylates optineurin (OPTN) and p62 (SQSTM1)
    and proteins involved innnate immunity
  • Enhances the binding of OPTN to the autophagosome
    protein LC3, facilitating the autophagic turnover of
    infectious bacteria, coated with ubiquitylated proteins, a
    specific cargo of the OPTN adaptor
  • Strengthens the importance of autophagy in ALS
    pathogenesis
  • TBK1 variants found in 1.097% of cases and 0.194% of controls
313
Q

How does Riluzole work?

A
  • an anti-epileptic drug,
  • targets voltage-dependent Na+ channels and
    reduces glutamate release
314
Q

What triggers ALS that is specific for motor neurones?

A
  • Constant excitatory activity (NMDA receptors) activated by Glutamate and D-serine
  • D-serine is significantly elevated in SALS
  • High levels of D-amino acid oxidase (DAO) are vital to metabolise and regulate D-serine levels
315
Q

What is the effect of R199WDAO?

A
  • A pathogenic mutation in DAO, R199WDAO, is an enzyme that metabolises D-serine was identified in FALS that is transmitted with disease
  • R199WDAO increases ubiquitinated protein aggregates
  • Autophagy: increase in autophagosomes and LC3-II in
    motor neuron cell line (NSC-34)
  • Significant loss of spinal cord motor neurons occurs in transgenic mice expressing R199WDAO and in sporadic cases
316
Q

What is the latest FDA approved drug for ALS?

A
  • Edavarone

- A free radical scavenger in stroke

317
Q

What is ENCALS statement on Edavarone?

A
  • FDA approval based on a single positive study showing that the drug may slow the progression of disease ONLY in a subgroup of patients.
  • An initial study of 100 patients with drug and 100 with placebo: no significant effect but a hint of an effect
  • Second smaller study for 6 months using only patients with mild to moderate swallowing and motor dysfunction (ALS FRS-R) within two years of diagnosis with normal respiratory function.
  • RESULT: Treated patients declined 5.1 points on the ALS-FRS compared to 7.5 points on placebo.
  • BUT previous studies show a decline of 5.6 in most ALS patients.
  • Recommendation: Longer studies (2 years) and testing the effect on survival
  • Cons: no effect on severely affected cases
318
Q

What is used in ALS treatment? (Drugs & Gene Therapy)

A
  • No effective cure but treatment of symptoms
  • Riluzole (since 1995): mean increased survival up to 3 months
  • Edavarone (2017): an anti-oxidant

Where the causal gene is known:
- Targeted gene delivery or gene deletion using direct
delivery of antisense oligonucleotides (ASOs) by
adeno-associated viral (AAV) vectors to “neutralise”
the mutation”. Phase 1 Clinical trial SOD1 Mutation
Intrathecal injection with adenovirus gene delivery.

  • CRISPR/Cas9 technology to target mutant genes and
    reintroduce wild type copies.
319
Q

What are possible treatment targets for ALS?

A
  • Motor neuron susceptibility and trigger factors?
  • Prevention of nuclear RNA foci (C9orf72 specific)?
  • Prevention of cytosolic inclusion formation?
  • Up-regulate UPR, UPS, autophagy?
  • Upregulate molecular chaperones (HSPs)?
  • Reduce D-serine levels?
  • Designer Drug treatment: 15,000 patients and
    7,500 controls Project MinE (US) to develop basis
    for treatment from Whole Genome Sequencing,
    metabolomics and proteomic analysis.
320
Q

What are symptoms of Parkinson’s Disease Dementia?

A
  • Mainly frontal synptoms
  • Visuospatial symptoms
  • Hallucinations
321
Q

What imaging is used for parkinsonism?

A
  • Fluorodopa (18F) —> PD: Bilateral loss of dopamine signal
  • Need to lose 80% dopamine or 50% dopaminergic neurons for symptoms
322
Q

What neurotransmitters are involved in PD?

A
  • Dopamine
  • Acetycholine
  • Excitatory amino acids (Serotonin, NA, Adenosine, Opioids)
323
Q

What motor symptoms appear in PD?

A
  • Responsive to medication: Tremor, Rigidity, Bradykinesia
  • Loss of Postural reflexes
  • Shuffling gait, Freezing episodes, Maskes facies
  • Symptoms worsen with time: Early stages (motor) —> Later stages (non-motor, severe loss of mobility and independence)
324
Q

What are non-motor symptoms of PD?

A
  • Neuropsychiatric: Hallucinations, confusion, depression (50%)
  • Autonomic : Bladder, bowel, hypotension
  • Sleep: restless legs, REM Sleep Behaviour Disorders
    • Symptoms worsen with time: Early stages (motor) —> Later stages (non-motor, severe loss of mobility and independence)
325
Q

What are NICE guidelines (2006) for PD treatment?

A
  • Physiotherapy
  • Occupational Therapy
  • Speech and Language Therapy
  • Exercise/Movement: Yoga, Tai-Chi, Le Trepidant (the shaking chair)
  • Pharmacological
326
Q

How is dopamine used in PD treatment?

A
  • Indirect agonists
  • Direct dopamine agonists
  • Enzyme blockers
327
Q

What are examples of indirect dopamine agonists?

A
  • L-DOPA (precursor, GOLD STANDARD, given with enzyme blockers
  • Amantadine (Increased DA release, MOA unknown)
  • N.B. protein load (food) may interfere with L-DOPA absorption as L-DOPA also relies on Amino Acid Transporters
  • L-DOPA benefits wears off - Therapeutic window: Low = no response, high = dyskinesia - requires surviving neurons
  • For Young-onset PD, give DA agonist (keep L-DOPA for future use), as diseases progresses –> decreased L-DOPA effectiveness
328
Q

What are examples of direct dopamine agonists?

A
  • Apomorphine
  • Ropinorole
  • More side effects (N&V, Gambling)
  • When effect wanes —> add L-DOPA
  • Early (delay L-DOPA use), late (Lower L-DOPA use)
329
Q

What are examples of enzyme blockers used in PD?

A
  • DOPA decarboxylase inhibitor: Sinemet
  • MAO inhibitor: Selegiline
  • COMT inhibitor: Entacapone
330
Q

What are some other examples of pharmacological therapy (apart from dopamine)?

A
  • Anticholinergics
  • Cell therapy
    Fetal Cell Transplant: extracting dopaminergic neurons from aborted foetuses and transplant into striatum
331
Q

How do you treat the secondary symptoms in PD?

A
  • Autonomic features: Decreased BP (Fluid, Salts, Fludrocortisone), Bladder freq/urgency (Desmopressin), Drooling (Anticholinergics)
  • Cognition: depression, anxiety, dementia, hallucinations (identify triggers)
  • Sleep (avoid drugs, treat depression, sleep hygiene), Pain
332
Q

Why is it difficult to stop progression of PD?

A
  • Widespread pathological CNS involvement
  • Infections may precipitate features, PD patients have a high risk of falls, Only adjust/add/remove one drug at a time
  • Not all PD patients have worsening symptoms due to illness or the treatment - PD patients can have other conditions
333
Q

Who do dopaminergic nenrons degenerate?

A
  • Oxidative stress
  • Ubiquitin-Proteasome dysfunction
  • Neuroinflammation
  • Mit. dysfunction
334
Q

What is the Ubiquitin-Proteosome pathway?

A
  • Polyubiquitin chain conjugated to substrate to tag it for degradation by Protease
  • Enzymes involved in Ubiquitination: E1, E2, E3 (Parkin gene associated with E3 ligase)
  • PD causing mutation (Parkin) disrupts Ubiquitination —> decreased degradation of damaged proteins —> protein aggregation —> cell death
335
Q

How do ROS make midbrain dopaminergic neurons vulnerable to neurodegeneration?

A
  • Dopamine and its metabolites have intrinsic tendency to form ROS
  • SNc is rich in Iron: Redox cycles of Iron generates ROS
  • Mitochondrial abnormalities (e.g. complex 1 defect) —> uncouples redox reactions and regenerates ROS
  • PD: deficient in Antioxidant molecules (Glutathione)
336
Q

How does mitochondrial dysfunction contribute to neuronal vulnerability?

A

Release of Cytochrome C —> Apoptosis

  • ROS affect mitochondria - PD: Complex 1 dysfunction —> mitochondria become inefficient
  • PD: alpha-synuclein aggregates inhibit Complex 1 of mitochondria
  • Damaged mitochondria —> disrupted mitochondrial potential - PD genes (DJ1) affect integrity of mit. Membrane
337
Q

How does neuroinflammation cause neuronal vulnerability?

A
  • Microglial inactivation from direct (MPTP, 6-OHDA- neuron death activate microglia) & indirect (LPS) neurotoxins
338
Q

Describe the environmental toxin theory of SNc dopaminergic neuron susceptibility?

A
  • Environmental toxins lead to specific degeneration of SNc neurons
  • MPTP-induced Parkinsonism accidentally discovered from Heroin users; MPTP is a Mitochondrial Complex 1 inhibitor
  • Uptake mechanisms of MPP+(MPTP metabolite) are specific to SNc DA neurons; MPP+ concentrates in mitochondria
  • This isn’t true PD- this is artificially killing DA neurons to produce PD-like state, Langston 1984
339
Q

Describe the transcriptional profile theory of SNc dopaminergic neuron susceptibility?

A
  • Transcriptional profile may confer inherent vulnerability of SNc dopaminergic neurons
  • Neurodevelopment defines the transcriptional profile of a cell which defines its properties
  • Neurodevelopment —> Neural stem progenitor cell —> mDA progenitor —> mDA mature neuron
  • (1) Defined as Midbrain neurons (2) Defined by Dopaminergic neurons (3) In adult, become survival/maintenance factors
  • (1) Regional identity: Otx2 (SHH, Engrailed, Wnt1) (2) Specficiation: LMX1a (FGF8, SHH) (3) Survival: Engrailed, Nurr1
340
Q

What does Nurr1 do?

A
  • Nurr1 regulates NT identify of neuron

- Nurr1 deficiency —> DA neurons cannot produce dopamine (Le WD)

341
Q

What does FoxA2 do?

A
  • Involved in late-stage DA neuron development

- Heterozygote FoxA2 (+/-) mice —> unilateral Da neuron degeneration (Ferri ALM)

342
Q

What are Engrailed genes?

A
  • Engrailed 1/2
  • Engrailed KO —> total loss of DA neurons (dose-dep)
  • Heterozygote: cell lost by P90 (Sgado)
343
Q

How are VTA neurons more resilient than SNc neurons?

A
  • Otx2: upregulated in VTA neurons > SNc
  • Otx2 overexpressionin SNc in neuroprotective (animal/cellular models) (Chung CY)
  • Overexpressionof pro-survival genes (found upregulated in VTA but downregulated in SNc) is neuroprotective
344
Q

What are features of SNCA?

A
  • 1st PD gene found
  • unknown role (possibly related to pre-synaptic vesicle trafficking)
  • Found as aggregates in Lewy Bodies
  • Pathological roles of alpha-synuclein: Proteasome inhibition, Complex 1 inhibition, Autophagy inhibition, form LBs
  • SNCA KO Mice show resistance to MPTP-induced dopaminergic toxicity
345
Q

What are features of Parkin?

A
  • Most common genetic cause
  • Autosomal recessive PD
  • Parkin = E3 ligase adds Ub + aids degradation
  • Parkin KO —> inability to remove/break down damaged proteins and organelles
346
Q

What are features of PINK-1?

A
  • Autosomal recessive
  • PINK-1 marks mitochondria (to be removed by Parkin)
  • Parkin overexpression rescues PINK-1 KO
347
Q

What are features of DJ1?

A
  • Inhibits aggregation of alpha-synuclein (via its chaperone activity)
  • Antioxidant
  • Modulates mit. membrane potential
  • DJ1 KO —> disrupted mit. membrane potential —> marked by PINK-1 to be removed by Parkin for degeneration
348
Q

What are causes of PD?

A
  • Sporadic PD
    Genetic risk factors: Tau, LRRK2, alpha-synuclein
    Environmental risk factors: Ageing, Toxins (MPTP)
  • Familial PD
    Autosomal dominant: LRRK2, alpha-synuclein
    Autosomal recessive: Parkin, PINK-1, DJ1
349
Q

What percentage of PD cases are familial?

A
  • 10%
350
Q

What are the principal gene mutations associated with familial PD?

A
  • SNCA
  • LRRK2
  • Parkin
  • PINK-1
  • DJ-1
351
Q

What are the features of SNCA?

A
  • SNCA is 1st genetic mutation identified (Polymeropoulous, 1997)
  • Found in the Brain and Heart
  • ?role in pre-syanptic vesicle trafficking
  • High penetrance, all 3 mutations cause disease, SNCA mutation —> alpha-synuclein more likely to misfold + aggregate
  • Pathological alpha-synuclein aggregates —> Proteasome inhibition, Complex 1 inhibition, Autophagy inhibition
  • When alpha-synuclein reaches certain level, cell may efflux them —> ?prion-like spread
352
Q

What are the features of LRRK2?

A
  • cytoplasmic kinase (many functions), low penetrance, (many mutations- same family, same mutation, different phenotypes)
  • LRRK2 interacts with Parkin, LRRK2 mutations results in abnormal shapes of alpha-synuclein pathology (pleomorphic pathology)
  • LRRK2 mutation results in variety of pathologies (Clinical Dx of PD may not be true PD at PM), Most common mutation of fPD
353
Q

What are the features of Parkin?

A
  • Ubiquitin E3 ligase

- Role in Mitophagy

354
Q

What are the features of PINK-1?

A
  • Mitochondrial kinase

- PINK-1 marks Mitochondria for Parkin to bind and induce mitophagy

355
Q

What are the features of DJ-1?

A
  • Protein chaperone
  • Protects cells from oxidative stress
  • Stabilises mit. membrane potential
  • DJ-1 mutation —> PINK1 marks mit.
356
Q

What are the risk genes associated with the development of idiopathic PD?

A
  • MAPT (Tau)
  • SNCA (alpha-synuclein)
  • LRRK2 (interacts with Parkin)
  • HLA-DRB5 (MHC Class II)
  • LAMP3
  • Identified by GWAS, suggests Tau in disease pathology rather than just age-related changes in Tau
357
Q

Which pathways do each SNP affect?

A
  • Ubiqutin-Proteasome system: Parkin
  • Protein aggregation: SNCA, MAPT
  • Mitochondrial clearance: Parkin, PINK-1, DJ-1
  • Protein/Membrane trafficking: LRRK2, MAPT
  • Neuroinflammation & Complement: HLA
  • Synaptic function: SCNA, LRRK2
358
Q

What are the relative risks of fPD and idio PD?

A
  • Familial PD —> Very rare, high risk (SNCA)

- idio PD —> Rare, medium risk (LRRK2) or Common, low risk (SNPs)

359
Q

How is neuroinflammation involved in PD?

A
  • PD tissues show neuroinflammation
  • Activated microglia may damage DA neurons
  • Anti-inflammatories may reduce cell loss
360
Q

What is the epidemiological evidence regarding PD neuroinflammation?

A
  • Regularly taking Ibuprofen has a lower incidence fo PD

- Glitazone (anti-inflammatory) for Diabetes given 2 days after 6-OHDA lesion in animal models: almost total protection

361
Q

How is Pioglitazone involved in PD?

A
  • PPAR-gamma agonist
  • Modules inflammation and induces neuroprotection in Parkinsonian monkeys
  • Pioglitazone Phase II Clinical Trial (multicentre, double-blind RCT): No benefit - too little too late? Few SNc neurons to rescue?
362
Q

Why may potential PD drugs be given too late?

A
  • Symptoms only arise after 60-70% loss of dopaminergic neurons in SNc BUT pathology occurs years before diagnosis of PD
363
Q

What is the premotor phase of PD?

A
  • Onset of neurodegeneration 5 - 10 years before diagnosis
  • Precursor symptoms: Anosmia, constipation, REM Sleep BD
  • Ideally target neuroprotection in premotor phase
364
Q

What are progressive symptoms of PD?

A
  • Motor symptoms

- Cognitive impairment

365
Q

What are the challenges in PD treatment?

A
  • PD pathogenesis is not well understood - what is the trigger?
  • Limitations in Clinical Trial Design (stratify rapid/slow progressers)
  • No validated biomarkers
  • 10% early stage patient - no PD
366
Q

What is epigenetics?

A
  • DNA Methylation
  • Physical blockage of DNA
  • Long-term repression
367
Q

What is histone modification?

A
  • Short-term repression, methylation/acetylation —> Increased electrostatic repulsion of histones —> Increased transcription factor accessibility —> gene expression
368
Q

What do histone acetyltransferases (HATs) and histone deacetylases (HDACs)?

A
  • HATs acetylate histones (Increased gene expression)
  • HDACs deacetylate histones (Decreased gene expression)
  • Neuronal death due to repression of essential proteins or expression of detrimental factors
369
Q

What are epigenetic changes in PD?

A
  • Misfolded alpha-synuclein enters nucleus —> binds to histone H3 –> supresses gene expression
370
Q

What is a potential epigenetic target for PD?

A
  • HDAC inhibition
371
Q

How does Valproate work?

A
  • General inhibition of HDACs (Class I & II)
372
Q

What is the unilateral Lactacystin lesion model of PD?

A
  • Lactacystin (proteasome inhibitor) injected directly into nigrostriatal pathway
  • Lactacystin —> Epigenetics (hypoacetylation —> Decreased gene expression of BDNF, hsp70 and Bcl-2 - factors for neuronal survival)
  • Valproate: reverses Histone acetylation —> Hyper-expression of BDNF, hsp70, Bcl-2, Dose-dependent neurorestoration
  • However when clinically translated, high dose Valproate induces S/E, Proof-of-principle of using epigenetics to treat PD
  • Future: potent selective HDAC inhibitor
373
Q

What are toxin-based models of PD?

A
  • Toxins injected locally or systematically (if can cross BBB) to kill DA neruons
  • Rodents bred in standardised conditions
  • Uniform brain at certain age
  • Can predict location of brain structures
374
Q

What is the 6-OHDA toxin-based model?

A
  • 6-OHDA: oxidative product of Dopamine, usually in tiny amounts that is cleared
  • Unilateral stereotactic injection: into SNc (rapid cell loss, 3d), into Medial forebrain bundle (7d), into Striatum (14d)
  • Dose-responsive loss of nigrostriatal DA neurons - ideally develop for diff. stages of cell loss (e.g. 60-70% cell loss)
  • PD Features: Mitochondrial inhibition, selective neuronal loss, oxidative stress, NO altered proteins
375
Q

What is the MPTP toxin-based model?

A
  • MPTP crosses BBB converted by Glia by MOA-B to MPP+ —> enters DA neuron (complex 1 mit. inhibitor) —> bilateral damage
  • Systemic administration - Only in susceptible species: Humans, Primates, Mice (C57Black) - Only loss in SNc not VTA/NAc
  • Behaviour changes reversed by standard PD treatment - However: high mortality, ethically difficult to use Primates
  • PD Features: Mitochondrial inhibiton, selective neuronal loss, oxidative stress, NO altered proteins - yes if +Probenicid
376
Q

What is the Lactacystine toxin-based model?

A
  • Lactacystine: Proteasome inhibitor, more stable model, but does not cross BBB
  • Unilateral stereotactic injection: into SNc/MFB, chronic progressive model (c.w. rapid cell loss in 6-OHDA and MPTP) + spread
  • PD Features: NO Mitochondrial inhibition, selective neuronal loss, oxidative stress, altered proteins
377
Q

What is the PSI toxin-based model?

A
  • Proteasome inhibitor —> Increased build up of abnormal/altered proteins —> Protein inclusions —> cell death
  • Systemic administration however not very reproducible model
378
Q

What are other toxin-based models are used?

A
  • Manganese (mining ore)
  • Carbon disulphide (rubber processing)
  • Cycad seeds (toxic seeds from Guam)
379
Q

What is the alpha-synuclein Drosophiliae model?

A
  • Either Increased alpha-syn expression or mutated alpha-syn —> selective dopaminergic neuronal death
  • Lewy Body-like structures
  • Movement disorder - change in climbing behaviour in Drosophiliae
380
Q

What is the alpha-synuclein transgenic mice model?

A
  • Need to wait 18 months for pathology
  • Transgenic animals are expensive
  • Increased WT 1x human alpha-synuclein expression —> neuronal inclusions (hLB sunflower structure, rLB is disorganised - no neuronal loss
  • Mice require 2-3 mutations in alpha-synuclein —> Age-dependent decreased in SNc TH cell number, decreased motor function, no inclusion formation
  • But no human has more than 1 alpha-syn mutation (as it has high penetrance)
  • Is double mutant model valid?
  • Expensive
381
Q

What is the rAAV alpha-synuclein overpexpression model?

A
  • Viral vector delivers alpha-synuclein (WT or mutated) to DA neurons —> Increased alpha-synuclein expression
  • Causes deficit in motor behaviour, decreased dopaminergic striatal terminals and cell bodies, progressive model (wait 6 months)
382
Q

What is the injection of pre-formed fibrils of alpha-synuclein model?

A
  • Stereotactic injection —> taken up by striatal injections —> Lewy Bodies
  • Oligomeric alpha-syn is toxic, inclusions spread over time, 30% nigrostriatal DA cell loss BUT no behavioural deficit
  • Injections of Protofibrils in SNc or gut mirrors spread of altered proteins in similar pattern to PD - Braak hypothesis
383
Q

What is the LRRK2 Transgenic Mice?

A
  • Cell death in Neuroblastoma cells and mouse cortical neurons
  • Movement dysfunction, abnormal proteins, no neuronal loss in SNc —> +MPTP to induce stress/neurodegeneration - is this PD?
  • Animal models can cope with slight genetic change due to lack of stress compared with humans
384
Q

What is the MitoPark Mouse model?

A
  • Increase in age leads to increase in mtDNA mutations, mitochondrial transcription factor A regulated mtDNA transcription
  • Tfam KO mice —> mitochondrial respiratory chain deficiency in DA neurons —> Decreased ATP —> neuronal loss
  • PD Features: Adult-onset progressive decrease in motor function - loss of DA neurons - loss of Str DA - Intraneuronal inclusions
385
Q

How are induced Pluripotent Stem cells used to model PD?

A
  • Dopaminergic neurons (‘Disease in a dish’) - carry the same mutations
386
Q

How can Gait be tested in PD animal models?

A
  • Forepaw reaching behaviour
  • Amphetamine-induced rotational assessment
  • Walking on a beam (number of falls recorded)
387
Q

Describe forepaw reaching behaviour

A
  • Measure R and L paw use in Perspex cylinder for Push off, Exploration, Landing
  • Unilateral lesion: asymmetry in paw use
388
Q

Describe the Amphetamine-induced rotational assessment

A
  • unilateral DA release (inhibition on intact side) - turn TOWARDS
  • Asymmetry causes animals to walk in circles
  • Number of turns correlates with size of lesions
389
Q

How can cognitive dysfunction be tested in PD animal models?

A
  • Using learning paradigms
390
Q

Critically evaluate the use of animals in PD modelling

A
  • PD can results in many motor and non-motor symptoms - cannot mirror all these symptoms, can only mirror certain processes
391
Q

What is an example of a drug which has been developed for PD?

A
  • Deferiprone (iron chelator)
  • PD have increased iron in SNc (iron redox —> ROS)
  • Animal model (Ferrocene deposits iron globally, not just SNc like PD)
  • Animal models show iron chelators to be neuroprotective

NMH BSc (7 decks)

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