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

Question

How does inflammation play a part in stroke?

Answer 1

- 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)

Answer 2

- 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)

Answer 3

- 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

Answer 4

- 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.

Answer 5

- 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)

Answer 6

- 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.

Answer 7

- 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

Answer 8

- 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

Answer 9

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

Answer 10

Artery: - Acute Ischaemic Stroke (AIS) - Lacunar Venous: - Cerebral Venous Sinus Thrombosis (CVST)

Answer 11

Artery: - Aneurysm - AVM - Primary Intracerebral Haemorrhage (PICH) - Extradural haemorrhage Venous: - Subdural haemorrhage - Cerebral Venous Sinus Thrombosis (CVST) - Cavernoma

Answer 12

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

Answer 13

- Thromboembolism - Hypoperfusion - Lacunar infarction (Causes include aging, diabetes, hypertension)

Answer 14

Acute Syndromes: - Pure motor - Pure sensory - Ataxia-hemiparesis - Dysarthria- clumsy hand

Answer 15

Chronic Syndromes: - Executive cognitive impairment, bradyphrenia - Lower body parkinsonism, gait apraxia

Answer 16

MCA, ACA, PCA and brainstem infarction

Answer 17

- Blockage of main branch (horizontal M1 ---> wedge infarction) - Blockage of Lenticulostriate arteries (end-arteries)

Answer 18

- Affects medial Brain ---> contralateral leg weakness

Answer 19

- Affects Occipital cortex ----> Homonymous hemianopia, Neglect

Answer 20

- E.g. PICA infarct ---> Contralateral limb symptoms, Ipsilateral Cranial Nerve symptoms

Answer 21

- Stroke ---> Increased ICP ---> Midline shift ---> Coning ---> Respiratory depression - Tx: Hemi-craniectomy ---> relieve pressure ---> 50% survive

Answer 22

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

Answer 23

- Herniation ---> Respiratory depression - Pneumonia (inability to swallow/cough) - PE (bedbound/VT)

Answer 24

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

Answer 25

- Affects 2.5 million people worldwide | - Female > Male (2:1)

Answer 26

- Latitude Effect - Time of exposure - Viral hypothesis - Genetic factors - Role of hormones

Answer 27

- 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

Answer 28

- 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)

Answer 29

- 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

Answer 30

- 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

Answer 31

- During pregnancy ---> Decreased MS relapses - Post-partum ---> Increased MS relapses PRIMS study

Answer 32

- 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

Answer 33

- Insidious onset of irreversible accumulation of neurological deficit >1yr (Retrospective Dx)

Answer 34

- 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)

Answer 35

- Secondary progressive MS - Shift RR MS (inflammation) ---> SP MS (degeneration) - 10 years from disease onset - Increased irreversible disability

Answer 36

- Primary progressive MS (20% of MS) - Disease starts with progression - Progressive paraparesis - 40% have superimposed paralysis

Answer 37

- 1st MS-like attack | - No DIT for clinically definite MS

Answer 38

- 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

Answer 39

- 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)

Answer 40

- 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

Answer 41

- 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)

Answer 42

- 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

Answer 43

- ADEM (Acute disseminated encephalomyelitis) | - NMO (Neuromyelitis optica

Answer 44

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

Answer 45

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

Answer 46

- 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)

Answer 47

Poor prognostic factors: - Older age of onset - PP MS - Early relapses - MRI lesion load - Male

Answer 48

- Focal: Fractures | Contusions | Haemorrhage ---> CT/MRI | - Diffuse: Diffuse Axonal Injury | Diffuse Vascular Injury ---> "Advanced MRI"

Answer 49

- 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

Answer 50

- Fast - Cheap - Better than MRI for bony abnormalities - Useful for imaging Acute bleeds and fractures

Answer 51

- Poor resolution | - Can't see subtle changes in brain structure

Answer 52

- Large magnet aligns all protons, 2nd RF misaligns protons which relax to original position releasing energy which is detected

Answer 53

- Good tissue discrimination - Dark CSF - Bright fat dark lesions

Answer 54

- Sensitive to water (oedema) - Bright CSF - Dark fat bright lesions

Answer 55

- Sensitive to water (oedema) - Dark CSF - Dark fat bright lesions

Answer 56

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

Answer 57

- 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

Answer 58

- 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)

Answer 59

- Creutzfeldt-Jacob Disease - Gerstmann-Straussler-Sheinker Syndrome - Fatal familial insomnia

Answer 60

- Scrapie - Bovine Spongiform Encephalopathy - Feline Spongiform Encephalopathy - Chronic Wasting Disease - Transmissible Mink Encephalopathy

Answer 61

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

Answer 62

- 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

Answer 63

- Progressive dementia - Ataxia - EEG changes - Death within one year - Biopsy/Autopsy for Dx

Answer 64

Can be caused by - GH (extracted from cadaveric pituitatries) - Dural transplant - Neurosurgery - Slow incubation period

Answer 65

(Genetic version of CJD) - Autosomal dominant - Progressive dementia - Mild phenotype (4-5 years)

Answer 66

- Autosomal dominant - Sleep disturbances - Neuropsychiatric presentation (tiredness, psychoses) - Late dementia

Answer 67

- Normal cellular protein , PrPc - Expressed in neurons and glia - Chromosome 20 - Membrane associated - Unknown function

Answer 68

- 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

Answer 69

- 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

Answer 70

- 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)

Answer 71

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)

Answer 72

- 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

Answer 73

- Type 1 = 20kDa band predominant - Type 2 = 19kDa band predominant - A = A band (monoglycosylated 25kDa) predominant - B = B band (19kDa band predominant)

Answer 74

- 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

Answer 75

- 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)

Answer 76

1) & 2) Beekes et al., FEBS, 2007, 274; 588-605 | 3) Frost B & Diamond MI (2010) Nat Rev Neurosci 11 155-159

Answer 77

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

Answer 78

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

Answer 79

- 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

Answer 80

- Non-missile - Missile - Focal or Diffuse

Answer 81

- Acceleration/deceleration - Rotation force (midline structures vulnerable) - RTA, falls, assaults

Answer 82

- Acceleration/deceleration - Rotation forces (midline structures vulnerable) - RTA, Falls, Assaults

Answer 83

- Conflict-related

Answer 84

- Fractures - Contusions - Haemorrhage ---> CT/MRI

Answer 85

- Diffuse Axonal Injury | - Diffuse Vascular Injury ---> Advanced MRI

Answer 86

- Damage that has occurred, cannot be changed | - Depends on cause, type, location, age, drugs, pre-existing disease, genetics

Answer 87

- 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

Answer 88

- Base of skull fracture ---> CSF leakage ---> Otorrhea/Rhinorrhoea, Battle's sign/Racoon's eyes

Answer 89

High risk areas: - Orbitofrontal cortex - Temporal lobe - Occipital lobe - Inferior surface of the brain - Coup-contrecoup damage associated with acceleration/deceleration injury

Answer 90

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

Answer 91

- 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

Answer 92

- Tear of axolemma ---> Ca2+ influx ---> activate proteases ---> cytoskeletal dysfunction ---> disconnect

Answer 93

- Rupture ---> membrane sealing (imperfect stabilisation) ---> highly susceptible to secondary insult (rugby)

Answer 94

- Shearing forces ---> Axotomy ---> Stops normal axonal transport ---> Build-up of toxic proteins within the Axon

Answer 95

- Immunostaining for APP (undergoes axonal transporter, marker of axonal damage) or Silver staining

Answer 96

- Ischaemia/Hypoxia - Cerebral swelling - Infection (if open head injury) - Seizure (Glutamate excitotoxicity)

Answer 97

- 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

Answer 98

- Subfalcine herniation (under falx cerebri) - Tentorial herniation (under tentorium cerebelli) - Tonsillar herniation (cerebella tonsils under foramen magnum) - Coning (brainstem into foramen magnum)

Answer 99

(Similar to ischaemic damage in Stroke Lectures) - Neurodegeneration: acute head injury may initiate protective response, if chronic, may cause neurodegeneration

Answer 100

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

Answer 101

- 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

Answer 102

- 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?

Answer 103

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

Answer 104

- 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

Answer 105

- 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

Answer 106

- Visualises Tau pathology in vivo (useful for CTE and AD) | - A beta is less relevant for CTE

Answer 107

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

Answer 108

- Age-related Tau-Astrogliopathy - ARTAG has no clinical phenotype - Age-related Tau pathology in Astrocytes - ARTAG confounds CTE

Answer 109

- Need longitudinal studies to follow progression of retired sportsman to assess cognitive capacity and imaging changes

Answer 110

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

Answer 111

- Education and counselling - Management of acute attacks - Prevention of disease activity (disease modifying treatments) - Symptomatic therapy - Physical therapy - Treatment of complications

Answer 112

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

Answer 113

- 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

Answer 114

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

Answer 115

- IFN-beta | - Glatiramer acetate

Answer 116

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

Answer 117

ADVANCE trial - RRMS: 30% Decrease in ARR ? delay progression - CIS: delay 2nd episode

Answer 118

- yes - Injection site infection - Flu-like Sx

Answer 119

- 1st line active MS | - 1st DMT available for RRMS

Answer 120

- Decoy effect | Resembles MBP

Answer 121

- RRMS: 30% Decrease in ARR

Answer 122

- 1st line active MS | - Only DMT for emergency

Answer 123

- Fingolimod | - Dimethyl fumerate

Answer 124

- Prevents T cells leaving lymph nodes (Decreased T cell sensitivity to chemotactic cues) (S1P1 receptor agonist ---> S1P1 receptor internalisation)

Answer 125

TRANSFORM trial - 50% decrease in ARR vs IFN-beta FREEDOM trial - 50% decrease in ARR vs placebo - Decreased disability progression

Answer 126

- Increased infections - Lymphopaenia - Bradycardia

Answer 127

- For highly active MS | - 1st oral DMT for RRMS

Answer 128

- Decreasd pro-inflammatory cytokine production

Answer 129

DEFINE - 50% decrease in ARR vs placebo - Decreased disability progression - Decreased MRI lesions

Answer 130

- Safer than Fingolimod S/E - Flushing - GI S/E

Answer 131

- 1st line active MS | - 1st oral drug offered as 1st line (choice)

Answer 132

- Natalizumab - Alemtuzumab - Ocrelizumab

Answer 133

- Decreased transmigration | block VLA-4 & VCAM-1 interaction

Answer 134

AFFIRM - 70% decrease in ARR vs placebo - Decreased disease progression - Decreased MRI lesions (90%)

Answer 135

Rare S/E - Herpes - PML (4 in 1000) - 20% mortality - rapid decreased cognition

Answer 136

- For highly active MS

Answer 137

- Depletes T and B cells | - Immune population rebuilds

Answer 138

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)

Answer 139

- Opportunistic infections | - Autoimmunity (50% Graves' in 5 years)

Answer 140

- 1st line active MS | - 2x injections

Answer 141

- Targets CD20+ B cells

Answer 142

OPERA - 50% decrease in ARR vs IFN-beta - PPMS: 25% decrease in disability progression vs Placebo

Answer 143

- 1st line active MS | - PPMS: 1st DMT for PPMS

Answer 144

- Harvest stem cells - Immunosuppression - Repopulate with stem cells - Atkins, 2006: n = 24 had no further disease

Answer 145

- Unpredictable attacks which may or may not leave permanent deficits followed by remission

Answer 146

- Steady increase in disability without attacks

Answer 147

- Initial relapse-remitting MS that suddenly begins to decline without periods of remission

Answer 148

- Steady decline since onset with super-imposed attacks

Answer 149

- 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?

Answer 150

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

Answer 151

- CD4 and CD8 T-Cells | - CD20 B-Cells

Answer 152

- 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

Answer 153

- By-stander effect | - Autoimmune-mediated degradation of myelin sheath and oligodendrocytes

Answer 154

- 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

Answer 155

- Macrophage-mediated - Presence of anti-myelin antibodies against multiple antigens (MOG, MBP...) - Epitope spreading ---> oligoclonal bands - Complement activatio

Answer 156

- 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

Answer 157

- 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

Answer 158

- 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

Answer 159

- Inflammation can be resolved, remyelination can be repaired but axon and neuronal loss is irreversible - Irreversible but there is spare capacity

Answer 160

- 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

Answer 161

- 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

Answer 162

- Positive correlation

Answer 163

- 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

Answer 164

- 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

Answer 165

- 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)

Answer 166

- 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

Answer 167

- Abnormal synchronised discharge of neurones

Answer 168

- Distance between electrodes within 10-20% of AP and lateral dimensions of skull

Answer 169

- Synchronised discharge of set of cerebral neurons ---> Na+ influx ---> Sudden depletion in Na+ ions ---> EEG -ve deflection

Answer 170

- Many layers of scalp diminish signal - Bell's reflex (blinking artefact) - Scalp muscles give artefact

Answer 171

- Spike and slow wave | - Normal variation: sharp transient (commonly misdiagnosed as epilepsy)

Answer 172

- 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%

Answer 173

1000 deaths per year in UK due to - SUDEP - Status epilepticus (seizures fail to self-resolve ---> can't breathe ---> hypoxia) - LOC ---> Drowning

Answer 174

- Genetic disposition (normal brain with no obvious cause e.g. idiopathic) - Secondary to Brain Injury

Answer 175

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)

Answer 176

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)

Answer 177

- 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)

Answer 178

Focal epilepsy = Localised, synchronised discharge on part of the brain - Simple Partial (no LOC) - Complex Partial (with LOC) - Secondary Generalised (Partial ---> Generalised)

Answer 179

- 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

Answer 180

- Increased GABA inhibition - Decreased Glutamate mediation - Decreased voltage-gated Na+ channel activity - Decreased voltage-gated Ca2+ channel activity

Answer 181

- 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

Answer 182

- Presynaptic: Levetiracetam binds to presynaptic vesicle protein SV2A ---> Decreased exocytosis - Postsynaptic: Parampanel: AMPA receptor antagonist, Felbamate: NMDA receptor antagonist

Answer 183

- Phenytoin, Carbamazepine, Valproate | - Use-dependent blockage (only blocks during seizures, minimises S/E)

Answer 184

- Inhibits alpha2-beta subunit of Ca2+ channel ---> decreased Ca2+ influx ---> Decreased exocytosis

Answer 185

- Bradykinesia - Rigidity - Rest tremor - Response to L-dopa

Answer 186

- Idiopathic PD - Drug-induced PD - MSA - PSP - CBD - FTLD

Answer 187

- Parkinsonism-type (MSA-P) | - Cerebellar type (MSA-C)

Answer 188

- Cortical atrophy - Cerebellar atrophy - Pallor of locus coerulus - Pallor of SN

Answer 189

- Mixed neuronal and glia alpha-synuclein pathology | - Papp-Lantos bodies (Olig inclusions of alpha-syn)

Answer 190

- Cerebellar signs, PD Sx

Answer 191

- Alien limb phenomenon - Taupathy - PD Sx

Answer 192

- Fronto-parietal atrophy - Deep cerebellar nuclei affected - SN affected

Answer 193

- Mixed neuronal and glial pathology - Astrocytic plaques (tau in astrocytes) - Balloon Neurons (enlarged neurons with tau)

Answer 194

- Tauopathy | - Supranuclear gaze palsy (lack of vertical eye movement)

Answer 195

- Atrophy of basal ganglia, subthalamic nucleus and brainstem - Neuronal loss - Reactive gliosis

Answer 196

- Neuronal and glial Tau +ve inclusion - Tufted astrocytes (many processes) - Coiled bodies (Oligoinclusions of Tau)

Answer 197

- 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)

Answer 198

- 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

Answer 199

- Biomarkers | - Imaging

Answer 200

- 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

Answer 201

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

Answer 202

- Autoreactive T and B cells reacting to an unknown antigen

Answer 203

- Perivascular infiltrates - Axonal damage - Neurodegeneration

Answer 204

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

Answer 205

- Perivascular and meningeal locations | - Isolate B cells in parenchyma (active) or perivascular (chronic)

Answer 206

- 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

Answer 207

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

Answer 208

- Myelin basic protein (MBP) - Proteolipid protein (PLP) - MOG

Answer 209

- CD4 Th1 | - CD4 Th17

Answer 210

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)

Answer 211

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)

Answer 212

- CD4 Th2 | - CD4 Treg

Answer 213

BOTH ANTI-INFLAMMATORY CELLS: Induces M2 microglia ---> Maintain tolerance in the CNS - Th2 secretes anti-inflammatory cytokines (IL-4, IL-5, IL-13)

Answer 214

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

Answer 215

- 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

Answer 216

- 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

Answer 217

- 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

Answer 218

- Macrophages produce ROS ---> axonal damage | - Microglia primedto M1 (pro-inflammatory) or M2 (anti-inflammatory)

Answer 219

- 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)

Answer 220

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

Answer 221

- 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

Answer 222

- 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

Answer 223

- 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

Answer 224

- CSF oligoclonal bands in >90% MS cases | Increased leukocytes, Increased CSF protein

Answer 225

- Increased freq of T cells responding to myelin antigens | Decreased Treg activity (to autoreactive T cells)

Answer 226

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

Answer 227

- 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

Answer 228

- Bradykinesia - Tremor - Postural instability - Rigidity

Answer 229

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

Answer 230

- Clinical syndrome with some or all of these clinical features: - Bradykinesia - Tremor - Postural instability - Rigidity

Answer 231

- Disorders in which Parkinsonism is a prominent feature = akinetic-rigid disorders

Answer 232

- In the caudate/putamen of PD patients dopamine concentrations were only 10% of those found in controls

Answer 233

- 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

Answer 234

- 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

Answer 235

- SN | - Akinetic-rigid syndrome

Answer 236

- SN, cerebral cortex | - Dementia more than one year after PD Dx

Answer 237

- SN, cerebral cortex | - Dementia less than one year after akinetic-rigid syndrome

Answer 238

- Sympathetic neurons in the spinal cord | - Autonomic failure

Answer 239

- Dorsal vagal nucleus | - Dysphagia

Answer 240

- 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.

Answer 241

- 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

Answer 242

- 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

Answer 243

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

Answer 244

- 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

Answer 245

- 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

Answer 246

- 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

Answer 247

- alpha-synuclein proximity ligation assay

Answer 248

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

Answer 249

- New cases per annum: roughly 2/100,00 per year | - M > F

Answer 250

- 5/8 per 100,000

Answer 251

- M: 1 in 350 | - F: 1 in 472

Answer 252

- 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

Answer 253

- 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

Answer 254

- 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')

Answer 255

- Muscle biopsy | - Electromyogram (nerve conduction test)

Answer 256

- muscle weakness - wasting - fasciculations - cramps

Answer 257

- stiffness and slowness of movement - slow and clumsy speech - Babinski signs are often present

Answer 258

- Effects on UMNs predominate, spasticity, hyperreflexia, surivial is 20 years

Answer 259

- 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

Answer 260

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

Answer 261

- 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*

Answer 262

- ~97% ALS cases (Familial ALS and Sporadic ALS) | - ~50% FTD (familial and sporadic, FTLD-TDP)

Answer 263

- SOD1 - TARDBP - FUS - c9ORF72 - Abnormalities in RNA binding proteins, proteostasis, cytoskeletal proteins

Answer 264

- 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

Answer 265

- 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).

Answer 266

- Repressor - Exon skipping Binds to CFTR pre mRNA UG intronic tract

Answer 267

- ACTIVATOR nuclear hormone receptors, NFkB. (RNA polymerase complex) - Part of spliceosome machinery

Answer 268

- 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

Answer 269

- 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)

Answer 270

- 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

Answer 271

- Nuclear proteins (TDP-43 and FUS) that mislocalise to the cytosol TARDBP, FUS, ageing ---> - TDP-43+ve/FUS+ve - Ubiquitinated protein aggregates ---> - Neurodegeneration

Answer 272

- Chromosome 9p locus

Answer 273

- 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

Answer 274

- 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)

Answer 275

- 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)

Answer 276

- Inconsistent results from biological studies and low sample number/ restricted number of anatomical regions/ limited antibody use

Answer 277

- 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

Answer 278

- 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

Answer 279

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

Answer 280

- 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)

Answer 281

- 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

Answer 282

- 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

Answer 283

- 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

Answer 284

- 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

Answer 285

- TANK-binding Kinase 1 (TBK1)

Answer 286

- 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

Answer 287

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

Answer 288

- 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

Answer 289

- 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

Answer 290

- Edavarone | - A free radical scavenger in stroke

Answer 291

- 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

Answer 292

- 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.

Answer 293

- 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.

Answer 294

- Mainly frontal synptoms - Visuospatial symptoms - Hallucinations

Answer 295

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

Answer 296

- Dopamine - Acetycholine - Excitatory amino acids (Serotonin, NA, Adenosine, Opioids)

Answer 297

- 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)

Answer 298

- 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)

Answer 299

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

Answer 300

- Indirect agonists - Direct dopamine agonists - Enzyme blockers

Answer 301

- 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

Answer 302

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

Answer 303

- DOPA decarboxylase inhibitor: Sinemet - MAO inhibitor: Selegiline - COMT inhibitor: Entacapone

Answer 304

- Anticholinergics - Cell therapy Fetal Cell Transplant: extracting dopaminergic neurons from aborted foetuses and transplant into striatum

Answer 305

- 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

Answer 306

- 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

Answer 307

- Oxidative stress - Ubiquitin-Proteasome dysfunction - Neuroinflammation - Mit. dysfunction

Answer 308

- 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

Answer 309

- 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)

Answer 310

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

Answer 311

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

Answer 312

- 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

Answer 313

- 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

Answer 314

- Nurr1 regulates NT identify of neuron | - Nurr1 deficiency ---> DA neurons cannot produce dopamine (Le WD)

Answer 315

- Involved in late-stage DA neuron development | - Heterozygote FoxA2 (+/-) mice ---> unilateral Da neuron degeneration (Ferri ALM)

Answer 316

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

Answer 317

- 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

Answer 318

- 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

Answer 319

- 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

Answer 320

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

Answer 321

- 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

Answer 322

- 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

Answer 323

- SNCA - LRRK2 - Parkin - PINK-1 - DJ-1

Answer 324

- 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

Answer 325

- 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

Answer 326

- Ubiquitin E3 ligase | - Role in Mitophagy

Answer 327

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

Answer 328

- Protein chaperone - Protects cells from oxidative stress - Stabilises mit. membrane potential - DJ-1 mutation ---> PINK1 marks mit.

Answer 329

- 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

Answer 330

- 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

Answer 331

- Familial PD ---> Very rare, high risk (SNCA) | - idio PD ---> Rare, medium risk (LRRK2) or Common, low risk (SNPs)

Answer 332

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

Answer 333

- 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

Answer 334

- 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?

Answer 335

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

Answer 336

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

Answer 337

- Motor symptoms | - Cognitive impairment

Answer 338

- 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

Answer 339

- DNA Methylation - Physical blockage of DNA - Long-term repression

Answer 340

- Short-term repression, methylation/acetylation ---> Increased electrostatic repulsion of histones ---> Increased transcription factor accessibility ---> gene expression

Answer 341

- 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

Answer 342

- Misfolded alpha-synuclein enters nucleus ---> binds to histone H3 --> supresses gene expression

Answer 343

- HDAC inhibition

Answer 344

- General inhibition of HDACs (Class I & II)

Answer 345

- 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

Answer 346

- 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

Answer 347

- 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

Answer 348

- 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

Answer 349

- 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

Answer 350

- Proteasome inhibitor ---> Increased build up of abnormal/altered proteins ---> Protein inclusions ---> cell death - Systemic administration however not very reproducible model

Answer 351

- Manganese (mining ore) - Carbon disulphide (rubber processing) - Cycad seeds (toxic seeds from Guam)

Answer 352

- 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

Answer 353

- 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

Answer 354

- 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)

Answer 355

- 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

Answer 356

- 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

Answer 357

- 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

Answer 358

- Dopaminergic neurons ('Disease in a dish') - carry the same mutations

Answer 359

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

Answer 360

- Measure R and L paw use in Perspex cylinder for Push off, Exploration, Landing - Unilateral lesion: asymmetry in paw use

Answer 361

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

Answer 362

- Using learning paradigms

Answer 363

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

Answer 364

- 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