Review of Lectures 1–4: CNS Injury, Neurodegeneration, Diabetes & Cancer – Exam Prep Notes

Exam Logistics & Strategy

  • Session details

    • Date & time: Next Tuesday at 03:10 PM (normal lecture slot)

    • Venue: LG 04 (all semester tests & final exam will use this room)

    • Format: In-person, closed-book, 1 hour, 7 medium-answer questions

    • ≈2 questions drawn from each of the four lecture topics

    • Plan ~8–9 min/question (half-page answers on average)

  • Preparation tips

    • Read the wording carefully; only answer what is asked

    • Depth proportional to mark value & time—do not write multi-page essays

    • Use abbreviations (e.g. CSPG, TBI) to save time; full expansions not required

    • Bring student ID; if illness occurs, obtain medical certificate to request special consideration

Example Question Types (from tutorial)

  • Describe the physiological sequence when blood glucose rises

  • Propose a disease-modifying therapy for Alzheimer’s and explain its rationale

  • Define a Lewy body and state its origin

  • Explain the stroke penumbra and its therapeutic relevance

  • (Cisplatin example was illustrative; not examinable this test)

Common Themes Across Lectures

  • Identify primary injury/cause ➜ cellular & molecular cascades ➜ clinical sequelae ➜ therapeutic targets

  • Focus on mechanism first; symptom control second

  • Disease-modifying vs symptomatic therapies—be able to distinguish

Basic Neurobiology Refresher

  • Neuron anatomy

    • Cell body (soma + nucleus)

    • Dendrites (input), axon (output), myelin sheaths with Nodes of Ranvier

    • Axon terminals form chemical synapses with post-synaptic dendrites

  • Gray vs white matter

    • Gray = neuronal cell bodies (cortex, nuclei)

    • White = myelinated axon tracts (fat-rich, lower density)

  • Synaptic transmission: neurotransmitter release, receptor binding, downstream signalling

Lecture 1 – CNS Injury

Traumatic Brain Injury (TBI)

  • Definition: External mechanical force → disruption of brain function/structure

  • Mechanisms

    • Direct impact (head hits object / object hits head)

    • Acceleration–deceleration (e.g. whiplash); rotational component worsens injury

    • Blast waves (military/industrial) → density mismatch damage

  • Pathology

    • Diffuse axonal injury: stretching/tearing of axons at gray–white interface

    • Microtubule disruption; delayed repair if axon not transected

    • Possible vascular rupture → haematoma → raised intracranial pressure (ICP)

  • Acute management

    • Decompressive craniotomy or burr-hole drain for ICP

  • Clinical spectrum

    • Concussion = mild TBI with transient neurological dysfunction (no massive focal necrosis)

    • Moderate/severe TBI shows focal contusions, necrosis, long-term deficits

Spinal Cord Injury (SCI)

  • Injury types

    • Transection (dislocation, penetrating trauma)

    • Compression (tumour, disc, fracture fragments)

    • Contusion (blunt impact)

  • Level matters

    • Cervical → quadriplegia ⬄ Lumbar → paraplegia; thoracic affects trunk/legs ± hands

  • Complete vs incomplete lesions depending on spared white-matter tracts

Stroke

  • Interruption of cerebral blood flow → energy failure

  • Time course at single-cell level

    • <30\text{ s} altered metabolism → <2\text{ min} metabolic arrest → <5\text{ min} necrotic death

  • Core vs Penumbra

    • Core: rapid necrosis, irreversible

    • Penumbra: hypo-perfused, apoptotic death over ~72 h72\text{ h}; salvageable

  • Stroke sub-types

    • Ischemic (≈85 %)

    • Thrombotic: in-situ atherosclerotic plaque rupture/occlusion

    • Embolic: clot from heart/carotids travels & lodges distally

    • Transient Ischemic Attack (TIA): micro-emboli, deficits <24 h, warning sign

    • Hemorrhagic (≈15 %): rupture (e.g. aneurysm) → intracerebral or subarachnoid bleed

  • Reperfusion therapy

    • tPA (tissue plasminogen activator) within ≈3 h\approx 3\text{ h}—beyond that risk of reperfusion injury outweighs benefit

  • Lateralisation

    • Left hemisphere lesion → right-sided weakness, aphasia

    • Right hemisphere lesion → left-sided weakness, spatial neglect

Shared Barriers to CNS Repair

  • Neurons do not divide (except limited SVZ/hippocampus) – lost circuitry hard to recreate

  • Axons fail to regenerate due to

    • Intrinsic gene silencing (growth-associated genes OFF; inhibitors like PTEN,  SOX 3\text{PTEN},\;\text{SOX 3} ON)

    • Extrinsic inhibition

    • Myelin-associated ligands (NoGo-A, MAG, OMgp) bind axonal NgR/TROY/p75/LINGO\text{NgR}/\text{TROY}/\text{p75}/\text{LINGO} → RhoA→ROCK\text{RhoA}\to\text{ROCK} → cytoskeletal collapse

    • Reactive astrocyte CSPGs bind PTPσ\text{PTPσ} & NgR

  • Therapeutic avenues

    • Neuroprotection (antioxidants, anti-apoptotics)

    • Revascularisation (tPA, mechanical thrombectomy)

    • ROCK inhibitors, decoy receptors, gene editing to remove PTEN, etc.

    • Cell replacement (oligodendrocyte re-myelination, neural stem cells)

Lecture 2 – Neurodegenerative Diseases

Alzheimer’s Disease (AD)

  • Key pathologies

    • Extracellular Aβ-42 plaques (β + γ secretase cleavage of APP)

    • Intracellular hyper-phosphorylated Tau → neurofibrillary tangles

    • Basal forebrain cholinergic deficit

  • Interactions: Aβ accumulation may trigger Tau phosphorylation cascades (e.g. via kinases activated by chronic stress ➜ CRF-R1)

  • Therapies

    • Symptomatic: cholinesterase inhibitors ↑ACh, memantine (NMDA modulator)

    • Disease-modifying: monoclonal antibodies against Aβ (FDA-approved), anti-Tau immunotherapy (in trials)

Parkinson’s Disease (PD)

  • Pathology

    • Loss of dopaminergic neurons in substantia nigra pars compacta → ↓dopamine in striatum (basal ganglia loop)

    • Lewy bodies = α-synuclein aggregates; also cause Parkinson’s dementia

  • Treatments

    • Symptomatic: levodopa (crosses BBB, decarboxylated), dopamine agonists, MAO-B/COMT inhibitors, deep-brain stimulation

    • Disease-modifying (experimental):

    • Immunotherapy vs α-synuclein

    • Cell replacement: fetal or autologous iPSC-derived dopaminergic grafts

Huntington’s Disease (HD)

  • Genetics: autosomal dominant CAG repeat expansion in HTT gene → poly-glutamine mutant huntingtin (mHTT)

    • Repeat length correlates with earlier onset & severity

  • Cellular toxicity

    • mHTT forms intranuclear inclusions ➜ sequesters transcription factors ➜ widespread transcriptional dysregulation

  • Clinical: chorea, psychiatric changes, cognitive decline

  • Experimental therapies

    • Transcriptional re-activation (HDAC inhibitors)

    • Gene silencing: antisense oligos, RNAi, CRISPR editing targeting mHTT

Lecture 3 – Diabetes Mellitus

  • Glucose homeostasis (healthy state)

    1. ↑Blood glucose sensed by pancreatic β-cells

    2. Glucose enters via GLUT2 ➜ glycolysis/oxidative phosphorylation ➜ ↑ATP/ADP\text{ATP/ADP}

    3. ATP closes KATPK_{ATP} channel ➜ membrane depolarisation

    4. Voltage-gated Ca2+Ca^{2+} influx ➜ exocytosis of insulin

    5. Insulin binds receptor on muscle/fat/liver ➜ PI3K → translocation of GLUT4 ➜ cellular glucose uptake, glycogenesis, lipogenesis

  • Pathological types

    • Type 1: autoimmune β-cell destruction ➜ absolute insulin deficiency

    • Type 2: insulin resistance ± β-cell dysfunction

  • Complications: micro- (retinopathy, nephropathy, neuropathy) & macro-vascular (MI, stroke)

  • Therapies

    • Lifestyle, exogenous insulin, metformin, GLP-1 analogues (e.g. exenatide—being tested for PD but trial negative), SGLT2 inhibitors, etc.

Lecture 4 – Cancer (overview only for this test)

  • Cisplatin example (not assessed)

    • Platinum-based chemotherapeutic → DNA cross-links in rapidly dividing tumour cells

  • General principles discussed by guest lecturer Linda

    • Hallmarks of cancer (self-sufficiency in growth signals, evading apoptosis, angiogenesis, etc.)

    • Targeted vs cytotoxic chemotherapy, immunotherapy, molecular diagnostics

Study Checklist

  • Master learning outcomes

    • Pathological features of TBI, stroke, SCI

    • Basic neuronal unit & synapse

    • Mechanistic commonalities & shared therapeutic targets

  • Be able to sketch/label

    • Neuron with major compartments

    • Stroke core + penumbra, brain cross-section (gray/white)

    • Basal ganglia circuit showing SNpc→striatum (PD)

  • Memorise key numbers

    • Neuron death: 30 s metabolism change, 2 min stop, 5 min necrosis

    • Stroke tPA window ≈ 3 h, penumbra salvage ≤ 72 h

  • Terminology quick-fire

    • DAI, ICP, TIA, CSPG, NgR, RAGs, Aβ-42, Tau, Lewy body, mHTT, GLUT4, KATPK_{ATP}

  • Understand disease-modifying vs symptomatic treatments and be ready to give clear examples

Good luck—arrive early, bring pens, concise handwriting, and prioritise mechanism + therapy links for full marks.