Neurodegenerative Diseases Practice Flashcards

Alzheimer's Disease: Anatomy, Pathophysiology, and Memory Systems

• Relevant Anatomy for Memory Processing:

  • Dynamic Loop of the Limbic System: The creation and maintenance of long-term memories depend on a core backbone consisting of the Hippocampus, Hypothalamus, and Thalamus.

  • Hippocampus (The Encoder & Indexer): This structure is responsible for Long-Term Potentiation (LTP). LTP is a process where repeated neural firing strengthens synaptic connections, facilitating the conversion of short-term neural activity into lasting structural changes.

  • Hypothalamus (Mammillary Bodies - The Relay Point): These bodies receive signals directly from the hippocampus through a nerve tract known as the fornix. They act as a critical relay hub, sending information to the thalamus.

  • Thalamus (The Central Router & Gating Unit): This unit filters and directs incoming signals between subcortical structures and the cerebral cortex. It helps direct focused attention to ensure relevant details are highlighted for long-term encoding.

• Memory Consolidation Process:

  • Temporary Storage: Newly formed memories are fragile and live in the hippocampus for days to months.

  • Cortex Hand-off: During deep sleep (specifically slow-wave sleep), the hippocampus replays firing patterns through the Papez loop to the neocortex.

  • Permanent Storage: Over time, synaptic connections across the cortex strengthen, allowing the neocortex to reconstruct memories independently of the hippocampus.

• Pathophysiology and Misfolded Proteins:

  • Amyloid-Beta ($A\beta$) Plaques: These are clusters of protein fragments ($A\beta_{1-42}$, $A\beta_{1-40}$) that accumulate outside neurons (extracellular). They block synaptic transmission and trigger localized neuroinflammation via microglia activation.

  • Neurofibrillary Tangles (Tau): Twisted fibers of tau protein that accumulate inside neurons (intracellular). Tau normally provides structural scaffolding for internal transport; its collapse into tangles causes the neuron to lose its supply line and starve.

  • Anatomical Progression: Tau pathology specifically targets the entorhinal cortex (the main doorway to the hippocampus) before spreading to the hippocampus itself. As these neurons die, the fornix (nerve fiber tract) degenerates, leading to the atrophy of the mammillary bodies and the thalamus due to deafferentation (loss of incoming signals).

  • Extreme Brain Changes: AD results in extreme shrinkage of the cerebral cortex, extreme shrinkage of the hippocampus, and severely enlarged ventricles.

• Biochemical Signaling and Hypotheses:

  • Cholinergic Hypothesis: AD severely damages the basal forebrain (specifically the Nucleus Basalis of Meynert), the primary producer of Acetylcholine (ACh). ACh acts as a "chemical lubricant" for synaptic plasticity; low levels make neurons less efficient at communicating.

  • Glutamate Excitotoxicity Hypothesis: Overstimulation of NMDA receptors (NMDAR) by glutamate leads to intracellular calcium ($Ca^{2+}$) dyshomeostasis, resulting in mitochondrial dysfunction, increase of Reactive Oxygen Species (ROS), and cell death.

  • Metal Ion and Oxidative Stress Hypothesis: Overload of metals like $Fe$, $Pb$, $Mn$, $Cd$, $Cu$, $Al$, and $Zn$ contributes to ROS and oxidative stress.

  • Autophagy Hypothesis: Abnormalities in the initiation, nucleation, and maturation of the autolysosome lead to impaired clearance of pathological protein aggregates.

• Treatment Overview for Alzheimer's:

  • Monoclonal Antibodies (Lecanemab, Donanemab): First-line Disease-Modifying Therapy (DMT) for Mild Cognitive Impairment or early AD. They clear amyloid pathology to slow cognitive decline.

  • AChE Inhibitors (Donepezil, Rivastigmine, Galantamine): First-line symptomatic treatment for mild to moderate AD. They enhance synaptic signaling by preventing the breakdown of ACh.

  • NMDA Antagonist (Memantine): Second-line or adjunctive treatment for moderate to severe AD. Acts as an uncompetitive antagonist at NMDA receptors to prevent excitotoxic cell death.

Parkinson's Disease: Motor Circuits and Pathophysiology

• Anatomy of the Basal Ganglia (The Motor Gatekeeper):

  • Striatum: Composed of the Caudate Nucleus (Cognitive & Spatial Planner) and the Putamen. This is the primary input zone.

  • Substantia Nigra: Located in the midbrain; contains dopamine-producing neurons colored dark by neuromelanin.

  • Thalamus (Ventral Anterior & Ventral Lateral Nuclei): The motor accelerator that excites the motor cortex.

• Initiation of Movement ("GO" Signaling Phase):

  • Dopamine Signaling (Direct Pathway): Dopamine binds to $D_1$ receptors on Direct-pathway Medium Spiny Neurons (dMSNs). $D_1$ couples to $G_{s/olf}$, activating Adenylyl Cyclase (AC), increasing $cAMP$, and activating Protein Kinase A (PKA), which depolarizes the neuron.

  • Dopamine Signaling (Indirect Pathway Inhibition): Dopamine binds to $D_2$ receptors on Indirect-pathway neurons (iMSNs). $D_2$ couples to $G_{i/o}$, inhibiting AC and decreasing $cAMP/PKA$ signaling to suppress the "NO-GO" pathway.

  • GABAergic Disinhibition: Activated dMSNs release GABA onto the Globus Pallidus internus (GPi) and Substantia Nigra pars reticulata (SNr). This influx of $Cl^-$ via $GABA_A$ receptors hyperpolarizes the GPi/SNr, lifting the inhibitory "brake" on the Thalamus. The Thalamus then fires excitatory glutamatergic signals to the motor cortex.

• Cessation and Fine-Tuning ("STOP/NO-GO" Signaling Phase):

  • ACh Signaling (Indirect Pathway Excitation): ACh binds to $M_1$ muscarinic receptors on iMSNs. $M_1$ couples to $G_{q/11}$, activating Phospholipase C (PLC) to yield $IP_3$ and Diacylglycerol (DAG). $IP_3$ releases intracellular $Ca^{2+}$ and DAG activates Protein Kinase C (PKC), depolarizing the iMSNs to drive the "STOP" signal.

  • ACh Signaling (Direct Pathway Suppression): ACh binds to $M_4$ receptors on dMSNs. $M_4$ couples to $G_{i/o}$, opposing $D_1$-mediated $cAMP$ production.

  • Cessation Cascade: Activated iMSNs release GABA to the Globus Pallidus externus (GPe). Suppressing the GPe disinhibits the Subthalamic Nucleus (STN). The STN releases excitatory Glutamate onto the GPi/SNr, which then release GABA onto the Thalamus to halt motor stimulation.

• Non-Motor Symptoms and Acetylcholine Depletion:

  • Parkinson's Disease Dementia (PDD): Loss of ACh in the prefrontal cortex and hippocampus impairs executive function.

  • Visual Hallucinations: Disruption of cholinergic gating in visual processing.

  • Gait Freezing: Degeneration of cholinergic neurons in the Pedunculopontine Nucleus (PPN) impairs automatic postural adjustments.

  • REM Sleep Behavior Disorder (RBD): Loss of brainstem cholinergic tone destroys muscle atonia during REM sleep.

• Treatment Overview for Parkinson's:

  • Carbidopa-Levodopa (Sinemet, Rytary): Gold-standard/First-line. Levodopa is a direct precursor to dopamine. Carbidopa inhibits peripheral aromatic L-amino acid decarboxylase (AADC) to prevent peripheral breakdown.

  • Dopamine Agonists (Pramipexole, Ropinirole, Rotigotine): First-line for patients < 60 years old. Direct post-synaptic receptor stimulation.

  • MAO-B Inhibitors (Rasagiline, Selegiline): First-line for very mild symptoms. Prevents enzymatic breakdown of dopamine.

  • COMT Inhibitors (Entacapone, Tolcapone): Second-line adjunct given only WITH Levodopa to prevent its degradation.

Headache Disorders: Classifications and Mechanisms

• Neurogenic Inflammation and the Trigeminovascular System (TGVS):

  • Triggered by cortical spreading depression, trigeminal ganglion neurons fire action potentials peripherally toward dural blood vessels (antidromic firing).

  • Vasodilation: Meningeal vessels dilate, stretching nerve endings.

  • Plasma Protein Extravasation (PPE): Gaps open between vascular endothelial cells, allowing plasma fluids to leak and cause edema.

  • Mast Cell Degranulation: Release of histamine, prostaglandins, and cytokines.

• Specific Neuropeptides:

  • Substance P (SP) & Neurokinins: Primary driver of PPE; triggers mast cell degranulation and nociceptor sensitization.

  • Vasoactive Intestinal Peptide (VIP): Induces potent, long-lasting vasodilation by increasing $cAMP$. Key mediator of cranial autonomic symptoms (lacrimation, rhinorrhea) in cluster headaches.

• Classifications:

  • Tension-Type: Bilateral, dull/tight band-like pain. Mild to moderate severity.

  • Migraine (Without Aura): Unilateral ($70\%$), throbbing/pulsating. Moderate to severe. Lasts $4$ to $72$ hours.

  • Migraine with Aura: Includes visual changes or sensory disturbances (aura lasts $5$ to $60$ minutes) prior to pain.

  • Cluster Headache ("Suicide Headache"): Strictly unilateral, periorbital, sharp/searing pain. High frequency ($1$ to $8$ attacks per day during a cluster). Associated with extreme restlessness and pacing.

• Management Strategies:

  • Acute (Abortive): Taken at the first sign of headache to stop rapid vasodilation. Risk of Medication Overuse Headache (MOH).

  • Prophylactic (Preventative): Taken daily to lower attack frequency. Includes Beta-blockers, Calcium Channel Blockers (specifically for cluster headaches), and CGRP Monoclonal Antibodies.

Seizure Disorders: Signaling and Pharmacology

• Electrical Signaling Balance:

  • Glutamate (Excitatory): Involves $Na^+$ and $Ca^{2+}$ influx via AMPA and NMDA receptors. Moves membrane toward threshold.

  • GABA (Inhibitory): Involves $Cl^-$ influx or $K^+$ efflux via $GABA_A$ and $GABA_B$ receptors. Moves membrane further from threshold.

  • Paroxysmal Depolarizing Shift (PDS): The hallmark electrical event of seizure onset at the single-neuron level, characterized by high-voltage depolarization and intracellular $Ca^{2+}$ overload.

• Classifications and Semiology:

  • Focal Onset: Limited to one hemisphere. Categories include Focal Aware and Focal Impaired Awareness.

  • Semiology: Temporal lobe (epigastric rising, fear, automatisms), Frontal lobe (fencer's posture, bicycling movements), Occipital lobe (visual flashing lights).

  • Generalized Onset:

    • Tonic-Clonic: Tonic phase ($10$ to $20$ seconds, "epileptic cry"); Clonic phase ($30$ to $90$ seconds, rhythmic jerking, tongue biting).

    • Atonic: "Drop attacks," sudden loss of muscle tone (< 2 seconds).

    • Absence: Non-motor, brief staring spells characteristic of $3$-Hz spike-and-wave discharges on EEG.

• Mechanisms of Action of Antiseizure Drugs:

  • Sodium ($Na^+$) Channel Blockers (Lamotrigine, Carbamazepine): Bind to voltage-gated channels in the inactivated state. Side effects: Ataxia, SJS/TEN rash, Hyponatremia.

  • Calcium ($Ca^{2+}$) Channel Blockers (Ethosuximide): Selectively blocks T-type channels in thalamic relay neurons to treat absence seizures.

  • Benzodiazepines vs. Barbiturates:

    • Benzodiazepines (e.g., Lorazepam, Diazepam): Increase $GABA_A$ channel opening FREQUENCY. Dependent on endogenous GABA. Used for acute Status Epilepticus.

    • Barbiturates (e.g., Phenobarbital): Increase $GABA_A$ channel opening DURATION. Can open channels independent of GABA at high doses. Direct AMPA/Kainate receptor blockade.

Movement Disorders: NMJ and Inflammatory Pathophysiology

• The Neuromuscular Signaling Sequence:

  1. Action potential reaches the presynaptic terminal.

  2. Voltage-gated $Ca^{2+}$ channels open; $Ca^{2+}$ influx occurs.

  3. Exocytosis of Acetylcholine (ACh).

  4. ACh binds to Nicotinic Acetylcholine Receptors (nAChR) on the motor end-plate.

  5. $Na^+$ influx generates an End-Plate Potential (EPP).

  6. Muscle Action Potential is initiated via nearby voltage-gated $Na^+$ channels.

  7. Muscle contraction occurs via $Ca^{2+}$ release from the sarcoplasmic reticulum.

  8. Termination: Acetylcholinesterase (AChE) hydrolyzes ACh.

• Multiple Sclerosis (MS) vs. Amyotrophic Lateral Sclerosis (ALS):

  • MS (CNS Demyelination): Inflammatory destruction of myelin by T-cells and microglia. Causes loss of saltatory conduction and conduction block. Site of failure: upper motor neuron pathways. hallmark: Spasticity.

  • ALS (Motor Neuron Degeneration): Loss of astrocytic EAAT2 leads to glutamate excitotoxicity. "Dying-back" hypothesis: degeneration begins at the NMJ distal tip. Features motor neuron death and muscle atrophy.

• Pharmacotherapy by Disease:

  • MS Treatments:

    • Spasticity: Oral Baclofen ($GABA_B$ agonist) or Tizanidine ($\alpha_2$-adrenergic agonist).

    • Spastic Bladder: Antimuscarinics (Oxybutynin) or $\beta_3$-adrenergic agonists (Mirabegron).

    • Optic Neuritis: High-dose IV Corticosteroids; Plasma Exchange (PLEX) as rescue.

  • ALS Treatments:

    • Riluzole: Blocks presynaptic $Na^+$ channels, inhibits NMDA/AMPA receptors, and stimulates EAAT2. Modestly extends survival by $2$ to $3$ months.

    • Edaravone: Free radical scavenger that neutralizes ROS/RNS (peroxynitrite $ONOO^-$ and hydroxyl radicals $\cdot OH$).

Questions & Clinical Review

• Q1-Q3 (Alzheimer's Early Changes): Initial pathological changes are detected in the Entorhinal cortex. Neurodegeneration in the basal forebrain (Nucleus Basalis of Meynert) leads to a deficit in Acetylcholine. Soluble $A\beta$ oligomers result in the Inhibition of Long-Term Potentiation (LTP).

• Q4-Q6 (AD Treatment and Biology): Memantine is the uncompetitive NMDA antagonist. Adverse effects of Donepezil (nausea/diarrhea) are caused by increased synaptic ACh enhancing parasympathetic activity. The ion dislodged from the NMDA receptor pore during overstimulation is Magnesium ($Mg^{2+}$).

• Q7-Q9 (Parkinson's Diagnosis): A patient acting out dreams (RBD), losing sense of smell (hyposmia), and having constipation is in the Prodromal phase (pathology affecting brainstem/autonomics before substantia nigra). Motor deficits result from the Nigrostriatal pathway. The primary pathological hallmark is the aggregation of $\alpha$-Synuclein.

• Q10-Q11 (PD Treatment): Carbidopa is used to inhibit peripheral AADC, preventing breakdown of Levodopa. Entacapone improves symptoms by inhibiting peripheral COMT to prevent degradation of L-DOPA into $3$-O-methyldopa.

• Q12-Q15 (Headaches): Zig-zag lines and tingling arm represent the Aura phase (present in ~$33\%$ of patients). Cutaneous allodynia (sensitivity to touch) is driven by peripheral and central sensitization from CGRP/Substance P. Propranolol is ideal prophylaxis for patients with comorbid anxiety/hypertension. Galcanezumab is a monoclonal antibody targeting CGRP.

• Q16-Q18 (Cluster Headaches): First-line acute therapy for cluster headache in the ED is inhaled $100\%$ oxygen. Cyclical periodicity suggests Hypothalamus dysfunction. Prophylactic treatment often uses Verapamil.

• Q19-Q22 (ALS and MS): Secondary electrophysiological event accelerating $Ca^{2+}$ overload in ALS motor neurons is the reversal of the $Na^+/Ca^{2+}$ exchanger. Riluzole requires monitoring of Liver enzymes (ALT/AST). MS progressing gradually after earlier relapses is categorized as Secondary Progressive MS (SPMS). Natalizumab works by blocking $\alpha_4\beta_1$ and $\alpha_4\beta_7$ integrin receptors to prevent leukocyte migration across the BBB.