22. Neurodegenerative Disorders

• The lecture covers epilepsy, neurodegenerative disorders (Parkinson's and Alzheimer's disease), and amyotrophic lateral sclerosis (ALS) and Huntington's disease

Learning Objectives

• Define seizure and epilepsy
• Classify different seizure types and epilepsy syndromes
• Understand the main medical and surgical treatments for epilepsy
• Identify and distinguish the clinical features of various movement disorders
• Explain medical and surgical treatments for movement disorders
• Identify Alzheimer's disease based on neuropathology and pathogenesis
• Explain pharmacologic and nonpharmacologic management of Alzheimer's disease

History of Epilepsy

• Epilepsy has been referenced in historical texts dating back to 2000 B.C. in Assyria, ancient Greece, and ancient Egypt
• Epilepsy was often attributed to mystical and supernatural causes.
• The physical basis became clear in the 18th century on through 19th century
• The electrical basis in the brain was established by Fritz & Hitzig in 1870

Epidemiology

• Epilepsy affects 0.5-1% of the population (450k in UK, 30k new cases p.a)
• Approximately 2% of people experience at least one seizure in their lifetime
• 30% of epilepsy cases are resistant to drug treatments, and 20-30% do not improve with surgery.
• There are 1000 epilepsy-related deaths per year in the UK
• Up to 90% of cases are undiagnosed or untreated in developing countries

Pathophysiology

• Epilepsy is a chronic neurological disorder
• Characterized by repeated epileptic seizures
• Paroxysmal uncontrolled discharges of neurons within the CNS (grey matter disease)
• Risks includes loss of consciousness, physical injury, tonic-clonic seizures, status epilepticus, brain damage, SUDEP and quality of life issues

Seizure Classification

• Partial/focal seizures account for 80% of adult epilepsies
• Simple partial seizures
• Complex partial seizures
• Partial seizures secondarily generalized
• Generalized seizures
• Tonic-clonic
• Tonic
• Clonic
• Atonic
• Myoclonic
• Absence
• Unclassified seizures

Partial/Focal Seizures

• Simple: motor, sensory, vegetative, or psychic symptoms with consciousness usually retained
• Complex: initial subjective feeling (aura), loss of consciousness, and abnormal behavior
• Partial seizures can evolve into tonic/clonic convulsions, known as secondary generalized tonic/clonic seizures (SGTCS)

Generalised Seizures

• Tonic-clonic: tonic phase with loss of consciousness followed by 1-3 minute clonic phase ("grand mal")
• Tonic: stiffness and rigidity of muscles, common in sleep, may retain consciousness (if awake)
• Clonic: rhythmic spasm/jerking of muscles in leg/neck/elbows, slows down as seizure subsides (rare)
• Myoclonic: Brief jerking of muscles, generally consciousness retained.
• Absence: Brief period of lack of responsiveness in children; "petit mal"
• Prolonged seizures become harder to stop
• Non-convulsive SE is harder to recognize
• Risk of pyrexia, coma, circulatory collapse, 5-10% fatal

Status Epilepticus

• Sustained epileptic crisis is a medical emergency
• Seizure lasts over 5 minutes, or repetitive epileptic attacks occur without recovery time
• SE defined by time of seizure persistence: proceeds to established SE and then Refractory SE

Diagnosis

• Diagnosis includes EEG
• Paroxysmal depolarization shift (PDS) is the pathophysiologic cellular phenomenon that underlies all types of epileptic seizures
• Increase the diagnostic value of the EEG; within 24 hours of the seizure episode and during sleep

Causes of Epilepsy

• Idiopathic (genetic) causes account for ~75% of cases
• Brain damage can result from trauma, infection, brain tumor, stroke (leading cause age >35), and prenatal damage
• Developmental disorders such as autism spectrum disorder and neurofibromatosis
• Genetic risk factors include 13 genes associated with epilepsy (2014) and affect all ion channels/ionotropic receptors
• Most antiepileptic drugs target channels and receptors and vesicle associated proteins, metabolic proteins
• Ictogenesis: generation of hyperexcitability events result from unclear genetics which vary heavily and depend on the epileptic syndrome

Leading Hypothesis

• Abnormal synaptic Activity: Vulnerabilities to aberrant synaptic activity

Treatments

• Drugs:
  • Na+ channel blockers
  • HVA Ca2+ channel blockers
  • LVA Ca2+ channel blockers
  • GABAergic pathway facilitators
  • Vesicle release drugs
  • Multi-mechanism drugs
• Surgery:
  • Removal of epileptogenic tissue

Specific Epilepsy Drugs

• Carbamazepine: blocks repetitive activation of Na+ channels.
• Lacosamide: enhances slow inactivation of Na+ channels
• Valproic acid: blocks T-type Ca2+ channels
• Carbamazepine (CBZ): inhibits voltage-gated Na+ channels.

Lecture Aims - Neurodegenerative Disorders

• Describe the prevalence of common and rare movement disorders
• Describe and explain the aetiology, pathophysiology, and treatments for Parkinson's and Alzheimer's disease
• Describe current research for developing new treatments for neurodegenerative disorders.

Movement Disorders

• Most common is essential tremor affecting 400 per 100,000
• Often mild, often do not seek treatment
• Parkinson's disease is most common in clinic affecting 200 per 100,000 with indirect costs(US) $25 billion/year.
• Rare diseases include Huntington's disease affecting 7 per 100,000

Parkinson's Disease

• James Parkinson (1817) described `shaking palsy
• Frederic Lewy (1912) described microscopic particles in affected brains
• Incurable and progressive but not (directly) lethal with life expectancy 10-15 years
• More common in elderly, especially men

Symptoms

• Progressive loss of dopaminergic neurons projecting from SNc mostly affects motor system
• Motor: tremor, slowness of movement (bradykinesia), rigidity, postural instability, micrographia.
• Neuropsychiatric: executive dysfunction (risk taking, impulsivity), dementia
• Onset after 20-40% dopamine loss

PD Pathophysiology

• Generation of insoluble protein aggregations or `Lewy bodies'
• α-synuclein leads to death of astrocytes and increased number of activated microglia
• Impairments in `proteostasis': Aggregation, trafficking, disposal via ubiquitin-proteasome

Lewy Bodies

• Pale bodies consist of abnormal cytoplasmic protein aggregates of α-synuclein
• May be multiple per neuron, contain ubiquitin, tau, and parkin
• May misfold, increasing chance of aggregation through Phosphorylation, ubiquitination, and/or C-terminus truncation

PD - Pathophysiology

• Lewy bodies may affect membrane spores resulting in loss of ion homeostasis, Mitochondria to accumulation impairs function and Cell survival which makes most oligomers toxic
• Microglial and Astrocyte activation

Braak Staging

• Classification for degree of pathology in PD based on Lewy body distribution and lesions.
• Six stages can be described:
  • Stages 1-2 = dorsal motor nucleus ,anterior olfactory nucleus, raphe nuclei, reticular nucleus, locus coeruleus
  • Stages 3-4 = SNc, basal forebrain, amygdala, thalamus
  • Stages 5-6 = neocortex

PD Risk Factors

• Multifactorial condition (~95% sporadic, 5% genetic)
• Genes account for 10-15% of cases with family history (not Mendelian)
• LRRK2, PRKN, PINK1, SNCA, GBA1 are genes of note
• Environmental risk factors include Brain injury, Smoking (↓), caffeine(delays), pesticides, heavy metals, Drug-induced Parkinsonism

PD Risk Factors - Nicotine

• Strong evidence of inverse correlation with smoking & PD incidence
• Activation of nAChRs in DA neurons is neuroprotective in experimental models

PD Risk Factors - Caffeine

• Caffeine (adenosine A2AR antagonist) neuroprotective in PD?
• Possibility of A2A antagonist treatments for PD

PD Diagnosis

• Diagnosis based on presence of at least 2 of the 4 cardinal Parkinsonian symptoms

Treatments

• Pharmacological DA precursor like levodopa (L-DOPA)
• Immunotherapy:
  • Antibodies to remove toxic forms of a-synuclein, active or passive

Deep Brain Stimulation (DBS)

• Surgical implantation of electrode and approved by FDA for PD and epilepsy
• Being studied for chronic pain, depression
• Mechanism unclear, involves Inhibitory/excitatory?, Neurotransmitter release? Circutit Oscillations

Future Treatment

• Stem cell transplantation with new generation of stem cells

Alzheimer's Disease (AD)

• First characterised by Alois Alzheimer (1907)
• Most common neurodegenerative disease ~6% of over-65s; 20-30% over-80s
• Memory loss (+ wider cognitive, sensory, motor problems);
• Synaptic failure & loss and Cell death in numerous cortical regions or Atrophy of associated brain regions: general brain shrinkage

AD - stages

• Normal ageing: Forgetting things occasionally
• Early stage Alzheimer's: Not remembering episodes of forgetfulness
• Middle stage: Greater difficulty remembering recently learned info
• Late stage: Poor ability to think and Increased abusive, anxious, or paranoid behaviour

Genetics

• 3 genes heavily associated with familial AD, encoding Amyloid precursor protein (APP), presenilin 1, presenilin 2
• Over 40 genes associated with AD and Risk genes for sporadic AD such as and TAU tangles

AD - Pathophysiology

• Loss of neurons beyond natural ageing
• Amyloidosis, Neuronal dysfunction, ApoE4 TREM2, Microglia, DEMENTIA
• Solanezumab, CAD106

Beta- Amyloid Plaques

• Derived from amyloid precursor protein (APP), cleavage by B-secretase & y-secretase
• Increase in Aβ production, esp. toxic Aβ42 oligomers
• Aggregation into beta amyloid plaques (extracellular) and Stages of plaque build-up by brain region and density

AD - Treatments

• Drugs to improve cognitive function prescribed in varied instances
• Antidepressants are prescribed for anxiety/depression and Antipsychotics/carbamazepine for severe aggression

ALS - Amyotrophic Lateral Sclerosis

• Motor neurone disease, Lou Gehrig's disease and most common neurodegenerative disease
• First described by Jean-Martin Charcot (1869)
• Lifespan from diagnosis usually 2-5 years
• Death of motor neurones (upper and lower), Loss of co-ordination, weakness, slurred speech, eventually Neuropathic pain

ALS Etiology and Pathophysiology

• Genetics with both sporadic (sALS) or familial (fALS) aspects
• Environmental factors with no family history of the disease is present
• Presence of inclusion bodies known as Bunina bodies in the cytoplasm of motor neurons
• Mutations result in mislocalisation to cytoplasm

ALS Treatments

• Diagnosis can be clinical
• Treatment involves novel therapies and biologics
• Novel therapies in clinical trials to prevent progression and Mostly biologics (reduce neuroinflammation)

Huntington's Disease (HD)

• First description of the disease was by George Huntington (1872) with both genetic and pathological aspects
• Prevalence and Onset described and symptoms described
• Triad of motor, cognitive, and psychiatric symptoms and Genetics/Classifications include autosomal dominant inheritance
• Involves Huntingtin gene (HTT) & protein and results may be affected depending on repeat range