Case 3 - neuroinflammatory diseases

Question 1

PD - symptoms

Answer 1

o PD is a heterogeneous disorder with a variety of motor and non-motor symptoms (see image presentation). The symptomatology evolves throughout the course of the disease, with prodromal symptoms such as impaired sense of smell (anosmia, hyposmia), constipation, depression and REM sleep behavior disorder being present years before onset of motor symptoms (and thus clinical diagnosis).
o As PD is a progressive neurodegenerative disease, symptoms will worsen over time. In advanced stages, PD may result in dementia and/or psychosis, and motor and non-motor impairments that are already present in earlier stages generally worsen, leading to an overall increase in disability

Question 2

PD - pathophysiological mech (microglia)

Answer 2

• In the context of PD, the initial microglial response is thought to increase neuronal survival and rescue injured DAn.
  o However, if a sustained and excessive activation of microglia is maintained over time, this has been linked to a deregulated release of proinflammatory cytokines, thereby making microglial cells promoters or contributors to neuropathological and toxicity processes in PD.
• Additionally, genetic alterations in PD-associated genes, together with α-Syn aggregation and propagation, were also found as key players disrupting other vital microglial processes such as mitochondrial dysfunction, autophagy, and possibly phagocytosis, thereby leading to neuroinflammation (NFkB and inflammasome) and consequently PD development.
• Activated microglia can polarize into several different phenotypes during inflammatory events.
• The most well-known activation phenotypes are conventionally termed M1 or M2.
• Activation of M2 microglia by aggregates, ROS, cytokines, DAMPs etc leads to enhancemnet of neuroinflammation

Question 3

PD - pathophysiology (astroyctes)

Answer 3

• Under pathological conditions and inflammatory reactions, astrocytes can communicate with microglia to amplify the immune response and activate apoptotic mechanisms inducing DAn death.
• The presence of α-Syn has been shown to cause severe astrogliosis, disrupting extracellular glutamate homeostasis, cytokine and chemokine production.
  o Accordingly, a significant decrease in glutamate and aspartate transporter (GLAST) and glutamate transporter type 1 (GLT1) was observed.
  o Since these are the main transporters of glutamate, their loss of function leads to their accumulation in the synaptic cleft (glutamate excitotoxicity), contributing to astrocytic and microglial reactivity and the development of neuroinflammation and neuronal injury

Question 4

PD -diagnosis

Answer 4

• Diagnosis of PD is primarily determined by the patient’s medical history and physical examinations.
  o Medical history refers to the presence of aforementioned prodromal symptoms, as well as family relatives with PD or known PD genes within the family.
  o For physical examinations and PD diagnosis, a combination of bradykinesia with rigidity and/or tremor suffices (bradykinesia should always be present).
  o Further verification of PD diagnosis is subsequently achieved by considering features that are potentially indicative of atypical parkinsonism, and (in case atypical parkinsonism is not suspected) assessing the response of the patient to levodopa

Question 5

PD - treatments

Answer 5

• symptomatic: levodopa and cardidopa –> dopaminergic therapy
• NSAIDs lower PD incidence –> reduced neuroinflammation

Question 6

ALS - general

Answer 6

• Fatal and progressive neurodegenerative disease characterised by degeneration and loss of upper and/or lower motor neurons; median survival depends on the subtype: between 1.5 (respiratory phenotype) to 10 years (pure UMN).
• Relatively rare – 1-2 people in 100,000 people. Incidence increases with age but there’s a lot of variability depending on the subtype

Question 7

ALS - symptoms

Answer 7

• A combination of upper motor neuron (UMN) – cortex and the brainstem – increased and pathological reflexes (Hoffmann’s sign, Babinski), increased muscle tone; and spasticity (abnormal muscle tightness)
• And lower motor neuron (LMN) - brainstem cranial motor nerve nuclei or anterior horn cells; dysfunction affecting the bulbar, cervival, thoracic or lumbar segments; it is characterised by muscle weakness, atrophy and fasciculations (involuntary rapid muscle twitches)
• It can start with focal onset in one body segment which progresses to the contralateral side and then to adjacent anatomical segments
• Bulbar onset and spinal-onset (cervical and lumbar) ALS are the most common presentations.

Question 8

ALS - types

Answer 8

• Bulbar ALS – phenotype presents with weakness starting in the muscles controlling speech and swallowing – both LMN and UMN signs are present
• Cervical-onset ALS – a subset of classical ALS with weakness commencing in the upper limbs, especially hand weakness
• Lumbar-onset symptoms ALS – a subset of classical ALS with weakness commencing in the lower limbs, especially foot drop
• Respiratory onset - LMN and UMN dysfunction causing weakness commencing in the respiratory muscles

Question 9

ALS - prognosis

Answer 9

• Median survival is 2-4 years individual differences
  o 50% of patients die within 30 months of symptom onset
  o 20% of patients survive between 5 years and 10 years after symptom onset
  o Older age at symptom onset, early respiratory muscle dysfunction, and bulbar-onset disease are associated with reduced survival
• Some ALS subtypes tend to lead to a better prognosis
• Dysphagia develops in most patients with ALS
  o weight loss and malnutrition are associated with poor prognosis
• Respiratory compromise develops in most cases
  o progressive weakening of the respiratory muscles leads to respiratory failure, often precipitated by pneumonia
  o respiratory failure is the main cause of death in ALS

Question 10

ALS - diagnosis

Answer 10

• Clinical history
  o Symptoms (e.g. dysphagia, weakness etc. and time course)
  o Family history of ALS
• Neurological examination
  o Signs of UMN and LMN dysfunction
  o Unexplained weight loss, cognition or executive dysfunction, pseudobulbar affect
• Electrodiagnostic testing
  o Nerve conduction studies and needle electromyography to confirm LMN signs – important to rule out other diseases such as multifocal motor neuropathy with conduction block
   Peripheral nerve conduction studies (NCS)
• Findings consist with ALS – normal or decreased compound muscle action potential (CMAP), slowing of conduction velocity; sensory nerve conduction should be normal (otherwise it may suggest other diseases)
   Needle EMG
• Inserting a needle into an affected muscle and observing the muscle’s electrical activity without any stimulation
• MRI
  o Imaging of the spinal cord by MRI to rule out more common diagnoses (e.g. herniated disc or cord compression)

Question 11

ALS - pathophysiology

Answer 11

• The pathology of ALS is characterized by the degeneration of upper corticospinal motor neurons and lower bulbospinal motor neurons as well as reactive gliosis
• In 5-10% of patients with ALS the disease is familial and in 90-95% of patients the disease is sporadic, however genetic factors still play an important role in disease progression even if there is no family history
• Mutations in the C9orf72, FUS, and TDP-43 genes result in dysregulated RNA metabolism leading to abnormalities of translation and formation of intracellular neuronal aggregates, while mutations in the SOD1 gene increases oxidative stress, induces mitochondrial dysfunction, leads to intracellular aggregates, and defective axonal transport.
• Mitochondrial dysfunction is a hallmark feature of ALS and leads to the production of reactive oxygen species (ROS).
  o Oxidative stress (OS) may result from excess levels of ROS which contributes to neuronal injury by changing the structure and function of proteins, lipids, DNA, and RNA.
  o OS can promote protein misfolding and aggregation of SOD1 as well as the formation of toxic TDP-43 protein aggregates which can lead to impaired RNA binding and further mitochondrial dysfunction.
  o OS can also activate neuroinflammatory responses from glial cells which release pro-inflammatory cytokines and ROS which further exacerbate OS and promote neuronal injury.
  o OS can also trigger glutamate excitotoxicity by disrupting glutamate transport and promoting the activation of glutamate receptors on neurons.
   Glutamate excitotoxicity is a process in which excessive glutamate release leads to neuronal damage and degeneration of neurons.
   Motor neurons are vulnerable to excitotoxic injury

Question 12

ALS - treatments

Answer 12

• Riluzole: inhibits glutamate release ALS linked to glutamatergic excitotoxicity
  o Inhibition of voltage gated Na+ channels and indirect antagonism of glutamate receptors
• Edaravone
  o Iv or oral
  o Antioxidant reduces oxidative stress and free radicals
  o Generally safe
  o proven to delay the degeneration of motor neuron dysfunction in the brain and spinal cord