Alterations in Normal Nervous System Function

Alterations in Normal Nervous System Function

Introduction

  • Presented by Prof. Susanna Park
  • Neuroscience Theme, School of Medical Sciences, The University of Sydney

Learning Objectives

  • By the end of this lecture, students should be able to discuss alterations to normal function that occur as a result of:
    • Dementia
    • Alzheimer’s Disease
    • Parkinson’s Disease
    • Motor Neuron Disease
    • Multiple Sclerosis
    • Cerebrovascular Disorders
    • Spinal Cord Injury

Neurodegenerative Disorders

Definition

  • Neurodegenerative disorders cause progressive loss of brain functions and chronic deterioration of the CNS.
  • Diverse clinical manifestations reflecting loss of specific neurons and synapses in distinct brain regions.
  • Share common features and mechanisms.

Examples of Neurodegenerative Disorders

  • Alzheimer’s Disease (AD)
  • Huntington’s Disease (HD)
  • Parkinson’s Disease (PD)
  • Spinocerebellar Ataxia (SCA)
  • Frontotemporal Dementia (FTD)
  • Amyotrophic Lateral Sclerosis (ALS)
    (Referencing Gan et al. 2018, Nature Rev Neurosci)

Susceptibility to Neurodegeneration

  • High energy demand
  • High rate of oxidative stress: greater production of reactive oxygen species
  • High lipid content leading to lipid peroxidation
  • Reliance on axonal transport of organelles

Common Pathways of Neurodegeneration

  • Metabolic failure
  • Disruption of axonal transport
  • Mitochondrial dysfunction
  • Excitotoxicity
  • Disruption of protein degradation
  • Protein aggregation
  • Triggered cell death

Protein Aggregates and Neurodegeneration

  • Alzheimer's Disease: Amyloid-β protein.
  • Parkinson's Disease: α-synuclein.
  • Huntington's Disease: Huntingtin protein and ataxins.
  • Amyotrophic Lateral Sclerosis (ALS): TDP-43 and SOD1.
  • Frontotemporal Degeneration: Tau protein.
  • General concept of abnormal protein misfolding and aggregation leading to disease.

Dementia

Definition

  • Umbrella term for multiple disorders (>100 disorders) resulting in a collection of symptoms caused by brain disorders, leading to progressive loss of memory, orientation, attention, and speech.
    • Most common causes: Alzheimer's disease and vascular dementia.

Statistics

  • Estimated 487,500 Australians live with dementia.
  • More than two-thirds of aged care residents exhibit moderate to severe cognitive impairment.
  • 70% of individuals with dementia reside in the community.

Key Cognitive Symptoms

  • Memory loss
  • Difficulty communicating or finding words
  • Difficulty with visual and spatial abilities
  • Difficulty with problem-solving and complex tasks
  • Difficulty with planning and organization
  • Confusion and deterioration

Psychological Changes

  • Personality changes
  • Depression and anxiety
  • Inappropriate behavior
  • Agitation
  • Paranoia

Awareness

  • Dementia is not a normal part of aging.
  • Any change in cognition should be investigated.
  • Differentiation from delirium and confusion (e.g., due to urinary tract infection).

Alzheimer's Disease

Overview

  • Most common cause of dementia (accounts for 60-80% of dementia cases).
    • AH vs D: Alzheimer’s is a specific brain disease; Dementia is a general term for cognitive decline.

Symptoms and Progression

  • Progressive symptoms leading to death.
  • Most cases are sporadic; 2-3% are inherited (younger onset).

Risk Factors for Sporadic Alzheimer’s Disease

  • Apolipoprotein E4 genotype: increases risk by 3x.
  • Age.
  • Lifestyle and vascular risk factors.

Classical Hallmarks of Alzheimer’s Disease

  • Amyloid plaques (amyloid beta protein).
  • Neurofibrillary tangles (phosphorylated tau).
  • Brain atrophy (loss of synapses and neurons).
  • Role of microglia in pathogenesis.
    (Referencing Congdon and Sigurdsson, 2018; Scheltens et al, 2021)

Treatment

  • Current treatments are symptomatic, not disease-modifying, including:
    • Cholinesterase inhibitors.
    • Memantine.
  • Notable developments:
    • 2021: First Alzheimer’s medication in 20 years approved in the USA (antibody targeting amyloid beta protein).
    • 2023: Lecanemab approved for the treatment of Alzheimer’s disease.

New Treatments

  • Lecanemab and Donanemab: Monoclonal antibodies approved for mild Alzheimer’s disease.
  • Treatments are costly, with risks of serious side effects requiring monitoring.

Alzheimer’s Disease Drug Development Pipeline

Overview

  • 141 agents in trials for Alzheimer's disease covering various target classes, including:
    • Amyloid
    • Inflammation/Immunity
    • Neurotransmitter Receptors
    • Tau
    • Others (details of each category).

Parkinson’s Disease

Overview

  • Estimated 100,000 people with Parkinson’s disease in Australia.
  • More prevalent in men than women.
  • Characterized by the loss of dopaminergic neurons, primarily in the substantia nigra, and accumulation of alpha synuclein in Lewy bodies.

Key Motor Symptoms

  • Bradykinesia (slowed movement) or akinesia (absence of spontaneous movement).
  • Rigidity/stiffness.
  • Resting tremor.
  • Posture and balance instability.

Non-Motor Symptoms

  • Cognitive impairment.
  • Depression and anxiety.
  • Sleep dysfunction.

Progression of Disease

  • Diagnosis occurs with the onset of motor symptoms, typically in late fifties, preceded by a prodromal phase with non-motor symptoms.
  • Progressive disability driven by motor and non-motor symptom severity.

Treatment Options

  • No cure available; treatments focus on symptomatic relief including:
    • Medication (dopaminergic modulation).
    • Surgical options (deep brain stimulation).
    • Rehabilitation to maximize function.

Motor Neuron Disease (MND)

Overview

  • Also known as Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig’s disease.
  • Characterized by muscle atrophy, weakness, respiratory involvement, and death.
  • Average life expectancy around 27 months; 2 people diagnosed with ALS daily in Australia.

Connection to Frontotemporal Dementia (FTD)

  • FTD associated with behavioral and cognitive impairments.
  • 50% of ALS patients show overlapping features with FTD; 15% have both conditions.
  • Common pathological hallmark: ubiquinated TDP-43 protein aggregates.

Multiple Sclerosis (MS)

Overview

  • Chronic autoimmune demyelinating disorder impacting myelin integrity in the brain and spinal cord.
  • Characterized by demyelinating lesions in both white and grey matter.

Symptoms

  • Heterogeneous presentation can be relapsing or remitting over time.
  • Key symptoms include:
    • Visual disturbances.
    • Pain and numbness.
    • Fatigue.
    • Cognitive issues.
    • Balance and coordination problems.

Treatment Options

  • No cure but >13 disease-modifying treatments currently available in Australia to reduce relapse risk and disease progression.

Cerebrovascular Disorders - Stroke

Overview

  • Caused by occlusion or hemorrhage of blood vessels supplying the brain.
  • Ischemic stroke is more common than hemorrhagic strokes.

Statistics

  • An Australian will experience a stroke every 19 minutes.
  • Over 445,087 Australians are living with effects of stroke.
  • Costs the Australian economy $6.2 billion; regional Australians more likely to suffer than metro residents.

Signs of Stroke - F.A.S.T.

  • Face drooping?
  • Arms cannot be raised?
  • Speech slurred or confused?
  • Time is critical: call 000 immediately.

Sequence of Damaging Events in Stroke

  1. Blood clot halts blood flow to brain region.
  2. Neurons degenerate due to lack of oxygen and glucose.
  3. Rapid firing neurons release glutamate; no reuptake occurs due to energy lack.
  4. Excessive calcium and zinc enter postsynaptic neurons, leading to cell death (excitotoxicity).

Possible Treatments

  • Thrombolytics (like tissue plasminogen activator/tPA).
  • Drugs that inhibit sodium channels.
  • Glutamate receptor blockers.
  • Calcium channel blockers.

Stroke Areas

  • Ischemic core: area with severe cell loss.
  • Penumbra: area with constricted blood flow; target for therapy.

Spinal Cord Injury (SCI)

Overview

  • Traumatic and non-traumatic causes.
  • Complete and incomplete injuries relate to the level of function below the injury.
  • Complete Injury: Total loss of function. Incomplete Injury: Partial function.

Types of Injury

  • Paraplegia: paralysis of torso and lower limbs.
  • Quadriplegia: paralysis of all limbs.

Associated Issues

  • SCI symptoms include loss of bladder/bowel control, temperature control, touch sensation, sexual function, and much more.

Autonomic Dysreflexia

  • Noisy stimulus activates sympathetic nervous system, causing dangerously high blood pressure.
  • Resulting symptoms include headaches, blurred vision, and sweating above the lesion.
    • Compensatory mechanisms are blocked below the lesion due to the spinal cord injury.

Conclusion

  • Understanding the alterations to normal nervous system functions regarding various disorders is critical for developing effective treatments and interventions.