Case 14: Andrea Holmes - Delirium

CNS Neurons: Axon

Same structure as peripheral nerves

Supporting cells:

• Astrocytes

• Microglia

• Ependymal cells

• Tanycytes

• Oligodendrocytes

CNS: Astrocytes

Physical support

Remove excess NTs

Glycogen reserve

Tissue repair: Proliferate + hypertrophy after injury

Foot processes = Part of BBB

CNS: Microglia

Phagocytic: Response to CNS tissue damage

Release inflammatory mediators (NO)

CNS: Ependymal Cells

Epithelial lining in ventricles and central canal (spinal cord)

Cilia circulate + absorb CSF

CNS: Tanycytes

Transport between blood + ventricles

CNS: Oligodendrocytes

Myelination in CNS + CN II = Increase conduction speed (saltatory)

1 cell/several axons

Neuron Synapse

Chemical synapse

Transmit signal via chemical NT

NT Mechanism

1. Synthesis

2. Sorage

3. Release

4. Binding

5. Action termination

NT Synthesis

Amino acids accumulate in presynaptic neuron = Metabolized → NT

NT Storage

In vesicles

Ex: Synaptophysin

NT Release

AP in presynaptic neuron = Open voltage-gated Ca2+ channels = Ca2+ influx

Ca2+ bind vesicle membrane proteins = Vesicle dock to presynaptic membrane + form SNARE complex = Membrane fuse + release NT into synaptic cleft

• SNARE: Soluble NSF Attachment protein Receptor complex

NT Binding

NT bind receptors on postsynaptic membrane = Ion influx into postsynaptic cell = AP

NT Action Termination

Reuptake: Transporter protein on presynaptic neuron or glial cells re-store NT in vesicles

Degradation: Enzymes in synaptic cleft breakdown NT

Diffusion: NT diffuse out of synaptic cleft

Dementia (Major Neurocognitive Disorder): Description

Progressive cognitive function disorder interfering with everyday activities

Types:

• Neurodegenerative

  • Alzheimer’s Disease (AD)

  • Frontotemporal

  • Lewy Body

• Vascular

• Rapidly progressive

AD

Gradual + progressive disorder impairing cognition + memory

Most common cause of dementia

Frontotemporal Dementia

Progressive frontal/temporal lobe degeneration

Lewy Body Dementia

Progressive cognitive impairment, visual hallucinations, and parkinsonism

Vascular Dementia

Cerebrovasculature damage/occlusion = Ischemia/infarct

Rapidly Progressive Dementia

< 2 years between first symptom → Dementia

Dementia: Epidmeiology

Risk factors…

• Older age > 65 years

• Family history

• Genetics: Early-onset AD (EOAD)

  • Mutations in…

    • Presenilin (PSEN)-1/2

    • Amyloid precursor protein (APP)

    • Apolipoprotein E (APOE)

• Chronic conditions

  • Systemic vascular disease

  • DM

  • HTN

  • Hyperlipidemia

• Social isolation

Dementia: Etiology

DEMENTIAS

• Degenerative

• Emotional

• Metabolic

• Nutritional

• Traumatic

• Infectious

• Autoimmune

• Stroke

Dementia Etiology: Degenerative

AD > 50%

Parkinson

Huntington

Frontotemporal

Lewy bodies

Dementia Etiology: Emotional

Depression

Psychosis

Dementia Etiology: Metabolic

Uremia

Electrolyte imbalances

Toxins + drugs/alcohol

Dementia Etiology: Endocrine

Hypo/hyperthyroidism

Hypo/hyperparathyroidism

Dementia Etiology: Nutritional

Vit deficiencies

Dementia Etiology: Traumatic

TBI

Dementia Etiology: Infectious

Syphilis

HIV

Crutzfeld-Jakob disease

Dementia Etiology: Stroke

20%

Multi-infarct + hypoxic brain damage

Diffuse white matter disease (cerebral ischemia)

Dementia AD: Pathophysiology

APP produce amyloid-beta protein = Stimulate tau protein hyperphosphorylation = Amyloid-beta + tau aggregate → Amyloid plaques + Neurofibrillary tangles (NFTs)

Disrupt axon transport + mitochondrial function = Neuronal degeneration

Frontotemporal Dementia: Pathophysiology

Protein (tau OR TDP) mutation = Aggregate in neuron cytoplasm = Neurodegeneration

Lewy Body Dementia: Pathophysiology

Alpha-synuclein protein midfolding = Aggregate into Lewy bodies = Increase ROS production = Damage neuron soma + axons

Vascular Dementia: Pathophysiology

Atherosclerosis = Decrease cerebral blood flow = Lacunar (small vessel) infarct + chronic hypoperfusion = Neuron damage + death

Dementia: Clinical Presentation

Step-wise/progressive

Memory impairment

Cognitive impairment

• Speech: Aphasia

• Reasoning + planning

• Spatial-temporal awareness

Mood + behaviour changes

• Depression

• Apathy

Dementia: Diagnostic Criteria

DSM-5

• Decline in ≥ 1 domain

  • Learning + memory

    • Immediate (registration)

    • Short-term (recall)

  • Language

    • Object naming

    • Word-finding

    • Fluency

    • Grammar

  • Executive function

  • Attention

  • Perceptual-motor

  • Social cognition

• Also:

  • Deficits interfering with life

  • No other diagnoses (NOT depression or delirium)

Dementia: Investigations

Evaluate cognitive impairment/dementia

Lab tests

Imaging

Genotyping

EEG

Dementia Investigations: Evaluate Cognitive Impairment

Mini-mental state exam (MMSE)

Mini-cog

Clock-drawing test

Dementia Investigations: Lab Tests

Vit B12

TSH: Hypothyroidism

CBC: Anemia

CMP

• Liver/kidney disease

• Hypo/hyperglycemia

Urinalysis: UTI

Dementia Investigations: Imaging

MRI/CT

Detect structural abnormalities + brain atrophy/infarct

Dementia Investigations: Genotyping

For symptomatic pts

Assess risk of EOAD

Dementia Investigations: EEG

R/O delirium

Dementia: Treatment/Management

Supportive therapy

Pharmacological

Dementia Management: Supportive Therapy

Regular assessment

Maintain predictable schedule + familiar home environment

Manage behavioural + psychological symptoms

Dementia Management: Pharmacological

Cholinesterase inhibitors

NMDA-receptor antagonists

Monoclonal Abs

Dementia Pharmacologicals: Cholinesterase Inhibitors

Ex: Donepezil, galantamine, rivastigmine

MOA: Inhibit AChE = Decrease ACh breakdown = Increase ACh = Improve neuron conduction = Improve memory

Indications: Mild to moderate AD

Adverse Effects:

• Bradycardia

• Hypotension

• Increased sweating

• Muscle weakness + paralysis

Dementia Pharmacologicals: NMDA-Receptor Antagonists

Ex: Memantine

MOA: Inhibit NMDA receptors = Increase dopamine release + decrease dopamine reuptake = Improve neuron conduction = Improve memory

Indications: Moderate to severe AD

Adverse Effects:

• Atazia

• Livedo reticularis (reticular reddish-blue skin discolouration)

• Peripheral edema

Dementia Pharmacologicals: Monoclonal Abs

Ex: Lecanemab, donanemab

MOA: Abs against beta-amyloid = Prevent aggregation + plaque formation

Indications: Mild AD

Adverse Effects:

• Allergic reaction

• Headache

Dementia: Complications

Difficulty eating

• Dysphagia

• Refusal

Infections

• UTI

• Respiratory (aspiration pneumonia)

Dementia vs Delirium: Onset

Delirium: Sudden

Dementia: Insidious

Dementia vs Delirium: Course

Delirium: Rapid + fluctuating

Dementia: Slow + progressive deterioration

Dementia vs Delirium: Memory Impairment

Delirium: Recent memory loss

Dementia: Recent → Remote memory loss

Dementia vs Delirium: Hallucinations

Delirium: Visual + tactile

Dementia: Usually in advanced disease only

Dementia vs Delirium: EEG

Delirium: Abnormal

Dementia: Normal

Dementia vs Delirium: Reversibility

Delirium: Reversible

Dementia: Irreversible