Memory, Amnesia & Alzheimer's Disease

Memory, Amnesia & Alzheimer's Disease

Overview

  • Sources: Alzheimer’s Association and various research publications.

  • General structure:
      1. Dementias
      2. Alzheimer's Disease
      3. A Case of Exceptional Memory
      4. Amnesias

  • Neurofeedback and alexithymia will be discussed if time allows.

Final Exam Information

  • Date and Time:
      - Final Exam: Saturday, April 25, 12-1:30 pm (SRC 220C)
      - Q&A Session: Friday, April 24, 4-5 pm (Zoom)

Dementias

  • Definition: "Dementia" was historically a broad term for any kind of mental illness, literally meaning "to be outside one’s own mind."

  • Historical Context:
      - Earliest records date back approximately 5000 years to ancient Egypt.
      - In the 18th Century, Phillipe Pinel categorized mental disorders into:
        - Dementia
        - Idiocy
        - Melancholia
        - Mania with delirium
        - Mania without delirium

Early History of Dementias

  • 19th Century:
      - Dementia was seen as a terminal stage of mental illness.
      - Emil Kraeplin distinguished between early and late forms of dementia.
      - Jean-Etienne Esquirol discussed senile dementia related to aging, noting alterations in memory and attention.
      - Etienne-Jean Georget advocated for the concept of irreversibility in dementia; however, this is considered invalid today.

Common Types of Dementia

  • Statistics:
      - Alzheimer’s Disease: 60%
      - Vascular Dementia: 20%
      - Dementia with Lewy Bodies: 5%
      - Fronto-Temporal Dementia: 2%
      - Parkinson’s Disease with Dementia (PDD):

  • General notes:
      - Dementias are complex with no single clear cause, often resulting from repeated strokes.
      - Includes clumping of proteins in Parkinson’s Disease affecting memory and inhibition functions.

Causes of Dementia

  • Primary causes include:
      - Alzheimer's disease
      - Vascular dementia
      - Dementia with Lewy bodies
      - Fronto-temporal dementia
      - Parkinson's disease
      - Alcohol-related (Korsakoff Syndrome)
      - Huntington's disease
      - Creutzfeldt-Jakob disease
      - HIV
      - Multiple sclerosis
      - Neurosyphilis
      - Normal-pressure hydrocephalus
      - Chronic subdural hematoma
      - Cerebral tumors
      - Hypothyroidism
      - Progressive supranuclear palsy
      - Tuberculosis

  • Prion diseases contribute to misfolding of proteins through pathological spread hypotheses (Holmes & Amin, 2020).

Historical Context of Alzheimer’s Disease

  • Early 20th Century:
      - Alois Alzheimer presents a case of pre-senile dementia at a conference in conjunction with a post-mortem examination revealing plaques and tangles.
      - The term "Alzheimer's Disease" was initially reserved for pre-senile dementia but gained wider usage over time.
      - The 1960s saw major changes in research with advancements like electron microscopy.

Diagnostic Criteria in DSM

  • DSM-I (1952): No mention of dementias.

  • DSM-II (1968): Alzheimer’s Disease classified as pre-senile dementia.

  • DSM-III-R (1987): Inclusion of pre-senile and senile forms of Alzheimer’s.

  • DSM-5 (2013): The term "dementia" replaced with "major neurocognitive disorder."

Alzheimer's Disease

  • Progression:
      - A progressive disorder leading to dementia and eventual death.

  • Symptoms:
      - Early: Selective memory decline
      - Later: Confusion, irritability, anxiety, deteriorating speech
      - Advanced: Severe issues with basic functions (swallowing, bladder control).

Types of Alzheimer's Disease

  • Early-Onset Alzheimer's Disease (EOAD):
      - Diagnosis before age 65; accounts for 5-10% of cases.

  • Late-Onset Alzheimer's Disease (LOAD):
      - Diagnosis after age 65; 90-95% of cases.

  • Mild Cognitive Impairment (MCI): Preliminary cognitive symptoms leading to AD diagnosis, but not definitive.

Memory Characteristics in Alzheimer's Disease

  • Selective memory declines occur progressively.
      - Initial classic signs: Short-term memory loss and prospective memory issues.

  • Early Phase: Memory for new facts affected; older memories less so.

  • Medium Phase: Long-term episodic memory begins to decline.

  • Early signs may manifest in forgetting future plans.

Defining Characteristics of Alzheimer’s Disease

  1. Neurofibrillary tangles (tau) – stabilization molecule.

  2. Amyloid plaques (β-amyloid) – pathological aggregates.

  3. Substantial decrease in brain volume – loss of neuronal processes and shrinkage of synapses.

Hallmarks of Alzheimer’s Disease in the Brain

  • Alzheimer's disease is associated with:
      - Amyloid plaques – abnormal clusters between neurons.
      - Tau tangles – stabilize microtubules, but when they misfold and accumulate, they cause neurodegeneration.
      - Microglia: Initially protect neurons but can trigger inflammation and worsen cognitive decline.
      - Astrocytes: Assist in clean-up of damaged neurons.

Structural Changes in Alzheimer's Disease

  • Brain structure changes:
      - The hippocampus is severely affected, crucial for memory.
      - Noticeable shrinkage of the cerebral cortex; increased fluid-filled ventricles.

  • Microscopic changes visible with:
      - Accumulation of beta-amyloid plaques.
      - Neurofibrillary tangles.

Differential Diagnosis for Late-Onset Alzheimer's Disease

  • Memory disorders associated with:
      - Age-related mild memory impairment
      - Mild cognitive impairment
      - Depression
      - Other dementias (Vascular dementia, Dementia with Lewy Bodies, Frontotemporal Dementia)
      - Rare but treatable causes (Vitamin B12 deficiency, Normal-pressure hydrocephalus, Hypothyroidism, Neurosyphilis).

Biomarkers for Alzheimer’s Disease

  1. Low beta-amyloid levels in cerebrospinal fluid.

  2. High tau levels in cerebrospinal fluid.

  3. Decreased hippocampal volume (as shown by MRI).

  4. Decreased brain metabolism (FDG-PET).

  5. Investigational blood tests for beta-amyloid.

Theories of Pathogenesis

  1. Amyloid cascade hypothesis – suggests beta-amyloid plaques trigger cell death and neuroinflammation.

  2. Neurofibrillary (tau) hypothesis – aggregates of tau protein disrupt neuron function.

  3. Inflammation hypothesis (microglia) – chronic neuroinflammation contributes to disease progression.

  4. Pathogenic Spread hypothesis – relates to the spreading of misfolded proteins.

  5. Down Syndrome: Increased risk of developing Alzheimer's due to trisomy 21.

Microglia Involvement in Alzheimer’s Disease

  • Healthy Functions: Microglia monitor and clear damaged cells.

  • In Disease:
      - Overreact leading to excessive inflammation and neuronal death.
      - Mislabel synaptic connections as threats, contributing to synapse loss.

Current Treatments for Alzheimer's Disease

  • Acetylcholinesterase Inhibitors (e.g., donepezil) improve cognitive function.

  • NMDA-Receptor Antagonists (e.g., memantine for moderate/severe AD) limit neurotoxic effects and aid cognition.

  • Aducanumab, an antibody, targets amyloid plaques (controversial FDA approval in 2021).

  • SSRIs are used for depression with limited evidence for effectiveness.

  • Atypical antipsychotics may help with psychotic symptoms and agitation.

Case Study of Exceptional Memory

  • A.R. Luria studied a mnemonist known as S. over 30 years.

  • S. displayed extraordinary memory capabilities, able to recite detailed numerical tables after brief exposure (Table 1 from Luria, 1968).

S.'s Mental Imagery

  • Developed associations with numbers and color-coded images to enhance recall:
      - Example: 1 as a proud man, 2 as a high-spirited woman, etc.

Case of H.M.

  • Bilateral medial temporal lobectomy was performed resulting in profound anterograde amnesia.

  • Types of Amnesia Related to H.M.:
      - Retrograde Amnesia: Inability to recall memories from prior to the surgery.
      - Anterograde Amnesia: Difficulty forming new memories post-surgery.
      - H.M.'s short-term memory (up to 30 seconds) remained intact shown by his adequate performance on digit span tests.

Testing Memory

  • Digit Span Test: Participants recall lists of digits read sequentially.
      - H.M.’s Results:
        - Could not exceed 8 digits after multiple trials, while others typically recall 15 digits.

Explicit vs. Implicit Memory

  • Mirror Drawing Test: H.M. improved at the task without retaining memory of having performed it, demonstrating intact implicit memory while lacking explicit memory.

Quotes from H.M.

  • Illustrate his conscious experience while living with amnesia:
    "Every day is alone in itself…" (H.M.; quoted in Milner et al., 1968).

Amnesia of Korsakoff’s Syndrome

  • Resulting from thiamine (vitamin B1) deficiency, often linked to chronic alcohol misuse.

  • Symptoms include both anterograde and retrograde amnesia, along with cognitive and personality changes.

  • Medial diencephalic amnesia implicates damage in specific thalamic nuclei.