Alzheimer’s & Frontotemporal Dementia Flashcards
Behavioural symptoms of Alzheimer’s (5)
- Capgrass syndrome, reduplicative paramnesia, phantom border syndrome
APATHY, DEPRESSION, ANXIETY:
- Apathy: Lack of interest and motivation, impaired emotional expression
- Depression and anxiety prevalent as AD progresses (38%)
- Tend to have catastrophic reactions (intense emotional outbursts of short duration in rxn to enviro stressors or inability to do self-care)
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ANOSOGNOSIA:
- Unawareness of illness/deficits (20-80% prevalence)
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PSYCHOSIS:
- Delusions and hallucinations in middle to late stages (40% prevalence)
- Hallucinations: False sensory perception in absence of external stimulus (usually visual, sometimes auditory); deceased family, unknown intruders, animals
- Delusions: Firmly held beliefs in things not real, usually persecutory (Capgras syndrome-Belief that spouse is imposter; Reduplicative paramnesia-Belief that place has been duplicated/relocated; Phantom border syndrome-Sensation that someone uninvited is in their home)
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AGITATION:
- Verbal aggression more common than physical, often associated with w/ delusions and delusional misidentification or wanting to do own self-care (60% prevalence)
- Nonaggressive behavs involve wandering (impaired visuospatial skills and delusional misidentification), repetitive behavs (rummaging thru drawers to find items they can’t name or describe), delusions of theft (contribute to frequent searching and sorting of personal items)
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SUNDOWNING:
- Start or increase in confusion and behav symptoms in afternoon and evening (20% prevalence)
- May be caused by tiredness, low lighting/shadows, disruption of circadian rhythm they deterioration of suprchiasmatic nucleus
Sleep disorders in Alzheimer’s include? (3)
- Correlates with what?
Excessive awakenings, daytime sleepiness, complete day/night sleep pattern reversal
Correlate w/ severity of cognitive decline
Cholinergic hypothesis (Davies and Maloney, 1976)
- Explain acetylcholinesterase (AChE) + its inhibitors (donepezil, galantamine, rivastigmine) do
- N-methyl-D-aspartate (NMDA) receptor antagonist (memantine)
(Alzheimer’s)
Activity of choline acetyltransferase was greatly reduced in amygdala, hippocampus, and cortex of ppl w/ AD
- Assoc w/ decreased concentration of acetylcholine in synapse
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AChE breaks down acetylcholine after it’s released into the synapse
- Inhibitors block breakdown of acetylcholine by binding to active site of AChE, increasing lvl of acetylcholine in synapse and its duration - Efficacy of this reduces w/ AD
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- Used in conjunction w/ AChE inhibitors to treat moderate to severe AD
- Blocks open channel of NMDA receptors in voltage-dependent manner, restores glutamatergic homeostasis which is disrupted in AD
- But efficacy is low
Amyloid-cascade hypothesis
- B-secretase (BACE1) inhibitors
- Aducanumab and lecanemab
(Alzheimer’s)
B-secretase and Y-secretase break down amyloid precursor protein (APP) to make AB peptides, which misfold and aggregate into amyloid plaques and drive tau pathology
- Inhibitor aims to reduce AB by inhibiting B-secretase but they’ve failed to improve or even worsen cognitive decline
- Immunotherapies that target and remove AB and amyloid plaques; approved for MCI or mild dementia but mixed effectiveness in aducanumab at slowing cognitive decline
Tau propagation hypothesis
- Kinase inhibitors and vaccines
(Alzheimer’s)
Tau proteins become hyperphosphorylated, dissociate from microtubules, adopt abnormal shapes, move from axons to cell bodies, and form tangles
- Block paired helical filaments or block detachment of tau from microtubules after phosphorylation w/ inhibitor or vaccine
- Effectiveness too early to tell
Glial-lymphatic (glymphatic) system
- Steps (5)
- More active in day or night?
- Dysfunctions w/ aging and AD
- Waste clearance system in brain
1) CSF enters ventricles, some get caught up in periarterial space and flow alongside artery
2) Pulses from artery will drive CSF deep unto brain into fluid filled spaces between neurons (interstitial fluid)
3) Fluid collects molecules and waste products as it moves between neurons
4) Pushes back into perivascular space on the venous side (perivenous space)
5) Drained out if brain via lymphatic vessels, taking waste products with it
— - More active at night during sleep (Tau and AB cleared more rapidly during sleep in rodents)
— - Arterial walls stiffen (limiting push of CSF they system), less CSF production, and reduced time spent in slow-wave sleep w/ age
2 subtypes of frontotemporal dementia
- Age of onset
- Behavioural (frontal) variant FTD
- Primary progressive aphasia (PPA)
- Onset is 50-60 years old, some as young as teens or 20s
Diagnostic evaluation of frontotemporal dementia
- Clinical history and physician evaluation
- Neuropsychological evaluation
- Biomarker studies
Clinical history and physician evaluation:
- Examine progression of behav changes, family history, behav in face to face interviews
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Neuropsychological evaluation:
- Performance in neuropsychological tests (longitudinal to look at gradual decline)
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Biomarker studies:
- Neuroimaging and blood tests to rule out other possible causes
Symptoms of behavioural (frontal) variant FTD (6)
APATHY:
- Lack of empathy, decreased interest in social and other daily activities, poor personal hygiene
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BEHAVIOURAL DISINHIBITION:
- Socially inappropriate behavs, impulsiveness, carelessness
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REPETITIVE BEHAVIOURS:
- Compulsive ritualistic behavs, repetitive use of verbal expressions, repetitive motor movements
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EATING AND ORAL BEHAVIOURS:
- Binge eating, increased sweets/alcohol consumption, hyperorality (compulsively put things in mouth)
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EXECUTIVE DYSFUNCTION:
- Lack of insight into own behavs and its consequences, poor judgment, inflexibility or rigid thinking
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LANGUAGE IMPAIRMENT:
- Impaired verbal fluency and naming
Loss of gray matter and increase in ventricle size in which frontotemporal regions in FTD? (4)
Which areas spared initially? (3)
Medial prefrontal cortex
Orbifrontal cortex
Insular cortex
Anterior temporal loves
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Occipital, parietal, dorsolateral prefrontal cortex
(Primary progressive aphasia, PPA)
- Subtypes (2)
- Which PPA is associated with Alzheimer’s?
- Main symptom for first 2 years?
SEMANTIC VARIANT
NON-FLUENT
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- Logopenic variant POA assoc w/ Alzheimer’s
- Esp considered if early deficits in episodic + visual memory and visuoperceptual skills
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- Main symptom for first 2 years is language dysfunction
Semantic variant PPA
- Symptoms (5)
- Difficulties when atrophy of anterior temporal lobes left first vs right first
- Anomia (Word-finding difficulty, esp nouns)
- Impaired word comprehension
- Agnosia (Impaired recognition of objects/people)
- Surface dyslexia and dysgraphia
- Behavioural disturbances (Irritability, emotional withdrawal, strict/selective eating); happens during spread from temporal lobe to OFC
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Left -> Language difficulties (more common)
Right -> Behavioural difficulties (often presents as behavioural variant FTD)
Non-fluent variant PPA
- Symptoms (6)
- Atrophy where? (3)
- Apraxia of speech (slow, laboured, halting speech production)
- Agrammatism (Omission or misuse of grammar)
- Impaired comprehension of complex sentences
- Minimal behav disturbances
- Mild anomia for nouns
- Some may have intact writing ability despite speaking deficits
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Left posterior frontal and insula regions, left basal ganglia
ASL-Frontotemporal spectrum disorder
- More likely to develop in what kind of PPA?
FTD subtypes of parkinson-plus syndromes:
- Corticobasal syndrome
- Progressive supranuclear palsy
- More likely to develop in which PPA?
Neurodegenerative disease w/ loss of upper and lower motor neurons, leading to paralysis and eventual respiratory failure
- More likely to develop in behavioural variant
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- Corticobasal syndrome: Rigidity, bradykinesia/akinesia, dystonia beginning unilaterally
- Progressive supranuclear palsy: Oculomotor abnormalities, postural instability w/ frequent falls, slurred speech, dysphagia
- More likely to develop in behavioural variant; then nonfluent variant
Pathology of frontotemporal dementia (FTD):
- FTLD-Tau
- FTLD-TDP
- FTLD-FUS
- Tau positive inckusions
- Pick bodies (disordered tau fibrils) can be seen in behavioural variant FTD, Pick’s disease
- 36-50% of cases
- Assoc w/ behavioural variant FTD
— - TAR DNA-binding protein w/ molecular weight 43 kDa (TDP-43) positive inclusions
- TDP-43 misfolds to cause cell death
- 50% of cases
- Multiple subtypes:
- TYPE A: Nonfluent variant PPA and behavioural variant FTD; atrophy in lateral frontal, temporal lobe, orbifrontal, ACC, inferior parietal
- TYPE B: Behavioural variant FTD; Atrophy in medial PFC, insula, cingulate, temporal
- TYPE C: Semantic variant PPA; atrophy in asymmetric anterior temporal lobe w/ amygdala and hippocampus, orbifrontal, insula
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- Fused-in-sarcoma (FUS) protein positive inclusions
- <10% of cases
- Associated w/ behavioural variant FTD
