57 - Neurodegenerative Diseases Flashcards
Dementia - Practical Definition
Decline in cognitive functioning
From a previously elevated baseline
Impairs activities of daily living
Diagnostic tools for detecting dementia
MMSE
Exam
History
Family Member Accounts
Mild Cognitive Impairment
Subjective complaint
Activities of daily living not affected
10% annually progress to dementia (Alzheimer’s)
Causes of Dementia
Primary Neurodegenerative Disorders Vascular Dementias Inflammatory Dementias Infectious Dementias Neoplastic Dementias Physical Dementias Metabolic Dementias
Alzheimer Disease
Most common cause of
Most cases sporadic
Alzheimer Disease - Strongest risk factor
Age
Alzheimer Disease - Signs
Memory impairment (Earliest)
Language impairment also common early in presentation (semantic)
Motor and sensory symptoms absent or present late in disease course
Alzheimer Disease - Definite Diagnosis
Neuropathology
Alzheimer - Gross Path
Thinning of gyri
Widening of sulci
Occipital sparing (until the very end)
Alzheimer Disease - Hippocampus
Loss of neurons and damage earliest in the disease
Alzheimer Disease - Histology
Neuritic Plaques = Beta Amyloid Plaques (Hippocampus)
Dense core = more demented
See plaques in normal aging, though!!! Plaques don’t correlate
Beta Amyloid Formation
APP
Step 1 - Cleaved by α-secretatse (good) or β-secretase (bad)
Step 2 - Cleaved by γ-secretase
Good pathway - no plaque
Bad pathway - plaque
Alzheimer Disease - Deposits that correlate more
Tau - Neurofibrillary Tangles (INSIDE the neuron)
Tau normally stabilizes microtubules
Begins in transentorhinal cortex and hippocampus
Progresses to other areas of temporal cortex, amygdala, limbic areas
Spreads to neocortex in frontal, parietal areas
Finally reaches primary motor cortex and primary visual cortex
Ghost tangles
Tombstones! Neuron dies but deposit remains
Genes involved in AD
Genetic changes all related to β-amyloid!!
APP - Chromosome 21
Presenilin 1 & 2 (part of γ-secretase complex)
Trisomy 21
ApoE ε4 - Lipoprotein produced in liver & brain, transports β-amyloid, involved in sporadic cases
ApoE ε2 seems to be PROTECTIVE though. Weirdsies.
Which happens earlier? β-amyloid or Tau?
β-amyloid
Alzheimer Disease - Therapy
Cholinesterase Inhibitors:
Donepezil
Rivastigmine
Galantamine
NMDA partial antagonists:
Memantine
Alzheimer Disease - Future Therapies
Clear β-amyloid from brain
Inhibit β-amyloid oligimerization
Remove phospho-tau or prevent tau phosphorylation
Rescuing synaptic dysfunction
Parkinson Disease - Locations
Dorsal nucleus of vagus Locus Coeruleus Pars compacta of Substantia Nigra Hypothalamus Substantia Innominata -> Mesolimbic Cortex
Parkinsonism - Criteria
Bradykinesia
Tremor (resting)
Rigidity
Postural Instability
Parkinson’s Disease
Most common cause of Parkinsonism
Mean age of onset - 61
Mean duration - 13 years
Neuronal loss with Lewy Bodies (α-synuclein)
Parkinson’s Disease - Symptoms
Parkinsonism
Autonomic dysfunction
Cognitive Disturbances
Dysphagia
Lewy Bodies
Round Cytoplasmic 8 - 30 μm α-synuclein Ubiquitin 5% asymptomatic
Concentric look, lightens neuromelanin
Diffuse Lewy Body Disease - Clinical
Similar symptoms to AD Fluctuations in cognitive ability Visual hallucinations Neuropsychiatric symptoms (anxiety, depression) Parkinsonism
Oft comorbid with AD
