Neurodegenerative Disorders Flashcards
What can be found in the brain of patients with Alzheimer’s Disease?
- amyloid plaques of A-beta peptides extracellularly
- neurofibrillary tangles made of hyperphosphorylated tau in paired helical filaments intracellularly
- endosomal malfunction: mutation in the retromer protein resulting in increased trafficking of APP and beta-secretases to the same compartment
How are A-beta peptides formed?
- APP goes through secretory pathway and is normally cleaved by alpha- and gamma- secretases to form fragments
- in Alzheimers, there is abnormal cleavage by beta-secretases which form A-beta peptides
What are the important biomarkers for Alzheimer’s Disease?
Structure (CT/MRI): grey matter shrinkage (esp. medial temporal lobe)
Function (PET): perfusion SPECT to image variations in regional cerebral blood flow
Amyloid/tau PET: using specific reading agents which are labelled to quantify the toxic proteins in the brain
CSF: test for amyloid-beta42, total tau, and p-tau
What is the targets and treatment of Alzheimer’s Disease?
- slow neurochemical changes occuring in the brain
- most significant loss is in ACh neurons (causes learning and memory deficit) so use drugs that act on ACh receptor or AChE (galantamine, donepezil, rivastigmine)
- target excitotoxicity (recruitment of extra-synaptic receptors due to glutamate release from astrocytes in response to loss of neurons)
- memantine (blocks current through glutamate channels)
What can be found in the brain of patients with Parkinson’s Disease?
- aggregation of alpha-synuclein protein
- termed Lewy bodies in large aggregations in substantia nigra
- endosomal malfunctioning promoting alpha-synuclein aggregations
Contrast Parkinson’s disease and LBD
- Parkinson’s usually starts as a movement disorder with majority progressing to dementia. Has different genetic predispositions
- LBD starts with dementia and can then progress with parkinsonism movement disorders later. Different genetic associations but usually not familial
- Lewy bodies present in both
Describe the symptoms and mechanisms of ALS
Symptoms:
- fasciculations in arm, leg, shoulder, tongue
- muscle cramps
- tight, stiff muscles
- weakness of arm, leg, neck, diaphragm
- slurred and nasal speech
- difficulty chewing or swallowing
Mechanism:
- motor neuron disease involving UMN and LMN death
- protein aggregation in motor neurons and glial cells
- excitotoxicity
What is the treatment for ALS?
- riluzole
- decreases glutamate release and uptake into astrocutes
What are the 3 main features of dementia?
Neuropsychological deficits: amnesia, aphasia, agnosia, apraxia
Neuropsychiatric features: behaviour symptoms, psychological symptoms, psychiatric symptoms
Affected ADL: instrumental, basic
Describe the cognitive assessments you could carry out on a dementia patient
Sequencing and fluency (frontal lobes):
- luria hand sequencing tast
- verbal fluency 1-minute words
Memory and speech (temporal):
- address test
- object recall
Spatial awareness and language (parietal):
- naming objects
- clock face
Define mild cognitive impairment
subjective memory impairment and cognitive impairment not meeting dementia diagnostic criteria (mainly not impairing core ADLs)
Describe the challenges of clinical trials involving neurodegenerative disorders
Most testing:
- has been developed for more severe dementia meaning symptoms need to be severe to register changes
- cognitive domains known to be impaired at early stages of disease are not measured
- majority of subjects score the maximum in over half of the subcategories even in mild dementia/MCI
- lack of definitive diagnostic indicators
- difficult to measure precisely or reproducibly without bias
