Neurodegenerative Disease Flashcards
What is the major risk factor for most neurodegenerative diseases?
Old age
What is the biggest growing demographic group in the UK?
> 80 years
How many people have dementia?
- 50 m (world)
- Will rise to 140m by 2050
- Around 900,000 in UK
How many people have Parkinsons disease in the UK?
130,000
What is the average life expectancy for someone with motor neuron disease?
3 years
What percentage of Dementia is Alzheimer’s?
70%
What is the prevelance of AD in different age groups?
- 1% at 65
- 40% at 90
(Doubles every 5 years)
Is AD more common in men or women?
Women
What percetage of ADs are familial?
~ 10%
What are the signature proteins (aggreagates) of AD?
- Extracellular amyloid plaques (largely composed of AB peptides)
- Intracellular fibrils (neurofibrilary tangles) (predominantly composed of tau) (MT stabilising protein)
- Tau in tangles is hyperphosphorylated + forms paired helical filaments
What is the AB peptide made from?
Amyloid Precursor Peptide being cleaved by secretases abnormally
What are some genes which cause autosomal dominant familial Alzheimer’s?
- Amyloid precursor protein gene (downs, mutations, duplications)
- Presenilin-1 gene
- Presenilin-2 gene
What is the most common gene disorder which causes familial Alzheimer’s?
Presenilin-1 (80% of early onset cases)
What are major risk genes associated with Alzheimer’s?
- ApoE4 (lipoprotein affects SORL1 trafficking)
- TREM2 (binds ApoE, functions in recycling)
- SORL1 (endocytic sorting in retromer)
What is at the heart of generating the Alzheimer phenotype?
- Membrane trafficking and dysfunctional retromeres
- Endosome enlargement occurs earlier than Tau or Amyloid
- Aberrant trafficking results in mixing of Beta-secretase and APP
Key components of retromer are depressed in what area in AD patients?
Hippocampus
What is seen on CT/MRI in Alzheimer’s?
Grey matter shrinkage (e.g medial temporal lobe, posterior cingulate and precuneus)
- Not specific to AD
What will perfusion SPECT show in AD?
VAriations in regional cerebral blood flow - noticable early in AD
WHat can FDG-PET show in AD?
Uptake of FDG proportional to cerebral glucose metabolism, reflects cerebral metabolism better than amylois PET for assessing function in AD
WHat does Amyloid PET scan show in AD?
C-PiB crosses blood-brain barrier, binds to ABeta quantitative imaging. More recent probe is 18F-flutemetamol binds to amyloid deposits in AD
What does a Tau PET show in AD?
18F-flortaucipir binds to neurofibrillary tangles in AD
WHat are the main CSF biomarkers in AD?
- Amyloid-B42
- total tau
- Phosphorylated tau (p-tau)
What can pTau 181 assay (peripheral bllod flow) detect in established AD?
- Established AD correlates with tangles/plaques distinguished from other dementias
- Increases the risk of developing AD by 11fold
What did old/ineffective AD therpies focus on?
- ANtibodies to toxic aggregates amyloid beta and tau
- Phosphorylation -countering and Microtubule-modifying drugs
- Often caused inflammatory changes in brain
What is the new approach to treating AD?
Focus on developing molecular chaperones to improve retromer functions and remove trafficking defect (TPT-172; in development no human trials yet)
What chemicals are specifically reduced in AD?
- Ach, related to neuronal loss from nucleus basalis of Meynert
- Loss of GABA from cortex to secondary neuronal loss
- Serotonin (5HT) input from dorsal raphe nuclei reduced
- NA input from locus coeruleus reduced
Loss of what neurons is thought to be mostly responsible for memory and learning defects?
Ach
What drugs affect Ach turnover and are used to treat AD?
- Galantamine
- Donepezil
- Rivastigmine
What is excitotoxicity?
NEuronal death caused by the overactivation of excitatory amino acid receptors - happens in AD - glutamte causes extrasynaptic activity which promotes cell death
What drug to treat AD is associated with reducing excitotoxity?
Memantine (moderate to severe AD)
Parkinon’s disease is primarily due to to the accumulation of what aggregate?
Alpha-synuclein create Lewy bodies
What area of the brain does PD primarily affect?
Substantia nigra
How are Lewy body dementia and PDs linked to each other?
- PD starts with movement disorder then progresses to dementia (70% of the time)
- Lewy Body dementia starts as dementia but can progress to a movement disorder
- Both have Lewy bodies which contain alpha-synuclein present in cell bodies
What percentage of dementia’s are Lewy Bodies?
5% of new cases (15% of all dementia)
What kind of genes are associated with PD?
- Genes associated with endosomes e.g VPS35 retromer component
- Links to alpha-synuclein aggregation
What are some different types of Motorneuron diseases?
- Amyotrophic Lateral Sclerosis (UMN and LMN)
- Progressive Muscular Atrophy (LMN)
- Primary Lateral Sclerosis (UMN)
- Spinal Muscular Atrophy
- Lou Gehrig’s disease
What is by farthe most common for of MND?
Amylotrophic lateral Sclerosis (ALS)
What is associated with Amylotrophic lateral Sclerosis?
- Affects UMNs and LMNs
- Most patients die within 3-5 years
- Fasiculations
- Muscle cramps
- Tight and stiff muscles
- Muscle weakness affecting an arm, a leg, neck or diaphragm
- Slurred and nasal speech
- Difficulty chewing or swallowing
What is Superoxide Dismutase 1?
- Amylotrophic Lateral Sclerosis - type of MND
- Familial type (5-10% of ALS diseases)
What are the different proteins responsible for ALS?
- Superoxide Dismutase 1
- TAR DNA Binding Protein (TDP-43)
- Fused in sarcoma (FUS)
- C9orf72 (most common also in FTD)
What drug can be used to treat ALS?
Riluzole
How does Riluzole thought to work?
- Reduces Glutamate release (calcium block)
- Increases astrocyte glutamate uptake
- Decreases glutamate levels
- Inhibits TDP43 metabolism via CK1delta (casein kinase) inhibition
What are the Neuropsychological deficits associated with dementia?
- Amnesia
- Aphasia
- Agnosia
- Apraxia
What are the frontal lobes associated with?
Sequencing and fluency
What are the temporal lobes associated with?
Memory speech (L)
WHat are the parietal lobes associated with?
Spatial awareness (R), Laungauage (L)
How does one test frontal lobe function?
- Luria hand sequencing task
- Verbal fluency 1 minute words F,A,S, animals
How does one test temporal lobe function?
- Address test
- Object recall
- Serial 7s
How does one test parietal lobe function?
- Clock face
- Naming objects
- Drawing cube, interlocking infinity
- Agnosia
What tests can be used to diagnose dementia?
- Mini-mental state Examination (MMSE)
- ACE (mobile) (100% specific; 84% sensitive)
What is MCI (Mild Cognitive Impairment)?
Subjective impairment and cognitive impairment but does not meet dementia diagnostic criteria - able to complete activities of daily living (ADL)
- May progress to dementia
What is the aim of demntia detecting treatment effects?
reliably, reproducibly and sensitively detect and monitor cognitive state/dementia
What would be the optimal features of a dementia detecting treatment?
- Test to test reproducible
- Tester to tester reproducible
- Invariant or adjustable to gender and age difference
- Detectiong of predementia/MCI
- Sensitive scale with no ceiling effects
What was the problem with ADAS-cog?
Does not produce linear scale - ceiling effects, need to be pretty demented to register change
What are some of the difficulties associated with doing trials on neurodegenerative diseases?
- Sensitivity, subjectivity and inherent bias can limit the usefulness of many traditional methods
- Diseases difficult to detect
- Measurement is problematic - how to measure precisely, reproducibly without bias the states of function and importantly how rto measure and be sensitive to changes in function
- Precision of data will be impaired by variability and poor measurement scales
