L53 - Molecular basis of neurological disease II - Alzheimer's and Parkinson's Flashcards
Epidemiology of Parkinson’s? Prevalence ?
2nd most common neurodegenerative disorder
1.5 times more common in men than in women
Majority = sporadic; 10-20%: family history Minority = monogenic (rare)
Inheritance pattern of Parkinson’s?
Inheritance depends on the mutant gene (PARK 1 -11 mutation all have different inheritance patterns)
- All autosomal inheritance, split between AR and AD
List 6 cardinal features of Parkinson’s?
- Tremor at rest (asymmetric)
- Bradykinesia
- Back Rigidity with forward tilt + abnormal gait
- Loss of postural reflex
- Flexed posture of neck, trunk and limbs
- Freezing phenomenon
Which brain region is most affected by Parkinson’s?
substantia nigra pars compacta (SNpc),
locus ceruleus (LC)
Describe the pathological changes to brain areas affected in Parkinson’s?
At substantia nigra pars compacta (SNpc), locus ceruleus (LC):
- Depigmentation due to dopamine depletion»_space; loss of neuromelanin
- Loss of monoamine neurons causing dopamine depletion
- Presence of Lewy bodies ( intracytoplasmic eosinophilic
inclusion bodies) + Increased glial cells
Lewy- bodies is a pathological hallmark specific to Parkinson’s. T or F?
False
pathologic hallmark of PD, but not specific
(found in 10% brains with other neurodegenerative diseases)
Composition of Lewy-bodies? Pathological function in PD?
α-synuclein*** + other proteins (e.g. ubiquitin)
Cause mitochondrial dysfunction and neurodegeneration
Explain how neurological changes in Parkinsons cause motor deficit?
Loss of monoamine neurons at substantia nigra pars compacta + Locus ceruleus
> > dopamine depletion in substantia nigra and nigrostriatal pathway to caudate, putamen
> > Less direct pathway, More indirect pathway = increase inhibition of thalamus and more output to supplementary motor area
> > Bradykinesia, rigidity, other parkinsonian signs
List the 2 most important genes in the pathogenesis of PD?
PARK1: a- synuclein mutation
PARK2: Parkin (ubiquitin ligase) mutation
Compare the normal and pathological function of a-synuclein?
Normal:
- Dynamic aggregation to form α-helix-like structures
- Associated with membrane, in equilibrium with cytosol
Pathological:
- mutated α-synuclein aggregates via small oligomeric intermediates into larger fibrillar forms (β-sheet)
- bound by ubiquitin into Lewy bodies*****
Compare the normal and pathological function of Parkin (ubiquitin ligase)?
Normal:
Involved in ubiquitin-proteasome pathway: E3 ubiquitin ligase/ Parkin
» Tag polyubiquitin chains to proteins for degradation
Pathological:
2 defective copies of Parkin = no Parkin
» Parkin substrates accumulate in neurons
» OXIDATIVE TOXICITY to dopaminergic (DA) nigral neurons *****
Explain why Parkin mutation exerts more effect on neurons in substantia nigra?
Dopaminergic nigral neurons:
- intrinsic exposure to oxidative stress***
» easier protein damage and misfolding
» More vulnerable to Parkin mutation
Classify Alzheimer’s by onset and family history
By the age of onset:
Early onset <= 65
Late onset >65
By family history:
Familial case (~10%): genes with high penetrance, large effect
Sporadic case: commoner risk alleles with small effect size
List the 3 autosomal dominant genes responsible for almost all early-onset AD
APP
PSEN1
PSEN2
2 pathological hallmarks of AD in brain?
1) Amyloid plaques:
Amyloid protein, other associated proteins, non-nerve cells
2) Neurofibrillary tangles:
abnormal form of the microtubule associated protein tau
Twin concordance rate of AD?
Twins concordance rate: monozygotic (40-50%) vs. dizygotic (10-20%)
Criteria for dx of AD? (3)
- Deficits in 2 or more areas of cognition
- MMSE score < 24
- neuropsychological test evaluation shows progressive worsening of cognitive function
What is the most common cause of dementia in elderlies?
AD
List some risk factors for AD?
- Age **
- Down’s syndrome
- Family history dementia especially early onset **
- Severe head injury
- Vascular risk factors?
- Genetic factors **
- Lifestyles **
Describe the defects in memory caused by AD?
Impaired anterograde episodic memory: cannot remember recent events but can remember long-term
Delayed recall of stories
Difficulty in Paired associates (visual memory and new learning)
Working memory is spared
Describe the attentional and executive deficits caused by AD?
Poor concentration, selective attention
Problem with complex tasks, e.g. Wisconsin Card Sorting Test
Describe the language and knowledge deficits caused by AD?
Impaired semantics, category fluency, word definitions, word finding
Later phonological, syntactic deficits
Describe the visuospatial, perceptual deficits caused by AD?
Impaired drawing (especially 3D)
Apraxia (mainly conceptual, e.g. cannot plan specific movement)
List some neuropsychiatric features of AD?
Common:
- Apathy
- Anxiety
- Depression
Late symptoms:
- Agitation, disruptive behavior
- Delusion
- Paranoia (theft of items)
- Phantom lodger
