Dementia with Lewy Bodies and Biomarkers Flashcards
Where does alpha-synucleinopathy typically begin?
Around the brain stem
BUT can originate in other areas such as cortex, midbrain, and gut
What is the main protein involved in DLB pathology?
Alpha-synuclein (abnormal accumulations forming Lewy bodies)
What are the main challenges surrounding DLB?
▪️ Under-diagnosed
▪️ Under-treated
▪️ Under-researched
▪️ No licensed therapies - often highly sensitive to CNS-related side-effects with medications such as antiparkinsons and cholinesterase inhibitors
What are the core clinical features of DLB?
▪️ Fluctuating cognition (particularly attention and alertness)
▪️ Visual hallucinations
▪️ REM sleep behvaiour disorder (may precede cognitive decline)
▪️ One or more spontaneous features of parkinsonism
What are the supportive clinical features of DLB?
▪️ Sensitivity to antipsychotics
▪️ Postural instability
▪️ Autonomic dysfunction (e.g., constipation)
▪️ Hyposmia
▪️ etc….
What are the best indicative biomarker of DLB?
Reduced dopamine transporter uptake in basal ganglia as seen with SPECT/PET
What other biomarkers can be used to indicate DLB?
▪️ Abnormal iodine-MIBG myocardial scintigraphy
▪️ Polysomnographic confirmation of REM without atonia
What biomarkers can be used to SUPPORT diagnosis of DLB?
▪️ Relative preservation of mTL on imaging scan
▪️ Posterior slow-wave activity on EEG with fluctuations in pre-alpha/theta range
▪️ Increased EEG variability
▪️ Occipital hypoactivity on FDG-PET
How do you differentiate Dementia with Lewy Bodies from Parkinson’s Disease Dementia?
1-year rule:
▪️ DLB = dementia before or concurrently with parkinsonism
▪️ PDD = dementia in the context of PD, over a year between onset
What other pathology may be present in those with DLB and what does this suggest?
Alzheimer’s-like plaques
Mixed diagnosis/more severe disease
What symptoms may be reported in prodromal DLB?
▪️ Hyposmia
▪️ RBD
▪️ MCI (typically non-amnestic)
▪️ Isolated visual hallucinations
▪️ Primary autonomic dysfunction
▪️ Delirium-tendency
▪️ Motor symptoms (subtle, less specific?)
▪️ Depression
How common is DLB?
~16-24% of dementia
Why is it difficult to estimate the exact prevalence of DLB?
Patients may present to a range of clinics depending on first symptoms (e.g., sleep, memory, autonomic, motor)
How does outcome with DLB differ from AD?
Poorer:
▪️ Higher mortality
▪️ Higher caregiver burden
▪️ Longer hospital stay
▪️ Quicker transition to nursing home
Where is Lewy body pathology most likely to be found in the early stages?
▪️ Diffuse neocortical
▪️ Limbic
Where in the neuron does alpha-synucleinopathy thought to start in DLB?
At the presynaptic terminals
How is alpha-synucleinopathy though to cause symptoms in DLB?
▪️ Accumulation in presynaptic terminals
▪️ Synapse are lost (synaptopathy)
▪️ Dying-back-like neurodegeneration
What types of neurons are particularly sensitive to alpha-synuclein pathology?
Highly branched neurons (e.g., dopaminergic neurons in substantia nigra, serotonergic neurons)
More complex = higher energy demand = greater sensitivity to change
What investigations can NOT yet be used for diagnostic markers of DLB?
▪️ Molecular PET for alpha-synuclein
▪️ Proteomics (alpha-synuclein in blood and CSF)
▪️ Biopsy
What does an FDG-PET scan show?
Metabolism - will be reduced in areas of degeneration
Typically reduced in occipital lobe and PCC in DLB
What can MRI be used for in DLB?
Mainly excluding other causes of dementia - no specific DLB signs
How useful is EEG as a biomarker of DLB?
Very!
Found 100% of MCI-DLB had abnormal EEG compared to 7% of MCI-AD - good for distinguishing between the two
BUT not widely used yet
How useful are total alpha-synuclein CSF levels as a marker of DLB?
Not very - inconsistent results with most showing reduced levels but others showing increased or no change
What is Real-Time Quaking-Induced Conversion (RT-QUIC)?
A seeding technique whereby pathogenic proteins induce conformational changes in normal protein (not seen in healthy proteins)
Can then measure these changes
How can RT-QUIC be used for DLB?
▪️ High sensitivity and specificity for CSF alpha-synuclein
▪️ Promising findings for prodromal LB
▪️ Separating MCI-DLB from MCI-AD?
How can seeding techniques be used to detect pathological alpha-synuclein in blood?
Isolate nucleus-originating exosomes
What drugs show the best evidence for cognition in DLB?
Cholinesterase inhibitors (e.g, donepezil, rivastigmine)
(Memantine = inconsistent evidence)
What can be used to treat hallucinations in DLB?
Possibly antipsychotics (e.g., clozapine, quetiapine) although insufficient evidence and patients more sensitive to AE such as worsened cognition, parkinsonism
What is pimavanserin and what could it be used for?
New-style antipsychotic which has shown effectiveness for hallucinations in PD and psychotic symptoms in dementia, so may be promising in DLB but not yet available in Europe
What is the main issue with pharmacological treatment of DLB?
Insufficient evidence for most drugs with exception of cholinesterase inhibitors for cognition
Most medications used off-license
What might be considered for REM sleep behaviour disorder in DLB?
▪️ Melatonin
▪️ Clonazepam
▪️ Memantine
What might be considered for daytime sleepiness in DLB?
Modafinil
What might be considered for parkinsonism in DLB?
▪️ L-dopa
▪️ Zonisamide (currently RCTs in Asia)
How does pimavanserin work and why might this benefit DLB?
Serotonergic effect with no dopamine blocking hence may be beneficial in DLB patients who are sensitive to traditional antipsychotics
What approaches may be taken for disease-modification therapy to reduce alpha-synuclein toxicity?
▪️ Reduce gene transcription/translation
▪️ Reduce aggregation
▪️ Enhance degradation/clearance (e.g., tyrosine kinase inhibitors, GBA-active drugs)
▪️ Decrease release (memantine?)
▪️ Immunisation with antibodies
What is the current evidence for non-pharmacological interventions for DLB?
▪️ Very few interventions studies
▪️ Lack of/inconsistent evidence
▪️ More general management may improve prognosis
