Dementia with Lewy Bodies and Biomarkers

Question 1

Where does alpha-synucleinopathy typically begin?

Answer 1

Around the brain stem

BUT can originate in other areas such as cortex, midbrain, and gut

Question 2

What is the main protein involved in DLB pathology?

Answer 2

Alpha-synuclein (abnormal accumulations forming Lewy bodies)

Question 3

What are the main challenges surrounding DLB?

Answer 3

▪️ 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

Question 4

What are the core clinical features of DLB?

Answer 4

▪️ Fluctuating cognition (particularly attention and alertness)
▪️ Visual hallucinations
▪️ REM sleep behvaiour disorder (may precede cognitive decline)
▪️ One or more spontaneous features of parkinsonism

Question 5

What are the supportive clinical features of DLB?

Answer 5

▪️ Sensitivity to antipsychotics
▪️ Postural instability
▪️ Autonomic dysfunction (e.g., constipation)
▪️ Hyposmia
▪️ etc….

Question 6

What are the best indicative biomarker of DLB?

Answer 6

Reduced dopamine transporter uptake in basal ganglia as seen with SPECT/PET

Question 7

What other biomarkers can be used to indicate DLB?

Answer 7

▪️ Abnormal iodine-MIBG myocardial scintigraphy
▪️ Polysomnographic confirmation of REM without atonia

Question 8

What biomarkers can be used to SUPPORT diagnosis of DLB?

Answer 8

▪️ 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

Question 9

How do you differentiate Dementia with Lewy Bodies from Parkinson’s Disease Dementia?

Answer 9

1-year rule:

▪️ DLB = dementia before or concurrently with parkinsonism
▪️ PDD = dementia in the context of PD, over a year between onset

Question 10

What other pathology may be present in those with DLB and what does this suggest?

Answer 10

Alzheimer’s-like plaques

Mixed diagnosis/more severe disease

Question 11

What symptoms may be reported in prodromal DLB?

Answer 11

▪️ Hyposmia
▪️ RBD
▪️ MCI (typically non-amnestic)
▪️ Isolated visual hallucinations
▪️ Primary autonomic dysfunction
▪️ Delirium-tendency
▪️ Motor symptoms (subtle, less specific?)
▪️ Depression

Question 12

How common is DLB?

Answer 12

~16-24% of dementia

Question 13

Why is it difficult to estimate the exact prevalence of DLB?

Answer 13

Patients may present to a range of clinics depending on first symptoms (e.g., sleep, memory, autonomic, motor)

Question 14

How does outcome with DLB differ from AD?

Answer 14

Poorer:

▪️ Higher mortality
▪️ Higher caregiver burden
▪️ Longer hospital stay
▪️ Quicker transition to nursing home

Question 15

Where is Lewy body pathology most likely to be found in the early stages?

Answer 15

▪️ Diffuse neocortical
▪️ Limbic

Question 16

Where in the neuron does alpha-synucleinopathy thought to start in DLB?

Answer 16

At the presynaptic terminals

Question 17

How is alpha-synucleinopathy though to cause symptoms in DLB?

Answer 17

▪️ Accumulation in presynaptic terminals
▪️ Synapse are lost (synaptopathy)
▪️ Dying-back-like neurodegeneration

Question 18

What types of neurons are particularly sensitive to alpha-synuclein pathology?

Answer 18

Highly branched neurons (e.g., dopaminergic neurons in substantia nigra, serotonergic neurons)

More complex = higher energy demand = greater sensitivity to change

Question 19

What investigations can NOT yet be used for diagnostic markers of DLB?

Answer 19

▪️ Molecular PET for alpha-synuclein
▪️ Proteomics (alpha-synuclein in blood and CSF)
▪️ Biopsy

Question 20

What does an FDG-PET scan show?

Answer 20

Metabolism - will be reduced in areas of degeneration

Typically reduced in occipital lobe and PCC in DLB

Question 21

What can MRI be used for in DLB?

Answer 21

Mainly excluding other causes of dementia - no specific DLB signs

Question 22

How useful is EEG as a biomarker of DLB?

Answer 22

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

Question 23

How useful are total alpha-synuclein CSF levels as a marker of DLB?

Answer 23

Not very - inconsistent results with most showing reduced levels but others showing increased or no change

Question 24

What is Real-Time Quaking-Induced Conversion (RT-QUIC)?

Answer 24

A seeding technique whereby pathogenic proteins induce conformational changes in normal protein (not seen in healthy proteins)

Can then measure these changes

Question 25

How can RT-QUIC be used for DLB?

Answer 25

▪️ High sensitivity and specificity for CSF alpha-synuclein ▪️ Promising findings for prodromal LB ▪️ Separating MCI-DLB from MCI-AD?

Question 26

How can seeding techniques be used to detect pathological alpha-synuclein in blood?

Answer 26

Isolate nucleus-originating exosomes

Question 27

What drugs show the best evidence for cognition in DLB?

Answer 27

Cholinesterase inhibitors (e.g, donepezil, rivastigmine) (Memantine = inconsistent evidence)

Question 28

What can be used to treat hallucinations in DLB?

Answer 28

Possibly antipsychotics (e.g., clozapine, quetiapine) although insufficient evidence and patients more sensitive to AE such as worsened cognition, parkinsonism

Question 29

What is pimavanserin and what could it be used for?

Answer 29

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

Question 30

What is the main issue with pharmacological treatment of DLB?

Answer 30

Insufficient evidence for most drugs with exception of cholinesterase inhibitors for cognition Most medications used off-license

Question 31

What might be considered for REM sleep behaviour disorder in DLB?

Answer 31

▪️ Melatonin ▪️ Clonazepam ▪️ Memantine

Question 32

What might be considered for daytime sleepiness in DLB?

Answer 32

Modafinil

Question 33

What might be considered for parkinsonism in DLB?

Answer 33

▪️ L-dopa ▪️ Zonisamide (currently RCTs in Asia)

Question 34

How does pimavanserin work and why might this benefit DLB?

Answer 34

Serotonergic effect with no dopamine blocking hence may be beneficial in DLB patients who are sensitive to traditional antipsychotics

Question 35

What approaches may be taken for disease-modification therapy to reduce alpha-synuclein toxicity?

Answer 35

▪️ Reduce gene transcription/translation ▪️ Reduce aggregation ▪️ Enhance degradation/clearance (e.g., tyrosine kinase inhibitors, GBA-active drugs) ▪️ Decrease release (memantine?) ▪️ Immunisation with antibodies

Question 36

What is the current evidence for non-pharmacological interventions for DLB?

Answer 36

▪️ Very few interventions studies ▪️ Lack of/inconsistent evidence ▪️ More general management may improve prognosis