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Neuropsychiatric Disorders > Dementia with Lewy Bodies and Biomarkers > Flashcards

Dementia with Lewy Bodies and Biomarkers Flashcards

1
Q

Where does alpha-synucleinopathy typically begin?

A

Around the brain stem

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

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2
Q

What is the main protein involved in DLB pathology?

A

Alpha-synuclein (abnormal accumulations forming Lewy bodies)

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3
Q

What are the main challenges surrounding DLB?

A

▪️ 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

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4
Q

What are the core clinical features of DLB?

A

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

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5
Q

What are the supportive clinical features of DLB?

A

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

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6
Q

What are the best indicative biomarker of DLB?

A

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

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7
Q

What other biomarkers can be used to indicate DLB?

A

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

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8
Q

What biomarkers can be used to SUPPORT diagnosis of DLB?

A

▪️ 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

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9
Q

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

A

1-year rule:

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

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10
Q

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

A

Alzheimer’s-like plaques

Mixed diagnosis/more severe disease

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11
Q

What symptoms may be reported in prodromal DLB?

A

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

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12
Q

How common is DLB?

A

~16-24% of dementia

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13
Q

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

A

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

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14
Q

How does outcome with DLB differ from AD?

A

Poorer:

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

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15
Q

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

A

▪️ Diffuse neocortical
▪️ Limbic

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16
Q

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

A

At the presynaptic terminals

17
Q

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

A

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

18
Q

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

A

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

More complex = higher energy demand = greater sensitivity to change

19
Q

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

A

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

20
Q

What does an FDG-PET scan show?

A

Metabolism - will be reduced in areas of degeneration

Typically reduced in occipital lobe and PCC in DLB

21
Q

What can MRI be used for in DLB?

A

Mainly excluding other causes of dementia - no specific DLB signs

22
Q

How useful is EEG as a biomarker of DLB?

A

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

23
Q

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

A

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

24
Q

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

A

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

Can then measure these changes

25
Q

How can RT-QUIC be used for DLB?

A

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

26
Q

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

A

Isolate nucleus-originating exosomes

27
Q

What drugs show the best evidence for cognition in DLB?

A

Cholinesterase inhibitors (e.g, donepezil, rivastigmine)

(Memantine = inconsistent evidence)

28
Q

What can be used to treat hallucinations in DLB?

A

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

29
Q

What is pimavanserin and what could it be used for?

A

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

30
Q

What is the main issue with pharmacological treatment of DLB?

A

Insufficient evidence for most drugs with exception of cholinesterase inhibitors for cognition

Most medications used off-license

31
Q

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

A

▪️ Melatonin
▪️ Clonazepam
▪️ Memantine

32
Q

What might be considered for daytime sleepiness in DLB?

A

Modafinil

33
Q

What might be considered for parkinsonism in DLB?

A

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

34
Q

How does pimavanserin work and why might this benefit DLB?

A

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

35
Q

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

A

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

36
Q

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

A

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

Neuropsychiatric Disorders (30 decks)

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