Lewy body and FTD

Question 1

Describe lewy body dementia with symptoms

Answer 1

Often mistaken for AD if no significant motor dysfunction is evident: thought to account for up to 20% of all dementia diagnoses.

Symptoms: violent nightmares with movement (REM sleep disorder), extreme sensitivity to antipsychotics (so cannot be used for treatment), frequent visual hallucinations in 80% of patients.

Motor symptoms: rigidity, gait disturbance, intention tremor.

Question 2

How does Lewy Body dementia compare to AD?

Answer 2

DLB: fluctuating disease course, dementia with extrapyramidal symptoms, visual hallucinations, hypersensitity to antipsychotics.
Neuropathy - lewy bodies, ABeta plaques and alpha-synucleinopathy.
Delirium: 63% of patients present 3 of: daytime drowsiness and lethargy, daytime sleep of 2+ hours, staring into space, episodes of disorganised speech compared to 12% AD.

AD: gradual disease course, no extrapyramidal, delusions > hallucinations, motor symptoms only present in later stages.
Neuropathy - ABeta, tau tangles.
* No hypersensitivity to antipsychotics.

Question 3

How does Lewy Body dementia compare to parkinson’s disease dementia.

Answer 3

PDD: does not present with dementia (occurs around 2 years after extrapyramidal symptoms).
Neuropathy - brainstem lewy bodies and alpha-synucleinopathy.

Therefore, if dementia develops before or alongside motor this is Lewy Body but if develops after establishment of Parkinson’s this is PDD.

Question 4

How is LBD diagnosed?

Answer 4

Must meet criteria for dementia as well as 2 of the following:
Parkinsonism, repeated visual hallucinations, changes in thinking/attention/alertness, REM sleep disorder.

Loss of smell and excessive daytime sleepiness also help support diagnosis.

Question 5

Theory of why hallucinations are present in LBD?

Answer 5

Specific patterns of neuronal loss in Pulvinar Nucleus in dementia with Lewy Bodies: affect these nuclei more than other conditions.

Pulvinar nucleus is found in the thalamus and role in processing visual information.

“The lateral pulvinar of AD cases also showed a significant reduction in neuron number when compared to control cases and, whilst this reduction was less than that found between DLB and control cases, there was no significant difference between DLB and AD.”

However, AD cases there is more significant loss in other visual regions of thalamus such as LGN (visual processing).

Erskine et al., 2017

Question 6

Outline LBD biomarkers

Answer 6

There are no direct biomarkers but the following are indirect…
* REM sleep disorder
*Reduced atropy of MTL and DAT uptake in basal ganglia
* EEG abnormalities: pre-alpha dominant frequency that is either stable ot intermixed with alpha/theta/delta - over 90% predictive value for diagnosis of LBD compared to AD and correlate positively to severity of cognitive fluctuations possibly seen at MCI stage of dementia.

Question 7

What are Lewy Bodies?

Answer 7

Dr Lewy discovered spherical neuronal inclusions in brain of deceased Parkinson’s patient: eosinophilic (as stained by methyl-blue eosin mixture) cytoplasmic inclusions that contain alpha-synuclein (synucleinopathy).

They displace other cellular components (cause nucleus to move to the side) and associated with deficits in ACh and DA. Risk of developing increases with age.
* Thought to pathologically and biochemically fall inbetween AD and Parksinson’s.

Question 8

What brain areas are affected by Lewy Bodies?

Answer 8

Cerebral cortex, limbic, hippocampus, midbrain, basal ganglia, brainstem, olfactory system.

Where they first appear in brain thought to control whether you get Parkinson’s or Dementia.

Question 9

What are the two types of Lewy bodies?

Answer 9

1) Halo: midbrain and basal ganglia
* acidophilic and argyrophilic core.
* Pale staining halo that is strongly immunoreactive for alpha-synuclein.
2) Circular: cortex
* no halo

Question 10

What are the risk factors of LBD?

Answer 10

Not well known.
1) Positive family history of dementia and LBD (siblings of affected are 2.3X more likely to develop LBD).
2) Genetic factors play role in 36% of cases.
-SNCA (encodes alpha-synuclein).
-APP
- PSEN1/2 (presenilin gene)
-APOE
-MAPT (also associated with FTLD)
-GBA (LBD 8X more likely to be carriers of mutation)

Question 11

Outline how alpha-synuclein is implicated in LBD

Answer 11

Missense mutation SNCA gene caused rare, familial form of PD and LBs shown to be immunoreactive for alpha-synuclein, can cause LBD

Increase in gene dosage can also cause dementia: number of copies of particular gene in genome.
* Greater number of copies = more product that can be produced.

Question 12

How do we treat dementia with Lewy Bodies?

Answer 12

Currently, treatments aim to diminish symptoms.

Dementia - improve cognition.
Delirium - decrease fluctuations in cognition: cholinesterase inhibitors (avoid antipsychotics with D2 affinity).
Parkinson’s symptoms - improve mobility: Levodopa.
REM sleep disorder - improve sleep: Clonezepam.
Visual hallucinations - reduce number: Cholinesterase inhibitors.

Question 13

Outline Cholinergic hypothesis in AD.

Answer 13

The cholinergic hypothesis

Reported substantial neocortical deficits in cholineacetyltransferase that is needed to produce acetylcholine.

• reduce choline uptake
• reduced ACh release
• Loss of cholinergic neurons all together.

Furthermore, ACh has role in learning and memory so evidence supports idea of degeneration of cholinergic neurons in basal forebrain caused associated loss of transmission in cortex which leads to AD.

Neurochemical changes: in initial stages of disease ACh is selectively reduced. Later on GABA, 5HT and DAT are impacted.

• loss of ACh is correlated with cognitive decline but so is loss of synapses…
• Some AD patients do not show decrease in ChAT activity.

Pharmacological:

scopolamine (muscarinic antagonist) induces amnesia in young healthy subject comparable to old untreated.

Francis et al., 1999

Question 14

Outline how Donepezil works.

Answer 14

Donepezil is a reversible
acetylcholinesterase inhibitor
Like any anticholinesterase, it increases
the concentration of ACh at the synapse
by preventing its breakdown

Only useful for mild-moderate AD, some
evidence for LBD, PDD and mixed
dementia (e.g. AD plus vascular) – might
reduce hallucinations and boost cognitive abilities but doesn’t work at all for some people.

Unfortunately, as disease progresses, aren’t enough cholinergic neurons to boost no matter how much you block AChE action.

Question 15

Outline how Memantine works.

Answer 15

Glutamate blocker – blocks NMDARs
* Suitable for those who can’t take AChE inhibitors
* Side effects, although temporary, include headaches, dizziness,
sleepiness and constipation
* Seems to improve global clinical status and behavioural symptoms of
patients with mild to moderate DLB, and might be an option for
treatment of these patients
* but symptomatic effects may be variable

Question 16

Give roles of frontal and temporal lobes

Answer 16

Frontal lobe: voluntary movement, expressive language and high level executive movement.

Temporal lobe: processing auditory information and encoding memory (object recognition)

Question 17

Outline FTLD

Answer 17

Collection of diff neurodegenerative diseases including but not limited to.
1) Frontal variant: personality and behaviour, memory remains relatively intact.
2) Primary progressive aphasia: trouble communicating (ability to write, read, understand and express thoughts - can lead to inability to speak), problems with memory and ability to recognise faces.

Occurs earlier in life 45-65 compared to other dementias.
- 3rd most common NDD after AD and PD.

Some patients have Pick’s bodies: tau accumulation

Question 18

Outline what happens in FTLD

Answer 18

Lobes shrink due to neurons dying, cause of this is unknown.

Mutations in genes…

Pick bodies that contain abnormal proteins found in brains of some individuals with FTLD.

Question 19

Prognosis for FTLD

Answer 19

Generally poor.
Steady progression of disease that is often rapid ranging from less than 2yrs to 10years.
* some individuals will require 24hour care.

Question 20

Treatment for FTLD

Answer 20

No cure or treatment to slow progression.

Behavour modification and speech therapy can help.

Antidepressants shown to improve some symptoms.

Question 21

Behavioural-variant FTLD symptoms?

Answer 21

Changes in social conduct and behaviour, apathy, lack of empathy, disinhibition, lack of insight.

Question 22

Primary progressive aphasia FTLD symptoms

Answer 22

2 types:
1) Semantic: loss of semantic knowledge, impaired word comprehension and object naming. Fluent speech.
2) Progressive nonfluent aphasia: apraxia and effortful speech, spared object knowledge and word comprehension.

Question 23

TDP-43 in dementia

Answer 23

Amyloid fibrils (fibrous, rope-like structures) are found in brains of patients
with Alzheimer’s, Parkinson’s, Huntington’s and ALS (TDP-43 present)
(Cascella et al., 2023)
* Intracellular inclusions of TDP-43 (Transactive response DNA-binding
protein 43), the hallmark pathology in FTLD, are also often observed in
DLB, with prevalence rates reported to be between 0-56% (Outeiro et al.,
2019)
* The distribution of TDP-43 pathology differs in DLB compared to FTLD,
with limbic structures affected early in the degenerative process (Outeiro
et al., 2019)
* Evidence suggests that endoplasmic reticulum (ER) stress and the unfolded
protein response (UPR) are important players in TDP-43 pathology - like prions self aggregation

Role: initiation of transcription, mRNA (processing, transport and stability).
* it accumulates after moving from nucleus into cytoplasm.

43 inclusions impact: cell survival via axonal transport and autophagy

Question 24

TMEM106B

Answer 24

Major subtype of FTLD is characterized by
neuronal inclusions containing TDP-43 –
50% of all cases are FTLD-TDP
* Recently, been found in patients with
FTLD, but with a different protein:
TMEM106B
* Aged TMEM106N-/-
show motor
impairment, gait deficits as well as
Purkinje cells loss
* Most important modifier of disease risk in
patients with progranulin (GRN)
mutations (Cabron et al., 2023)

Question 25

Nfl as a biomarker

Answer 25

Neurofilament light (NfL) levels were elevated in all types of FTLD
* Levels increased with the severity of the disease
* Could be useful for the early detection of FTLD

Question 26

Outline formation of Lewy Bodies

Answer 26

Alpha-synuclein spreads = patients who recieved fetal graft tissue Lewy bodies found in new tissue.

• conversion into beta sheets allows for monomers to collect.
• The greater the levels of alpha syn the more likely to fibrillize (duplication or triplication often leads to PD).

Mitochondra: MPTP inhibits mitochondria and chronic admin causes formation of alpha-syn aggregates.

• Alpha KO mice = no effect.

Hijaz and Volpicelli-Daley, 2020

Question 27

Effect of Lewy Bodies on cells

Answer 27

1)Blocks ER-golgi transport which leads to ER becoming stressed and golgi fragmentation = leads to decreased synaptic vesicle release.
2) Impaired energy production which induces apoptosis.
3) Accumulation of CMA substrates that target lysosomes therefore autophagy is impacted.

Question 28

Outline MRI as biomarkers for LBD

Answer 28

Insular thinning and gray matter volume loss

• medial frontal loss occurs in prodromal relative to healthy controls and seen using MRI.
• AD there is more extensive loss: temporal, frontal, parietal etc.

McKeith et al., 2020

Question 29

Outline proposed role of presenilin-1 in AD

Answer 29

Role of PSEN1: encodes PS1 = catalytic subunit of gamma secretase.

• Mutations cuase loss of PS1

ABeta 42 is more hydophobic and therefore aggregates.

2 hypotheses.

1) amyloid - mutations initiate disease pathogenesis by increasing production of ABeta 42.

• in patients with mutations higher ABeta 42 plasma levels.
• Study by Sun et al = detectable production of ABeta 40 and 42 decreased by 30% with mutation which goes against hypothesis.
• Can increase ratio of 42 to 40 but does this only by decreasing 40 made…

2) Presenilin hypothesis - mutations cause loss of presnilin function in brain.

• Needed for learning, memory and neuronal survival.

Kelleher and Shen, 2017

Question 30

What does treatment with levodopa do?

Answer 30

Levodopa: effective treatment to reduce motor but not cognitive symptoms. Precursor to dopamine so raises levels.

• Later on in disease lose up to 90% of dopaminergic neurons so need strategies to prevent neuronal loss.

Used in LBD and PDD Hijaz and Volpicelli-Daley, 2020