Lewy Body Dementia; Frontotemporal lobar degeneration (FTLD) Flashcards
Describe the pathophysiology of LBD [+]
Lewy body dementia (LBD) represents a spectrum of cognitive disorders characterised by the presence of Lewy bodies, which are intracellular inclusions composed primarily of misfolded alpha-synuclein proteins. These cause:
* Direct neurotoxicity
* Impaired proteostasis
* Synaptic dysfunction
Furthermore, many patients with LBD also show signs of Alzheimer’s disease pathology, such as amyloid plaques and neurofibrillary tangles. This suggests a potential synergistic effect between alpha-synuclein, beta-amyloid and tau proteins in the pathogenesis of LBD.
NB: In Parkinson’s Lewy bodies are mainly deposited in the substantia nigra, whereas they are more widespread in Lewy body dementia.
Describe the clinical manifestations of LBD depending on where the Lewy-Bodies are located [4]
Cognitive impairment:
- Predominantly results from Lewy body formation and subsequent neurodegeneration in cortical regions including the frontal and temporal lobes.
Parkinsonism:
- Occurs due to involvement of substantia nigra pars compacta, causing dopaminergic neuron loss which leads to motor symptoms such as bradykinesia, rigidity and tremor.
Visual hallucinations:
- Likely related to involvement of occipital cortex and other visual processing areas.
Autonomic dysfunction:
- Results from involvement of the peripheral autonomic nervous system, including cardiac sympathetic denervation and enteric nervous system degeneration.
Describe the clinical features of LBD [4]
progressive cognitive impairment
* in contrast to Alzheimer’s, early impairments in attention and executive function rather than just memory loss
* cognition may be fluctuating, in contrast to other forms of dementia
* usually develops before parkinsonism
* problems multitasking and performing complex cognitive actions are commonly the primary issue (rather than memory).
parkinsonism
visual hallucinations (other features such as delusions and non-visual hallucinations may also be seen)
There are several core clinical features that are specific to DLB. These include: [4]
- Fluctuating cognition with pronounced variations in attention and alertness
- Recurrent visual hallucinations that are typically well formed and detailed
- REM sleep behaviour disorder, which may precede cognitive decline
- One or more spontaneous cardinal features of parkinsonism (e.g. bradykinesia, rest tremor, rigidity)
How do you differentiate LBD from Parkinsons? [1]
If physical symptoms precede cognitive decline by more than a year, the diagnosis is often Parkinson’s, with superimposed cognitive decline.
Investigations for LBD? [2]
usually clinical
single-photon emission computed tomography (SPECT) is increasingly used. It is currently commercially known as a DaTscan.
Describe the treatment for LBW [3]
both acetylcholinesterase inhibitors can be used as they are in Alzheimer’s
- donepezil, rivastigmine
- memantine limited efficacy in DLB
Melatonin: may be used in refractory REM sleep disorders
Levodopa: this is an antiparkinson medication that may be used for severe, disabling Parkinsonism features
neuroleptics should be avoided in Lewy body dementia as patients are extremely sensitive and may develop irreversible parkinsonism.
Which factors are associated with a worse outcome of DLB? [3]
Factors associated with a worse prognosis include cognitive fluctuations, early hallucinations, and gait abnormalities
Cognitive impairment, parkinsonism, visual hallucinations - Lewy body dementia
A 70-year-old man is noted to have progressive loss of short term memory associated with visual hallucinations. On examination he is noted to have a resting tremor - Lewy body dementia
Describe the age of onset of FTD [1]
FTD is a common cause of early onset dementia (< 65 years old):
- mean age of onset is 58 years old
Describe the pathophysiology of FTD
Characterised by tissue deposition of aggregated proteins including phosphorylated tau or transactive response DNA-binding protein 43 (TDP-43).:
- Tau is the major protein of ‘Pick bodies’ that may be seen in certain pathological subtypes
MRI or CT shows symmetrical atrophy predominantly affecting the frontal and/ or temporal lobes
FTD is strongly genetically linked.
Name three genes which are linked to FTD [3]
MAPT:
- Leads to a propensity of tau to form neurotoxic aggregates
Granulin precursor - GRN:
C9ORF72 gene: found on chromosome 9. Most common genetic cause of inherited FTD. Also implicated in hereditary motor neuron disease. Usually results in bvFTD with or without MND.
Describe the different symptomatic classifications of FTD [3]
Behavioural variant Frontotemporal Dementia (bvFTD):
- Most common form
- changes in personality and behaviour, including disinhibition, apathy, loss of empathy or compulsive behaviours
Semantic Dementia (SD):
- loss of semantic knowledge - patients have difficulty understanding words or recognising familiar people or objects
Progressive Nonfluent Aphasia (PNFA):
* Characterised by progressive language disorder with non-fluent speech and grammatical errors.
* Patients may also show signs of agrammatism or apraxia of speech.
Describe the different neuropathological classifications of FTD [3]
Tau-positive FTLD:
- tau proteins accumulate abnormally within neurons leading to neurofibrillary tangles.
- Three major types exist based on the morphology and distribution of tau inclusions: Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy.
TDP-43 positive FTLD:
- Characterised by the accumulation of transactive response DNA binding protein 43 (TDP-43).
- Four subtypes exist (A to D) based on the distribution and morphology of TDP-43 inclusions.
FUS-positive FTLD:
- Less common, characterised by the presence of fused in sarcoma (FUS) protein within inclusion bodies
- These are typically seen in younger patients and often associated with a more aggressive disease course.
