Risk factors for dementia:
- Sociodemographic
- Vascular / metabolic
- Lifestyle
- Genetic
Risk factors for dementia:
- Sociodemographic: Age, Race, Education
- Vascular / metabolic: HTN, Hyperipidaemia, DM
- Lifestyle: Diet, Obesity, Smoking, Head injury
- Genetic: ApoE4 (especially 2 alleles)
Four key elements of dementia as a syndrome:
- Affects cognition
(memory, attention, perception, abstract thought, judgement, abilities to think, organise, learn and execute purposeful action) - Global (several areas of cognition are affected)
- Affects function (represents a decline in function)
- Absence of delirium
- Not due to other medical or psychiatric conditions
Is mild cognitive impairment just early dementia?
It may be - approx. 15%/year progress to dementia.
However, some people may have MCI that does not progress (eg. due to stroke).
it is important to recognise that dementia is about global dysfunction. There are other variants (single deficit) such as language loss without dementia
What are the 4 main types of dementia?
- Alzheimer’s disease
- Vascular (multi-infarct) dementia
- Lewy body dementia
- Fronto-temporal lobe dementias
Others: Parkinson’s, metabolic, drugs / toxins, white matter disease, mass effects, depression, infections.
Why is it important to identify Dementia with Lewy Bodies early?
- Avoid neuroleptics (ie. dopamine-blocking agents such as haloperidol) - potentially severe ASEs in DLB.
(Often require ECT for psychotic features)
- May have beneficial response to Cholinesterase Inhibitors (cholinergic deficits > in AD).
However, ChEIs not subsidised for DLB in Australia presently.
What are the three features of Dementia with Lewy Bodies (DLB) that overlap with Parkinson’s disease with dementia (PDD)?
what is the neuropathological change (deposition) that we see in both of these conditions?
- Fluctuating attention - this leads them to be confused with delirium
- Visual hallucinations - such as ants coming out of carpet
- Visuo-perceptual deficits
there is deposition of the alpha-synuclein protein
What is the pathology underlying Fronto-temporal lobar degeneration syndromes?
the pathological substrates are:
Tauopathy / TDP-43 proteinopathy.
underneath it all there are probably some genetic mutations such as:
tau
progranulin genes
Clinical phenotypes of frontotemporal dementia:
- Behavioural
- Linguistic
- Parkinsonian movement disorders
- Clinical or subclinical movement disorder
By which mechanism can alcohol contribute to cognitive impairment?
- Diffuse neuronal cell loss (potent neurotoxin)
- Cerebral atrophy
- SDHs
- Wernicke-Korsakoff syndrome (need to distinguish from dementia)
“Rapidly” progressive dementia - what should you investigate / rule out?
- Mass lesion (CT/MRI)
- Infection (TB, abscess, HIV) (CT /MRI, LP, Serology)
- Creutzfeld-Jakob disease (EEG, LP)
- Metabolic problem (bloods)
DDx of dementia + gait disorder:
Lewy body dementia Vascular dementia Normal pressure hydrocephalus Mass lesion (tumour / haematoma) "Parkinson plus" syndrome Dementia + gait disturbance from other cause (co-incidence)
Typical triad of normal pressure hydrocephalus:
- Dementia
- Gait disturbance
- Urinary incontinence
Investigations in dementia:
- Usual bloods + B12, TSH
- CXR
- Consider VDRL, HIV testing if risk factors
- CT / MRI head (unless clinically Alzheimer’s and already quite advanced)
- EEG: if rapidly progressive OR myoclonus OR suspect superimposed complex partial seizures
- LP if syphilis serology +ve, or if suspicion of immunosuppression.
+/- SPECT or PET
SPECT blood flow mapping has a 90% correlation with histopathology post-mortem.
Decreased blood flow in which brain areas are helpful in differentiating dementia type?
Dementia type and area of reduced blood flow seen on SPECT:
- AD: cingulate & hippocampus (the hippocampus is associated with the memory loss in AD)
- Lewy body: posterior temporal, occipital
- Parkinson’s: caudate
SPECT is a substitute for PET (if PET unavailable; less expensive than PET).
Overview of pharmacologic treatments for Dementia:
what are the treatment recommendations for neuropsychiatric symptoms?
- Symptomatic treatments:
(a) Cholinesterase inhibitors
(b) Memantine - Treatments for neuropsychiatric symptoms:
(a) Atypical antipsychotics (risperidone, quetiapine, olanzapine)
(b) Antidepressants (citalopram, sertraline)
(c) Anticonvulsants (carbamazepine)
Trials of disease-modifying agents ongoing, but most not very promising (e.g. amyloid aggregators).
Immunotherapy (bapineuzumab) currently being trialled.
Cholinesterase inhibitors in AD - mechanism?
Patients with Alzheimer disease (AD) have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function.
- acetylcholine precursors proved ineffective
- post-synaptic cholinergic Receptor agonists had unacceptable ASEs.
- cholinesterase inhibitors have less ASEs and some benefit (albeit modest in most cases).
There are many reasons that ChEi’s are not more beneficial in AD.
One is that the effects may be too far “downstream” (cf. dopaminergic augmentation in PD).
The cholinergic deficit in AD implies loss of acetylcholine producing (presynaptic) neurons, but ChEi’s affect the post-synaptic neurons.
In AD, the response to cholinesterase inhibitors may be quite variable:
30-50% may show no benefit, while up to 20% may show >average response.
There is evidence for benefit in which outcomes?
The average benefit of cholinesterase inhibitors in patients with dementia is a small improvement in:
- Cognition and
- ADLs
It is doubtful that these drugs
significantly improve long-term outcomes:
- Need for nursing home admission or
- Maintaining critical activities of daily living (ADLs) (ie progression of disability).
ChEi’s are licensed for use in mild-mod cognitive impairment (MMSE 10-26), and have shown to improve MMSE scores by 1.5-2 points on average in 6-12 months.
Several studies suggest similar benefit in severe dementia.
From lecture: essentially ChEi’s “buy you six months of time”, but don’t slow progression (ie. “turn the clock back 6 months, but then progress at the same rate”).
Are cholinesterase inhibitors of use in dementias other than AD?
Yes, but are not licensed for these (except if mixed with AD):
- Vascular dementia: yes
- Mixed dementia: yes
- Lewy body dementia: yes, trial warranted - can improve cognition, behaviour, hallucinations.
- Parkinson’s dementia - maybe (?in subset with hallucinations)
- Frontotemporal dementia: not supported by literature - trial may still be warranted, esp. Dx uncertain (AD vs FTD)
- MCI: no evidence that it changes progression to dementia.
- Huntington’s dementia: no evidence
- Dementia in MS: mixed results
What is the mechanism of action for memantine in dementia?
Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist and is proposed to be neuroprotective.
The mechanism of action of memantine is distinct from those of the cholinergic agents.
Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the NMDA receptor, which is involved in learning and memory.
Excessive NMDA stimulation can be induced by ischemia and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia. In addition, the physiologic function of the remaining neurons could be restored, resulting in symptomatic improvement.
In which types of dementia is memantine beneficial?
In which is it not likely to beneficial?
- Moderate-to-severe AD: statistically significant improvement in cognition, function, global outcome and neuropsychiatric symptoms over 6 months in 3 trials.
[unclear whether it is beneficial in mild AD - not licensed for this].
Note: fewer ASEs than ChEi’s.
(main ASE of memantine = dizziness)
Some evidence of benefit of ChEi + memantine.
- Vascular dementia: Some efficacy
- Dementia with Lewy Bodies: some reports that memantine worsens delusions and hallucinations
Adverse side effects of cholinesterase inhibitors:
Nausea, vomiting
Diarrhoea
Urinary frequency
Symptomatic bradycardia
What is “Mild Cognitive Impairment”?
MCI = cognitive impairment that does not meet the criteria for dementia.
ie. a measurable deficit in cognition in at least one domain, in the absence of dementia or impairment in activities of daily living.
Several criteria / subtypes proposed, eg.
Amnestic MCI:
- Significantly memory impairment but do not meet criteria for dementia.
- Often progress to meet criteria for AD or vascular dementia; in a minority of cases, the cognitive profile may simply reflect normal ageing.
Non-amnestic MCI:
- Relatively isolated impairment in a single non-memory domain, such as executive functioning, language, or visual spatial skills.
- At higher risk of progressing to: frontotemporal dementia (FTD), primary progressive aphasia, dementia with Lewy bodies, progressive supranuclear palsy, or corticobasal degeneration.
in dementia, which types of COGNITIVE symptoms are associated with cortical deficits and which subcortical?
cortical includes:
amnesia, apraxia, aphasia and agnosia
(the 4 As)
subcortical:
dysmnesia, delay (slowing down of cognition), dysexecutive and depletion (apathy and depression)
what are the subtypes of CJD? what are the clinical scenarios?
classical CJD - older people. is it largely sporadic.
familial CJD - this accounts for about 15% of classical CJD
variant CJD is younger people and is associated with BSE
iatrogenic CJD will become a bigger thing in the future. recall the 60s-80s use of human (cadaver) derived GH
