Dementia

Question 1

Working definition of dementia?

Answer 1

1. Impaired memory and at least one other cognitive domain (executive function, visuospatial, executive)
2. Alert and clear sensorium
3. Loss of functional independence

Question 2

Go through your dementia systems review.

Answer 2

First divide into cognitive and non cognitive deficits:

Cognitive:

1. Episodic memory loss (rapid forgetting)
2. Language (anomia, empty speech, logopenic aphasia)
3. Visuospatial (constructional, ideomotor apraxia)
4. Executive (judgement, problem solving, abstraction)
5. Visual deficits (contrast and spatial frequency, motion detection)
6. Anosognosia (denial of illness, impaired insight)

Non-cognitive

1. Apathy
2. Depression
3. Paranoia
4. Agitaiton, delusions
5. Misidentifications (Capgras syndrome, reduplicative paramnesia)

Behavioural
1. emotional 40% depressed
2. Thought content and delusions
Motor eg restlessness, seizures, myoclonus
4. Circadian rhythm changes
5. Weight loss common and early predicts higher mortality

Functional
1. work, driving, instrumental and domestic ADLs

Question 3

What is logopenic aphasia?

Answer 3

Although patients with the logopenic variant of PPA are still able to produce speech, their speech rate may be significantly slowed down due to word retrieval difficulty; composed clinically of speech paucity (scarcity) and dysfluency (impairment of the ability to produce smooth, fluent speech).[

Question 4

Ideomotor apraxia

Answer 4

The inability to correctly imitate hand gestures and voluntarily mime tool use, e.g. pretend to brush one’s hair

Question 5

Capgras phenomenon

Answer 5

A delusion that a friend, spouse, parent, or other close family member (or pet) has been replaced by an identical-looking impostor.

Question 6

Reduplicative paramnesia

Answer 6

belief that a place has been duplicated and exists in two locations or has been moved and is one place.

Often seen with simultaneous damage to the right hemisphere and both frontal lobes

Question 7

Is weight loss or gain more associated with AD?

Answer 7

Loss

Question 8

Is weight loss or gain more associated with FTD?

Answer 8

Gain

Question 9

What are the types of aphasia that you get with AD?

Answer 9

Fluent (anatomic)- lose word selection rather than motor problem
Non-fluent (logopenic)- hesitate, effortful, but grammar ok

Question 10

Balint’s syndrome

Answer 10

Inability to perceive the visual field as a whole (simultanagnosia), difficulty in fixating the eyes (oculomotor apraxia), and inability to move the hand to a specific object by using vision (optic ataxia)

Question 11

What are some rapidly progressive dementias?

Answer 11

Prion disease
Alzhemiers disease, DLB
FTD variants
sporadic/paraneoplastic limbic encephalitis
Vasculitis, primary CNS lymphoma, encephalitis
metabolic, iatrogenic, and toxic disorders
Hashimoto’s encephalopaty

Question 12

What is the incidence of AD?

Answer 12

1% at age 60 then doubles every 5 years eg 32% at age 85

Question 13

What are the microscopic features of AD?

Answer 13

Plaques- neocortex, dystrophic neurites
Tangles esp medial temporal lobe
synaptic loss that correlates with cog defect
Neuronal loss that correlates with cog defect
Hirano bodies (eosinophilic)
Granulovacuolar degeneration
Congophilic angiopathy- present in 90%, unclear if from brain or circulation. A/beta is toxic to endothelium and leads to lobar haemorrhage and amyloid angiitis

Question 14

What is thought to be the pathophysiology of AD?

Answer 14

Pathological hallmarks are AMYLOID between cells and tangles TAU within neurons.

Mis folded protein accumulation is the likely basis

Beta amyloid oligomers (A/beta42)–>disrupt synapses

Fibrillar beta amyloid- forms plaques from dimers, probably non toxic but can see with PET ligands in vivo

Tau pathology- may be secondary to beta amyloid accumulation

Question 15

What is the name of the protein from which amyloid protein is cleaved?

Answer 15

Amyloid precursor protein

A transmembrane protein
The enzymes gamma secretase and alpha secretase cleave at the “beta site” –>overproduction of Abeta monomers–>soluble form most neurotoxic to synapses

Cognitive deficit correlates with oligomer burden rather than total brain burden

Question 16

Which gene codes for amyloid precursor protein

Answer 16

APP gene on chromosome 21

Question 17

Why are neurofibrillary tangles important?

Answer 17

1. Correlate with clinical features more than total amyloid

2. Newer PET ligands can now image in vivo in AD

Question 18

Why do downs syndrome people get more Alzheimers?

Answer 18

Chromosome 21 is where APP is coded–>overproduction

Question 19

What is the defect in familial early onset AD?

Answer 19

PS 1 and 2 mutations
presenillin 1 and 2
PS 1 is one of four proteins forming gamma secretase- also modulates calcium homeostasis (esp in ER)

Question 20

Tell us about the icelandic A673T mutation

Answer 20

This reduces Abeta formation by 40%
Found in some icelanders after genome wide sequencing
Low incidence AD

Question 21

What is the role of Apolipoprotein E in AD

Answer 21

ApoE exists as three alleles: e2 e3 e4
Frequency of e4 allele in Aust: approx 26% carry one and 2% carry 2 e4 allels
if you have one- RR of x 4 and if you have 2- RR 19 x

NO role for screening as half of AD patients are negative and even double patients may not get AD

Question 22

What are the risk factors for AD?

Answer 22

Age
Family history, or 1st degree relative with AD or Down syndrome
Female gender when older
CV risk factors
?head injury
low education, leisure activities, socialisation

Question 23

Protective factors

Answer 23

Exercise proven to slow rate of decline
?education and stimulation
?oestrogen and HRT (but not shown in prospective studies)

Question 24

Does CSF Abeta42 go up or down as disease progresses?

Answer 24

Down! CSF tau goes up!

Question 25

What about imaging?

Answer 25

PET can now show uptake of 11C-PiB PET- uptake in DLB and AD but not FTD "Neurostat" but can have positive amyloid accumulation without cognitive decline

Question 26

What are some treatment options for AD?

Answer 26

Acetylcholinesterase inhibitors- Donepezil Rivastigmine (patch) Galantamine PBS approved for mild- mod AD, needing re-evaluation for clinically meaningful improvement after six months Causes stabilisation of symptoms for 9-12 months CANNOT give in PUD, asthma, conduction defects also efficacy in mod-severe AD, DLB, (rivastigmine better than donepezil), vascular dementia No evidence for use in MCI (mild cognitive impairment)

Question 27

Most common symptoms of acetylcholinesterase inhibitors

Answer 27

``` GIT cramps insomnia cholinergic bradycardia ```

Question 28

Most exciting new treatment? it's a -mab

Answer 28

Aducanumab 6-12 months plateauing at highest dose in small trial Removes the amyloid from the brain!

Question 29

What are the three CORE features of Lewy Body Dementia?

Answer 29

1. Fluctuating cognition 2. Recurrent visual hallucinations 3. spontaneous features of parkinsonism 1 year later than parkinsonism- axial, less tremor, slowed gait, less response to L dopa

Question 30

What are the non core but supporting features for DLB?

Answer 30

REM sleep behaviour-acting out dreaming Severe neuroleptic sensitivity; haloperidol and risperidone Low DA transporter uptake in basal ganglia on SPECT or PET ``` Falls, autonomic dysfunction, blackouts Delusions and depression Executive dysfunction Excessive sleepiness Relatively preserved memory Marked attention difficulties and visuospatial changes ```

Question 31

Does DLB respond well or poorly to cholinesterase inhibitors?

Answer 31

Often very well 30% improvement with rivastigmine BUT can lead to worsening of the tremor and drooling

Question 32

Galantamine MOA

Answer 32

Centrally-acting cholinesterase inhibitor (competitive and reversible). It elevates acetylcholine in cerebral cortex by slowing the degradation of acetylcholine. Modulates nicotinic acetylcholine receptor to increase acetylcholine from surviving presynaptic nerve terminals. May increase glutamate and serotonin levels. Galantamine appears to have similar efficacy to donepezil in patients with AD but may have more gastrointestinal side effects.

Question 33

Rivastigmine MOA

Answer 33

Increases acetylcholine in the central nervous system through reversible inhibition of its hydrolysis by cholinesterase

Question 34

What symptoms may be improved by cholinesterase inhibitors in AD?

Answer 34

attention/concentration apathy anxiety and depression

Question 35

Memantine MOA

Answer 35

NMDA antagonist Glutamate, the primary excitatory amino acid in the CNS, may contribute to the pathogenesis of Alzheimer's disease (AD) by overstimulating various glutamate receptors leading to excitotoxicity and neuronal cell death. Memantine is an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors, located throughout the brain. Under normal physiologic conditions, the (unstimulated) NMDA receptor ion channel is blocked by magnesium ions, which are displaced after agonist-induced depolarization. Pathologic or excessive receptor activation, as postulated to occur during AD, prevents magnesium from reentering and blocking the channel pore resulting in a chronically open state and excessive calcium influx. Memantine binds to the intra-pore magnesium site, but with longer dwell time, and thus functions as an effective receptor blocker only under conditions of excessive stimulation; memantine does not affect normal neurotransmission.

Question 36

memantine side effects

Answer 36

hypertension constipation dizziness headache

Question 37

When do you use memantine?

Answer 37

Good in agitation and aggression MMSE 10-14 on PBS need to show some improvement in some domain Few studies show moderate results for Vad, AD and mixed in moderately severe stages

Question 38

What are the behavioural and psychological symptoms of dementia?

Answer 38

``` Delusions, misidentifications, hallucinations Depression Personality change Hostility/aggression Shadowing, hoarding, sundowning ``` Cholinesterase inhibitors modest reduction in agitation/aggression, apathy, hallucinations.

Question 39

Which atypical antispychotic has the best evidence for aggression?

Answer 39

Risperidone best evidence (small effect) | Olanzapine, quetiapine- probably ineffective

Question 40

Why do patients on long term atypical antipsychotics die sooner?

Answer 40

Cardiovascular risk and stroke For every 100 patients over 10-12 weeks, one person dies Other side effects: falls, hypotension, confusion, pneumonia, EPSE

Question 41

What is the evidence for using paracetamol in BPSD?

Answer 41

In one BMJ trial in 2011- paracetamol significant difference with reduction in aggression and agitation by 17%!!

Question 42

side effects of donepezil

Answer 42

GI side effects