1
Q
Give four main types of Dementia disorders
A
- Alzheimer’s disease
- Dementia with Lewy bodies
- Frontotemporal dementia
- Vascular dementia
2
Q
How does Alzheimer’s dementia present?
what is the biological cause?
A
- Gradual onset of impaired memory, planning and functional skills
- due to degeneration of the cerebral cortex, with cortical atrophy, neurofibrillary tangles, amyloid formation and reduction in acetylcholine
3
Q
What are the two ways to look at the Neuropathlogically presentations of dementia
A
- Microscopically
- Intra neuronal inclusion bodies
- Extra neuronal changes (plaques)
- Macroscopically
- Generalised brain atrophy
- Region specific atrophy depending on dementia disorder
- Enlarged ventricles
4
Q
Give some microscopic causes of Dementia
A
- Misfolding of proteins
- Abnormal accumulation
- Neuroinflammatory environment
- Damaged neurons
- Cell death
- Damaged neurons
- Proteins involved:
- Amyloid
- Tau
- Synuclein
5
Q
What dementia disease is caused by Tau abnormalities?
A
- Alzheimer’s disease
- can also be caused by Amyloid abnormalities
- Frontotemporal dementia
6
Q
What is Tau?
A
- a highly soluble protein found mostly in the brain
- it is mostly present in axons
- it has 6 isoforms and disease process lead to hyperphosphorylated forms of the protein
Functions
- modulate the stability of axonal microtubules
- transport
7
Q
Abnormalities in Tau
A
Hyperphosphorylated forms of Tau
- Paired helical filaments (PHF)
- Neurofibrillary tangles (NFTs)
- PHFs –> NFTs –> Neurodegeneration
- Phosphorylation of tau is regulated by activated kinases
- Hyperphosphorylation of tau can result in the self-assembly of tangles of paired helical filaments (PHF).
8
Q
Explain Neurofibrillary tangles
A
Described by Alois Alzheimer: consist of paired 10-nanometer diameter filaments twisted around each other in a helical manner (paired helical filaments HF)
- Seen in neurons after staining
- Hematoxylin
- Eosin
- Bielschowsky
- Bodian
- Congo red
- Most commonly found in temporal lobe structures
- Hippocampus
- Amygdala
9
Q
Amyloid Precursor Protein (APP) in normal and diseased brains
A
- APP is a transmembrane glycoprotein which is broken down and eliminated in normal brain
- APP is split by enzymes ß-secretase then y-secretase.
- ß-amyloid is a peptide of 39–43 amino acids
- Most common isoforms are Aβ40 and Aβ42
- Aβ40 is more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states.
- Fragments accumulate to form plaques, the build-up of ß-amyloid plaques cause neuronal damage
10
Q
Frontotemporal Dementia (FTD)
A
- Tau pathology, Pick’s disease described by Arnold Pick 1892
- Pick bodies
- rounded, microscopic structures found within neurons
- Aggregates of tau
- Hirano bodies
- Neurons swell, taking on a “ballooned” appearance. Hence, called balloon cells.
- Plaques and tangles are not found in Pick’s disease.
- FTD is present in frontal and anterior temporal lobes.
11
Q
What is the presentation of Frontotemporal dementia?
A
- Typical symptoms include changes in personality and behaviour (disinhibition) and difficulty in language
- Usually, develop at a younger age (60y)
12
Q
What are Synuclein abnormalities?
A
- Parkinson disease
- Dementia with Lewy bodies
- Fibrillary aggregates of alpha-synuclein protein
13
Q
What are Synuclein?
A
- Small, presynaptic neuronal proteins comprised of α-, β-, γ-synucleins of which only α-synuclein aggregates
- Proteins of 140 amino acids, that is expressed predominantly in neurons
- Found in neurons and glial cells
- Function as lipid vesicle binding, inhibition of phospholipase D2 and protein kinase C, dopamine uptake and as a chaperone have been ascribed to α-synuclein.
- Predominantly expressed in neocortex, hippocampus, substantia nigra and cerebellum.
- Can aggregate to form intracytoplasmic inclusions in neurons (Lewy bodies).
14
Q
What are Lewy bodies?
A
- Spherical, intranuclear, cytoplasmic eosinophilic inclusions
- Abnormally truncated and phosphorylated neurofilament proteins
- Contain:
- Alpha-synuclein
- Ubiquitin
- Associated enzymes.
15
Q
What is the cause of Vascular dementia and its presentation
A
- Due to cerebrovascular disease (1 large stroke or small multi-infarcts)
- stepwise decline presents similarly to Alzheimer’s disease initially but patients often have more insight
16
Q
What is the presentation of Dementia with Lewy bodies?
A
- a triad of C_ognitive fluctuation_, Vivid visual hallucinations and Parkinsonism
- this is due to Lewy body deposition
17
Q
Vascular dementia
A
- Can result from ischemic or hemorrhagic brain damage.
- The three most common mechanisms causing disease
- Single, strategically placed infarcts
- multiple cortical infarcts
- subcortical small-vessel disease.
- Clinical deficits are determined by the size, location, and type of cerebral damage.
- Because of the variety of pathogenic mechanisms involved in vascular dementia, clinical manifestations can vary.
18
Q
What steps need to be taking to reach a diagnostic conclusion of a Dementia disease?
A
- History
- Examination
- Bloods/ECG
- Neuropsychological
- Behavioural/Activities of Daily Living
- Neuroimaging
19
Q
What examinations are done when Dementia is a differential diagnosis?
A
- General examination
- Neurological examination
- Mental State Examination
20
Q
What bloods/ ECG would be taken for a neurological consultation?
A
- FBC
- ESR
- U/Es
- LFT
- TFT
- B12/folate
- Syphilis serology
- ECG
21
Q
What Imaging can be done during a neurologic consultation?
A
- CT
- MRI
- SPECT
- PET
22
Q
What treatment can be given for Alzheimer’s dementia?
A
- Donepezil,
- Rivastigmine,
- Galantamine,
- Memantine
23
Q
What treatment can be given for Vascular Dementia
A
- Identify & Treat vascular risk factors
- Hypertension
- Diabetes
- Hyperlipidaemia
- AF
- Carotid disease
- put patients on anticoagulants
24
Q
Treatment for Frontotemporal dementia
A
- SSRI antidepressants
25
Treatment for Dementia with Lewy Bodies
* Donepezil
* Rivastigmine
26
What are future management strategies for dementia?
* Prevention
* Slow down progression
* Introduce disease-modifying treatment
* Cure
Overall supports patients to live well with dementia
27
What are the fixed risk factors for dementia?
* Age
* Genetics
* Brain injury
* Education level
* Alcoholism
28
What are changeable risk factors fro dementia?
* Diabetes
* Hypertension
* Brain injury
* Sleep disorders
* Depression
* Obesity
* Physical Health
29
What methods can be used to slow down the progression of dementia?
* Use available drugs: Donepezil, Rivastigmine, Galantamine, Memantine, Huperzine A
* Psychological support
* Lifestyle changes: Vitamins B12 and D, diet, exercise, cognitive stimulation
* Timely diagnosis and treatment of physical and mental health conditions
30
The use of Vitamin E in dementia treatment
* improves cognition due to anti-inflammatory effect
31
The use of NSAIDs in Dementia treatment
not recommended by NICE for use in slowing down Dementia unless it is in a trial
32
The use of Ginkgo Biloba in Dementia treatment
* Extract EGb 761
* 17 active metabolites; 3 antioxidants
* Dose: 120-240 mg
* Side Effects
* Allergy
* Bleeding
* Skin reactions
* GIT
* Drug interaction
33
What other variables cause an acceleration in decline?
* Psychosis
* Anti-psychotic treatment
* Depression
* Delirium
* Infections
* Anaesthesia
* Decreased cognitive reserve
* Physical Inactivity
* Genetic status
* Age
* Polypharmacy
* Hypothyroidism/vitamins deficiency?
34
What methods can be used to modify the disease?
Targeting the **Tau** and **Amyloid** proteins that misfold and accumulate in the brains of patients with AD
* Anti-amyloid treatment:
* destroys existing amyloid plaques: *Bapineuzumab, Solanezumab, Crenezumab & Gantenerumab*
* *CNS clearance hypothesis*
* *peripheral sink hypothesis*
* stops aggregation: through agents blocking or modulating beta and gamma secretases
* Anti-Tau treatment
* reformulated methylene blue
* reduces levels of aggregated or misfolded Tau proteins
35
What are the causes of Delirium?
* D= Drugs (withdrawal/toxicity)/Dehydration
* E= Environment/Energy
* L= Level of pain
* I= Infection/Inflammation (post surgery)
* R= Respiratory failure (hypoxia, hypercapnia)
* I= Impaction of faeces
* U= Urinary retention
* M= Metabolic disorder (liver/renal failure/thyroid, hypoglycaemia). Myocardial infarction
36
What are the subtypes of delirium and how do they present?
Hyperactive delirium
Heightened arousal
Restless, distressed
Hypoactive delirium
Withdrawn, quiet
Sleepy
Mixed delirium
37
What are the pharmacological treatment of Delirium
* Lorazepam 1st line
* Haloperidol 2nd line – avoid PD/DLB
→ would use non-pharmacologically, calming, redirecting techniques first, use as last resort
→ Use the lowest dose for the shortest period of time
**→ PO vs IM NEVER IV**
→ Consider side effects and contraindications
38
How does ICD-10 define dementia?
dementia is a syndrome due to a disease of the brain, usually of chronic or progressive nature, in which there is impairment of **_more than one_** cognitive domain, including:
* memory,
* language, fluency,
* complex attention, executive function,
* visuospatial, perceptual,
* and social cognition
* accompanied by **_impairment of function_**
39
What is the prevalence of the various types of Dementia?
1. Alzheimer's dementia
2. Vascular dementia
3. Mixed dementia
4. Lewy Body dementia
5. Fronto-temporal dementia
6. Parkinson's dementia
40
What are the tests use to Asses Confusion?
* SQiD: Single Question in Delirium
* is this person more confused than they usually would be
* have to do a more formal assessment if yes
* AMTS: Abbreviated Mental Test Score
* CAM: Confusion Assessment Method
* MMSE: Mini-Mental Sate Examination
41
What Questions are on the AMTS?
42
What questions are on the CAM, and how is a diagnosis of delirium made?
1. **Acute onset of the fluctuating course**
2. **Inattention, distractibility**
3. **Disorganized thinking, illogical or unclear ideas**
4. **Alteration in consciousness**
Diagnosis of delirium requires the presence of both features of 1 AND 2 pus EITHER feature 3 or 4
43
What is the method in taking a Collateral history regarding the Cognition of a patient?
MAPLE - V
* **Memory:** acute/ chronic, duration
* **Attention**: the ability to focus on tasks
* **Personality:** includes mood and behaviour
* **Language:** difficulty in understanding or communicating
* **Executive function:** the ability to plan and perform complex tasks e.g driving, dressing
* **Visuospatial perception:** recognise objects, hand-eye coordination, recognise faces
44
# VANISHED
What conditions can present similarly to dementia?
**VANISHED**
* **V**: vascular, vit deficiency: B1, B6, B12, folate
* **A**: Alzheimer's disease, autoimmune: cerebral vasculitis, systemic lupus erythematosus
* **N**: normal pressure hydrocephalus, neoplasia
* **I**: infection e,g Creutxfedt-Jakob disease, herpes simplex encephalitis, prior diseases, tertiary syphilis, HIV/AIDS
* **S**: substance abuse, serum abnormalities e.g. hyperammonemia, uremia, Wilson disease
* **H**: hormones: hypothyroidism, hyperparathyroidism
* **E**: elective disturbances: hyponatremia, hypokalemia, hypo-/hypercalcemia
* **D**: depression (pseudodementia)
45
What assessments are done in suspected Dementia?
* Brian imaging - CT, MRI, DAT (autopsy)
* DaTSCAN™ is a specific type of single-photon emission computed tomography (SPECT) imaging technique used to detect the presence of dopamine transporters (DaT) in the brain
* Patient history and collateral history
* Cognitive assessment tools: GPCog, Addenbrookes cognitive examination
* looking at: memory, language, fluency, complex attention, executive function, visuospatial, perceptual, social cognition
46
What are risk factors for Dementia?
* Early life: less formal schooling
* Mid-life: hearing loss, hypertension, obesity, smoking
* Late-life: Smoking depression, physical inactivity, low social contact, diabetes
35% of these are modifiable
47
What is the cut-off score in Addenbrookes Cognitive Examination?
not a clear cut-off, might ask them to come back in a year to see if there is any degeneration in cognition
* Below 88/100 (sensitivity =1.0; specificity =0.96)
* dementia wont get missed but may be incorrect diagnosis
* Below 82/10 (sensitivity =0.93; specificity =1.0)
* you can be confident that this is a dementia, but some cases may get missed
48
What is seen radiographically in Alzheimer's disease?
* CT: shows a characteristic pattern of cortical atrophy
* Medial temporal atrophy: hippocampus, entorhinal cortex, perirhinal cortex
* temporoparietal cortical atrophy
* an MRI would be more sensitive
49
What is seen radiographically in Dementia with Lewy Bodies?
* MRI shows
* generalised decrease in cerebral volume
* enlargement of the lateral ventricles
* DaTSCAN shows: a loss of functional dopaminergic neuron terminals in the striatum
50
What is seen radiographically in Vascular Dementia?
* CT or MRI (morse sensitive): white matter small vessel ischaemic changes - "hyperintensities"
51
What is seen radiographically in Frontotemporal Dementia?
* CT or MRI (morse sensitive): frontal and temporal atrophy, asymmetric with causate head volume loss
52
What type of dementia does this history suggest?
* 79 year old woman, lives with Husband.*
* Husband reports change in memory over a few months. Patient asks repetitive questions. Often forgets how to get home from unfamiliar places. When pushed, husband realises he hasn’t let her go outside alone for more than a year and changes happening over many years. Starting to need help getting dressed. Doesn’t follow the news on the radio any more.*
Alzheimer dementia
53
What type of dementia does this history suggest?
* 67 year old man, lives alone*
* Admitted to hospital recently due to self-neglect at home. Had been fine up until two years ago, very active in local bowls club. Now, unable to play. Concern from bowls club members led to safe guarding assessment. Used to be very knowledgeable about golf and other sports but stopped around 18 months ago. Had been doing well up until now. During admission, episode of slurred speech lasted around 3 hours.*
Vascular Dementia
| (slurred speech)
54
What type of dementia does this history suggest?
* 65 year old man, recently retired, lives with wife*
* Referred to clinic by GP as concern with ‘unusual behaviour’. Seen with wife who is very distressed. Recently retired and become disinterested in things at home. Doesn’t concentrate on TV but will sit in front of it all day long. Used to do all the washing/ironing but now keeps stopping part way through leaving the iron on. Wife gets very tearful and frustrated but patient laughs in response. Has been making inappropriate sexual comments to their female neighbours.*
Fronto-temporal
(dis-inhibition in behaviour, apathetic )
55
What type of dementia does this history suggest?
* 70 year old man, lives alone*
* Admitted via A and E with a fall. Recent car accident after driving wrong way down street. Concern from GP as has been showing up to practise for appointments on wrong day, or from previous day. GP noticed a shuffling gait and some stiffness on examination. Concern from A and E nurses as reporting seeing small animals and children in ward. Speaking to Nephew, he has been saying things like this for the last year.*
Dementia with Lewy bodies
(shuffling gate, parkinsonian feature → dopamine-related)
56
What are the treatment/management of Alzheimer's dementia (Vascular Lewy bodies) patients?
Biological/ Psychological/ Social
**Biological:**
* Mild/moderate AD - Acetyl Cholinesterase Inhibitors (AChEi) – donepezil, galantamine (daffodils), rivastigmine (Dementia with Lewy Bodies)
* Severe AD - NMDA receptor antagonist – Memantine
* Vascular dementia - address vascular risk factors – diet, smoking, aspirin, antihypertensive, statins
**Psychological:**
* Cognitive stimulation therapy, group reminiscence therapy, behavioural support planning
**Social:**
* Respite placements, Adult Social Care,
* Attendance allowance,
* Advanced care planning
57
What are clinically discriminating features of **behavioural-variant Frontotemporal Dementia (bvFTD)** ( Pick's disease)
* Disinhibition (loss of manners, decorum, socially inappropriate behaviour)
* Apathy/inertia
* Loss of sympathy/empathy
* Perseverative/compulsive behaviours (eg. simple repetitive movements, ritualistic behaviours)
* Hyperorolality (eg. oral exploration of objects, increased consumption of alcohol/cigarettes, altered food preferences)
* Executive dysfunction with relative sparing of memory and visuospatial functions.
58
What is the typical clinical presentation of Dementia with Lewy bodies?
* Hallucinations,
* Fluctuating levels of consciousness/cognition ('good and bad days'),
* REM-sleep behaviour disorder and
* Parkinsonism: usually presents a year after cognitive decline
59
What are the cognitive symptoms of dementia?
*– memory:* can’t learn, can’t remember, or learn then forget
*– executive :*‘remembering to do something’, organising, multi-tasking, efficiency
*– language:* word-finding, wrong sounds in a word, short phrases, loss of word meaning
– *visuospatial:* gets lost, puts things in wrong places, can’t judge distance
*– social-behavioural:* poor ‘manners’, doesn’t care, obsessive, apathetic, childlike
*–* *Psychiatric* low mood, anxious over minor things, paranoid, visual hallucinations
60
What are risk factor for Alzheimers disease?
* One common genetic polymorphism: apolipoprotein E (ApoE, three alleles, ε4 highest risk)
* Rare dominantly inherited single genes: PSEN1, PSEN2, APP (onset in early-mid adulthood)
* Some residual genetic risk, presumably many interacting loci each with small effect
* Cognitive reserve: stronger cognitive function pre-morbidly =\> later diagnosis
* Vascular risk factors: CVD worsens AlzD symptoms, but does it hasten AlzD pathology?
61
What treatment is there for Alzheimers disease?
No known treatment affects the disease process
AChE inhibitors and memantine boost cognitive function
Don’t make it worse: vascular risk factors, drugs (antimuscarinics, antipsychotics
306: Elderly
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