Psychiatry SC052: My Grandmother Keeps Forgetting Things: Geriatric Psychiatry, Dementia

Question 1

Dementia

Answer 1

Definition:
Syndrome due to disease of the **brain, usually of a **chronic / **progressive nature, in which there is **global impairment of higher cortical functions, but ***without impairment of consciousness

(vs other neurocognitive impairment: more specific impairment, not global)

Etiology:
1. **Degenerative (Primary)
- Alzheimer’s disease (AD) (most common)
- Frontotemporal dementia (FTD)
- Dementia with Lewy bodies (DLB)
2. Endocrine
3. Mass lesion
4. Nutritional
5. Traumatic
6. Infectious
7. Autoimmune
8. **Vascular

Top 3 causes:
1. Alzheimer’s disease (AD) (most common)
2. Vascular dementia
3. Dementia with Lewy bodies (DLB)
(Mixed dementia: AD + Vascular)

Prevalence:
- Over 30 million people has dementia worldwide
- 6-10% over 65 year-old in North America
- 9.1% dementia prevalent rate in HK
- “Milder” cognitive impairment from 3-23%
- Huge burdens to societies by 2050

Question 2

Diagnosis of Dementia

Answer 2

ICD-10:
Syndrome due to disease of the brain
1. Decline in memory and learning
2. Decline in other cognitive abilities characterized by deterioration in judgment, thinking and general processing of information
3. Decline in cognition > 6 months
4. Impaired performance in daily living
5. Clear consciousness
6. Types:
- Alzheimer’s Disease (F00)
- Vascular dementia (F01)
- Dementia in other diseases classified elsewhere (F02) (e.g. Pick’s, CJD, Parkinson’s, Huntington’s, HIV…)
- Unspecified dementia (F03)

DSM-5:
Evidence of cognitive decline from a **previous level of performance in **>=1 cognitive domains
1. Major neurocognitive disorder
- **Significant decline in cognition + **Interfere with independence in everyday activities
2. Mild neurocognitive disorder
- **Modest decline in cognition + **NOT interfere with capacity for independence in everyday activities
3. Specify for **etiologies
- Alzheimer’s disease
- Frontotemporal lobar degeneration
- Lewy body disease
- Vascular disease
- Traumatic brain injury
- HIV infection
- Prion disease
- Parkinson’s disease
- Huntington’s disease
- Substance use
4. Specify whether with / without **behaviour disturbance

Terminology:
1. Dementia
2. Neurocognitive disorder (NCD) (mild / major)
3. Mild cognitive impairment (MCI)

NB: Dementia / NCD is much more than cognitive decline

Question 3

Mild cognitive impairment (MCI)

Answer 3

• Common term which not used in ICD-10 / DSM-5
• ***Debatable concept, no very well consensus on the criteria
• Usually defined as **Subjective + **Objective cognitive impairment ***without significant functional impairment
• Intermediate stage between normal aging and dementia / major NCD
• Amnestic vs Non-amnestic subtype
• Single domain vs Multiple domains
• Different etiologies
• ***NOT all patients with MCI will progress to dementia (Annual rate 5-30% (SpC Psychi PP))

Question 4

***Clinical presentations of Dementia

Answer 4

1. ***Cognition (LAPLES)
   - Complex attention
   - Executive function
   - Learning + Memory
   - Language
   - Perceptual-Motor
   - Social cognition
2. ***Behaviour and Psychological symptoms of dementia (BPSD) (>80% patients)
   - Aggression / Agitation
   - Anxiety
   - Apathy
   - Delusions
   - Disinhibition
   - Dysphoria / Depression
   - Euphoria
   - Hallucinations
   - Irritability
   - Motor behaviour abnormality
   - Night-time behavioural disturbance
3. ***Activities of daily living (ADL)
   - Basic ADL (B-ADL) (eating, bathing, dressing, toileting)
   - Instrumental ADL (I-ADL) (finance, transportation, preparing meals, communication, shopping, medications etc.)

Question 5

1. Cognition

Answer 5

1. Complex attention
   - e.g. sustained, selective, divided attention + processing speed
2. Executive function
   - e.g. planning, decision making, working memory, error correction, inhibition, mental flexibility
3. Learning + Memory
   - e.g. immediate memory, recent memory, long term memory
4. Language
   - e.g. expressive language including naming, word finding, receptive language
5. Perceptual-Motor
   - e.g. visual perception, visuo-constructional, praxis + gnosis
6. Social cognition
   - e.g. recognition of emotions, theory of mind

Question 6

Alzheimer’s disease

Answer 6

Diagnosis:
1. **NINCDS-ADRDA Criteria for diagnosis of AD:
- Definite / Probable / Possible AD
—> Definite: With AD **histopathology
—> Probable: Dementia by various testing, **absence of other brain disease
—> Possible: Dementia, but **not typical AD

Supportive:
- Progression
- Family history
- Behaviour
- ADL disturbances
- EEG
- CT changes

2. DSM-5:
   Insidious onset + gradual progression of impairment in **>=1 cognitive domains (for major neurocognitive disorder, **>=2 domains must be impaired)

Probable AD:
All of the following are present:
A. Clear evidence of decline in memory and learning and at least one other cognitive domain (based on detailed history or serial neuropsychological testing)
B. Steadily progressive, gradual decline in cognition, without extended plateaus
C. No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological, mental, or systemic disease or condition likely contributing to cognitive decline)
OR
Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing (APP, PSEN1, PSEN2)

Possible AD:
- Either or the abovementioned is present

3. NIA-AA criteria:
   For probable AD with evidence of AD pathophysiological process:
   - Biomarkers of brain **amyloid-beta protein deposition
   —> **↓ CSF Aβ42
   —> Positive PET amyloid imaging
   - Biomarkers of neuronal degeneration or injury
   —> **↑ CSF total / phosphorylated **tau
   —> ***↓ FDG uptake on PET in temporoparietal cortex
   —> Disproportionate atrophy in medial, basal & lateral temporal & medial parietal lobe on MRI

Prevalence:
- 50-60% of all dementia cases
- Increases with ***age: 10% at 65, 25% at 85
- Early onset <65 vs Late onset >=65
- Duration of disease: diagnosis to death 8-10 years

Risk factors:
1. **Age
2. Genetics (PS1 and PS2, APP, **ApoE)
3. ***Female
4. Family history
5. Head trauma
6. Low education
7. Cardiovascular dysfunction

Pathology:
1. Deposition of β-Amyloid peptides / Amyloid plaque (extracellular) (Amyloid cascade hypothesis)
2. **Neurofibrillary Tangles (NFTs) (Intracellular) (Formation of highly ordered aggregates of hyper-phosphorylated Tau)
3. Usually involve **Temporal lobe at the beginning affecting **Hippocampus (atrophy) —> Memory impairment
4. **Cholinergic deficit
- Loss of cholinergic biosynthetic machinery
- Loss of basal forebrain cholinergic neurons
- Contribute to impairment of memory + attention

Progression:
β-Amyloid deposition (~30 yo)
—> Microglial activation (~40 yo)
—> Neurofibrillary tangles (~50 yo)
—> Neuronal loss / Neurochemical changes (~60 yo)
—> Dementia (~70 yo)
(NB: Process is continuous despite no symptoms (subclinical): once clinical symptoms develop —> rapid deterioration)

Question 7

APP, β-Amyloid

Answer 7

Dominantly inherited forms of AD: **Missense mutations in APP / Presenilin 1 or 2 genes —> Increased Aβ42 production **throughout life
or
Non-dominant forms of AD (including Sporadic AD): **Failure of Aβ clearance mechanisms (e.g. ApoE4 inheritance, faulty Aβ degradation etc.) —> **Gradual rise Aβ42 levels in brain
—> Accumulation + Oligomerisation of Aβ42 in limbic + association cortices
—> Subtle effects of Aβ oligomers on synaptic efficacy
—> Gradual deposition of Aβ42 oligomers as diffuse plaques
—> Microglial + Astrocytic activation + attendant inflammatory responses
—> Altered neuronal ionic homeostasis + Oxidative injury
—> Altered kinase / phosphatase activities lead to tangles
—> Widespread neuronal / synaptic dysfunction + selective neuronal loss with attendant neurotransmitter deficits
—> Dementia

(From HNS53, 54
APP gene (AD gene):
One domain of **Transmembrane protein
- β-secretase —> cleave APP to form C99 —> **γ-secretase (encoded by PSEN1) —> Aβ40/Aβ42 (—> degraded by Neprilysin, IDE, APOE)
- α-secretase —> cleave APP to produce C83

Mutation of APP / PSEN1:
- affect cleavage activity —> ↑ Aβ40/Aβ42 —> Amyloid-β accumulation —> Amyloid plaque)

(ApoE (from HNS 53, 54):
- Risk factor for **Sporadic AD
- Mechanism for association with AD: likely **Aβ clearance + ***neuronal repair

Apolipoprotein E:
- transport plasma lipids within tissues
- ***clearance of Amyloid-β at BBB
- immune response
- synaptic maintenance
- 3 alleles:
—> ε3 (most common, normal allele)
—> ε2 (protective: ↓ frequency in AD cases but risk factor for CVD)
—> ε4 (risk allele: ↑ frequency in AD cases)

***ε4 allele:
- ↑ risk of developing AD
- ↓ age of onset of AD)

Question 8

Neurofibrillary tangles

Answer 8

• NFT expression needed for ***Aβ toxicity
• NFT ***correlates with AD severity
• NFT load higher in patients with ApoE4
• ***NOT specific for AD
• Tauopathies share common end point

(From HNS53, 54:
Tau protein:
- structural protein in neuron
—> binds and **stabilise microtubule
—> help to **transport

Alzheimer’s disease:
- Tau protein **hyperphosphorylated
—> Tau **sequestered / captured in Neurofibrillary tangles
—> loss of Tau binding to microtubules
—> microtubule **dissociation
—> reduced **axonal transport
—> AD)

Question 9

Diagnosis of AD

Answer 9

1. History (collaterals very important)
2. P/E
3. Neuropsychological tests
   **Global cognition:
   - Mini-Mental Status Examination (MMSE)
   - Montreal Cognitive Assessment (MoCA)
   **Specific cognition:
   - Alzheimer’s Disease Assessment Scale-Cog (ADAS-Cog): Memory
   - ***Score affected by 3 Ws (Who, Where, When)
4. CBC, LRFT, Glucose, TSH, B12, folate, VDRL
5. ECG, CXR, EEG (in specific case)
6. Neuroimaging
   - CT —> Exclude other causes of dementia such as Tumor, Stroke, Abscess, NPH etc.
   - MRI —> Atrophy changes (Hippocampus particularly) + Structural lesion detail assessment
   - PET
   —> FDG-PET: Functional assessment of brain regions
   —> **PIB-PET (Pittsburgh Compound B (PIB): **Amyloid deposition
   - SPECT —> Functional assessment of brain regions
7. CSF (Total Tau, Phosphorylated Tau, β-Amyloid) (seldom done in HK clinical setting)

Question 10

Mini Mental Status Examination (MMSE) vs Montreal Cognitive Assessment (HK version: HK-MoCA)

Answer 10

MMSE:
- Interview
- 10 minutes
1. Orientation
2. Attention
3. Short term memory
4. Language
5. Motor
6. Visuospatial functioning

Advantages:
- **Short
- Sensitive to changes
- **Reliably tested across cultures

Limitations:
- **NOT assess executive function / frontal lobe
- **Ceiling effect (low sensitivity for mild problems)
- Paper-pencil test
- Age and Educational background dependent
- Less sensitive to mild impairment
- ***Copyright issue

HK-MoCA:
- 30-question test
- Approximately 10-15 minutes to administer
- Scored out of 30 points
- **Add 1 point to the total score if <=12 years education
- Total score >=26 = Normal
- **More challenging questions —> More appropriate for normals, SCD (Subjective cognitive decline) and MCI
(- Classify severity based percentile)
1. Visuospatial / Executive
2. Naming
3. Attention
4. Language
5. Memory
6. Abstraction
7. Orientation

MoCA (SpC FM):
- 2 versions: Cantonese MoCA vs HK-MoCA
- Only HK-MoCA has norm data for local HK chinese (adjusted for age + education level)

Cut-off for MoCA:
- >16th centile: Normal
- 16th - 2nd centile: Mild NCD (Neurocognitive disorder)
- <=7th centile: MCI (Mild cognitive impairment)
- <=2nd centile: Major NCD

Question 11

Special awareness to MoCA (SpC FM)

Answer 11

• Gives a very general impression only
• Low score may not equal to dementia
• Influenced by many factors e.g. sleep, medications, mood
• Learning effects if repeated too close to previous one
• Does not help diagnosis of dementia type

Test itself:
- Too difficult
- Some are uneducated / illiterate in HK
- Impaired vision / dexterity (e.g. arthritis / clumsy hand of stroke) —> overcome by visuospatial / executive test printed magnified + done on A4 paper
- Unfamiliar test items from different cultural background
- Communication problems: impaired hearing / vision / aphasia / learning difficulty / different dialect
- Complication from low mood / anxiety
- Apathy (gives up easily, give all wrong answers)
- Loss of face (anger)
- Relatives helping / distracting

Question 12

Abbreviated mental test (AMT) (SpC FM)

Answer 12

Some use to screen first:
- If AMT <5/6 —> Proceed to MoCA
- Not evidence based
- New cognitive test being designed for HK use

Question 13

Management of AD

Answer 13

Aim at Cognition:
Non-pharmacological:
1. Cognitive stimulation
2. Cognitive training
3. Cognitive rehabilitation
4. Exercise

Medication:
1. Acetylcholinesterase Inhibitor (AChEI)
- Donepezil, Rivastigmine, Galantamine
- Mild - Moderate dementia in AD
- Compensate the cholinergic deficit
- Effective in AD and DLB (***NOT in FTD)

2. Memantine
   - Moderate - Severe dementia in AD
   - Antagonist at N-methyl-D-aspartate (NMDA) receptors
   - Neuroprotective + Disease modifying agent (in theory)
3. Aduhelm (aducanumab)
   - Human monoclonal antibody: selectively targets aggregated Aβ
   - Approved in 2021 by FDA (based on 2 clinical trials EMERGE and ENGAGE)
   - Monthly IV infusions
   - First treatment directed at Aβ plaques in the brain
   - ***Amyloid-related imaging abnormalities (ARIA): brain swelling and bleeding
   - Monitoring: MRIs prior to initiating therapy, during the titration of the drug + at any time the patient has symptoms suggestive of ARIA
   - Effectiveness still under debate

Aim at BPSD:
- Exclude physical illness potentially precipitating
Non-pharmacological:
1. Behaviour modifications
2. Environmental modifications

Medications:
1. AChEI / Memantine
2. Antipsychotic
3. Antidepressant
4. Other neuroleptics
!!!Keep **lowest dose + **shortest period if possible, don’t prescribe medications unless significant BPSD!!!

Natural history of AD and Stage-specific drugs:
Normal aging
—> Amnestic (MCI)
—> Mild Dementia: **Antidepressants, **AChEI
—> Loss of functional independence: **AChEI, **Memantine
—> Behavioural symptoms: **Memantine, **AChEI, **Atypical neuroleptics
—> Nursing home stage: **Memantine, **AChEI, **Atypical neuroleptics
—> Severe stage

Question 14

Caring for Caregiver (“Hidden patient”)

Answer 14

1. Information to patient and caregiver
2. Medical, psychiatric, personal histories
3. Risk assessment
4. Case manager in family doctor or specialist clinic
5. Liaise with community agencies (e.g. Alzheimer Society)

Question 15

Summary

Answer 15

• Dementia (e.g. AD) is common
• “Being senile” is not a normal part of aging
• Vigilant on EARLY diagnosis
• Prevention may be more useful
• Treatment is multidisciplinary
• Treat the “Hidden patient”
• Be aware of ***ELDERLY ABUSE

Question 16

SpC Psychiatry: Vascular Dementia

Answer 16

• ~15% of dementia
• Subcortical vascular disease (rather than large cortical infarcts) accounts for most cases

DSM-5:
- Clinical features consistent with vascular etiology:
1. Onset of the cognitive deficits is **temporally related to **>=1 cerebrovascular events, OR
2. Evidence for decline is prominent in **complex attention (including processing speed) and **frontal-executive function

• Evidence of the presence of ***cerebrovascular disease from history, physical examination, and/or neuroimaging considered sufficient to account for the neurocognitive deficits

Probable VaD:
One of the following is present:
A. Clinical criteria are supported by ***neuroimaging evidence of significant parenchymal injury attributed to cerebrovascular disease (neuroimaging supported)
B. Neurocognitive syndrome is temporally related to one or more documented cerebrovascular events
C. Both clinical and genetic (eg, CADASIL) evidence of cerebrovascular disease is present

Possible VaD:
Clinical criteria met but neuroimaging not a/v & temporal relationship with cerebrovascular events not established

Clinical features:
Much more variable than AD, depending on the particular neural substrates affected by vascular pathology:
1. Acute **stepwise or **fluctuating decline, gradual onset with slow progression, rapid development of deficits followed by relative stability, etc.
2. Cognitive decline is typically most prominent in **speed of information processing, **complex attention, and **frontal-executive functioning (subcortical vascular pathology interrupts frontostriatal circuits)
3. Memory, language, and praxis is affected to various extents in VaD
4. **Depression and apathy are particularly prominent in those with VaD, and other BPSD such as delusions and hallucinations are less frequent

Subtypes:
1. Cortical vascular dementia (Multi-infarct dementia)
- multiple cortical infarcts

2. Subcortical vascular dementia (Small vessel dementia)
   - lacunar infarct, extensive white matter lesions
   - pathologically: infarcts, demyelination, gliosis
3. Strategic infarct dementia
   - infarct in a particular location e.g. thalamus
4. Hypoperfusion dementia
   - watershed infarcts, white matter lesions
   - pathologically: incomplete infarcts in white matter
5. Haemorrhagic dementia
   - haemorrhagic changes, may be associated with amyloid angiopathy
6. Hereditary vascular dementia (CADASIL)
   - multiple lacunes and white matter lesions
   - temporal lobe white matter affected
7. Alzheimer’s disease with cardiovascular disease
   - combination of vascular changes and atrophy, esp. medial temporal lobe
   - pathologically: mixture of vascular + degenerative pathology (plaque + tangle)

Question 17

Biomarkers of Vascular dementia

Answer 17

1. Omics / microRNA
   - Identifying subcellular components of VaD
2. Genetic biomarkers
   - Identifying genes involved in cerebrovascular disease
3. ***Neuroimaging biomarkers (correlate well with underlying pathological processes)
   - Structural + Functional imaging
4. Biochemical biomarkers
   - Serum, plasma, CSF biomarkers
5. Pathological biomarkers
   - Identifying cellular / histological changes
6. Clinical biomarkers
   - Neurobehavioural assessment

Question 18

Lewy body dementia

Answer 18

• 10-15% of dementia

DSM-5:
Core diagnostic features:
1. Fluctuating cognition with pronounced variations in **attention and **alertness
2. Recurrent **visual hallucinations that are well formed and detailed (DLB consortium: **precede cognitive decline)
3. Spontaneous features of ***parkinsonism, with onset subsequent to the development of cognitive decline

Suggestive diagnostic features:
1. Meets criteria for **REM sleep behavior disorder
2. Severe **neuroleptic sensitivity

Probable DLB:
- 2 core features or 1 suggestive feature + >=1 core features

Possible DLB:
- Only 1 core feature, or ≥1 suggestive features

Types:
1. **Dementia with Lewy bodies
2. **Parkinson’s disease dementia
- Differ in the sequence of onset of dementia and parkinsonism
- With progression, both syndromes and underlying pathological changes become similar
- A continuum rather than dichotomous entities
- Competing criteria
- Dementia with Lewy bodies consortium criteria (DLB Consortium): good specificity when core and suggestive features are present but sensitivity is only moderate

Pathology:
1. ***α-synuclein neuronal inclusions (Lewy bodies and Lewy neurites) (neuroprotective or neurotoxic?)

2. Accompanied by neuronal loss
3. Underlying pathology is often mixed
   - Cortical **α-synuclein pathology (strongest candidate substrate for PDD, while **Amyloid β has a more prominent role in DLB)
   - Even in PDD, presence of cortical tau-containing NFT and amyloid β pathology leads to more advanced dementia, implying that the two pathologies work together

Clinical features:
- Progressive cognitive impairment
- Typical in following domains:
1. **Attention (may fluctuate)
2. **Executive function
3. **Visuospatial function
4. **Free recall (usually improves with cueing)

Question 19

Biomarkers of DLB

Answer 19

Indicative:
1. Reduced **dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET
2. Abnormal (low uptake) **123I-MIBG myocardial scintigraphy
- Quantifies postganglionic sympathetic cardiac innervation (reduced in DLB)
3. **Polysomnographic confirmation of **REM sleep without atonia

Supportive:
1. Relative preservation of medial temporal lobe structures on CT/MRI scan
2. Generalised low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity ± the cingulate island sign on FDG-PET imaging
3. Prominent posterior slow-wave activity on EEG with periodic fluctuations in the pre-alpha/theta range

Question 20

Frontotemporal dementia

Answer 20

• 3rd most common form of degenerative dementia
• **Leading type of **early-onset dementia

3 clinical variants:
1. ***Behavioural-variant frontotemporal dementia (BV-FTD)
- Early behavioural + executive deficits

2. ***Non-fluent variant primary progressive aphasia (NFV-PPA)
   - Progressive deficits in speech, grammar, and word output
3. ***Semantic-variant primary progressive aphasia (SV-PPA) (語意)
   - Progressive disorder of semantic knowledge and naming

• As FTD progresses, symptoms of 3 clinical variants can ***converge —> Initially focal degeneration becomes more diffuse and spreads to affect large regions in the frontal and temporal lobes
• Over time, patients develop
  —> Global cognitive impairment
  —> Motor deficits (e.g. parkinsonism, motor neuron disease) in some patients
  —> End stage: difficulty eating, moving, and swallowing
  —> Death usually happens about 8 years after symptom onset and typically caused by pneumonia or other secondary infections

DSM-5:
- Insidious onset and gradual progression
- Relative sparing of **learning and memory and **perceptual-motor function

Behavioural variant:
1. >=3 behavioural symptoms (behavioural disinhibition; apathy or inertia; loss of sympathy or empathy; perseverative, stereotyped or compulsive/ritualistic behavior; hyperorality and dietary changes)
2. Prominent decline in social cognition and/or executive abilities

Language variant:
1. Prominent decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension

Probable FTD:
- Evidence of a causative FTD genetic mutation, from either family history or genetic testing (e.g. genes encoding MAPT and granulin, C9ORF72, TDP 43, valosin containing protein, chromatin modifying protein 2B, FUS)
or
- Evidence of disproportionate frontal and/or temporal lobe involvement from neuroimaging

Possible FTD:
- If none of the abovementioned is present

Question 21

Pathology of FTD

Answer 21

Imaging (Assist differentiating from AD):
- Structural MRI and CT: predominant **frontal or **temporal atrophy, and atrophy in the ***frontoinsular region is especially indicative of FTD
- FDG-PET, fMRI, and SPECT: disproportionate hypoperfusion and hypometabolism in these regions
- Amyloid PET: amyloid deposition is NOT a neuropathological feature of FTD
- Diffusion tensor imaging: widespread white matter degeneration in FTD (c.f. AD)
- Functional connectivity network mapping: decreased intrinsic connectivity within the salience network in bv-FTD in association with increased activity in the default mode network of brain regions. This pattern is reversed in AD

Neuropathology:
- 36-50%: Microtubule-associated protein tau (MAPT) —> e.g. Pick’s disease, corticobasal degeneration, progressive supranuclear palsy
- 50%: TAR DNA-binding protein with molecular weight 43 kDa (TDP-43) —> e.g. NFV-PPA, SV-PPA, BV-FTD, corticobasal degeneration
- 10%: Fused-in-sarcoma (FUS) protein
- A few FTD have ubiquitin-only or p62-only positive inclusions, or no inclusions

Genetics:
- Family history of dementia reported in up to 40% of FTD
- Autosomal dominant history accounts for only 10%

Question 22

1. Behavioural-variant frontotemporal dementia (BV-FTD)

Answer 22

1. ***Behavioural disinhibition
   - Tactless and socially inappropriate behaviour (e.g. approaching strangers without respect for physical and social boundaries)
   - Impulsive or careless actions (e.g. reckless spending)
   - New criminal behaviours (e.g. theft, urination in public, sexual advances, or hit and run accidents)
   - Embarrassing personal remarks
   - Bad fiscal decisions that lead to financial ruin
2. ***Apathy
   - Reduced interest in work, hobbies, social interaction, and hygiene
   - Can be mistaken for depression
3. ***Loss of sympathy and empathy
   - Decrease in social interest and responsiveness to the emotions and needs of other people (e.g. more concerned about going to the grocery store than attending the funeral of his spouse’s parent)
4. ***Stereotypical, compulsive, or perseverative behaviour
5. Hyperorality or dietary changes
   - Binge eating, increased consumption of sweets or alcohol, and weight gain
6. Often show deficits in executive tasks
7. Visuospatial skills are fairly normal at first
8. 40% with mild features of motor neuron, 20% with early parkinsonism
9. Patients have little insight into their own behaviour and may not recognise many of the changes that are reported by a knowledgeable informant
10. Some have decreased sensitivity to pain

Question 23

2. Primary progressive aphasia (PPA)

Answer 23

• Progressive, insidious decline in linguistic skills during the initial phase of the disease
• Language dysfunction is the main symptom for the first 2 years of the illness
• Language deficit is the main cause of impaired activities of daily living
• Should not show behavioural disturbances during the initial disease phase
• PPA more often associated with FTD. But should consider AD if prominent visuospatial impairment or episodic or visual memory impairments are present

1. Semantic variant primary progressive aphasia (SV-PPA)
   - Impaired confrontation naming
   - Impaired single word comprehension
   - >=3: impaired object knowledge, surface dyslexia or dysgraphia, spared repetition, spared speech production
2. Non-fluent variant primary progressive aphasia (NFV PPA)
   - >=1: agrammatism in production, apraxia of speech
   - >=2: impaired comprehension of complex sentences, spared single-word comprehension, spared object knowledge

Question 24

Biomarkers of FTD

Answer 24

1. Grey matter atrophy
2. Alterations in brain metabolism as detected by 18Ffluorodeoxyglucose-PET
3. CSF levels of amyloid-β1–42, phospho-tau181 and total-tau

Question 25

***Assessment of Dementia

Answer 25

1. History
   - Informant, family, personal
2. Examination
   - Physical
   - Mental
3. Routine investigations
   - Full blood count
   - Electrolytes
   - Glucose
   - LRFT
   - TFT
   - Vitamin B12 / folate
   - Syphilis serology
4. Neuroimaging
   - CT
   - MRI
   - SPECT
   - PET
5. Special investigations
   - EEG
   - LP

Question 26

***DDx of Dementia

Answer 26

1. Delirium
   - **Inattention and fluctuating level of consciousness
   - Disorientation common
   - **Reversible causes may be present and should be corrected
   - ***Fluctuating course, worse at night time
   - Fragmentary, fleeting hallucinatory experiences; visual, tactile, or auditory in form
2. Depression
   - Hallmark features are depressed mood + loss of interest/pleasure in usual activities
   - **Memory loss is not the predominant or a common feature
   - Depression may present acutely
   - **Negative cognitions, preserved visuospatial function, and biological symptoms may help to differentiate
3. All types of dementia (AD, VaD, FTD, DLB)

VaD:
- Deficits include memory loss, emotional liability, Parkinsonism, and focal neurological deficits consistent with stroke location
- **Cardiovascular risk factors may be present
- Further cognitive and functional decline occurs in a stepwise manner
- Subcortical depression and apathy are common
- Clinical history of temporally associated **stroke symptoms supports this diagnosis

FTD:
- **Behavioural variant: impulsive, socially inappropriate behaviour; marked apathy or inertia; loss of empathy; hyperorality; marked executive dysfunction
- Personality change and behavioural disturbance occur early and are prominent features
- **Language variants may be progressive nonfluent aphasia, semantic dementia (word meaning), or logopenic (impaired word finding and difficulty with repetition)
- Onset often at the ages of 50 to 60 years, but may present at a younger age
- Progresses more rapidly than AD

DLB:
- **Vivid visual hallucinations and **Parkinson’s features (shuffling gait, bradykinesia, and falls) are characteristic
- Rapid eye movement (REM) sleep disorder may be present
- Progression of disease is more rapid than AD