Dementia

• Over 30 million people have dementia worldwide ^[3]. Current estimates (2024–2025) place this closer to 55 million globally, projected to reach ~139 million by 2050 due to population ageing.
• Dementia is a leading cause of disability and dependency among older adults worldwide.

• 9.1% dementia prevalence rate in Hong Kong (aged > 65) ^[3][2].
• "Milder" cognitive impairment ranges from 3 to 23% ^[3].
• Huge burdens to societies by 2050 ^[3] — Hong Kong's rapidly ageing population means the absolute number of dementia cases will rise dramatically. By some projections, HK's dementia population could triple by 2050.

• Prevalence increases with age: 10% at 65; 25% at 85 ^[3][4].
• Prevalence roughly doubles every 5 years after age 65 ^[2].
• 6 to 10% over 65 year-old in North America ^[3].

• Presenile (Early onset): < 65 years — more commonly FTD, CJD; more often genetically implicated; more rapid progression.
• Senile (Late onset): ≥ 65 years — AD remains most common in both groups, but DLB and VaD are more common in late-onset.

• Overall, females are at slightly higher risk (especially for AD — partly because women live longer, and oestrogen loss post-menopause may play a role).
• DLB has a male predominance (M:F = 4:1) ^[2].

• Hippocampus: The gateway for new episodic memory encoding. This is why AD (which starts in the entorhinal cortex/hippocampus) presents first with anterograde amnesia — new memories cannot be laid down.
• Entorhinal cortex: The "relay station" between hippocampus and neocortex. First region affected in AD (Braak stage I-II).
• Basal nucleus of Meynert: Major source of cholinergic projections to the cortex. Its degeneration in AD leads to widespread ACh depletion → basis for cholinesterase inhibitor therapy ^[5].
• Frontal lobes: Executive function, personality, social conduct, motivation. Damage → disinhibition, apathy, poor planning (as in FTD).
• Parietal lobes: Visuospatial processing, praxis. Damage → apraxia, agnosia, spatial disorientation.
• Temporal lobes: Memory (medial), language (lateral dominant hemisphere), semantic knowledge (anterior). Damage → amnesia, aphasia.
• Basal ganglia/thalamus/subcortical white matter: Processing speed, procedural memory, attention. Damage → subcortical dementia pattern (slowness, forgetfulness improved by cueing, apathy).

This classification is clinically useful for pattern recognition:

The top three causes of dementia are: Alzheimer's Disease (most common), Vascular Dementia, and Dementia with Lewy Bodies (DLB) ^[3].

Mixed dementia usually means AD mixed with vascular ^[3].

Mnemonic for reversible causes: "DEMENTIA"
D — Drugs/toxins (anticholinergics, benzodiazepines, alcohol)
E — Endocrine (hypothyroidism, Cushing's, Addison's)
M — Metabolic (B12, folate, renal failure, hepatic failure, Wilson's)
E — Emotional (depression → pseudodementia)
N — Normal pressure hydrocephalus
T — Tumour/mass lesion (frontal, corpus callosum, 3rd ventricle)
I — Infectious (HIV, neurosyphilis, CJD)
A — Autoimmune (cerebral vasculitis, SLE, autoimmune encephalitis)

Vascular Dementia is the second most common cause of dementia ^[3].

• "Vascular" = relating to blood vessels → brain damage from cerebrovascular disease.
• Onset typically in late 60s–70s.
• Risk factors: All vascular risk factors — HTN, prior stroke, IHD, peripheral vascular disease, DM, AF, smoking, dyslipidaemia ^[2].
• May be mixed with AD — this is extremely common and called mixed dementia ^[3].

Pathophysiological mechanisms ^[2]:

These are critical because they are treatable. Missing a reversible cause is unforgivable.

• AD, VaD, Mixed (AD + VaD), FTD, DLB, PDD, CJD, NPH, alcohol-related, etc.

• Presenile (Early onset, < 65): More commonly FTD, CJD; more commonly genetically implicated; more rapid progression.
• Senile (Late onset, ≥ 65): DLB and VaD more common; AD still most common in both groups.

FTD is divided into two major subtypes with prominent behavioural/psychiatric symptoms ^[2]:

Creutzfeldt-Jakob Disease (CJD) ^[2]:

• Rapidly progressive dementia (weeks to months, not years)
• Myoclonic jerks, seizures, cerebellar ataxia
• Young onset with early psychiatric symptoms in variant CJD (vCJD — linked to BSE)
• Caused by prion protein (PrPSc) misfolding → spongiform change → rapid neuronal death

Normal Pressure Hydrocephalus (NPH) ^[2]:

• Classical triad: Frontal dementia ("wet, wacky, and wobbly" = urinary incontinence, dementia, gait apraxia)
• Mental slowing, apathy, inattention (subcortical/frontal pattern)
• Commonest in 50–70 year age group
• Why? CSF circulation impaired → ventriculomegaly → stretching of periventricular white matter fibres (especially those serving the legs → gait affected first, then bladder, then cognition)
• Importantly reversible with VP shunting

Alcohol-Related Dementia ^[2]:

• ~50–70% of alcohol abusers have some cognitive deficits
• Multifactorial: direct ethanol neurotoxicity + head injury + vascular changes + nutritional deficiency (thiamine)
• Clinical picture simulates frontal lobe dementia ^[2] — Why? Frontal lobes are most susceptible to alcohol neurotoxicity
• Neuroimaging: cerebral cortical atrophy with enlarged lateral ventricles, loss of grey matter, white matter changes with demyelination ^[2]
• Diagnosed 8 weeks after abstinence (to allow acute effects to clear)

• F-A-S test (phonemic fluency): Name words starting with F, A, S in 1 minute each — tests executive function and language ^[2].
• Category fluency (semantic fluency): Name animals in 1 minute — tests semantic memory and executive function.
• Trail Making Test A & B: Tests attention and executive function (set-shifting).
• Rey-Osterrieth Complex Figure: Tests visuospatial construction and visual memory.

• Collateral history is essential — patients with dementia often lack insight and minimise symptoms. Always speak to a family member/carer.
• Onset and progression: Insidious (AD, FTD) vs stepwise (VaD) vs rapid (CJD) vs fluctuating (DLB)?
• First symptoms: Memory (AD) vs behaviour (FTD) vs visuospatial (DLB) vs executive (VaD)?
• BPSD: Hallucinations, delusions, depression, aggression, wandering, sleep disturbance?
• Functional decline: IADLs (finances, medication, transport, cooking) → BADLs (dressing, bathing, eating)?
• Medical history: Vascular RFs, prior stroke, head injury, thyroid disease, alcohol use, medications (anticholinergics!)?
• Family history: Dementia, psychiatric disease, movement disorders?
• Drug history: Many medications worsen cognition — anticholinergics (diphenhydramine, oxybutynin), benzodiazepines, opioids, antihistamines.

• General: Nutritional status, thyroid examination
• Neurological: Focal deficits (VaD), Parkinsonism (DLB/PDD), primitive reflexes (FTD), myoclonus (CJD), gait (NPH)
• Cardiovascular: AF, carotid bruits, BP (vascular RFs)
• Mental state examination: Including cognitive screening (MMSE/MoCA)

This is the most important mimic of dementia, accounting for ~10% of presumed dementia ^[2].

The term "pseudodementia" (literally "false dementia") refers to cognitive impairment caused by a primary psychiatric disorder — overwhelmingly depression in the elderly. Why does depression cause cognitive problems? Because depression causes:

• Reduced motivation and effort → poor performance on cognitive tasks (but not true inability)
• Impaired concentration and attention → the patient can't focus, so new information isn't encoded properly
• Psychomotor retardation → slowed thinking and responses, mimicking bradyphrenia
• Hippocampal dysfunction → chronic cortisol elevation from HPA axis dysregulation actually causes reversible hippocampal volume reduction

As differentiation between them may be difficult, it may be prudent to treat depressive symptoms if present before concluding on a diagnosis of dementia ^[2].

Key principle: Cognitive fluctuations may occur in dementia, especially in DLB and as sundowning in AD. Delirium should be ruled out if there is any change in pattern of fluctuation from baseline ^[7]. This is crucial — a patient with known dementia who acutely worsens likely has a superimposed delirium (infection, medication change, dehydration, constipation).

Why is this distinction so important? Because delirium has a treatable underlying cause and carries significant mortality (up to 25% in hospitalised elderly) if missed. Dementia patients are also at high risk for developing delirium — dementia is the single strongest predisposing factor for delirium.

By definition, amnestic syndrome is associated with severe disruption of memory with minimal involvement of other domains ^[2]. This is the key distinction — dementia requires impairment in multiple cognitive domains, whereas amnestic syndrome is essentially isolated memory loss.

• Confabulation may be prominent, especially in diencephalic amnesias ^[2] (e.g. Korsakoff syndrome — the patient fills memory gaps with fabricated but plausible stories, without intent to deceive).
• Look for past history of alcoholism, risk factors for nutritional deficiencies, and evidence of brain disease (diencephalic, medial temporal lesions) as potential causes ^[2].
• Classic example: Korsakoff syndrome — thiamine deficiency → mammillary body and dorsomedial thalamic damage → severe anterograde amnesia + confabulation, but other cognitive domains relatively preserved.

MCI is an intermediate stage between normal ageing and dementia/major NCD ^[3].

Key points from the lecture slides:

• Common term which is not used in ICD-10 and DSM-V ^[3] (DSM-5 uses "Mild NCD"; ICD-10 uses F06.7 which is not quite the same entity)
• Debatable concept, no very well consensus on the criteria ^[3]
• Usually defined as subjective + objective cognitive impairment without significant functional impairment ^[3]
• Amnestic vs non-amnestic subtype ^[3]
• Single domain vs multiple domains ^[3]
• Different aetiologies ^[3]
• Not all patients with MCI will progress to dementia ^[3] — approximately 10–15% per year convert from MCI to dementia, but some remain stable or even revert to normal

Why the distinction matters: MCI does not meet criteria for dementia because independence in everyday activities is preserved (though the patient may need greater effort). The patient is "at risk" but not yet impaired enough to warrant a dementia diagnosis.

Normal ageing produces mild cognitive changes:

• Slightly slower processing speed
• Minor word-finding difficulties (tip-of-the-tongue phenomenon)
• Mild decline in episodic memory (but encoding is preserved — retrieval is slower)

These do not interfere with daily functioning and are within normal limits on neuropsychological testing. The threshold between normal ageing and MCI is subjective complaint + objective deficit; between MCI and dementia is functional impairment.

From the senior notes, the key d/dx for AD specifically:

• Vascular dementia: Hx, S/S and imaging evidence of stroke, stepwise progression, labile mood, focal neurological S/S ^[2]
• DLB: early prominent visual hallucinations, cognitive fluctuations, motor Parkinsonism, neuroleptic sensitivity, REM sleep behaviour disorder ^[2]
• FTD: usually with earlier onset; bvFTD with early personality, behavioural and executive function deficits; PPA with early isolated language deficits ^[2]

• PD-dementia: differentiation is arbitrary; by convention PD-dementia is diagnosed only if dementia occurs ≥1 year from onset of PD (otherwise diagnosis of DLB should be made) ^[2]
• Other dementia + superimposed delirium: rule out systemic causes of fluctuating clinical features ^[2]
• NPH: no psychiatric symptoms, sleep disorder, or dysautonomic features ^[2] (NPH has the classic triad of gait apraxia, urinary incontinence, and frontal dementia)

ICD-10: "A syndrome due to disease of the brain" ^[8]:

• Decline in memory and learning ^[8]
• Decline in other cognitive abilities characterised by deterioration in judgement, thinking and general processing of information ^[8]
• Decline in cognition > 6 months ^[8]
• Impaired performance in daily living ^[8]
• Clear consciousness ^[8]

The ICD-10 criteria are worth dissecting because every element serves a clinical purpose ^[2]:

ICD-10 codes: 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) ^[8].

DSM-V: "evidence of cognitive decline from a previous level of performance in one or more cognitive domains…" ^[9]:

• Major neurocognitive disorder — significant decline in cognition + interfere with independence in everyday activities ^[9]
• Mild neurocognitive disorder — modest decline in cognition + don't interfere with capacity for independence in everyday activities ^[9]
• Specify for aetiologies and with/without behaviour disturbance ^[9]

The full DSM-5 criteria expanded ^[2]:

MCI is usually defined as subjective + objective cognitive impairment without significant functional impairment ^[3]. This is the intermediate stage between normal ageing and dementia ^[3].

ICD-10 Criteria for Dementia in AD (F00) ^[2]:

The following features are essential:

• (a) Presence of a dementia as described above
• (b) Insidious onset with slow deterioration. While the onset usually seems difficult to pinpoint in time, realisation by others that the defects exist may come suddenly. An apparent plateau may occur in the progression ^[2]
• (c) Absence of clinical evidence or findings from special investigations to suggest that the mental state may be due to other systemic or brain disease which can induce a dementia ^[2]
• (d) Absence of a sudden, apoplectic onset or of neurological signs of focal damage occurring early in the illness ^[2]

Note: double coding (F00 + F01) is used if features of both AD and VaD are present ^[2].

NINCDS-ADRDA Criteria (the classic research/clinical criteria) ^[4]:

NINCDS-ADRDA classifies AD as "definite", "probable", and "possible" AD ^[4]:

Progression, family history, behaviour, ADL disturbances, EEG and CT changes are supportive ^[4].

DSM-5 Criteria for Major NCD due to AD ^[2]:

NIA-AA 2011 / AT(N) Research Framework (2018) — A brief note on modern biomarker-based criteria:

The field is moving towards a biological definition of AD based on biomarkers, classified as:

• A = Amyloid (CSF Aβ42 ↓, amyloid PET +)
• T = Tau (CSF p-tau ↑, tau PET +)
• N = Neurodegeneration (CSF total tau ↑, FDG-PET hypometabolism, MRI atrophy)

An individual is "on the Alzheimer's continuum" if A+ (amyloid positive), regardless of symptoms. This is primarily a research framework and not yet standard clinical practice in Hong Kong, but it represents the direction the field is heading.

The diagnosis of VaD requires ^[2]:

1. Presence of dementia (meeting general criteria)
2. Uneven/patchy cognitive deficits (some functions may be relatively preserved)
3. Evidence of cerebrovascular disease — clinical (focal neurological signs, history of stroke) AND radiological (infarcts, white matter lesions on MRI)
4. Temporal relationship between cerebrovascular disease and dementia onset

Clinical tools:

• Hachinski Ischaemic Score ^[2]: ≥7 = multi-infarct dementia; 5–6 = mixed; ≤4 = AD
• MoCA more appropriate for VaD assessment because executive function deficits are prominent ^[2]
• MRI more sensitive than CT for detecting small vessel disease ^[2]

Probable DLB = dementia + ≥2 core features, OR ≥1 core + ≥1 indicative biomarker. Possible DLB = dementia + 1 core feature, OR ≥1 indicative biomarker alone.

bvFTD (International Consensus Criteria, Rascovsky 2011):

• Possible bvFTD: ≥3 of 6 behavioural/cognitive features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviour, hyperorality/dietary changes, executive deficits with relative sparing of memory and visuospatial function) + functional disability
• Probable bvFTD: Possible bvFTD + significant frontal/anterior temporal atrophy on imaging OR frontotemporal hypoperfusion/hypometabolism on PET/SPECT
• Definite bvFTD: Possible/probable bvFTD + histopathological confirmation OR known pathogenic mutation

The mnemonic "I FOR GET ABC" captures the essential dementia screen ^[2]:

Additional blood tests as indicated ^[2]:

• VDRL for neurosyphilis
• ESR / vasculitic screen for cerebral vasculitis
• LFT for hepatic encephalopathy
• HIV serology in at-risk patients
• Copper studies (ceruloplasmin, 24h urine copper) for Wilson's disease in young-onset cases

From the lecture slides, the recommended AD workup includes ^[10]:

AD Diagnosis investigations ^[10]:

• Patient history (collaterals very important)
• Physical examination
• Neuropsychological tests
• CBC, L/RFT, BG, TSH, B12, folate, VDRL
• ECG, CXR, EEG (in specific case)
• Neuroimaging (CT, MRI; non-essential: PET, SPECT)
• CSF (total tau, phosphorylated tau and amyloid-beta) — seldom done in HK clinical setting

CSF (total tau, phosphorylated tau and amyloid-beta) — seldom done in HK clinical setting ^[10].

The combination of low Aβ42 + high p-tau has high sensitivity and specificity (> 85%) for AD and can be useful in differentiating AD from FTD or depression.

Non-pharmacological interventions are used often in combination with medication ^[2]. The evidence varies, but several are recommended by guidelines.

Grossly speaking, AD patients have a 3–4 point/year drop in MMSE. With Rx alone, this is reduced to ~2 points/year. With Rx + cognitive stimulation, this is further reduced to ~1 point/year ^[2]. This is a powerful teaching point — medication alone is not sufficient.

The case from the lecture slides illustrates a typical management plan:

Diagnosed with AD. Treatment ^[18]:

1. Acetylcholinesterase inhibitor
2. Behavioural modification
3. Counselling (patient and caregiver)
4. Social worker referral

Why are AChEIs sometimes used in VaD despite limited evidence? Because mixed dementia (AD + VaD) is extremely common — a patient diagnosed with VaD often has co-existing AD pathology contributing to their cholinergic deficit. Treating "empirically" for the AD component is often pragmatically sensible.

Treatment: symptomatic (no disease-modifying treatment available) ^[2]:

Management: symptomatic only ^[2]:

• Why? Advanced dementia → immobility (bedbound ^[2]) → sustained pressure on bony prominences (sacrum, heels, greater trochanter) → tissue ischaemia → ulceration.
• Compounded by: malnutrition (impaired healing), incontinence (skin maceration), inability to communicate pain (so the patient cannot tell you they're uncomfortable).

• Why? Immobility (Virchow's triad — stasis) + dehydration (haemoconcentration). Dementia patients cannot mobilise themselves and may not complain of leg swelling or dyspnoea.

• Why? (1) Frontal lobe damage → loss of social inhibition of micturition/defaecation (patient doesn't recognise the need to go to a toilet). (2) Visuospatial dysfunction → can't find the toilet. (3) Apraxia → can't manage clothing/toilet mechanics. (4) Late-stage autonomic dysfunction → true neurogenic bladder/bowel.
• Consequence: Skin breakdown, UTIs, social embarrassment (contributes to caregiver burden and institutionalisation), significant cost of continence products/care.

• Seizures: occur in 10–20%, usually in later stages of AD ^[2].
• Why? Widespread cortical neuronal loss → aberrant electrical networks. Aβ oligomers may also have direct pro-epileptogenic properties by disrupting synaptic inhibition (enhancing excitatory glutamatergic transmission relative to GABAergic inhibition).
• Seizures may present atypically in dementia — as unexplained episodes of confusion, staring, or falls — and can be mistaken for BPSD or disease progression.