Dementia

Dementia is a chronic, progressive decline in cognitive function—including memory, reasoning, and behavior—sufficient to impair daily functioning, resulting from various neurodegenerative or vascular conditions.

Dementia is a syndrome due to disease of the brain, usually of a chronic or progressive nature, in which there is disturbance of multiple higher cortical functions ^[1]^[2]. Let's break this definition down from the ICD-10 piece by piece, because every word matters clinically:

"Syndrome" — not a single disease, but a clinical constellation of symptoms and signs arising from many possible aetiologies. You must always look for the cause.
"Due to disease of the brain" — distinguishes it from functional psychiatric disorders (e.g. depression causing pseudodementia).
"Usually chronic or progressive" — this separates it from delirium (acute, fluctuating consciousness) and other acute neurological insults. However, some dementias (e.g. CJD) can be rapidly progressive.
"Disturbance of multiple higher cortical functions" — typically affecting ≥2 cognitive domains (memory, executive function, language, visuospatial, social cognition, complex attention). The DSM-5 requires decline in ≥1 domain, but classically ≥2 are involved.
"Without impairment of consciousness" — a critical distinction from delirium. If consciousness is clouded, you cannot diagnose dementia at that moment (though the two can co-exist).

DSM-5 Terminology: Major Neurocognitive Disorder

The DSM-5 (2013, updated DSM-5-TR 2022) replaced "dementia" with Major Neurocognitive Disorder (Major NCD), though "dementia" remains acceptable as a descriptor, especially for degenerative conditions. The key DSM-5 criteria are ^[2]:

DSM-5 Criterion	Explanation
A. Evidence of significant cognitive decline from a previous level of performance in ≥1 cognitive domain (complex attention, executive function, learning and memory, language, perceptual-motor, social cognition)	Based on (1) concern of patient/informant/clinician AND (2) substantial impairment on standardised neuropsychological testing (typically ≥2 SD below mean)
B. The cognitive deficits interfere with independence in everyday activities	At minimum, requires assistance with complex instrumental ADLs (e.g. managing finances, medications)
C. Not occurring exclusively in the context of delirium	Must rule out acute confusional state
D. Not better explained by another mental disorder (e.g. major depression, schizophrenia)	Pseudodementia must be excluded

The distinction between Major NCD (dementia) and Mild NCD (mild cognitive impairment, MCI) is functional: in Mild NCD, cognitive decline is present but independence in daily activities is preserved (perhaps with greater effort or compensatory strategies).

Dementia vs Delirium vs Depression — The 3 D's

A classic exam trap. Delirium has acute onset, fluctuating consciousness, and inattention. Depression can cause "pseudodementia" with poor concentration and apparent memory loss but the patient typically complains about memory (unlike true dementia where insight is often lost). All three can co-exist, especially in the elderly. Always rule out delirium before diagnosing dementia.

2. Epidemiology

3. Risk Factors

Understanding risk factors is essential because some are modifiable — and modification is currently our best strategy for prevention (the Lancet Commission 2020/2024 identifies 14 modifiable risk factors accounting for ~45% of dementia cases).

Factor	Explanation
Age	Single strongest risk factor. Incidence doubles every 5 years after 65.
Family history ^[4]	10–30% increased risk; up to 30% of AD cases are familial ^[2]. First-degree relative with dementia roughly doubles your risk.
Genetics ^[4]	Early-onset AD: autosomal dominant mutations in APP (Ch21), PSEN1 (Ch14, >70% of familial early-onset AD), PSEN2 (Ch1). Late-onset AD: APOE ε4 allele (heterozygous: 3× risk; homozygous: 12× risk; accounts for ~50% of vulnerability to late-onset AD) ^[2].
Female sex ^[4]	Especially for AD.
Down syndrome (Trisomy 21)	APP gene is on chromosome 21 → extra copy → lifelong overproduction of Aβ → virtually all individuals with Down syndrome develop AD pathology by age 40.

Factor	Mechanism / Explanation
Low education ^[4]	Lower cognitive reserve → less capacity to compensate for neuropathology. Education builds synaptic density and neural networks ("cognitive reserve hypothesis").
Cardiovascular dysfunction ^[4] — HTN, dyslipidaemia, IHD	Vascular risk factors damage cerebral vasculature → chronic hypoperfusion, white matter ischaemia, and promote amyloid deposition. HTN in midlife is particularly important.
Diabetes mellitus (Type 2)	Insulin resistance → impaired cerebral glucose metabolism + promotes neuroinflammation + accelerates amyloid pathology.
Obesity (midlife)	Adipokine-mediated neuroinflammation + vascular risk.
Physical inactivity	Exercise promotes BDNF, cerebral perfusion, and amyloid clearance via the glymphatic system.
Head trauma ^[4]	Traumatic brain injury (even single moderate-severe TBI) → diffuse axonal injury, tau pathology, chronic neuroinflammation (cf. chronic traumatic encephalopathy).
Smoking	Vascular damage + direct neurotoxicity + oxidative stress.
Excessive alcohol	Direct neurotoxicity (especially frontal lobe), thiamine deficiency → Wernicke-Korsakoff, and vascular damage ^[2].
Depression	Chronic depression → hippocampal atrophy via sustained cortisol exposure (HPA axis dysregulation). Also reduces social/cognitive engagement.
Social isolation	Reduced cognitive stimulation → less cognitive reserve building.
Hearing loss (midlife)	Reduced auditory input → cognitive load shift + social withdrawal + accelerated temporal lobe atrophy. Now considered the single largest modifiable risk factor.
Air pollution	Fine particulate matter (PM2.5) → neuroinflammation + amyloid deposition.
Untreated vision loss	Similar to hearing loss — sensory deprivation reduces cognitive stimulation.

High Yield — Modifiable Risk Factors

The Lancet Commission (2024) estimates that addressing all 14 modifiable risk factors could prevent or delay up to 45% of dementia cases. For exams, remember the big hitters: hearing loss, low education, hypertension, smoking, obesity, depression, physical inactivity, diabetes, excessive alcohol, TBI, air pollution, social isolation, and untreated vision loss. In Hong Kong, vascular risk factors (HTN, DM, dyslipidaemia) are especially prevalent and important.

4. Anatomy and Function — The Cognitive Domains

To understand dementia, you need to understand what is being damaged. The DSM-5 defines 6 cognitive domains, each mapped to specific brain regions. Dementia is essentially the progressive destruction of these networks.

Domain	Brain Region(s)	What It Does	How Decline Presents
Complex Attention	Prefrontal cortex, reticular activating system, right parietal	Sustained, divided, selective attention; processing speed	Easily distracted, can't follow conversations, loses track of tasks, slow processing
Executive Function	Prefrontal cortex (dorsolateral, orbitofrontal), anterior cingulate	Planning, decision-making, working memory, mental flexibility, error correction, inhibition	Poor judgement, can't manage finances, difficulty multitasking, rigid thinking, perseveration
Learning and Memory	Hippocampus (encoding), entorhinal cortex, medial temporal lobe, mammillary bodies, anterior thalamus (Papez circuit)	Encoding, storage, retrieval of new information (episodic, semantic, procedural)	Repeats questions, forgets recent events, needs reminders, eventually loses remote memories
Language	Left perisylvian cortex: Broca's area (expressive), Wernicke's area (receptive), arcuate fasciculus	Expressive and receptive language, naming, fluency, comprehension	Word-finding difficulty, circumlocution, paraphasias, eventually mutism
Perceptual-Motor (Visuospatial)	Parietal-occipital cortex (dorsal "where" stream), inferior temporal cortex (ventral "what" stream)	Spatial orientation, face recognition, object recognition, constructional ability	Gets lost in familiar places, can't park car, difficulty with copying drawings, prosopagnosia
Social Cognition ^[2]	Orbitofrontal cortex, anterior temporal lobe, amygdala, anterior cingulate	Emotion recognition, theory of mind, social appropriateness	Socially inappropriate behaviour, loss of empathy, insensitivity to social cues, disinhibition

This classification is clinically useful for pattern recognition:

Feature	Cortical Dementia	Subcortical Dementia
Prototypes	AD, FTD	VaD (subcortical type), PD-dementia, PSP, HD, CJD
Memory	True amnesia (encoding failure — can't register new information; prompting doesn't help)	"Forgetfulness" (retrieval failure — recognition > recall; improved by prompting/cueing)
Language	Aphasia (word-finding difficulty → fluent aphasia → global)	Preserved but with reduced verbal fluency
Higher cortical functions	Apraxia, agnosia, acalculia	Typically preserved
Speed of thought	Relatively preserved early	Slowed (bradyphrenia)
Personality/mood	Often preserved until late (AD) or early change (FTD)	Apathy, flat affect, depression early
Motor signs	Usually absent until late	Dysarthria, movement disorders early

Feature	Anterior Dementia (Frontal)	Posterior Dementia (Parietal-Temporal)
Key features	Behavioural changes, disinhibition, antisocial behaviour, apathy	Memory loss, language disturbance with relatively preserved behaviour
Prototypes	FTD, NPH, Huntington's disease	Alzheimer's disease

5. Aetiology

The causes of dementia can be broadly categorised into degenerative (primary) and secondary causes. This is critical because secondary causes may be reversible — missing them is a clinical catastrophe.

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)

5.2 Degenerative (Primary) Causes [1][2]

i. Alzheimer's Disease (AD) — 50–70% of all dementia

AD accounts for about "50%–60%" of all dementia cases ^[4].

Prevalence increases with age: 10% at 65; 25% at 85 ^[4].
Early onset ( < 65 y.o.), late onset (≥ 65 y.o.) ^[4].
Duration of disease: diagnosis to death 8 to 10 years ^[4].
Risk factors: genetics (PS1 and PS2, APP, ApoE), female, family history, head trauma, low education, cardiovascular dysfunction ^[4].

Pathophysiology of AD — understanding this is essential:

AD pathology ^[5]:

Deposition of beta amyloid peptides/amyloid plaque (extracellular) — amyloid cascade hypothesis ^[5]
Formation of highly ordered aggregates of hyper-phosphorylated tau — Neurofibrillary Tangles, NFTs (intracellular) ^[5]
AD pathology usually involves the temporal lobe at the beginning, affecting hippocampus → memory impairment ^[5]
Cholinergic deficit: ^[5]
- Loss of cholinergic biosynthetic machinery
- Loss of basal forebrain cholinergic neurons
- Cholinergic deficit contributes to the impairment of memory and attention

The Amyloid Cascade Hypothesis ^[2]^[5]^[6]:

This is the most influential hypothesis. The timeline graphic from the lecture slides is key ^[6]:

β-amyloid deposition begins decades before clinical symptoms (age ~30–40), followed by microglial activation, then neurofibrillary tangles, then neuronal loss/neurochemical changes, and finally clinical DEMENTIA (age ~70–90) ^[6].

Step-by-step:

Amyloid Precursor Protein (APP) is a normal transmembrane protein (on chromosome 21). It is cleaved by secretases:
- Non-amyloidogenic pathway (normal): α-secretase cleaves within the Aβ domain → no toxic amyloid formed.
- Amyloidogenic pathway (pathological): β-secretase (BACE1) and then γ-secretase cleave APP → produces Aβ peptides, particularly the 42-amino acid variant (Aβ42), which is highly hydrophobic and prone to aggregation.
In familial (early-onset) AD: Mutations in APP, PSEN1, or PSEN2 (the latter two are subunits/regulators of γ-secretase) → increased Aβ42 production throughout life ^[2].
In sporadic (late-onset) AD: Failure of Aβ clearance mechanisms (e.g. APOE4 is less efficient at clearing Aβ, neuroinflammation impairs microglial phagocytosis) → gradual accumulation ^[2].
Consequence: Aβ42 accumulates → forms oligomers (soluble, highly toxic) → then fibrils → then plaques (neuritic plaques = degenerated axons/synapses around amyloid core) in limbic and association cortices.
Downstream effects: Oligomeric Aβ → synaptic toxicity → microglial/astrocytic activation → neuroinflammation → altered ionic homeostasis → oxidative injury → tau hyperphosphorylation → neurofibrillary tangles (NFTs) → neuronal and synaptic loss ^[2].
Tau pathology follows a stereotypical spread (Braak staging):
- Stage I–II: Entorhinal cortex (transentorhinal)
- Stage III–IV: Hippocampus, limbic structures
- Stage V–VI: Neocortex (widespread) ^[2]

Why Aβ42 specifically? Because the 42-amino acid form is more hydrophobic than Aβ40 and thus more prone to aggregation and toxicity.

The Cholinergic Hypothesis ^[2]^[5]:

Was the prior prevailing view but now considered incomplete.
Observation: Degeneration of cholinergic neurons from the basal nucleus of Meynert → severe and widespread loss of acetylcholine (ACh).
ACh is critical for memory consolidation and attention — its loss accounts for core cognitive symptoms.
Clinical significance: Led to development of acetylcholinesterase inhibitors (AChEIs) — donepezil, rivastigmine, galantamine — which remain first-line symptomatic treatment.

Genetics of AD in detail ^[2]^[4]:

Gene	Chromosome	Protein	Mechanism	Onset
APP	21	Amyloid Precursor Protein	Mutations alter cleavage → ↑Aβ42	Early ( < 65)
PSEN1	14	Presenilin 1 (γ-secretase subunit)	↑Aβ42 production; accounts for > 70% of familial early-onset AD	Early ( < 65)
PSEN2	1	Presenilin 2 (γ-secretase regulator)	↑Aβ42 production; rarer	Early ( < 65)
APOE	19	Apolipoprotein E (ε4 allele)	Less efficient Aβ clearance; accounts for ~50% of late-onset AD vulnerability; less penetrant	Late (≥ 65)

Why does Down syndrome (Trisomy 21) lead to early AD? Because APP is on chromosome 21 — having 3 copies means lifelong overproduction of Aβ.

ii. Frontotemporal Dementia (FTD) — ~5% ^[1]^[2]

"Fronto" = frontal lobe; "temporal" = temporal lobe → the name tells you where the pathology is and therefore predicts the clinical features (behaviour/personality from frontal; language from temporal).
Common cause of early-onset dementia (average onset 58 years, unusual before 40 or after 70).
Highly heritable (~40% have FHx for dementia/psychiatric disease); ~10–25% autosomal dominant inheritance.
Key genes: C9ORF72 (most common genetic cause), MAPT (tau), GRN (progranulin).
Gross pathology: Frontotemporal lobar atrophy → classically "knife-blade" atrophy (razor-thin gyri) ^[2].
Microscopic: Microvacuolation, neuronal loss, swollen neurons. Half show tau inclusions (Pick's bodies — round, silver-staining intracytoplasmic inclusions); others show TDP-43 or FUS inclusions ^[2].

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]:

Subtype	Mechanism	Location
Large artery infarcts (post-stroke dementia)	Single strategic infarct or multiple cortical infarcts	Usually cortical, but may be subcortical
Small artery (lacunar) infarcts (multi-infarct dementia)	Multiple small vessel occlusions → lacunes	Exclusively subcortical (basal ganglia, thalamus, internal capsule, cerebellum, brainstem)
Chronic subcortical ischaemia (Binswanger's disease)	Chronic hypoperfusion → periventricular white matter damage	White matter, without discrete stroke episodes
CADASIL	Autosomal dominant mutation in NOTCH3 → vasculopathy in small cerebral vessels	Subcortical infarcts + leukoencephalopathy
Haemorrhagic dementia	Repeated cerebral haemorrhages (e.g. CAA)	Variable
Hypoperfusion dementia	Global cerebral hypoperfusion (e.g. cardiac arrest, severe hypotension)	Watershed zones

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

Category	Examples	Why It Causes Dementia
Endocrine/Metabolic	Hypothyroidism, renal failure, hepatic failure, hypercalcaemia, hyponatraemia	Metabolic encephalopathy → impaired neuronal function
Mass Lesions/Structural	NPH, frontal tumours, corpus callosum tumours, 3rd ventricle tumours	Direct compression/displacement of brain tissue; NPH → distortion of periventricular white matter fibres
Nutritional/Toxins	B12 deficiency, folate deficiency, alcohol, heavy metals, organic solvents, organophosphates	B12: impaired methylation → myelin damage + homocysteine accumulation → neurotoxicity. Alcohol: direct neurotoxicity + thiamine deficiency ^[2]
Traumatic	Chronic SDH, chronic traumatic encephalopathy (CTE, "punch-drunk")	Chronic SDH: slow compression. CTE: repeated TBI → tau deposits (perivascular pattern)
Infectious	CJD, neurosyphilis, HIV, PML, AIDS-dementia complex, SSPE	CJD: prion protein misfolding → spongiform change. HIV: direct viral neurotoxicity + opportunistic infections
Autoimmune	Autoimmune/paraneoplastic encephalitis, cerebral lupus, cerebral vasculitis, MS	Antibody-mediated neuronal injury or vasculitic ischaemia

Reversible Causes — Must Screen!

In every patient presenting with cognitive decline, you must screen for reversible causes. The standard "dementia screen" blood tests include: TFTs (hypothyroidism), B12/folate, calcium, glucose/HbA1c, LFTs, RFTs, CBC, syphilis serology (RPR/VDRL), and HIV (in appropriate patients). Brain imaging (CT or MRI) is also mandatory to exclude structural causes (tumours, NPH, chronic SDH).

6. Classification of Dementia

Dementia can be classified in multiple complementary ways ^[2]:

Stage	DSM-5 Term	Functional Status	Typical Neuropsych Score
Subjective Cognitive Decline	—	Normal function, subjective complaints	Normal testing
Mild Cognitive Impairment (MCI)	Mild NCD	Independent (with greater effort); may need help with complex IADLs	1–2 SD below mean
Dementia (Mild)	Major NCD — Mild	Needs help with IADLs (finances, medications, transport)	≥2 SD below mean
Dementia (Moderate)	Major NCD — Moderate	Needs help with basic ADLs (dressing, bathing)	Significant impairment
Dementia (Severe)	Major NCD — Severe	Fully dependent for all ADLs	Profound impairment

Classification	Key Features	Prototype Diseases
Anterior (Frontal)	Behavioural changes, disinhibition, antisocial behaviour, irresponsibility	FTD, NPH, Huntington's
Posterior (Parietal-Temporal)	Memory loss, language disturbance, relatively preserved behaviour	AD
Cortical	Higher cortical dysfunction: aphasia, agnosia, apraxia, acalculia, true amnesia	AD, FTD
Subcortical	"Forgetfulness" (retrieval > encoding, improved by prompting), bradyphrenia, difficulty with complex tasks, apathy, flat/depressed mood, dysarthria, movement disorders	PD-dementia, PSP, CJD, HD, subcortical VaD

7. Clinical Features

The clinical approach separates cognitive symptoms from neuropsychiatric (behavioural and psychological) symptoms of dementia (BPSD), and neurological signs. We will cover each major dementia subtype.

7.1 Alzheimer's Disease — Clinical Features [2][4][5]

AD usually presents with memory deficit followed by other deficits, with an insidious onset and gradual progression.

Symptom	Description	Pathophysiological Basis
Progressive memory impairment (first abnormality)	Characteristic anterograde recent episodic amnesia early on ^[2]. Patient cannot learn new information — repeats questions, forgets appointments, misplaces items. Develops insidiously, gradually spreading to affect other aspects of memory.	Earliest pathology is in the entorhinal cortex → hippocampus (Braak stage I–III), the structures essential for encoding new episodic memories. Cholinergic loss from basal nucleus of Meynert further impairs memory consolidation.
Executive dysfunction	↓ organisation, problems with planning, abstract reasoning ^[2]. Difficulty managing finances, cooking complex meals, following recipes.	Spread of pathology to prefrontal cortex and disruption of frontal-subcortical circuits. Also related to cholinergic depletion affecting frontal networks.
Language (aphasia)	Word-finding or naming difficulties, impairment in verbal fluency ^[2]. Initially anomia → progresses to fluent aphasia → eventually global aphasia and mutism.	Spread to left perisylvian cortex (temporoparietal junction, Wernicke's area). Semantic store degradation as temporal neocortex is affected.
Visuospatial (apraxia, agnosia)	Difficulty in copying pictures, learning way round unfamiliar environment, disorientation (late) ^[2]. Gets lost, can't park, difficulty dressing.	Involvement of parietal association cortex (dorsal "where" stream). Posterior cortical atrophy variant presents predominantly with this.
Anosognosia (loss of insight)	Insight (anosognosia) is common but variable ^[2]. Patient is unaware of or minimises deficits.	Damage to right parietal lobe and frontal self-monitoring networks. This contrasts with depression where patients often overestimate their cognitive problems.

Neuropsychiatric symptoms are common in AD, especially in the middle-to-late course ^[2]:

Symptom	Prevalence / Details	Pathophysiological Basis
Depression	Major depression in 10%; less marked depression in > 50% ^[2]	Serotonergic and noradrenergic neuronal loss (raphe nuclei, locus coeruleus). Also a reactive/psychological response to awareness of decline.
Psychosis	Hallucinations (10–25%), delusions (10–50%), often persecutory themes including theft, phantom lodger ^[2]	Cholinergic depletion (especially in temporal/parietal cortex) + disrupted reality-monitoring networks. Misidentification syndromes from right hemisphere/parietal damage.
Behavioural disturbance	Aggression, wandering, sundowning (↑motor activity in evening), sexual dysfunction (disinhibition or ↓libido) ^[2]	Frontal lobe involvement → loss of inhibitory control. Sundowning may relate to disrupted circadian rhythm (suprachiasmatic nucleus degeneration) + evening fatigue + reduced environmental cues.
Sleep disturbance	Spend ↑time in bed awake, fragmented sleep ^[2]	Degeneration of suprachiasmatic nucleus + cholinergic/orexinergic system disruption → circadian dysregulation.

Sign	Timing	Pathophysiological Basis
Anosmia	Often occurs early but usually neglected ^[2]	Early involvement of olfactory bulb and entorhinal cortex (which receives olfactory input). This is why anosmia can precede memory loss.
Seizures	Occur in 10–20%, usually in later stages ^[2]	Widespread cortical neuronal loss → aberrant electrical activity. Aβ itself may have pro-epileptogenic properties by disrupting synaptic inhibition.
Motor signs (pyramidal/extrapyramidal)	Usually in late stages ^[2]	Late spread to motor cortex and basal ganglia pathways. Extrapyramidal signs may reflect co-existing Lewy body pathology (mixed pathology is common).

7.2 Vascular Dementia — Clinical Features [2]

The hallmark is stepwise deterioration with usually preserved insight ^[2]:

Symptom	Description	Pathophysiological Basis
Stepwise/fluctuating cognitive decline	Periods of stability punctuated by sudden worsening (each step = new vascular event)	Each new infarct/haemorrhage destroys additional brain tissue → cumulative cognitive damage.
Executive dysfunction (prominent)	Problems with planning, sequencing, mental flexibility; may be more prominent than memory loss	Subcortical lacunar infarcts disrupt frontal-subcortical circuits. White matter ischaemia disconnects frontal lobes from subcortical structures.
Patchy cognitive deficits	Variable pattern depending on which vascular territories are affected	Unlike AD's relatively uniform progression, VaD depends on which specific vessels are occluded. A strategic infarct (e.g. thalamus, angular gyrus) can cause sudden dramatic decline.
Relatively preserved memory (early)	Especially in subcortical VaD — retrieval-type "forgetfulness" rather than encoding failure	Hippocampus may be spared if infarcts are subcortical. Retrieval pathways (frontal-subcortical) are disrupted rather than storage (hippocampus).

Symptom	Pathophysiological Basis
Depression (more common than in AD)	Disruption of frontal-limbic circuits by white matter lesions; "vascular depression" hypothesis.
Labile mood, pseudobulbar affect	Bilateral disruption of corticobulbar tracts → disinhibition of emotional expression centres in brainstem. Pseudobulbar affect = pathological laughing/crying disproportionate to emotion.
Apathy, anxiety	Frontal-subcortical circuit disruption.
Personality changes	Frontal lobe ischaemia.
Abulia (amotivation)	Bilateral medial frontal/anterior cingulate damage → loss of drive/initiative.

Sign	Basis
Focal neurological deficits	Correspond to specific infarct locations (hemiparesis, hemianopia, hemisensory loss, etc.)
Gait disturbance (early)	Subcortical white matter damage → small-stepped, shuffling "marche à petits pas"
Pseudobulbar palsy	Bilateral corticobulbar tract damage → dysarthria, dysphagia, exaggerated jaw jerk, pseudobulbar affect
Extrapyramidal signs	Basal ganglia lacunar infarcts
Urinary incontinence (early)	Frontal lobe damage → loss of social inhibition of micturition; also disruption of pontine micturition centre pathways

7.3 Dementia with Lewy Bodies — Clinical Features [2]

DLB presents with a characteristic combination of cortical + subcortical features:

Feature	Prevalence	Description	Pathophysiological Basis
Cognitive fluctuations	60–80%	Fluctuation of attention, alertness and cognitive performance. Episodes of "blanking out", daytime drowsiness, bizarre behaviour, interspersed with periods of near-normal function ^[2]	Fluctuating cholinergic transmission in cortex + brainstem arousal system dysfunction (Lewy bodies in brainstem reticular formation, pedunculopontine nucleus).
Visual hallucinations	67%	Occurs early in the illness; typically well-formed and detailed ^[2] (e.g. seeing people, animals, children — often not distressing initially)	Lewy body pathology in occipital visual cortex + cholinergic depletion affecting visual processing. Also posterior cortical dysfunction releasing "top-down" imagery.
REM sleep behaviour disorder (RBD)	85%	Characterised by dream enactment behaviour, e.g. vocalisation, complex motor behaviour ^[2] (acting out dreams — punching, kicking, shouting in sleep)	Loss of normal REM atonia due to Lewy body pathology in brainstem nuclei (sublaterodorsal nucleus/subcoeruleus region) that normally inhibit spinal motor neurons during REM.
Parkinsonism	70–90%	Usually more bilaterally symmetric and milder than in PD ^[2]	Lewy bodies in substantia nigra → dopaminergic loss. More symmetric because cortical/limbic Lewy body burden may be more diffuse compared to PD.

Feature	Significance
Antipsychotic sensitivity (30–50%)	Acute irreversible Parkinsonism, LOC ± NMS towards antipsychotics ^[2]. This is a critical clinical point — never give typical antipsychotics (haloperidol) to suspected DLB! Even atypicals can worsen. This occurs because dopaminergic pathways are already severely compromised; blocking the few remaining D2 receptors → catastrophic motor and autonomic deterioration.
Repeated falls, syncope, transient LOC	Autonomic dysfunction (Lewy bodies in sympathetic ganglia, brainstem autonomic centres) → orthostatic hypotension.
Autonomic dysfunction	Constipation, urinary incontinence, postural hypotension — all from peripheral and central autonomic Lewy body deposits.
Hypersomnia, hyposmia	Brainstem and olfactory bulb pathology.
Other hallucinations, systematised delusions, apathy/anxiety/depression	Cortical Lewy body burden affecting multiple circuits.

DLB vs AD — Key Distinguishing Points

DLB: Early visuospatial/executive deficits, cognitive fluctuations, visual hallucinations, RBD, Parkinsonism, preserved medial temporal lobe on MRI, antipsychotic sensitivity. AD: Early memory loss (episodic, anterograde), gradual progression without fluctuations, hallucinations/motor signs usually late, hippocampal atrophy on MRI.

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

Feature	Behavioural variant FTD (bvFTD)	Primary Progressive Aphasia (PPA)
Core presentation	Behavioural and personality changes	Early, progressive language disturbance with relative sparing of other domains
Specific features	Behavioural disinhibition (e.g. public urination, inappropriate sexual comments) — Why? Orbitofrontal cortex damage → loss of social inhibition.	Non-fluent variant (nfvPPA): Articulation difficulty, agrammatism — Why? Left posterior frontoinsular atrophy (Broca's area region).
	Apathy/inertia and loss of empathy — Why? Medial frontal and anterior cingulate damage → loss of motivation and emotional processing.	Semantic variant (svPPA): Impaired word comprehension and object knowledge — Why? Anterior temporal lobe atrophy (semantic memory store).
	Executive dysfunction: Perseveration, hyperorality (putting inappropriate things in mouth, dietary changes — sweet food craving), ritualistic behaviour — Why? Dorsolateral prefrontal and orbitofrontal dysfunction.	Logopenic variant: Word-finding pauses, sentence repetition difficulty — Why? Left temporoparietal junction; often underlying AD pathology.
	Early loss of insight — Why? Right frontal lobe → self-awareness.
	Primitive reflexes (grasp, palmomental) — Why? Frontal lobe release signs when frontal cortex damaged.
Key distinction from AD	Behaviour and personality change dominate EARLY; memory relatively preserved initially.	Language deficits are the dominant and earliest feature, not memory.

Feature	AD	VaD	DLB	FTD
Onset	Insidious, > 65	Variable, late 60s–70s	~75y, M > F	~58y, presenile
First symptom	Memory (episodic)	Variable (executive common)	Attention/visuospatial	Behaviour/language
Progression	Gradual, relentless	Stepwise	Fluctuating	Variable
Memory	Early, severe	Variable, retrieval-type	Late	Relatively preserved
Hallucinations	Late (10–25%)	Uncommon	Early, visual, well-formed	Uncommon
Motor signs	Late	Focal deficits, gait	Parkinsonism (symmetric, mild)	Primitive reflexes
Insight	Lost early	Preserved	Variable	Lost early
Key neuroimaging	Hippocampal/MTL atrophy	Infarcts, WML	Preserved MTL	Frontal/temporal atrophy
Unique features	Aphasia, apraxia, agnosia	Pseudobulbar affect, urinary incontinence	RBD, cognitive fluctuations, antipsychotic sensitivity	Disinhibition, hyperorality, loss of empathy

8. Neuropsychological Assessment

Understanding how we test for dementia is clinically important:

Tool	Description	Strengths	Limitations
MMSE (Mini-Mental State Examination)	30-point scale; tests orientation, registration, recall, attention, language, visuospatial	Widely used, quick (5–10 min)	Biased by education level; poor for executive function, visuospatial; copyright issues
MoCA (Montreal Cognitive Assessment)	30-point scale; better coverage of executive function, visuospatial, abstraction	More sensitive for MCI; better for subcortical/executive deficits; MoCA more appropriate for VaD ^[2]	Slightly longer; also education-biased
CDT (Clock Drawing Test)	Ask patient to draw clock face with all numbers and set hands to specific time	Quick screen for executive + visuospatial; captures frontal and parietal dysfunction	Cannot be used alone; not comprehensive

9. Approach to a Patient with Suspected Dementia [2]

The clinical approach involves three steps:

Assessment of severity and clinical profile: From history and neuropsychological testing ^[2]
Establishing the diagnosis of dementia: Rule out alternative differentials by physical examination and investigations ^[2]
Identifying the underlying cause: From symptoms/signs ± neuroimaging ^[2]

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)

High Yield Summary

Definition: Dementia = chronic, progressive syndrome of global cognitive decline (≥1 domain, DSM-5; ≥2, ICD-10) without impaired consciousness, causing functional impairment. DSM-5 term: Major Neurocognitive Disorder.

Epidemiology: 9.1% prevalence in HK > 65y; prevalence doubles every 5 years after 65; projected to triple by 2050.

Top 3 causes: AD (50–60%) > VaD (10–20%) > DLB (~10%). Mixed dementia (AD + VaD) is very common.

AD pathophysiology: Aβ42 accumulation (amyloid cascade) + tau hyperphosphorylation (NFTs) → neuronal loss. Starts in entorhinal cortex/hippocampus → spreads cortically. Cholinergic deficit from basal nucleus of Meynert degeneration.

AD genetics: Early-onset: APP, PSEN1 (>70%), PSEN2 (all autosomal dominant). Late-onset: APOE ε4 (~50% of vulnerability).

AD clinical: Insidious onset, anterograde episodic amnesia first, then executive → language → visuospatial → BPSD → motor signs. Duration 8–10 years.

VaD: Stepwise decline, preserved insight, executive dysfunction prominent, focal neurology, depression/labile mood. RF management is key.

DLB: Early visuospatial/executive deficits, cognitive fluctuations, visual hallucinations (early, well-formed), RBD, symmetric mild Parkinsonism, antipsychotic sensitivity (NEVER give typical antipsychotics), preserved MTL on MRI.

FTD: Young onset (~58y), bvFTD (disinhibition, apathy, loss of empathy, hyperorality) vs PPA (language variants). Highly heritable (C9ORF72, MAPT, GRN). Pick's bodies (tau inclusions).

Reversible causes: Always screen — "DEMENTIA" mnemonic. Blood tests: TFTs, B12/folate, calcium, glucose, LFTs, RFTs, syphilis serology. Brain imaging mandatory.

Classification: By severity (MCI vs dementia), aetiology, age of onset (presenile < 65 vs senile ≥ 65), anatomy (cortical vs subcortical, anterior vs posterior).

Cortical vs Subcortical: Cortical = true amnesia, aphasia, apraxia, agnosia (AD, FTD). Subcortical = retrieval-type forgetfulness (improved by prompting), bradyphrenia, apathy, movement disorders (VaD subcortical, PDD, HD).

Active Recall - Dementia (Definition to Clinical Features)

Differential Diagnosis of Dementia

The differential diagnosis of dementia operates on two levels simultaneously. First, you must determine whether the patient truly has dementia — or whether something else is mimicking it (the "Is this really dementia?" question). Second, once dementia is established, you must differentiate between the underlying aetiologies (the "What type of dementia?" question). Both levels are critical because missing a reversible mimic or a treatable cause is a clinical failure.

Let's work through this systematically, starting with the mimics, then the inter-dementia differentiation.

Level 1: "Is This Really Dementia?" — Non-Dementia Differentials

These are conditions that can present with cognitive decline but are not dementia. Missing these is dangerous because most are treatable or reversible.

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

Feature	Depression (Pseudodementia)	True Dementia
Onset	More well-defined, more rapid decline ^[2]	Insidious, gradual
Insight	Tends to complain/worry about poor memory more; presents by themselves ^[2]	Poor insight (anosognosia); brought to doctor by family ^[2]
Effort on testing	Tends to give less effort; "I don't know" answers ^[2]	Tends to try hard but responds with incorrect answers ^[2]
Cognitive pattern	Poor concentration and attention more than memory ^[2]; can often perform if motivated	True amnesia (encoding failure); cannot perform even with effort
Language and motor skills	Slow but not impaired ^[2]	Truly impaired (aphasia, apraxia)
Mood features	Morning dysphoria, psychomotor retardation, sleep/appetite disturbance, guilt, anhedonia ^[2]	Mood symptoms typically appear later in disease course
Consistency	Variable performance; may do well on some days	Consistently impaired

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].

Depression and Dementia Can Co-Exist!

Depression is extremely common within dementia (>50% in AD have depressive symptoms). So the question is not always "depression OR dementia" — it can be both. A treatment trial of antidepressants is reasonable if depression is suspected; improvement in cognition supports pseudodementia, while persistence of deficits despite mood improvement suggests underlying dementia.

Feature	Delirium	Dementia
Onset	Acute (hours to days) ^[7]	Chronic (months to years)
Course	Fluctuating, with lucid intervals ^[7]	Progressive (though DLB can fluctuate)
Consciousness	Clouded; attention characteristically impaired ^[2]	Clear consciousness ^[1]
Perceptual disturbance	Common (vivid hallucinations, illusions)	Only appears in late stages of dementia ^[2] (except DLB — early visual hallucinations)
Precipitant	Usually precipitated by acute medical illness or new drug use ^[2]	No acute precipitant
Reversibility	Reversible if cause treated	Usually irreversible
Sleep-wake cycle	Grossly disrupted	May be disrupted but less acutely

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.

Condition	Key Differentiating Features
Medication-induced cognitive impairment	Anticholinergics (oxybutynin, diphenhydramine, TCAs), benzodiazepines, opioids, anticonvulsants → reversible with drug withdrawal. Always review the medication list.
Non-convulsive status epilepticus	No classical ictal features; supportive features include bilateral facial twitching, unexplained nystagmoid eye movements, automatisms; EEG required for diagnosis ^[7]
Focal neurological disorders	Wernicke's aphasia (isolated language), bitemporal lesions, Anton's syndrome (cortical blindness with denial), bifrontal lesions; neuroimaging required ^[7]
Psychosis (late-onset schizophrenia)	Prominent delusions and hallucinations with relatively preserved cognition; onset history and thought disorder pattern differ.
Sensory impairment	Profound deafness or visual loss can mimic cognitive decline in elderly → always check hearing and vision.

Level 2: "What Type of Dementia?" — Inter-Dementia Differentiation

Once you've established that the patient truly has dementia, the next step is identifying the underlying cause. The clinical approach uses pattern recognition based on onset, clinical profile, progression pattern, and neuroimaging.

Feature	AD (62%)	VaD (17%)	DLB (4%)	FTD (2%)
Onset age	Usually > 65y; insidious	Late 60s–70s	~75y; M > F	~58y (early onset)
Onset pattern	Insidious, gradual	Variable; often stepwise	Insidious with fluctuations	Insidious
First symptom	Memory (anterograde, episodic)	Executive/variable; depends on infarct location	Attention, executive, visuospatial (memory late)	Behaviour/personality (bvFTD) or language (PPA)
Progression	Gradual, relentless	Stepwise with periods of deterioration and improvement	Fluctuating	Variable
Memory	Severely impaired early (encoding failure)	Variable; retrieval-type (improved by cueing)	Relatively preserved until late	Relatively preserved early
Executive function	Impaired (later)	Prominent early	Impaired early	Impaired early (perseveration, set-shifting failure)
Hallucinations	Late (10–25%)	Uncommon	Early, visual, well-formed, detailed	Uncommon
Parkinsonism	Late motor signs	Focal neurology, gait disturbance	Bilaterally symmetric, mild	Rare (primitive reflexes instead)
Insight	Lost early	Usually preserved	Variable	Lost very early
Mood	Depression (>50%)	Depression, labile mood, pseudobulbar affect	Depression/apathy	Apathy, loss of empathy
Unique features	Aphasia → apraxia → agnosia; anosmia early	Focal deficits, stepwise, urinary incontinence early	RBD, cognitive fluctuations, antipsychotic sensitivity	Disinhibition, hyperorality, ritualistic behaviour, knife-blade atrophy
Neuroimaging	Hippocampal/medial temporal lobe atrophy; ↓metabolism parietotemporal on FDG-PET ^[2]	Infarcts (lacunar/cortical), white matter lesions on MRI ^[2]	Preserved medial temporal lobe; ↓perfusion/metabolism most marked in occipital areas ^[2]	Focal frontotemporal atrophy; knife-blade atrophy; bvFTD: orbitofrontal/medial frontal; PPA: asymmetric left-sided ^[2]

Aetiology	Key Distinguishing Features	Neuroimaging
PD-Dementia (~2%)	Similar to DLB but motor PD established > 1 year before dementia onset	Similar to DLB
CJD	Rapidly progressive dementia (months, not years); myoclonic jerks, seizures, cerebellar ataxia; young onset with early psychiatric symptoms in variant CJD ^[2]	Normal structural appearance; MRI cortical ribboning on DWI/FLAIR; vCJD: pulvinar sign ^[2]
NPH	Classical triad: frontal dementia + apraxic gait + urinary incontinence ("wet, wacky, wobbly"); mental slowing, apathy, inattention; commonest in 50–70y ^[2]	ALL ventricles enlarged disproportionate to sulcal effacement; periventricular lucency on FLAIR ^[2]

Mixed Dementia — The Practical Reality

In clinical practice, mixed dementia usually means AD mixed with vascular ^[4]. Pure forms of any single dementia are probably less common than we teach. Many elderly patients have overlapping Alzheimer and vascular pathology. This is why the clinical differentiation between AD and VaD can be so difficult — and why cholinesterase inhibitors are sometimes used in VaD despite limited evidence, because coexisting AD pathology is very likely ^[2].

This is a clinical scoring tool specifically designed to help distinguish vascular dementia from Alzheimer's disease:

Feature	Score
Abrupt onset	2
Stepwise deterioration	1
Fluctuating course	2
Nocturnal confusion	1
Relative preservation of personality	1
Depression	1
Somatic complaints	1
Emotional incontinence	1
History of hypertension	1
History of strokes	2
Evidence of associated atherosclerosis	1
Focal neurological symptoms	2
Focal neurological signs	2

Interpretation ^[2]:

≥ 7: Multi-infarct (vascular) dementia
5–6: Mixed dementia
≤ 4: Alzheimer's disease

The Hachinski score works because it essentially tallies up features that point towards a vascular aetiology (stroke history, abrupt onset, focal signs, vascular risk factors). A high score means more "vascular" features are present. However, it was designed before modern neuroimaging and has limitations — MRI findings often trump the clinical score.

One of the most useful clinical shortcuts is thinking about how fast the cognitive decline occurred, because this immediately narrows the differential:

Speed of Onset	Timeframe	Likely Diagnoses
Acute (hours–days)	Hours to days	Delirium (not dementia — but consider in any acute change in a dementia patient)
Subacute (weeks–months)	Weeks to months	CJD (rapidly progressive), autoimmune encephalitis, CNS lymphoma, paraneoplastic
Chronic gradual (months–years)	Months to years, insidious	AD, DLB, FTD
Chronic stepwise (months–years)	Months to years, stepwise	VaD
Chronic with specific triggers	Variable	Drug-induced, alcohol-related, post-TBI

While the full diagnostic algorithm will be covered in the next section, certain investigations are particularly useful at the differential diagnosis stage:

Investigation	What It Helps Differentiate
MRI brain	AD (hippocampal atrophy) vs VaD (infarcts, WML) vs FTD (frontotemporal atrophy) vs DLB (preserved MTL) vs NPH (ventriculomegaly disproportionate to sulcal atrophy) vs CJD (cortical ribboning on DWI)
FDG-PET	AD (parietotemporal hypometabolism) vs DLB (occipital hypometabolism) vs FTD (frontotemporal hypometabolism)
DaTSCAN (dopamine transporter SPECT)	DLB/PDD (reduced dopamine transporter uptake in striatum) vs AD (normal)
EEG	CJD (periodic sharp wave complexes) vs non-convulsive status epilepticus
CSF biomarkers	AD (↓Aβ42, ↑total tau, ↑phospho-tau) vs CJD (↑14-3-3 protein, ↑total tau)
Blood tests	Reversible causes: TFTs, B12/folate, calcium, syphilis, HIV

Key Exam Point — AD NINCDS-ADRDA Classification

The NINCDS-ADRDA criteria classify AD as ^[4]:

"Possible": dementia, but not typical AD
"Probable": dementia by various testing, absence of other brain disease
"Definite": with AD histopathology

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

This means that a "definite" diagnosis of AD technically requires neuropathological confirmation (at autopsy or biopsy). In clinical practice, we work with "probable" AD. The 2011 NIA-AA criteria and the 2018 AT(N) research framework now incorporate biomarkers (amyloid PET, CSF Aβ42/tau), but the clinical criteria remain the backbone of diagnosis.

High Yield Summary — Differential Diagnosis of Dementia

Depression (pseudodementia) is the most important mimic (~10%). Key differences: more rapid onset, patient complains of memory loss (good insight), gives "don't know" answers, concentration > memory affected, slow but not impaired language/motor skills. Treat depression first if unsure.
Delirium: Acute onset, fluctuating consciousness, impaired attention, usually precipitated by acute illness/drugs. Must be ruled out before diagnosing dementia. Dementia patients are at high risk for superimposed delirium.
MCI: Objective cognitive deficit but preserved functional independence. Not all MCI progresses to dementia (~10–15%/year conversion).
Amnestic syndrome: Isolated memory loss without other domain involvement (e.g. Korsakoff's). Confabulation may be prominent.
Inter-dementia differentiation: Use onset pattern (insidious vs stepwise vs rapid), first symptom (memory vs behaviour vs visuospatial vs language), unique features (fluctuations, hallucinations, Parkinsonism, disinhibition), and neuroimaging.
AD vs VaD: Hachinski score: ≥ 7 = vascular, ≤ 4 = AD, 5–6 = mixed. In practice, mixed dementia is very common.
DLB vs PDD: The 1-year rule — PDD if motor PD > 1 year before dementia; DLB if dementia within 1 year of or before Parkinsonism.
Always screen for reversible causes: TFTs, B12/folate, calcium, glucose, RFTs, LFTs, syphilis, CT/MRI brain.

Active Recall - Differential Diagnosis of Dementia

References

^[1] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p8 (ICD-10 diagnosis — Dementia) ^[2] Senior notes: ryanho-psych.md (Sections 4.2.1–4.2.5: Approach to Dementia, differential diagnosis tables, clinical evaluation, Alzheimer's D/dx, DLB D/dx, VaD, FTD, delirium differentials) ^[3] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p15 (Mild cognitive impairment) ^[4] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p17–18 (Top three causes of Dementia; Alzheimer's Disease NINCDS-ADRDA) ^[7] Senior notes: ryanho-psych.md (DSM-5 Delirium criteria and differential diagnoses of delirium, including dementia vs delirium table)

Diagnostic Criteria for Dementia

Diagnosing dementia is a multi-layered process. You need to answer three questions in sequence: (1) Does this patient have dementia at all? (2) How severe is it? (3) What is the underlying aetiology? Each layer has its own set of criteria. Let's work through them systematically.

1. Establishing the Syndrome of Dementia — General Criteria

Before you can say "this patient has Alzheimer's" or "this is vascular dementia", you must first establish that the patient meets criteria for the syndrome of dementia itself. Two major classification systems are used:

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 Element	Clinical Rationale
Decline in memory AND thinking	Must have impairment in ≥2 domains — memory is emphasised as a core requirement. This is why ICD-10 is sometimes criticised: it is "AD-centric" because not all dementias start with memory loss (e.g. FTD starts with behaviour, DLB with visuospatial/executive).
> 6 months	This duration requirement distinguishes dementia from delirium and other transient states. Practically, it ensures you're dealing with a chronic process.
Impaired daily living	The threshold that separates dementia from MCI — functional impairment is the watershed.
Clear consciousness	Rules out delirium. If consciousness is clouded, you cannot reliably assess cognition.

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]:

Criterion	Details	Explanation
A	Evidence of significant cognitive decline from a previous level of performance in ≥1 cognitive domain (complex attention, executive function, learning/memory, language, perceptual-motor, social cognition)	Based on: (1) concern by patient, informant, or clinician; AND (2) substantial impairment on standardised neuropsychological testing (typically ≥2 SD below mean)
B	The cognitive deficits interfere with independence in everyday activities	At minimum, requires assistance with complex instrumental ADLs (e.g. managing finances, medications, transport)
C	Not occurring exclusively in the context of a delirium	Must rule out acute confusional state — cannot diagnose dementia during active delirium
D	Not better explained by another mental disorder (e.g. major depression, schizophrenia)	Rules out pseudodementia and late-onset psychotic disorders

ICD-10 vs DSM-5 — Key Differences

The ICD-10 requires memory impairment as a core feature, making it somewhat AD-centric. The DSM-5 removed memory as mandatory — decline in ≥1 of any 6 cognitive domains suffices. This is more inclusive of non-amnestic dementias like bvFTD (behaviour), DLB (visuospatial/executive), and PPA (language). For exams, know both, but DSM-5 is conceptually more modern.

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].

Feature	MCI (Mild NCD)	Dementia (Major NCD)
Cognitive decline	Modest (1–2 SD below mean)	Significant (≥2 SD below mean)
Functional independence	Preserved (may need more effort/compensatory strategies)	Impaired (needs assistance with IADLs at minimum)
DSM-5 term	Mild Neurocognitive Disorder	Major Neurocognitive Disorder
Prognosis	~10–15%/year convert to dementia; not all patients with MCI will progress to dementia ^[3]	Progressive in most degenerative causes

2. Aetiology-Specific Diagnostic Criteria

Once the syndrome of dementia is established, you apply aetiology-specific criteria to determine the underlying cause.

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]:

Level	Criteria
"Possible" AD	Dementia, but not typical AD ^[4] — atypical features, mixed presentation, or single cognitive domain impaired
"Probable" AD	Dementia by various testing, absence of other brain disease ^[4] — meets clinical criteria with documented progressive decline, no alternative explanation
"Definite" AD	With AD histopathology ^[4] — requires neuropathological confirmation (biopsy or autopsy)

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

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

Criterion	Details
A	Criteria are met for major or mild neurocognitive disorder
B	Insidious onset and gradual progression in ≥1 cognitive domains (≥2 domains must be impaired for major NCD due to AD)
C	Criteria for probable or possible AD: Probable if ≥1 of: (1) evidence of causative AD genetic mutation from FHx or genetic tests, OR for mild NCD only; Possible if: all three of (a) clear evidence of decline in memory and learning + ≥1 other domain, (b) steadily progressive gradual decline without extended plateaus, (c) no evidence of mixed aetiology
D	Not better explained by cerebrovascular disease, another neurodegenerative disease, effects of a substance, or another disorder

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.

Criterion	Details
Essential	Dementia (progressive cognitive decline sufficient to interfere with function); early prominent deficits in attention, executive, and visuospatial function; memory may not be impaired early
Core clinical features (need ≥2 for probable, ≥1 for possible)	(1) Fluctuating cognition with pronounced variation in attention/alertness; (2) Recurrent well-formed visual hallucinations; (3) REM sleep behaviour disorder; (4) Spontaneous Parkinsonism
Indicative biomarkers (count same as core features)	(1) Reduced dopamine transporter uptake on DaTSCAN/PET; (2) Abnormal MIBG myocardial scintigraphy (reduced cardiac sympathetic innervation); (3) Polysomnographic confirmation of REM sleep without atonia
Supportive features	Antipsychotic sensitivity, postural instability, repeated falls, syncope, autonomic dysfunction, hypersomnia, hyposmia, other hallucinations, systematised delusions, apathy/anxiety/depression

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

4. Investigation Modalities — Detailed Guide

The investigations in dementia serve two purposes: (1) exclude reversible/treatable causes and (2) support the aetiological diagnosis. Let's go through each modality systematically.

A. Bedside / Clinical Investigations

This is the standardised method to assess severity and profile of cognitive deficits. It serves as both a diagnostic tool and a baseline for monitoring progression.

Tool	What It Tests	Key Features	Scoring / Interpretation
MMSE (Mini-Mental State Examination)	Orientation, registration, recall, attention/calculation, language, visuoconstruction	30-point scale; takes 5–10 min; widely used but limited	< 24/30 suggests cognitive impairment; < 20 = moderate; < 10 = severe. Education-adjusted cut-offs needed.
MoCA (Montreal Cognitive Assessment)	Executive function, visuospatial, naming, memory, attention, language, abstraction, orientation	30-point scale; more sensitive than MMSE for MCI and for executive/visuospatial deficits; MoCA more appropriate for VaD ^[2]	< 26/30 suggests MCI; +1 point if ≤12 years education
Clock Drawing Test (CDT)	Executive function, visuospatial ability, semantic memory	Quick bedside screen; patient draws clock face with numbers, sets hands to "10 past 11"	Qualitative scoring — errors in number placement (parietal), hand errors (executive), perseveration (frontal)
Formal neuropsychological battery	All 6 DSM-5 domains in detail	Usually performed by clinical psychologist or OT; takes 1–3 hours	Provides detailed cognitive profile to guide aetiological diagnosis and functional recommendations

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

Letter	Investigation	What You're Screening For	Why
I	Imaging	Structural brain pathology	Mass lesions, NPH, SDH, infarcts, atrophy pattern
G	Glucose	Diabetes mellitus, hypoglycaemia	Chronic hyperglycaemia → vascular damage + direct neuronal injury; hypoglycaemia → acute cognitive dysfunction
E	Electrolytes (RFT, Ca)	Renal failure, hypercalcaemia	Uraemic encephalopathy; hypercalcaemia → "stones, bones, groans, moans, and psychic overtones"
T	Thyroid (TFTs)	Hypothyroidism	Thyroid hormone is essential for neuronal metabolism; hypothyroidism → reversible cognitive slowing, apathy, and even frank dementia
A	Anaemia (CBC)	Anaemia, haematological disorders	Severe anaemia → chronic cerebral hypoxia
B	B12, folate	Vitamin deficiency	B12 deficiency → impaired methylation → myelin damage + ↑homocysteine → direct neurotoxicity. Folate deficiency → similar but less common as sole cause
C	Calcium	Hypercalcaemia	Can cause confusion, cognitive slowing, psychiatric symptoms

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

C. Neuroimaging — The Core of Aetiological Diagnosis

Neuroimaging is indispensable. It has two roles: (1) excluding structural/reversible causes (SDH, tumour, NPH) and (2) supporting the specific dementia diagnosis through characteristic atrophy/metabolic patterns.

CT — mainly excludes other causes of dementia such as tumour, stroke, abscess, normal pressure hydrocephalus ^[11].

Finding	Significance
Space-occupying lesion	Tumour, abscess — treatable!
Chronic subdural haematoma	Hyperdense crescent (acute) → isodense → hypodense (chronic); treatable with burr hole drainage
Hydrocephalus disproportionate to sulcal atrophy	NPH — all ventricles enlarged but cortical sulci not proportionally widened. Treatable with VP shunt.
Infarcts	Old strokes → VaD
Generalised atrophy	Nonspecific — seen in AD, FTD, alcohol-related dementia

MRI — atrophy changes (particularly hippocampus); detailed assessment of structural lesions ^[11].

MRI is superior to CT for dementia assessment because of its superior soft-tissue contrast, ability to detect white matter changes, and specific atrophy patterns.

Finding	Dementia Subtype	Explanation
Unilateral/bilateral perihippocampal atrophy (early); generalised atrophy (late) ^[2]	AD	Earliest pathology (Braak stages I–III) involves entorhinal cortex and hippocampus → medial temporal lobe atrophy is the hallmark. Medial temporal atrophy (MTA) scoring (Scheltens scale 0–4) is used clinically.
Widened sulci, dilated ventricles ^[2]	AD (late)	Generalised cortical neuronal loss → ex vacuo ventricular dilatation
Infarcts: non-lacunar ( > 15mm, cortical), lacunar (≤15mm, subcortical) ^[2]	VaD	Direct evidence of cerebrovascular disease causing cognitive damage
White matter lesions: hyperintense on T2W/FLAIR ^[2]	VaD (subcortical)	Chronic subcortical ischaemia → periventricular white matter damage (Binswanger-type). Graded by Fazekas score (0–3).
Microbleeds, superficial siderosis ^[2]	VaD / Cerebral amyloid angiopathy	Microbleeds on SWI/GRE suggest small vessel disease or CAA (lobar distribution → CAA; deep → hypertensive)
Relatively preserved medial temporal lobe structures ^[2]	DLB	Unlike AD, hippocampus is relatively spared in DLB — this is a useful distinguishing feature!
Focal atrophy in orbitofrontal, medial frontal, anterior cingulate, anterior insular cortices and amygdala ^[2]	bvFTD	Atrophy pattern maps directly to the clinical features (orbitofrontal → disinhibition; medial frontal/anterior cingulate → apathy; amygdala → loss of empathy)
Asymmetrical frontotemporal "knife-blade" atrophy affecting the left ^[2]	PPA	Left-lateralised because language networks are predominantly left hemisphere
ALL ventricles enlarged disproportionate to sulcal effacement; periventricular lucency on FLAIR ^[2]	NPH	CSF circulation impaired → ventriculomegaly, but cortical atrophy is NOT proportional (unlike AD where atrophy causes ventricular enlargement proportionally)
Cortical ribboning on DWI/FLAIR ^[2]	CJD	Restricted diffusion in cortical ribbon — highly specific for sporadic CJD. Prion-induced spongiform change → cytotoxic oedema in cortical neurons.
Pulvinar sign (bilateral hyperintensity at pulvinar nucleus) ^[2]	Variant CJD	Selective vulnerability of pulvinar nucleus in vCJD

PET ^[11]:

FDG-PET — functional assessment of brain regions ^[11]
PIB-PET — amyloid deposition ^[11]

SPECT — functional assessment of brain regions ^[11]

Modality	What It Shows	Key Findings by Dementia Subtype
FDG-PET (fluorodeoxyglucose)	Regional cerebral glucose metabolism — reflects neuronal activity	AD: ↓metabolism in parietotemporal and hippocampal regions ^[2] (posterior cingulate earliest). DLB: Generalised ↓perfusion and ↓metabolism, most marked in occipital areas ^[2] — the occipital hypometabolism distinguishes DLB from AD. FTD: ↓metabolism in frontal and anterior temporal regions.
Amyloid PET (e.g. PiB, florbetapir)	Direct visualisation of amyloid plaque burden in the brain	AD: Positive (high amyloid uptake). DLB: Often positive (many DLB patients have concomitant amyloid). FTD: Usually negative. Normal elderly: Can be positive! (~20–30% of cognitively normal elderly have amyloid on PET — so positive amyloid PET alone does not diagnose AD).
Tau PET (e.g. flortaucipir)	Direct visualisation of tau neurofibrillary tangle distribution	AD: Positive, follows Braak staging pattern (medial temporal → lateral temporal/parietal → frontal). Still primarily a research tool.
SPECT (e.g. HMPAO)	Regional cerebral blood flow (a surrogate for metabolic activity)	Similar patterns to FDG-PET but lower resolution. Useful when PET is unavailable.
DaTSCAN (dopamine transporter SPECT)	Dopamine transporter density in the striatum	DLB/PDD: Reduced uptake in caudate and putamen (dopaminergic degeneration). AD: Normal. This is an indicative biomarker for DLB in the 2017 criteria.

FDG-PET Pattern Recognition for Exams

Three key patterns to remember:

AD: Parietotemporal hypometabolism (+ posterior cingulate early) — reflects posterior cortical neuronal loss
DLB: Occipital hypometabolism — this is the distinguishing feature from AD
FTD: Frontal and anterior temporal hypometabolism — maps to the atrophy pattern

Why does DLB show occipital hypometabolism? Because Lewy body pathology prominently affects the primary visual cortex and visual association areas, which explains both the metabolic deficit AND the characteristic well-formed visual hallucinations.

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

Biomarker	Direction in AD	What It Reflects
CSF Aβ42	↓ (decreased)	Aβ42 is "trapped" in brain plaques → less left in the CSF. A low CSF Aβ42 correlates with high cortical amyloid deposition.
CSF Total tau (t-tau)	↑ (increased)	Released from dying/damaged neurons → reflects intensity of neurodegeneration. Nonspecific — also elevated in CJD, stroke, TBI.
CSF Phosphorylated tau (p-tau)	↑ (increased)	Reflects neurofibrillary tangle formation — more specific to AD pathology than total tau.
CSF 14-3-3 protein	↑ in CJD	Released from rapidly dying neurons — highly suggestive of CJD when clinical picture is consistent.

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.

Investigation	When to Use	What It Shows
EEG	CJD, metabolic encephalopathy, non-convulsive status epilepticus	CJD: Periodic sharp wave complexes (triphasic waves) at 1–2 Hz — pathognomonic in sporadic CJD. Metabolic encephalopathy: Generalised slowing. NCSE: Continuous epileptiform discharges.
LP (lumbar puncture)	Suspected CNS infection, neurosyphilis, autoimmune encephalitis, CSF biomarkers	CSF cell count, protein, glucose, VDRL, oligoclonal bands, specific antibodies, biomarkers
Genetic testing	FHx-positive cases, early-onset ( < 65), strong suspicion of genetic cause	APP, PSEN1, PSEN2 (early-onset AD); APOE genotyping (risk stratification, not diagnostic); C9ORF72, MAPT, GRN (FTD); PRNP (familial CJD); HTT (Huntington's)
ECG, CXR ^[10]	Baseline assessment	ECG: AF (risk for stroke/VaD); CXR: malignancy (paraneoplastic), heart failure
MIBG myocardial scintigraphy	Suspected DLB	Reduced cardiac uptake due to postganglionic sympathetic denervation — indicative biomarker for DLB
Polysomnography	Suspected RBD (DLB)	Confirms REM sleep without atonia — indicative biomarker for DLB

Dementia	Key Imaging Finding	Key Biochemical/Other Finding
AD	MRI: hippocampal/MTL atrophy. FDG-PET: parietotemporal hypometabolism. Amyloid PET: positive.	CSF: ↓Aβ42, ↑p-tau, ↑t-tau
VaD	MRI: infarcts (lacunar/cortical), white matter lesions on FLAIR, microbleeds	Hachinski score ≥7. Vascular imaging (carotid USS, CTA/MRA)
DLB	MRI: preserved MTL. FDG-PET: occipital hypometabolism. DaTSCAN: reduced striatal uptake.	MIBG: reduced cardiac uptake. PSG: REM without atonia
FTD	MRI: frontotemporal atrophy (knife-blade). FDG-PET: frontal/anterior temporal hypometabolism	Genetic testing: C9ORF72, MAPT, GRN. CSF: usually normal Aβ42 (helps exclude AD)
CJD	MRI: cortical ribboning on DWI. vCJD: pulvinar sign	EEG: periodic sharp wave complexes. CSF: ↑14-3-3, ↑t-tau (markedly elevated)
NPH	MRI/CT: ventriculomegaly disproportionate to sulcal atrophy. FLAIR: periventricular lucency	Tap test (large volume LP): improvement in gait after CSF removal supports diagnosis and predicts shunt response

High Yield Summary — Diagnosis of Dementia

General diagnostic criteria: ICD-10 requires decline in memory + thinking, > 6 months, impaired ADLs, clear consciousness. DSM-5 requires significant decline in ≥1 cognitive domain + functional impairment + no delirium + no better explanation.

Key difference: ICD-10 mandates memory impairment; DSM-5 does not (any domain suffices). DSM-5 is more inclusive of non-amnestic dementias.

MCI vs Dementia: The threshold is functional independence — MCI preserves independence; dementia impairs it.

AD diagnostic levels: NINCDS-ADRDA: Possible (atypical) → Probable (clinical diagnosis, no other cause) → Definite (histopathology). Clinical practice operates at "probable" level.

Minimum investigations (NICE/lecture slides): CBC, TFTs, B12/folate, RFT, Ca, glucose, VDRL + CT/MRI brain. Mnemonic: I FOR GET ABC.

Neuroimaging patterns: AD = hippocampal atrophy + parietotemporal hypometabolism; VaD = infarcts + WML; DLB = preserved MTL + occipital hypometabolism + reduced DaTSCAN; FTD = frontotemporal knife-blade atrophy; CJD = cortical ribboning on DWI; NPH = ventriculomegaly disproportionate to sulcal atrophy.

CSF biomarkers for AD: ↓Aβ42, ↑total tau, ↑phospho-tau. Seldom done in HK clinical setting but increasingly used in research and selected cases.

Active Recall - Diagnostic Criteria and Investigations for Dementia

References

^[1] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p7 (Aetiology of Dementia) ^[2] Senior notes: ryanho-psych.md (Sections 4.2.1–4.2.5: Approach to Dementia, diagnostic criteria, clinical evaluation, investigations, AD evaluation, VaD evaluation, DLB diagnosis, FTD criteria, differential diagnosis tables) ^[3] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p15 (Mild cognitive impairment) ^[4] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p18 (Alzheimer's Disease NINCDS-ADRDA) ^[8] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p8 (ICD-10 diagnosis — Dementia) ^[9] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p9 (DSM-V diagnosis — Major and Mild neurocognitive disorder) ^[10] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p27 (AD Diagnosis) ^[11] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p33 (Neuroimaging)

Management of Dementia

The management of dementia is fundamentally multidisciplinary and holistic. There is no cure for most degenerative dementias — our goals are to: (1) treat any reversible causes, (2) slow cognitive decline where possible, (3) manage BPSD, (4) maintain function and quality of life, (5) support caregivers, and (6) plan for the future (advance directives, capacity, guardianship). Think of it as managing a chronic condition rather than curing a disease.

Treatment is multidisciplinary ^[12]. Treat the "hidden patient(s)" — this refers to the caregivers, who are often as distressed (or more) than the patient themselves ^[12].

Before starting any symptomatic treatment, you must first address any treatable underlying cause. This was covered in the diagnostic section but bears repeating because it's the single most impactful intervention:

Reversible Cause	Treatment
Hypothyroidism	Levothyroxine replacement
B12 deficiency	IM hydroxocobalamin → oral maintenance
Folate deficiency	Oral folic acid supplementation
NPH	VP shunt (gait improves most; cognition improvement variable)
Chronic SDH	Burr hole drainage
Neurosyphilis	IV benzylpenicillin
Drug-induced cognitive impairment	Withdraw offending drug (anticholinergics, benzodiazepines, opioids)
Depression (pseudodementia)	Antidepressant trial

2. Management of Cognition

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

Intervention	Description	Evidence	Explanation
Cognitive stimulation	Group-based activities involving general cognitive function and orientation, emphasising enjoyment of activities	1.41 MMSE points better than placebo; recommended by NICE ^[2]	Works by engaging multiple cognitive networks through social interaction and structured activities. Not about drilling — it's about stimulation and engagement.
Cognitive training	Individualized/grouped training specifically geared to train specific cognitive abilities with practice and repetition	No evidence for efficacy (Cochrane 2013); not recommended by NICE ^[2]	Rote practice of single tasks doesn't generalise to overall function — the brain needs integrated engagement, not isolated drilling.
Cognitive rehabilitation	Individualized training in the person's natural environment to train cognitive abilities required for personally relevant everyday tasks	Evidence still limited but promising; rarely done in HK ^[2]	Goal-oriented, practical — e.g. teaching someone specific strategies to remember medication schedules. Most ecologically valid but resource-intensive.
Exercise programmes	Physical activity interventions	Improve physical functioning, slow functioning decline, but little effect on cognitive functioning ^[2]	Exercise promotes cerebral blood flow, BDNF release, and neuroplasticity. The main benefit is maintaining physical function and reducing falls — which is critical since falls are a major cause of morbidity in dementia.
Others	Social activities, diet supervision, vascular RF control	Variable evidence	Maintain social engagement, Mediterranean diet (anti-inflammatory), control HTN/DM/dyslipidaemia

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.

B. Pharmacological Approaches for Cognition

"Acetyl-cholin-esterase inhibitor" → "acetyl" = acetyl group, "cholin" = choline, "esterase" = enzyme that breaks an ester bond, "inhibitor" = blocks. These drugs inhibit the enzyme that breaks down acetylcholine at the synapse, thereby increasing the amount of ACh available for neurotransmission.

Acetylcholinesterase Inhibitor (AChEI) — donepezil, rivastigmine and galantamine ^[13]:

Mild to moderate dementia in AD ^[13]
Compensate the cholinergic deficit ^[13]

Property	Details
Drugs	Donepezil (Aricept), Galantamine (Reminyl), Rivastigmine (Exelon)
Indication	Mild to moderate dementia in AD ^[13] (less evidence when MMSE < 12) ^[2]. Also used in DLB (often first-line because antipsychotics are contraindicated) and sometimes VaD (limited evidence) ^[2]
Mechanism of Action	Inhibit acetylcholinesterase at synaptic cleft → ↓ACh breakdown → ↑cholinergic transmission. Based on the cholinergic hypothesis — degeneration of cholinergic neurons from the basal nucleus of Meynert causes widespread ACh depletion contributing to memory and attention deficits.
Efficacy	Modest improvement in cognition: MMSE 1.37 points, ADAS-Cog 2.7 points at 6–12 months ^[2]. Also improves neuropsychiatric symptoms and ADLs. Delays decline by ~2 months/year but little evidence for long-term disease modification ^[2].
Side effects	Very commonly GI upset (diarrhoea, N/V), anorexia/weight loss, bradycardia/↓BP, sleep disturbances ^[2]. These are all predictable from the pharmacology — increasing ACh systemically stimulates the parasympathetic nervous system (vagal tone → bradycardia; GI motility → nausea/diarrhoea; cholinergic activation in brainstem → vivid dreams).
Contraindications	Sick sinus syndrome, AV block (bradycardia risk), active peptic ulcer disease (↑gastric acid secretion via vagal stimulation), severe hepatic impairment
Practical points	Start low, titrate slow. Donepezil: start 5mg OD → 10mg after 4–6 weeks. Take at bedtime (may cause insomnia if taken in morning). Rivastigmine available as transdermal patch (better GI tolerability).

Differences between the three AChEIs:

Drug	Selectivity	Route	Unique Features
Donepezil	Selective AChE inhibitor	Oral (OD dosing)	Longest half-life (~70h); most commonly prescribed; once-daily dosing improves compliance
Rivastigmine	Inhibits both AChE AND butyrylcholinesterase (BuChE)	Oral / transdermal patch	Patch formulation reduces GI side effects; dual enzyme inhibition may offer additional benefit in later stages when BuChE becomes relatively more important
Galantamine	AChE inhibitor + allosteric modulator of nicotinic ACh receptors	Oral (BD or MR OD)	Dual mechanism; the nicotinic receptor modulation may enhance presynaptic ACh release

"Memantine" — an NMDA receptor antagonist. NMDA = N-methyl-D-aspartate, a type of glutamate receptor.

Memantine ^[13]:

Moderate to severe dementia in AD ^[13]
Antagonist at N-methyl-D-aspartate (NMDA) receptors ^[13]
Neuroprotective and disease-modifying agent in theory ^[13]

Property	Details
Drug	Memantine (Ebixa)
Indication	Moderate to advanced dementia ^[2]^[13]. Limited evidence for mild dementia.
Mechanism of Action	Low-affinity, uncompetitive NMDA receptor antagonist → blocks excessive glutamate-mediated excitotoxicity. In AD, damaged neurons release excess glutamate → overactivation of NMDA receptors → calcium influx → excitotoxic neuronal death. Memantine provides a voltage-dependent block that allows physiological NMDA signalling (needed for memory) while blocking pathological tonic overactivation. Think of it as "noise reduction" — it reduces the background excitotoxic "noise" while preserving the signal.
Efficacy	Modest benefit in moderate/advanced dementia; may have synergistic effect with cholinesterase inhibitor ^[2]. Often used in combination with AChEI.
Side effects	Uncommon: dizziness, confusion/hallucinations (rare) ^[2]. Generally well tolerated — much better side-effect profile than AChEIs.
Contraindications	Severe renal impairment (renally excreted); epilepsy (may lower seizure threshold at high doses, though this is debated)
Practical points	Start 5mg OD → titrate by 5mg weekly → target 10mg BD (20mg/day). Can be combined with AChEI.

Aduhelm (aducanumab) ^[14]:

Human monoclonal antibody — selectively targets aggregated Aβ ^[14]
Approved in 2021 by FDA (based on 2 clinical trials EMERGE and ENGAGE) ^[14]
Monthly intravenous infusions ^[14]
First treatment directed at amyloid beta plaques in the brain ^[14]
Amyloid-related imaging abnormalities (ARIA) — brain swelling and bleeding ^[14]
Monitoring — MRIs prior to initiating therapy, during the titration of the drug, and at any time the patient has symptoms suggestive of ARIA ^[14]
The effectiveness is still under debate ^[14]

Since these lecture slides, the landscape has evolved significantly:

Drug	Status (as of 2025–2026)	Mechanism	Key Considerations
Aducanumab (Aduhelm)	Withdrawn from market (2024) by Biogen	Anti-amyloid mAb targeting aggregated Aβ	Controversial approval; inconsistent trial results; withdrawn due to low uptake and uncertain efficacy
Lecanemab (Leqembi)	FDA fully approved (2023); available in some centres	Anti-amyloid mAb targeting Aβ protofibrils (soluble aggregates)	CLARITY-AD trial: 27% slowing of cognitive decline over 18 months. ARIA risk (~13% ARIA-E, ~17% ARIA-H). Requires regular MRI monitoring. Monthly IV infusions.
Donanemab (Kisunla)	FDA approved (2024)	Anti-amyloid mAb targeting N-terminal pyroglutamate Aβ (deposited plaque)	TRAILBLAZER-ALZ 2: 35% slowing of decline in "intermediate" tau group. Time-limited therapy — can stop once amyloid cleared. ARIA risk similar to lecanemab.

Why anti-amyloid antibodies? These drugs directly attack the amyloid cascade — they bind to and promote clearance of Aβ aggregates/plaques. They are the first disease-modifying (not just symptomatic) treatments for AD, though the clinical benefit is modest and must be weighed against significant risks (ARIA).

What is ARIA? ARIA-E = amyloid-related imaging abnormalities — oEdema (brain swelling from vascular leakage as amyloid is cleared from vessel walls). ARIA-H = Haemosiderin deposits (microbleeds/superficial siderosis). APOE4 homozygotes are at highest risk for ARIA.

Anti-Amyloid Antibodies — Current State

These drugs are NOT yet available in standard clinical practice in Hong Kong and remain controversial. They are very expensive (US$26,000+/year), require IV infusions and regular MRI monitoring, and the clinical benefit (slowing of decline by ~27–35%) translates to modest real-world improvement. They are indicated only for early AD (MCI or mild AD with confirmed amyloid positivity on PET or CSF). Know their existence for exams but they are unlikely to feature as a standard treatment in HK clinical scenarios currently.

Agent	Status
Antioxidants (Vitamin E, selegiline)	Mild to moderate AD; currently NOT recommended within standard guidelines ^[2]. Modest benefit but side effects prominent for selegiline ^[2]. High-dose vitamin E (2000 IU/day) showed some benefit in one trial but concerns about cardiovascular mortality.

The lecture slides provide an important timeline showing which drugs are used at each stage of AD:

Natural history of Alzheimer's disease and stage-specific symptomatic drugs ^[15]:

Stage	Treatments
Amnestic MCI	Consider AChEI (off-label, evidence limited)
Mild dementia	Antidepressants (for depression) + AChEI ^[15]
Loss of functional independence	AChEI + Memantine ^[15]
Behavioural symptoms stage	Memantine + AChEI + (atypical) neuroleptics ^[15]
Nursing home / severe stage	Memantine + AChEI + (atypical) neuroleptics ^[15]

Drug Selection by AD Stage

Simple rule of thumb:

Mild–moderate AD → AChEI (donepezil first-line)
Moderate–severe AD → Add memantine (often combined with AChEI)
BPSD → Non-pharmacological first; then consider SSRI (depression/agitation), low-dose atypical antipsychotic (severe psychosis/aggression only)
AChEIs and memantine are continued throughout the disease course once started, unless side effects are intolerable or the patient reaches end-stage disease.

BPSD management deserves special attention because over 80% of dementia patients develop BPSD ^[16], and it is often more distressing than cognitive symptoms ^[2] — both to the patient and especially to caregivers.

Why are behaviour disturbances (BPSD) important? ^[16]:

Over 80% of dementia patients
Delusions 60%
Affective symptoms 40%
Anxiety 35%
Verbal outburst 33%
Hallucination 20%
Aggression 13%
Caregiver stress
Institutionalisation

The Approach to BPSD [2][17]

Management of BPSD ^[17]:

Exclude physical illness potentially precipitating
Non-pharmacological — behaviour modifications, environmental modifications
Medications — AChEI/memantine, antipsychotic, antidepressant, other neuroleptics
Keep lowest dose and shortest period if possible, don't prescribe medications unless significant BPSD!!! ^[17]

The stepwise approach ^[2]:

Step 1: Assessment and Precipitant Search

Identify problems, duration and severity
Consider and treat medical problems — UTI, constipation, pain, medication side effects → may precipitate BPSD and should be reversed ^[2]
Consider and treat psychiatric comorbidities (depression, psychosis, anxiety)
Reverse any other aggravating factors (environmental changes, caregiver changes)

Why is this step so important? Because an elderly patient with dementia who becomes suddenly agitated may have a UTI, faecal impaction, unrecognised pain (hip fracture, toothache), or medication side effects. Treating the precipitant often resolves the BPSD without any psychotropic medication.

Step 2: Non-Pharmacological Interventions ^[2]

Non-pharmacological treatment should always be first-line treatment for BPSD ^[2]:

Category	Interventions	Rationale
Environmental modifications	Non-stressful, constant, familiar, comfortable environment ^[2]. Wandering space with safety features (digital locks, artificial partitions). Stable daily schedule. Structured daytime activities.	Dementia patients have reduced ability to adapt to change. A familiar, predictable environment reduces confusion and anxiety. Unstructured time leads to wandering and agitation.
Sensory stimulation	Music therapy, aromatherapy (e.g. lavender oil), bright light therapy (↑circadian rhythm), massage/touch, passive heating (improve sleep) ^[2]	Engages preserved sensory processing pathways. Music therapy is particularly effective — even in severe dementia, musical memories are often preserved (stored in cerebellum and supplementary motor area, relatively spared in AD). Bright light therapy helps entrain the disrupted circadian rhythm.
Behavioural intervention	Simple behavioural modification techniques (e.g. star charts, differential reinforcement, stimulus control) ^[2]	Positive reinforcement of desired behaviours; removing triggers for unwanted behaviours
Caregiver intervention	Psychoeducation, psychotherapeutic support ^[2]	Caregivers who understand the disease are less likely to react negatively to BPSD, which in turn reduces patient agitation. Caregiver stress is a major driver of institutionalisation.
Social contact	Social gatherings, one-to-one interactions, pet therapy ^[2]	Reduces isolation and provides meaningful engagement

Step 3: Pharmacological Treatment ^[2]

Only when non-pharmacological measures fail AND BPSD is significant/dangerous.

Pharmacological treatment: reserved to significant BPSD only, at lowest dose for shortest duration ^[2].

Efficacy is modest at best, associated with mortality and cognitive decline → should be prescribed only after addressing precipitating factors + non-pharmacological treatment ^[2].

Indication	Drug Class	Specific Drugs and Doses ^[2]	Evidence / Considerations
Mild agitation	Trazodone, SSRIs	Trazodone 50–100mg ^[2]; Citalopram 10–20mg ^[2]; Carbamazepine 50–300mg; Sodium valproate 250–1000mg ^[2]	Trazodone is a serotonin antagonist/reuptake inhibitor with sedative properties — useful for agitation and sleep disturbance. SSRIs help with anxiety and irritability. Mood stabilisers (carbamazepine, valproate) have limited evidence.
Severe agitation with psychosis	Atypical antipsychotics (SGAs)	Quetiapine 25–200mg; Risperidone 0.5–3mg; Olanzapine 2.5–10mg ^[2]	Robust evidence limited to short-term management of aggression only ^[2]. Numerous side effects, dose-related mortality and risk of stroke, may precipitate irreversible Parkinsonism especially in DLB, may ↑rate of cognitive decline ^[2].
Depression	Antidepressants	SSRI (as above); Mirtazapine 15–45mg ^[2]	SSRIs are first-line. Mirtazapine has the advantage of appetite stimulation (useful in anorexic dementia patients) and sedation (helps sleep). Avoid TCAs — anticholinergic effects worsen cognition.
Severe behavioural problems	Typical antipsychotics	Haloperidol in small doses (0.5–4mg), for a limited time ^[2]	Last resort. Higher risk of EPS, mortality, and stroke than SGAs.
RBD in DLB	Melatonin, clonazepam	Melatonin first-line; clonazepam low-dose if needed ^[2]	Melatonin restores circadian rhythm and has REM-modulating properties. Clonazepam suppresses REM sleep motor activity but carries fall risk.

Antipsychotics in Dementia — Critical Safety Concerns

All antipsychotics carry a FDA black-box warning for increased mortality in elderly patients with dementia (1.6–1.7× risk, primarily from cerebrovascular events and infections). Specific concerns:

DLB patients: Antipsychotic sensitivity (30–50%) — acute irreversible Parkinsonism, LOC ± NMS ^[2]. NEVER give typical antipsychotics to suspected DLB. Even atypical antipsychotics should be used only at very low doses when absolutely necessary. Quetiapine is generally considered safest in DLB due to lowest D2 affinity.
Stroke risk: Dose-related increased risk of cerebrovascular events.
Cognitive decline: May accelerate cognitive deterioration.
Metabolic effects: Weight gain, diabetes, dyslipidaemia (especially with olanzapine).

Rule: Lowest dose, shortest duration, regular review, clear documentation of indication and risk-benefit discussion.

Drugs to AVOID in dementia ^[2]:

Benzodiazepines: ↑fall risk, dependence ^[2] — elderly patients metabolise BDZs slowly; accumulation → excessive sedation, falls, paradoxical disinhibition
Antihistamines: anticholinergic effects → worsening cognition ^[2] — they block the already-depleted cholinergic system
Tricyclic antidepressants: Potent anticholinergic properties → cognitive worsening. Use SSRIs instead.
Anticholinergic drugs in general: Oxybutynin (for incontinence), diphenhydramine, promethazine — all worsen cognition. Use alternatives where possible.

4. Aetiology-Specific Management

Component	Approach
Risk factor management	Healthy lifestyle, HTN control, DM management, statins, aspirin ^[2]. Apart from lifestyle changes, most RF management interventions are probably more effective in preventing further stroke events than dementia ^[2].
Pharmacological therapy	Cholinesterase inhibitors: small benefit of uncertain clinical significance. Memantine: benefit uncertain ^[2]. Evidence for use of these drugs in VaD is limited, but they are often used due to the well-known co-association between AD and VaD and the clinical difficulty in differentiating between the two ^[2].
Other	Same BPSD management principles as AD

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]:

Domain	Management	Rationale
Cognition and neuropsychiatric symptoms	Cholinesterase inhibitor: often first-line due to C/I to antipsychotics ^[2]	DLB has a profound cholinergic deficit (even more than AD), so AChEIs are particularly effective. Also first-line for visual hallucinations in DLB.
	Memantine: mixed evidence, minimal effect ^[2]	Can be tried as add-on
	Atypical antipsychotics: low dose only, only when BPSD is very severe ^[2]	Due to antipsychotic sensitivity. Quetiapine preferred (lowest D2 affinity).
	SSRIs: for depression ^[2]
REM sleep behaviour disorder	Melatonin, clonazepam ^[2]	Melatonin first-line; clonazepam if insufficient
Parkinsonism	Similar to treatment in PD ^[2]	Low-dose levodopa; avoid high doses (may worsen hallucinations). Avoid anticholinergic anti-Parkinson drugs (worsen cognition and hallucinations).

Management: symptomatic only ^[2]:

Domain	Treatment
Neurobehavioural features	SSRI, trazodone, SGAs ^[2]
Cognitive dysfunction	NO available treatment ^[2] — AChEIs are NOT effective (FTD is not primarily a cholinergic disorder)
Parkinsonism (if present)	Generally NOT responsive to dopaminergic agents ^[2]

This is arguably as important as the pharmacological management. Treat the "hidden patient(s)" ^[12] — caregivers of dementia patients have high rates of depression, anxiety, and burnout.

Intervention	Details
Psychoeducation	Explain the disease, expected course, and how to manage challenging behaviours. Understanding that BPSD is part of the disease (not intentional) reduces caregiver frustration.
Respite care	Day care centres, temporary residential care — gives caregivers a break
Support groups	Peer support from other caregivers; organisations like the Alzheimer's Disease Foundation (Hong Kong)
Social worker referral ^[18]	Financial planning, home modifications, community services, day centre placement
Occupational therapy	Home safety assessment, adaptive equipment, caregiver training in ADL assistance
Advance care planning	While the patient still has capacity — discuss future preferences for care, resuscitation status, feeding options

Dementia patients will progressively lose capacity to make decisions. Understanding the legal framework is essential, particularly in Hong Kong.

Mentally Incapacitated Person (MIP): Adults with a mental disorder or mental handicap (e.g. dementia, brain injured, mental illness, mental retardation) ^[19].

Incapacity for consent to treatment = inability to understand the general nature and effect of the treatment or special treatment ^[19].

Key principles from the Mental Health Ordinance (MHO) ^[20]^[2]:

Situation	Approach
Patient has capacity	Respect the patient's autonomous decision — even if you disagree. Any treatment without consent = assault/battery.
Patient lacks capacity — No guardian	Doctor can provide treatment under Part IVC of the MHO if it is necessary and in the patient's best interests. Next-of-kin have no legal authority to consent — the decision lies with the doctor ^[2].
Patient lacks capacity — Has guardian	Guardian with power to consent can give consent. If guardian refuses or patient strongly objects → seek Court approval ^[20].
Urgent treatment	Can treat straight away for any person if consent cannot be obtained, but treatment should be limited to what is immediately necessary ^[2].
Best interests	(1) Save life; (2) Prevent damage/deterioration; (3) Bring about improvement in physical/mental health and wellbeing. Also consider: previously expressed wishes, least restrictive alternative ^[2].

When is guardianship required? ^[2]

Not needed in most cases (takes months to process)
Required when: disagreement between family and healthcare team; MIP strongly resists treatment in best interests; doctors unwilling to provide treatment without proxy consent for complex/controversial procedures

Be aware of ELDERLY ABUSE ^[12] — dementia patients are vulnerable to financial exploitation, neglect, physical abuse, and psychological abuse. Clinicians have a duty to be vigilant.

Capacity in Dementia — A Common Exam Scenario

Capacity is time-specific and decision-specific. A patient with mild dementia may have capacity to consent to taking paracetamol but NOT to refuse a life-saving surgery. You must assess capacity for each specific decision at the time it needs to be made. Dementia does NOT automatically mean incapacity.

The test for capacity: Can the patient (1) understand the information, (2) retain it long enough to make a decision, (3) weigh the information (pros and cons), and (4) communicate their decision?

Summary ^[12]:

Dementia (e.g. AD) is common
"Being senile" is not a normal part of ageing
Vigilant on EARLY diagnosis
Prevention may be more useful
Treatment is multidisciplinary
Treat the "hidden patient(s)"
Be aware of ELDERLY ABUSE

High Yield Summary — Management of Dementia

Treat reversible causes first — always screen and treat hypothyroidism, B12 deficiency, NPH, chronic SDH, neurosyphilis, drug-induced cognitive impairment.

Cognitive management:

Non-pharmacological: cognitive stimulation (NICE-recommended; +1.41 MMSE points) + exercise + social activities + vascular RF control
AChEIs (donepezil, rivastigmine, galantamine): mild–moderate AD. MoA: ↑ACh at synapse by blocking acetylcholinesterase. Side effects: GI upset, bradycardia (parasympathetic activation).
Memantine: moderate–severe AD. MoA: NMDA receptor antagonist → ↓glutamate excitotoxicity. Side effects: minimal (dizziness, rare confusion).
Combination AChEI + memantine is common in moderate–severe AD.
Anti-amyloid mAbs (lecanemab, donanemab): early AD only, not standard in HK yet. Risk: ARIA.

BPSD management: Step 1 → Exclude precipitants (UTI, pain, constipation, drugs). Step 2 → Non-pharmacological first (environmental modification, sensory stimulation, behavioural techniques, caregiver support). Step 3 → Pharmacological only if significant BPSD: lowest dose, shortest duration. SSRIs/trazodone for mild agitation/depression; low-dose SGAs for severe psychosis/aggression only.

Antipsychotics: AVOID in DLB (antipsychotic sensitivity → irreversible Parkinsonism, NMS). Use quetiapine if absolutely necessary. All carry FDA black-box warning for increased mortality in dementia.

Drugs to AVOID: Benzodiazepines (falls, dependence), antihistamines (anticholinergic → worsened cognition), TCAs (anticholinergic).

Aetiology-specific: VaD → vascular RF management primary; AChEIs/memantine limited evidence but often used (mixed pathology). DLB → AChEI first-line (no antipsychotics); melatonin/clonazepam for RBD. FTD → SSRI/trazodone for behaviour; NO AChEI.

Caregiver support: Psychoeducation, respite care, support groups, social worker referral. Treat the "hidden patients."

Legal: Capacity is time- and decision-specific. MHO Part IVC governs treatment of MIPs. Next-of-kin have no legal authority — decision rests with doctor in best interests. Guardianship for complex disagreements.

Active Recall - Management of Dementia

References

^[2] Senior notes: ryanho-psych.md (Sections 4.2.1–4.2.5: Approach to Dementia management, AD pharmacological management, BPSD management, VaD management, DLB treatment, FTD management, capacity and guardianship) ^[12] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p45 (Summary) ^[13] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p38 (Medication for Cognition — AChEI and Memantine) ^[14] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p39 (Medication for Cognition — Aducanumab) ^[15] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p42 (Natural history of AD and stage-specific drugs) ^[16] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p40 (Management of BPSD — Why important) ^[17] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p41 (Management of BPSD — Approach) ^[18] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p44 (The case continues — AD treatment plan) ^[19] Lecture slides: GC 173. Why should I be locked up Ethics in psychiatry, Consent and Refusal in Treatment.pdf, p20 (Mentally Incapacitated Person) ^[20] Lecture slides: GC 173. Why should I be locked up Ethics in psychiatry, Consent and Refusal in Treatment.pdf, p31 (Treatment decision flowchart for MIP)

Complications of Dementia

Dementia is not merely a cognitive disorder — it is a progressive, systemic illness that generates a cascade of complications affecting virtually every organ system, the patient's safety, their psychiatric wellbeing, their family, and society. Understanding these complications from first principles means tracing each one back to the specific cognitive, motor, or behavioural deficit that causes it.

The complications can be organised into: (1) Direct neuropsychiatric complications, (2) Medical/physical complications, (3) Functional decline and safety hazards, (4) Iatrogenic complications, (5) Caregiver and social complications, and (6) End-of-life complications.

Behavioural and psychological symptoms of dementia (BPSD) are themselves a major complication of the disease process, occurring in over 80% of dementia patients ^[16] and escalating with disease severity ^[2].

BPSD includes ^[21]^[16]:

Observed behaviours: screaming, restlessness, wandering, aggression, agitation, culturally inappropriate behaviour ^[21]
Elicited psychological symptoms: depression, anxiety, hallucination, delusion ^[21]

BPSD Category	Specific Complications	Pathophysiological Basis
Depression	Major depression in 10%; depressive symptoms in > 50% of AD ^[2]. Leads to appetite loss, weight loss, social withdrawal, refusal of care, increased mortality.	Degeneration of serotonergic (raphe nuclei) and noradrenergic (locus coeruleus) pathways + reactive grief to perceived losses + social isolation.
Psychosis	Delusions 60%; hallucinations 20% ^[16]. Persecutory delusions (theft, infidelity, "phantom boarder") → agitation, aggression, refusal to eat (fears poisoning), relationship breakdown with carers.	Cholinergic depletion disrupts reality monitoring. Temporal-parietal degeneration → misidentification syndromes. In DLB, visual cortex Lewy body pathology → vivid visual hallucinations.
Agitation and aggression	Aggression 13% ^[16]. Physical harm to patient and carers. Major driver of institutionalisation and emergency department presentations.	Loss of frontal inhibitory control over limbic system (amygdala). Often precipitated by unrecognised pain, infection, or environmental over-stimulation in a patient who cannot articulate distress.
Wandering	Getting lost, exposure to weather, traffic accidents, elopement from care facilities. A significant cause of death in community-dwelling dementia patients.	Hippocampal and parietal degeneration → spatial disorientation + executive dysfunction → inability to plan a route or recognise being lost. Restlessness from frontal pathology drives purposeless ambulation.
Sundowning	↑motor activity in evening ^[2] — worsening confusion, agitation, and behavioural disturbance in the late afternoon/evening.	Degeneration of the suprachiasmatic nucleus (SCN, the master circadian clock) → disrupted circadian rhythm. Compounded by evening fatigue, reduced ambient light (fewer environmental cues for orientation), and accumulated sensory overload throughout the day.
Sleep disturbance	Insomnia, disrupted sleep, phase delay in diurnal rhythm, parasomnia, excessive daytime sleepiness ^[2]. Fragmented sleep worsens cognition and increases fall risk. Also severely disrupts caregiver sleep.	SCN degeneration + cholinergic/orexinergic system disruption. In DLB, REM sleep behaviour disorder from brainstem pathology causes dream enactment with potential for self-injury or partner injury.
Sexual dysfunction	Disinhibition or ↓libido ^[2]. Sexual disinhibition → inappropriate touching, public exposure → distressing for family, potential legal/safeguarding consequences.	Orbitofrontal cortex damage → loss of social behavioural inhibition. Medial temporal/hypothalamic involvement may also affect libido regulation.

BPSD — The Most Distressing Complication

BPSD is often more distressing than cognitive symptoms ^[2] — primarily to caregivers. It is the leading driver of institutionalisation, caregiver burnout, and emergency presentations. Always ask about BPSD systematically in every dementia review. The precipitant is often a treatable medical problem (UTI, pain, constipation).

2. Medical and Physical Complications

As dementia progresses, patients lose the ability to perform activities of daily living, maintain their own health, and protect themselves from harm. Each complication can be traced to a specific deficit:

Aspect	Details
Prevalence	Dementia patients have 2–3× the fall rate of cognitively intact elderly. Falls are the commonest cause of injury-related death in dementia.
Why?	(1) Visuospatial dysfunction → misjudge distances, miss steps, trip over obstacles. (2) Executive dysfunction → cannot plan safe movement, poor judgement about capabilities. (3) Gait apraxia → especially in VaD and NPH. (4) Parkinsonism → in DLB/PDD, impaired postural reflexes and rigidity. (5) Medications → sedating drugs (BDZs, antipsychotics) ↑fall risk. (6) Orthostatic hypotension → autonomic dysfunction in DLB, or drug-induced (antipsychotics, AChEIs).
Consequence	Hip fractures are devastating — 30-day mortality ~10%; 1-year mortality ~30% in elderly with dementia. Immobilisation from fracture → rapid functional decline, pressure ulcers, pneumonia, DVT/PE.
Prevention	Home safety assessment (OT), remove rugs and obstacles, grab rails, adequate lighting, review medications, exercise programmes for balance, vitamin D supplementation, treat osteoporosis.

Aspect	Details
Why?	Progressive involvement of cortical and brainstem swallowing centres → swallowing apraxia/dysphagia. Patients forget to chew properly, pocket food in cheeks, have impaired cough reflex, and lose the coordinated sequence of swallowing. Reduced consciousness/attention → food/liquid enters airway.
Significance	The most common cause of death in advanced dementia. Aspiration of oral/gastric contents → chemical and bacterial pneumonitis → sepsis.
Clinical context	In severe AD: bedbound, no speech, incontinent, basic psychomotor skills lost ^[2] → swallowing is one of the last motor functions to deteriorate, but when it does, the prognosis is very poor.
Management	Speech therapy assessment, modified diet textures, upright positioning during feeding, careful hand-feeding (often preferred over PEG tube in advanced dementia — PEG does NOT reduce aspiration risk and raises ethical concerns). Advance care planning is critical at this stage.

Infection	Mechanism
Urinary tract infections	Incontinence → catheterisation → catheter-associated UTI. Also poor hygiene from functional decline. UTIs are the most common cause of delirium superimposed on dementia — an acute worsening that is treatable.
Pneumonia (non-aspiration)	Immobility → reduced lung expansion → atelectasis → pneumonia. Malnutrition → immunosuppression.
Skin and soft tissue infections	Pressure ulcers (from immobility) → secondary infection → cellulitis/sepsis.

Aspect

Details

Why?

(1) Forgetting to eat (memory loss). (2) Apraxia of eating (can't coordinate utensil use → spoon to mouth). (3) Agnosia for food (doesn't recognise food as food). (4) Anorexia from depression or medications (AChEI side effects → GI upset/anorexia). (5) Hyperorality with non-food items in FTD (paradoxically — they eat, but eat the wrong things). (6) Dysphagia in late stages. (7) Dehydration from forgetting to drink + unable to express thirst.

Consequence

Weight loss, sarcopenia (muscle wasting → further ↑fall risk), micronutrient deficiencies, impaired wound healing, immunosuppression, electrolyte imbalance, renal impairment, constipation (which itself precipitates BPSD and delirium).

This deserves its own section because it is the single most important acute complication of dementia.

Aspect	Details
Prevalence	Dementia is the strongest predisposing factor for delirium. Up to 50% of hospitalised dementia patients develop delirium. Delirium incidence is 5× higher in dementia patients ^[2].
Why?	The dementia brain has reduced "cognitive reserve" — it is operating at the edge of its capacity. Any additional insult (infection, medication, metabolic derangement, pain, constipation) tips it over the threshold into delirium. Think of it as a system with no safety margin.
Why it matters	(1) Delirium itself carries significant mortality (14% at 1 month, 22% at 6 months ^[2]). (2) Delirium may accelerate the pace of cognitive decline ^[2] — each episode of delirium causes additional neuronal damage. (3) It signals an underlying treatable medical problem that must be found and addressed.
Challenge	Distinguishing delirium from worsening BPSD can be very difficult. The key is any acute change from baseline — particularly in level of consciousness, attention, and presence of new perceptual disturbance. If in doubt, assume delirium until proven otherwise.
Common precipitants	UTI (most common), pneumonia, constipation, pain (especially hip fracture), medication changes (especially anticholinergics, BDZs, opioids), dehydration, urinary retention, environmental change (e.g. hospitalisation).

Dementia patients are particularly vulnerable to complications from the very medications and interventions intended to help them:

Complication	Cause	Mechanism
Antipsychotic-related mortality	SGAs and FGAs prescribed for BPSD	All antipsychotics carry a 1.6–1.7× increased mortality risk in dementia patients (primarily from cerebrovascular events and infections). This is why the principle is lowest dose, shortest duration.
Antipsychotic sensitivity in DLB	Typical antipsychotics (or even atypicals) in DLB	Antipsychotic sensitivity (30–50%) → acute irreversible Parkinsonism, LOC ± NMS ^[2]. Dopaminergic pathways already severely depleted by Lewy body pathology — blocking residual D2 receptors is catastrophic.
AChEI side effects	Donepezil, rivastigmine, galantamine	GI upset (nausea, diarrhoea, anorexia/weight loss — worsening malnutrition), bradycardia/syncope (↑vagal tone → falls), sleep disturbance.
Benzodiazepine harms	BDZs prescribed for agitation/insomnia	↑fall risk, dependence ^[2], excessive sedation, paradoxical disinhibition, respiratory depression, worsened cognition. Slow metabolism in elderly → accumulation.
Anticholinergic burden	Multiple medications with anticholinergic properties	Cumulative anticholinergic effects from polypharmacy → worsened confusion, urinary retention, constipation, dry mouth, blurred vision. Common offenders: oxybutynin, TCAs, antihistamines, some antipsychotics.
Polypharmacy	Multiple comorbidities typical in elderly	Drug-drug interactions, increased adverse effects, reduced compliance, medication errors (patient cannot manage medications independently).
Hospitalisation-related decompensation	Admission for any medical reason	Unfamiliar environment → acute disorientation → delirium. Immobility → deconditioning. Hospital-acquired infections. Falls in unfamiliar setting. Often results in a "step-down" in functional status that is never recovered.

The clinical staging from the lecture slides captures the trajectory of functional decline ^[2]^[15]^[22]:

Stage	Functional Status	ADL Impact
MCI	Complaints of memory loss, intact activities of daily living ^[2]	Fully independent
Mild AD	Forgetfulness, short memory loss, repetitive questions, hobbies/interests lost, impaired activities of daily living ^[2]	Loses complex I-ADLs: finance, transportation, preparing meals, communication, shopping, medications ^[22]
Moderate AD	Progression of cognitive deficits, dysexecutive syndrome, further impaired ADLs, transitions in care, emergence of BPSD ^[2]	Needs help with basic B-ADLs: eating, bathing, dressing, toileting ^[22]
Severe AD	Agitation, altered sleep patterns, assistance required in dressing, feeding, bathing, established BPSD ^[2]	Fully dependent for all ADLs
Very severe AD	Bedbound, no speech, incontinent, basic psychomotor skills lost ^[2]	Total care required; life-sustaining functions compromised

The mnemonic for ADLs ^[2]: DEATH SHAFT — B-ADL: Dressing, Eating, Ambulation, Toilet, Hygiene. I-ADL: Shopping, Housekeeping, Accounting, Food preparation, Telephone/transportation.

Loss of I-ADLs first (they require more complex cognitive processing — planning, sequencing, judgement), then B-ADLs (which are more procedural/habitual and thus preserved longer). This follows the "retrogenesis" pattern — functional abilities are lost in the reverse order of childhood development.

Hazard	Mechanism	Consequence
Driving	Visuospatial dysfunction + executive dysfunction + slowed reaction time + poor judgement	Motor vehicle accidents. Driving capacity should be assessed and licence revoked when unsafe. Many jurisdictions require mandatory reporting.
Fire/cooking accidents	Forgetting to turn off stove, leaving items on heat, inability to respond appropriately to fire alarm	Burns, house fires. Kitchen safety assessment and modifications essential (automatic stove shut-off, microwave instead of gas).
Financial exploitation	Loss of judgement + trust + inability to manage complex transactions	Vulnerability to scams, fraud, and exploitation by strangers or even family members. Power of attorney/guardianship should be arranged early.
Medication errors	Forgetting doses, double-dosing, taking wrong medication	Toxicity or therapeutic failure. Medication management systems (dosette boxes, blister packs, supervised dosing) are critical.
Elderly abuse ^[12]	Vulnerability from dependence + inability to report/recognise abuse	Be aware of ELDERLY ABUSE ^[12]. Can be physical, psychological, financial, sexual, or neglect. Clinicians must be vigilant — unexplained bruises, malnutrition, fearfulness, withdrawal of finances.

Treat the "hidden patient(s)" ^[12] — this is one of the most important lecture slide points and deserves serious emphasis.

Caregiver Complication	Details	Mechanism
Depression	30–50% of dementia caregivers develop clinical depression	Chronic stress, grief (anticipatory and ongoing — "ambiguous loss" as the person they knew fades), sleep deprivation, social isolation, physical exhaustion
Anxiety	High prevalence	Constant worry about patient safety, wandering, unpredictable BPSD, financial burden, future planning
Physical health decline	↑cardiovascular disease, ↑immune dysfunction, ↑mortality	Chronic cortisol elevation (HPA axis dysregulation from sustained stress), neglect of own health (missed appointments, poor diet, reduced exercise)
Social isolation	Progressive withdrawal from social life	Cannot leave patient alone; embarrassment about patient's behaviour in public; friends/family withdraw
Financial burden	Cost of care escalates as disease progresses	Loss of income (caregiver may quit work), cost of medications, home modifications, day care, residential care. In Hong Kong, residential care costs can exceed HK$10,000–30,000+/month.
Caregiver stress → institutionalisation ^[16]	BPSD (especially aggression, night-time disturbance, incontinence, wandering) is the primary driver	When caregiver capacity is exceeded, residential/nursing home placement becomes necessary
Burnout	Complete physical and emotional exhaustion	When demands chronically exceed resources with inadequate support

In the terminal stages of dementia, the patient faces complications that are often the proximate cause of death:

Complication	Mechanism	Management Considerations
Aspiration pneumonia	Swallowing apraxia → most common cause of death in advanced dementia	Goals-of-care discussion: treat with antibiotics? Comfort measures only? Advance directive critical.
Cachexia	Progressive inability to eat → severe malnutrition → muscle wasting → organ failure	PEG feeding is controversial in advanced dementia — does NOT improve survival, comfort, or reduce aspiration. Hand-feeding with comfort-focused approach is generally preferred.
Immobility-related complications	Pressure ulcers, DVT/PE, contractures, pneumonia	Palliative care approach: positioning, skin care, pain management
Loss of communication	Complete aphasia/mutism in end-stage	Cannot express pain, hunger, thirst → increased suffering if not proactively assessed. Non-verbal pain assessment tools (e.g. PAINAD scale) are essential.
Ethical dilemmas	Capacity loss → decisions about resuscitation, hospitalisation, feeding, treatment of intercurrent illness	Advance care planning should ideally occur early in the disease when the patient still has capacity. Without advance directives, best-interests decisions under MHO Part IVC ^[2].

Subtype	Median Survival	Key Prognostic Features
AD	5–7 years (senior notes); 8–10 years (lecture slides) ^[2]^[15]	Survival associated with older age of onset and rapid cognitive decline ^[2]. Death usually from aspiration pneumonia or intercurrent infection.
VaD	~5 years; ~50% dying from IHD ^[2]	Stepwise decline; each vascular event risks significant step-down. Cardiovascular disease is both the cause and the killer.
DLB	Average lifespan 7.7 years ^[2]	Gradual deterioration ^[2]. Antipsychotic sensitivity can precipitate rapid decline.
FTD	Average survival 8–10 years (shorter for bvFTD) ^[2]	Progresses faster than AD ^[2]. FTD-MND overlap has very poor prognosis (2–3 years).
CJD	Months (sporadic); ~14 months (variant)	Rapidly fatal; no effective treatment

High Yield Summary — Complications of Dementia

BPSD (> 80% prevalence): Depression, psychosis (delusions 60%, hallucinations 20%), agitation/aggression, wandering, sundowning, sleep disturbance, sexual dysfunction. Often more distressing than cognitive symptoms. Leading cause of caregiver stress and institutionalisation.

Falls (2–3× rate): Due to visuospatial dysfunction, gait apraxia, Parkinsonism (DLB), medications, orthostatic hypotension. Hip fracture mortality ~30% at 1 year.

Aspiration pneumonia: Most common cause of death in advanced dementia. Due to swallowing apraxia/dysphagia. PEG tube does NOT reduce aspiration risk.

Delirium superimposed on dementia: 5× incidence. Dementia is the strongest predisposing factor. Usually precipitated by UTI, pneumonia, pain, constipation, medication. Accelerates cognitive decline. Always assume delirium if acute change from baseline.

Iatrogenic: Antipsychotics → 1.6× mortality, stroke risk, irreversible Parkinsonism in DLB. BDZs → falls, sedation. Anticholinergic burden → worsened cognition. Hospitalisation → decompensation.

Functional decline: I-ADLs lost first (finance, medications, cooking), then B-ADLs (dressing, eating, toileting). End-stage: bedbound, no speech, incontinent.

Safety: Driving accidents, fires, financial exploitation, medication errors, ELDERLY ABUSE.

Caregivers ("hidden patients"): 30–50% develop depression. Social isolation, financial burden, physical health decline. Caregiver stress is the primary driver of institutionalisation.

Prognosis: AD 5–10y, VaD ~5y (50% die of IHD), DLB ~7.7y, FTD 8–10y, CJD months.

Active Recall - Complications of Dementia

References

^[2] Senior notes: ryanho-psych.md (Sections 4.2.1–4.2.5: Clinical features, BPSD, AD clinical course and severity staging, VaD prognosis, DLB prognosis, FTD prognosis, delirium and dementia relationship) ^[12] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p45 (Summary — treat the hidden patients, elderly abuse) ^[15] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p42 (Natural history of AD and stage-specific drugs) ^[16] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p40 (Management of BPSD — prevalence and significance) ^[21] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p14 (BPSD — observed behaviours and elicited psychological symptoms) ^[22] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf, p11 (Clinical aspects of dementia — ADL)