NeurologyTier 1Disease (DEADMAN)

Dementia syndromes

Description

Acquired, progressive decline in >=1 cognitive domain causing loss of independent function, without delirium
- Domains: memory, executive function, language, visuospatial, attention, social cognition
MCI = objective deficit, function preserved; converts to dementia at ~10-15%/yr

The four common syndromes - lead with the pattern, not the scan

	First symptom	Course	Signature
Alzheimer disease	Episodic memory - anterograde, hippocampal	Gradual, insidious	Temporoparietal atrophy; apraxia, anomia; insight lost early
Vascular	Executive dysfunction, slowing	Stepwise or gradual	Focal signs, gait disturbance, vascular risk factors, imaging burden
DLB	Fluctuating attention + visual hallucinations	Fluctuating	Parkinsonism, RBD, severe neuroleptic sensitivity, autonomic failure
FTD	Behaviour or language, memory relatively spared	Younger (45-65)	Frontal/anterior temporal atrophy; disinhibition, apathy, loss of empathy

FTD subtypes

bvFTD - behavioural variant (commonest)
Primary progressive aphasia:

Variant	Fluency	Comprehension	Repetition
Semantic (svPPA)	Fluent	Impaired word meaning, anomia, cannot define words	Preserved
Non-fluent/agrammatic (nfvPPA)	Effortful, groping, agrammatic, apraxia of speech, phonemic paraphasias, loss of prosody	Preserved	Impaired for sentences
Logopenic	Frequent word-finding pauses, anomia	Word meaning preserved	Poor sentence repetition. Usually Alzheimer pathology

Others worth recognising

PD dementia - parkinsonism >=1 year before dementia (DLB = within 1 year)
PSP, CBD - dementia with an atypical parkinsonian syndrome
Normal pressure hydrocephalus - gait apraxia (magnetic, "feet stuck to the floor") + urinary incontinence + cognitive slowing; gait comes first and responds best
CJD - rapidly progressive dementia + myoclonus + ataxia, weeks-months
Alcohol-related brain injury, Korsakoff, HIV, neurosyphilis, Huntington disease, CADASIL, limbic encephalitis

Epidemiology

~430,000 Australians; leading cause of death in Australian women, second overall
Prevalence ~1% at 60-65, doubles every 5 years, ~30% over 90
Alzheimer disease ~60-70% of all dementia
DLB ~15-20% - the second commonest cause overall
Vascular ~15-20%; mixed AD + vascular pathology is the commonest finding at autopsy
FTD - the second commonest cause in the under-65s, onset 45-65, M=F
- Strongest family history of the common dementias - up to 30-40% when MND is included
Modifiable risk accounts for ~40-45% of dementia (Lancet Commission): hearing loss, education, smoking, hypertension, obesity, alcohol, depression, physical inactivity, diabetes, social isolation, air pollution, head injury, untreated vision loss, high LDL

Aetiopathogenesis

Alzheimer disease

Extracellular amyloid-beta plaques (APP cleaved by beta- and gamma-secretase) + intracellular neurofibrillary tangles of hyperphosphorylated tau
Tau pathology (Braak staging) tracks the clinical syndrome far better than amyloid burden
Cholinergic loss from the nucleus basalis of Meynert - the rationale for cholinesterase inhibitors
Genetics
- APOE e4 - the major risk allele: 1 copy ~3x, 2 copies ~12-15x, earlier onset; not deterministic, and now also determines eligibility for anti-amyloid therapy
- Autosomal dominant early onset (<1%): APP, PSEN1, PSEN2
- Trisomy 21 - near-universal AD pathology by age 40 (APP gene dose)

Vascular

Large vessel infarcts, strategic single infarcts (thalamus, angular gyrus), multi-infarct, or small vessel disease (lacunes, white matter hyperintensity)
CADASIL - NOTCH3, AD inheritance, migraine with aura -> strokes -> dementia in mid-life; anterior temporal pole white matter change

DLB / PD dementia

Alpha-synuclein Lewy bodies in cortex and brainstem; cholinergic and dopaminergic deficit
- The cholinergic deficit is greater than in AD - hence cholinesterase inhibitors work well

FTD

Frontal and anterior temporal degeneration; TDP-43 (~50%), tau (~40%), FUS
Genes: C9orf72 (also causes ALS), MAPT, GRN - autosomal dominant
ALS-FTD is one disease spectrum; ask about weakness and fasciculations in every FTD

Reversible / treatable contributors - look for these in everyone

B12, thyroid, hyponatraemia, hypercalcaemia
Depression (pseudodementia) - complains of memory loss, "don't know" answers, prominent anhedonia, abrupt onset
Medications - anticholinergics, benzodiazepines, opioids, antihistamines, oxybutynin
Alcohol, thiamine deficiency, sleep apnoea, hearing and vision impairment
Neurosyphilis, HIV, chronic subdural haematoma, NPH, tumour, limbic/autoimmune encephalitis

Diagnosis

Clinical assessment

Collateral history is mandatory - onset, course, functional impact, behaviour, driving, finances, safety
Cognitive testing: MoCA (more sensitive to MCI and executive dysfunction than MMSE), RUDAS (culturally fair, less education-dependent), ACE-III, KICA-Cog for Aboriginal and Torres Strait Islander people
Function: ADLs and instrumental ADLs
Examination: focal signs, parkinsonism, gait, primitive reflexes, fasciculations (ALS-FTD), myoclonus
Screen for depression and delirium first - both mimic and both are treatable

bvFTD criteria - >=3 of 6 for possible bvFTD

1. Disinhibition

2. Apathy / inertia

3. Loss of sympathy or empathy

4. Perseverative, stereotyped or ritualistic behaviour

5. Hyperorality and dietary change (sweet craving, binge eating)

6. Executive/generative deficits with relative sparing of memory and visuospatial function

Probable adds functional decline + supportive imaging (frontal/anterior temporal atrophy or hypometabolism)
Definite requires pathology or a causative mutation

DLB

Core features: fluctuating cognition with variation in attention/alertness | recurrent well-formed visual hallucinations | REM sleep behaviour disorder | spontaneous parkinsonism
- 2 core features = probable DLB
Indicative biomarkers: reduced dopamine transporter uptake (DaTSCAN), abnormal MIBG cardiac scintigraphy, polysomnography-confirmed REM sleep without atonia
*Severe neuroleptic sensitivity - can be fatal; never give a typical antipsychotic*

Investigations - in everyone

FBE, UEC, LFT, calcium, glucose/HbA1c, TSH, B12, folate; syphilis serology and HIV if risk factors
Structural imaging: MRI (or CT) - hippocampal/temporoparietal atrophy (AD), frontal/anterior temporal (FTD), vascular burden, subdural, tumour, hydrocephalus
Selected: EEG (CJD - periodic triphasic sharp wave complexes; non-convulsive status), sleep study, neuropsychology

Selected advanced tests

FDG-PET - temporoparietal hypometabolism (AD) vs frontotemporal (FTD)
Amyloid PET or CSF (Abeta42, total tau, p-tau) - confirms or excludes AD pathology
Plasma p-tau217 - now the leading blood-based biomarker, closely tracking amyloid PET; use only in specialist settings with a defined pathway
- Increasingly the gateway test before anti-amyloid therapy - but a positive result in an asymptomatic person is not a diagnosis
DaTSCAN - DLB vs AD (abnormal in DLB; does not separate DLB from PSP/MSA)
CSF RT-QuIC and 14-3-3, MRI DWI cortical ribboning / pulvinar sign - CJD
Autoimmune/paraneoplastic encephalitis antibodies if rapid onset, seizures, psychiatric features or movement disorder
Genetic testing in young onset or strong family history - counsel first
NPH: large-volume lumbar drainage ("tap test") with pre- and post- gait timing predicts shunt response

Management

A. Non-pharmacological - first, and for everyone

Cognitive stimulation therapy, exercise, structured routine, sensory correction (hearing aids, glasses)
Advance care planning, enduring power of attorney and guardianship while capacity remains
Driving assessment and mandatory reporting to the licensing authority
Home safety, wandering and firearm/stove risk; My Aged Care, ACAT assessment, respite, carer support and carer depression screening
Dementia Australia; carer education is one of the few interventions that delays institutionalisation

B. Treat the reversible and modifiable

Correct B12, thyroid, sodium, calcium
Deprescribe anticholinergics, benzodiazepines, sedating antihistamines, oxybutynin
Treat depression, sleep apnoea, pain, constipation, hearing and vision loss
Vascular risk factor control - BP, lipids, diabetes, smoking, AF (benefits vascular and Alzheimer dementia)
NPH -> ventriculoperitoneal shunt in tap-test responders; subdural haematoma -> neurosurgery

C. Cognitive pharmacotherapy

Agent	Indication
Cholinesterase inhibitors - donepezil, rivastigmine, galantamine	Mild-moderate AD, DLB and PD dementia (largest benefit here). Modest symptomatic benefit. Bradycardia, syncope, GI upset, nightmares, weight loss - ECG before starting
Memantine (NMDA antagonist)	Moderate-severe AD; may be combined with a cholinesterase inhibitor
Avoid cholinesterase inhibitors in FTD	*May worsen agitation and disinhibition*

D. Anti-amyloid monoclonal antibodies - the new class

Donanemab (TGA-approved May 2025) and lecanemab (TGA-approved September 2025), for mild cognitive impairment or mild dementia due to Alzheimer disease
- Lecanemab is restricted to ApoE e4 non-carriers or heterozygotes - homozygotes are excluded because of ARIA risk
Requirements: confirmed amyloid pathology (PET or CSF), IV infusion, serial MRI monitoring
ARIA - amyloid-related imaging abnormalities: ARIA-E (oedema) and ARIA-H (microhaemorrhage/siderosis)
- Mostly asymptomatic but can be fatal; risk rises with ApoE e4 dose and with anticoagulation
- Exclude patients on anticoagulants, with >4 microbleeds, prior lobar haemorrhage or suspected cerebral amyloid angiopathy
Effect size: slowing of decline by roughly one third over 18 months - a slowing, not a reversal or a cure
- Not PBS-subsidised; access, infusion capacity and MRI monitoring are the practical barriers in Australia

E. Behavioural and psychological symptoms (BPSD)

Look for the cause first: pain, infection, constipation, urinary retention, drugs, boredom, fear, over- or under-stimulation
Non-pharmacological strategies are first-line and often sufficient - routine, music, familiar environment, carer communication training
Antipsychotics: last resort, lowest dose, shortest duration, and only for risk of harm or severe distress
- Increase mortality (stroke, pneumonia) - discuss and document this
- Risperidone is the only agent with an Australian indication for BPSD, and for a limited period; review and cease
- *Never in DLB - severe neuroleptic sensitivity. If essential, quetiapine at very low dose*
FTD-specific: SSRIs for disinhibition, compulsions, aggression and overeating; venlafaxine for apathy; cholinesterase inhibitors are not indicated and may worsen behaviour
PD dementia/DLB psychosis: reduce dopaminergics, then quetiapine or clozapine only
Depression: SSRI (avoid tricyclics - anticholinergic)
Avoid benzodiazepines - falls, delirium, paradoxical agitation

F. Advanced disease and palliative care

Advanced dementia is a terminal illness - frame it that way with families
Swallowing decline: careful hand feeding; PEG feeding does not prolong life or prevent aspiration in advanced dementia
Focus on comfort, avoid burdensome transfers and investigations, deprescribe
Anticipatory prescribing, review resuscitation status and hospital transfer plans

Associations

Down syndrome - Alzheimer pathology by age 40, dementia typically by 50s
APOE e4; family history; C9orf72 (FTD-MND), MAPT, GRN
REM sleep behaviour disorder - prodromal to DLB, PD and MSA
Motor neurone disease - ALS-FTD
Vascular disease, atrial fibrillation, hypertension, diabetes, obesity
Hearing loss and untreated visual impairment - substantial modifiable risk
Depression - both a risk factor and an early manifestation
Traumatic brain injury, chronic traumatic encephalopathy
Alcohol use disorder; thiamine deficiency (Wernicke-Korsakoff)
Delirium - an episode of delirium accelerates cognitive decline and often unmasks unrecognised dementia
Falls, malnutrition, elder abuse, carer depression

Natural history & complications

	Typical survival from diagnosis
Alzheimer disease	8-10 years (3-20)
Vascular	5 years; stepwise, driven by further vascular events
DLB	~5-7 years - shorter than AD, more rapid functional decline
FTD	~6-8 years; ~2-3 years if ALS co-exists
CJD	Median <6 months

Course

AD: memory -> language and visuospatial -> apraxia and incontinence -> mutism, immobility, swallowing failure
Death usually from pneumonia (often aspiration), or from immobility complications
Behavioural symptoms peak in moderate disease and often settle in advanced disease
Institutionalisation is driven by behaviour, incontinence and carer breakdown, not by cognitive score

Monitor

Cognition and function 6-12 monthly; weight and swallow; falls
Driving fitness at every review
Carer strain and mood
Medication review - especially antipsychotics, anticholinergics and sedatives
Advance care plan revisited as function changes

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