Frontotemporal dementia is a group of neurodegenerative disorders characterized by progressive atrophy of the frontal and temporal lobes, leading to prominent changes in personality, behavior, and language with relative preservation of memory in early stages.

Exam domain	One-glance essentials
Definition / diagnosis	FTD is progressive frontal/anterior temporal degeneration causing early behaviour/personality or language change ^[1]^[2] Clinical FTD overlies heterogeneous FTLD pathology: tau, TDP-43 or FUS
Epidemiology / risks	Typical onset is 45–65 years; family history is common ^[1]^[2] Major genes: C9ORF72 repeat expansion, MAPT and GRN; consider testing with young onset, family history or MND overlap
Core mechanism	Orbitofrontal loss → disinhibition; anterior cingulate loss → apathy; anterior temporal loss → semantic failure FTLD-tau includes Pick bodies; FTLD-TDP links FTD with motor neurone disease Selective frontoinsular/Von Economo neuron loss impairs empathy and social cognition
Clinical picture	bvFTD: disinhibition, apathy, loss of empathy, compulsions, hyperorality and executive failure with early memory sparing ^[1]^[2] *Hyperorality and stereotyped, utilisation or repetitive behaviours should suggest FTD* ^[4] PPA: non-fluent/agrammatic speech or semantic loss; logopenic PPA is usually AD pathology Poor insight and progressive social/occupational dysfunction are characteristic
Investigations	Possible bvFTD: ≥3 of 6 core features; probable adds functional decline plus supportive imaging MRI: frontal/anterior temporal atrophy; SPECT/PET: bilateral frontal + temporal hypoperfusion ^[3] Exclude reversible causes; amyloid/CSF AD biomarkers and genetic testing resolve uncertain cases
Management	No disease-modifying or proven cognitive drug treatment ^[1]^[2] Behaviour: structured environment and caregiver strategies first; SSRI or trazodone may reduce disinhibition/compulsions PPA needs speech therapy/AAC; motor overlap needs PT/OT and syndrome-specific supportive care
Complications	Early: unsafe driving, financial/legal harm, self-neglect and obesity/metabolic disease from hyperorality FTD-MND → bulbar/respiratory failure and poor prognosis; PSP/CBD overlap → falls and dysphagia Late: aspiration pneumonia, immobility, pressure injury, VTE and severe caregiver burnout
Prevention / follow-up	Supervise money, driving, medication and food access; simplify routines and environment Genetic counselling before/after testing in familial disease Arrange capacity, enduring power of attorney, respite and advance care planning early
Exam traps	FTD is dementia without obligatory early memory loss Apathy lacks sadness; progressive disinhibition/hyperorality argues against depression Do not use cholinesterase inhibitors routinely: they lack benefit and may worsen behaviour Acute fluctuation is delirium, not expected FTD progression

References

Frontotemporal Dementia (FTD) — Clinical Features, Etiology & Pathophysiology

Frontotemporal dementia (FTD) is a clinicopathological syndrome characterised by disturbances in behaviour, personality and language accompanied by focal degeneration of the frontal and/or temporal lobes ^[1]^[2]. Historically called Pick's disease (after Arnold Pick, who described the first case in 1892), the term "FTD" is now preferred because Pick's bodies (a specific histological finding) are present in only about half of cases.

Breaking down the name:

Fronto- = frontal lobes (executive function, personality, social behaviour, motor planning)
Temporal = temporal lobes (language, semantic memory, emotional processing)
Dementia = progressive cognitive decline impairing daily function

The underlying neuropathological substrate is called frontotemporal lobar degeneration (FTLD) — this is the pathological term for the disease process, while FTD is the clinical syndrome. Think of it like "heart failure" (the clinical syndrome) versus "dilated cardiomyopathy" (the pathological substrate).

Key distinction: FTD is the most common cause of dementia in patients < 65 years and is often misdiagnosed as a psychiatric disorder because behavioural symptoms dominate early, while memory is relatively preserved — the exact opposite pattern to Alzheimer's disease (AD).

Parameter	Detail
Incidence	~3.5/100,000/year (UK data) ^[1]^[2]
Prevalence	~15–22/100,000 in the 45–65 age group
Demographics	Average onset ~58 years; unusual before 40 or after 70 years ^[1]^[2]
Sex	Slight male predominance for bvFTD; PPA subtypes roughly equal
Proportion of all dementias	~5–10% overall, but common cause of early-onset dementia (i.e. < 65 y) — second only to early-onset AD ^[1]^[2]
Family history	~40% have a family history of dementia or psychiatric disease; ~10–25% show autosomal dominant inheritance ^[1]^[2]

Hong Kong Context

In Hong Kong, Alzheimer's disease remains the most common dementia (~60–70%), followed by vascular dementia and mixed dementia. FTD accounts for a smaller but significant proportion. However, it is likely underdiagnosed because early behavioural symptoms are frequently attributed to depression, personality change, or mid-life crisis, and because awareness of FTD among non-specialists is lower than for AD.

3. Anatomy & Functional Correlates

Understanding the clinical features of FTD requires a solid grasp of frontal and temporal lobe anatomy. The symptoms make perfect sense once you map them onto the affected cortical regions.

The frontal lobe has three key prefrontal circuits relevant to FTD:

Circuit	Location	Normal Function	Deficit When Damaged
Dorsolateral prefrontal	Lateral convexity	Executive function (planning, working memory, cognitive flexibility, set-shifting)	Perseveration, poor planning, impaired abstract thinking
Orbitofrontal	Ventral/inferior surface	Social behaviour, impulse control, emotional regulation, reward processing	Disinhibition (socially inappropriate behaviour, impulsivity), poor judgment
Anterior cingulate / medial frontal	Medial surface, cingulate gyrus	Motivation, initiation of behaviour, error monitoring	Apathy, inertia, akinetic mutism in severe cases

Why does bvFTD cause disinhibition? Because the orbitofrontal cortex normally acts as a "brake" on impulsive behaviour. When it degenerates, patients lose this inhibitory control — they may make inappropriate sexual comments, steal from shops, or urinate in public. They are not "choosing" to be rude; they have lost the neural circuitry that suppresses these impulses.

Why does bvFTD cause apathy? Because the anterior cingulate/medial frontal region drives motivation. When it degenerates, patients lose the will to initiate activities. This is often the most distressing symptom for carers and is commonly mistaken for depression — but unlike depression, patients with apathy from FTD do not feel sad.

Region	Normal Function	Deficit When Damaged
Anterior temporal lobe (left)	Semantic memory (knowledge of word meanings, object concepts)	Impaired single-word comprehension and object naming (semantic variant PPA)
Posterior inferior frontal / insular cortex (left)	Motor speech programming, grammar	Non-fluent/agrammatic speech (non-fluent variant PPA)
Left temporoparietal junction	Phonological loop, word retrieval	Impaired word retrieval and sentence repetition (logopenic variant — though this is now considered more AD-related pathologically)
Amygdala (bilateral)	Emotional processing, fear conditioning, social cognition	Loss of empathy, emotional blunting, inability to read facial emotions
Anterior insula	Interoception, disgust, emotional awareness	Altered food preferences, reduced autonomic awareness

Different types of dementia typically present with different patterns of perfusion changes ^[3]:

AD: bilateral posterior temporal + parietal hypoperfusion ^[3]
FTD: bilateral frontal + temporal hypoperfusion ^[3]

This pattern on 99mTc-HMPAO cerebral perfusion SPECT or FDG-PET is a key differentiator from AD.

On structural MRI:

bvFTD: focal atrophy in orbitofrontal, medial frontal, anterior cingulate, anterior insula cortices and amygdala ^[1]^[2]
PPA: typically asymmetric frontotemporal "knife-blade" atrophy affecting the left hemisphere ^[2]

"Knife-blade atrophy" refers to the extremely sharp, thin gyri that result from severe cortical loss — the gyri look like the edge of a knife. This is particularly dramatic in the temporal poles in semantic variant PPA.

4. Etiology

FTD is the most heritable of the common neurodegenerative dementias. ~40% have FHx of dementia or psychiatric disease; ~10–25% show autosomal dominant (AD) inheritance ^[1]^[2].

The three major causative genes (high yield):

Gene	Chromosome	Protein	Mechanism	Associated Clinical Phenotype
C9ORF72	9p21	C9orf72 (involved in autophagy and vesicle trafficking)	GGGGCC hexanucleotide repeat expansion → toxic RNA foci + dipeptide repeat proteins → neuronal toxicity	bvFTD, FTD-MND (motor neurone disease), ALS, psychosis; most common genetic cause of FTD in Caucasians
MAPT	17q21	Tau protein (microtubule-associated protein tau)	Mutations → abnormal tau → hyperphosphorylation → neurofibrillary tangles + Pick bodies	bvFTD, PSP-like, CBD-like syndromes
GRN (progranulin)	17q21	Progranulin (growth factor, anti-inflammatory)	Haploinsufficiency (loss-of-function) → reduced progranulin → TDP-43 accumulation	bvFTD, PPA (often asymmetric), parkinsonism

Exam Pearl

Both MAPT and GRN are on chromosome 17 — but they cause disease through completely different mechanisms. MAPT mutations produce toxic gain-of-function tau pathology, while GRN mutations cause loss-of-function with TDP-43 pathology. This is a favourite exam distinction.

The majority (~60%) of FTD cases are sporadic (no clear family history). Risk factors for sporadic FTD are less well-defined than for AD, but include:

Head trauma (especially repetitive, e.g. contact sports — chronic traumatic encephalopathy can mimic bvFTD)
Low education (weaker association than in AD)
Autoimmune disease (emerging association)

Notably, the APOE4 allele — the major genetic risk factor for AD — is NOT a significant risk factor for FTD. This is an important negative fact.

5. Pathophysiology

5.1 Neuropathological Classification (FTLD Subtypes)

The clinical syndrome "FTD" maps onto the pathological entity frontotemporal lobar degeneration (FTLD), which is classified by the predominant abnormal protein inclusion:

FTLD Subtype	Abnormal Protein	Proportion	Key Associations
FTLD-tau	Tau inclusions (Pick bodies in ~50%) ^[1]^[2]	~40%	MAPT mutations, Pick's disease, CBD, PSP
FTLD-TDP	TDP-43 inclusions	~50%	GRN mutations, C9ORF72 expansion, FTD-MND
FTLD-FUS	FUS (fused in sarcoma) protein	~5–10%	Young-onset sporadic bvFTD

Microscopic pathology: microvacuolation and neuronal loss with swollen neurones (ballooned neurons), associated with either tau inclusions (i.e. Pick's bodies, ~1/2) or other inclusions (e.g. ubiquitin) ^[1]^[2].

Pick bodies are round, intraneuronal inclusions composed of hyperphosphorylated 3-repeat tau protein. They are silver-stain positive and found predominantly in the hippocampus and frontotemporal cortex. They are pathognomonic of Pick's disease (a subtype of FTLD-tau) but are NOT present in all FTD cases — hence why we no longer call all FTD "Pick's disease."

TDP-43 (TAR DNA-binding protein 43) is normally a nuclear protein involved in RNA processing. In FTLD-TDP, it becomes hyperphosphorylated, ubiquitinated, and mislocalised to the cytoplasm, forming toxic aggregates. Interestingly, TDP-43 pathology is also found in ALS (amyotrophic lateral sclerosis/motor neurone disease), which explains the clinical overlap between FTD and MND.

The concept of selective vulnerability is crucial: different neuronal populations are preferentially affected in different FTD subtypes. Von Economo neurons (large spindle-shaped neurons in the anterior cingulate and frontoinsular cortex involved in social cognition and self-awareness) are particularly vulnerable in bvFTD — their early loss explains the striking deficits in empathy and social behaviour.

FTD exists on a spectrum with several motor neurodegenerative diseases:

Associated motor syndromes: FTD may be associated with the following motor syndromes ^[1]:

Motor neurone disease (MND/ALS): associated with bvFTD ^[1] — ~15% of bvFTD patients develop MND, and ~15% of ALS patients develop bvFTD. Both share C9ORF72 and TDP-43 pathology.
Corticobasal degeneration (CBD): often frontal-dominant → may present initially as bvFTD or svPPA ^[1]
Progressive supranuclear palsy (PSP): associated with bvFTD ^[1]

FTD-MND Overlap

Always screen FTD patients for motor neurone disease features (fasciculations, wasting, upper motor neuron signs) and vice versa. Missing the FTD-MND overlap is a common clinical error. The combination carries a worse prognosis (mean survival ~3 years from symptom onset).

6. Classification

FTD is clinically divided into two major subtypes, which are further subdivided:

*Note: Logopenic variant PPA is now considered to be pathologically more closely related to Alzheimer's disease (underlying amyloid/tau AD pathology) rather than FTLD, but it is still classified under PPA clinically.

Feature	bvFTD	nfvPPA	svPPA	lvPPA
Core domain	Behaviour & personality	Speech production	Word meaning	Word finding
Speech	Normal (early)	Effortful, agrammatic, halting	Fluent but empty (loss of content words)	Fluent with word-finding pauses
Comprehension	Preserved (early)	Preserved (single words)	Impaired single-word comprehension ^[2]	Preserved (single words)
Repetition	Preserved	Impaired	Preserved	Impaired
Object naming	Preserved (early)	Relatively preserved	Impaired ^[2]	Impaired
Predominant atrophy	Bilateral frontal (orbitofrontal, medial)	Left posterior frontal, insula	Left anterior temporal (temporal pole)	Left posterior temporal / temporoparietal
Typical underlying pathology	FTLD-tau or FTLD-TDP	FTLD-tau	FTLD-TDP	AD (amyloid + tau)
Age of onset	~58 y	~60–65 y	~58–65 y	~60–65 y

7. Clinical Features

7.1 Behavioural Variant FTD (bvFTD)

bvFTD accounts for ~60% of all FTD cases. The hallmark is progressive change in personality and social behaviour with relative preservation of episodic memory (at least early on).

Symptom	Description	Pathophysiological Basis
Behavioural disinhibition	e.g. public urination, making inappropriate sexual comments, shoplifting, rude remarks to strangers, loss of social decorum ^[1]^[2]	Degeneration of orbitofrontal cortex → loss of impulse inhibition circuitry. The OFC normally suppresses socially inappropriate urges.
Apathy / inertia	Loss of motivation, sitting idle for hours, abandoning hobbies and work, reduced spontaneous speech and activity ^[1]^[2]	Degeneration of anterior cingulate cortex and medial frontal structures → loss of drive/motivational circuitry
Loss of empathy	Indifference to others' feelings, inability to recognise others' distress, cold and detached demeanour ^[1]^[2]	Loss of Von Economo neurons in anterior cingulate/frontoinsular cortex + amygdala degeneration → impaired theory of mind and emotional processing
Hyperorality and dietary changes	Puts excessive food in mouth, craves sweets/carbohydrates, may eat non-food items (pica), increased alcohol/cigarette consumption ^[1]^[2]	Degeneration of orbitofrontal cortex and anterior insula → disinhibited eating behaviour + altered reward/taste processing. The hypothalamic feeding circuitry receives frontal inhibitory input that is lost.
Compulsive/stereotyped/ritualistic behaviour	Perseveration (repeating the same word, phrase, or action), clock-watching, rigid adherence to fixed routines, hoarding, repetitive motor behaviours (e.g. humming, clapping, pacing a fixed route) ^[1]^[2]	Loss of frontostriatal circuits → release of basal ganglia-mediated repetitive motor programmes. Perseveration = failure of frontal set-shifting ability.
Decline in social cognition	Poor judgment in social situations, gullibility, inability to detect sarcasm or deceit ^[2]	Prefrontal + anterior temporal degeneration → impaired mentalising networks (theory of mind)
Decline in executive function	Poor planning, inability to multitask, difficulty with abstract reasoning, concrete thinking ^[2]	Dorsolateral prefrontal cortex degeneration → loss of working memory and cognitive flexibility
Mental rigidity and inflexibility	Insists on sameness, difficulty adapting to new situations	Frontostriatal circuit dysfunction
Loss of insight (anosognosia)	Patient is typically unaware of their behavioural changes — it is the family who brings them to attention	Orbitofrontal and anterior cingulate degeneration → impaired self-monitoring
Emotional blunting	Flat affect, reduced emotional reactivity, "doesn't care" about sad or happy events	Amygdala and orbitofrontal degeneration → impaired emotional valence processing

Clinical Pearl — FTD vs Depression

Both FTD and depression can present with apathy, social withdrawal, and loss of interest. However:

In FTD: there is no subjective distress (the patient doesn't feel sad), there is disinhibition (which is never seen in depression), and insight is lost
In depression: the patient feels low, has guilt, and typically retains insight into their condition This distinction is critical because ~50% of bvFTD patients are initially misdiagnosed with a psychiatric disorder.

Sign	Description	Pathophysiological Basis
Primitive reflexes (frontal release signs)	Grasp reflex, palmomental reflex, snout reflex, rooting reflex	These reflexes are normally suppressed by mature frontal cortex. Frontal degeneration "releases" them (hence "release signs").
Utilisation behaviour	Patient automatically uses objects placed in front of them (e.g. picks up a comb and combs hair, drinks from an empty cup)	Loss of frontal inhibition over parietal-driven motor programmes
Perseveration on examination	Repeats same response despite changing stimulus (e.g. continues drawing circles when asked to draw a triangle)	Frontostriatal circuit damage → inability to shift set
Echolalia	Repeats examiner's words	Frontal damage → loss of inhibition over imitative behaviour
Emotional lability (some cases)	Inappropriate laughing or crying	Disruption of frontal-subcortical emotional regulation
Executive dysfunction on cognitive testing	Poor performance on: Wisconsin Card Sorting Test, Stroop test, verbal fluency (especially letter fluency), Trail Making Test B	These tests specifically require frontal lobe function (set-shifting, inhibition, generation)
Relatively preserved episodic memory (early)	Can recall recent events when tested; orientation preserved	Hippocampus is relatively spared early (unlike AD). This is a KEY differentiator.
Relatively preserved visuospatial function (early)	Clock drawing, copy tasks may be normal	Parietal lobes spared (unlike AD)
Motor signs (late or with overlap syndromes)	Parkinsonism (rigidity, bradykinesia), fasciculations, upper/lower motor neuron signs	Associated CBD, PSP, or MND overlap

Exam High Yield — Memory in FTD vs AD

A common exam question: "How do you differentiate FTD from AD?"

FTD: Behaviour and personality change FIRST, memory relatively preserved early
AD: Memory loss FIRST (especially recent/episodic memory), personality preserved early This is because AD targets the hippocampus first, while FTD targets the frontal/anterior temporal cortex first.

7.2 Primary Progressive Aphasia (PPA)

PPA is defined as progressive, isolated language impairment for at least 2 years, with other cognitive domains and activities of daily living relatively preserved (at least initially). There are three variants:

Feature	Detail	Pathophysiological Basis
Articulation difficulty ^[2]	Effortful, halting speech; distorted sounds (apraxia of speech); requires significant effort to produce words	Degeneration of left posterior inferior frontal gyrus (Broca's area) and anterior insula → loss of motor speech programming
Agrammatism	Simplified grammar, omission of function words (e.g. "the," "is"), telegraphic speech (e.g. "me... go... shop")	Left inferior frontal damage → disrupted syntactic processing
Relatively preserved single-word comprehension	Understands individual words	Temporal lobe semantic areas preserved early
Impaired sentence comprehension	Difficulty with complex grammatical structures	Cannot parse syntax
Impaired repetition	Cannot repeat sentences accurately	Disrupted speech production circuitry

Atrophy pattern: Left posterior frontal cortex and insula. Often FTLD-tau pathology.

Feature	Detail	Pathophysiological Basis
Impaired single-word comprehension ^[1]^[2]	Asks "What does that mean?" for common words; cannot match words to pictures	Left anterior temporal lobe (temporal pole) degeneration → loss of the "semantic hub" where meaning is stored
Impaired object naming ^[1]^[2]	Cannot name common objects (e.g. shown a watch: "That thing you wear on your hand")	Loss of semantic representations → cannot access the concept to retrieve the word
Fluent but empty speech	Speech is grammatically correct and effortless but lacks content words — uses vague terms ("thing," "stuff")	Speech production circuitry intact (Broca's area preserved); semantic store depleted
Surface dyslexia/dysgraphia	Regularises irregular words (e.g. reads "yacht" as "yatched")	Loss of whole-word reading (lexical route) → relies on phonological (sound-it-out) route
Preserved repetition	Can repeat words and sentences accurately	Phonological loop intact
Loss of object/face knowledge (later)	Cannot recognise familiar faces (prosopagnosia) or common objects by sight	Bilateral anterior temporal atrophy (right > left for faces)
Behavioural features (later)	Develops bvFTD-like features as disease spreads to frontal lobes	Frontal lobe involvement in later stages

Atrophy pattern: Asymmetric, left > right anterior temporal lobe ("knife-blade" atrophy of temporal poles). Usually FTLD-TDP pathology.

Feature	Detail	Pathophysiological Basis
Impaired single-word retrieval ^[2]	Frequent word-finding pauses in spontaneous speech; "tip of the tongue" phenomenon	Left temporoparietal junction degeneration → impaired phonological access
Impaired repetition (especially sentences) ^[2]	Cannot repeat long sentences or phrases	Disrupted phonological short-term memory
Relatively preserved single-word comprehension	Understands individual words	Semantic store intact
Preserved grammar and motor speech	No agrammatism, no apraxia of speech	Broca's area intact
Phonological errors	Sound-based errors (e.g. "aminal" for "animal")	Phonological processing impairment

Atrophy pattern: Left posterior temporal / temporoparietal junction. Pathology is usually AD (amyloid + tau), NOT FTLD — making this variant a "wolf in sheep's clothing" that looks like PPA but is pathologically Alzheimer's.

PPA Variant Summary — Exam Favourite

	nfvPPA	svPPA	lvPPA
Fluency	NON-fluent	Fluent	Fluent (with pauses)
Comprehension (single word)	Preserved	IMPAIRED	Preserved
Repetition	Impaired	Preserved	Impaired
Naming	Relatively preserved	IMPAIRED	Impaired
Grammar	IMPAIRED	Preserved	Preserved
Underlying pathology	FTLD-tau	FTLD-TDP	AD

Feature	FTD	Alzheimer's Disease	DLB	Vascular Dementia
Age of onset	~58y (younger)	Typically > 65y	Typically > 65y	Variable
Earliest symptom	Personality/behaviour OR language	Memory loss (recent)	Visual hallucinations, fluctuating cognition, parkinsonism	Stepwise decline, focal neuro deficits
Memory	Preserved early	Impaired early	Impaired	Variable
Visuospatial	Preserved early	Impaired (parietal)	IMPAIRED	Variable
Hallucinations	Rare	Late	Early (visual, formed, detailed)	Rare
Parkinsonism	Late (or with overlap syndromes)	Late	EARLY	Variable
Behavioural change	EARLY and prominent	Late	Moderate	Variable
Atrophy pattern	Frontal + anterior temporal	Medial temporal (hippocampus) + parietal	Relatively preserved cortex	Cortical/subcortical infarcts, white matter changes

Progresses faster than AD; average survival = 8–10 years ^[1]
Shorter survival for bvFTD ^[1] (especially with MND overlap: ~3 years)
PPA variants may have somewhat longer courses (especially svPPA)
Death typically from aspiration pneumonia, inanition, or complications of immobility
Behavioural symptoms tend to worsen and spread: PPA patients often develop behavioural features as disease spreads to frontal lobes, and bvFTD patients may develop language deficits

High Yield Summary

FTD = progressive degeneration of frontal and/or temporal lobes → behaviour/personality change OR progressive language disturbance
Epidemiology: onset ~58y, most common cause of dementia < 65y, highly heritable (~40% FHx), 10–25% autosomal dominant
Three key genes: C9ORF72 (repeat expansion, FTD-MND), MAPT (tau), GRN (progranulin haploinsufficiency → TDP-43)
Pathology = FTLD: ~40% FTLD-tau (Pick bodies), ~50% FTLD-TDP, ~5–10% FTLD-FUS
Two clinical subtypes:
- bvFTD (~60%): disinhibition, apathy, loss of empathy, hyperorality, compulsive behaviour, executive dysfunction; memory PRESERVED early
- PPA: progressive isolated language impairment — nfvPPA (effortful agrammatic speech), svPPA (loss of word meaning), lvPPA (word-finding difficulty, impaired repetition — usually AD pathology)
Key differentiator from AD: behaviour first (not memory), younger onset, frontal/temporal atrophy (not hippocampal/parietal)
Imaging: bilateral frontal + temporal hypoperfusion on SPECT/PET; focal frontal (bvFTD) or temporal (PPA) atrophy on MRI
Motor overlaps: MND, CBD, PSP
Prognosis: 8–10y, faster than AD; worst with MND overlap (~3y)

Active Recall - Frontotemporal Dementia

Differential Diagnosis of Frontotemporal Dementia

Before diving into the list, let's understand why FTD is so commonly misdiagnosed:

bvFTD mimics psychiatric disorders. Early behavioural changes (apathy, disinhibition, compulsive behaviour) look like depression, mania, OCD, or even late-onset schizophrenia. Memory is preserved, so patients don't "look" demented at first glance.
PPA mimics stroke-related aphasia or other dementias. Progressive language decline can be confused with cerebrovascular disease, brain tumours, or even early AD (especially the logopenic variant).
Age of onset is younger (~58 years), so clinicians may not consider dementia in a 50-year-old with personality change.
Motor overlap syndromes (MND, CBD, PSP) blur the boundary between FTD and primary movement disorders.

The differential diagnosis therefore splits naturally by clinical presentation — are you dealing primarily with behavioural/personality change (bvFTD mimics) or progressive language disturbance (PPA mimics)?

3. Detailed Differential Diagnosis

The differentials listed below are drawn directly from lecture slides and senior notes, then expanded with clinical reasoning.

3.1 Differentials for Behavioural Variant FTD (bvFTD)

Psychiatric disorders, e.g. depression ^[1]^[2]

This is the single most important differential — roughly 50% of bvFTD patients receive a psychiatric diagnosis first.

Condition	Why It Mimics bvFTD	How to Differentiate
Major depression	Apathy, social withdrawal, loss of interest, reduced speech output	Depression: subjective sadness/guilt, preserved insight, responds to antidepressants. bvFTD: no subjective distress, disinhibition present, loss of insight, does NOT respond to antidepressants
Bipolar disorder (mania)	Disinhibition, impulsivity, hypersexuality, poor judgment	Mania: episodic (not progressive), grandiosity, pressured speech, sleep reduced but not sleepy. bvFTD: insidious progressive course, no grandiosity, no pressured speech
OCD	Compulsive, ritualistic, repetitive behaviours	OCD: ego-dystonic (patient recognises behaviour is irrational and is distressed by it). bvFTD: ego-syntonic (patient is unbothered), compulsions are simpler/more stereotyped
Late-onset schizophrenia	Social withdrawal, bizarre behaviour, flat affect	Schizophrenia: prominent auditory hallucinations, systematised delusions, formal thought disorder. bvFTD: hallucinations uncommon (except in C9ORF72 carriers), no formal thought disorder
Alcohol and the Brain ^[4]	Personality change, disinhibition, frontal cognitive dysfunction, apathy	Alcohol-related: clear history of heavy alcohol use, cerebellar signs, peripheral neuropathy, Wernicke features; MRI shows mammillary body/thalamic changes and global atrophy rather than selective frontotemporal atrophy

GC High Yield — Psychogeriatric Assessment

Hyperorality and stereotyped, utilization or repetitive behaviours may suggest frontotemporal dementia ^[5]. This point from the GC Psychogeriatrics Seminar is a classic exam cue — when you see these features in a psychiatric assessment station, think FTD, not OCD or mania.

Common Mistake

Do not diagnose "late-onset depression" in a patient with progressive apathy, loss of empathy, and disinhibition without considering bvFTD. The key differentiator is that depressed patients FEEL sad and retain insight, while bvFTD patients do NOT feel sad and have LOST insight. Always ask the family — they will describe a personality change that the patient denies or is indifferent to.

Early onset Alzheimer's disease ^[1]^[2]

AD can present before age 65 (early-onset AD, ~5% of AD cases), and atypical "frontal variant AD" can mimic bvFTD with prominent executive dysfunction and behavioural changes
Key differentiators:
- AD: memory deficit is typically the earliest and most prominent feature — anterograde episodic amnesia ^[6]. Also expect parietal cortical symptoms (aphasia, apraxia, agnosia)
- FTD: behaviour/personality change FIRST, memory relatively preserved early
- Imaging: AD → bilateral perihippocampal atrophy ^[6], posterior temporal + parietal hypoperfusion. FTD → frontal + anterior temporal atrophy ^[1]^[2], bilateral frontal + temporal hypoperfusion ^[3]
Amyloid PET or CSF biomarkers (Aβ42, phospho-tau) can definitively differentiate AD from FTD pathology

Dementia with Lewy bodies ^[1]^[2]

DLB is a synucleinopathy characterised by:

Progressive cognitive decline interfering with normal social or occupational function ^[7]
Prominent and early deficits in attention, executive function, and visuoperceptual processing ^[7]
Core clinical features: fluctuating cognition, recurrent well-formed visual hallucinations, REM sleep behaviour disorder, parkinsonism ^[7]^[8]
Supportive features: severe sensitivity to antipsychotics, hypersomnia, postural instability, hyposmia ^[7]

Feature	DLB	bvFTD
Visual hallucinations	EARLY, detailed, formed (people, animals)	Rare (except C9ORF72)
Cognitive fluctuation	Pronounced, day-to-day	Not typical
Parkinsonism	EARLY (within 1 year of cognitive decline)	Late, or only with overlap syndromes
Visuospatial impairment	PROMINENT	Preserved
Behavioural change	Moderate (apathy, delusions)	PROMINENT and earliest feature
RBD	Present	Not typical
Antipsychotic sensitivity	Severe ^[7]	Generally tolerated (though caution needed)
Imaging	Relative preservation of medial temporal lobe; reduced occipital activity on FDG-PET ^[7]	Frontal and anterior temporal atrophy

Dopamine transporter imaging is most helpful in distinguishing DLB from Alzheimer disease ^[7] — this can also help differentiate DLB from FTD, as FTD does not show reduced dopamine transporter uptake unless there is an associated movement disorder.

If dementia occurs before or within 1 year of motor symptoms of bradykinesia, rigidity, or resting tremor, a diagnosis of DLB can be established ^[7]. This "1-year rule" distinguishes DLB from Parkinson's disease dementia.

Huntington's disease: autosomal dominant condition caused by CAG trinucleotide repeats on chromosome 4p16.3, leading to atrophy of the caudate and putamen. The triad of chorea, psychiatric manifestations including depression and psychosis, and progressive dementia ^[9]

Why it mimics bvFTD: personality change, apathy, disinhibition, irritability can precede chorea by years
How to differentiate: family history of HD (autosomal dominant with anticipation), choreiform movements, caudate atrophy on imaging (not frontal), genetic testing

General paresis (general paralysis of the insane): ~10–25 years after infection. S/S: progressive memory deficit, dementia ± depression, mania, psychosis ^[10]

Cerebral atrophy that mainly affects frontal and temporal cortex due to chronic meningoencephalitis ^[10]

This is a treatable mimic of FTD — the atrophy pattern is similar (frontal and temporal), and patients present with personality change, behavioural disinhibition, and progressive dementia. Always check syphilis serology (EIA-syphilis, VDRL/RPR) in any young-onset dementia, especially with psychiatric features.

Corticobasal degeneration (CBD): progressive asymmetrical movement disorders with symptoms initially affecting one limb — combinations of akinesia, rigidity, dystonia, focal myoclonus, ideomotor apraxia and alien limb phenomenon. Cognitive impairment is a common manifestation including executive dysfunction, aphasia, apraxia, behavioral change and visuospatial dysfunction ^[11]

Progressive supranuclear palsy (PSP): supranuclear vertical gaze palsy is the hallmark — initially downward palsy followed by upward palsy. Gait disturbance resulting in falls is a typical initial feature ^[11]

Both CBD and PSP share tau pathology with FTD and exist on the same spectrum:

FTD may be associated with CBD: often frontal-dominant → may present initially as bvFTD or svPPA ^[1]
FTD may be associated with PSP: associated with bvFTD ^[1]
The MDS criteria for PD even list "diagnosis of probable behavioral variant frontotemporal dementia or primary progressive aphasia within 5 years of disease" as an absolute exclusion criterion for PD ^[11] — this highlights how FTD-spectrum motor syndromes must be differentiated from idiopathic PD

Feature	CBD	PSP	bvFTD
Motor features	Asymmetric, alien limb, apraxia, myoclonus	Early falls, vertical gaze palsy	Late or absent
Cognitive	Executive dysfunction, aphasia	Subcortical pattern	Behavioural/personality dominant
Imaging	Asymmetric frontoparietal atrophy	Hummingbird sign (midbrain atrophy) ^[11]	Bilateral frontal + anterior temporal atrophy

Slow-growing mass lesions, e.g. brain tumour ^[1]^[2]

Frontal meningiomas, gliomas, or lymphomas can present insidiously with personality change, apathy, disinhibition, and executive dysfunction — mimicking bvFTD perfectly
Key differentiators: headache, papilloedema, focal neurological deficits, seizures; MRI will show a mass lesion with surrounding oedema rather than atrophy
This is a critical "don't-miss" diagnosis because it may be treatable

Classic triad: wet (urinary incontinence), wobbly (gait apraxia), wacky (dementia — often frontal-subcortical type with apathy and executive dysfunction)
Why it mimics bvFTD: apathy, executive dysfunction, personality change
How to differentiate: gait disturbance and incontinence are EARLY (in FTD these are late); MRI shows ventriculomegaly out of proportion to cortical atrophy; CSF tap test improves gait
Treatable with ventriculoperitoneal shunt

TB meningitis may present as dementia-like: slowly progressive dementia over months characterized by personality change, social withdrawal, loss of libido, memory deficits ^[12]

In Hong Kong, TB remains relevant. A subacute dementia-like presentation with personality change in a younger patient should prompt consideration of TBM
Differentiators: fever, meningism, cranial nerve palsies, CSF findings (lymphocytic pleocytosis, elevated protein, low glucose)

Alcohol and the Brain: From Psychiatric to Neuropsychiatric Perspectives ^[4]

Chronic alcohol use causes frontal lobe atrophy and can produce apathy, disinhibition, executive dysfunction, and personality change — an FTD phenocopy
Key differentiators: clear alcohol history, peripheral neuropathy, cerebellar ataxia, Wernicke-Korsakoff features, hepatic stigmata; MRI shows diffuse (not selective frontotemporal) atrophy, mammillary body shrinkage

Cerebrovascular disease and slow-growing mass lesions, e.g. brain tumour ^[1]^[2]

Condition	Why It Mimics PPA	How to Differentiate
Stroke / vascular aphasia	Sudden or stepwise language decline (Broca's, Wernicke's, global aphasia)	Stroke: acute onset, vascular risk factors, MRI/CT shows infarct. PPA: insidious progressive onset over months–years
Vascular cognitive impairment/dementia ^[13]	Stepwise cognitive decline with aphasia if strategic infarcts affect language areas	Requires neuroimaging evidence of CeVD; supportive features include mood disturbance, personality change, apathy ^[13]. FTD lacks infarcts/white matter changes
Brain tumour (left frontotemporal)	Slowly progressive aphasia	Mass lesion, perilesional oedema, possible seizures on MRI
Creutzfeldt-Jakob disease (CJD)	Rapidly progressive dementia, may present with aphasia	Much faster course (weeks to months vs years), myoclonus, characteristic DWI/FLAIR changes on MRI, 14-3-3 protein in CSF
Logopenic variant PPA (AD pathology)	Progressive word-finding difficulty and impaired repetition	Underlying AD pathology (amyloid-positive), posterior temporal/parietal atrophy rather than anterior temporal/frontal

Acute onset and fluctuating course of symptoms is the hallmark of delirium rather than dementia ^[14]^[15]. In any patient with known or suspected FTD who acutely deteriorates, always exclude delirium from intercurrent illness (UTI, pneumonia, medications, metabolic derangement). Delirium is characterised by:

Acute onset (hours to days)
Fluctuating level of consciousness
Inattention
Disorganised thinking

This contrasts with FTD's insidious, progressive course over years.

GC High Yield — Delirium vs Dementia

Acute onset and fluctuating course of symptoms distinguishes delirium from dementia exacerbation ^[14]. This was tested in the GC/AOS Geriatrics material and is a favourite exam question.

Differential	Key Distinguishing Features from FTD
Depression	Subjective sadness, guilt, preserved insight, responds to antidepressants
Mania	Episodic (not progressive), grandiosity, pressured speech
OCD	Ego-dystonic compulsions, preserved insight, distressed by symptoms
Late-onset schizophrenia	Auditory hallucinations, systematised delusions, formal thought disorder
Early-onset AD	Memory first, hippocampal/parietal atrophy, amyloid-positive
DLB	Visual hallucinations, fluctuating cognition, RBD, parkinsonism, visuospatial impairment, antipsychotic sensitivity
Huntington's disease	Chorea, autosomal dominant FHx, caudate atrophy
Neurosyphilis (general paresis)	Positive syphilis serology, treatable
CBD / PSP	Asymmetric motor signs (CBD), vertical gaze palsy (PSP), poor levodopa response
Frontal brain tumour	Mass lesion on MRI, seizures, papilloedema
NPH	Gait apraxia + incontinence EARLY, ventriculomegaly, treatable
Vascular dementia	Stepwise decline, vascular risk factors, infarcts/WMH on MRI
CJD	Rapidly progressive (weeks–months), myoclonus, DWI changes
TBM (dementia-like)	Fever, meningism, CN palsies, CSF abnormalities
Alcohol-related	Clear alcohol history, cerebellar/peripheral signs, mammillary body atrophy
Delirium	Acute onset, fluctuating consciousness, inattention, reversible cause

The practical bedside approach:

Timeline: Insidious and progressive? → Neurodegenerative (FTD, AD, DLB, HD). Acute? → Delirium, stroke. Stepwise? → Vascular. Rapid (weeks)? → CJD, autoimmune.
Age: < 65 → FTD, HD, early-onset AD, Wilson's disease. > 65 → AD, DLB, VaD more common.
Dominant symptom: Behaviour first → bvFTD (or psychiatric mimic). Memory first → AD. Hallucinations/parkinsonism → DLB. Language first → PPA.
Family history: Strong FHx of dementia/psychiatric disease → FTD (40% FHx), HD (AD inheritance), familial AD.
Examination: Primitive reflexes + executive dysfunction + preserved memory → FTD. Parkinsonism → DLB, CBD, PSP. Chorea → HD. Alien limb → CBD. Vertical gaze palsy → PSP.
Investigations: MRI pattern of atrophy, SPECT/PET perfusion, amyloid PET, CSF biomarkers, genetic testing, syphilis serology, HIV serology, TFTs, B12/folate, metabolic screen.

Different types of dementia typically present with different patterns of perfusion changes ^[3]:

AD: bilateral posterior temporal + parietal hypoperfusion

FTD: bilateral frontal + temporal hypoperfusion

High Yield Summary — DDx of FTD

bvFTD DDx (from lecture slides): psychiatric disorders (depression), DLB, early-onset AD, cerebrovascular disease, slow-growing mass lesions
PPA DDx (from lecture slides): cerebrovascular disease, slow-growing mass lesions
Most commonly confused with: psychiatric disorders (~50% misdiagnosed initially) — depression, mania, OCD, schizophrenia
Must-not-miss treatable mimics: brain tumour, NPH, neurosyphilis, TBM
Key differentiators from AD: behaviour first (not memory), frontal atrophy (not hippocampal), younger onset
Key differentiators from DLB: no visual hallucinations, no fluctuating cognition, no RBD, no early parkinsonism, no visuospatial impairment
Motor overlap (FTD spectrum): MND, CBD, PSP — shared tau/TDP-43 pathology
Always exclude delirium in acute deterioration — hallmark is acute onset and fluctuating consciousness
Imaging patterns: FTD = frontal + temporal; AD = posterior temporal + parietal; DLB = preserved medial temporal, reduced occipital activity; VaD = infarcts/WMH

Active Recall - DDx of FTD

References

^[1] Senior notes: Ryan Ho Neurology.pdf (Section 5.4.4 Frontotemporal Dementia, p.133) ^[2] Senior notes: Ryan Ho Psychiatry.pdf (Section 4.2.4 Frontotemporal Dementia, p.94) ^[3] Senior notes: Ryan Ho Diagnostic Radiology.pdf (Section 8a Cerebral Perfusion Study, p.69) ^[4] Lecture slides: GC 161. Alcohol and the Brain From Psychiatric to Neuropsychiatric Perspectives.pdf ^[5] Lecture slides: Seminar 4 - Assessment for Psychogeriatrics - Dr CPW Cheng.pdf (Slide: Posture and Movement) ^[6] Senior notes: Ryan Ho Neurology.pdf (Section on Alzheimer's disease, p.131) ^[7] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf (Table 2-4, Criteria for DLB) ^[8] Senior notes: Maksim Medicine Notes.pdf (DLB section, p.253) ^[9] Senior notes: learning_points_output.txt (Neurology - Two Cases of Movement Disorders) ^[10] Senior notes: Ryan Ho Urogenital.pdf (Neurosyphilis section, p.246) ^[11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Differential diagnosis of PD, p.1298–1306) ^[12] Senior notes: Ryan Ho Respiratory.pdf (TB meningitis, p.79) ^[13] Lecture slides: GC 241. Reference (2) - New vascular neurocognitive disorder criteria JAMA.pdf (VCID criteria) ^[14] AOS material: AOS - Geriatrics.pdf (Delirium vs Dementia question, p.3–4) ^[15] Lecture slides: Seminar 4 - Assessment for Psychogeriatrics - Dr CPW Cheng.pdf (Common diagnosis in PGT)

Diagnostic Criteria, Algorithm & Investigations for Frontotemporal Dementia

1. Diagnostic Criteria

Before diagnosing FTD specifically, you must first establish that the patient meets criteria for dementia (now termed "major neurocognitive disorder" in DSM-5). This is the gateway.

DSM-5 criteria for major neurocognitive disorder (dementia) ^[16]^[17]:

Evidence of decline from a previous level of performance in ≥1 cognitive domains: learning and memory, language, executive function, complex attention, perceptual-motor, social cognition
The cognitive deficits interfere with independence in everyday activities — at minimum, assistance required with complex instrumental activities of daily living (e.g. paying bills, managing medications)
Not fully explained by delirium or other mental disorder

Why does this matter for FTD? Because in bvFTD, memory may be relatively preserved — yet the patient still meets dementia criteria through decline in social cognition and executive function combined with functional impairment (can no longer manage finances, work, or social relationships). The DSM-5's expanded cognitive domain list (including social cognition) was specifically designed to capture syndromes like bvFTD that earlier criteria missed.

Important Distinction

Do NOT equate "dementia" with "memory loss." The DSM-5 requires decline in at least one cognitive domain — it does not need to be memory. FTD patients may score well on MMSE/MoCA recall items but still meet dementia criteria through executive/social cognition deficits and functional impairment.

1.2 Behavioural Variant FTD (bvFTD) — International Consensus Criteria (Rascovsky et al., 2011)

These are the gold-standard diagnostic criteria, still current in 2026. They operate on three levels of diagnostic certainty:

Requires ≥3 of the following 6 core features with progressive deterioration:

#	Feature	Description
A	Behavioural disinhibition	Socially inappropriate behaviour, loss of manners/decorum, impulsive/reckless actions
B	Apathy or inertia	Loss of interest, motivation, initiation of previously rewarding activities
C	Loss of sympathy or empathy	Diminished response to others' needs/feelings, diminished social interest/warmth
D	Perseverative, stereotyped, or compulsive/ritualistic behaviour	Simple repetitive movements, complex compulsive behaviours, stereotypy of speech
E	Hyperorality and dietary changes	Altered food preferences, binge eating, increased consumption of alcohol/cigarettes, oral exploration of inedible objects
F	Neuropsychological profile: executive/generation deficits with relative sparing of memory and visuospatial functions	Poor performance on executive tasks (e.g. letter fluency, set-shifting) but relatively preserved episodic memory and visuospatial skills

The first 5 features (A–E) are behavioural; the 6th (F) is a neuropsychological pattern. You need any 3 of 6.

All of the following:

Meets criteria for possible bvFTD (≥3/6 features)
Significant functional decline (reported by carer or demonstrated on validated scales)
Neuroimaging consistent with bvFTD: frontal and/or anterior temporal atrophy on MRI, OR frontal and/or anterior temporal hypoperfusion/hypometabolism on SPECT/PET

Requires EITHER:

Histopathological evidence of FTLD on biopsy or at post-mortem, OR
Presence of a known pathogenic mutation (e.g. MAPT, GRN, C9ORF72)

GC High Yield — bvFTD Diagnostic Criteria

The 6 core features of bvFTD (disinhibition, apathy, loss of empathy, perseverative/compulsive behaviour, hyperorality, executive deficit with spared memory/visuospatial) are extremely high yield. The criteria require ≥3 of 6 for "possible," plus functional decline AND supporting imaging for "probable."

Hyperorality and stereotyped, utilization or repetitive behaviours may suggest frontotemporal dementia ^[5] — this GC Psychogeriatrics point maps directly onto criteria D and E.

1.3 Primary Progressive Aphasia (PPA) — Gorno-Tempini Classification (2011)

All three must be present:

Most prominent clinical feature is difficulty with language
Language deficits are the principal cause of impaired daily living activities
Language deficit should be the most prominent deficit at symptom onset and for the initial phases of the disease

Variant	Core Features Required	Supporting Features
Non-fluent / Agrammatic (nfvPPA)	At least ONE of: (1) Agrammatism in language production, (2) Effortful, halting speech with inconsistent speech sound errors (apraxia of speech)	Impaired comprehension of syntactically complex sentences; spared single-word comprehension; spared object knowledge
Semantic (svPPA)	BOTH: (1) Impaired confrontation naming, (2) Impaired single-word comprehension	Loss of object/concept knowledge (especially for low-frequency/low-familiarity items); surface dyslexia or dysgraphia; spared repetition; spared speech production (grammar and motor speech)
Logopenic (lvPPA)	BOTH: (1) Impaired single-word retrieval in spontaneous speech and naming, (2) Impaired repetition of sentences and phrases	Phonological errors in speech; spared single-word comprehension and object knowledge; spared motor speech; absence of agrammatism

nfvPPA: left posterior frontoinsular atrophy/hypoperfusion
svPPA: left anterior temporal atrophy ("knife-blade" atrophy) / hypoperfusion
lvPPA: left posterior perisylvian / temporoparietal atrophy / hypoperfusion

Clinical diagnosis + histopathological evidence of FTLD (nfvPPA, svPPA) or AD pathology (lvPPA), OR known pathogenic mutation.

The DSM-5 also provides its own criteria, which are broader and less operationalised than the research consensus criteria above:

Criteria for major or mild neurocognitive disorder are met
Insidious onset and gradual progression
Either behavioural variant (≥3 of: disinhibition, apathy/inertia, loss of empathy, perseverative/stereotyped/compulsive behaviour, hyperorality/dietary changes) OR language variant (prominent decline in language ability)
Relative sparing of learning and memory and perceptual-motor function
Not better explained by cerebrovascular disease, another neurodegenerative disease, substance effects, or another disorder
Probable if either evidence of a causative FTLD genetic mutation (from family history or genetic testing), or disproportionate frontal and/or temporal lobe involvement on neuroimaging. Otherwise classified as "possible."

3. Investigations

The approach to investigating suspected FTD serves three purposes:

Exclude reversible/treatable mimics (the "dementia screen")
Support the diagnosis of FTD (neuroimaging, neuropsychological testing)
Determine the aetiology (genetic testing, CSF biomarkers)

Every patient with suspected dementia must have a standard workup to exclude treatable causes. 10–15% of dementia can be reversed ^[16].

Investigation	What You're Excluding	Key Findings
CBC	Anaemia (B12/folate deficiency), infection	Macrocytic anaemia → B12/folate deficiency
RFT (U&E, creatinine)	Uraemic encephalopathy, electrolyte disturbance	Elevated urea/creatinine
LFT	Hepatic encephalopathy	Elevated ammonia, deranged LFT
TFTs	Hypothyroidism (reversible cognitive decline)	Elevated TSH, low fT4
Serum B12 and folate	Nutritional deficiency	Low B12 → subacute combined degeneration, cognitive decline
Glucose / HbA1c	Hypoglycaemia, uncontrolled DM	Hypoglycaemia can mimic cognitive impairment
Calcium	Hyper/hypocalcaemia	Hypercalcaemia → confusion, cognitive decline
Syphilis serology	General paresis (neurosyphilis) ^[10]	Positive EIA-syphilis/VDRL
HIV serology	HIV-associated neurocognitive disorder	Positive HIV test
ESR / CRP	Vasculitis, chronic infection, inflammatory conditions	Elevated inflammatory markers
Urinalysis	UTI (common precipitant of delirium superimposed on dementia)	Leukocytes, nitrites

Exam Pearl

The mnemonic "DEMENTIA" for reversible causes: Drugs, Emotional (depression), Metabolic (thyroid, B12, folate, calcium), Eyes/Ears (sensory deprivation), Normal pressure hydrocephalus, Tumour/Trauma (SDH), Infection (syphilis, HIV, TBM), Alcohol. These must be excluded before diagnosing a neurodegenerative cause.

Tool	What It Tests	FTD-Specific Findings	Limitations
MMSE (Mini-Mental State Exam)	Orientation, registration, recall, attention, language, visuospatial	May be deceptively normal in early bvFTD (tests memory and orientation heavily, NOT executive function)	Not sensitive for frontal dysfunction
MoCA (Montreal Cognitive Assessment)	Includes executive function (Trail Making, verbal fluency, abstraction) in addition to memory, language, visuospatial	Preferred over MMSE ^[6] — better at detecting executive dysfunction. bvFTD: poor verbal fluency, poor Trail Making, preserved delayed recall	Still may miss subtle social cognition deficits
Frontal Assessment Battery (FAB)	6 subtests targeting frontal lobe function: similarities (abstraction), lexical fluency, motor series (Luria), conflicting instructions, go-no-go, prehension behaviour	Poor scores in bvFTD; specifically tests frontal circuits	Ceiling effect in mild cases
Addenbrooke's Cognitive Examination (ACE-III)	Comprehensive: attention, memory, fluency, language, visuospatial	Generates subscores — FTD shows disproportionate fluency/language deficit relative to memory/visuospatial. The VLOM ratio (Verbal fluency + Language vs Orientation + Memory) helps discriminate FTD from AD	Takes longer (~20 min)
Formal neuropsychological battery	Detailed assessment of all cognitive domains, including executive function, social cognition, theory of mind	Gold standard for characterising the cognitive profile. Includes Wisconsin Card Sorting Test, Stroop, Trail Making B, Iowa Gambling Task, emotion recognition tasks	Time-consuming, requires trained neuropsychologist

Why might a bvFTD patient score 28/30 on MMSE yet be profoundly impaired? Because the MMSE is heavily weighted towards memory and orientation (medial temporal/parietal functions) and barely tests executive function or social cognition (frontal functions). A patient with severe frontal dysfunction can "pass" the MMSE while being completely unable to function in daily life. This is why MoCA is preferred — it includes executive subtests.

MRI is the primary imaging modality for supporting FTD diagnosis. The patterns of atrophy are characteristic and help differentiate FTD subtypes from each other and from other dementias.

FTD Subtype	MRI Atrophy Pattern	Interpretation
bvFTD	Focal atrophy in orbitofrontal, medial frontal, anterior cingulate, anterior insula cortices and amygdala ^[1]^[2]	Bilateral (may be asymmetric); frontal predominance. Atrophy correlates with behavioural features: orbitofrontal = disinhibition, medial frontal/cingulate = apathy
svPPA	Asymmetric frontotemporal "knife-blade" atrophy affecting the left ^[2] — especially left anterior temporal pole	Severe temporal pole atrophy with widened sylvian fissure; left > right. Right temporal involvement → prosopagnosia
nfvPPA	Left posterior inferior frontal (Broca's area) and anterior insula atrophy	Asymmetric; left-lateralised
lvPPA	Left posterior temporal / temporoparietal junction atrophy	Pattern more consistent with AD than FTLD
FTD-MND	Frontal atrophy + upper motor neuron tract signal changes on FLAIR/T2	Corticospinal tract hyperintensity

Comparison with other dementias on MRI:

Dementia Type	Characteristic MRI Finding
AD	Bilateral perihippocampal atrophy ^[6] (medial temporal lobe atrophy on coronal MRI), later generalised cortical atrophy
DLB	Relative preservation of medial temporal lobe structures ^[7]; relatively preserved cortical volume
VaD	Multiple cortical/subcortical infarcts, extensive white matter hyperintensities, lacunes
NPH	Ventriculomegaly out of proportion to cortical atrophy (Evans index > 0.3), periventricular FLAIR changes
CJD	Cortical ribboning on DWI; caudate and putamen hyperintensity

CT brain can be used to rule out structural causes (tumour, SDH, NPH, calcification) ^[8] but is inferior to MRI for detecting selective cortical atrophy patterns. MRI is strongly preferred.

Early MRI in bvFTD May Be Normal

In the earliest stages of bvFTD, structural MRI may show minimal or no atrophy. This does NOT rule out FTD. Serial imaging (repeat MRI in 12 months) may show progressive atrophy. Functional imaging (SPECT/PET) may detect abnormalities before structural changes are apparent.

3.4 Functional Neuroimaging — SPECT and PET

Clinical indication: aid diagnosis of dementia ^[3]

Radiopharmaceutical used: 99mTc-HMPAO ^[3] (hexamethylpropyleneamine oxime — a lipophilic tracer that crosses the blood-brain barrier and distributes proportionally to cerebral blood flow)

Different types of dementia typically present with different patterns of perfusion changes. Visualization of hypoperfusion to specific areas indicates brain degeneration in those areas ^[3]:

Dementia	SPECT Perfusion Pattern
AD	Bilateral posterior temporal + parietal hypoperfusion ^[3]
FTD	Bilateral frontal + temporal hypoperfusion ^[3]
DLB	Posterior cortical hypoperfusion with occipital involvement (unlike AD)

Why does hypoperfusion indicate degeneration? Because neuronal loss → reduced metabolic demand → reduced blood flow to that region. The perfusion pattern mirrors the pattern of neurodegeneration.

Measures regional glucose metabolism (a surrogate for neuronal activity)
More sensitive and specific than SPECT
FTD: frontal and anterior temporal hypometabolism
AD: posterior temporoparietal and posterior cingulate hypometabolism
DLB: reduced occipital activity and posterior cingulate island sign ^[7] — the posterior cingulate is relatively spared in DLB compared to AD (the "cingulate island sign" helps differentiate DLB from AD)

Uses tracers like ¹¹C-PiB or ¹⁸F-florbetapir to detect amyloid-β plaques in vivo
FTD: amyloid-NEGATIVE (no amyloid plaques — this is FTLD, not AD)
AD: amyloid-POSITIVE
Critical role: Amyloid PET is the definitive way to differentiate FTD from early-onset AD when clinical/structural imaging is ambiguous. A negative amyloid PET effectively rules out AD as the cause.
Exception: lvPPA is amyloid-positive (because it is pathologically AD)

Emerging modality using tracers that bind to tau aggregates (e.g. ¹⁸F-flortaucipir)
Can demonstrate tau deposition in FTD subtypes with tau pathology (FTLD-tau)
Current generation tracers have limitations in detecting non-AD tauopathies; next-generation tracers are under development

Dopamine transporter imaging is most helpful in distinguishing DLB from Alzheimer disease ^[7]
Reduced dopamine transporter uptake in basal ganglia → supports DLB (or PD/CBD/PSP)
Normal in pure FTD and AD
Useful when differentiating bvFTD (normal DaTscan) from DLB (abnormal DaTscan)

Biomarker	AD	FTD	Interpretation
Aβ42	↓ (sequestered in plaques)	Normal	Low Aβ42 supports AD, normal Aβ42 argues against AD (supports FTD)
Total tau (t-tau)	↑	Variable (may be ↑ in FTLD-tau)	Non-specific marker of neurodegeneration
Phospho-tau (p-tau181/217)	↑ (specific for AD)	Normal	Elevated p-tau is highly specific for AD pathology — normal p-tau in the context of dementia supports a non-AD cause like FTD
Neurofilament light chain (NfL)	Mildly ↑	Markedly ↑ (especially FTD-MND)	Non-specific marker of axonal damage; very high levels in FTD, especially with MND overlap. Useful for tracking disease progression.
α-synuclein SAA	Negative	Negative	Positive in DLB/PD — helps exclude synucleinopathy
14-3-3 protein	Negative	Negative	Positive in CJD

Practical use: CSF biomarkers are most useful for ruling OUT AD. If Aβ42 is normal and p-tau is normal in a patient with frontotemporal-type symptoms, the diagnosis of FTD is strongly supported.

The Alzheimer's Association Clinical Practice Guideline on blood-based biomarkers ^[18] has established guidance for the use of plasma biomarkers in specialised care:

Plasma p-tau217: Most promising blood biomarker for AD pathology. High accuracy for detecting amyloid and tau positivity.
Plasma Aβ42/40 ratio: Low ratio suggests amyloid positivity (AD).
Plasma NfL: Elevated in neurodegeneration generally; very high in FTD (especially FTD-MND).
Plasma GFAP: Elevated in AD and neuroinflammation.

For FTD specifically: Blood-based biomarkers are currently most useful as a screen to exclude AD (normal plasma p-tau217 and normal Aβ42/40 ratio argues against AD). There is no FTD-specific blood biomarker in routine clinical use yet, though plasma NfL correlates with disease severity and progression in FTD.

Exam Pearl — Biomarker Logic

Think of biomarkers in terms of what they EXCLUDE, not just what they confirm:

Normal CSF Aβ42 + normal p-tau → rules out AD → supports FTD
Negative amyloid PET → rules out AD → supports FTD
Normal DaTscan → rules out DLB → supports FTD or AD
Positive α-synuclein SAA → rules in synucleinopathy → supports DLB, not FTD

When to Test	What to Test	Interpretation
Strong family history (≥1 first-degree relative with dementia or MND)	C9ORF72, MAPT, GRN ^[1]^[2]	Positive mutation → definite FTD diagnosis; enables family counselling and predictive testing
Young onset ( < 50 years) even without clear FHx	C9ORF72 (most common genetic cause), MAPT, GRN	C9ORF72 repeat expansions can arise de novo or have low penetrance → family history may be absent
FTD-MND phenotype	C9ORF72 (most common cause of familial FTD-MND and familial ALS)	Important for prognosis and genetic counselling
Atypical features (psychosis in bvFTD)	C9ORF72 (associated with psychiatric features, including hallucinations and delusions)	May explain phenotypic overlap with schizophrenia

Genetic counselling MUST be offered before and after testing. Pre-symptomatic testing in family members raises significant ethical and psychological issues.

Generally normal or shows only mild non-specific changes in early FTD
This contrasts with:
- DLB: posterior slow-wave activity with periodic fluctuations ^[7]
- CJD: periodic sharp wave complexes
EEG is therefore more useful for excluding DLB and CJD than for confirming FTD

Investigation	Indication	Expected Finding in FTD
EMG / Nerve conduction studies	Suspected FTD-MND overlap (fasciculations, wasting, UMN signs)	Evidence of widespread denervation (consistent with MND)
Polysomnography	Suspected DLB overlap (dream-enacting behaviour)	Normal in FTD; REM sleep without atonia confirms RBD in DLB ^[7]
MIBG myocardial scintigraphy	Differentiating DLB from FTD	Low uptake in DLB ^[7] (postganglionic sympathetic denervation); normal in FTD

Investigation Category	Modality	Primary Role in FTD Workup
Exclude reversible causes	Bloods (CBC, RFT, LFT, TFTs, B12, folate, Ca, glucose, syphilis, HIV)	Rule out treatable mimics
Cognitive assessment	MoCA, ACE-III, FAB, formal neuropsychology	Characterise cognitive profile; demonstrate executive > memory deficit
Structural imaging	MRI brain (T1, T2, FLAIR, coronal through temporal lobes)	Demonstrate frontal/temporal atrophy pattern; exclude tumour, NPH, infarcts
Functional imaging	SPECT (99mTc-HMPAO) or FDG-PET	Demonstrate frontal/temporal hypoperfusion/hypometabolism
Amyloid imaging	Amyloid PET	Rule out AD (FTD = amyloid-negative)
CSF biomarkers	Aβ42, p-tau, NfL	Rule out AD (normal Aβ42/p-tau); NfL for severity
Blood biomarkers	Plasma p-tau217, NfL	Emerging screen to exclude AD
Genetic testing	C9ORF72, MAPT, GRN	Confirm genetic cause; family counselling
Electrophysiology	EEG	Exclude DLB, CJD
Motor assessment	EMG/NCS	Detect MND overlap

High Yield Summary — Diagnosis of FTD

bvFTD diagnostic criteria (Rascovsky 2011): ≥3 of 6 core features (disinhibition, apathy, loss of empathy, perseverative/compulsive behaviour, hyperorality, executive deficit with spared memory) for POSSIBLE; + functional decline + supporting neuroimaging for PROBABLE; + pathology or known mutation for DEFINITE
PPA diagnostic criteria (Gorno-Tempini 2011): Progressive language difficulty as the principal deficit → classify into nfvPPA, svPPA, or lvPPA by fluency, comprehension, repetition, and naming patterns
MRI pattern: Frontal + anterior temporal atrophy (bvFTD); left anterior temporal "knife-blade" atrophy (svPPA); left posterior frontoinsular (nfvPPA)
SPECT/PET: Bilateral frontal + temporal hypoperfusion/hypometabolism (vs posterior temporal + parietal in AD)
Amyloid PET negative = rules out AD, supports FTD
CSF: Normal Aβ42 and p-tau (unlike AD); high NfL (especially FTD-MND)
Cognitive testing: MoCA preferred over MMSE — better at detecting executive dysfunction
Genetic testing: C9ORF72, MAPT, GRN in familial cases, young onset, or FTD-MND
Always exclude reversible causes first — 10–15% of dementia is treatable

Active Recall - FTD Diagnosis & Investigations

References

^[1] Senior notes: Ryan Ho Neurology.pdf (Section 5.4.4 Frontotemporal Dementia, p.133) ^[2] Senior notes: Ryan Ho Psychiatry.pdf (Section 4.2.4 Frontotemporal Dementia, p.94) ^[3] Senior notes: Ryan Ho Diagnostic Radiology.pdf (Section 8a Cerebral Perfusion Study, p.69) ^[5] Lecture slides: Seminar 4 - Assessment for Psychogeriatrics - Dr CPW Cheng.pdf (Slide: Posture and Movement) ^[6] Senior notes: Ryan Ho Neurology.pdf (Section 5.4.1 Approach to Dementia, p.128; Section on Alzheimer's disease, p.131) ^[7] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf (Tables 2-2, 2-4; Diagnostic criteria for DLB) ^[8] Senior notes: Maksim Medicine Notes.pdf (DLB section, p.253) ^[10] Senior notes: Ryan Ho Urogenital.pdf (Neurosyphilis section, p.246) ^[16] Senior notes: Ryan Ho Neurology.pdf (Section 5.4.1 Approach to Dementia, p.128) ^[17] Senior notes: Ryan Ho Psychiatry.pdf (Diagnostic criteria for AD/dementia, p.92) ^[18] Lecture slides: Alzheimers Dementia - Palmqvist - Alzheimer's Association Clinical Practice Guideline on the use of blood-based.pdf

Management of Frontotemporal Dementia

Before we get into specifics, let's establish the hard truths about FTD management:

Management is symptomatic only ^[1]^[2]. There is no disease-modifying therapy for FTD as of 2026. Unlike Alzheimer's disease, where cholinesterase inhibitors and anti-amyloid antibodies (e.g. lecanemab, donanemab) target the underlying pathology, FTD lacks equivalent targeted treatments. This is because:

FTD is pathologically heterogeneous (tau, TDP-43, FUS) — no single molecular target
Cognitive dysfunction: NO available treatment ^[1]^[2] — cholinesterase inhibitors do NOT work (and may worsen behavioural symptoms)
Parkinsonism: generally NOT responsive to dopaminergic agents ^[1]^[2] — because the nigrostriatal pathway is not the primary site of pathology (unlike PD)

Management therefore centres on:

Pharmacological symptom control (behaviour, mood, motor features)
Non-pharmacological interventions (behavioural management, speech therapy, caregiver support)
Advance care planning and end-of-life care
Genetic counselling (for familial cases)

3. Pharmacological Management

3.1 Neurobehavioural Symptoms

This is the primary target of pharmacotherapy in FTD. The behavioural symptoms — disinhibition, agitation, compulsive behaviour, apathy, hyperorality — cause the most distress to carers and are the main reason patients are brought to attention.

Neurobehavioural features: SSRI, trazodone, atypical antipsychotics ^[1]^[2]

Drug	Mechanism of Action	Target Symptoms	Dose Range	Evidence & Rationale
SSRIs (e.g. sertraline, fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine)	Selective serotonin reuptake inhibition → ↑ serotonergic transmission in frontal circuits	Disinhibition, compulsive/repetitive behaviours, hyperorality, irritability, agitation, depressive symptoms	Sertraline 50–200 mg/d; citalopram 10–20 mg/d; fluvoxamine 50–150 mg/d	Best available evidence in FTD. Rationale: serotonergic neurons projecting from the raphe nuclei to the frontal cortex degenerate in FTD → relative serotonin deficit → SSRIs partially compensate. Multiple RCTs and open-label studies show modest benefit for behavioural symptoms.
Trazodone	Serotonin antagonist and reuptake inhibitor (SARI); also antagonises 5-HT₂A receptors and has mild sedative/anxiolytic properties via histamine H₁ blockade	Agitation, irritability, restlessness, sleep disturbance, anxiety, stereotyped behaviours	50–300 mg/d (often given at night due to sedation)	RCT by Lebert et al. showed significant improvement in behavioural symptoms (NPI scores). Particularly useful when agitation and sleep disturbance coexist. The sedative effect can be therapeutically useful for managing hyperactivity but limits daytime dosing.

Why SSRIs work in FTD but NOT cholinesterase inhibitors: In AD, the cholinergic system (nucleus basalis of Meynert → cortex) degenerates, so boosting acetylcholine with AChEIs helps. In FTD, the cholinergic system is relatively preserved but the serotonergic system degenerates. Therefore, SSRIs (which boost serotonin) are effective, while AChEIs offer no benefit and may worsen agitation. This is a fundamental pharmacological distinction driven by the different neurotransmitter deficits in each disease.

Neurobehavioural features: SSRI, trazodone, SGAs (second-generation antipsychotics) ^[2]

Drug	Mechanism	Target Symptoms	Dose Range	Important Considerations
Quetiapine	D₂ and 5-HT₂A antagonism; low D₂ affinity → lower EPS risk	Agitation, aggression, psychosis (if present, especially in C9ORF72 carriers), severe behavioural disturbance not responding to SSRIs	12.5–100 mg/d	Preferred SGA in FTD because of low EPS risk. Use the lowest effective dose.
Olanzapine	D₂ and 5-HT₂A antagonism; also has anticholinergic, antihistaminic effects	Agitation, aggression	2.5–10 mg/d	Higher metabolic side effects (weight gain, hyperglycaemia) — problematic in patients already hyperphagic from FTD
Risperidone	Potent D₂ antagonism + 5-HT₂A antagonism	Agitation, aggression, psychosis	0.25–2 mg/d	Higher EPS risk at higher doses; use cautiously
Aripiprazole	Partial D₂ agonist; 5-HT₁A partial agonist, 5-HT₂A antagonist	Agitation, irritability	2–15 mg/d	Lower metabolic and EPS risk; emerging use

Critical Warning — Antipsychotics in Dementia

All antipsychotics carry a black box warning for increased risk of cerebrovascular events (stroke) and mortality in elderly patients with dementia-related psychosis. This risk applies to both typical and atypical antipsychotics. They should be used:

Only when non-pharmacological measures have failed
At the lowest effective dose for the shortest possible duration
With regular reassessment (every 6–12 weeks) of continued need
With informed consent from patient/substitute decision-maker

Rx for behavioural symptoms: ONLY to agitated patients at risk of harming others or own safety ^[19]. This principle from delirium management applies equally to dementia.

Additionally, patients with DLB have severe sensitivity to antipsychotics ^[7] — always confirm FTD (not DLB) before using antipsychotics. If there is any diagnostic uncertainty, avoid typical antipsychotics entirely and use quetiapine or clozapine at minimal doses.

Drug	Target Symptom	Mechanism	Notes
Oxytocin (intranasal)	Loss of empathy, social cognition deficits	Neuropeptide involved in social bonding and trust; FTD patients have reduced oxytocin receptor expression	Experimental — small RCTs show modest improvement in facial emotion recognition and social cognition, but not yet standard of care
Methylphenidate / dexamfetamine	Apathy, inertia (when severe and distressing)	Dopaminergic/noradrenergic stimulant → ↑ motivation circuitry in prefrontal cortex	Limited evidence; small studies show modest benefit for apathy. Use cautiously — may worsen disinhibition or agitation. Off-label.
Dextromethorphan/quinidine (Nuedexta)	Pseudobulbar affect (inappropriate crying/laughing)	NMDA antagonist + sigma-1 agonist (dextromethorphan); quinidine inhibits CYP2D6 metabolism to maintain drug levels	FDA-approved for pseudobulbar affect; can occur in FTD-MND overlap. Quinidine component requires cardiac monitoring (QT prolongation risk).
Topiramate / valproate	Hyperorality, binge eating, weight gain	Anticonvulsants with appetite-suppressing properties	Limited evidence; topiramate may reduce carbohydrate craving. Valproate use declining due to hepatotoxicity, teratogenicity, and limited evidence.
Melatonin	Sleep-wake disturbance	Physiological sleep hormone; regulates circadian rhythm	Safe, well-tolerated; useful for reversal of sleep-wake cycle common in FTD

Cognitive dysfunction: NO available treatment ^[1]^[2]

This is perhaps the most important management point to emphasise:

Drug Class	Evidence in FTD	Explanation
Cholinesterase inhibitors (donepezil, rivastigmine, galantamine)	NOT effective; may WORSEN symptoms	The cholinergic system is relatively preserved in FTD (unlike AD). AChEIs increase cholinergic tone without addressing the true deficit (serotonergic/glutamatergic). They may paradoxically worsen agitation and disinhibition. AChEIs are contraindicated in FTD.
Memantine (NMDA receptor antagonist)	No proven benefit	Small RCTs showed no improvement in cognition or behaviour; one study suggested possible worsening. Not routinely recommended.

GC High Yield — Do NOT Use AChEIs in FTD

This is a classic exam trap: a patient with early-onset dementia and personality change is started on donepezil and gets WORSE. The clue is the clinical profile (behavioural change first, preserved memory) which should have prompted FTD diagnosis, not AD. AChEIs are specific to AD (cholinergic deficit) and are harmful in FTD. Always match the treatment to the correct dementia subtype.

3.3 Motor Symptoms

Parkinsonism: generally NOT responsive to dopaminergic agents ^[1]^[2]

Scenario	Approach	Rationale
FTD with parkinsonism (CBD/PSP overlap)	Trial of levodopa (e.g. levodopa-carbidopa 100/25 mg TDS, uptitrate) — but expect poor or no response	In CBD/PSP, the postsynaptic dopamine receptors in the striatum are damaged (unlike PD where presynaptic terminals are lost but receptors are intact). Levodopa works by replacing dopamine at intact receptors — if the receptors themselves are gone, the drug cannot work.
If partial response	Continue levodopa at lowest effective dose	A minority of patients show mild transient improvement
Non-responsive	Discontinue levodopa; focus on physiotherapy, fall prevention, mobility aids	No point continuing an ineffective drug

FTD may be associated with motor neurone disease: associated with bvFTD ^[1]

Management of the MND component follows standard MND/ALS guidelines:

Riluzole 50 mg BD — the only drug shown to modestly extend survival in ALS (~2–3 months). MoA: inhibits glutamate release → reduces excitotoxicity
Multidisciplinary team (MDT): neurologist, respiratory physician, dietitian, speech therapist, physiotherapist, occupational therapist, palliative care
Non-invasive ventilation (NIV): for respiratory muscle weakness (diaphragmatic weakness). Improves survival and quality of life. Indicated when FVC < 50% predicted or orthopnoea develops
PEG/RIG feeding tube: for dysphagia and nutritional failure (see section on advance care planning)
Communication aids: eye-gaze technology, communication boards when speech fails

FTD-MND has the worst prognosis of all FTD subtypes — mean survival ~3 years from onset. Early palliative care involvement is essential.

4. Non-Pharmacological Management

Non-pharmacological strategies are the backbone of FTD management and are often more effective than drugs for behavioural symptoms.

Strategy	Rationale	Examples
Structured daily routine	FTD patients lack executive function to plan and adapt → a predictable routine reduces confusion, anxiety, and behavioural outbursts	Fixed mealtimes, activity schedule, consistent sleep-wake times
Environmental modification	Reduce overstimulation and remove triggers for inappropriate behaviour	Simplify the home environment; remove access to car keys (unsafe driving), credit cards (impulsive spending), alcohol; secure the home (wandering risk)
Distraction and redirection	Direct confrontation of inappropriate behaviour is counterproductive (the patient lacks insight and will not understand why their behaviour is wrong)	When disinhibited behaviour occurs, calmly redirect to another activity rather than arguing or correcting
Positive reinforcement	Reward appropriate behaviour rather than punishing inappropriate behaviour	Verbal praise, preferred activities
Manage hyperorality	Control excessive/inappropriate eating	Portion control, lock food cupboards, provide healthy snacks at scheduled times, reduce access to sweets

PPA Variant	Therapeutic Approach
nfvPPA	Script training (practising functional phrases), articulatory exercises, augmentative and alternative communication (AAC) devices as speech deteriorates
svPPA	Word relearning programmes (errorless learning for high-frequency personally relevant words), use of semantic feature analysis, communication partner training
lvPPA	Phonological therapy, word-finding strategies, circumlocution training
All variants (late stage)	Communication boards, picture-based systems, electronic speech-generating devices, gesture-based communication

Physiotherapy: Maintain mobility, prevent falls (especially in CBD/PSP overlap), gait training, balance exercises
Occupational therapy: ADL adaptation, home safety assessment, cognitive aids (visual cues, labels), assistive devices

This is arguably the most important non-pharmacological intervention. FTD imposes an enormous burden on carers because:

Patients are often young (spouse may be working; children may be in school)
Behavioural symptoms are socially embarrassing and exhausting
Loss of empathy means patients cannot appreciate the carer's distress
The long disease course (8–10 years) leads to carer burnout

Intervention	Details
Psychoeducation	Explain the diagnosis, prognosis, and that behavioural changes are due to brain disease — not willful rudeness. This reduces carer guilt and frustration.
Carer support groups	Connect with FTD-specific support organisations (e.g. Hong Kong Alzheimer's Disease Association, Jockey Club Centre for Positive Ageing)
Respite care	Day care centres, short-term residential respite to prevent carer burnout
Legal and financial planning	Early involvement of social workers; power of attorney, enduring power of attorney (EPA), financial planning while patient can still participate in decision-making
Psychological support for carers	Screening for carer depression and anxiety; referral for counselling

5. Advance Care Planning & End-of-Life Issues

FTD inevitably progresses to a state of complete dependence. Advance care planning should begin early — while the patient retains sufficient capacity to participate.

Decision	Considerations
Enduring Power of Attorney (EPA)	Must be arranged EARLY while the patient has mental capacity. In Hong Kong, under the Enduring Powers of Attorney Ordinance (Cap. 501), the donor must understand the nature and effect of the EPA. Once capacity is lost, it is too late.
Advance directives	Document the patient's wishes regarding life-sustaining treatment, resuscitation, mechanical ventilation, and tube feeding
Feeding decisions	As FTD progresses, swallowing difficulties and aspiration risk increase. The decision of whether to insert a PEG/nasogastric tube is a major ethical and practical question (see below)
Place of care	Home vs residential care facility vs hospice — depends on disease stage, carer capacity, and available community support

GC/AOS High Yield — Decisions About Feeding Tubes in Advanced Dementia

In advanced dementia, artificial nutrition (PEG tubes) has NOT been shown to prolong survival, prevent aspiration pneumonia, reduce pressure ulcers, or improve quality of life ^[20]. In contrast, careful hand-feeding offers comfort, social interaction, and dignity.

Key points:

The goals of eating in advanced dementia shift from nutrition to comfort and pleasure
Aspiration is common regardless of feeding method (PEG does not prevent aspiration — reflux of tube feeds still occurs)
PEG tubes may cause complications: local infection, tube dislodgement, agitation leading to restraint
Careful hand-feeding is generally preferred as a comfort measure
The exception is FTD-MND where dysphagia may develop earlier and PEG/RIG placement may be discussed in the context of ALS guidelines (inserted while FVC is still adequate)

This is distinct from early/moderate FTD where eating is preserved and the issue is hyperorality rather than dysphagia.

For patients with end-stage frailty, the most appropriate management often involves palliative care — prioritizing symptom control, comfort, dignity, and respecting the patient's and family's wishes ^[21].

Symptom	Palliative Approach
Agitation/restlessness	Low-dose SGA (quetiapine), benzodiazepines (midazolam SC for terminal agitation), trazodone
Pain	Assess for non-verbal pain cues (facial grimacing, guarding); paracetamol regular, opioids if needed
Respiratory secretions	Hyoscine hydrobromide or glycopyrrolate
Dyspnoea	Fan, positioning, low-dose morphine
Existential/spiritual distress	Chaplaincy, psychological support for family

Therapy	Target	Status (2026)
Anti-tau immunotherapy (e.g. semorinemab, tilavonemab)	FTLD-tau (MAPT mutations, Pick's disease)	Phase II/III trials — results mixed; some showed target engagement but no clinical benefit. Active area of research.
Antisense oligonucleotides (ASOs) for C9ORF72	Reduce toxic repeat RNA in C9ORF72 FTD/ALS	Phase I/II trials ongoing. Promising in preclinical models. Delivered intrathecally.
Progranulin-boosting therapies for GRN mutations	Restore progranulin levels (gene therapy, anti-sortilin antibodies like latozinemab, small molecules)	Phase II/III trials underway. Latozinemab (anti-sortilin antibody) blocks progranulin degradation → raises progranulin levels. Most advanced approach for genetic FTD.
Gene therapy (AAV-mediated GRN delivery)	Direct replacement of progranulin in GRN mutation carriers	Early phase trials
HDAC inhibitors	Epigenetic modulation of gene expression in FTD	Preclinical

Why is genetic FTD a particularly attractive target for drug development? Because you have a defined molecular target: C9ORF72 repeat → reduce toxic RNA; GRN haploinsufficiency → increase progranulin. This is precision medicine — targeting the upstream cause rather than downstream symptoms. While these therapies are not yet clinically available, they represent the most promising pipeline for future FTD treatment.

Domain	Approach	Key Points
Behavioural symptoms	SSRIs (1st line), trazodone (1st line), atypical antipsychotics (2nd line) ^[1]^[2]	SSRIs target serotonergic deficit. Antipsychotics: lowest dose, shortest duration, regular review. Black box warning for mortality/stroke in elderly with dementia.
Cognitive dysfunction	NO available treatment ^[1]^[2]	AChEIs contraindicated (may worsen). Memantine not effective.
Parkinsonism	Generally NOT responsive to dopaminergic agents ^[1]^[2]	Trial of levodopa; discontinue if no response. Focus on physiotherapy.
FTD-MND motor	Riluzole, NIV, PEG, MDT	Follow ALS guidelines for motor component. Worst prognosis (~3 y).
Language (PPA)	Speech & language therapy, AAC devices	Tailor to variant (nfvPPA vs svPPA vs lvPPA).
Non-pharmacological	Structured routine, environmental modification, carer education, respite	Backbone of management. Often more effective than drugs.
Advance care planning	EPA, advance directives, feeding decisions	Arrange EARLY while capacity exists. Hand-feeding preferred over PEG in advanced dementia.
Palliative care	Symptom control, comfort, dignity	Essential in end-stage disease.
Genetic counselling	C9ORF72, MAPT, GRN testing	For familial/young-onset cases. Pre-test counselling mandatory.

High Yield Summary — FTD Management

Management is symptomatic only — no disease-modifying therapy available
Behavioural symptoms: 1st line = SSRI or trazodone; 2nd line = atypical antipsychotic (quetiapine preferred) at lowest dose
Cognitive dysfunction: NO available treatment — AChEIs are contraindicated (worsen behaviour); memantine not effective
Parkinsonism: generally NOT responsive to dopaminergic agents — trial of levodopa but expect poor response
SSRIs work because FTD has a serotonergic deficit (not cholinergic as in AD)
Antipsychotics: black box warning for stroke/mortality in elderly dementia patients; use only if non-pharmacological measures fail; ALWAYS confirm FTD (not DLB, which has severe antipsychotic sensitivity)
Non-pharmacological: structured routines, environmental modification, speech therapy, caregiver support = backbone of management
Advance care planning: arrange EPA early; hand-feeding preferred over PEG in advanced dementia
FTD-MND: riluzole, NIV, PEG, MDT; worst prognosis (~3 years)
Emerging: anti-tau immunotherapy, ASOs for C9ORF72, progranulin-boosting for GRN mutations — watch this space

Active Recall - FTD Management

References

^[1] Senior notes: Ryan Ho Neurology.pdf (Section 5.4.4 Frontotemporal Dementia, p.133) ^[2] Senior notes: Ryan Ho Psychiatry.pdf (Section 4.2.4 Frontotemporal Dementia, p.94) ^[7] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf (Table 2-4, Criteria for DLB) ^[19] Senior notes: Ryan Ho Neurology.pdf (Section on Delirium Management, p.96); Senior notes: Ryan Ho Fundamentals.pdf (Section on Delirium, p.326) ^[20] Lecture slides: Backgrounder - Decisions about Feeding Tubes in Advanced Dementia.pdf ^[21] AOS material: AOS - Geriatrics.pdf (End-stage frailty and palliative care, p.29)

Complications of Frontotemporal Dementia

FTD complications arise from two interacting processes:

Progressive neurodegeneration → worsening cognitive, behavioural, language, and eventually motor function → functional dependence → immobility → complications of immobility
The specific pattern of frontal/temporal degeneration → unique complications not seen (or seen later) in other dementias — e.g. reckless behaviour leading to legal problems, hyperorality leading to metabolic disease, loss of insight leading to non-compliance and carer burnout

FTD progresses faster than AD; average survival = 8–10 years (shorter for bvFTD) ^[1]^[2]. The complications below are organised by the phase of disease in which they typically dominate.

2. Behavioural and Psychosocial Complications (Early–Mid Stage)

These complications are relatively unique to FTD (particularly bvFTD) and often dominate the early-to-mid disease course, when the patient is still ambulant but increasingly disinhibited and lacking judgment.

Complication	Mechanism (First Principles)	Examples
Criminal behaviour / legal problems	Behavioural disinhibition ^[1]^[2] → loss of orbitofrontal inhibitory control → patients act on impulses without considering consequences. They have lost the neural "brake" on socially unacceptable behaviour.	Shoplifting, public urination, sexual harassment, indecent exposure, traffic violations, trespassing. Patients may be arrested. Courts increasingly recognise FTD as a mitigating factor, but this requires formal medicolegal assessment.
Financial mismanagement	Executive dysfunction (dorsolateral prefrontal) → inability to plan, organise, or evaluate risk; disinhibition → impulsive spending	Squandering savings, giving money to strangers, falling for scams (gullibility from impaired social cognition), gambling. May lead to financial ruin of the family.
Driving risk	Executive dysfunction → poor judgment, impaired decision-making, slow reaction time; disinhibition → reckless driving; apathy → inattentive driving	Traffic accidents, driving licence revocation. Assessment of driving capacity should be performed early; in Hong Kong, a medical fitness certificate is required, and doctors have a duty to advise cessation of driving when unsafe.
Wandering and getting lost	Loss of executive planning and spatial orientation (later stages); compulsive walking behaviour	Risk of exposure, dehydration, injury. May require GPS tracking devices, secure home environment, or residential care.
Self-neglect	Apathy/inertia (medial frontal/anterior cingulate degeneration) → failure to maintain personal hygiene, nutrition, medications, home upkeep	Progressive decline in self-care; may present with malnutrition, dental caries (especially with hyperorality for sweets), skin breakdown

Clinical Pearl — Legal Implications

FTD patients who commit antisocial acts are NOT doing so out of malice — they have lost the neural circuitry for impulse control. It is the clinician's responsibility to document the diagnosis, explain the behavioural basis to families and legal authorities, and arrange protective measures (e.g. supervised access to money, driving cessation). Always document capacity assessments.

Complication	Mechanism	Clinical Consequence
Obesity and metabolic syndrome	Hyperorality and dietary changes ^[1]^[2] → binge eating, carbohydrate craving, compulsive eating of large quantities → excessive caloric intake. Orbitofrontal and insular degeneration disrupts satiety signalling.	Weight gain, type 2 diabetes, dyslipidaemia, cardiovascular disease. Paradoxically, FTD patients may become obese early in the course (unlike AD patients who tend to lose weight).
Dental disease	Hyperorality + preference for sweets + self-neglect (failure to brush teeth)	Severe caries, dental abscesses, tooth loss — may complicate feeding later
Pica and foreign body ingestion	Oral exploration of inedible objects (hyperorality extending to non-food items due to loss of discriminative prefrontal control)	Choking hazard, bowel obstruction, toxicity
Alcohol excess	Increased consumption of alcohol (disinhibition + hyperorality) in patients with pre-existing access	Hepatotoxicity, falls, worsening cognition, interactions with psychotropic medications

Complication	Mechanism	Notes
Depression (in carers AND patients)	Carers: prolonged grief, social isolation, exhaustion. Patients: emerging mood symptoms as disease spreads.	Carer depression rates ~40–50%; higher than in AD carers because of the younger age of patients, loss of emotional reciprocity, and social embarrassment
Psychosis	Especially in C9ORF72 expansion carriers — may develop delusions and hallucinations	May be misdiagnosed as late-onset schizophrenia; treat cautiously with low-dose atypical antipsychotics
Anxiety and agitation	Loss of coping mechanisms; inability to process environmental stimuli appropriately; rigid thinking with inability to adapt to change	Common trigger for antipsychotic use; non-pharmacological strategies should be tried first

3. Motor and Overlap Syndrome Complications (Mid–Late Stage)

FTD may be associated with the following motor syndromes ^[1]^[2]:

Motor neurone disease: associated with bvFTD ^[1]^[2]

Complication	Mechanism	Clinical Significance
Bulbar dysfunction → dysphagia, dysarthria	Upper and lower motor neuron degeneration affecting bulbar muscles (tongue, pharynx, larynx)	Aspiration risk, malnutrition, communication failure. Necessitates early speech therapy, modified diet, consideration of PEG placement.
Respiratory failure	Diaphragmatic and intercostal muscle weakness → reduced FVC → hypoventilation, nocturnal hypoventilation → eventually daytime respiratory failure	Most common cause of death in MND. Managed with non-invasive ventilation (NIV). FVC monitoring essential.
Fasciculations and wasting	Lower motor neuron degeneration → denervation of skeletal muscle	Progressive weakness, falls, inability to perform ADLs

FTD-MND carries the worst prognosis of any FTD subtype — mean survival ~3 years from symptom onset. The combination of cognitive/behavioural impairment AND motor neurone disease creates a uniquely devastating clinical picture where the patient cannot cooperate with interventions (e.g. NIV mask compliance, PEG care) due to cognitive deficits.

Corticobasal degeneration: often frontal-dominant → may present initially as bvFTD or svPPA ^[1] Progressive supranuclear palsy: associated with bvFTD ^[1]

Complication	Mechanism	Clinical Significance
Falls (especially PSP)	Postural instability + axial rigidity + vertical gaze palsy (cannot see where they are stepping) ^[22] → fall backwards	Hip fractures, head injuries, subdural haematoma. Parkinsonism generally NOT responsive to dopaminergic agents ^[1]^[2] → falls not prevented by medication. Physiotherapy and environmental modification essential.
Dysphagia (pseudobulbar palsy in PSP)	Pseudobulbar palsy: dysarthria, dysphagia ^[22] → supranuclear involvement of brainstem swallowing centres	Aspiration pneumonia (see below), malnutrition
Limb apraxia and alien limb (CBD)	Cortical signs: limb apraxia, agnosia, alien limb phenomenon ^[22] → loss of purposeful limb control	Functional dependence, inability to use affected limb, self-injury from uncontrolled limb movements

Complication	PPA Variant Most Affected	Mechanism	Consequence
Complete loss of speech (mutism)	nfvPPA → eventual mutism	Progressive degeneration of speech production networks (Broca's area, insula) → speech becomes increasingly effortful until output ceases entirely	Social isolation, inability to express needs/pain/distress, complete reliance on non-verbal/AAC communication
Loss of semantic knowledge	svPPA	Progressive temporal lobe degeneration → loss of conceptual knowledge → cannot recognise objects, faces, or words	Cannot use household appliances, cannot identify danger (e.g. fire, sharp objects), progressive prosopagnosia (cannot recognise family members' faces)
Behavioural features emerging in PPA	All PPA variants (late)	As neurodegeneration spreads from temporal to frontal lobes, bvFTD-like features emerge	Disinhibition, apathy, compulsive behaviour develop on top of existing language deficits — compound functional disability

As FTD progresses to the advanced stage, patients become bedbound and fully dependent — similar to late-stage AD or any end-stage neurodegenerative disease. The complications mirror those of prolonged immobility.

Complication	Mechanism	Prevention/Management
Aspiration pneumonia	Dysphagia (bulbar involvement in FTD-MND/PSP, or late-stage general decline) → food/secretions enter airway → bacterial pneumonia	Modified diet texture, speech therapy, upright positioning during feeding, careful hand-feeding preferred over PEG in advanced dementia ^[20]. Aspiration pneumonia is the most common cause of death in FTD.
Pressure ulcers (bedsores)	Immobility → sustained pressure over bony prominences → tissue ischaemia → skin breakdown	Regular repositioning (every 2 hours), pressure-relieving mattress, skin inspection, nutritional optimisation, skin/bedsore care ^[19]
Venous thromboembolism (VTE)	Immobility → venous stasis → DVT → PE	Mobilization (↓VTE) ^[19]; TED stockings, pharmacological prophylaxis if hospitalised
Urinary tract infection (UTI)	Incontinence → urinary stasis, catheterisation (if used) → ascending infection	Avoid Foley's catheters ^[19] when possible; prompted voiding, incontinence pads, treat UTI promptly
Contractures	Prolonged immobility → muscle shortening and joint capsule fibrosis	Physiotherapy, passive range-of-motion exercises, splinting
Constipation and faecal impaction	Immobility + reduced fluid intake + medications (anticholinergic side effects of some psychotropics)	Adequate hydration, fibre, laxatives, bowel care protocol
Malnutrition and dehydration	Dysphagia, apathy/inertia (cannot be bothered to eat), inability to self-feed, hyperorality paradoxically resolves as disease progresses to apathy	Dietitian input, modified diet, careful hand-feeding, fluid monitoring
Incontinence	Loss of frontal inhibitory control over bladder (early urge incontinence in bvFTD); later: complete loss of bladder and bowel control due to generalised cortical degeneration	Prompted voiding schedules, incontinence products, skin care

Most Common Cause of Death in FTD

Like most neurodegenerative dementias, the most common causes of death in FTD are:

Aspiration pneumonia — from dysphagia and loss of protective airway reflexes
Respiratory failure — especially in FTD-MND (diaphragmatic weakness)
Inanition / failure to thrive — progressive cachexia, inability to eat adequately
Complications of falls — fractures, head injury (especially in PSP overlap)

Compare with DLB where the most common cause of death was failure to thrive (65%), followed by pneumonia and swallowing difficulties (23%), other medical conditions (19%), and complications from a fall (10%) ^[23]. FTD follows a broadly similar pattern, with respiratory failure being proportionately more prominent in FTD-MND.

Complication	Mechanism	Key Points
Delirium	Reduced cognitive reserve from underlying neurodegeneration → lower threshold for developing delirium from any acute stressor (UTI, pneumonia, constipation, medications, dehydration, pain, hospital admission)	Acute onset and fluctuating course distinguishes delirium from progression of FTD ^[14]. Always look for a treatable precipitant. Search for underlying causes: CBC, L/RFT, electrolytes; MSU, CXR, blood culture; blood glucose/ketones ^[19].

Complication	Cause	Explanation
Worsening of symptoms from AChEIs	Prescribing cholinesterase inhibitors (donepezil, rivastigmine) when FTD is misdiagnosed as AD	Cognitive dysfunction: NO available treatment ^[1]^[2]; AChEIs may worsen agitation and disinhibition in FTD because the cholinergic system is relatively intact
Extrapyramidal side effects from antipsychotics	Using typical antipsychotics or high-dose SGAs	FTD patients (especially those with Parkinson-plus overlap) are susceptible to EPS. Quetiapine preferred for its low D₂ affinity.
Falls from sedation	Over-sedation from trazodone, benzodiazepines, or antipsychotics	Already at fall risk from executive dysfunction; sedating medications compound this. Use lowest effective doses.
Metabolic syndrome from SGAs	Weight gain, hyperglycaemia, dyslipidaemia from olanzapine, quetiapine	Especially problematic in patients already obese from hyperorality
QT prolongation	Citalopram/escitalopram at higher doses; antipsychotics	ECG monitoring recommended, especially in elderly; citalopram max 20 mg/d in patients > 65y

These are often overlooked but are among the most devastating consequences of FTD.

Complication	Mechanism	Impact
Caregiver burnout	Young onset → carer is often a working-age spouse; behavioural symptoms are embarrassing, exhausting, and relentless; loss of empathy means the patient cannot recognise the carer's distress; disease course is long (8–10 years)	Depression (~40–50%), anxiety, social isolation, physical illness, financial hardship
Relationship breakdown	Loss of empathy, emotional blunting, disinhibition (inappropriate sexual behaviour or total loss of intimacy), personality change → the carer "grieves for someone who is still alive"	Anticipatory grief; high rates of marital distress; children of FTD patients are also profoundly affected
Social isolation	Patient's disinhibited behaviour causes embarrassment in public → family withdraws from social activities; stigma of a "psychiatric" diagnosis in a young person	Loss of social support network exactly when it is most needed

Disease Stage	Typical Complications
Early (1–3 years)	Medicolegal issues (shoplifting, driving offences), financial mismanagement, misdiagnosis as psychiatric disorder, carer distress, obesity from hyperorality
Mid (3–6 years)	Worsening behavioural management, emergence of motor symptoms (MND/CBD/PSP if overlap), language deterioration, need for structured supervision/residential care, medication side effects
Late (6–10+ years)	Complete functional dependence, dysphagia, aspiration pneumonia, immobility complications (pressure ulcers, VTE, contractures), incontinence, respiratory failure (FTD-MND), delirium, end-of-life care decisions

High Yield Summary — FTD Complications

Unique early complications of bvFTD: criminal behaviour (disinhibition), financial ruin, driving risk, obesity/metabolic syndrome (hyperorality), dental disease, self-neglect
Motor overlap complications: FTD-MND (dysphagia, respiratory failure — worst prognosis ~3 years), PSP (falls, pseudobulbar palsy), CBD (limb apraxia, alien limb)
PPA complications: progressive mutism (nfvPPA), loss of object/face recognition (svPPA), emergence of behavioural features as disease spreads
Late-stage complications of immobility: aspiration pneumonia (most common cause of death), pressure ulcers, VTE, contractures, UTI, malnutrition
Medication complications: AChEIs worsen FTD; antipsychotic risks (stroke/mortality warning, EPS); sedation-related falls
Delirium: lower threshold due to reduced cognitive reserve — always seek treatable precipitant
Caregiver burnout: depression in ~40–50% of carers; young onset and loss of empathy make FTD particularly devastating for families

Active Recall - FTD Complications

References

^[1] Senior notes: Ryan Ho Neurology.pdf (Section 5.4.4 Frontotemporal Dementia, p.133) ^[2] Senior notes: Ryan Ho Psychiatry.pdf (Section 4.2.4 Frontotemporal Dementia, p.94) ^[14] AOS material: AOS - Geriatrics.pdf (Delirium vs Dementia question, p.3–4) ^[19] Senior notes: Ryan Ho Neurology.pdf (Section on Delirium Management, p.96); Senior notes: Ryan Ho Fundamentals.pdf (Section on Delirium, p.326) ^[20] Lecture slides: Backgrounder - Decisions about Feeding Tubes in Advanced Dementia.pdf ^[22] Senior notes: Maksim Medicine Notes.pdf (Parkinson-plus syndromes, p.253) ^[23] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf (Disease Progression, p.20)

High Yield Summary

FTD = progressive degeneration of frontal and/or temporal lobes → behaviour/personality change OR progressive language disturbance
Epidemiology: onset ~58y, most common cause of dementia < 65y, highly heritable (~40% FHx), 10–25% autosomal dominant
Three key genes: C9ORF72 (repeat expansion, FTD-MND), MAPT (tau), GRN (progranulin haploinsufficiency → TDP-43)
Pathology = FTLD: ~40% FTLD-tau (Pick bodies), ~50% FTLD-TDP, ~5–10% FTLD-FUS
Two clinical subtypes:
- bvFTD (~60%): disinhibition, apathy, loss of empathy, hyperorality, compulsive behaviour, executive dysfunction; memory PRESERVED early
- PPA: progressive isolated language impairment — nfvPPA (effortful agrammatic speech), svPPA (loss of word meaning), lvPPA (word-finding difficulty, impaired repetition — usually AD pathology)
Key differentiator from AD: behaviour first (not memory), younger onset, frontal/temporal atrophy (not hippocampal/parietal)
Imaging: bilateral frontal + temporal hypoperfusion on SPECT/PET; focal frontal (bvFTD) or temporal (PPA) atrophy on MRI
Motor overlaps: MND, CBD, PSP
Prognosis: 8–10y, faster than AD; worst with MND overlap (~3y)

High Yield Summary — DDx of FTD

bvFTD DDx (from lecture slides): psychiatric disorders (depression), DLB, early-onset AD, cerebrovascular disease, slow-growing mass lesions
PPA DDx (from lecture slides): cerebrovascular disease, slow-growing mass lesions
Most commonly confused with: psychiatric disorders (~50% misdiagnosed initially) — depression, mania, OCD, schizophrenia
Must-not-miss treatable mimics: brain tumour, NPH, neurosyphilis, TBM
Key differentiators from AD: behaviour first (not memory), frontal atrophy (not hippocampal), younger onset
Key differentiators from DLB: no visual hallucinations, no fluctuating cognition, no RBD, no early parkinsonism, no visuospatial impairment
Motor overlap (FTD spectrum): MND, CBD, PSP — shared tau/TDP-43 pathology
Always exclude delirium in acute deterioration — hallmark is acute onset and fluctuating consciousness
Imaging patterns: FTD = frontal + temporal; AD = posterior temporal + parietal; DLB = preserved medial temporal, reduced occipital activity; VaD = infarcts/WMH

High Yield Summary — Diagnosis of FTD

bvFTD diagnostic criteria (Rascovsky 2011): ≥3 of 6 core features (disinhibition, apathy, loss of empathy, perseverative/compulsive behaviour, hyperorality, executive deficit with spared memory) for POSSIBLE; + functional decline + supporting neuroimaging for PROBABLE; + pathology or known mutation for DEFINITE
PPA diagnostic criteria (Gorno-Tempini 2011): Progressive language difficulty as the principal deficit → classify into nfvPPA, svPPA, or lvPPA by fluency, comprehension, repetition, and naming patterns
MRI pattern: Frontal + anterior temporal atrophy (bvFTD); left anterior temporal "knife-blade" atrophy (svPPA); left posterior frontoinsular (nfvPPA)
SPECT/PET: Bilateral frontal + temporal hypoperfusion/hypometabolism (vs posterior temporal + parietal in AD)
Amyloid PET negative = rules out AD, supports FTD
CSF: Normal Aβ42 and p-tau (unlike AD); high NfL (especially FTD-MND)
Cognitive testing: MoCA preferred over MMSE — better at detecting executive dysfunction
Genetic testing: C9ORF72, MAPT, GRN in familial cases, young onset, or FTD-MND
Always exclude reversible causes first — 10–15% of dementia is treatable

High Yield Summary — FTD Management

Management is symptomatic only — no disease-modifying therapy available
Behavioural symptoms: 1st line = SSRI or trazodone; 2nd line = atypical antipsychotic (quetiapine preferred) at lowest dose
Cognitive dysfunction: NO available treatment — AChEIs are contraindicated (worsen behaviour); memantine not effective
Parkinsonism: generally NOT responsive to dopaminergic agents — trial of levodopa but expect poor response
SSRIs work because FTD has a serotonergic deficit (not cholinergic as in AD)
Antipsychotics: black box warning for stroke/mortality in elderly dementia patients; use only if non-pharmacological measures fail; ALWAYS confirm FTD (not DLB, which has severe antipsychotic sensitivity)
Non-pharmacological: structured routines, environmental modification, speech therapy, caregiver support = backbone of management
Advance care planning: arrange EPA early; hand-feeding preferred over PEG in advanced dementia
FTD-MND: riluzole, NIV, PEG, MDT; worst prognosis (~3 years)
Emerging: anti-tau immunotherapy, ASOs for C9ORF72, progranulin-boosting for GRN mutations — watch this space

High Yield Summary — FTD Complications

Unique early complications of bvFTD: criminal behaviour (disinhibition), financial ruin, driving risk, obesity/metabolic syndrome (hyperorality), dental disease, self-neglect
Motor overlap complications: FTD-MND (dysphagia, respiratory failure — worst prognosis ~3 years), PSP (falls, pseudobulbar palsy), CBD (limb apraxia, alien limb)
PPA complications: progressive mutism (nfvPPA), loss of object/face recognition (svPPA), emergence of behavioural features as disease spreads
Late-stage complications of immobility: aspiration pneumonia (most common cause of death), pressure ulcers, VTE, contractures, UTI, malnutrition
Medication complications: AChEIs worsen FTD; antipsychotic risks (stroke/mortality warning, EPS); sedation-related falls
Delirium: lower threshold due to reduced cognitive reserve — always seek treatable precipitant
Caregiver burnout: depression in ~40–50% of carers; young onset and loss of empathy make FTD particularly devastating for families

Frontotemporal Dementia

1. Definition

2. Epidemiology

3. Anatomy & Functional Correlates

3.1 Frontal Lobe Circuits

3.2 Temporal Lobe Regions

3.3 Imaging Correlation

4. Etiology

4.1 Genetic Causes

4.2 Sporadic Cases

5. Pathophysiology

5.1 Neuropathological Classification (FTLD Subtypes)

What are Pick Bodies?

What is TDP-43?

5.2 Pathophysiological Cascade

5.3 Relationship to Other Neurodegenerative Diseases

6. Classification

6.1 Overview

6.2 Detailed Subtype Comparison

7. Clinical Features

7.1 Behavioural Variant FTD (bvFTD)

7.1.1 Symptoms (with pathophysiological basis)

7.1.2 Signs (with pathophysiological basis)

7.2 Primary Progressive Aphasia (PPA)

7.2.1 Non-fluent/Agrammatic Variant PPA (nfvPPA)

7.2.2 Semantic Variant PPA (svPPA)

7.2.3 Logopenic Variant PPA (lvPPA)

8. Key Differentiating Features from Other Dementias

9. Natural History & Prognosis

Active Recall - Frontotemporal Dementia

References

1. Conceptual Framework — Why is DDx of FTD Difficult?

2. DDx Algorithm — Mermaid Diagram

3. Detailed Differential Diagnosis

3.1 Differentials for Behavioural Variant FTD (bvFTD)

3.1.1 Psychiatric Disorders

3.1.2 Early-Onset Alzheimer's Disease

3.1.3 Dementia with Lewy Bodies (DLB)

3.1.4 Huntington's Disease

3.1.5 General Paresis (Neurosyphilis)

3.1.6 Parkinson-Plus Syndromes (CBD, PSP)

3.1.7 Structural Lesions

3.1.8 Normal Pressure Hydrocephalus (NPH)

3.1.9 TB Meningitis (Dementia-Like Presentation)

3.1.10 Alcohol-Related Brain Damage

3.2 Differentials for Primary Progressive Aphasia (PPA)

3.3 Delirium Superimposed on Dementia

4. Summary Table — DDx of FTD at a Glance

5. Clinical Approach to Narrowing the DDx

Active Recall - DDx of FTD

1. Diagnostic Criteria

1.1 General Dementia Criteria — The Foundation

1.2 Behavioural Variant FTD (bvFTD) — International Consensus Criteria (Rascovsky et al., 2011)

Level 1: Possible bvFTD

Level 2: Probable bvFTD

Level 3: Definite bvFTD (Pathological)

1.3 Primary Progressive Aphasia (PPA) — Gorno-Tempini Classification (2011)

Step 1: Establish PPA Diagnosis (Root Criteria)

Step 2: Classify the PPA Variant

Step 3: Imaging-Supported PPA

Step 4: Definite PPA (Pathological)

1.4 DSM-5 Criteria for Major or Mild Neurocognitive Disorder Due to Frontotemporal Lobar Degeneration

2. Diagnostic Algorithm

3. Investigations

3.1 Baseline "Dementia Screen" — Exclude Reversible Causes

3.2 Cognitive and Neuropsychological Assessment

3.3 Structural Neuroimaging — MRI Brain

3.4 Functional Neuroimaging — SPECT and PET

3.4.1 Cerebral Perfusion SPECT

3.4.2 FDG-PET (Fluorodeoxyglucose PET)

3.4.3 Amyloid PET

3.4.4 Tau PET

3.4.5 Dopamine Transporter Imaging (DaTscan)

3.5 Cerebrospinal Fluid (CSF) Biomarkers

3.6 Blood-Based Biomarkers (Emerging)

3.7 Genetic Testing

3.8 Electrophysiology (EEG)

3.9 Other Investigations

4. Putting It All Together — Investigation Summary Table

Active Recall - FTD Diagnosis & Investigations