2 Neuroscience2.13 Neurodegeneration

2.13.4 Pick's disease and frontotemporal dementias

Creator: Resident Doctor Committee
Published: 2026-10-14T21:05:16.259Z

3 min read2 figures

Written by Resident Doctor Committee · Published 14 October 2026

Terms and epidemiology

Frontotemporal dementia (FTD) names the behaviour-led and language-led clinical syndromes; frontotemporal lobar degeneration (FTLD) names the underlying pathology, which histology establishes.
FTD without motor neurone disease, including pure frontal lobe degeneration, affects men and women in close to equal numbers.

Behavioural-variant frontotemporal dementia

Behavioural-variant FTD is a behaviour-led dementia with frontal and anterior temporal atrophy on magnetic resonance imaging (MRI) and relative posterior sparing. Its features are disinhibition, apathy, loss of empathy, compulsions and stereotypies, hyperorality and a dysexecutive profile.

Telling it from Alzheimer's disease

Feature	Behavioural-variant FTD	Alzheimer's disease
First problem	Behaviour, personality or empathy	Episodic memory
MRI atrophy	Frontal and anterior temporal	Medial temporal and temporoparietal
Fluorodeoxyglucose positron emission tomography	Frontal and anterior temporal pattern	Temporoparietal and posterior cingulate pattern

Progressive aphasias

Syndrome	Deficit	Spared	Site
Semantic variant (semantic dementia)	Loss of word and object meaning	Fluency, repetition, grammar	Anterior temporal, often left
Non-fluent (agrammatic) variant	Effortful speech, agrammatism, speech apraxia	Single-word meaning	Left fronto-insular

Logopenic aphasia, with difficulty finding words and repeating sentences, more often reflects Alzheimer pathology.

Pathology

FTLD is classified by the protein in its inclusions.

Group	Share	Linked with
TDP-43 positive, tau negative	Largest, roughly half	GRN, C9orf72, motor neurone disease
Tau positive	Second, roughly 40%	Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), MAPT
FUS positive	Rare	Young onset

Reactive astrocytic gliosis with neuronal loss in frontal and anterior temporal cortex is the generic feature of every subtype; the inclusions tell them apart.
In tauopathies, tau is abnormally phosphorylated and detaches from axonal microtubules, which destabilises them, so axonal transport fails and neurones die.
Pick's disease is the three-repeat (3R) tauopathy; PSP and CBD are four-repeat (4R), Alzheimer's disease has both, and TDP-43 pathology has no tau.

Pick's disease

Knife-blade (knife-edge) atrophy is the gross hallmark: sharply demarcated thinning of frontal and anterior temporal gyri, sparing the posterior superior temporal gyrus, parietal and occipital cortex.
Pick bodies are round, silver-staining 3R tau inclusions inside neurones, found in dentate granule cells and frontotemporal cortex and labelled by anti-tau and anti-ubiquitin immunohistochemistry.
Ballooned neurones (Pick cells) are swollen, pale neurones that have lost Nissl substance and are specific to Pick's disease; Hirano bodies are non-specific, occurring in Alzheimer's disease and normal ageing.
Pick's disease is diagnosed after death by tau-positive neuronal inclusions, circumscribed frontal and anterior temporal atrophy and no amyloid, unlike the tangles, plaques and hippocampal atrophy of Alzheimer's disease.

Lateral gross photograph of a fixed brain on a black background, with many narrowed, shrunken gyri separated by widened sulci; the cerebellum sits at the lower left. — Look at the thin, sharply narrowed gyri and the gaping sulci between them: this is knife-blade atrophy, the gross hallmark of Pick's disease and frontotemporal lobar degeneration. CC BY-SA 3.0, via Wikimedia Commons

Two micrographs side by side. On the left, pink H&E-stained cortex with arrows on two large, swollen, pale neurones; on the right, silver-stained dentate granule cells, many holding a round black inclusion beside a pale nucleus, with one arrowed. — Panel A shows ballooned neurones (Pick cells), which are swollen and pale after losing their Nissl substance, and panel B shows round, black, silver-staining Pick bodies inside dentate granule cells. Ravasia K, Hirsch-Reinshagen V. Free Neuropathol 2025;6:11, Figure 1B and 1C, doi:10.17879/freeneuropathology-2025-5812, CC BY 4.0

Genetics

Familial FTD is autosomal dominant and is caused mainly by mutations in three genes.

Gene	Change	Pathology	Phenotype
MAPT (tau), chromosome 17q21	Altered tau	Primary tauopathy	FTD with parkinsonism linked to chromosome 17 (FTDP-17), which this locus named; early onset; symmetrical anteromedial temporal and orbitofrontal atrophy
GRN (progranulin), chromosome 17q21	Lowered progranulin	Tau-negative, ubiquitin- and TDP-43-positive inclusions	Later onset; asymmetrical atrophy
C9orf72	GGGGCC hexanucleotide repeat expansion	TDP-43 inclusions	FTD, amyotrophic lateral sclerosis (ALS) or both

C9orf72 is the commonest genetic cause of familial FTD and of ALS, and the gene tied to FTD with motor neurone disease.
GRN mutations are also given as a cause of familial FTD with parkinsonism.

Movement disorders at the edge of FTD

Disorder	Protein	Features
PSP	4R tau	Falls, vertical gaze impairment, axial rigidity, frontal symptoms
CBD	4R tau	Asymmetric limb syndrome: levodopa-unresponsive rigidity and myoclonus, with limb apraxia, alien limb and cortical sensory loss
Multiple system atrophy	Alpha-synuclein in oligodendrocytes	A synucleinopathy grouped with Parkinson's disease and dementia with Lewy bodies, so outside the FTD spectrum

Substantia nigra pallor occurs in both PSP and Parkinson's disease, because both lose pigmented dopaminergic neurones, so it cannot separate them; midbrain atrophy is specific to PSP.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.