1. Fronto-temporal Dementia:
Neural circuits, genetics and
neuropathology
Dr Ravi Soni
Senior Resident
Dept. of Geriatric Mental Health
KGMC

2. Functional areas of Brain

3. Prefrontal cortex
1. Orbitofrontal cortex
2. Lateral prefrontal cortex
3. Ventromedial cortex
4. Limbic system

5. Frontal lobe Functional circuit

6. Temporal lobe
consideration
• In Semantic Dementia: The
regions of most prominent
atrophy are in the anterolateral
temporal cortex, especially the
temporal pole and inferior and
middle temporal gyri particularly
on left side..(Mummery CJ et
al.1999, 2000)
• In Lexical Anomia: left posterior
Inferior temporal gyrus is
critically involved in lexical
phonological retrieval (early to
develop in alzheimer’s disease).
(Mummery CJ et al.1999)

7.  Patients with bvFTD show classic bilateral atrophy in mesial and orbital frontal
regions, extending to the temporal pole and hippocampal formation as disease
progresses (blue).
 In semantic dementia, the typical pattern of atrophy is lateralized (generally
left>right hemisphere), chiefly targeting the anterior temporal lobes and temporal
pole, including the hippocampal formation and amygdala, and spreading to
ventromedial prefrontal cortical regions as the disease progresses (yellow).

8. Fronto-temporal Dementia
• Frontotemporal dementia (FTD), with its initial description as Pick’s
disease (1892) encompasses a group of progressive neurodegenerative
syndromes.

9. Basic Consideration
• Frontotemporal dementia (FTD) is a progressive
neurodegenerative syndrome occurring between 45 and 65
years
• The syndrome is also called frontotemporal lobar
degeneration (FTLD).
• FTLD refers to a larger group of disorders, FTD being one of its
subgroups. The other subgroups of FTLD are progressive
nonfluent aphasia (PFNA), and semantic dementia (SD).
• FTLD is characterized by atrophy of prefrontal and anterior
temporal cortices.

10. Continued….
• FTD occurs in 5–15% of patients with dementia and it is the
third most common degenerative dementia.
• FTD occurs with equal frequency in both sexes.
• The age of onset is usually between 45 and 65 years though it
may range anywhere from 21 to 81 years.
• There is progressive clinicopathological deterioration with
mortality within 6-8 years.
• Strong genetic basis and family history of FTD is seen in 40-
50% of cases.

11. FTD Types
1. Behavioral variant
frontotemporal dementia (bvFTD)
• Also called frontal variant frontotemporal
dementia (fvFTD) or Pick’s disease
• Negatively impacts social
skills, emotions, personal conduct, and
self-awareness.
• People with bvFTD might act in
inappropriate ways, show a lack of
judgment or inhibition, neglect to
maintain personal hygiene, do something
compulsively or repetitively, or feel
euphoric or apathetic.
• bvFTD is the most common form of
frontotemporal dementia.

12. 2. Semantic Dementia:
• also called temporal variant
frontotemporal dementia,
• People with SD have difficulty
remembering what words signify, what is
the meaning of the word
• People speak easily, but their words
convey less and less meaning.
• They tend to use broad general
terms, such as "animal" when they mean
"cat."
• Language comprehension also declines.
• They may use similar category
words, like, tiger instead of lion.
• Fluent spontaneous speech is retained

13. 3. Progressive non-fluent aphasia
• Deterioration in their ability to produce speech.
• These patients first become hesitant in their speech, begin to talk
less, and eventually become mute.
• They are unable to communicate fluently.
• They make speak slowly, have trouble pronouncing words, or get
confused when processing complex sentence structure
• Fundamental loss is, deterioration in knowledge of the grammatical
organization and the production of sounds for language.

14. Genetics
• Genetically complex disorder
• Inherited as an autosomal dominant trait with high penetrance in
majority of cases
• Genetic linkage studies have revealed FTLD loci on chromosome
3p, 9, 9p, and 17q.
• The most prevalent genes are PGRN (progranulin) and MAPT
(microtubule-associated protein tau), both located on chromosome
17q21.
• Other potential genes are
– VCP (Valosin-containing protein) gene,
– chromosome 9 open reading frame 72 (C9ORF72),
– TAR DNA binding protein (TARDBP) and
– charged multivesicular body protein (CHMP2B) — are linked to
frontotemporal dementia.
• Presenilin-1 gene (PSEN1) and Lrrk2 (leucine-rich repeat kinase) are
being studied for their possible role in frontotemporal dementia
• The autosomal dominant form of FTLD linked to chromosome
17q21 is termed FTDP-17.

15. Genetics
 Autosomal dominant pattern of inheritance
• About 10% of people with frontotemporal
dementia inherited in an autosomal dominant pattern
 Familial pattern of inheritance
• A large group of families (20-40%) have an inheritance
pattern that is termed familial,
 Sporadic pattern of inheritance
• The majority of frontotemporal dementia (50-70%) is
sporadic.
• This means the disorder does NOT appear to be
inherited, and the risk to family members is almost the
same as that of the general population

16. PGRN Gene
• Encodes for PGRN protein
• PGRN, expressed in neurons and
activated microglia
• involved in tissue remodeling by
activating signaling cascades that
control cell cycle progression and cell
motility
• PGRN mutations occur in 26% of
familial FTD cases.
• PGRN mutation is associated with
the expression of truncated and
hyperphosphorylated isoforms of
TDP-43 (TAR DNA binding protein 43).
• Under pathologic conditions, TDP-
43 relocates from the neuronal
nucleus to the cytoplasm resulting in
loss of TDP-43 nuclear functions
(Presence of this ubiquinated protein outside the
nucleus, in cytoplasm suggest that it has some important
regulatory functions in cell, and loss of which results in
death of affected neurons, same mutation is seen in
patients with ALS)

17. MAPT Gene
• MAPT having 37 mutations within the microtubule-binding region or exon
10, produce tau isoforms with either three microtubule-binding repeats
(3R-tau) or four repeats (4R-tau).
• In Pick’s disease 3R-tau accumulates.
• Missense and deletion mutations disrupts the binding of tau to
microtubules resulting in accumulation of unbound tau.
• MAPT mutations on exons 1, 9, and 11 to 13 account for the dementia-
dominant phenotype.
• The parkinsonism-plus–predominant phenotype is associated with
mutations within intron and exon 10, leading to the overproduction of 4R-
tau isoforms.

18. Do Specific Mutations Cause Specific Forms of
Frontotemporal Dementia?
• PGRN mutations: bvFTD, PNFA, CBS, PSP but not to ALS
• C9ORF72 mutations: FTD and ALS
• VCP mutations: FTD and paget disease of bone
• CHMP2B mutations: FTD, FTD-ALS and ALS
• TARDBP mutations: both sporadic and familial ALS

19. Neuropathology
• Gross morphological
• Microscopic
• Neuroimaging

20. Gross Morphological
• General: atrophy in frontal and temporal lobes
• Ventricles may be enlarged
• Depending upon the stages, the atrophy may be subtle to severe
• Later stages it may produce the so called “KNIFE BLADE” appearance of
the affected gyri
• Atrophy may be asymmetric, a feature of PNFA and SD.

21. Subgroupwise atrophy
• The three main FTD syndromes, bvFTD, SD and
PNFA, have somewhat distinct patterns of atrophy.
• The bvFTD is associated with atrophy affecting bilateral
frontal lobes, particularly the medial frontal lobes, and
anterior temporal lobes, whereas
• SD is associated with bilateral, although usually
asymmetric, middle, inferior, and medial anterior
temporal lobe atrophy.
• PNFA shows left perisylvian atrophy.

22. Functional Imaging-SPECT,PET
• In bvFTD, there is involvement of the medial
prefrontal cortex, and to a variable degree the
posterior orbitofrontal/ subcallosal
cortex, dorsolateral prefrontal regions and
insula.
• may also show changes in basal-ganglia and
thalamus.
 Imaging in FTD related conditions:
• Cortico basal degeneration (CBD): Posterior
frontal and superior parietal atrophy
• PSP: subcortical atrophy affecting the superior
cerebellar peduncle and midbrain
• Patients who have AOS show atrophy of the
supplemental motor area and superior posterior
frontal lobe.

23. Neuro-pathological features
• More than 15 different pathologies may underlie
FTD and related disorders.
 Immunohistochemical analysis defines four major
types of pathological features:
a) Microvacuolation without neuronal
inclusions, that is, dementia lacking distinctive
histological (DLDH) features.
b) Microvacuolation with ubiquitinated rounded
intraneuronal inclusions and dystrophic neurites
within layer 2 of frontal and temporal neocortex
and hippocampal dentate gyrus cells designated
FTLD ubiquitinated (FTLD-U) type.
c) Transcortical gliosis with tau-reactive rounded
intraneuronal inclusions (Pick’s bodies) and
swollen achromatic neurons (Pick’s cells).
d) Microvacuolation and taupositive neurofibrillary
tangles or Pick-like bodies in neurons, and
sometimes tangles in glial cells of the cerebral
cortical white matter. This is associated with
familial FTD because of mutations in the tau gene.
• Types c and d are referred to as tauopathies.

24. Neuro-pathological features
• DLDH characterized by neuronal loss, and gliosis affecting superficial
cortical lamina and absence of the typical pathological findings of AD.
• most common pathology associated with FTD was thought to be DLDH
• Many DLDH now considered as FTLD-U
• Some DLDH has evidence of motor neuron degeneration called as FTLD-
MND
• One of the major ubiquitinated proteins in FTLD-U, FTLD-MND is TDP-43.
• These disorders are therefore called TDP-43 proteinopathies and majority
of FTLD cases are TDP-43 proteinopathies.
• The other significant groups of FTLD are characterized by the presence of
MAPT and are called tauopathies.
• More than 90% of cases of FTD and related disorders can be classified as
TDP-43 proteinopathy or tauopathy

28. An algorithm for the neuropathological diagnosis of
patients with clinical frontotemporal dementia.
3R-tau, tau isoforms with three microtubule-binding repeats; 4R-tau, tau isoforms with four microtubule-binding
repeats; AGD, agyrophilic grain disease; CBD, corticobasal degeneration; DLDH, dementia lacking distinctive
histopathology; FTDP-17, FTD with Parkinsonism linked to chromosome 17; FTLD, frontotemporal lobar
degeneration, an alternative term for DLDH; FTLD-U, FTD with ubiquitin-positive but tau- and -synuclein-negative
inclusions; LBVAD, Lewy body variant of AD; NFID, neuronal intermediate filament disease; PiD, Pick's disease;
PSP, progressive supranuclear palsy; TPSD, tangle predominant senile dementia.

29. References
• Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester
Groups. (1994). Journal of neurology, neurosurgery, and psychiatry, 57(4), 416–8. Retrieved from
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1072868&tool=pmcentrez&rendertyp
e=abstract
• Hodges, J. R., & Patterson, K. (2007). Semantic dementia: a unique clinicopathological syndrome.
Lancet neurology, 6(11), 1004–14. doi:10.1016/S1474-4422(07)70266-1
• Mummery, C. J., Patterson, K., Price, C. J., Ashburner, J., Frackowiak, R. S., & Hodges, J. R. (2000). A
voxel-based morphometry study of semantic dementia: relationship between temporal lobe
atrophy and semantic memory. Annals of neurology, 47(1), 36–45. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/10632099
• Mummery, C. J., Patterson, K., Wise, R. J., Vandenberghe, R., Vandenbergh, R., Price, C. J., &
Hodges, J. R. (1999). Disrupted temporal lobe connections in semantic dementia. Brain : a journal
of neurology, 122 ( Pt 1, 61–73. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10050895
• Muñoz, D. G. (2000). [Neuropathology of frontotemporal dementia]. Neurología
(Barcelona, Spain), 15 Suppl 1, 2–8. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/10723169
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neurology, 48(11), 998. Retrieved from http://europepmc.org/abstract/MED/19198143/reload=0
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30. THE END
THANKS