Frontotemporal dementia (FTD) is the second most common early-onset dementia. There are several variants of FTD including behavioral variant FTD and primary progressive aphasias like semantic dementia and progressive nonfluent aphasia. Genetic causes include mutations in MAPT, GRN, and C9ORF72 genes. Neuroimaging shows characteristic patterns of frontal and temporal lobe atrophy depending on the variant. Biomarkers like increased blood GFAP levels may help with diagnosis. Currently, there are no approved disease-modifying treatments, but some medications may help treat symptoms. Research focuses on new targets like gene therapy to potentially slow progression in the future.

1. Frontotemporal
dementia
Presented by
Heba Mohamed Tawfik
Associate Professor of Geriatrics and
Gerontology
Faculty of Medicine
Ain-Shams University

2. Frontotemporal dementia (FTD) is the second most common
neurodegenerative early onset dementia occurring before the age of 65
The prevalence of FTD is underestimated. Approximately 15-20 per 100,000
persons aged 45 to 64 have FTD. Another 10% of FTD occurs before age 45
and may be in thirties, and about 30% of cases occurs after age 65 may be up
to eighties.
Both males and females are affected equally

3. Types of FTD
1.Behavioral (or frontal) Variant (bvFTD)
2.Semantic variant primary progressive aphasia (svPPA, or
PPA-S)
3.Non-fluent (agrammatic) variant primary progressive
aphasia (nfvPPA or nfaPPA)
4.Logopenic variant primary progressive aphasia (lvPPA or
PPA-L)
5.There is FTD overlaps with other tauopathies,
including progressive supranuclear palsy (PSP), corticobasal
degeneration (CBD).

4. Genetics
 More than half cases are sporadic.
 There are three main causative autosomal dominant genetic mutations (out of 8
genetic mutations) :
• Microtubule-associated protein tau (MAPT; 17q21)
• Progranulin (GRN; 17q21)
• Chromosome 9 hexanucleotide repeat expansion in C9ORF72.
 In genetic FTD, bvFTD, nfaPPA, and CBS variants are typical, while svPPA and
PSP are almost always sporadic.
 MAPT is also related to parkinsonian syndromes, and C9ORF72 to amyotrophic
lateral sclerosis (ALS).
 Variants in TMEM106B appear to be protective from delayed onset of C9ORF72-
and GRN-associated FTLD.

5. PATHOPHYSIOLOGY
• There is neuronal loss, microvacuolation, and a variable degree of astrocytic gliosis
• Neuronal damage is due to the accumulation of one of several protein aggregates, including:
 Tau
 43-kDa TAR DNA-binding protein (TDP-43)
 RNA-binding protein fused in sarcoma (FUS)
 Ubiquitin-positive proteins
• Tau aggregations can be found in people with bvFTD, nfaPPA, and MAPT-associated FTD, but are rare in
those with svPPA.
• FUS pathology is associated with an earlier age of onset with faster progression and prominent
neuropsychiatric features.
• Most cases of bvFTD are due to tau or TDP-43 (equally), but a small proportion are caused by FUS or a
predominantly frontal variant of Alzheimer’s disease.
• Pick bodies are a specific cellular morphologic subtype of tau accumulation that is not present in all cases.
So “Pick’s disease” should no longer be used as a clinical diagnostic term.

6. Pathologic
changes
and their
associated
clinical
findings
include
the
following
structures:
Anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) and
apathy;
Orbitofrontal cortex (OFC)/ frontoinsular cortex and disinhibition;
Frontoinsular cortex/ anterior temporal lobes and loss of
compassion;
Ventral striato-pallidum and stereotypies/compulsions;
Frontoinsular cortex/ventral striatum/hypothalamus and aberrant
eating behavior;
Dorsolateral prefrontal cortex (dlPFC) and executive dysfunction

7. Criteria and diagnosis
of various types of
FTD

8. Diagnostic criteria for bvFTD
(Neary et al. 1998 ; Rascovsky et
al. 2011 )

9. Criteria for diagnosis of bvFTD
Lanata and Miller, 2016

10. Criteria for diagnosis of bvFTD
(continued)
Lanata and Miller, 2016

11. • In early stage bvFTD, behavior may appear normal due to limited observation time .
• Evidence of apathy (eg, poor hygiene ) or disinhibition (eg, attempting to embrace clinic staff
or picking up items from the examiner’s desk)
• Affect ranges from flat to childlike .
• Patients may be restless, or inert and lack spontaneous speech or movement entirely.
• Frontal release signs may be present but are not sensitive or specific for FTD.
• The remainder of the examination is typically normal. Individuals may demonstrate
pyramidal, extrapyramidal, or oculomotor symptoms especially in overlap syndrome.
Neurologic Examination
• Executive dysfunction with relative sparing of temporo-limbic episodic memory and lateral
parietal visuospatial networks is typical.
• bvFTD often perform poorly on tasks of facial expression recognition (especially for negative
emotions) and show impairment in determining the mental state of others (eg, theory of
mind tasks)
• Episodic memory affection in some patients should not exclude FTD
Neuropsychologic Testing

12. How to differentiate
bvFTD from primary
psychiatric disorder?
Ducharme et al., 2015

13. Behavioral features of bvFTD

14. Behavioral features of bvFTD
(continued)
Rascovsky et al., 2011

15. Semantic dementia [semantic variant of primary
progressive aphasia (svPPA)]
Affects knowledge of the meaning of words (Familiar) for
example in a menu (“What is spaghetti?”) pathognomonic of
semantic dementia (affection of dominant temporal lobe).
Speech is fluent with preserved grammar but empty,
circumlocutory with early prominent difficulty retrieving names
Impaired comprehension of single word meanings
Early in the disease, the semantic deficit may be well
compensated and discovered with detailed assessment

16. With disease progression, semantic impairment
also affects visual information [impaired
recognition of familiar faces (prosopagnosia)]
/or recognition of visual objects (visual agnosia)
due to spread to posterior temporal structures
and nondominant pole]
Impaired recognition of odours and flavours,
and behavioural disturbances develop late in
the disease (due to spread to the right anterior
temporal lobe)

17. Neuropsychologic
Testing
Inability to define single
words when asked
(characteristic).
Loss of word meaning and
surface dyslexia (eg, saying
pint instead of mint).
Impairment on tests of
semantic associations for
words as well as visual
semantic associations (eg,
Pyramids and Palm Trees
test, categorization).
Word production rate during
picture descriptions is
normal or near-normal, but
with vague descriptions.
Neurologic
Examination
Speech that is empty,
tangential, or repetitive is
observed.
The remainder of the
neurologic examination is
normal
Frontal release is typically
absent.

18. Progressive non-fluent aphasia (nfaPPA)
Progressive breakdown in language output with effortful non-fluent
speech with grammatic errors.
Speech sound (phonemic) or articulatory (phonetic, speech) errors may be the
dominant feature with speech apraxia (impaired motor speech planning and
articulation deficits with groping speech, despite intact bulbar motor functions)
Apraxia of other orofacial movements or swallowing often accompanies speech
apraxia and is tested by asking the patient to cough or yawn, which they are
unable to do to command, although they can as a reflex.
Impaired sentence comprehension can generally be demonstrated on
neuropsychological assessment
The disease may be due to overlap syndrome with atypical parkinsonism or motor
neurone features.
Patients often develop mutism

19. Neuropsychologic Testing
• Although comprehension is typically
preserved early, there may be difficulty
understanding complex sentences
• Repetition is typically better than
spontaneous speech, although
grammatical and paraphasic errors with
problems in articulation may be seen.

20. Neurologic Examination
• Although deficits may be mild at first, patients with nfaPPA have slow speech with
word-finding pauses or stuttering, circumlocutions, phonemic paraphasic
errors, and agrammatism with relative preservation of comprehension (single
words).
• Subtle right-sided motor symptoms may be present (ie, slowed fine finger
movements ) with pathologic spread throughout the dominant hemisphere.
• Patients may also demonstrate or develop clinical features of underlying pathologic
processes including bvFTD, CBD or PSP.

21. Logopenic aphasia
Presents with hesitant but grammatically correct speech with word-
finding pauses, anomia, and impaired phonological working memory.
Disproportionate difficulty repeating spoken phrases versus single
words.
Most cases will have underlying Alzheimer pathology, and more
widespread cognitive deficits similar to those accompanying other
Alzheimer phenotypes emerge later in the disease course.

22. Diagnostic
criteria for PPA
(Neary et al. 1998 ; Mesulam 2001 ;
Gorno-Tempini et al. 2011 ; Rabinovici et
al. 2008 )

25. Arround 30% of people with amyotrophic
lateral sclerosis (ALS) have symptoms of
FTD, most commonly features of bvFTD or
nfaPPA.
In 50% of people with ALS, milder executive
and verbal fluency deficits are seen.
Psychotic features are more common in
those with FTD-ALS.

26. Psychometric assessment

27. Bedside assessment
of frontal lobe
function
Chan et al., 2011

28. Assessment tests
for FTD
Hategan et al., 2018

29. Alternating sequence test
Scott And Schoenberg , 2010

30. Theory of mind (TOM)
Part of social cognition
Understanding the thoughts, feelings, beliefs, and
intentions of ourselves and others
Assessment
The Reading the Mind in the Eyes test (detecting mental
and emotional states from different characters’ eye-
region photo-graphs),
The Faux Pas test (detecting a socially incorrect behavior
without intentionality)

31. Categorization task
(category and shape -short
version)
Garcin et al., 2018

32. Frontal assessment
battery (FAB)

33. Frontal
behavioral
inventory

34. Neuroimaging

35. Neuroimaging of
various types of FTD
(described before)
Taylor and Finger, 2019
In (A,B) bvFTD there is atrophy of right frontal lobe and relative sparing
of posterior structures (mostly there is bilateral frontal atrophy in
bvFTD but right> left)
In (C,D) svPPA there is left anterior temporal atrophy
In (F) non-fluent agrammatic variant PPA there is inferior frontal
atrophy and its adjacent areas

36. Neuroimaging
in FTD
Peet et al., 2021

37. Genetic FTD is associated with characteristic patterns of atrophy. With C9ORF72
mutations, atrophy in the frontal lobes predominates, and milder atrophy is seen in the
anterior temporal, parietal, and occipital lobes, cerebellum and thalamus. With MAPT mutations,
anteromedial temporal atrophy predominates. With GRN mutations, there is asymmetric
temporal, insular, and parietal lobe atrophy.
Imaging in late stage FTD and patients with GRN mutations may show extensive white matter
hyperintensities.
On fluorodeoxyglucose-positron emission tomography (FDGPET) and single photon emission
tomography (SPECT), bvFTD demonstrates hypometabolism or hypoperfusion in the bilateral
frontal lobes, or the right temporal lobe, distinguishing it from AD with diagnostic accuracy of
80% for SPECT and 90% for FDG-PET.

38. [18 F]-FDG-PET in bvFTD:
right fronto (temporal)
hypometabolism
SPECT study of a patient suffering from FTD. Transaxial slices
from bottom to top . Moderate to severe cortical hypoperfusion
of the frontal lobes, especially on the left , and slight
hypoperfusion of the temporal poles
Dierckx et al., 2014
According to NICE guidelines, 2018
If the diagnosis is uncertain and frontotemporal dementia is suspected, use either: FDG-PET or perfusion
SPECT.

39. Structural MRI and FDG-
PET
In the case of bvFTD, significant
bilateral frontal lobe atrophy and
hypometabolism is seen.
In the case of nfvPPA, atrophy and
hypometabolism greatly impacts
the left frontal lobe more so than the
right.
Peet et al., 2021

40. New markers of FTD
A new study by researchers at the University of Eastern
Finland shows for the first time that blood-based
measurement of glial fibrillary acidic protein (GFAP) can
distinguish patients with FTD from those with
primary psychiatric disorders or healthy individuals.
The levels of GFAP were significantly higher in FTD
patients.
sGFAP enabled differentiation of patients with FTLD and
paranoid personality disease (PPD) and associated with
shorter survival and more severe brain atrophy in patients
with FTLD.

41. Treatment of FTD

42. Guidelines for prescription of
antidementia medications
NICE guidelines 2018
Do not offer AChE inhibitors or memantine to
people with frontotemporal dementia.
Note that logopenic aphasia,has now been shown
to most commonly be caused by Alzheimer's
disease
NHS guidelines 2020
Do not offer AChEIs or memantine to people with
frontotemporal dementia.

43. Treatment for various
symptoms of FTD
Hategan et al., 2018

44. Antidepressants can have some efficacy in reducing disinhibition, repetitive behaviors, sexually inappropriate
behaviors, and hyperorality.
Atypical antipsychotics may decrease agitation and aggression.
Although the evidence is lacking in FTD, cognitive enhancers (e.g., cholinesterase inhibitors and memantine)
have been used to slow the progression of clinical symptoms in some studies while other studies show
memantine may worsen cognitive functions. A 2 RCTs using memantine showed for 26 and 52 weeks showed
improved Clinical Global Impression scores and A 6-month treatment clinical trial in China found improved
neuropsychiatric profile in moderate to severe bvFTD.
Studies suggest that cholinesterase inhibitors are particularly not recommended especially in bvFTD in which
worsening agitation may occur with these agents.

45. A trial of a cholinesterase inhibitor may be prescribed for people with CBS or
nfaPPA with memory deficits, because up to 40% of these individuals have
underlying AD pathology.
Promising results are emerging in rodents including gene therapy (targeting
C9ORF72, and TMEM106B) and replenishing progranulin deficiency. Ongoing
phase 2 clinical trials include gene therapy targeting of MAPT in AD , and
monoclonal antibodies targeting tau in PSP and other primary tauopathies.
Clinical trials targeting gene expression, and related proteins pathways for tau,
progranulin, and C9ORF72 in FTD are anticipated in the future.

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