An overview of Frontotemporal dementias and discussion on various genetic variants.

1. Frontotemporal Dementia –
Current Concepts…..
DR VAIBHAV MATHUR
Assistant Professor, Neurology
SMS Medical college, Jaipur

2. History
 Frontotemporal dementia was first described by
Arnold Pick in 1892, and since then it was known as
Pick's Disease.
 Common symptoms that are noticed early on in the
diagnosis are personality and emotional changes,
as well as deterioration of language. Many who are
diagnosed with Pick's disease can be impulsive,
apathetic, and euphoric.
 While some of the symptoms can initially be alleviated,
the disease progresses, and patients often die
within two to ten years.
 A defining characteristic of the disease is build-up
of tau. Agyrophilic globular neuronal cytoplasmic
inclusions (Pick bodies) are present in 20% of FTD ;
thus, the term Pick’s disease is used to describe FTD
with Pick’s pathology.

3. INTRODUCTION
• Frontotemporal dementia (FTD) is a term used to describe a group of
neurocognitive disorders that encompass progressive dysfunction
in executive functioning, behaviour, and language.
 It is considered the third most common form of dementia following
Alzheimer’s disease (AD) and dementia with Lewy bodies and the most
common form of dementia in people under the age of 60.
• FTD is a cluster of syndromes that result from degeneration of the frontal
and temporal lobes, and is subdivided into two categories
1. behavioural subtype that accounts for about half of FTD cases.
2. language subtype - further subdivided into
• Non-fluent primary progressive aphasia (PPA) – Apraxia of speech (or)
Agrammatism
• Semantic variant of primary progressive aphasia (PPA) - deficits of
semantic knowledge but with preserved speech fluency,

4. Neuropsychological testing
 Bv-FTD
 defective executive tasks with minimal or no involvement of visuospatial
domains and memory. Impaired motor luria test, defective executive
functions in clock drawing. Neuroimaging may show predominant atrophy
of right temporal or frontal lobe and the atrophic patterns may vary
between different mutations (discussed later in neuro-imaging).
 svPPA
 Patients with svPPA exhibit single word comprehension deficit. Patients
may have a different pattern of episodic memory deficit in which they
recall recent events, with difficulty in recalling remote memory.
Neuroimaging may show dominant anterior temporal lobe atrophy which
is typically asymmetric at the time of onset.
 Agrammatic PPA
 In patients with Agrammatic PPA, there is reduced speech production with
word finding difficulties, circumlocutions, and grammatical errors.
Imaging in these patients may be associated with atrophy of dominant
inferior frontal lobe.

5. DIAGNOSTIC CRITERIA OF bvFTD
 Required Criterion
 Progressive deterioration of behaviour and/or cognition by observation or history (as
provided by a knowledgeable informant.)
 Possible bvFTD
 Three of the following persistent or recurrent behavioural/cognitive symptoms
(A–F) must be present to meet criteria.
 A. Early behavioural disinhibition
 B. Early apathy or inertia
 C. Early loss of sympathy or empathy
 D. Early perseverative, stereotyped or compulsive/ritualistic behaviour
 E. Hyperorality and dietary changes
 F. Executive deficits with relative sparing of memory and visuospatial functions

6.  Other possible features
(1) distractibility, disorganization, mental rigidity, and other forms of executive
dysfunction (dorsolateral prefrontal cortex)
(2) semantic loss, especially for emotions and faces (right more than left anterior
temporal lobe);
(3) aphasia, often manifesting as an abulic, adynamic aphasia (left anterior
midcingulate and presupplementary motor area);
(4) memory loss (entorhinal-hippocampal complex);
(5) motor impairment that may include parkinsonism (substantia nigra, striatum)
(6) oculomotor control problems (frontal eye fields, dorsal midbrain), or
(7) motor neuron disease (upper and lower motor neurons).

7.  Probable bvFTD
 All the following symptoms (A–C) must be present to meet criteria.
 A. Meets criteria for possible bvFTD
 B. Exhibits significant functional decline
 C. Imaging results consistent with bvFTD [one of the following must be present]:
 C.1. Frontal and/or anterior temporal atrophy on MRI or CT
 C.2. Frontal and/or anterior temporal hypoperfusion or hypometabolism on PET or
SPECT
 Definite bv- FTLD
 Criterion A and either criterion B or C must be present to meet criteria.
 A. Meets criteria for possible or probable bvFTD
 B. Histopathological evidence of FTLD on biopsy or at post-mortem
 C. Presence of a known pathogenic mutation

8.  Exclusionary criteria for bvFTD
 Criteria A and B must be answered negatively for any bvFTD diagnosis.
 Criterion C can be positive for possible bvFTD but must be negative for
probable bvFTD.
 A. Pattern of deficits is better accounted for by other non-degenerative
nervous system or medical disorders
 B. Behavioural disturbance is better accounted for by a psychiatric
diagnosis.
 C. Biomarkers strongly indicative of Alzheimer’s disease or other
neurodegenerative process

9.  The diagnosis of FTD can be challenging due to a symptom overlap with
 Alzheimer’s disease (short-term memory problems, difficulty in
performing visuospatial tasks, but social behaviours are spared),
 dementia with Lewy bodies (fluctuating course, hallucinations and
parkinsonism),
 vascular dementia (stepwise progression, pseudobulbar palsy)
and
 Huntington’s disease (chorea and dementia)
 Primary Psychiatric Disease- In depth past history required,
apathy v/s anhedonia, disinhibition vs mania, compulsive
behaviours vs anxious OCD, loss of empathy vs autistic disorders
are important discriminations required for diagnosis.
Unheralded midlife psychosis, compulsivity, and mania-like
episodes favour bv-FTD.
 Substance Abuse – History, Toxicology screen and Brain MRI help
to distinguish.
 Frontotemporal Brain Sagging Syndrome – Correctable rare
differential, Intracranial hypotension with meningeal enhancement
and tension on frontal insular temporal cortical pathways.

10. Common Facts about FTD
 Early onset dementia:
around 50 – 60 years
of age
 Progressive loss of
brain cells in frontal
and temporal lobes
 Inheritance plays an
important role

11. NEUROPATHOLOGY
 FTD is characterized predominantly by gliosis, neuronal loss, and
microvacuolar changes, which were predominantly seen in anterior
temporal lobe, frontal lobe, insular cortex, and anterior cingulate cortex
(initial changes in most cases).
 In these areas, there are specialized neurons situated in layer 5 termed as
von economo neurons that mediate high-speed connections necessary for
initiative, judgment, and emotional responsiveness.
 Early onset of degeneration in these neurons may be possible pathology in
FTD. Either TAR DNA-binding protein 43 (TDP-43) (or) Tau proteins (or) Fused
in sarcoma (FUS) protein account for almost all cases of FTLD.
 Based on this, the FTD was sub categorized into FTLD-TDP, FTLD-Tau,
FTLD-FUS.

12.  FTLD-TDP
 Around 50% cases of FTLD accounts for FTLD-TDP.
 On the basis of patterns of internuclear or cytoplasmic or cortical association, they are
subclassified into A, B, and C subtypes.
 FTLD-Tau
 Approximately 36%–50% of FTLD patients accounts for FTLD-Tau.
 The most common subtype in this entity include corticobasal degeneration (35%),
progressive supranuclear palsy (31%). and Pick’s disease (30%) in decreasing order
of frequency.
 FTLD-Fus
 Nearly 10% cases of FTLD accounts for FTLD-Fus.
 Most often, these patients present with early onset psychosis, disinhibition, and other
behavioral abnormalities without any motor deficits, and they demonstrate the
presence of FUS-immuno reactive inclusions predominantly in dentate gyrus

13. Heritability, genes and phenotype
 FTD is a highly
heritable disorder
but almost uniquely
within the
neurodegenerative
disease spectrum,
 It is neither purely
genetic (like
Huntington’s
disease, HD) nor a
mainly sporadic
condition (like
Alzheimer’s
disease)

14. Heritability, genes and phenotype
 Nearly 40% of FTD cases are familial.
 Much of the heritability (60%) of FTD is accounted for by
autosomal dominant mutations in:
 Microtubule-associated protein tau (MAPT) genes (chr. 17q21.1)
- MAPT mutations were the first to be identified as the cause of
inherited FTD. These mutations lead to microtubule instability with
increased propensity of Tau self-aggregation which may lead to
neurodegeneration.
 Progranulin (GRN) (17q21.32) – (2nd m/c) - involved in modulation
of inflammation, axonal growth, and wound repair. Any mutations
involving GRN may lead to loss of functional progranulin levels in
cerebrospinal fluid and serum.
 Chromosome 9 open reading frame 72 (C9orf72) (most
common - 25%) - due to expansion of noncoding GGGGCC
hexanucleotide repeats.

15. Age at onset
 Generational analysis showed
mean age of symptom
onset was
65·5 years (SD 9·1) in
GRN FTD
62·3 years (SD 10·9)
in C9orf72, and
51·4 years (9·5) in
MAPT

16. Cognition
 Executive function deficits seem common
across the different genetic groups, specific
patterns of cognitive decline have been identified
at a pre symptomatic stage in MAPT, GRN and
C9orf72 carriers.
 A number of studies have now shown that MAPT
carriers have both naming and episodic
memory difficulties, consistent with early
medial temporal lobe atrophy.
 Of most people of bvFTD, some develop PPA,
and decline on phonology and letter fluency
tasks was predictive of conversion to a nonfluent
variant PPA phenotype in GRN carriers.

17.  Episodic memory problems, parkinsonism with
akinetic-rigid syndrome and cerebellar signs may
also occur, accompanied by visual and auditory
hallucinations and delusions in FTD with
C9orf72 expansion.
 C9ORF72 mutation carriers (especially those
without neurological signs) can be diagnosed
with a mood disorder or schizophrenia prior to
the FTD diagnosis

18. MOTOR SYMPTOMS OF bvFTD
 Motor symptoms are most commonly seen with Bv-FTD.
 Around 40% of patients with Bv-FTD may have motor
neuron disease in which they may present either with
lower motor neuron signs or upper motor neuron signs.
 Around 20% of patients with Bv-FTD may present with
early Parkinsonism, corticobasal syndrome or
progressive supranuclear palsy in which earlier may be
associated with alien limb phenomenon, asymmetrical
Parkinsonism, and dystonia.

19. Phenotype
 Behavioral variant FTD (bvFTD) is the most
common diagnosis in each of the genetic groups,
although
 MAPT mutation carriers may have prominent
semantic or episodic memory impairment but
that is rarely a presenting feature, nor are other
forms of PPA; however, CBS and, in rare cases,
PSP may both occur.
 In contrast, GRN mutations can present as a PPA
syndrome, either a non-fluent variant of PPA or a
mixed phenotype, not clearly fitting into one of the
three described subtypes. CBS may occur either
alone or in conjunction with PPA, but PSP and FTD-

20.  C9orf72 expansion carriers may have an atypical
neuropsychiatric presentation of bv-FTD with associated
hallucinations or delusions and significantly, family members
of C9orf72 carriers have a greater risk of psychiatric disorders
including autistic spectrum disorders, psychotic illnesses
including schizophrenia, mood disorders and suicide.
 Unlike the other two major genetic groups, C9orf72 expansions
can cause FTD-ALS or ALS alone. PPA is a rare phenotype but
is usually a non-fluent variant when present, and similarly
parkinsonian disorders can occur but are infrequent as a
presenting syndrome.
 Also unlike the other genetic groups, hyperkinetic movement
disorders may occur, and C9orf72 is said to be associated
with a Huntington’s disease-like phenotype on some
occasions.
 The phenotype in the other genetic groups is less clear. TBK1
mutations can cause bvFTD, PPA, CBS, FTD-ALS and ALS
alone—this unique combination within a single family can

21. Imaging
 In presymptomatic MAPT carriers, atrophy is present about 15 years
prior to symptom onset in the anterior and medial temporal lobes,
orbitofrontal lobe and insula.
 In GRN carriers, presymptomatic atrophy can be observed in frontal,
parietal, and insular cortex as well as the striatum around 10 years
prior to symptom onset. Symptomatic GRN carriers commonly have
a very asymmetrical pattern of brain atrophy, and this asymmetry
can be observed around 5 years prior to onset.
 C9orf72 mutation carriers appear to have earlier grey matter
volume loss than the other two groups, before the age of 40, and
potentially more than 25 years prior to symptom onset. This
appears to be particularly focused on the posterior thalamus and its
cortical connections.

23. Advanced Neuroimaging
 1. SPECT
 SPECT with Tc-9 9m Ethylcysteinate dimer (Tc-99m ECD) is the compound, which is essential in
differentiating FTD from Alzheimer’s disease. Tripathi et al. reported a sensitivity of 96%
and specificity of 98% for SPECT in detection of FTD with a positive predictive value of
96% and negative predictive value of 98%.
 2. FDG-PET
 Can detect alteration in brain metabolism that may occur before the appearance of gray matter
atrophy. Asymmetrical low glucose metabolism in orbitofrontal cortex, dorsolateral frontal cortex,
and anterior temporal poles is highly specific for Bv-FTD with a sensitivity and specificity of 80%–
95%. This may vary between different subtypes of PPA, such as asymmetrical bilateral temporal
hypometabolism seen in SV PPA, whereas in nfvPPA, left inferior frontal gyrus, dorsolateral fontal
cortex, and anterior cingulate cortex hypometabolism are seen.
 3. Arterial spin labeling
 Arterial spin labeling (ASL) measures brain perfusion noninvasively in which water protons in arterial
blood are magnetically labeled. It has several advantages over FDG-PET in that it is noninvasive, no
radiation effects, widely available, and low cost. ASL may show hypoperfusion in amygdala,
insula, and medial frontal lobes in FTD. The brain perfusion measured by ASL can be
used as an early biomarker in preclinical stage of genetic FTD, such as decrease in
cerebral blood flow can be seen in pre symptomatic individual who carry GRN or MAPT
mutation.

24. Advanced Neuroimaging
 4. Diffusion Tensor imaging
 Intrinsic functional connectivity between different brain regions can be
measured by resting state functional magnetic resonance imaging (RS-f
MRI). In FTD, there is decreased connectivity between anterior cingulate
cortex and frontoinsular region. In SV PPA, there is reduced connectivity of
temporal lobe is seen. In GRN, mutations left frontal connectivity is
reduced.
 5. Amyloid and Tau PET tracers
 Used to differentiating between FTD and Alzheimer’s disease, such as PET
with amyloid tracer (Pittsburgh compound) can detect amyloid beta
deposits with high sensitivity which may indicate Alzheimer’s disease. In
FTD patients with MAPT mutations associated with 3-repeat and 4-repeat
Tau pathology, there is increased uptake of F-Av-1451 Ligand

25. Blood and CSF biomarkers
 Recent work has identified three markers which will play an important role
in forthcoming trials:
 Neurofilament light chain (NfL),
 progranulin and
 poly(GP) dipeptide repeat proteins (DPRs).
 Increased NfL levels (both in CSF and blood) reflect axonal damage and
appear to be a measure of disease severity, and predict progression and
survival in genetic FTD. Levels are highest in C9orf72-associated ALS and
lowest in MAPT mutation carriers.
 Low serum, plasma or CSF progranulin levels have almost perfect
sensitivity and specificity for detecting pathogenic GRN mutations.
 Increased poly(GP) levels have been identified in the CSF of C9orf72
expansion carriers both presymptomatically and symptomatically.

26. The major FTD Genetic Variants
• MAPT mutation - Mostly a ventral subtype . Midlife onset, strong family history.
• First affects Amygdala, hippocampus, entorhinal cortex, temporal pole, then progresses to anterior insula,
orbitofrontal cortex, ventral straitum.
• Clinically, patients have prominent semantic and episodic memory deficits accompanying the behaviour change.
• GRN mutation – Variable age of onset, familial occurrence at different ages.
• R > L lateralized affection , posterior areas like posterior cingulate, precuneus, parietal neocortex affection seen.
• Patients have associated alexia, agraphia, acalculia, visuospatial and rarely logopenic deficits .
• C9orf72 mutation – m/c genetic cause. Anticipation seen.
• Medial (Pulvinar) thalamic atrophy more common than frontocortical atrophy. Cerebellar atrophy rarely possible.
• Clinically patients may emerge Motor neuron disease with, before, or after bv-FTD syndrome.
• Prominent psychiatric features like Delusions/hallucinations/ fugue like events may occur.
• TBK1, TIA1, TARDBP
, FUS, CHMP2B and VCP mutations – other bvFTD mutations.

28. Differential diagnosis
 Enquiry into the family history and history of progression of behavioral
changes, neuropsychological testing, imaging, and behavioral changes.
 Hematological work up including kidney and liver function tests, thyroid
function tests, vitamin B12 assessment, and complete blood count
 Other reversible causes of dementia such as toxic (metals and drugs) and
infectious causes should be kept in the differentials before arriving a diagnosis
of FTD.
 FTD requires differentiation from AD and DLB.
 History of dysphagia, postural instability with early falls,and pseudobulbar
features help in differentiating progressive supranuclear palsy (PSP) from FTD.
However, PSP and Corticobasal degeneration (CBD) may present as nfvPPA
or bvFTD in the initial stages.[47]
 Due to overlap of symptoms between the two; more often bvFTD is
misdiagnosed as psychiatric illness.
 Mutations affecting C9orf72 have been found to have affiliation with bipolar
disorders and Schizophrenia

29. Management
• SSRI have some role to treat compulsive symptoms.
• No role of Acetylcholinesterase inhibitors.

30. Myths and Pitfalls
• FTD may be early as well as late onset. (GRN mutation).
• FTD mostly spares memory but may have severe amnesia. (when
associated with hippocampal sclerosis or MAPT mutation).
• MRI shows frontotemporal atrophy but may be unrevealing (eg.
C9orf72 mutation), or even have just thalamic or asymmetric
involvement.
• Early memory dysfunction is classic of AD but may occur with MAPT
FTD. Frontal features may be prominent in AD as well. (connection
with family members is preserved in some form).

31. THANK YOU