Part 1: Background Information
Clinically, neuroanatomically, and pathologically heterogeneous group of neurodegenerative
diseases that share a propensity to target the frontal and temporal lobes of the brain
Clinically heterogenous and comprises behavioural FTD and language impairments
Neurodegeneration concentrated at frontal and temporal lobes spares parietal and occipital lobes
Distinguishment from AD: Behavioural disturbances (BvFTD)/language dysfunction
(svPPA/nfvPPA) memory dysfunction
3rd most common early onset dementia
Clinical condition: FTD
Pathological substrate: FTLD
Early onset < 65 yrs • Prevalence of 11/100,000
Strong genetic component: 30-40% familial (10-20% caused by just 3 genes),
Disease progression can vary for 2 (FTD-MND) to 10 years (bvFTD or svPPA)
No cure
The 3 most common FTD genes / three major causal genes account for large majority (>80%) of
familial FTD:
1. C9orf72 (non coding repeat expansion in C9orf72 on chromosome 9p): most common cause
(25% familiar and 5% sporadic)
2. Microtubule-associated protein tau (MAPT)/Tau = chromosome 17
3. Progranulin (GRN) = chromosome 17
At the neuropathological level, protein aggregates containing either MAPT, TARDBP, or FUS are
onbserved in neurons of FTD patients
our knowledge of these disease-causing genes has improved, however, there is still no effective
treatment for FTD
Clinical Presentations
FTD: group of clinical syndromes that result from the degeneration of the frontal and temporal lobes
predominantly. FTD is divided into 2 main canonically variant syndromes based on clinical presentation
1. Behavioural variant FTD (bvFTD), the most common of the major FTD phenotypes characterized
by cognitive decline and behavioural dysfunctions
2. Primary progressive aphasia Language decline:
a. Semantic dementia variant PPA (svPPA)
i. Loss of vocab and degrades semantic knowledge of sensory objects and nonverbal
concepts + words
b. Progressive nonfluent/agrammatic aphasia variant PPA (nfvPPA)
i. Impaired motor speech production and or sentence construction
c. Logopenic variant PPA (lvPPA)
,Note: there is an overlap between the FTD variants and PPA variants semantic + agrammatic variants
of FTD and PPA and bvFTD are associated with FTLD pathology while logopenic variant of PPA is
associated with AD pathology
Patients can develop concomitant parkinsonism or MND at an early or late stage in the disease
course which results in broad clinical phenotype ranging from ALS, to PSP and corticobasal
syndrome
Frontotemporal lobar degeneration (FTLD): umbrella term for the spectrum of FTD related pathologies
Postmortem examination of brains of people clinically presenting with FTD reveals frontotemporal
lobar degeneration associated with tau, TDP-43, or FUS
Part 2: Variants of FTD
BvFTD
Symptoms similar to those detected in psychiatric disorders, clues that such features are FTD may
include a lack of any prior psychiatric history and emergence of certain specific symptoms such as
changes in eating behaviour or social faux pas.
Characterised by:
o Lack of insight
o Impulsive and inappropriate behaviour
o Hypersexuality
o Lack of mental flexibility
o Apathy
o Poor hygiene
o Utilization behaviour
o Change in dietary preference
o OCD traits
Progressive personality and behavioural changes, apathy, and disinhibition in interpersonal
interactions.
Imaging
o Frontal/anterior temporal lobe atrophy via CT or MRI
o Frontal/anterior temporal lobe hypoperfusion or hypometabolism on SPECT or PET
SvPPA
Characterised by:
o Anomia with loss of word meaning
o Object agnosia
o prosopganosia
Language dysfunction is the main symptom during the first 2 years of PPA. Deficits in object
naming, syntax, or word comprehension may become apparent during conversation or may be
identified using speech and language assessment
Maintain fluent speech and correct grammar during the early stages of this disease
Bheavioural changed can be prominenet in patients where right temporal lobe more severely
affected than left temporal lobe
If language is dominant feature, syndrome is subsumed under PPA and term PPA-semantic is used
instead
Part 3: Pathophysiology of FTD
Characterised by the accumulation of protein deposits most cases have inclusions containing
either tau (FTLD-tau) or TDP-43 (FTLD-TDP)
o Current classification based on one of 3 markers (shown by immunohistochemistry)
i. Microtubule-associated protein Tau (in various combinations of 3R and 4R tau)
ii. Transactive response DNA binding protein of 43kD (TDP-43) DNA/RNA
binding protein (FTLD-TD43)
iii. Tumour associated protein FUS (FTLD-FUS)
iv. P62: protein product of SQSTM1 gene that define the FTLD-ubiquitin proteasome
category
v. Ewings sarcoma: protein product of EWS gene
, vi. TATA binding protein associated factor 15: protein product o
Tau/MAPT
Tau protein promotes microtubule assembly and stabilization of microtubules
Under pathological conditions, tau protein becomes hyperphosphorylated, leading to destabilization
of the microtubule
Mutations disrupt microtubule binding and promote tau aggregation
Mutations disrupt alternative splicing at exon 10, increasing 4R tau isoforms, increasing 4R/3R tau
ratio
FTLD-Tau
Diseases are defined by combination of lobar degeneration of inclusions containing 3R tau, 4R tau,
or both forms
Tau is a microtubule-associated protein that promotes microtubule assembly and stability which are
crucial for maintaining neuronal integrity and microtubule transport
Tau is encoded by the MAPT gene comprising 16 exons.
Alternative splicing of MAPT results in 6 isoforms ranging from 352 to 441 amino acids.
Tau isoforms are named based on the number of amino-terminal inserts (0N, 1N, and 2N) or
carboxyl-terminal microtubule binding domain repeats (3R and 4R).
Pathologies with tau as the major abnormal protein include:
o PiD (30%) 3 repeat binding domains spliced in and is a 3-repeat (3R) tauopathy
o PSP (31%) 4R tauopathy
o CBD (35%) 4R tauopathy
o Argyrophilic grains disease (AGD) (4%) 4R tauopathy
Pick Disease
Sporadic dementia
Characteristically beginning in 5th and 6th decades of life
Characterized by presence of Pick bodies – rounded, homogenous neuronal cytoplasmic inclusion
faintly visible on H&E stanining
o Immunohistochemical staining shows these inclusions contain 3R
o Strongly argyrophilic + detected using silver stains
o Pick cells (ballooned neurons) present
Severe behavioural changes
Clinical pattern of symptoms corresponds to distribution of lesions (frontal lobe early in disease
course)
Gross Appearance
Cerebral atrophy is most evident in frontal loves
Typically spares posterior third of the superior temporal gyrus
Severe involvement of hippocampus can be present results in memory loss
Parietal cortex rarely involved
Occipital cortex always spared
Greater dilation of the anterior portion of the frontal and temporal horns of the lateral ventricles
accentuated when there is also striatal atrophy
Microscopic lesions
Regions of cerebral cortex show neuronal loss associated with dense astrocytic gliosis + cortical
microvaculoation
White atter in gyri show secondary attentuation
TDP-43
Main component of the ubiquitin-positive inclusions in the majority of FTLD-U
Clinically, neuroanatomically, and pathologically heterogeneous group of neurodegenerative
diseases that share a propensity to target the frontal and temporal lobes of the brain
Clinically heterogenous and comprises behavioural FTD and language impairments
Neurodegeneration concentrated at frontal and temporal lobes spares parietal and occipital lobes
Distinguishment from AD: Behavioural disturbances (BvFTD)/language dysfunction
(svPPA/nfvPPA) memory dysfunction
3rd most common early onset dementia
Clinical condition: FTD
Pathological substrate: FTLD
Early onset < 65 yrs • Prevalence of 11/100,000
Strong genetic component: 30-40% familial (10-20% caused by just 3 genes),
Disease progression can vary for 2 (FTD-MND) to 10 years (bvFTD or svPPA)
No cure
The 3 most common FTD genes / three major causal genes account for large majority (>80%) of
familial FTD:
1. C9orf72 (non coding repeat expansion in C9orf72 on chromosome 9p): most common cause
(25% familiar and 5% sporadic)
2. Microtubule-associated protein tau (MAPT)/Tau = chromosome 17
3. Progranulin (GRN) = chromosome 17
At the neuropathological level, protein aggregates containing either MAPT, TARDBP, or FUS are
onbserved in neurons of FTD patients
our knowledge of these disease-causing genes has improved, however, there is still no effective
treatment for FTD
Clinical Presentations
FTD: group of clinical syndromes that result from the degeneration of the frontal and temporal lobes
predominantly. FTD is divided into 2 main canonically variant syndromes based on clinical presentation
1. Behavioural variant FTD (bvFTD), the most common of the major FTD phenotypes characterized
by cognitive decline and behavioural dysfunctions
2. Primary progressive aphasia Language decline:
a. Semantic dementia variant PPA (svPPA)
i. Loss of vocab and degrades semantic knowledge of sensory objects and nonverbal
concepts + words
b. Progressive nonfluent/agrammatic aphasia variant PPA (nfvPPA)
i. Impaired motor speech production and or sentence construction
c. Logopenic variant PPA (lvPPA)
,Note: there is an overlap between the FTD variants and PPA variants semantic + agrammatic variants
of FTD and PPA and bvFTD are associated with FTLD pathology while logopenic variant of PPA is
associated with AD pathology
Patients can develop concomitant parkinsonism or MND at an early or late stage in the disease
course which results in broad clinical phenotype ranging from ALS, to PSP and corticobasal
syndrome
Frontotemporal lobar degeneration (FTLD): umbrella term for the spectrum of FTD related pathologies
Postmortem examination of brains of people clinically presenting with FTD reveals frontotemporal
lobar degeneration associated with tau, TDP-43, or FUS
Part 2: Variants of FTD
BvFTD
Symptoms similar to those detected in psychiatric disorders, clues that such features are FTD may
include a lack of any prior psychiatric history and emergence of certain specific symptoms such as
changes in eating behaviour or social faux pas.
Characterised by:
o Lack of insight
o Impulsive and inappropriate behaviour
o Hypersexuality
o Lack of mental flexibility
o Apathy
o Poor hygiene
o Utilization behaviour
o Change in dietary preference
o OCD traits
Progressive personality and behavioural changes, apathy, and disinhibition in interpersonal
interactions.
Imaging
o Frontal/anterior temporal lobe atrophy via CT or MRI
o Frontal/anterior temporal lobe hypoperfusion or hypometabolism on SPECT or PET
SvPPA
Characterised by:
o Anomia with loss of word meaning
o Object agnosia
o prosopganosia
Language dysfunction is the main symptom during the first 2 years of PPA. Deficits in object
naming, syntax, or word comprehension may become apparent during conversation or may be
identified using speech and language assessment
Maintain fluent speech and correct grammar during the early stages of this disease
Bheavioural changed can be prominenet in patients where right temporal lobe more severely
affected than left temporal lobe
If language is dominant feature, syndrome is subsumed under PPA and term PPA-semantic is used
instead
Part 3: Pathophysiology of FTD
Characterised by the accumulation of protein deposits most cases have inclusions containing
either tau (FTLD-tau) or TDP-43 (FTLD-TDP)
o Current classification based on one of 3 markers (shown by immunohistochemistry)
i. Microtubule-associated protein Tau (in various combinations of 3R and 4R tau)
ii. Transactive response DNA binding protein of 43kD (TDP-43) DNA/RNA
binding protein (FTLD-TD43)
iii. Tumour associated protein FUS (FTLD-FUS)
iv. P62: protein product of SQSTM1 gene that define the FTLD-ubiquitin proteasome
category
v. Ewings sarcoma: protein product of EWS gene
, vi. TATA binding protein associated factor 15: protein product o
Tau/MAPT
Tau protein promotes microtubule assembly and stabilization of microtubules
Under pathological conditions, tau protein becomes hyperphosphorylated, leading to destabilization
of the microtubule
Mutations disrupt microtubule binding and promote tau aggregation
Mutations disrupt alternative splicing at exon 10, increasing 4R tau isoforms, increasing 4R/3R tau
ratio
FTLD-Tau
Diseases are defined by combination of lobar degeneration of inclusions containing 3R tau, 4R tau,
or both forms
Tau is a microtubule-associated protein that promotes microtubule assembly and stability which are
crucial for maintaining neuronal integrity and microtubule transport
Tau is encoded by the MAPT gene comprising 16 exons.
Alternative splicing of MAPT results in 6 isoforms ranging from 352 to 441 amino acids.
Tau isoforms are named based on the number of amino-terminal inserts (0N, 1N, and 2N) or
carboxyl-terminal microtubule binding domain repeats (3R and 4R).
Pathologies with tau as the major abnormal protein include:
o PiD (30%) 3 repeat binding domains spliced in and is a 3-repeat (3R) tauopathy
o PSP (31%) 4R tauopathy
o CBD (35%) 4R tauopathy
o Argyrophilic grains disease (AGD) (4%) 4R tauopathy
Pick Disease
Sporadic dementia
Characteristically beginning in 5th and 6th decades of life
Characterized by presence of Pick bodies – rounded, homogenous neuronal cytoplasmic inclusion
faintly visible on H&E stanining
o Immunohistochemical staining shows these inclusions contain 3R
o Strongly argyrophilic + detected using silver stains
o Pick cells (ballooned neurons) present
Severe behavioural changes
Clinical pattern of symptoms corresponds to distribution of lesions (frontal lobe early in disease
course)
Gross Appearance
Cerebral atrophy is most evident in frontal loves
Typically spares posterior third of the superior temporal gyrus
Severe involvement of hippocampus can be present results in memory loss
Parietal cortex rarely involved
Occipital cortex always spared
Greater dilation of the anterior portion of the frontal and temporal horns of the lateral ventricles
accentuated when there is also striatal atrophy
Microscopic lesions
Regions of cerebral cortex show neuronal loss associated with dense astrocytic gliosis + cortical
microvaculoation
White atter in gyri show secondary attentuation
TDP-43
Main component of the ubiquitin-positive inclusions in the majority of FTLD-U
