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Frontotemporal Lobar Dementia Exam/Essay Summary Notes

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  • Course
  • NEUR0010 Neurobiology of Brain Injury and Disease (NEUR0010)
  • Institution
  • University College London (UCL)

Summary of notes structured in exam and essay format complete with point, evidence, analysis, and critical thinking. Structured based on marking criteria.

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  • October 10, 2022
  • 17
  • 2022/2023
  • Summary

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  • frontotemporal lobar dementia

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  • University College London (UCL)
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  • NEUR0010 Neurobiology of Brain Injury and Disease (NEUR0010)
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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

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