Fronto-temporal Dementia:Neural circuits, genetics and neuropathology

Dr Ravi SoniSenior Resident

Dept. of Geriatric Mental HealthKGMC

Functional areas of Brain

Prefrontal cortex

1. Orbitofrontal cortex2. Lateral prefrontal cortex

3. Ventromedial cortex4. Limbic system

Frontal lobe Functional circuit

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)

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).

Fronto-temporal Dementia• Frontotemporal dementia (FTD), with its initial description as Pick’s

disease (1892) encompasses a group of progressive neurodegenerative syndromes.

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.

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.

FTD Types1. 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.

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

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.

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.

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

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)

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.

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

Neuropathology• Gross morphological

• Microscopic

• Neuroimaging

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.

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.

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.

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.

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

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.

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&rendertype=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

• Murayama, S. (2008). [Neuropathology of frontotemporal dementia]. Rinshō shinkeigaku = Clinical neurology, 48(11), 998. Retrieved from http://europepmc.org/abstract/MED/19198143/reload=0

• Mohandas, E., & Rajmohan, V. (2009). Frontotemporal dementia: An updated overview. Indian journal of psychiatry, 51 Suppl 1(January), S65–9. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3038533&tool=pmcentrez&rendertype=abstract

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