Frontotemporal lobar degeneration

Frontotemporal lobar degeneration
A human brain showing frontotemporal lobar degeneration causing frontotemporal dementia.
OMIM	600274
DiseasesDB	10034
MeSH	D003704

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

Synonyms and keywords:

Frontotemporal lobar degeneration, FTD, FTLD, Frontotemporal dementia, Pick’s disease

Overview

Frontotemporal lobar degeneration (FTLD) is an umbrella term that refers to a group of progressive brain diseases, which are heterogeneous concerning neuropathology and etiology but share atrophy of the frontal and/or temporal cortex as a morphological feature. The clinical manifestations of the disorder depend on the primary site of atrophy and dominated by behavior alterations and language impairment. The mean survival after diagnosis is from 3 to 10 years.

Historical Perspective

Historically, patients having symptoms of frontotemporal lobe degeneration were diagnosed as Pick disease after Arnold Pick described a 71-year-old man with dementia with behavioral symptoms and sensory aphasia for the first time in 1892. This patient demonstrated severe atrophy of frontotemporal lobes on autopsy.Histopathologic examination of tissue samples showed “ballooned” achromatic neurons, which was referred to as Pick cells and argyrophilic inclusions within frontal neurons that were referred to as Pick bodies( composed of insoluble filaments of the microtubule-associated protein tau). Later on, autosomal dominant forms of Pick disease were reported, and the mutations in the gene encoding the microtubule-associated protein tau (MAPT) located at 17q21 were identified. At present, 42 mutations in MAPT have been described in 119 families with FTLD or related disorders. However, in an estimated 60% to 70% of all patients with FTLD undergoing autopsy, no tau pathologic characteristics can be demonstrated. This autopy finding suggets that insoluble tau is not necessary for the clinical phenotype to develop..

Classification

Frontotemporal lobe degeneration patients can be classified into three different clinical syndromes depending on the early and predominant symptoms. The overlap between these clinical syndromes can occur as the disease progresses to involve both temporal and frontal lobes more diffusely.

1. Behavioural-Variant Frontotemporal Dementia (bvFTD)

1. Semantic Dementia (SD)
2. Progressive Nonfluent Aphasia (PNFA)

Behavioural-Variant Frontotemporal Dementia (bvFTD)

Behavioral variant frontotemporal dementia is characterized by a progressive decline in executive and interpersonal skills, with altered emotions and the emergence of a variety of abnormal behaviors including disinhibition, obsessions, apathy, and stereotypes. The bvFTD can develop indolently, and early detection may depend on small changes of social circumstances, reduced libido, idiosyncratic lapses of taste or social awareness, and altered dietary or musical preferences.

Semantic Dementia (SD)

Semantic dementia is also known as semantic variant primary progressive aphasia (svPPA) is a highly characteristic syndrome led by the progressive breakdown of semantic memory—a type of long term memory system that stores knowledge about concepts and objects based on the individual’s accumulated experience of the world. Typically, semantic dementia initially presents with progressive loss of semantic knowledge about words, concepts and objects.

Progressive Nonfluent Aphasia (PNFA)

Progressive Nonfluent Aphasia (PNFA) is characterized by a progressive breakdown in language output with slow, impaired production, effortful speech, and comprehension of grammar, and motor speech deficits. Apraxia of speech is highly characteristic of PNFA, and dysarthria is more variably present. Some patients have expressive agrammatism with terse telegraphic phrases as the dominant feature of the disease, whereas, in others, the syndrome is dominated by speech sound (phonemic) or articulatory (phonetic, speech apraxic) errors.

Frontotemporal Lobar Degeneration (FTLD) Overlap Syndromes

The frontotemporal degeneration spectrum overlaps with the syndromes of corticobasal degeneration(CBD), progressive supranuclear palsy(PSP), and FTD with motor neuron disease. CBD patients present with dystonia, limb apraxia, postural instability, Axial, and limb rigidity, myoclonus, supranuclear gaze palsies, the ‘alien limb phenomenon,’ and cortical sensory loss. The progressive supranuclear palsy syndrome(PSP) is characterized by impairment of vertical gaze, frontal behavioral changes with marked cognitive slowing, and early postural instability with falls.

Pathophysiology

The gross finding of frontotemporal lobar degeneration is likely produced by several etiologically distinct processes, with unique genetic and histopathological findings. Accordingly, there are a number of possible histopathological findings at post-mortem:

• tau inclusions (either with Pick bodies or without)
• ubiquitin positive (tau-negative) inclusions - in the majority of cases that have this type of pathology the ubiquitinated inclusions contain a protein called TDP-43. There are three subtypes of this type of pathology. Mackenzie et al (and subsequently Davidson et al) describe the following: type 1 with intranuclear inclusions; type 2 with neurites predominantly and type 3 with cytoplasmic inclusions predominantly. It should be noted that not all ubiquitin-positive, tau negative cases stain for TDP-43 e.g. the CHMP2B cases but also other cases.
• Dementia lacking distinctive histology (DLDH) - A rare and controversial entity - new analyses have allowed many cases to be reclassified into one of the positively-defined subgroups.

Genetics

Many cases (possibly up to 50%) of FTLD are genetic rather than sporadic. Mutations in the Tau gene (on chromosome 17q21 - known as MAPT or Microtubule Associated Protein Tau) can cause FTLD and there are over 40 known mutations at present. A series of new mutations associated with FTLD has been recently described in the progranulin gene which is remarkably also on chromosome 17q21. Patients with progranulin mutations have type 1 TDP-43 positive, tau negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, whereas the mutations seen in the progranulin gene associated with FTLD suggests a deficit in progranulin may be the problem. There are currently 2 other known genes that can cause FTLD: CHMP2B (on chromosome 3) which is associated with a behavioural syndrome (mainly in a large Jutland cohort); and VCP (valosin-containing protein, on chromosome 9) which is associated with the IBMPFD syndrome (inclusion body myopathy, Paget's disease and frontotemporal dementia). These 2 genes only account for a tiny proportion of cases. A locus on chromosome 9 is associated with FTD-MND (or FTD-ALS) i.e. frontotemporal dementia associated with motor neurone disease (or amyotrophic lateral sclerosis) - the hunt for this gene is currently the focus of a number of research labs around the world.

Causes

FTD patients have an abnormal buildup of altered brain proteins in the frontal and temporal lobes of the brain, the tau protein, and the transactive response DNA binding protein-43 (TDP-43) are commonly involved. The specific functions of these proteins are not entirely known, but these proteins are critical for the proper function of neurons. In patients with FTD, these proteins are misfolded, clumped, or aggregate together, leading to atrophy of frontal and temporal lobes.

• Almost 60% of patients have sporadic or non familial form of disease
• Almost 40% of patients have family history of neurodegenerative disorder
• Almost 10-25% of patients following major gene mutations have been identified.
  • MAPT
  • GRN
  • C9ORF72
• Following gene mutations are rare causes of FTD.
  • VCP
  • TARDBP,
  • FUS
  • CHMP2B
  • TBK1

Differential Diagnosis Of Major or Mild Frontotemporal Neurocognitive Disorder

• Other neurocognitive disorders

• Alzheimer's disease
• Lewy bodies
• Parkinson's disease

• Other neurological conditions

• Corticobasal degeneration
• Motor neuron disease
• Progressive supranuclear palsy

• Other mental disorders and medical conditions

• Bipolar disorders
• Major depression
• Schizophrenia

• The following table outlines the main findings of the diseases which must be differentiated from dementia with frontotemporal lobar degeneration as they may share common characteristics of cognitive impairment:

Cause of dementia	Clinical features											Associated features	Nature of progression	Histopathological findings
	Cognitive impairment
	Recall	Recollection	Cue requirement for recall	Infirngement of thoughts	Semantic memory	Procedural memory	Working memory	Awareness	Attention	Executive functioning issues	Visuo-spatial skills
Alzheimer's disease	+++ (Slow cognitive and functional decline with early loss of awareness)	+++	Not helpful	+++	++	-	++	+++	++	++	++	Focal neurological signs absent during early stage (may develop later) Mild extrapyramidal signs	Has the following clinical stages: Pre-clinical Mild cognitive impairment Advanced dementia (full blown dementia)	Neurofibrillary tangles Senile (neuritic) plaques
Lewy body dementia	++	-	Helpful	+++	+	+	+++	+	+++	+++	+++	Focal neurological signs present in majority Strongly associated with extrapyramidal signs Autonomic changes	Early visual hallucinations Muscle rigidity Sleep disturbance	α-synuclein deposits present in neurons
Frontotemporal lobar degeneration	+/-	-	Helpful	+++	+	-	+++	+++	++	+++	-	Focal neurological signs present (motor neuron disease) Extrapyramidal signs present (familial frontotemporal lobar degeneration) Onset in young age Strong familial association Focal atrophy of frontal and temporal lobes Knife-edge atrophy noted on MRI Personality and behavioral changes Language impairment	Two major variants: Progressive nonfluent aphasia Semantic variant Progressive supranuclear palsy	Pick bodies Corticobasal degeneration Ubiquitinated inclusions
Vascular dementia	+ (Dysexecutive syndrome)	-	Helpful	+	+	+	++	-	++	+++	+	Focal neurological signs present typically Mild extrapyramidal signs Depression Mild motor signs in subcortical vascular dementia Slowed processing speed Presentation might be similar to Alzheimer's disease	Stepwise progression and focal neurologic signs (also known as multi-infarct dementia or poststroke dementia)	Multifocal and/or diffuse lesions (lacunes and microinfarcts) The following brain areas may be involved: Subcortical area Thalamus Frontobasallimbic system White matter lesions Hippocampal sclerosis Diffuse post-ischemic lesions

Epidemiology and Demographics

The prevalence of FTD in population-based studies varied from 2.7/100,00 to 9.4 /100,000 in the 60-69-year-old group in the Zuid-Holland district, Netherlands. Two studies reported a similar incidence of FLD in adults with early-onset dementia in Cambridge, UK( 3.5/100,000 person-years in 45-64 years old group), and Rochester, USA( 3.3/100,000 person-years in 50-59 age group).

The majority of the patients manifest the disease in the sixth decade of life, but the age of onset can vary widely from the third to the ninth decade. Although FTLD is generally considered presenile dementia, individuals over the age of 65 years account for almost 20–25% of all cases.

Risk Factors

• Genetic predisposition
• Motor neuron disease

Diagnosis

Symptoms

• Parkinsonism with dystonia
• Dementia
• Urinary incontinence
• Neck stiffness
• Memory loss

Physical Examination

Neuro

• Ocular motility abnormalities
• Pyramidal tract dysfunction
• Frontal lobe release signs
• Perseverative vocalizations
• Bradykinesia
• Postural instability

DSM-V Diagnostic Criteria for Major Or Mild Frontotemporal Neurocognitive Disorder

“

A.The criteria are met for major or mild neurocognitive disorder. AND B.The disturbance has insidious onset and gradual progression. AND C.Either (1) or (2); 1.Behavioral variant; a.Three or more of the following behavioral symptoms: i.Behavioral disinhibition. ii.Apathy or inertia. iii.Loss of sympathy or empathy. iv.Perseverative, stereotyped or compulsive/ritualistic behavior. v.Hyperorality and dietary changes. b.Prominent decline in social cognition and/or executive abilities. 2.Language variant: a.Prominent decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension. AND D.Relative sparing of learning and memory and perceptual-motor function. AND E.The disturbance is not better explained by cerebrovascular disease, another neurodegenerative disease, the effects of a substance, or another mental, neurological, or systemic disorder. Probable frontotemporal neurocognitive disorderis diagnosed if either of the following is present; otherwise, possible frontotemporal neurocognitive disorder should be diagnosed: 1.Evidence of a causative frontotemporal neurocognitive disorder genetic mutation, from either family history or genetic testing. 2.Evidence of disproportionate frontal and/or temporal lobe involvement from neuro imaging. Possible frontotemporal neurocognitive disorderis diagnosed if there is no evidence of a genetic mutation, and neuro imaging has not been performed.

”

See also

• Corticobasal degeneration

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