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  Disease summary:

  
  
  
  
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    Frontotemporal lobar degeneration (FTLD) is a nonamnestic primary neurodegenerative disorder that is clinically, neuropathologically, and genetically heterogeneous. Characteristic symptoms include progressive behavioral disturbance and/or language impairment, with variable underlying neuropathologic substrates.

    
    
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    Clinically FTLD is comprised of two major subtypes:

    
    
    
    
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      The behavioral variant (bvFTD), a progressive cognitive or behavioral syndrome

      
      
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      Primary progressive aphasia (PPA), a degenerative language disorder

      
      
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      PPA variants are further subdivided into three variants based on the specific language abnormality present: the nonfluent-agrammatic variant (naPPA), semantic variant (svPPA), and logopenic variant (lvPPA). lvPPA is considered an atypical presentation of Alzheimer disease (AD) and will not be further discussed as an FTLD clinical syndrome.

    
    
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    FTLD patients may present with or acquire concomitant motor disorders including parkinsonism or the motor neuron disease, amyotrophic lateral sclerosis (ALS-FTLD). There is also overlap with the extrapyramidal movement disorders progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).

    
    
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    FTLD clinical spectrum disorders occur most commonly in patients before the age of 65 years, and have a similar prevalence to AD in this age group.

    
    
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    The only known nongenetic risk factor for FTLD is a history of head trauma.

    
    
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    Neuropathologically FTLD can be broadly divided into two major categories: tauopathies (FTLD-tau), a class of neurodegenerative diseases which contain aggregations of the abnormally modified microtubule-binding protein tau, and FTLD-TDP, characterized by inclusion bodies formed from the DNA-binding protein, TDP-43.

    
    
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    FTLD-tau consists of clinical FTLD-spectrum disorders with neuropathologic diagnoses of Pick disease, corticobasal degeneration (CBD), PSP, argyrophilic grain disease, multisystem tauopathy, or FTLD with parkinsonism linked to chromosome 17 (FTDP-17).

    
    
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    FTLD-TDP has four major subtypes (A-D) based on the morphology of TDP-43 positive inclusions and cortical layers involved. All FTLD-spectrum clinical disorders can be associated with each of these subtypes, while most genetic etiologies of FTLD-TDP are generally associated with a specific neuropathologic subtype.

    
    
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    A minority of FTLD cases have inclusions composed of the fused in sarcoma (FUS) protein (FTLD-FUS), a RNA-binding protein similar to TDP-43, and in a small number of others the pathologic protein has not yet been identified.

  
  
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  Hereditary basis:

  
  
  
  
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    Approximately 40% of FTLD patients have a family history of dementia and/or movement disorder and in 10% to 30% of cases an autosomal dominant inheritance pattern is detected. The remaining cases are apparent sporadic cases.

    
    
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    Autosomal dominant mutations in five genes have been associated with FTLD: MAPT, GRN, C9orf72, VCP, and CHMP2B. Of these, mutations in MAPT, GRN, and a hexanucleotide expansion mutation in C9orf72 are the most common, while mutations in VCP and CHMP2B are rare. Together these genes explain only about 30% of familial FTLD cases suggesting that there are still additional genes to be discovered.

    
    
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    Mutations in a few additional genes, TARDBP and FUS, which are primarily associated with ALS phenotypes have been identified in a few FTLD cases.

  
  
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  Differential diagnosis:

  
  
  
  
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    Includes other primary neurodegenerative conditions (AD, dementia with Lewy bodies [DLB], Parkinson disease dementia), nondegenerative primary central nervous system (CNS) conditions (cerebrovascular disease or vascular dementia, CNS malignancy, CNS trauma, CNS infections, and CNS inflammatory diseases—eg, vasculitis, systemic lupus erythematosus, neurosarcoidosis, multiple sclerosis), primary psychiatric (nonprogressive FTLD “phenocopy”) disorders (schizophrenia, late-onset psychosis, autism/Asperger spectrum disorders, decompensated personality disorders, depression, and bipolar disease), and systemic medical conditions (hypothyroidism, drug intoxication, medically induced delirium, vitamin B₁₂ deficiency, and other toxic or metabolic CNS insults). AD is a common misdiagnosis, and is encountered in approximately 20% of all FTLD clinical cases at autopsy.

Diagnostic Criteria for FTLD

Diagnostic evaluation should include (Fig. 123-1 algorithm)

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  Cognitive examination consistent with prominent early behavioral or executive impairment (bvFTD) or language impairment (PPA) with relative sparing of memory and visuospatial function.

  
  
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  Evaluation of symptoms for progression over time (≥1 year), as evidenced by serial examination or caregiver history.

  
  
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  Evaluation of symptoms for associated functional impairment.

  
  
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  Serum and cerebrospinal fluid (CSF) laboratory studies to exclude toxic, infectious, inflammatory, and metabolic etiologies if suspected.

  
  
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  Neuroimaging for regional atrophy or hypometabolism supportive of FTLD-spectrum diagnosis (see later) and exclusion of structural etiologies (eg, malignancy).

  
  
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  Detailed neurologic examination to detect comorbid motor neuron disease (ALS) or extrapyramidal movement disorder (parkinsonism including PSP and CBS).

  
  
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  Biomarker (CSF tau and beta-amyloid [Aβ] levels or Aβ ligand neuroimaging) evaluation to exclude patients with biomarkers suggestive of underlying AD neuropathology (recent FTLD and AD criteria indicate these measures have utility for research purposes but need to be validated for widespread clinical use).

And the absence of

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  Any other neurodegenerative, non-neurodegenerative primary CNS, medical, or psychiatric disorder that better accounts for the observed pattern of clinical deficits.

Clinical Characteristics

bvFTD

It is a cognitive or behavioral disorder associated with atrophy and neurodegeneration in the anterior cingulate gyrus, insular cortex, basal ganglia, and dorsolateral and ventromedial frontal lobes. Clinical features include behavioral disinhibition and obsessive, ritualistic behaviors. There is a loss of empathy or concern for others and patients can display difficulty multitasking and set-shifting (executive dysfunction). Dietary changes, including carbohydrate craving and hyperorality are common. As the disease progresses to involve more medial frontal areas, apathy and inertia often predominate. Problematic behaviors can be severely detrimental to patient’s functioning and extremely difficult for caregivers to manage. Often patients come to medical attention after resultant serious detrimental interpersonal problems such as loss of employment. At autopsy roughly equal numbers of patients have FTLD-tau and FTLD-TDP diagnoses.

naPPA

It is a primary language disorder characterized by grammatical comprehension and expressive deficits with associated effortful speech. A motor planning deficit and resulting articulation difficulties (apraxia of speech) and executive dysfunction are also common. Single word comprehension and object knowledge are not typically affected. Atrophy is most prominent in the dominant posterior or inferior frontal and anterior insular cortex. Extrapyramidal symptoms of comorbid CBS and PSP are frequent and can precede or emerge after symptoms of naPPA. The majority of naPPA cases have FTLD-tau pathology.

svPPA

This has the key feature of loss of word meaning and object knowledge. As patients lose the ability to identify objects, they progressively use more imprecise terms to describe them (eg, “animal” or “bird” to describe a “pelican”). Speech is fluent and grammatically correct; however, it is usually empty of meaningful content. These patients also have difficulty reading phonetically irregular words (eg, choir, yacht) due to loss of semantic knowledge required for correct pronunciation (surface dyslexia). Corresponding atrophy is in the dominant anterior temporal lobe. Behavioral features of ritualistic and compulsive behavior with loss of empathy may emerge, corresponding to nondominant anterior temporal lobe involvement. FTLD-TDP is the most common neuropathology associated with svPPA.

Parkinsonian Disorders

PSP and CBS are akinetic-rigid syndromes characterized by axial rigidity, early falls and vertical gaze palsy, and asymmetric rigidity, limb apraxia, and cortical sensory loss, respectively. Both, in contrast to idiopathic Parkinson disease, typically have a poor response to dopaminergic treatment. These syndromes can develop cognitive dysfunction consistent with naPPA and other FTLD-spectrum disorders, as earlier, and are considered a part of the FTLD-spectrum of clinical syndromes. Similar extrapyramidal symptoms (bradykinesia and rigidity) are also typical in FTDP-17.

FTLD-ALS

FTLD clinical syndromes can also accompany or precede clinical signs of ALS, which include upper motor neuron findings of spasticity and hyper-reflexia, and lower motor neuron signs of muscle wasting and fasciculations. In addition, some FTLD patients have subclinical signs of motor neuron disease on electromyographic testing and at autopsy. FTLD-ALS can include bvFTD and all other clinical FTLD syndromes, and is highly predictive of a TDP-43 proteinopathy (FTLD-TDP).