Frontotemporal degeneration (FTD) is a spectrum of neurodegenerative conditions that often occur in individuals younger than 65 years of age. (Knopman and Roberts, 2011). Many cases are familial, but sporadic cases suggest that environmental triggers also exist. Several genetic etiologies are known, but environmental triggers remain largely undefined.
FTD disorders are identified by their clinical symptoms which present as behavioral/cognitive changes, or language deficits, or decline in motor function. The underlying biology of these clinical diagnoses are diverse. Many affected individuals have overlapping symptoms, particularly as the disease progresses.
Two proteins most commonly aggregate in nerve cells in FTD disorders— tau protein or TDP-43 protein. These are the defining pathological hallmark of FTD.
Behavioral Variant FTD
The most common FTD subtype is behavioral variant FTD (bvFTD), characterized by changes in affect (emotional presentation of the individual), personality and social comportment. People with bvFTD typically have little insight into this change, though it is obvious to those around them. The key is that their behavior is clearly different from their prior functioning and inappropriate based on social norms. They are often disinhibited and impulsive, saying things and acting in ways that are incongruous with the situation. Childishness, lack of empathy, and an insensitive, self-centered demeanor are common features of the behavioral variant. Patients are sometimes apathetic. Obsessive-compulsive behaviors, changes in sexual drive, food cravings (especially carbohydrates, sweets or a specific food), and criminal or violent behavior can also occur.
In 2011, a multidisciplinary group expanded the specific clinical criteria for the diagnosis of bvFTD which both improved diagnostic accuracy and now allows for earlier diagnosis of “possible” as opposed to “probable” bvFTD (Rascovsky et al.,2011).
Primary Progressive Aphasia
Primary progressive aphasia (PPA) is the FTD subtype characterized by progressive loss of oral and written language skills. Comprehension and language expression may be involved. Consensus criteria for diagnosing the PPA variants was published in 2011 (Gorno-Tempini et al, 2011). When the problem is primarily with anomia and loss of word meaning, it is referred to as the semantic variant of PPA. Here, the meaning of specific words is lost, and both comprehension of the word and the ability to retrieve the name of an object may be lost. The patient retains fluent speech and proper grammar; however, paraphasias (word substitution errors) are common. This subtype of PPA is usually associated with TDP-43 pathology.
On the other end of the spectrum, the nonfluent/agrammatic variant of PPA primarily affects speech production. In this case, individuals lose proper grammar (especially their ability to use small connecting words) but have preserved language comprehension for specific items/objects. This causes speech to become effortful and hesitant; sentence length becomes progressively truncated. Writing and language comprehension may be affected in the same manner. This subtype of PPA is usually associated with tau pathology.
Logopenic PPA is the third major PPA variant. In this variant, speech is slow, but grammar and comprehension are less affected. Impairment in the repetition of multisyllabic words and particularly phrases is a key feature. Sound substitution (phonemic) paraphasias are also seen in this group, as in a false word that rhymes with the intended word. Logopenic aphasia is usually associated with an underlying Alzheimer’s pathology.
As many as 20% of FTD patients develop signs of motor neuron disease (MND), often called ALS in North America for Lou Gehrig’s disease. Likewise, approximately half of individuals diagnosed with the most common form of MND, amyotrophic lateral sclerosis (ALS) exhibit neuropsychological symptoms or cognitive decline (Strong, et al 2016, Elahi & Miller, 2017). A growing number of experts believe that ALS and FTD fall on a clinical continuum (Strong, et al, 2016). A smaller number of these patients develop full-blown FTD withALS. The most common genetic cause of familial FTD-ALS results from a mutation resulting in expanded repeats the C9orf72 gene.
With or without the C9 gene expansion, the addition of motor neuron disease to FTD is a compromising factor that greatly reduces median survival to less than three years (Olney, et. al 2005). Behavioral symptoms complicate the management of dysphagia (difficulty swallowing) as well as respiratory dysfunction as respiration therapy and percutaneous endoscopic gastrostomy (PEG) feeding tubes are not well tolerated by the patient. (Alagiakrishnan et al. 2013).
Although significant phenotypic heterogeneity exists among C9orf72 carriers, the majority present with either bvFTD or FTD-ALS. PPA variants, including nonfluent/agrammatic and semantic, are rare. Prominent psychosis with delusions and hallucinations are relatively common (Boeve et al. 2012). Research into the clinical features associated with the C9orf72 mutation is active and ongoing.
For more information on FTD and MND, consider this resource for general practitioners, offered by the UK-based MNDA.
Parkinsonian-like FTD Syndromes
FTD subtypes may also be associated with the Parkinson’s-plus syndromes of progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS). Frontal lobe degeneration and the presence of Tau protein aggregates in the brain have classified these as FTD disorders. PSP and CBS both demonstrate motor deficits as the dominant clinical symptom at diagnosis. PSP patients show early signs of postural instability and vertical gaze impairments. Some PSP patients can show clinical signs of bvFTD prior to the motor deficits. CBS-like symptoms of asymmetrical movement problems, abnormal muscle tone, complex tremors, myoclonus and limb apraxia form the core CBS phenotype. Like PSP, some CBS patients may present with bvFTD symptoms first. Five phenotypic presentations of CBS have recently been defined to support more accurate diagnosis (Armstrong et al., 2013).
- Clinical Criteria of Behavioral Variant FTD – In 2011, an international consortium developed and published revised guidelines for the diagnosis of behavioral variant frontotemporal dementia.
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