Clinical Features

Frontotemporal degeneration (FTD) is a neurodegenerative condition that often occurs in individuals younger than 65 years of age.  Although the overall incidence and prevalence is unknown, it may be as common as Alzheimer’s disease (AD) in this young-onset group.  In later years, AD is clearly more prevalent.  Many cases are familial, but sporadic cases suggest that environmental triggers also exist.  Several genetic etiologies are known but environmental triggers remain largely undefined.

The underlying biology of the FTD variants is diverse.  There are several clinical variants that involve cognition, behavior/affect and language.  One major subgroup involves affect and social comportment (behavioral variant or bvFTD, also commonly referred to as frontotemporal dementia), and another is the syndrome of primary progressive aphasia (PPA).  A dysexecutive syndrome may also be seen.  Many or most affected individuals have overlapping symptoms, particularly as the disease progresses.  The following descriptions of FTD subtypes present the most classic features of these subtypes. However, it is important to remember that the phenotype is highly variable and that many patients present with only some of the features or even with a memory disorder.

BEHAVIORAL VARIANT

One major FTD subtype is the behavioral variant.  This subtype includes disorders of affect, 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 and often inappropriate. They are often disinhibited and impulsive, saying things and acting in ways that are incongruous with the situation.  A lack of empathy, childishness and an insensitive, self-centered demeanor are also common features of the behavioral variant.  They are sometimes apathetic.  Obsessive compulsive behaviors, changes in sexual drive, food cravings (especially carbohydrates, sweets or a specific food), and criminal or violent behavior also occur.  In 2011, a multidisciplinary group developed specific clinical criteria for the diagnosis of this variant which both improves diagnostic accuracy and allows for earlier diagnosis of a “possible” as opposed to “probable” bvFTD.  See the associated FTD Clinical Criteria chart.

Another FTD subtype is the dysexecutive syndrome.  Here, an affected individual suffers from problems with complex reasoning and problem solving.  Planning, sequencing and goal- directed behavior are involved.  Problems with controlling attention and disinhibition underlie the syndrome; individuals can become stimulus-bound.  These individuals cannot multitask, and they need guidance to remain on simple tasks including basic activities of daily living.  In contrast, memory testing remains close to normal and these individuals may do well on simple mental status tests.

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.  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.  Speech remains fluent and grammar is good, 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, speech production may be the primary symptom, and the term nonfluent/agrammatic variant of PPA is used.  In this case, individuals lose grammar (the small connecting words) but have preserved language comprehension for specific items/objects.  This causes speech to become effortful, hesitant, and 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 these individuals, 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.

FTD AND MOTOR NEURON DISEASE

As many as 20% of FTD patients develop signs of motor neuron disease (MND).  Likewise approximately half of amyotrophic lateral sclerosis (ALS) patients develop some fronto-executive problems (Lomen-Hoerth et.al 2003).  A smaller number of these patients develop full-blown FTD-ALS. Many patients that have the combination syndrome carry an expansion in the C9orf72 gene, and thus a hereditary form of the disease (see Genetics section).

With or without the gene expansion, the addition of motor neuron disease to FTD is a compromising factor which greatly reduces median survival to less than 3 years (Olney, et. al 2005).  Behavioral symptoms complicate the management of dysphagia as well as respiratory dysfunction as respiration therapy and percutaneous endoscopic gastrostomy (PEG) feeding tubes are not well tolerated by the patient. PEG shows little survival benefit (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 on-going.

OTHER VARIANTS

FTD subtypes may also be associated with the Parkinson’s plus syndromes of progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS).  CBS-like symptoms of asymmetrical movement problems, abnormal muscle tone, complex tremors, myoclonus and limb apraxia form the core CBS pheonotype.  A recently appreciated speech/language variant known as primary progressive apraxia of speech (PPAOS) tends to precede the evolution into the nonfluent/agrammatic subtype; these patients experience articulatory difficulties but are not truly aphasic.

KEY REFERENCES

Clinical Criteria of Behavioral Variant FTD
In 2011, an international consortium developed and published revised guidelines for the diagnosis of behavioral variant frontotemporal dementia.

Full article
Rascovsky K et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011 Sep, 134(pt9): 2456-77. Epub 2011 Aug 2.

Summary of bvFTD criteria

Classification of PPA
PPA investigators convened over three occasions to operationalize earlier published clinical descriptions of PPA subtypes. These recommendations have been agreed upon and published by a large group of international experts to increase consistency of PPA classification in future studies.

Full article
Gorno-Tempini, ML, Hillis, AE, Weintraub, S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011 Mar 15;76(11):1006-14. Epub 2011 Feb 16.

FTD and MND

Alagiakrishnan K, Bhanji RA, Kurian M, Evaluation and management of oropharyngeal dysphagia in different types of dementia: a systematic review. Arch Gerontol Geriatr. 2013 Jan-Feb; 56(1):1-9.

Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, Rush BK, Machulda MM, Fields JA, Ferman TJ, Baker M, Rutherford NJ, Adamson J, Wszolek ZK, Adeli A, Savica R, Boot B, Kuntz KM, Gavrilova R, Reeves A, Whitwell J, Kantarci K, Jack CR Jr, Parisi JE, Lucas JA, Petersen RC. Rademakers R. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain. 2012 Mar;135 (Pt 3):765-83.)

Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology. 2003: 60 (7), 1094–1097.

Olney RK, Murphy J, Forshew D, Garwood E, Miller BL, Langmore S, et al. The effects of executive and behavioral dysfunction on the course of ALS. Neurology. 2005; 65:1774–7.