Frontotemporal Lobar Degeneration

Introduction

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition that selectively affects the frontal and anterior temporal lobes of the brain, resulting in progressive shortfalls in behavior and language. More than a century ago Arnold Pick, a Czechoslovakian neurologist and psychiatrist, first published a report on FTLD. He described a 71-year-old man who developed dementia with sensory aphasia and behavioral symptoms. Autopsy demonstrated severe atrophy of the frontotemporal lobes, swollen (“ballooned”) achromatic neurons, and argyrophilic inclusions within frontal neurons consisting of insoluble filaments of the microtubule associated protein tau, a protein crucial for intraneuronal transport and structural integrity of the cell. These tau-positive inclusions were later referred to as Pick bodies, and their presence was necessary for pathologists to come to a diagnosis of Pick disease. Gradually, the eponym was taken over by clinicians to diagnose patients with a dementia syndrome with disinhibited behavior. Today, after two decades of progress in clinical, pathologic, genetic, and cell biologic research, we recognize that FTLD is highly heterogeneous in its clinical presentation, pathologic substrate, and cause.

The increasing understanding of this causal heterogeneity is causing a shift in perspective from one that focuses on differences in clinical manifestation to one that is based on distinct proteinopathies. This distinction will be crucial in the diagnosis and management of these diseases, as well as for development of biomarkers and a curative treatment where none currently exists.

Epidemiology

FTLD is the third most common cause of neurodegenerative dementia, after Alzheimer disease (AD) and dementia with Lewy bodies. FTLD is mostly considered an early onset dementia, but reported onset ages vary from 21 to 89 years. Epidemiologic data are sparse, particularly on the older adult population, and estimates of prevalence and incidence vary widely. This can be explained, in part, by the heterogeneity of FTLD, regional differences in the contribution of genetic causes of FTLD, and evolving diagnostic criteria. Estimates of the proportion of patients with an onset after 65 years range from 25% to 70%. The incidence of FTLD in people aged 65 years or older ranges from 3.44 to 16.7 patients per 100,000 patient-years, compared to 0.64 to 4.1 per 100,000 patient-years in the group aged 64 or younger. FTLD does not appear to affect males and females differently. Disease duration is generally shorter than for other neurodegenerative diseases such as AD and is estimated to be, on average, 6 to 7 years but may be as long as 35 years. Although data on risk factors for FTLD are sparse, positive family history has long been recognized as a major risk factor for FTLD (see section Genetics ).

Clinical Presentation

The most frequent and best recognized clinical presentation of FTLD is frontotemporal dementia, also called behavioral variant FTLD (bvFTD), which typically presents with changes in personality, behavior, and social comportment and is associated with atrophy of the prefrontal and anterotemporal cortex. Less frequently, FTLD presents with language dysfunction in the context of a primary progressive aphasia (PPA), which can further be subdivided into a semantic variant (svPPA) and an agrammatic or nonfluent aphasia (nfvPPA). The nonfluent variant is characterized by dysfunction of expressive language and is associated with asymmetric atrophy of the left frontal and temporal cortices. On the other hand, the pattern of atrophy in svPPA is bilateral, although often asymmetric, affecting the middle and inferotemporal cortex, and language dysfunction mainly consists of impaired word comprehension. Of the clinical variants of FTLD, bvFTD is the most common, with an estimated frequency of 57% among FTLD patients. nfvPPA is estimated to occur in 24% and svPPA in 19% of all FTLD patients. Notwithstanding clear distinctions, considerable clinical overlap exists between these disorders, likely reflecting the expanding distribution of pathologic changes in different brain regions.

Individuals with bvFTD typically exhibit an insidious change of personality and behavioral abnormalities, such as loss of social awareness, poor insight, and blunting of affect. Other prominent symptoms include disinhibition, antisocial behavior, poor impulse control, and stereotypical or ritualized behavior, such as foot tapping or more complex behavioral routines, or repetitive use of a phrase, reflecting the topography of neurodegeneration. Behavioral symptoms seem to be most severe in patients with right hemisphere involvement. Cognitive impairment may be less prominent initially and mainly involves working memory and executive function. Cognitive changes include impaired attention, abstraction, problem solving, planning and organization and perseveration. Visuospatial skills are remarkably spared until late stages of the disease. Frequently, dietary changes are reported, such as cravings for sweets and gluttony, leading to weight gain in many patients. Apathy can be another prominent feature, often reflecting involvement of the medial frontal and anterior cingulate regions. Language changes may include echolalia, perseveration, and eventually mutism. During the course of the disease motor symptoms may develop, such as parkinsonian signs (akinesia and rigidity in ≈14%) or symptoms of motor neuron disease (MND) (4%-17%).

In patients with svPPA, communication is mainly impaired by difficulties in recognizing and understanding the meaning of words. Use of substitute words and semantic paraphasias is frequent in otherwise grammatically flawless speech. Loss of word comprehension is part of a more widespread loss of semantic knowledge of faces and emotions, facts, and objects. This puts additional strain on daily activities, for example, by inability to recognize ordinary household objects. svPPA patients often display disinhibited or compulsive behavior, which may be more prominent than in bvFTD. Episodic memory is relatively spared, but memory for autobiographic events is often affected.

In contrast to svPPA, patients with nfvPPA display decreased fluency of speech, while comprehension of single words is usually intact. Symptoms include word-finding difficulties, changes in pronunciation, grammatical errors, anomia, phonemic paraphasias, stuttering, and apraxia of speech. Semantic and episodic memories are preserved. Awareness of language deficits may explain socially withdrawn behavior and depression. Changes in behavior tend to occur later in the disease, and numerous patients eventually develop corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP).

Although FTLD may clearly present with one of the three disorders, in the natural course of the disease patients will invariably develop symptoms of the other FTLD syndromes. Moreover, overlap with symptoms of Parkinson disease (PD), CBS, PSP, amyotrophic lateral sclerosis (ALS), or AD is not exceptional ( Table 54-1 ). This may be due to progressive involvement of other brain regions in the disease process, but also to comorbidity, especially in older adult patients.