CLINICAL FEATURES

Varied terminology makes the literature on FTD somewhat confusing. This ultimately resulted in a consensus among experts in the field on preferred terminology (Table 73-1). Neary and associates (1998) outlined the clinical features commonly encountered in frontotemporal lobar degeneration (so-called Neary criteria).³ Pick’s complex of diseases is another term proposed for this group of disorders by Kertesz and colleagues (1998),⁴ but at present, frontotemporal dementia is the preferred term. The Neary classification describes three major clinical syndromes (Tables 73-2 to 73-4). The progressive aphasias include nonfluent primary progressive aphasia (PPA) and semantic dementia, which involve degeneration affecting the left frontal and temporal lobes respectively. The behavioral manifestation of FTD involves degeneration of both frontal lobes, although asymmetrical degeneration can occur. Although uncommon, cases of primarily right temporal degeneration exist with clinical features of prosopagnosia and/or associative agnosia. Unfortunately, clinical manifestations of FTD that do not strictly conform to the proposed criteria also occur. For example, aphasic dementias that do not meet criteria for PPA or semantic dementia exist, and some patients otherwise meeting criteria for an FTD syndrome may exhibit symptoms implicating parietal lobe involvement. The aphasic and behavioral manifestations of FTD can also overlap.

TABLE 73-1 Frontotemporal Dementia Terminology^*

* A problem with this preferred terminology is the persistent use of overlapping abbreviations for both clinical and pathologic aspects of these disorders, such as “FTD.”

TABLE 73-2 Frontal Lobe Dementia

Adapted from Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546-1554.

TABLE 73-3 Progressive Nonfluent Aphasia

Adapted from Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546-1554.

TABLE 73-4 Semantic Dementia/Progressive Fluent Aphasia

Adapted from Neary D, Snowden JS, Gustafson L, et al: Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51:1546–1554.

Other clinical features can occur in the setting of FTD and include parkinsonism, motor neuron disease, corticobasal degeneration, and progressive supranuclear palsy (PSP). All the various FTD subtypes share certain features: namely, insidious onset with gradual progression and onset often before age 65. Clinical features atypical of FTD include abrupt onset, severe amnesia early in the disease course, myoclonus, ataxia, and choreoathetosis. Nondegenerative causes of cognitive or behavioral disturbance such as recent head trauma, alcoholism, significant metabolic derangement, infection, and other neurological disorders are not features of FTD. Atypical imaging findings such as multifocal abnormalities or significant cerebrovascular disease also would not suggest FTD.

PATHOLOGY

Nearly a century after Pick first described the pathological features of frontotemporal degeneration, different pathological subtypes were described as well.⁸ Three major pathological divisions were identified: Pick’s disease type A, with neuronal loss, astrocytic gliosis, Pick bodies, and swollen neurons; Pick’s disease type B, with neuronal loss, astrocytic gliosis, and swollen neurons; and Pick’s disease type C, with neuronal loss and gliosis. Additional advances in the field of pathology have allowed further characterization of the FTDs through immunohistochemical and biochemical techniques.

Typical gross pathological findings include decreased whole brain weight (mild to severe) and sometimes striking atrophy of the frontal and temporal lobes. The regional atrophy may be asymmetrical, especially in cases with progressive aphasia. In grossly atrophic regions, there is thinning of the cortical ribbon with associated discoloration of the underlying white matter. Atrophy of the hippocampus and basal ganglia may be seen. Enlargement of the ventricular system is correlated with the degree of regional atrophy. For example, asymmetrical enlargement of the left lateral ventricle is often observed in cases of progressive aphasia. In certain cases, pallor of the substantia nigra and atrophy of the anterior nerve roots with discoloration of the lateral funiculus in the spinal cord may be seen.

Further classification of FTD is achieved through the use of microscopy. Affected cortical regions typically show neuronal loss, microvacuolation, astrocytic gliosis centered on cortical layer II, and, in some cases, ballooned neurons. A major biochemical subdivision of degenerative dementias, including FTD, involves the presence or absence of tau protein–related pathology. There are more than 20 recognized “tauopathies,” as shown in Table 73-5,⁹ with Pick’s disease, corticobasal degeneration, FTDP-17, PSP, and Alzheimer’s disease most commonly identified in cases with a clinical manifestation of FTD. Assays for ubiquitin-positive inclusions are required when no tau, synuclein, or amyloid pathology is identified. Intranuclear or cytoplasmic ubiquitin inclusions, as well as ubiquitinated neurites (axons and dendrites), may be noted. Such inclusions may also be found in motor neurons in amyotrophic lateral sclerosis, which furthers the overlap between motor neuron disease and FTD. Intraneuronal ubiquitin inclusions have been reported in familial cases of FTD, and a comprehensive review of the neuropathology of FTD is presented by Munoz and colleagues (2003).¹⁰ Neuronal intranuclear ubiquitin inclusions appear to be the distinction between familial and sporadic cases of FTD with ubiquitin immunoreactivity.¹¹ Presence of neuronal loss, gliosis, and microvacuolation in the absence of any recognizable inclusions defines dementia lacking distinctive histological features.¹² This entity less commonly identified as careful immunohistochemical analysis often reveals ubiquitin pathology. In addition to the identification of ubiquitin-immunoreactive inclusions, in many cases initially characterized as dementia lacking distinctive histological features, there also appears to be a high prevalence of hippocampal sclerosis.¹³

TABLE 73-5 Diseases in Which Filamentous Tau Protein Deposits Have Been Described

It is possible to further classify the tau protein–based forms of FTD. Six isoforms of the tau protein exist, one half referred to as “three-repeat forms” and the remainder as “four-repeat forms.” This terminology refers to the presence of three or four repeated sequences in the tau protein, representing microtubule binding sites. The fourth repeated sequence is coded for by exon 10 of the tau gene; alternate splicing of exon 10 generates three-repeat or four-repeat isoforms. Tauopathies characterized by four-repeat isoforms include corticobasal degeneration, PSP, and argyrophilic grain disease, whereas Pick’s disease is characterized by four-repeat isoforms, shown in Figure 73-1.

Figure 73-1 Cases of frontotemporal dementia with parkinsonism linked to chromosome 17 may exhibit either three-repeat or four-repeat isoforms or a combination of the two. Plus signs denote the presence and minus signs the absence of exon 2, 3, or 10, which generate different tau protein isoforms.

(From Munoz DG, Dickson DW, Bergeron C, et al: The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol 2003; 54(Suppl 5):S24-S28.

GENETICS

Although estimates among research groups vary, a family history of FTD is uncommon in most cases. Tau gene mutations account for most of the familial forms of FTD. Just as characterization of the genetics of familial forms of AD has revolutionized its treatment approaches, better understanding of the genetic forms of FTD is hoped to enable development of therapies targeting its underlying pathophysiology. Whether therapies effective for genetic forms of these diseases will apply to the more sporadic cases remains to be seen. The more heterogeneous pathology encountered in FTD also makes development of effective therapies challenging. The following section outlines the currently known genetic aspects of FTD.

Tau Gene

Tau mutations account for only a small percentage of FTD in general, although they constitute the most recognized genetic cause of FTD. FTDP-17 is inherited in an autosomal dominant manner; multiple kindreds have been recognized in many countries. Three mutations account for more than one half of the known cases of FTDP-17, despite there being more than 30 known mutations. These are the P301L mutation, the mutation of the 5′ splice site of exon 10 at position +16, and the N279K mutation, depicted in Figure 73-2. Each mutation can be associated with a classic FTD phenotype, although the +16 mutation and N279K mutation typically produce features of parkinsonism, the latter with features resembling PSP. Other features encountered in FTDP-17 include paranoid delusions, antisocial behavior, seizures, and, on occasion, amyotrophy. Most mutations affecting the splicing of exon 10 are associated with parkinsonism. Clinical differences among individuals harboring the same mutation suggest that other genetic or environmental factors influence phenotype.

Figure 73-2 Distribution of mutations within the Tau gene, grouped by exon. Number of mutations are in italics. Locations of the three most common tau mutations (N279K, P301L, and position +16) are shown.

Knowledge of tau protein biochemistry facilitates recognition of the effects of tau gene mutations, with an excellent review by Hutton (2000). The tau protein is soluble in the normal human brain. Microtubule binding is mediated by specific domains in the carboxy-terminal portion of the protein, coded for by exons 9, 10, 11, and 12 of the tau gene. These domains are composed of tandem repeat sequences of 31 amino acids with either three or four microtubule-binding domains present on the protein. Alternative splicing of exon 10 dictates the number of microtubule binding domains, and an approximate 1 : 1 ratio of three-repeat and four-repeat tau isoforms exists in the normal human brain. Disruption of this balance between three-repeat and four-repeat isoforms is associated with the pathological inclusions of FTDP-17. Nearly all mutations that have been identified in families with FTDP-17 are located from exons 9 to 13, or in the 5′ splice site of the intron after exon 10. Mutations in exon 10 and the intronic 5′ splice site after exon 10 (see Fig. 73-2) appear to increase the amount of four-repeat tau isoforms produced. The abnormal ratio of tau isoforms appears to decrease tau microtubule binding and to increase tau aggregation into insoluble filaments. Despite increased knowledge of the biochemical effects of these mutations, clinical heterogeneity remains largely unexplained. For example, phenotypes resembling the behavioral manifestations of FTD, corticobasal degeneration, and PSP have all been reported with the P301L mutation.

CLINICAL VIGNETTES

Cases 1 through 4 illustrate the clinical features outlined in the Neary criteria (see Table 73-1).

Case 1: Frontal Lobe Dementia

A 55-year-old right-handed attorney presented with a 2-year history of progressive cognitive and behavioral changes. Problems were first noted at work, in which she became excessively argumentative and confrontational with coworkers. This escalated until she lost her job. Her spouse noted that she did not seem to have significant problems with forgetfulness but rather seemed unable to remain focused on any task. For this reason, she stopped cooking and participating in essentially all complex activities of daily living. She exhibited some problems with personal hygiene, such as neglecting to remove her clothing before showering. She also had a tendency to wander, thus requiring constant supervision.

In addition to her irritability, there were also times when she seemed overly giddy and disinhibited. She made inappropriate comments about strangers in public. She developed a predilection for sweets, and her intake had to be monitored. Her actions also became repetitive; for example, repeatedly asking her spouse when it was time to leave and pacing when an outing was planned. She often echoed what others said and developed an unusual tendency to speak in a high-pitched, childlike voice at times.

The patient’s mother, maternal uncle, and maternal grandmother all had a history of cognitive decline in their 60s. No details regarding their clinical manifestations were available.

On examination, she scored 19 of 38 on a Short Test of Mental Status, missing points for orientation, digit span, learning, calculation, and construction. She recalled three of four items after a delay. Many of her difficulties stemmed from inattentiveness during testing, which necessitated frequent redirection. She would often perseverate, answering new questions with prior responses. No focal findings were noted on neurological examination. She did exhibit psychomotor agitation, getting up frequently during the history and examination and pacing around the room. Her laboratory studies were unrevealing, including spinal fluid analysis. An electroencephalogram was also unremarkable. Magnetic resonance imaging (MRI) of her brain showed prominent atrophy affecting primarily the frontal lobes bilaterally, with associated increased T2 signal in the frontal lobe white matter.

This case demonstrates typical clinical features of frontal lobe dementia in which prominent behavioral changes dominate the initial symptom complex. The family history is suggestive of a hereditary basis for her particular syndrome. Figure 73-3 demonstrates typical imaging findings in frontal lobe dementia.

Figure 73-3 Frontal lobe dementia. Axial magnetic resonance images (A and B) and positron emission tomographic images (C and D) demonstrate focal atrophy and hypometabolism affecting primarily the frontal lobes.

Case 2: Progressive Nonfluent Aphasia

An 87-year-old right-handed retired teacher presented for evaluation of progressive language difficulties. She noted that over approximately the prior 18 months, she had experienced progressive difficulties “getting her words out.” She denied problems comprehending what others were saying but found that she could not keep up with the pace of most conversations. For this reason, she became somewhat withdrawn socially. There was no history of significant forgetfulness or decline in ability to keep up with her personal affairs. She also denied any difficulties with disorientation. Family members corroborated her history. There was no known family history of any similar symptoms or other cognitive disorder.

On examination, she scored 34 of 38 on a Short Test of Mental Status, missing a point each for digit span, learning, construction, and delayed verbal recall. She did exhibit nonfluent speech, with paraphasic errors such as “sinced” for “since” and “kepiz me” for “keeps me.” She did not exhibit anomia and could comprehend simple and complex commands. She had mild difficulties with repetition. The remainder of the neurological examination findings were unremarkable. Laboratory study findings were within normal limits. MRI of her brain showed mild asymmetrical atrophy affecting primarily the left perisylvian region.

This case is illustrative of progressive nonfluent aphasia, a subtype of PPA. The preservation of general cognitive function despite the language disturbance is typical, as is the early absence of any significant behavioral disturbance (Fig. 73-4).

Figure 73-4 Progressive nonfluent aphasia. Axial magnetic resonance images (A and B) and positron emission tomographic images (C and D) demonstrate focal atrophy and hypometabolism affecting primarily the left frontal lobe and perisylvian region.

Case 3: Semantic Dementia

A 60-year-old right-handed owner of a flooring business presented with a 3-year history of difficulties “coming up with words.” He began noticing these problems when he would give presentations, in which he would be at a loss for words that he had previously known but would not use regularly, with relative preservation of words common to his profession. For example, he could not come up with the words “helicopter” and “scissors,” although he could readily and accurately describe them and their functions. He could still function fairly well at work but found he would often have to resort to simpler, related terms for words he could not recall or use gestures to describe what he meant.

He denied any problems keeping up with work or household responsibilities, which was confirmed by his spouse. She had noted that he had become somewhat irritable but believed that this was secondary to his frustration with his word-finding difficulties. No socially inappropriate behavior had been observed.

There was a family history of memory difficulties in the patient’s mother in her 80s but no clear language disturbance.

On examination, he scored 31 of 38 on the Short Test of Mental Status, missing points for calculation, verbal abstract thinking, general fund of knowledge, and delayed verbal recall. He exhibited prominent anomia on the Boston Naming Test during neuropsychological assessment. He frequently used general descriptors for names of items he could not recall, such as “whatchamacallit.” The general neurological examination revealed no additional findings. Laboratory study findings were unremarkable. MRI of his brain showed asymmetrical atrophy affecting the left anterior and superior temporal lobes.

This case demonstrates typical history and examination findings for semantic dementia, a subtype of PPA. Patients generally exhibit prominent anomia and progressively lose the meaning of words, initially less common ones but then even common words as the disease progresses. Figure 73-5 shows typical imaging findings in a case of semantic dementia.

Figure 73-5 Semantic dementia. Left parasagittal (A) and axial (B) magnetic resonance images and axial positron emission tomographic images (C and D) demonstrate focal atrophy and glucose hypometabolism affecting primarily the left temporal lobe.

Case 4: Progressive Prosopagnosia

A 73-year-old right-handed mechanic related a 5-year history of progressive difficulties recognizing people. These difficulties first involved acquaintances he encountered while at the store or church, but over time they progressed to include even family members. He often would greet people when addressed and would be able to recognize them only by the sound of their voice. This difficulty extended beyond recognizing people: He also found that he had developed problems recognizing different makes and models of vehicles, which he found quite frustrating in light of his prior occupation.

He denied any other difficulties from a cognitive or perceptual standpoint. He continued to keep up with his household affairs and hobbies without significant problems. His family noted that he seemed to be at a loss for words at times but not excessively. He admitted that he no longer enjoyed watching television, because he did not recognize any of the people in the news or other programs.

On examination, he scored 28 of 38 on a Short Test of Mental Status, missing points for digit span, learning, calculation, construction, and delayed recall. He could not recognize pictures of celebrities from a magazine, although he knew they were “famous people.” When shown a picture of a grizzly bear standing in a mountain stream and was asked what was depicted, he stated, “an animal.” When asked to elaborate, he speculated, “It might be a dog.” He exhibited moderate anomia on the Boston Naming Test during neuropsychological assessment. His general neurological examination findings were unremarkable. Laboratory studies were unrevealing. MRI of his brain showed bitemporal atrophy, greater on the right side than on the left.

This case demonstrates a case of progressive prosopagnosia with prominent difficulties recognizing familiar faces and even objects. The ability to recognize categories of items such as “vehicles” or “animals” with inability to subcategorize them can be seen and was evident in this particular patient. Figure 73-6 demonstrates typical imaging findings in a case of prosopagnosia related to prominent right temporal lobe degeneration.

Figure 73-6 Progressive prosopagnosia. Axial computed tomographic scans (A and B) and positron emission tomographic images (C and D) demonstrate focal atrophy and hypometabolism affecting primarily the right temporal lobe.

IMAGING

In all patients presenting with progressive impairment of cognitive or behavioral functions, an imaging study of the brain is warranted, to rule out mass lesions or other structural abnormalities. For example, a tumor involving the frontal lobes could produce manifestations mimicking the clinical features of FTD. In FTD, the frontal and temporal lobe atrophy is often evident on standard computed tomography and MRI of the brain. Asymmetrical atrophy may be evident in the setting of PPA and semantic dementia. Longitudinal volumetric MRI demonstrates predictable patterns of regional change among the subtypes of FTD; semantic dementia exhibits the most dramatic longitudinal change in the temporal lobe.²⁰ White matter abnormalities, best appreciated on fluid-attenuated inversion recovery MRI sequences, may also be evident in the underlying affected cortical regions. Functional neuroimaging may be helpful, especially in cases lacking obvious regional atrophy. Regional hypoperfusion on single photon emission computed tomography or hypometabolism on positron emission tomography may be evident in the frontal and temporal lobes, but further clinicopathological data are necessary to determine the diagnostic utility of these two imaging modalities.

THERAPY

There are no approved pharmacological therapies for FTD. Off-label use of cholinesterase inhibitors and memantine for the cognitive symptoms of FTD occurs, but their efficacy is not established. A randomized controlled trial of trazodone also demonstrated promising results for behavioral symptoms.²¹ Atypical neuroleptic agents and anticonvulsants with mood-stabilizing properties can also be considered.

As with other dementia syndromes that progressively impair judgment, the environment must be optimized for safety. Safeguarding or removing dangerous tools or other items is recommended. If patients have sufficient cognitive impairment to warrant a diagnosis of mild dementia, they should not drive. Patients with isolated language disturbance may be able to drive safely, but driving safety should periodically be reassessed.

Patients with PPA or semantic dementia may benefit from formal speech therapy. Caregiver burden is an important issue for all dementing illnesses, but because of the relatively younger age at onset in patients with FTD, this problem can be particularly difficult. Educational material about available community resources such as the Alzheimer’s Association should be made available. Social workers or geriatric counselors can provide invaluable information to patients and their families regarding care options. Internet resources for FTD are listed in Table 73-7.

TABLE 73-7 Internet Resources for Frontotemporal Dementia

FUTURE DIRECTIONS

In summary, the term frontotemporal dementia encompasses a group of disorders that have diverse clinical, pathological, biochemical, and genetic features. Better understanding of these disorders will be achieved only through collaboration of specialists in both the clinical and basic science disciplines. A multicenter initiative to monitor patients with FTD longitudinally is already under way and is hoped to enable additional therapeutic trials in the future. Powerful research tools such as transgenic animal models will expedite development of therapies specifically targeting the underlying pathophysiology of FTD and other degenerative disorders affecting the nervous system.²² Development of assays for biomarkers such as phosphorylated tau species may allow more accurate differentiation between FTD and other neurodegenerative disorders, especially early in the disease course.²³ Although research focusing on FTD may appear daunting in light of the heterogeneity of the condition, any advances made will potentially affect patients with a host of other related disorders and should therefore be avidly pursued.

ACKNOWLEDGMENTS

This paper was supported in part by a National Institute on Aging grant AG16574 and a grant from Clarice and Robert Smith.