FRONTOTEMPORAL DEMENTIA

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CHAPTER 73 FRONTOTEMPORAL DEMENTIA

After Alzheimer’s disease, Lewy body disease, and vascular dementia, frontotemporal dementias (FTDs) as a group constitute a significant percentage of the degenerative dementias, accounting for 5% to 7% of some autopsy series. FTD is overrepresented among the early-onset dementias (manifesting before the age of 70), accounting for 8% to 17% of patients in such cases. Arnold Pick provided the first clinical and pathological description of an aphasic dementia in 1892.1 The term Pick’s disease was subsequently used to describe patients with behavioral changes and circumscribed atrophy affecting frontal and temporal lobes of the brain. Mesulam (2001) later described the progressive aphasias in relation to preferential left hemisphere degeneration.2 Advances in the study of dementia have improved genetic and biochemical characterization of this group of disorders and are discussed in this chapter. Case examples are provided in order to familiarize the reader with approaches to evaluation of these disorders. Future directions of research are also discussed.

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.

Frontotemporal Dementia with Motor Neuron Disease

Clinical features of FTD and motor neuron disease can coexist in the same individual.6 There is no predictable temporal relationship between the cognitive and motor features of the syndrome. Also of interest are cases of clinically diagnosed FTD lacking motor symptoms in which pathological findings of motor neuron disease are encountered. Just as in classic amyotrophic lateral sclerosis, motor symptoms of dysphagia or respiratory failure adversely affect prognosis in patients with FTD.

Corticobasal Degeneration

Corticobasal degeneration is a pathological diagnosis and is clinically characterized by asymmetrical rigidity, apraxia, and alien limb phenomena. However, many patients with corticobasal degeneration do not have asymmetrical rigidity and apraxia.7 Relevant to this discussion is that pathological corticobasal degeneration may manifest clinically as FTD. This furthers the concept that both clinical and pathological findings implicating involvement of regions other than the frontal and temporal lobes should not prevent the diagnosis of 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

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