Frontotemporal Dementia

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FTD should be considered in patients who present with prominent changes in personality and behavior or isolated impairments of language early in the course of their dementia. Patients with FTD are much more likely to have a younger age of onset of symptoms and frequently have a family history of relatives that have suffered from a similar type of dementia. In the evaluation of FTD, it is important to perform a detailed assessment of noncogni-tive behavioral symptoms in addition to assessment of cognitive function to come to an accurate diagnosis. Although there is overlap between the behavioral and cognitive features of FTD and other causes of dementia, specific behavioral and neuropsychological features help in differentiating FTD from other causes. Evidence of frontal and temporal lobe atrophy on structural imaging (i.e., computed tomography [CT] or MRI ) and evidence of decreased perfusion or metabolism in these brain regions on functional imaging (i.e., single photon emission computed tomography [SPECT] or positron emission tomography [PET]) are supportive of a diagnosis of FTD. As in other degenerative dementia, a definitive diagnosis of FTD requires pathological confirmation. The pathology underlying FTD is diverse and results in at least five pathological subtypes. In this section, each of these aspects of the diagnosis of FTD is reviewed in more detail.

Three common clinical presentations of FTD are observed. In a consensus statement on clinical diagnostic criteria for FTD, these three clinical presentations have been labeled as frontotemporal dementia (also designated as frontal variant of FTD by others), semantic dementia (also called the temporal variant of FTD by others), and progressive nonfluent aphasia (also termed primary progressive aphasia by others). This consensus classification outlines clinical features that are required for a clinical diagnosis, that are supportive of a diagnosis, that exclude a diagnosis of FTD (Neary et al., 1998), and are an extension of the original consensus criteria for the diagnosis of FTD that are referred to as the Lund-Manchester research criteria (Lund and Manchester Groups, 1994). Recent modifications of these consensus criteria have made them more general, but they are similar to previous criteria (McKhann et al., 2001). These criteria, shown in Table 4.2, are supplemented by core features of the three common presentations of FTD outlined by Neary et al. All presentations of FTD have an insidious onset and gradual progression. Onset is frequently before age 65, and a family history of FTD is common. Features of motor neuron disease or parkinsonism can been seen during the course of FTD, but hyperkinetic movement disorders (e.g., myoclonus, chorea) are not seen. Clinical features that would suggest an alternative cause of dementia are used to exclude FTD, including evidence of vascular dementia, HIV-associated dementia, multiple sclerosis, chronic alcoholism, herpes simplex encephalitis, or dementia due to closed head injury.

The most common presentation of FTD is the frontal variant of FTD, characterized by prominent noncognitive behavioral symptoms (Hodges, 2001; Neary et al., 1998). Patients with the frontal variant of FTD present with an early decline in social interpersonal conduct. This is manifested as a decline in manners and social graces, including disinhibited comments and actions or antisocial behavior such as criminal acts (e.g., shoplifting). There is also a change in the regulation of personal conduct that often produces passivity or inertia but can produce overactivity and aggression. These changes in social and personal conduct are associated with a loss of insight and emotional blunting with evidence of emotional shallowness and

Table 4.2 Clinical Criteria for Diagnosing Frontotemporal Dementia

1. The development of behavioral or cognitive deficits manifested by either:

a. Early and progressive change in personality, characterized by difficulty in modulating behavior, often resulting in inappropriate responses or activities.

b. Early and progressive change in language, characterized by problems with expression of language or severe naming difficulties, and problems with word meaning.

2. The deficits in 1a and 1b cause significant impairment in social and occupational functioning and represent a decline from a previous level of functioning.

3. The course is characterized by gradual onset and continuing decline in function.

4. The deficits in 1a and 1b are not due to other nervous system conditions, do not occur exclusively during delirium, and are not better accounted for by a psychiatric diagnosis.

From "Clinical and Pathological Diagnosis of Frontotemporal Dementia," Report of a Work Group on Frontotemporal Dementia and Pick's Disease, by G. M. McKhan et al., 2001, Archives of Neurology, 58, pp. 1803-1809.

lack of empathy for others. Supportive behavioral features include a decline in personal hygiene, mental inflexibility, distractibility, hyperorality, stereotyped behavior, and stimulus-bound utilization behavior. Cognitively, FTD patients have impairments of executive cognitive function including difficulties with planning, sequencing, and set shifting. However, early in the disease course, orientation, memory, and visual-spatial skills are preserved. Typically, these behavioral and cognitive symptoms are associated with decreased speech output, characterized by FTD patients not initiating conversation as often; when they do respond to questions, they often reply only in short phrases or stereotyped utterances. Rarely, the opposite can occur and patients may monopolize conversations. Decreased speech output progresses to mutism over time in most patients. Incontinence and primitive reflexes, such as grasp, snout, and sucking reflexes, are common.

Focal and asymmetric presentations of FTD are observed, resulting in progressive nonfluent aphasia and semantic dementia (Hodges, 2001; Neary et al., 1998). In primary nonfluent aphasia, patients present with hesitant, effortful speech output that is associated with agrammatism, phonemic paraphasias, and/or anomia. Other common features include stuttering, impaired repetition, and alexia. The meaning of words is preserved, as are memory and visual-spatial abilities. The language disorder is the most prominent feature of primary nonfluent aphasia and should not be associated with significant behavioral symptoms early in the course of the dementia. However, the behavioral changes observed in the frontal variant of FTD can be seen later in the disease course. In semantic dementia, speech production is effortless and without hesitancies, but the content of the words conveys little precise information. This is due to reduced use of precise terms for naming objects and increased use of general terms (e.g., using the term animal instead of dog or using a term such as that thing). Semantic dementia patients have a selective and progressive loss of semantic memory, described as the component of long-term memory that contains the permanent representation of our knowledge about things in the world and their interrelationships (Hodges et al., 1999). This loss of semantic memory results in impairment of naming and word comprehension as tested by word definition tests and object-pointing tests. Orientation, memory, and visual-spatial abilities are relatively spared as in primary nonfluent aphasia. Behavioral changes similar to those seen in the frontal variant of FTD may appear late in the disease course as can parkinsonism. Patients with semantic dementia that involves the right temporal lobe display prosopagnosia (i.e., inability to recognize and name familiar faces).

Neuropsychological testing can aid in the diagnosis of FTD. On neuropsychological testing, patients with FTD demonstrate impairments on frontal lobe tests in the absence of severe amnesia or visuospatial impairments (Neary et al., 1998). Specific language and semantic impairments can be measured with neuropsychological testing in progressive nonfluent aphasia and semantic dementia (Hodges, 2001; Hodges et al., 1999). Early in the disease course, most patients with FTD perform poorly on frontal lobe tests such as the Wisconsin Card Sort, Stroop Test, verbal fluency tests, and the Trail Making tests. At the same time, orientation and memory test performance are relatively intact and visuospatial abilities are normal. However, in some patients, behavioral symptoms may be severe at a time when objective cognitive deficits are minimal. In addition, the typical pattern of cognitive deficits seen in FTD can overlap with other more common causes of dementia, including vascular dementia and focal presentations of Alzheimer's disease (Cherrier et al., 1997; JAGS, 1997). Bedside screening tests of cognition such as the Mini-Mental State Examination are unreliable for the detection and monitoring of FTD because they underestimate the degree of cognitive impairment. Table 4.3 lists ancillary tests used in the diagnosis of prion disease and frontotemporal dementia.

Standardized evaluations of noncognitive behavioral symptoms and use of the proposed clinical criteria for FTD are important aids in the clinical diagnosis of FTD. For example, the Neuropsychiatric Inventory has been used to systematically quantify behavioral abnormalities in FTD. When compared to AD, FTD patients exhibited more severe apathy, disinhibition, euphoria, and aberrant motor behavior (Levy, Miller, Cummings, Fairbanks, & Craig, 1996). Similarly, the Frontal Behavioral Inventory has been purposed as an instrument useful in documenting and quantifying behavioral changes characteristic of FTD (Kertesz, Nadkarni, Davidson, & Thomas, 2000). Per-severation, indifference, inattention, inappropriateness, and loss of insight were rated significantly higher in FTD patients than in non-FTD patients. In a study of the Lund-Manchester research criteria for FTD, the behavioral and clinical features that most clearly differentiated FTD from AD were loss of personal awareness, hyperorality, perseverative behavior, and progressive reduction of speech (Miller et al., 1997). Use of the National Institute of Neurological and Communicative Disorders and Stroke-AD and

Table 4.3 Useful Ancillary Tests in Prion Disease and Frontotemporal Dementia

Disease

Ancillary Test

Findings

Prion diseases Prion protein gene analysis.

EEG.

14-3-3 proteins in CSF. MRI.

Tonsil biopsy.

Frontotemporal Neuropsychological tests. dementia

Behavioral inventories.

Structural brain imaging.

Functional brain imaging.

Mutations in familial CJD, GSS, and FFI.

Increased risk if homozygous at codon 129.

Periodic sharp wave complexes.

Elevated levels in CSF.

Symmetric increased signal in the basal ganglia on T-2 images and increased signal in cortical and subcortical structures on diffusion-weighted images.

PrPSc detected (in vCJD patients only).

Impairment on frontal-lobe tests with relative sparing of memory, orientation, and visuospatial skills.

Presence of apathy, disinhibition, euphoria, perseveration, inappropriateness, and loss of insight.

Selective frontal and temporal lobe atrophy.

Decreased blood flow or metabolism in frontal and/or temporal lobes.

Related Disorders Association (NINCDS-ADRDA) criteria for AD in the diagnosis of dementia fails to accurately distinguish AD from FTD, resulting in many patients with FTD being diagnosed with AD (Varma et al., 1999). A lack of awareness of the main cognitive and behavioral symptoms of Pick's disease has been found to be the major cause of underrecognition of Pick's disease clinically and would apply to FTD in general (Litvan et al., 1997). Thus, use of standardized evaluations of noncognitive behavioral symptoms and use of consensus clinical criteria for FTD can improve significantly the sensitivity and specificity of the clinical diagnosis of FTD.

Structural and functional abnormalities can be detected in the frontal and temporal lobes of patients with FTD using brain imaging. Functional abnormalities precede structural changes in most patients with FTD, and PET has greater sensitivity in detecting subtle changes than does SPECT imaging. However, both SPECT and PET can assist in the diagnosis of FTD by demonstrating objective functional impairment in the frontal and temporal lobes, evaluating the degree of asymmetry of abnormalities, and ruling out significant posterior temporal and parietal lobe involvement. Initially, structural changes in FTD may be subtle and overlooked, especially in the frontal variant of FTD. However, as FTD progresses, frontal and temporal lobe atrophy becomes apparent. Voxel-based morphometry of MRI images in FTD patients has been compared to control subjects and reveals significant atrophy in FTD patients in the ventromedial frontal cortex, posterior orbital frontal cortex, the insula, and anterior cingulate cortex. In patients with the frontal variant of FTD, additional areas of atrophy were seen in the dorsolat-eral frontal cortex and premotor cortex, while patients with the temporal variant of FTD (i.e., semantic dementia) showed additional involvement of the anterior temporal cortex and amygdala/anterior hippocampal region (Rosen et al., 2002).

Pathologic evaluation of the brain is required to confirm the diagnosis of FTD. Recent criteria have been proposed to aid in classification of the pathology of the FTDs and describe five pathological subtypes (McKhann et al., 2001). Clinical subtypes of FTD do not correlate with specific pathological subtypes. At autopsy, gross pathology reveals selective atrophy of the frontal and temporal lobes in patients with FTD. Light microscopic findings of FTD include microvacuolation and astrocytic gliosis of the involved cortices, especially superficial cortical layers, as well as Pick cells and Pick bodies in some patients. The use of immunohistochemical techniques with antibodies against tau, ubiquitin, and crystalline has improved the categorization of FTD pathology (Cooper, Jackson, Lennox, Lowe, & Mann, 1995). In addition, biochemical analysis of insoluble tau inclusions (e.g., three or four microtubule-binding domains) is used to further categorize FTD pathology.

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