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(BQ) Part 2 book “Clinical manual of alzheimer disease and other dementias“ has contents: Traumatic brain injury, other causes of dementia, treatment of psychiatric disorders in people with dementia, pharmacological treatment of neuropsychiatric symptoms, supporting family caregivers,… and other contents.
9 Frontotemporal Dementia and Other Tauopathies Anne M Lipton, M.D., Ph.D Adam Boxer, M.D., Ph.D I n its broadest sense, the term frontotemporal dementia (FTD) refers to a number of neurodegenerative diseases that vary in clinical presentation and pathological findings FTD is also known as frontotemporal lobar degeneration (FTLD) (Neary et al 1998) The clinical and research nosology for this disease continue to evolve and sometimes create controversy or confusion Frontal-variant FTD (fvFTD) refers to the specific FTD clinical subtype characterized by executive dysfunction and apathy Although the clinical syndromes vary, they characteristically involve problems with language, behavior, and/or motor findings, such Preparation of portions of this chapter was supported by National Institutes of Health Grant K23NS048855 and the John Douglas French Foundation 219 220 Clinical Manual of Alzheimer Disease and Other Dementias as parkinsonism Research in FTD, including genetic discoveries and the application of modern neuroimaging techniques, has led to remarkable advances History The archetypal FTD is Pick disease, first clinically delineated by Arnold Pick (1892), who described language impairments and behavioral disturbances in the setting of focal brain atrophy Alois Alzheimer (1911) provided the first histopathological description of Pick disease with argyrophilic inclusions (later called Pick bodies) and swollen, achromatic cells (later called Pick cells) The Lund-Manchester criteria (Lund and Manchester Groups 1994) delineated the clinical features of FTD; these criteria were later refined by a consensus panel that used the term frontotemporal lobar degeneration (Neary et al 1998) Additional clinical consensus criteria for FTD have been published (McKhann et al 2001) FTD occurs, on average, in individuals in their 50s and may be the most common cause of dementia in this age group (Knopman et al 2004) Onset before age 65 years is one of the clinical diagnostic criteria for FTD (Neary et al 1998) Clinical Subtypes of FTD Patients with FTD present with the insidious onset of a behavioral syndrome or a language variant FTD progresses gradually, but survival is generally shorter than for Alzheimer disease Hodges et al (2003) reported that median survival from symptom onset and from diagnosis was about years for fvFTD and about years for FTD associated with motor neuron disease Frontal Variant FTD The frontal or behavioral variant of FTD is an FTD subtype characterized by executive dysfunction and problems with social conduct and interpersonal skills associated with abnormalities of the right frontotemporal lobe on neuroimaging (Mychack et al 2001) Lack of insight is a hallmark of the fvFTD subtype Patients are often impulsive and oblivious to societal or other limitations on their actions Compulsions, hoarding, and decline in hygiene frequently occur Frontotemporal Dementia and Other Tauopathies 221 An individual with fvFTD may display disinhibition, apathy, or both Patients with orbitofrontal dysfunction are more “disagreeable” and less modest and altruistic (Rankin et al 2004) Damage in the ventromedial frontal lobes is associated with disinhibited, impulsive, antisocial, and compulsive behaviors (Rosen et al 2002a) Patients with fvFTD may have some aspects of a KlüverBucy syndrome, including eating (or drinking) to excess, with an emphasis on carbohydrate-laden junk food Primary Progressive Aphasia Patients with a language variant of FTD—either progressive nonfluent aphasia or semantic dementia—frequently have one or more extensive evaluations for stroke due to their aphasia The aphasia worsens, and they may become mute Some also develop behaviors similar to those seen in fvFTD or in motor dysfunctions such as amyotrophic lateral sclerosis (ALS) or parkinsonism Artistic abilities often manifest in patients with a language variant of FTD, but they may emerge in patients with nonlanguage presentations of FTD as well (Miller et al 1998) These talents may manifest de novo or as a modification of a skill previously evident in an individual Progressive Nonfluent Aphasia Progressive nonfluent aphasia involves expressive aphasia with word finding difficulty, agrammatism, and phonemic paraphasias Unlike patients with the other forms of FTD, patients with progressive nonfluent aphasia usually have little functional or behavioral impairment until late in their disease Semantic Dementia Semantic dementia, also called the temporal lobe variant of FTD, is caused by a progressive loss of information about the world and is associated with degeneration of the anterior temporal lobes It usually manifests as a fluent dysphasia with impairment of semantic verbal memory (severe difficulty in naming and in understanding the meaning of words) and an associative agnosia (e.g., difficulty in stating or demonstrating the function of an object, such as a tool or utensil) in individuals with more left temporal lobe involvement Prosopagnosia (inability to recognize faces) may rarely occur and is associated with right temporal lobe damage More commonly, behavioral problems similar to those in fvFTD occur in individuals with more right lobar dysfunction 222 Clinical Manual of Alzheimer Disease and Other Dementias Overlap of FTD Clinical Syndromes Because the three FTD clinical syndromes often overlap (as can be seen in some of the above examples), and because they may also overlap with motor syndromes such as motor neuron disease/ALS and parkinsonism (including corticobasal syndrome and progressive supranuclear palsy [PSP]), some authors suggest the term Pick complex to encompass all of these syndromes The current consensus clinical criteria for FTD are useful but still lack precision New guidelines are in development The current clinical criteria fail to account for many neurogenetic and neuroimaging aspects of the diagnosis of FTD Rosen et al (2002b) found that the Neary et al (1998) clinical consensus criteria efficiently separated 30 autopsy-proven cases of Alzheimer disease and 30 autopsy-proven cases of FTLD They found that the following five clinical features best distinguished FTLD from Alzheimer disease: presence of social conduct disorders, hyperorality, akinesia, and absence of amnesia and perceptual disorder Clinical Syndromes Associated With FTD A number of diseases overlap clinically and pathologically with FTD, including motor neuron disease/ALS, corticobasal syndrome, and PSP Motor Neuron Disease/Amyotrophic Lateral Sclerosis Of 100 ALS patients studied prospectively with extensive neuropsychological assessment, about one-third met criteria for FTLD (Lomen-Hoerth et al 2003) Many patients clinically diagnosed with FTLD have motor neuron– type inclusions on histopathology, either with or without clinical motor neuron disease (Bigio et al 2003) Moreover, both chronic traumatic encephalopathy and FTLD may include TAR-DNA binding protein 43 (TDP-43)–positive inclusions in the brain These inclusions have been shown in the spinal cord in a few cases of chronic traumatic encephalopathy associated with motor neuron disease (McKee et al 2010) Corticobasal Syndrome Corticobasal syndrome is the current nomenclature used to describe the unifying clinical and pathological characteristics of FTD and corticobasal degeneration, Frontotemporal Dementia and Other Tauopathies 223 also known as corticobasal ganglionic degeneration (CBGD) CBGD is a Parkinson-plus syndrome (classically manifested as unilateral rigidity, apraxia, the alien hand syndrome, reflex myoclonus, and/or cortical sensory loss) that tends to progress more rapidly than Parkinson disease and is usually less amenable to treatment Progressive Supranuclear Palsy PSP is another Parkinson-plus syndrome possessing clinical and pathological overlap with FTD Both FTD and PSP are tauopathies (pathologically classified as abnormalities of the cytoskeletal protein tau) with clinical onset in late life PSP is characterized by balance difficulty, falls, visual disturbances, slurred speech, dysphagia, and personality change (Richardson et al 1963) The dementia of PSP is consistent with FTD A characteristic triad of ophthalmoplegia, pseudobulbar palsy, and axial dystonia develops First, downward gaze is impaired, then upward gaze, then voluntary gaze in all directions If the eyes are fixed on a target and the head is turned, full eye movement occurs (doll’s eye phenomenon), indicating that the motor nerves are intact The etiology of PSP is unknown Pathological findings include loss of neurons; gliosis; and the presence of neurofibrillary tangles in the surviving neurons in the midbrain, cerebellar peduncles, and subthalamic nucleus Functional impairment proceeds to anarthria and total immobility, usually within a few years Neuropathology FTD is pathologically distinct from Alzheimer disease Historically, the FTD disorders have been divided into Pick disease and non-Pick lobar atrophy (Dickson 1998) Both have grossly appreciable frontal and temporal atrophy Pick bodies are seen only in Pick disease Tau and ubiquitin immunohistochemistries are important in classifying pathological FTD subtypes Motor neuron–type, ubiquitin-positive inclusions are the most common histopathological type of FTLD (Lipton et al 2004) The chief protein associated with ubiquitinated inclusions is now recognized to be TDP-43 (Neumann et al 2006) Frontotemporal degeneration with neuronal loss and spongiosis has no tau or ubiquitin inclusions, but some of these cases are classifiable as FTLD–motor neuron disease (Lipton et al 2004) Cortico- 224 Clinical Manual of Alzheimer Disease and Other Dementias basal degeneration has tau-positive neuronal inclusions and glial plaques, along with ballooned neurons, in cortex, basal ganglia, brain stem, and cerebellum Despite the shared pathology in patients with FTD, there may be a variety of pathological findings within the same clinical FTD subtype Familial multiple system tauopathy is one of the many cases of familial FTD and parkinsonism linked to chromosome 17 (FTDP-17) These families have a variety of clinical presentations, including disinhibition-dementia-parkinsonismamyotrophy complex, and neuropathological findings always associated with tau deposition In contrast, individuals with progranulin mutations, an even more common form of autosomal dominant FTD, are found to have ubiquitin pathology at autopsy Validity of the FTLD diagnostic consensus criteria has been verified histopathologically (Knopman et al 2005) Diagnostic Evaluation Clinical evaluation, including history from a reliable collateral source, such as a close family member, is crucial in the diagnosis of FTD Family history of neurological disease and psychiatric illness is important, because FTD is hereditary in some cases and is often not diagnosed as FTD per se, but rather may manifest as motor neuron disease or parkinsonism, go undiagnosed, or be misdiagnosed (as depression, bipolar disorder, another form of dementia, etc.) Neurological evaluation may elicit abnormalities, such as motor weakness, parkinsonism, or frontal reflexes, that may provide additional diagnostic certainty Patients with FTD, particularly the FTD clinical profile, will often display echopraxia (imitating the examiner), perseveration, and motor impersistence Patients can also be tested for frontal release signs, such as suck, snout, rooting, palmomental, and Babinski reflexes Neuropsychological Testing A comprehensive neuropsychological evaluation is often helpful in diagnostic differentiation (see Chapter 3, “Neuropsychological Assessment”), if the patient can comprehend and cooperate with such testing Usual clinical tests, such as the Mini-Mental State Examination (MMSE; Folstein et al 1975), not directly assess executive functioning and may be relatively normal in patients with FTD (due to relative sparing of memory) or may show profound impairment in patients with the language variants of FTD However, MMSE scores Frontotemporal Dementia and Other Tauopathies 225 decline at a greater rate in FTD than in Alzheimer disease (Chow et al 2006) Neuropsychological evaluation may reveal executive dysfunction on commonly performed assessments, including the Stroop Test, the Trail Making Test, tests of verbal and design fluency, and the Wisconsin Card Sorting Test (Hodges and Graham 2001) Tests reported to be sensitive to FTD include the Frontal Behavioral Inventory (Kertesz et al 1997) and the Frontal Assessment Battery (FAB; Dubois et al 2000) The FAB has been shown to distinguish healthy control subjects from patients with mild Parkinson disease, multiple system atrophy, corticobasal degeneration, and PSP Total FAB scores did not differentiate FTLD from Alzheimer disease, but some subscores (of mental flexibility and environmental autonomy) did (Lipton et al 2005), and patients with Alzheimer disease and FTLD patients actually performed comparably on the Luria maneuver (Weiner et al 2011) Speech-Language Cognitive Evaluation A speech-language cognitive evaluation is often helpful, especially in diagnosing specific language variants (see also Chapter 1, “Neuropsychiatric Assessment and Diagnosis”) Some patients may also benefit from further therapy to assist in maintaining communication Neuroimaging Prominent frontal lobe atrophy on structural magnetic resonance imaging is a common feature of FTD, particularly in individuals without motor neuron disease (Figure 9–1) Neuroimaging with 18F-labeled fluorodeoxyglucose positron emission tomography (FDG-PET) is sometimes helpful in the differential diagnosis of FTD (Foster et al 2007) and has been approved by Medicare for this purpose in the context of a comprehensive clinical evaluation (see also Chapter 4, “Neuroimaging”) The amyloid imaging agent Pittsburgh compound B, or PIB, may be even more valuable for ruling out atypical forms of Alzheimer disease that mimic FTD (Rabinovici et al 2007) Electroencephalography Electroencephalography (EEG) is not generally helpful for diagnosis EEG has been shown to be normal in many cases One study showed that electroenceph- 226 Clinical Manual of Alzheimer Disease and Other Dementias alographic abnormalities correlated with severity of FTD but that this correlation was not helpful in differentiating FTD from Alzheimer disease (Chan et al 2004) Genetics Genetic tests are not available commercially but are a major area of research interest Multiple genetic loci (on chromosomes 3p, 9p, 9q, 17q21, and 17q24) and five genes (those for microtubule-associated protein tau, progranulin, valosin-containing protein, and charged multivesicular body protein 2B [CHMP2B]) have been associated with inherited FTD (Mackenzie and Rademakers 2007; Rademakers and Hutton 2007) FTD with parkinsonism (FTDP17) has been linked to mutations in the gene coding for the microtubule-associated protein tau (Hutton et al 1998) FTD with ubiquitin-positive inclusions (FTDU-17) is caused by loss-of-function mutations in the TAR-DNA binding protein gene coding for progranulin (PGRN), a growth factor involved in neuronal survival (Baker et al 2006) Treatment No treatment for FTD has been approved by the U.S Food and Drug Administration, but antidepressants, including selective serotonin reuptake inhibitors, are useful in treating many of the behavioral symptoms (Huey et al 2006) Trazodone is the only medication for FTD behavioral symptoms studied in a double-blind, randomized controlled trial (Lebert et al 2004) Trazodone is beneficial for a number of behavioral problems in FTD, including irritability, agitation, depressive symptoms, and eating disorders FTD does not entail a cholinergic deficit, and the use of cholinesterase inhibitors is controversial In an open-label study, rivastigmine ameliorated behavioral problems in FTD (Moretti et al 2004), but donepezil worsened behavioral symptoms (Mendez et al 2007) Other symptomatic treatments that have been tried are dopaminergic therapies for parkinsonism and language problems A prospective 26-week open-label trial of memantine 20 mg/day in FTD showed that patients with progressive nonfluent aphasia maintained relative cognitive stability over the 26 weeks, whereas the subjects with semantic aphasia had a decline in cognitive ability (Boxer et al 2009) In a double-blind study of memantine 20 mg/day in 18 human subjects with primary progres- Frontotemporal Dementia and Other Tauopathies 227 Figure 9–1 Magnetic resonance imaging (MRI) findings in frontotemporal dementia (FTD) FTD: parasagittal and coronal images from T1-weighted MRI Note asymmetric right frontal atrophy on coronal image (*), and lack of significant atrophy posterior to frontal lobe on sagittal image Semantic dementia (SD): axial and coronal images; atrophy is most severe anteriorly and involves both medial and lateral temporal lobe structures (*) Progressive nonfluent aphasia (PNFA): axial and coronal images show asymmetric left frontal atrophy with minimal temporal lobe involvement (*) Source Reprinted from Lipton AM, Boxer A: “Frontotemporal Dementia,” in The American Psychiatric Publishing Textbook of Alzheimer Disease and Other Dementias Edited by Weiner MF, Lipton AM Washington, DC, American Psychiatric Publishing, 2009, pp 219–227 Copyright 2009, American Psychiatric Publishing Used with permission 228 Clinical Manual of Alzheimer Disease and Other Dementias sive aphasia, the treated group showed less decline on the Western Aphasia Battery than did the placebo group (Johnson et al 2010) Key Clinical Points • Frontotemporal dementia (FTD) may be the most common cause of dementia for adults under age 65 • Gradual personality change with impaired judgment in the fifth or sixth decade of life should elicit suspicion for the frontal/ behavioral variant of FTD • FTD may manifest as a disorder of language expression or comprehension • FTD overlaps clinically and pathologically with a number of neurological syndromes, including amyotrophic lateral sclerosis, corticobasal syndrome, and progressive supranuclear palsy References Alzheimer A: Über eigenartige Krankheitsfälle des späteren Alters Zeitscrift für die gesamte Neurologie und Psychiatrie 4:356–385, 1911 Baker M, Mackenzie IR, Pickering-Brown SM, et al: Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Nature 24:916– 919, 2006 Bigio EH, Lipton AM, White CL III, et al: Frontotemporal and motor neuron degeneration with neurofilament inclusion bodies: additional evidence for overlap between FTD and ALS Neuropathol Appl Neurobiol 29:239–253, 2003 Boxer AL, Lipton AM, Womack K, et al: An open-label study of memantine treatment in types of frontotemporal lobar degeneration Alzheimer Dis Assoc Disord 23:211–217, 2009 Chan D, Walters RJ, Sampson EL, et al: EEG abnormalities in frontotemporal lobar degeneration Neurology 62:1628–1630, 2004 Chow TW, Hynan LS, Lipton AM: MMSE scores decline at a greater rate in frontotemporal degeneration than in AD Dement Geriatr Cogn Disord 22:194–199, 2006 Dickson DW: Pick’s disease: a modern approach Brain Pathol 8:339–354, 1998 Dubois B, Slachevsky A, Litvan I, et al: The FAB: a frontal assessment battery at bedside Neurology 55:1622–1625, 2000 ... Neuropathol Exp Neurol 69:918– 929 , 20 10 23 0 Clinical Manual of Alzheimer Disease and Other Dementias McKhann GM, Albert MS, Grossman M, et al: Clinical and pathological diagnosis of frontotemporal dementia... measures of short-term memory and was unable to perform any standardized executive function tasks 23 8 Clinical Manual of Alzheimer Disease and Other Dementias As shown in Figure 10 2, because of the... ubiquitin inclusions, but some of these cases are classifiable as FTLD–motor neuron disease (Lipton et al 20 04) Cortico- 22 4 Clinical Manual of Alzheimer Disease and Other Dementias basal degeneration