Primary Progressive Aphasia and Kindred Disorders

Handbook of Clinical Neurology, Vol. 89 (3rd series) Dementias C. Duyckaerts, I. Litvan, Editors # 2008 Elsevier B.V. All rights reserved Primary progressive aphasias Chapter 54 Primary progressive aphasia and kindred disorders MARSEL MESULAM* AND SANDRA WEINTRAUB Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University Feinberg School of Medicine, Chicago, USA 54.1. Introduction Bub, 1997; Kertesz et al., 2000, 2002; Hillis, 2002, 2004; Grossman and Moore, 2005). Terms such as The existence of progressive aphasias has been known progressive nonfluent aphasia (PNFA), semantic for more than 100 years. Pick (1892, 1904), Se´rieux dementia, aphasic variant of frontotemporal dementia (1893), Franceschi (1908), and Rosenfeld (1909) were (FTD), temporal variant of frontotemporal lobar among the first to report such patients. The current resur- degeneration (FTLD), Gogi aphasia and progressive gence of interest in this condition can be traced to a 1982 aphasia have been used, mostly implicitly, to denote report of six patients with a slowly progressive aphasia variants of PPA (Neary et al., 1998; Miller et al., and to the subsequent delineation of the primary progres- 1999). We prefer the PPA term as a root diagnosis sive aphasia (PPA) syndrome (Mesulam, 1982, 1987, for two reasons: not all progressive aphasias fulfill 2007; Mesulam and Weintraub, 1992). the PPA criteria and not all PPA cases are caused According to currently accepted criteria, the PPA by FTLD pathology. The word “primary” is a key diagnosis is made in any patient in whom a language descriptor that emphasizes the selective salience of impairment (aphasia), caused by a neurodegenerative the language disturbance and the relative preservation disease (progressive), constitutes the most salient aspect of other cognitive domains at initial stages. of the initial clinical picture (primary). The term lan- Acquired language disorders are known as aphasias. guage in this definition is used in its technical neurologi- Aphasias can be classified as being agrammatic, cal sense to refer to all component processes served by semantic, or anomic, depending on the specific aspect the left hemisphere language network, including phonol- of language that is most severely affected. Progressive ogy, morphology, syntax, semantics, naming, word- aphasias are not rare in neurological practice. Many finding, reading and spelling. The language impairment patients with Alzheimer’s disease (AD) eventually in PPA can be fluent or non-fluent and may or may not develop an aphasia. Aphasia can also arise in the interfere with word comprehension. Memory for recent course of motor neuron disease (MND), corticobasal events is preserved although memory scores obtained degenerations (CBD), behavioral variant of frontotem- in verbally mediated tests may be abnormal. The recog- poral dementia (bvFTD), and dementia associated with nition of familiar facts and objects is preserved (Adlam the posterior cortical atrophy (PCA) of Benson et al. et al., 2006). Minor changes in personality and behavior (1988). While all of these patients can be said to have may be present but are not the leading factors that bring progressive aphasias, the language impairment is not the patient to medical attention or that disrupt daily liv- “primary”, either because it is of lesser importance in ing activities. This selective clinical pattern is most con- comparison to other more salient deficits or because spicuous in the initial stages of the disease, covering an it is a late manifestation of the disease. interval of approximately 2 years after symptom onset. In a unique group of patients, a slowly progressive Hundreds of PPA cases have been reported and a aphasia arises in relative isolation, becomes the princi- sizable research literature on this topic has appeared pal cause of restrictions in daily living activities (Kertesz et al., 1994; Black, 1996; Westbury and (Wicklund et al., 2007), and remains the most salient *Correspondence to: M. Mesulam, 320 East Superior St, Chicago, IL 60611, USA. E-mail: [email protected], Tel: þ1-312-908-9339, Fax: þ1-312-908-8789. 574 M. MESULAM AND S. WEINTRAUB aspect of the clinical picture for several years. This among the presenting symptoms. Although the patient does not mean that all other cognitive and behavioral may forget names of people, word-finding during domains are intact, but that they are less severely conversation is usually not a major problem. In con- impaired than language. Such patients are said to have trast, the patient with PPA comes to medical attention a primary progressive aphasia or PPA. In contrast to because of word-finding difficulties, abnormal speech the clinical syndrome of probable Alzheimer’s disease patterns, or spelling errors of recent onset. Primary (PRAD), which designates a memory-based (amnestic) progressive aphasia is diagnosed when other mental dementia, or the behavioral variant of frontotemporal faculties such as memory for daily events, visuospatial dementia (bvFTD), which designates a behavior-based skills, face and object knowledge (assessed by the (comportmental) dementia, PPA designates a language- recognition of familiar faces and objects) and comport- based (aphasic) dementia. ment (assessed by history obtained from a third party) remain relatively intact; when language is the only area 54.2. Comments on the clinicopathological of major dysfunction early in the disease; and when nomenclature used in this chapter structural brain imaging does not reveal a specific lesion, other than atrophy, that can account for the There are currently no reliable in vivo markers for the language deficit (Mesulam and Weintraub, 1992; definitive identification of the underlying disease pro- Mesulam, 2001, 2003). cess in patients with non-familial neurodegenerative Standardized neuropsychological tests are helpful dementias. Furthermore, the same neuropathological for reaching an early diagnosis (Weintraub et al., entity can have multiple clinical manifestations depend- 1990; Weintraub and Mesulam, 1993, 1996). However, ing on its regional distribution in the brain. These are a strict reliance on neuropsychological tests, most of two reasons why nomenclature in this field can become which depend on verbal instructions, verbal responses, unusually confusing when the distinction between clini- or covert verbal reasoning, may occasionally lead to cal and neuropathological levels becomes blurred. the erroneous conclusion that areas other than language A physician can suspect that a dementia is caused by are also impaired. Scores on the Mini Mental Status Alzheimer’s disease or Pick’s disease but cannot confirm Examination (MMSE) (Folstein et al., 1975), for exam- this prediction until brain tissue is examined. This is of ple, can exaggerate the degree of disability. Although practical importance because the clinical patterns of the the language disorder in primary progressive aphasia two diseases can partially overlap despite differences in may interfere with the ability to memorize word lists the frequency of individual features (Weintraub and or solve reasoning tasks, the patient typically has no dif- Mesulam, 1993). This state of affairs makes it imperative ficulty recalling daily events or behaving with sound to distinguish clinical syndromes from neuropathological judgment, indicating that explicit memory, reasoning diagnoses. In this chapter, we will confine the use of acro- and social skills remain relatively intact. nyms such as PPA, bvFTD, and probable Alzheimer’s In some patients, the principal signs and symptoms disease (PRAD) to clinically identified syndromes of are confined to the area of language for as many as aphasic (Mesulam, 2003), amnestic (McKhann et al., 10–14 years. In others, impairments in other cognitive 1984) and comportmental (Neary et al., 1998)dementia, functions can emerge after the initial few years, but the respectively. The acronyms AD and FTLD will be re- language dysfunction remains the most salient feature served for neuropathological patterns identified by micro- and deteriorates most rapidly through many years scopy. Specifically, AD will refer to the presence of (Weintraub et al., 1990). Primary progressive aphasia amyloid plaques and neurofibrillary tangles in a certain is a form of dementia since it causes a gradual cogni- density and distribution (Hyman and Trojanowski, 1997), tive decline to the point where daily living functions whereas FTLD will refer to characteristic combinations become compromised. It is also an unusual dementia of focal neuronal loss with gliosis, superficial spongiosis, since core memory functions remain largely preserved. Pick bodies, other tau inclusions, and tau-negative ubi- In contrast to many patients with PRAD who tend to quitinated TDP-43 inclusions (McKhann et al., 2001; lose interest in recreational and social activities, some Neumann et al., 2006). patients with PPA maintain and even intensify their involvement in complex hobbies such as gardening, 54.3. Clinical features and diagnosis in carpentry, sculpting and painting. primary progressive aphasia Primary progressive aphasia should be differentiated from states of pure progressive dysarthria, speech The patient with PRAD comes to medical attention apraxia, or phonological disintegration where the for- because of forgetfulness. Misplacing personal objects, mation rather than usage of words becomes disrupted repeating questions, and forgetting recent events are (Broussolle et al., 1996). It should also

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