Abstract
Primary progressive aphasia (PPA) is a neurodegenerative disorder with language impairment as the primary feature. Different subtypes have been described and the 3 best characterized are progressive nonfluent aphasia (PNFA), semantic dementia (SD) and logopenic/phonological aphasia (LPA). Of these subtypes, LPA is most commonly associated with Alzheimer's disease (AD) pathology. However, the features of PPA associated with AD have not been fully defined. Here we retrospectively identified 14 patients with PPA and either pathologically confirmed AD or cerebrospinal fluid (CSF) biomarkers consistent with AD. Analysis of neurological and neuropsychological features revealed that all patients had a syndrome of LPA with relatively nonfluent spontaneous speech, phonemic errors, and reduced digit span; most patients also had impaired verbal episodic memory. Analysis of the pattern of cortical thinning in these patients revealed left posterior superior temporal, inferior parietal, medial temporal, and posterior cingulate involvement and in patients with more severe disease, increasing involvement of left anterior temporal and frontal cortices and right hemisphere areas in the temporo-parietal junction, posterior cingulate, and medial temporal lobe. We propose that LPA may be a “unihemispheric” presentation of AD, and discuss this concept in relation to accumulating evidence concerning language dysfunction in AD.
Primary progressive aphasia (PPA) refers to a group of neurodegenerative disorders with language impairment as the initial symptom (Mesulam, 1982, Mesulam, 2001 and Mesulam, 2003). These disorders are of high neurobiological and clinical importance because they illustrate the potentially focal nature of neurodegenerative disease and the potential heterogeneity of clinical presentations even where the underlying pathological process is uniform. The best characterized subtypes of PPA are progressive nonfluent aphasia (PNFA) and semantic dementia (SD). Patients with PNFA have nonfluent speech characterized by agrammatism and/or a motor speech impairment (usually an apraxia of speech, i.e., hesitancy and effortfulness attributable to impaired planning of articulation) (Ogar et al., 2007). SD presents with fluent aphasia, anomia, and single word comprehension deficits secondary to verbal semantic impairment (Hodges and Patterson, 2007). “Fluency” in this context refers to the flow of speech. However, dysfluency may arise from a variety of underlying deficits, including agrammatism, impaired articulation (motor deficits such as apraxia of speech), decreased phrase length or slower speech rate (e.g., due to word-finding pauses); patients referred to as having a “nonfluent aphasia” may have various more or less distinct primary language or speech impairments. This theme is well illustrated by the recently recognized entity of logopenic/phonological aphasia (LPA) (Gorno-Tempini et al., 2004 and Gorno-Tempini et al., 2008), which constitutes a third major syndrome within the PPA spectrum. Patients with LPA have word-finding pauses and anomia as well as impaired speech repetition, particularly sentences (Gorno-Tempini et al., 2008).
Most cases of PPA have a non-Alzheimer pathological substrate within the frontotemporal lobar degeneration spectrum, and are usually associated predominantly with either tau- or TAR (trans-activation-response) DNA binding protein 43 (TDP-43)-positive cellular inclusions (known as FTLD-tau or FTLD-TDP pathology), respectively (Knibb et al., 2006 and Snowden et al., 2007). However, it has long been recognized that PPA syndromes may also be associated with Alzheimer's disease (AD) pathology (Clark et al., 2003, Green et al., 1990, Greene et al., 1996, Karbe et al., 1993, Kempler et al., 1990, Li et al., 2000 and Pogacar and Williams, 1984) and in recent years more detailed series have been reported (Alladi et al., 2007, Croot et al., 2000, Davies et al., 2005, Galton et al., 2000, Josephs et al., 2008, Kertesz et al., 2005, Knibb et al., 2006 and Mesulam et al., 2008). In particular, recent evidence has suggested that LPA is underpinned by AD pathology in a high proportion of cases and may be the most common aphasia phenotype of AD (Gorno-Tempini et al., 2008, Mesulam et al., 2008 and Rabinovici et al., 2008). However both PNFA and SD have also been reported with AD pathology, as have syndromes that do not fit clearly into a single category, so-called “mixed” aphasia (Alladi et al., 2007 and Knibb et al., 2006). As AD is the most common neurodegenerative disease of later life, the range of phenotypic variation in AD and the mechanisms that drive this variation are key issues in the field of neurodegenerative disease.
Here we review the clinical, neuropsychological and cross-sectional neuroimaging features of a retrospective series of patients with a clinical diagnosis of PPA and AD pathology either demonstrated directly or presumed on the basis of cerebrospinal fluid (CSF) biomarker profiles. We consider these cases in relation to previously published series of PPA patients with either pathologically confirmed AD or a positive Pittsburgh compound B (PIB)-positron emission tomography (PET) scan suggestive of AD.
