The clinical syndrome of primary progressive aphasia is a diagnostic category applied to conditions in which individuals exhibit at least a 2-year history of progressive language deterioration not accompanied by other cognitive symptoms and not attributable to any vascular, neoplastic, metabolic, or infectious diseases. The disease is considered to be a focal cortical atrophy syndrome, as neuronal cell death is, at least initially, limited to circumscribed cortical regions and symptoms are isolated to specific abilities and behaviors subserved by the affected region (Polk and Kertesz, 1993; Black, 1996). Primary progressive aphasia (PPA) is characterized by the gradual worsening of language dysfunction in the context of preserved memory, judgment, insight, visuospatial skills, and overall comportment, at least until the later stages of the disease. Historically viewed as an atypical presentation of dementia, the isolated deterioration of language in the context of degenerative disease has been reported for more than 100 years. PPA was first recognized as a distinct clinical entity by Mesulam in 1982. Mesulam and Weintraub (1992) distinguished PPA from other degenerative neurological conditions such as Alzheimer's disease (AD) by its gradual progression of language dysfunction in the absence of more widespread cognitive or behavioral disturbances for a period of at least 2 years. In some cases, the syndrome may later become associated with cognitive and behavioral disturbances similar to those seen in frontal lobe or frontotemporal dementia or with motor speech disorders (dysarthria, apraxia of speech), as observed in corticobasal degeneration or upper motor neuron disease (e.g., primary lateral sclerosis) (Kertesz and Munoz, 1997). In other cases, the symptoms remain limited to the dissolution of language production and comprehension abilities throughout the duration of the affected individual's life.

The diagnosis of PPA is typically made based on a 2-year history of progressive language deterioration that emerges in the absence of any marked disturbance of other cognitive function and is not associated with any vascular, neoplastic, metabolic, or infectious disease (Duffy and Petersen, 1992; Mesulam and Weintraub, 1992). In addition to neurological examination, medical assessment typically includes neuroimaging and neuropsychological testing. During the first few years, computed tomographic and magnetic resonance imaging results tyipically are negative or reveal mild to moderate atrophy of the left perisylvian region. Metabolic neuroimaging (e.g., positron emission tomography) typically reveals left perisylvian hypometabolism and is sensitive to abnormalities earlier than structural neuroimaging methods (e.g., Kempler et al., 1990; McDaniel, Wagner, and Greenspan, 1991). Neuropsychological assessment typically reveals relative preservation of nonverbal cognitive function (e.g., abstract reasoning, visual short-term memory, visuoperceptual organization) in conjunction with below-normal performance on tests requiring verbal processing, such as immediate verbal recall, novel verbal learning, and verbal fluency (e.g., Sapin, Anderson, and Pulaski, 1989; Weintraub, Rubin, and Mesulam, 1990). Additionally, many studies have reported the presence of nonlinguistic sequelae known to frequently co-occur in nonprogressive forms of aphasia, such as acalculia, dysphagia, depression, limb apraxia, and apraxia of speech (Rogers and Alarcon, 1999).

At present, the cause of PPA is unknown. It is similarly unclear whether PPA is related to a distinct neuropathological entity. Investigations of the neuropathology associated with PPA yield heterogeneous findings (Black, 1996). Most case studies that include histological data report nonspecific neuronal loss in the left perisylvian region accompanied by spongiform changes in the superficial cortical layers (Snowden et al., 1992; Scheltens, Ravid, and Kamphorst, 1994). Other cases have been reported of individuals who initially presented with progressive language disturbances but eventually were diagnosed with AD (Pogacar and Williams, 1984; Kempler et al., 1990), Pick's disease (Holland et al., 1985; Graff-Radford et al., 1990; Scheltens et al., 1990; Kertesz et al., 1994), and Creutzfeldt-Jakob disease (Shuttleworth, Yates, and Paltan-Ortiz, 1985; Mandell, Alexander, and Carpenter, 1989). However, most of these cases do not meet the diagnostic criteria for PPA according to Mesulam's definition. Furthermore, it is possible that the onset of neuropathophysiological changes related to AD develop sometime after the onset of the focal cortical degeneration associated with PPA, thus explaining the initial appearance of isolated language symptoms, followed by the onset of more widespread cognitive involvement. Thus, autopsy findings of pathology associated with AD do not preclude the possibility that two distinct disease processes may co-occur within the same individual. Although PPA is recognized as a distinct clinical entity, the issue of whether it is a distinct pathological entity remains unresolved.

The course of the disease is quite varied. After a 2-year history of isolated language symptoms, some proportion of individuals diagnosed with PPA eventually exhibit more widespread cognitive involvement consistent with a diagnosis of dementia (i.e., deterioration in two or more cognitive areas such as memory, personality changes, and the ability to independently carry out activities of daily living due to cognitive as opposed to physical impairments). Mesulam (1982) suggested waiting 5 years after the onset of symptoms before trying to predict the course of cognitive involvement. However, there is no indication from the literature that after 5 years, individuals are less likely to develop dementia (Rogers and Alarcon, 1999). Estimates vary concerning the percentage of individuals who, after initially presenting with a 2-year history of isolated language dissolution, eventually exhibit widespread cognitive involvement. These estimates range from 30% to 50% (Duffy and Petersen, 1992; Mesulam and Weintraub, 1992; Rogers and Alarcon, 1999). Thus it is likely that between 50% and 70% of individuals diagnosed with PPA experience only the consequences of declining speech, language, and communication for many years. These individuals continue to drive, manage their own finances, and in all respects other than speech, language, and communication maintain baseline levels of performance on repeated testing over many years. Thus, the course is variable, with some patients progressing rapidly, but for others, the course can be quite prolonged, typically taking 6 or 7 years before they develop severe aphasia or mutism. For these individuals, the global cognitive deterioration does not occur as early in the disease process or to the same extent as seen in AD.

Researchers have attempted to identify clinical symptoms that could serve as reliable predictors of eventual cognitive status. The profile of speech and language dysfunction has been investigated as a prognostic indicator of whether an individual is likely to develop generalized dementia. The hypothesis that a language profile consistent with fluent aphasia as opposed to nonfluent aphasia predicts a course of earlier cognitive decline has been investigated through case study (e.g., Snowden et al., 1992) and systematic review of the literature (Duffy and Petersen, 1992; Mesulam and Weintraub, 1992; Rogers and Alarcon, 1999). The fluency dimension in aphasia refers to a dichotomous classification based on the nature of the spoken language disturbance. Individuals with fluent aphasia produce speech at normal to fast rates with normal to long phrase length and few, if any, phonological speech errors. Verbal output in fluent aphasia is characterized as logorrheic (running on and on) and neologistic (novel words), and it tends to be empty (devoid of meaningful content). Disturbances of auditory comprehension and anomia (i.e., word retrieval difficulties) were the primary symptoms in most cases of fluent PPA reviewed by Rogers and Alarcon (1999). Hodges and Patterson (1996) found these to be the primary presenting complaints in the individuals with fluent PPA that they labeled semantic dementia. Unlike individuals with AD, individuals with semantic dementia or fluent PPA have relatively spared episodic (both recent and old autobiographical) memory but exhibit loss of semantic memory, especially as concerns mapping concepts to their spoken form (Kertesz and Munoz, 1997).

A nonfluent profile is characterized by effortful speech, sparse output with decreased phrase length, impaired access to phonological word-form information, infrequent use of grammatical markers, and disturbed prosody, and is frequently associated with apraxia of speech. Auditory comprehension, while affected, generally deteriorates later than expressive language skills. Nonfluent spontaneous speech and the production of phonemic paraphasias in naming have been proposed as important characteristics distinguishing PPA from the aphasia-like symptoms in AD. However, the language disorder evinced by individuals with PPA rarely fits neatly and unambiguously into the fluency typology. Snowden et al. (1992) described a group of individuals with PPA who exhibited expressive and receptive disruptions of phonology and semantics. Be'land and Ska (1992) described an individual with PPA who presented with “a syntactic deficit as in Broca's … auditory comprehension deficits of the Wernicke's aphasia type … and phonemic approximations as found in conduction aphasia” (p. 358). Although there is no accepted classification for individuals exhibiting this profile, the term “mixed aphasia” has been applied (e.g., Snowden et al., 1992). Although reliable sorting of aphasia in PPA into the fluent or nonfluent classes has not been established, the hypothesis that individuals with a fluent profile are more likely to develop generalized cognitive involvement than those with a nonfluent profile has received much attention (e.g., Weintraub, Rubin, and Mesulam, 1990; Duffy and Peterson, 1992; Snowden et al., 1992; Rogers and Alarcon, 1999).

The hypothesis that the profile of language impairment may predict the course of generalized cognitive involvement has been investigated primarily through systematic review of the literature. Duffy and Peterson (1992) reviewed 28 reports, published between 1977 and 1990, describing 54 individuals with PPA. Approximately half of the 54 individuals developed generalized dementia, but none of the 12 patients identified with nonfluent profiles evinced generalized cognitive involvement. This finding was interpreted as supporting the hypothesis that a nonfluent profile may predict a longer duration of isolated language symptoms, or perhaps a lower probability of developing widespread cognitive involvement. Mesulam and Weintraub (1992) reviewed 63 cases of PPA. The average duration of isolated language symptoms was 5.2 years, and six individuals exhibited isolated language symptoms for more than 10 years. They reported that, compared to either probable or pathologically confirmed AD, the PPA group contained more males, a higher incidence of onset before age 65, and a greater incidence of nonfluent aphasia. A nonfluent profile was never observed in the AD group, whereas the distribution of fluent and nonfluent profiles in the PPA group was balanced (48% fluent, 44% nonfluent). According to Mesulam and Weintraub (1992), not all individuals with probable AD exhibit aphasic disturbances, but those who do, exhibit only the fluent aphasia subtype.

Rogers and Alarcon (1999) reviewed 57 articles published between 1982 and 1998 describing 147 individuals with relatively isolated deterioration of speech and language for at least 2 years. Thirty-seven patients had fluent PPA, 88 had nonfluent PPA, and in 22 cases the type of aphasia was indeterminate. Among the individuals with fluent PPA, 27% exhibited dementia at the time of the published report. Among the nonfluent PPA group, 37% were reported to have developed generalized dementia. Of the 22 individuals with an undetermined type of aphasia, 73% exhibited clinical symptoms of dementia. The average duration of isolated language symptoms among the 77 individuals who developed generalized dementia was 5 years (6.6 years in fluent PPA, 4.3 years in nonfluent PPA, and 3.7 years among those with an undetermined type of aphasia). The aggregate data in this review did not support the hypothesis that individuals with a nonfluent profile are less likely to develop generalized cognitive involvement than those with a fluent profile. Furthermore, the data did not support the hypothesis that a nonfluent profile predicts a longer duration of isolated language symptoms. Despite the unequal number of patients in each of the fluency groups, the lack of control regarding the time post onset across cases, and the possibility that there may be considerable impetus to report PPA in individuals who do not exhibit generalized dementia, it does not appear that the fluency profile is a reliable predictor of eventual cognitive status.

The initial symptoms of PPA vary from individual to individual, but anomia is the most commonly reported presenting complaint in patients with both fluent and nonfluent PPA (Mesulam, 1987; Rogers and Alarcon, 1999). Another early symptom, particularly in nonfluent PPA, is slow, hesitant speech, frequently punctuated by long pauses and filler words (“um,” “uh”). Although this may represent simply one of many manifestations of anomia, it also portends the language formulation difficulties that later render the speech of these individuals telegraphic (reduced mean length of utterance consisting primarily of content words). Impaired access to phonologic form is frequently associated with later-emerging spelling difficulties, although partial access to initial letters and syllable structure may be retained for many years (Rogers and Alarcon, 1998, 1999). Difficulties with phonologic encoding have also been reported in cases of fluent PPA. Tyler et al. (1997) described the anomic difficulties of one individual with fluent PPA as impaired mapping between the semantic lexicon and output phonology. More typically, individuals who eventually exhibit fluent PPA initially complain of difficulties understanding spoken language (Hodges and Patterson, 1996), whereas individuals with nonfluent PPA typically exhibit preserved language comprehension in the early stages (Karbe, Kertesz, and Polk, 1993). Some individuals with a nonfluent presentation of PPA initially exhibit motor symptoms consistent with a diagnosis of dysarthria or apraxia of speech. The initial symptom of progressive speech apraxia has been reported by Hart, Beach, and Taylor (1997). Dysarthria and orofacial apraxia have been reported as initial symptoms in a variation of PPA labeled slowly progressive anarthria (Broussolle et al., 1996). The relationships between and among nonfluent PPA, primary progressive apraxia, slowly progressive anarthria, corticobasal degeneration, primary lateral sclerosis, and Parkinson's disease is of interest, because these conditions exhibit considerable clinical overlap and in some cases share similar pathophysiology. In the later stages of all of these syndromes, individuals lose the ability to communicate by speech and are uniformly described as “mute,” despite apparent differences regarding the underlying nature of the specific impairment precluding the production of spoken language.

Regardless of the subtype of PPA, the progressive loss of language need not result in the total cessation of all communication, as there are augmentative and alternative communication tools and strategies that can be proactively established so that the individual with PPA can maximize communication competency at every stage, despite the relentless deterioration in speech and language (Rogers, King, and Alarcon, 2000).