Introduction

The first report of progressive cognitive decline limited to language was published in 1893 [1]. This case had declining speech fluency without difficulty in memory, social, or visuospatial domains. Mesulam described five cases of declining speech fluency he called slowly progressive aphasia [2]. The term “progressive non-fluent aphasia” was coined in 1992 to describe a subgroup of patients with primary progressive aphasia characterized by slowed speech but preserved comprehension [3], and a full characterization of the clinical and linguistic characteristics [4] and the underlying pathology [5, 6] of these patients were reported soon thereafter. More recently, consensus clinical research criteria for the non-fluent/agrammatic variant of primary progressive aphasia (naPPA) were published [7]. The reliability of these criteria has been demonstrated in independent laboratories [8, 9].

Primary progressive aphasia (PPA) refers to the core language deficits of this clinical syndrome. The aphasia disorder encompasses an impairment of specific central processes underlying language comprehension and expression. While some patients may have a peripheral motor deficit that slows speech or a sensory limitation that limits access to speech, pure sensory or motor deficits cannot entirely explain the full spectrum of central language impairments associated with PPA. The language impairment in patients with PPA is progressive in nature, resulting in an insidious decline over the course of several years. Aphasic syndromes with an acute onset such as the ischemic vascular syndrome of Broca’s aphasia may resemble naPPA, but the abrupt onset of a vascular syndrome discounts the likelihood of PPA. Likewise, other vascular disorders such as parenchymal or subarachnoid hemorrhage, and non-vascular disorders such as traumatic brain injury and primary and metastatic carcinomas, can be associated with a language disorder resembling PPA, but PPA is reserved for a primary language disorder without obvious cause. PPA syndromes do not necessarily occur in isolation, and may be seen in the context of other progressive neurodegenerative conditions, including: behavioral variant frontotemporal degeneration (bvFTD) characterized by a social disorder; extrapyramidal movement disorders such as corticobasal syndrome (CBS), progressive supranuclear palsy syndrome (PSPS), and Lewy body disease; and amyotrophic lateral sclerosis (ALS). There are important clinical reasons to recognize PPA even in the context of another clinical syndrome since we are highly dependent on language in day-to-day functioning, and a language disorder severely limits self-care activities and independence in daily living. There is a significant reduction in quality of life, and impaired communicative efficacy in PPA has profound consequences for psychological health and is associated with depression [10].

The clinical features of naPPA are detailed below; naPPA encompasses a spectrum of specific language and speech disorders that differs from other forms of PPA. Each can be recognized by its characteristic pattern of language difficulty. One variant of PPA is known as the semantic variant of PPA (svPPA), also called “semantic dementia” [11]. The core features of this disorder are deficits in object naming as well as word and object meaning. The second PPA variant is called logopenic variant PPA (lvPPA) or “logopenic progressive aphasia” [12]. This is marked by impaired word-finding and repetition difficulty, although others have referred to this as “progressive mixed aphasia” because of the inconstant speech fluency and lexical comprehension deficit associated with this disorder. Published clinical diagnostic recommendations help identify these forms of PPA, and distinguish them from naPPA [7]. While svPPA is reliably identified by the published criteria, the criteria for lvPPA do not appear to be reliable [8, 9]. These PPA syndromes are important to recognize because they may help screen for an associated underlying pathology [13, 146]. This is critical in the context of emerging, disease-modifying treatments. Following clinical screening, more definitive diagnosis may be supplemented by imaging, molecular and biofluid biomarkers [14].

Language characteristics of non-fluent/agrammatic primary progressive aphasia

The most recognizable clinical feature of naPPA is effortful, non-fluent speech. This is best quantified by a semi-structured speech sample. A conversational exchange may be long enough to give a patient the opportunity to express a variety of grammatical forms and speech sound combinations, but it is also important to collect a speech sample in a standardized manner with a known topic so that all participants have an opportunity to produce speech targeting the same content. One common method asks patients to review and then describe a picture or a wordless children’s picture story. Based on this technique, the rate of speech in naPPA averages about 45 words per minute, less than one-third the speech rate of healthy adults [15, 16, 17, 18, 19]. This slowed speech rate is a highly reliable marker of naPPA, and each individual with naPPA in our series differs significantly from healthy adult speakers by this measure. Also, naPPA patients produce significantly slower speech than patients with other forms of progressive aphasia. Speech does not emerge as a slow, steady flow. Instead, speech is interrupted by lengthy pauses within and between utterances. Even when controlling for pauses, naPPA patients produce fewer words per minute than controls [16]. Another clinical characteristic of effortful, non-fluent speech is the distortion of prosody. Prosody is the pattern of pitch contours spanning words and sentences that helps provide emphasis, is critical for marking questions, and reflects the emotional content of speech. Prosody loses its normal contours in naPPA.

A detailed analysis of semi-structured speech samples in naPPA reveals significant simplification of grammatical forms. There is also a significantly greater number of grammatical errors and omissions compared to controls and other PPA patients [16, 17, 19]. These characteristics also result in a significantly abbreviated mean length of utterance. Several factors may contribute to effortful, non-fluent speech in naPPA, including grammatical, motor, and executive factors, and an empirical assessment demonstrated that the most prominent factor is difficulty processing grammatical aspects of speech [17].

Nevertheless, the motor speech disorder known as apraxia of speech (AoS) also may be contributing to slowed, effortful speech in naPPA. Speech is slowed because the complex coordination of muscle groups underlying the motor speech apparatus has been compromised. Several reports describe an increased frequency of AoS in patients with naPPA [20, 21], and patients with naPPA produce more speech errors than other PPA patients [15, 22]. AoS is most prominent in conditions with co-occurring involuntary limb movements and poor limb motor control such as progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) [20, 23], although AoS can occur without an accompanying extrapyramidal disorder, and AoS can occur as an isolated entity without other evidence of the language impairments found in naPPA [24, 25].

There are at least two sources for the large number of speech sound errors in patients with naPPA: some of these errors may be due to a disturbance of the motor system responsible for coordinating and articulating speech sounds consistent with AoS, while other speech sound errors may be due to disturbance of the linguistic system of phonology that is responsible for the abstract representations of speech sounds and the rules governing their use in a speaker’s language. However, it has proven difficult to quantify AoS. One potential method involves identifying speech errors that are not part of the corpus of speech sounds in the speaker’s native language [22]. This is because “phonetic” speech errors of this sort are more likely to emerge when an impaired motor coordination system produces sounds due to misplaced articulators. This contrasts with “phonologic” speech sound errors that violate the abstract rules for representing and ordering phonemes in the speaker’s native language. This method captures only some examples of AoS and thus may under-represent the occurrence of AoS. With this caveat in mind, speech errors were documented in lengthy speech samples of a large cohort of patients with naPPA, but phonetic errors consistent with AoS characterized only 21% of the speech sound errors of these patients [22]. There is no evidence of an association between AoS and a parallel deficit forming letters in written output known as apractic agraphia. While there are errors in speech sound production, spelling is largely preserved.

While sentence-level speech is slowed in naPPA, oral production of over-learned sequences such as counting and repetition of phrases is relatively fluent. The ability to produce single words relatively promptly also appears to be preserved, such as in an oral naming task. However, there may be difficulty naming and understanding with single verbs [26, 27]. It is important to note that these exceptions for verb use may have implications for sentence level processing since verbs play such a critical role in structuring a sentence. Indeed, naPPA patients may use fewer verbs in their semi-structured speech samples [16].

To emphasize that the motor speech disorder cannot fully explain the naPPA syndrome, it is also possible to assess grammatical comprehension [4]. Grammatical comprehension difficulties have distinguished naPPA from healthy seniors and from other PPA variants [28, 29, 30]. Another mark of the “central” grammatical deficit in naPPA is the presence of parallel grammatical impairments in writing and reading, although this has been examined rarely [4]. Unfortunately, it has proven challenging to develop clinical measures assessing grammatical comprehension in an unconfounded manner. One task is entirely language-based and probes brief aural sentences varying in grammatical complexity with a simple question about “who did what to whom.” In the sentence “Boys that girls kick are unfriendly,” for example, naPPA patients often err when asked: “Who did the kicking?” [29]. The problem here is that this task depends heavily on working memory. Another task uses an anagram approach to determine whether patients can order words printed on cards into a grammatically complex utterance describing a picture [31]. The challenge here is to dissociate the executive component involved in ordering from the distinct rules characterizing grammar. In another approach, naPPA patients are asked to point to one of two pictures based on a sentence, where selecting the correct picture depends on appreciating the sentence’s grammatical structure [30, 32, 33]. While this measure minimizes working memory and executive confounds, the concern here is that impaired performance on this task can emerge because of difficulty interpreting the picture.

A broader problem with these “off-line” tasks is that they are under the control of an executive resource system that is making conscious, deliberative decisions to interpret sentence meaning. This is not natural, automatic, “on-line” sentence processing, and thus these techniques may not fully reflect day-to-day natural language use. Moreover, as noted below, naPPA patients have limited executive resources and working memory that can confound interpretation of performance on these language tasks. A small number of studies have examined “on-line” grammatical processing in sentences. This work attempts to minimize executive control during task performance by avoiding judgments about sentence material per se. Instead, patients are asked to perform a simple secondary task during the time window when grammatical processing is occurring, and this disturbs grammatical processing. One online study demonstrated slowed processing of grammatically complex sentences in naPPA patients who had difficulty with a traditional measure of grammatical comprehension. This suggested that grammatically relevant information may degrade in working memory during sentence comprehension [34]. In another study, naPPA patients were insensitive to grammatical violations but had preserved sensitivity to semantic violations in a sentence [35].

Although reliable diagnostic criteria have been described, and despite broad agreement on the language and speech characteristics of these patients, some controversies remain in the clinical identification of patients with naPPA. Effortful, non-fluent speech characteristic of naPPA can resemble the gradual diminution of speech initiation and ultimately muteness that can be seen in bvFTD patients with apathy. This form of slowed speech can be distinguished from that found in naPPA because there are response delays on other tasks such as single word naming and non-linguistic measures. Reduced speech fluency due to lengthy, word-finding pauses that can be seen in lvPPA and even svPPA may look like the effortful speech of naPPA. Cases of lvPPA may be particularly difficult to distinguish from patients with naPPA because lvPPA also may manifest impaired sentence processing related to auditory–verbal short-term memory deficits. This can interfere with processing lengthy sentences and thus resemble the grammatical deficits found in naPPA [36], although this was not confirmed in a sentence–picture matching task involving grammatically mediated sentences [32]. Since the deficit in lvPPA is often due to an auditory–verbal short-term memory impairment, written sentence materials can be used to help distinguish these patients from naPPA patients who are thought to have a multimodal grammatical deficit. lvPPA have difficulty with multisyllabic word and sentence repetition, a feature that is much less common in naPPA [36, 37]. While both lvPPA and naPPA may have gray matter atrophy in a left anterior perisylvian distribution, cortical disease extends into the posterior perisylvian region in lvPPA [38, 39]. Finally, since many patients with lvPPA can develop episodic memory deficits typical of clinical Alzheimer’s disease and often have underlying AD pathology at autopsy [13, 40, 41], the observation of minimal white matter disease [42, 43], a cerebrospinal fluid profile showing lower amyloid levels and an elevated tau: amyloid-beta ratio [44], and positive amyloid PET imaging [45] can be helpful in identifying patients more likely to have lvPPA rather than naPPA.

The condition of naPPA is a progressive disorder of language. Clinically, patients gradually lose the ability to speak, with speech degenerating to simple phrases, then single words, and ultimately muteness. Impairments in written sentence output generally lag behind oral output deficits by several months to a year. However, there have been few quantitative studies examining the longitudinal course of naPPA. Limited speech output in the later stages of the condition severely constrains the ability to quantify the key feature of agrammatism. Two studies nevertheless have documented progressive decline in grammatical comprehension in naPPA [46, 47]. One report described a validated algorithm to quantify declining speech in naPPA [48]. While longitudinal performance may worsen in several domains of language such as naming, reading, and spelling [25, 49], some suggest that effortful speech, grammatical deficits, and speech sound errors remain relatively more impaired throughout the course of the disease. Progressive deficits on measures of executive functioning are also found in naPPA [49]. Using a large screening battery, however, others suggest a broader decline in multiple language attributes over time [50]. Longitudinal characterization of progressive aphasia remains an important challenge.

In sum, patients with naPPA appear to have slowed and effortful speech that is often related to an impairment of grammatical comprehension and production as well as poor motor speech control, while many other aspects of language and cognitive functioning do not appear to decline as much.

Non-linguistic deficits in executive functioning in non-fluent/agrammatic primary progressive aphasia

The condition of naPPA is a disorder of the frontal lobes. Patients with naPPA thus regularly have limited executive resources. This includes difficulty with working memory, mental planning, and dual-tasking [51, 52]. Working memory is an important component of oral sentence processing since a listener must keep in mind the emergent speech signal in order to fully understand a sentence, and a speaker must retain the intended message in an active mental state until completely expressed. In this context, it is important to note that naPPA patients are impaired on non-linguistic measures of working memory such as reverse digit span, where a sequence of digits must be repeated in its reverse order, although the deficit does not appear to be as prominent as that seen in lvPPA. There is also difficulty on non-grammatical measures of category naming such as letter-guided naming fluency (e.g., providing as many words as possible beginning with a letter like “F” in 1 minute). However, these patients do not appear to be as impaired on measures of semantically guided category naming fluency (e.g., naming as many “animals” as possible in 1 minute). Patients decline significantly in their performance on these executive measures over time as well [53].

In contrast to performance on measures of executive functioning, patients with naPPA typically have relatively preserved episodic memory [52], although some patients with underlying AD pathology may ultimately develop episodic memory deficits. Visuospatial functioning also is relatively preserved, although there are some exceptions such as naPPA presenting in the context of CBS [53]. It is uncommon to observe a disorder of social functioning and personality early in the course of naPPA, although socially inappropriate behaviors seen in patients with behavioral variant FTD (bvFTD) can emerge over time, including apathy, disinhibition or repetitive behaviors with little empathy and poor self-insight [54, 55]. The non-language spectrum of cognitive deficits in naPPA thus appears to involve limitations in working memory and executive control, while other cognitive and social domains may emerge only later in the course of these conditions.

Language disorders in amyotrophic lateral sclerosis and akinetic–rigid extrapyramidal disorders

Many patients with naPPA have a normal elementary neurologic exam. However, naPPA can be seen in the context of a pyramidal motor system disorder. This clinical picture is associated with amyotrophic lateral sclerosis (ALS) [56], a disorder centered in the primary motor cortices of the frontal lobe. Bulbar and limb weakness, muscle wasting, fasciculations, abnormal myotactic reflexes, and an extensor great toe are the classic features of ALS, and these can be seen in the context of naPPA [57, 58]. With the genetic [59, 60, 61, 62, 63] and histopathologic [64, 65] overlap between FTD and ALS, it has been increasingly recognized that prefrontal involvement anterior to primary motor regions is regularly seen in ALS [66, 67, 68, 69, 70]. Executive deficits are now well documented in ALS [71, 72, 73], including deficits on measures that are not confounded by motor limitations [74, 75]. Recent observations suggest that patients with ALS may have language deficits more commonly than impaired executive functioning [76]. At a discourse level, we find poorly organized narrative speech in ALS that is related in part to their executive limitations [77]. At a sentence level, there appears to be significant difficulty with grammatical expression, including grammatical simplification, and frank grammatical errors in speech [78]. This can be distinguished from dysarthric speech errors and slowed speech related to bulbar disease compromising the muscles of speech articulation. We emphasize the dissociation between a motor disorder and a language disorder in unpublished work, where we demonstrate a significant deficit in grammatical comprehension in ALS patients using a two-alternative forced-choice sentence–picture matching task. Finally, at a single word level, there are deficits in comprehension and expression of verbs that name actions [79, 80, 81, 82]. This has been related in part to the degraded representation of action knowledge, consistent with grounding of semantic representations in neuroanatomically associated brain regions [83, 84].

Abnormalities on neurologic exam in naPPA, when present, may also involve an extrapyramidal disorder. This includes features of CBS such as unilateral rigidity, dystonia, myoclonus, and limb apraxia, and naPPA in well-characterized patients with CBS has been described [53, 85]. There may also be a disorder of vertical gaze and axial rigidity associated with PSPS [20, 86]. As noted above, AoS may be a prominent feature of the speech disorder in these patients. Some patients may present with isolated AoS, and these individuals can subsequently develop an extrapyramidal disorder such as PSP [87].

Imaging studies implicate frontal disease in non-fluent/agrammatic primary progressive aphasia

There is extensive imaging evidence emphasizing the link between naPPA and atrophy in the anterior portion of the left Sylvian fissure including the frontal lobe. Structural MRI studies of the brain underline gray matter atrophy in the inferior frontal region of the left hemisphere [12, 18, 29, 88]. This typically involves adjacent frontal operculum and anterior insula. The anatomic extent of atrophy often extends more dorsally into left prefrontal regions [18] and ventrally into superior portions of the left anterior temporal lobe [17]. This corresponds to the anatomic distribution of atrophy in patients with known tau pathology, a frequent cause of naPPA [89, 90]. In patients with prominent AoS, imaging changes have been reported in premotor and supplementary motor areas somewhat more dorsally in the left hemisphere [20, 22].

Functional imaging studies show a similar anatomic distribution of disease in naPPA. Single photon emission computed tomography, positron emission tomography (PET), and arterial spin labeling MRI all have been used to image functional deficits in naPPA. For example, PET glucose hypometabolism has been reported in the left inferior frontal lobe, including the frontal operculum and the anterior insula [91]. Other PET work also suggests that this can extend to the anterior superior temporal region of the left hemisphere [4].

Disease in naPPA also compromises white matter. This reflects histopathologic evidence for extensive white matter disease in these patients [43, 92, 93]. Recent work using diffusion tensor imaging (DTI) demonstrates reduced fractional anisotropy (FA) that underlines changes in white matter integrity in projections related to the inferior frontal lobe [89, 94].

Imaging studies also can contribute to understanding the cause of naPPA. While many naPPA patients have a tauopathy, up to 30% of patients with naPPA may have underlying AD pathology. Imaging evidence of disease extending posteriorly into the parietal lobe appears to be a marker of AD pathology in the non-fluent variant of PPA [38, 39]. Significant white matter disease in the superior longitudinal fasciculus (SLF) is associated with tau pathology [95], and the SLF is a crucial dorsal stream projection that mediates sentence processing [96, 97].

PET radioligand imaging with Pittsburgh compound B (PiB) can help determine the pathologic basis for naPPA more directly because PiB tags amyloid, a component of AD pathology that is not associated with FTLD spectrum pathology. PiB studies of PPA thus may help distinguish between naPPA due to AD and non-AD pathology [45, 98, 99]. Recently developed tau radioligands are expected to be more helpful in specifying the underlying pathology of naPPA [100, 101]. In a study of naPPA with MR spectroscopy occurring in the context of CBS [102], a reduction in the ratio of N-acetyl aspartate (NAA), a marker of neuronal integrity, was found in the left hemisphere.

Additional work has begun to demonstrate the functional consequences of disease in the left inferior frontal region, and together with degradation of the associated white matter tracts, a large-scale neural network is interrupted in naPPA. Regression analyses directly relate quantitative gray matter atrophy in inferior frontal and anterior superior temporal regions of the left hemisphere to reduced speech fluency quantified in semi-structured speech samples [16, 19, 47]. Likewise, difficulty associated with grammatical simplifications and errors overlap areas of cortical atrophy related to non-fluent speech, and this is most evident in left inferior frontal and anterior superior temporal regions [17]. Another study associated AoS with left inferior frontal atrophy [21].

Functional MRI also has been used to demonstrate the functional role of left inferior frontal disease in naPPA. In one study, healthy controls, patients with naPPA, and patients with bvFTD silently read sentences featuring a complex grammatical structure and a prepositional phrase that stresses working memory [103]. Controls activated both inferior portions of the left frontal lobe associated with grammatical processing and dorsal left frontal regions associated with working memory. By comparison, naPPA patients activated only dorsal portions of the left frontal lobe, but did not activate the inferior frontal region associated with grammatical processing. Non-aphasic patients with bvFTD activated the inferior frontal region but not the dorsal area, consistent with their prominent working memory deficit. Another fMRI study presented grammatically simple sentences and grammatically complex sentences to naPPA patients and healthy controls [33]. Controls activated left inferior frontal regions during grammatically complex sentences more than simple sentences, while naPPA patients did not show a difference in left inferior frontal activation for these two types of sentences. These findings emphasize the crucial contribution of left inferior frontal disease to the naPPA syndrome.

Non-fluent/agrammatic primary progressive aphasia is associated with frontal pathology

Gross pathology in naPPA shows focal atrophy centered in the left inferior frontal and anterior–superior temporal region of the left hemisphere [89]. This corresponds to the core area of disease seen in imaging studies during life. It has been proposed that the class of von Economo neurons found only in higher-order primates may be diseased in patients with FTLD [104]. These neurons are found in inferior frontal regions that support uniquely human capacities like grammar.

Several different microscopic pathologies can result in naPPA. Histopathologic examination of naPPA at autopsy often reveals frontotemporal lobar degeneration associated with a tauopathy (FTLD-tau). Some clinical–pathological series have associated naPPA only with tau-positive pathologies, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Pick bodies (PiD) [20, 105]. In other studies, the pathology associated with naPPA has been overwhelmingly associated with FTLD with transactive-response DNA-binding protein of ~43 kD (FTLD-TDP) [106]. Four different forms of TDP-43 histopathology have been described [107, 108, 109, 110], and the variant with frequent dystrophic neurites and neuronal cytoplasmic inclusions known as Type A was found to be particularly prominent in naPPA [111, 112].

In most series, however, the pathology underlying naPPA has been mixed, with a predominance of FTLD-tau pathology, some cases of AD pathology and FTLD-TDP pathology, and rare cases of dementia with Lewy bodies [41, 113, 114, 115, 116, 117, 118, 119, 120, 121]. Two summaries of clinical–pathological series such as these have suggested that about 70% of naPPA patients have tau pathology, and many of the remainder have AD pathology [13, 146]. While not definitive, the naPPA phenotype thus appears to be biased towards FTLD-tau pathology. In an era of disease-modifying treatments, the presence of naPPA thus may serve as a valuable and inexpensive screening tool for identifying patients likely to have FTLD-tau pathology who would then be eligible for additional, more expensive biomarker studies that provide a more definitive diagnosis of the underlying cause of their disorder.

Genetic and molecular biomarkers of non-fluent/agrammatic primary progressive aphasia

A strongly positive family history is found in about 25% of patients with FTLD [122, 123, 124, 125], and it is possible to identify the mutation or expansion associated with these families in up to 80% of these cases [125]. Each genetic mutation in FTD spectrum disorders is reliably associated with specific pathology. While most identified genetic associations of FTD spectrum disorders are inherited in an autosomal dominant manner with fairly high penetrance, the clinical syndrome of naPPA does not appear to be frequently inherited.

The first gene related to FTLD – MAPT – is associated with FTLD-tau pathology. Despite the association of naPPA with tau pathology in sporadic cases, an inherited tauopathy does not appear to predispose to naPPA. The H1/H1 haplotype that is linked to the region on chromosome 17 coding for tau nevertheless appears to be associated with PPA [126]. Mutations of MAPT have been related occasionally to naPPA. For example, one sister of a positive sib-pair with a MAPT mutation had reduced speech fluency and was impaired on the Token test assessment of grammatical comprehension [127]. In this context, it is worthwhile keeping in mind that the phenotype associated with a specific MAPT mutation within a family may be highly variable [128].

Another common mutation associated with FTLD – GRN – also can be found at times in individuals with a non-fluent speech syndrome [129, 130]. Here the the underlying pathology is a TDP-43 proteinopathy. Hereditary dysphasic dementia (HDDD) appears to be an FTLD-related disorder [131, 132, 133], and HDDD-2 has been associated with ubiquitin-positive, tau-negative pathology due to a GRN mutation [134]. Two other families with naPPA have been related to a GRN mutation [135, 136]. Families with naPPA and a co-occurring behavioral disorder due to a GRN mutation have been described [130, 137, 138, 139]. It is important to note that clinical FTLD syndromes in carriers of a GRN mutation can be highly variable even in members of a family with the identical mutation [138, 140].

The most common cause of familial FTLD and ALS is a hexanucleotide repeat expansion in a non-coding region on chromosome 9 (C9ORF72) [63, 141], and this too is associated with FTLD-TDP pathology. Occasional patients with a C9ORF72 repeat expansion may have a naPPA phenotype [62, 142]. Other less common chromosomal mutations associated with FTD include VCP on chromosome 9 [143], CHMP2B on chromosome 3 [144], and a mutation of TARDBP on chromosome 1 [145]. Only rarely is a non-fluent aphasic syndrome associated with these highly infrequent mutations. Although other genetic mechanisms of disease remain to be elucidated, chromosomal mutations associated with an autosomal dominant disorder do not appear to be disproportionately associated with naPPA.

Summary

The condition of naPPA is a progressive neurodegenerative syndrome that is associated with the frontal lobe. The primary clinical feature of naPPA is effortful, non-fluent speech. This can be quantified by reduced words per minute, and confirmed by grammatical simplifications and errors in grammatical comprehension and expression, and the presence of phonetic errors characteristic of AoS. A limitation of executive resources also is present, and this may contribute to the non-fluent and agrammatic characteristics of naPPA. Language and cognition become compromised over time, and additional longitudinal work is needed to optimize our clinical understanding of naPPA.

Many imaging modalities associate naPPA with disruption of a large-scale neural network centered in the inferior portions of the left frontal lobe. In addition to gray matter atrophy in this region, there is significant disease particularly in dorsal white matter tracts associated with the inferior frontal lobe. The mechanism underlying these white matter changes remains to be elucidated, such as distinguishing between Wallerian degeneration associated with cortical disease compared to white matter pathology seen in tauopathies that involve astrocytes and oligodendrocytes.

Disease-modifying treatments are emerging in FTD. One of the most important clinical issues for the field is improving our ability to identify the pathology associated with the PPAs during life. Sporadic naPPA is most commonly associated with FTLD-tau pathology, and thus the presence of this syndrome may indicate a higher likelihood of an underlying tauopathy: naPPA may be inherited very rarely, and there does not appear to be a reliable association between this syndrome and a pathogenic mutation. Additional biomarker work is needed to help identify the pathology associated with naPPA with greater reliability.

Acknowledgment: This work was supported in part by National Institutes of Health (AG017586, AG032953, NS044266, NS053488, and AG038490), the ALS Association, and the Wyncote Foundation.