Classification of primary progressive aphasia and its variants

Relationship between behaviorally defined PPA variants and biomarkers.

Considerable advances have been made in characterizing neuroimaging and biological features of PPA and it was collectively decided to incorporate these findings into the classification system.

Brain atrophy in PPA was initially thought to encompass widespread perisylvian regions within the left hemisphere.³ Later studies reported associations between different PPA clinical presentations and particular patterns of neuroanatomic damage: left posterior frontal and insular regions in nonfluent forms,^8,11,–,13 anterior temporal region in semantic dementia,^7,14 and left temporo-parietal regions in the logopenic variant.¹¹ These data showed that site of maximal anatomic damage within the language network determines the different clinical presentations in PPA, similar to aphasia caused by stroke, and prompted the introduction of neuroimaging findings in the proposed classification.

PPA is a clinical syndrome with heterogeneous neuropathologic causes. Current data show that most patients with PPA have been found to have tau-positive, ubiquitin/TDP43-positive frontotemporal lobar degeneration (FTLD) pathology,^13,15,16 or Alzheimer disease (AD) pathology.^17,18 Clinicopathologic studies have most often linked nonfluent progressive aphasia to tau-positive pathology,^13,19,20 semantic dementia to ubiquitin-positive, TDP43-positive pathology,^15,20,–,23 and the logopenic form to AD pathology²⁰ and to in vivo biomarkers suggestive of AD, such as PET-PIB positivity and decreased Aβ42 and increased tau in the CSF.^20,24 However, clinical-pathologic correlations in PPA reflect group-wide probabilities and there is no direct correspondence between each clinical and anatomic subtype and pathology, suggesting only relative vulnerability of certain neural networks for different pathologies.²⁵ In fact, each pathologic FTLD subtype and even AD pathology changes have been associated to each of the clinical presentations, although with different frequencies. Furthermore, PPA clinical-pathologic studies coming from different laboratories can be difficult to interpret in a unitary fashion because of underspecification and variability of the clinical criteria adopted across centers. Consistent clinical descriptions, supplemented by neuroimaging and other biomarkers, and larger patient groups are necessary to determine reliable frequency of associations between clinical and anatomic data and pathology.

The last decade has provided significant advances in the field of PPA genetics. PPA can be inherited in an autosomal dominant manner; the majority of these patients have mutations in the progranulin (GRN) gene.^26,–,28 The PPA phenotype associated with a GRN mutation has not been studied in detail. Initial reports indicated prominent anomia without development of motor speech impairment and relatively early single-word comprehension impairment.^{26,27,29,–,31} Other genes related to FTLD, such as the microtubule-associated protein tau (MAPT) gene, may be associated with PPA as well.^26,28 It is not yet clear how the classification reported here will apply to genetic cases but genetic information is included as definite etiologic evidence, equivalent to pathology.

Terminology.

The terms used to label the 3 variants were a matter of extensive discussion during the group meetings. The terminology proposed here represents a compromise between the existing literature and current understanding of the phenomenology. The terms were selected to parallel the behavioral variant FTD terminology since PPA has long been considered one of the possible clinical presentations of the frontotemporal spectrum disorders. It is advisable to include alternative terms in the key words of new articles, to facilitate the use of literature search engines. Furthermore, this classification scheme can be referred to even when applying older terminology.

Diagnostic process and the PPA classification.

Establishing a classification or “clinical diagnosis” involves a 2-step process. Patients should first meet basic PPA criteria, based on Mesulam's^32,33 initial and current guidelines (table 1). A PPA clinical diagnosis requires a prominent, isolated language deficit during the initial phase of the disease. There is an insidious onset and gradual progressive impairment of language production, object naming, syntax, or word comprehension that is apparent during conversation or through speech and language assessments. Activities of daily living are maintained except those related to language (e.g., using the telephone). Aphasia should be the most prominent deficit at symptom onset, for the initial phases of the disease and at time of examination.³⁴ Other cognitive functions may be affected later on, but language remains the most impaired domain throughout the course of the illness.^33,35

Exclusionary criteria include prominent episodic and nonverbal memory loss and visuospatial impairment during the initial stages of the illness. Specific causes of aphasia, such as stroke or tumor, are absent, as ascertained by neuroimaging. Behavioral disturbances can be early features in PPA (especially in the nonfluent and semantic variants), but they should not be the main complaint or the main cause of functional impairment. Similarly, a clear parkinsonian syndrome (rigidity, tremor) should not be present at time of diagnosis although mild limb apraxia and difficulty with fine finger movements can be noted. Cases with severe, isolated spastic dysphonia or repetitive language behaviors such as palilalia or echolalia should be excluded from the PPA syndrome because their deficit is nonlinguistic in nature.

Classification into PPA variants.

Once a PPA diagnosis is established, the relative presence or absence of salient speech and language features should be considered to classify PPA variants. The main language domains considered are speech production features (grammar, motor speech, sound errors, and word-finding pauses), repetition, single-word and syntax comprehension, confrontation naming, semantic knowledge, and reading/spelling. Clinical criteria for each variant are detailed in tables 2–4. Brief clinical evaluation of all these domains is necessary to correctly classify patients into PPA subtypes. A 20-minute bedside language examination could be sufficient, although detailed evaluation by a speech and language pathologist is likely to be more reliable. Suggested tasks for assessing speech and language functions are presented in table 5. Specific tests and cutoffs would be useful and have been proposed by Mesulam et al.³⁴ They are not suggested here because different clinical and research sites are likely to apply different measures.

The classification of PPA into one of the variants may occur at one of 3 levels: clinical, imaging-supported, or definite pathologic diagnosis. Clinical diagnosis occurs when a case presents with speech and language features that are characteristic of a specific variant. At least one of the core features should be present for the nonfluent/agrammatic variant, while both must be present for semantic and logopenic variants. At least 2 (for the nonfluent variant) or 3 (for the semantic and logopenic variants) other features should be present in order to make a clinical diagnosis of a specific syndrome.

For an imaging-supported diagnosis, the next level of classification, a case should meet clinical criteria but should also show the distribution of neuroimaging changes (structural or functional imaging) previously associated with each variant. Since there is a direct correspondence between language symptoms and site of anatomic damage, a consistent pattern of imaging change supports the clinical classification.

The third level, a definite pathology diagnosis, refers to cases that present with typical clinical characteristics (with or without neuroimaging evidence) of each variant and pathologic or genetic mutations associated with definite or FTLD spectrum, AD, or other specific etiology. The presence of definite pathology does not imply that the clinical syndrome is better defined clinically, but only that it has been associated with a known biological feature.

In the future, biological markers, such as PET-PIB and CSF, might also be considered here.

Nonfluent/agrammatic variant PPA (also known as progressive nonfluent aphasia and as PPA-agrammatic).

The criteria for the nonfluent/agrammatic variant (for convenience hereafter called nonfluent) are summarized in table 2. Agrammatism in language production and effortful speech are the core criteria, and at least one should be present. Agrammatism typically consists of short, simple phrases and omissions of grammatical morphemes (e.g., function words, inflections). Effortful speech refers to slow, labored speech production. An articulation planning deficit, i.e., apraxia of speech, is often the most common disturbance, and can be the initial sign of the disease.^11,13 Patients with the nonfluent variant typically make inconsistent speech sound errors, consisting of distortions, deletions, substitutions, insertions, or transpositions of speech sounds, of which they are often aware. Prosody is disrupted, and rate of speech is markedly reduced.^11,36 Effortful speech and production errors can be the first symptoms of this variant, even before clear apraxia of speech or agrammatic errors occur. In these cases, a written language production test (such as a written description of a picture) or syntax comprehension tasks can often reveal early, mild grammatical errors.

At least 2 of the other 3 features of the nonfluent variant should be present. Deficits in syntax comprehension are evidenced by impairment of sentence comprehension, initially only for the most difficult syntactic constructions, such as negative passives and object relative clauses (e.g., “The car that the truck hit was green”).^8,9,11,37,38 While sentence comprehension can also be impaired in logopenic variants, in the nonfluent presentation, the impairment is clearly influenced by the grammatical complexity of the sentence. Single-word comprehension and object knowledge are usually relatively spared in nonfluent patients and this feature is helpful in early differential diagnosis. It is now known that many patients with the nonfluent variant will eventually progress to a syndrome encompassing generalized motor problems compatible with a diagnosis of corticobasal syndrome or progressive supranuclear palsy.^13,19,23 A clinical diagnosis of nonfluent variant PPA, therefore, should be limited to patients who do not present with a clear motor syndrome that impacts daily activities, such as generalized rigidity or tremor. However, as stated above, the presence of mild apraxia or slowing of fine finger movements does not exclude a PPA diagnosis.

Imaging abnormalities in the left posterior fronto-insular region, i.e., inferior frontal gyrus, insula, premotor, and supplementary motor areas, are necessary to make a diagnosis of imaging-supported nonfluent variant.^8,11,–,13

Cases will be defined as nonfluent with definite pathology when patients present with the above reported clinical features, imaging-supported or not, and a known histopathologic diagnosis. Based on the literature, nonfluent patients with agrammatism or motor speech disturbance will most often show FTLD-tau or, less often, FTLD-TDP type of pathologic changes.

Semantic variant PPA (also known as semantic dementia, or as PPA-semantic).

The semantic variant is probably the most consistently defined PPA clinical syndrome. The criteria are summarized in table 3. In the current guidelines, anomia and single-word comprehension deficits are the core features, both essential for diagnosis. Although naming problems are present in other variants of PPA and in other neurodegenerative conditions causing aphasia, in the semantic variant the disturbance is severe, particularly when compared to relative sparing of other language domains. Single-word comprehension is severely impaired, especially for low-frequency items (e.g., “zebra” vs the more familiar/frequent “cat”). Inability to comprehend low-familiarity words can be the only symptom accompanying anomia at the earliest stages. Poor comprehension of single words is usually the earliest and most obvious manifestation of a widespread semantic memory deficit that causes impairments in object and person recognition, even when presented to other modalities of input such as visual (pictorial representations and real objects), tactile, olfactory, and gustatory.^{6,7,39,–,41} Semantic deficits in other modalities of input are therefore included among the other diagnostic features of the semantic variant. Semantic deficits are usually present for most categories (i.e., tools, animals, people), although rarer cases have been described with greater, or even selective, deficits for people and animals.^42,43 Others describe worse performance with concrete object concepts than abstract concepts.^5,44 These cases are usually associated with greater right temporal atrophy and early behavioral changes, such as loss of empathy and compulsions.⁴⁵

Surface dyslexia and dysgraphia are features of the semantic variant and refer to an impairment in reading and writing words with “irregular” or atypical relationship between spelling and pronunciation.⁴⁶ Patients typically “regularize” such words, so that “sew” is read as /su/.

Sparing of repetition and motor speech, even when semantic deficits are prominent, are the other 2 features. Although language production is usually grammatically accurate, it can at times contain some “paragrammatic” errors, such as substituting less appropriate closed class words or inflections, for instance, “I know what they're doing but I can't think the words what they're doing.”⁴⁷

Anatomically, the semantic variant has been associated with atrophy in the ventral and lateral portions of the anterior temporal lobes bilaterally, although damage is usually greater on the left.^{11,14,34,48,49}

Cases will be defined as semantic variant PPA with definite pathology when patients present with the above mentioned clinical features, imaging-supported or not, and a known histopathologic diagnosis. Based on the literature, in the case of semantic variant PPA, FTLD-TDP type pathologic changes will be the most common finding.^15,20,–,23

Logopenic variant PPA (also known as logopenic progressive aphasia or as logopenic PPA).

The logopenic variant is the most recently described variant of PPA.^11,50 The criteria are summarized in table 4. Word retrieval (in spontaneous speech and confrontation naming) and sentence repetition deficits are the core features of the logopenic variant. Spontaneous speech is characterized by slow rate, with frequent pauses due to significant word-finding problems, but there is no frank agrammatism. Speech production deficits are therefore distinct from those of patients with the nonfluent variant, who also speak in a slow and halting manner, but with output that is dysprosodic, and marked by motor speech errors or agrammatism.^8,50,51 The confrontation naming impairment is usually less severe in the logopenic than in the semantic variant, and errors are usually phonologic in nature.¹¹ A useful differentiating feature between these 2 variants is also the relative sparing of single-word comprehension in logopenic patients. Consistent with the hypothesis that a phonologic short-term memory deficit is a key cognitive mechanism underlying most language deficits in the logopenic variant,⁵⁰ sentence and phrase repetition is characteristically impaired, while reproduction of short, single words can be spared. This same mechanism can cause impairment in sentence comprehension, which is influenced more by length and probability of a sentence than by its grammatical complexity.

Other diagnostic features include phonologic paraphasias in spontaneous speech and naming. The sound substitutions that result in phonologic paraphasias in logopenic patients are usually well articulated, without distortions. Lack of frank agrammatic errors and preservation of articulation and prosody help distinguish the logopenic from the nonfluent variants.⁵²

Imaging abnormalities in the left temporo-parietal junction area, i.e., posterior temporal, supramarginal, and angular gyri, are necessary to make a diagnosis of imaging-supported logopenic variant.¹¹

Cases will be defined as having logopenic PPA with definite pathology when they present with the clinical features, imaging-supported or not, and a known histopathologic picture. Recent evidence shows that AD might be the most common underlying pathology.^20,24