Root diagnosis of PPA
The root diagnosis of PPA is based on the objective impairment of language while other cognitive domains (episodic and topographical memory, constructional praxis, etc.) are relatively preserved [6]. In the initial disease stages, impacts on the instrumental activities of daily living are entirely attributable to language problems.
Confusion may arise when the root diagnostic criterion is not fulfilled and the subtyping is applied nevertheless. In that respect it is of particular importance not to confuse PPA or any of its subtypes with the left hemisphere-dominant type of clinically probable AD with prominent language symptoms, a disease entity that has been well-known for a long time [7, 8]. In PPA due to AD, tests of nonverbal domains—for instance, copy of the overlapping pentagons in the Mini Mental State examination or ideomotor praxis—should be, by definition, preserved. On the other hand, in left hemisphere-dominant clinically probable AD, some other cognitive domains besides language are, by definition, also affected and the PPA root criterion is therefore not fulfilled. Some clinical features may be particularly discriminative, such as tests for constructional praxis. Other tests, e.g., of verbal episodic memory, may be less reliable as they will be influenced by the language problems. Neither are nonverbal episodic memory tests particularly useful in this respect in our experience as encoding and retrieval can be affected by the executive dysfunction that can occur in PPA.
Of patients who fulfilled the root criterion of PPA, 40 % had underlying AD [9]. When AD causes PPA, the neuropathology is atypical because of the asymmetric, left hemisphere-dominant distribution of tangles and because of the higher ratio of neocortical-to-entorhinal tangles [10].
The logopenic variant
In PPA LV, spontaneous speech is halting and characterized by fluency disruptions with incomplete words and hesitations [11]. Word finding pauses frequently occur after determiners preceding content words [12]. Grammatical processing and motor speech are relatively preserved (Fig. 1).
Testing repetition is key to the diagnosis of LV. It is critical not to rely on a global repetition score but to take into account the subscores for the different types of materials. In LV, the repetition deficit characteristically affects repetition of longer or complex sentences [13] rather than single polysyllabic words [13, 14]. This differs from NFV with speech apraxia where polysyllabic words will be affected by the motor speech deficit, in particular when consonant clusters are present. One of the least specific and most sensitive tests for repetition concerns the repetition of a string of function words, as in the MiniMental State Examination test. This item can be impaired across the entire spectrum of PPA as well as early in typical AD.
The cognitive deficit underlying the repetition deficit in LV is most likely a short-term phonological memory deficit [3]. In LV, the digit span forward is typically decreased and this deficit does not extend to short-term memory for tones or for location [15]. This clearly differs from SV where digit span forward is often preserved until late into the disease course.
In a hierarchical clustering analysis of 32 cases with PPA excluding semantic variant, cases could be grouped into four clusters [13]. Cluster 1 was characterized by anomia and deficient repetition of sentences and corresponded to LV PPA, cluster 2 to NFV. Cluster 1a was further characterized by phonological paraphasias while cluster 1b lacked these. In cluster 1a all cases were amyloid-positive on positron emission tomography (PET) compared with three out of seven cases in cluster 1b [13]. Across the entire group of non-SV PPA [13], the tests that best discriminated the amyloid-positive from the amyloid-negative cases were the presence of phonological paraphasias and the absence of agrammatism and motor speech disorder. Sentence comprehension and anomia as such did not have discriminative value within this non-SV PPA group [13].
This and other studies suggest that the LV encompasses at least two subtypes [12–14, 16]: one closely resembles left hemisphere-dominant probable AD and the other constitutes a more restricted clinical and anatomical phenotype more similar to the original description [2]. This led Teichmann et al. [12] to propose the term “logopenic aphasia complex”.
In LV, as the disease progresses [16], language impairment may become more widespread [12], leading to problems with single word comprehension [16, 17], single word repetition, syntax production, and verbal memory [14]. Non-language cognitive domains may become affected [14] (for instance, constructional praxis) in such a way that the pattern blends with left hemisphere-dominant clinically probable AD [16]. This clinical course is distinct from that seen in SV where the steady progression typically remains restricted to language, semantic memory, and executive dysfunction [16]. Other patients with LV retain a very circumscribed deficit restricted for years to sentence repetition and word finding difficulties and focal atrophy.
In LV cluster 1a [13], the group-based pattern of atrophy, perfusion, and metabolism resembled that seen in the left hemisphere-dominant, clinically probable AD cases [12, 14, 18, 19] (Figs. 1 and 2a). In cluster 1b the damage was more restricted [13] to the temporoparietal transition zone, as originally described by Gorno-Tempini et al. [2, 3] (Fig. 2b). This probably is the key region responsible for the repetition deficit in LV and belongs to the dorsal language pathway [20]. Atrophy in the temporoparietal transition zone correlates with repetition scores and with gesture imitation scores in PPA [21]. In LV, the white matter tracts underneath this cortical region, i.e., the temporoparietal portion of the superior longitudinal fascicle, are also damaged [22].
A second, nearby region that has been implicated in the phonological errors seen in LV is the posterior superior temporal cortex [12, 13]. The posterior superior temporal sulcus is an area of predilection in typical AD from the preclinical [23] to the early clinical stage [24] and activity in this region correlates with word finding scores in clinically probable AD [24] as well as naming latency in preclinical AD [23]. Gray matter density in this region also correlates in LV with scores on lexical decision for words with a meaning that strongly relates to sounds (such as “thunder”) [25].
The positive predictive value of the LV phenotype for a pathological diagnosis of AD is 50–60 % [9, 26, 27], which is lower than what is found in in vivo amyloid biomarker studies in LV (60–90 % [12, 28]). In a meta-analysis of PPA LV series from different centers, the remaining 38 % were due to Tar DNA binding protein 43 (TDP)-associated frontotemporal lobar degeneration (FTLD) [26], with 5–10 % caused by tau-associated FTLD [26]. LV can also be caused by AD combined with Lewy body pathology [9, 27].
The semantic variant
PPA SV is a distinct disease entity throughout the disease course clinically, anatomically, and neuropathologically—hence the frequently used name “semantic dementia” [5]. Characteristic features apart from anomia are word comprehension deficit and object recognition problems (Fig. 1). In SV, spontaneous speech is fluent, with proportionally fewer nouns and open-content words than in any of the other subtypes and an increase in generic words [11]. As the disease progresses, spontaneous speech becomes restricted to stereotyped utterances consisting of a handful of connected words that may persist for several years and also echolalia. Even in an advanced stage, the clinical neurological examination often remains relatively intact.
Confrontation naming is often severely impaired, and more so than in LV at a comparable stage [6, 9]. Naming errors occur initially, mainly for unfamiliar or atypical items [29], and consist of semantic paraphasias, generalizations, omissions, and circumlocutions. Patients may be able to comprehend the words that they cannot retrieve [30], but as the disease advances they may also not be able to comprehend the word. Object recognition problems and loss of knowledge of visual features of objects further contribute to the confrontation naming deficit in SV. In the written modality, loss of word meaning leads to surface dyslexia [31]. Patients may also experience problems identifying persons (knowledge about individuals) beyond proper name anomia.
The severity of comportmental and personality changes may vary in SV. Both anatomically and clinically, SV can overlap with frontotemporal dementia behavioral variant (FTD bv). The relative preponderance of aphasia versus comportmental disturbances depends on the direction and degree of the left–right asymmetry in the anterior temporal cortex [32].
During stages when word comprehension and object identification are still relatively preserved, SV can resemble LV, but in these circumstances the repetition deficit for specific types of materials, i.e., complex sentences with high working memory demands and the digit span forward, is a discriminative sign in favor of LV. If impaired repetition occurs in an early stage of SV, it is most often restricted to series of function words, a sensitive test for repetition deficit across all three types of PPA.
SV is characterized by a very distinct pattern of anterior temporal atrophy and hypometabolism (Figs. 1 and 3). This may be lateralized to the left or may also affect the right side. Different regions within the anterior temporal cortex may contribute different aspects to the clinical syndrome of SV. Perirhinal cortex belongs to the region of atrophy in semantic dementia [33–35] and scores on tests of semantic memory as well as confrontation naming scores correlate with volume loss in temporopolar cortex and perirhinal cortex [33, 34]. In healthy individuals functional MRI activity patterns in perirhinal cortex, overlapping with the atrophic regions in SV, reflect the semantic similarities between written words [36]. In typical SV, the atrophy may often also impinge on anterior inferior frontal cortex and orbitofrontal cortex [19], which is connected with the anterior temporal pole through the uncinate fascicle. The uncinate fascicle is damaged in SV compared with LV, as well as the inferior longitudinal fascicle [22, 37]. The latter may contribute to functional effects at a distance in the posterior fusiform cortex or the ventral occipitotemporal transition zone. This may account for the visuoperceptual identification problems (structural description system) and the loss of knowledge of visual features that are an integral part of the clinical picture in many SV patients, despite the fact that these regions as such are structurally relatively intact [29, 38].
In rare cases, the anterior temporal damage may be part of a more distributed atrophy and hypometabolism extending contiguously into more posterior temporal cortex and even inferior parietal cortex (Fig. 3b, c). Such a pattern then corresponds to the typical SV anterior temporal region plus the typical AD posterior temporal and inferior parietal region. Distinguishing between SV and left hemisphere-dominant clinically probable AD may require biomarker examination in these circumstances.
In a multicenter series, SV was associated with FTLD-TDP in 69–83 % of cases [26, 39], usually of type C [9]. AD has been described in up to 25 % of PPA SV cases [9, 26], although in most series prevalence of AD in SV is substantially lower (10 %) [40]. In SV due to AD, there is more entorhinal, hippocampal, parahippocampal, and temporal neocortical volume loss compared with non-AD SV [40]. FTLD-tau, principally Pick’s disease, can also occur as a cause [26, 39].
Nonfluent/agrammatic variant
PPA NFV is characterized by agrammatism and/or speech apraxia (Fig. 1). Agrammatism refers to pathological changes in the morphology of nouns and verbs, word order, and argument structure, with a decrease in mean length of utterance and a decrease in sentence complexity [11]. For a detailed description of the diagnostic features of speech apraxia we refer to Josephs et al. [41, 42]. Schematically, speech apraxia is diagnosed based on abnormal duration of voxels and of inter-segmental intervals (with segments referring to sounds, syllables, or words), unevenness in loudness and pitch and abnormalities in intonational stress, and sound distortions and substitutions, in particular for utterances of increased length and articulatory complexity [41]. This leads to phonetic errors. Phonetic errors must be distinguished from phonological errors which occur in LV in the context of normal prosody and normal sound production and from starting errors that are seen in LV. According to an automated analysis of the speech characteristics in NFV, the changes in relative duration and intensity of vowels as well as the pauses during reading are the most distinctive features [43]. Other qualitative features that may be helpful in the diagnosis of speech apraxia consist of sound and syllable repetitions, groping and effortful speech, speech initiation problems, and abnormalities in coordination with breathing [41].
Most often agrammatism and motor speech deficits occur together (9 out of 25 PPA in Mesulam et al. [6]). More rarely, the motor speech deficit may occur in isolation (1 out of 25 in Mesulam et al. [6]). The latter phenotype has been termed “progressive apraxia of speech” [41]. Since the deficit is limited to motor speech and does not affect language processing strictly speaking, Josephs et al. [41] have argued that this should be set apart from PPA. Inversely, agrammatism can also occur without speech apraxia: a hierarchical clustering analysis in 32 non-SV PPA patients revealed two clusters corresponding to NFV, one in which motor speech disorder co-occurred with agrammatism and one with agrammatism alone [13]. Phenotypically, therefore, one can distinguish three further subtypes within NFV PPA, depending on whether the agrammatism and speech apraxia occur in isolation or together. Over time the exclusivity may disappear [44].
A conspicuous source of heterogeneity within NFV are the associated neurological signs and symptoms that may be present at the initial clinical examination or may appear over the disease course [44]. These signs may point to progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) as the underlying cause. In 13 patients with progressive apraxia of speech, five evolved into a PSP-like syndrome while in the remaining subjects the speech problems continued to be the most prominent symptom along with progressive extrapyramidal signs [44].
In progressive apraxia of speech, FDG-PET mainly reveals hypometabolism in superior premotor and supplementary motor areas [44, 45] (Fig. 4). Superior premotor involvement correlates with the degree of speech apraxia [45]. As the disease progresses, regions at a distance may become involved, such as inferior parietal or posterior temporal cortex [19]. In the agrammatic variant a more distributed network is involved, including pars orbitalis, triangularis, and opercularis along with superior temporal gyrus and inferior parietal lobule [6, 45]. Therefore, speech apraxia and agrammatism rely on anatomically dissociable mechanisms. Likewise, the white matter tracts involved differ depending on the degree of speech apraxia versus agrammatism [22]: speech production scores mainly correlate with the white matter tract from the inferior frontal gyrus (Brodmann area (BA) 44) and the anterior insula to premotor (BA6 face/mouth area) and supplementary motor cortex (the Aslant tract [46]) as well as connections with putamen and caudate [47]. Sentence comprehension/production, on the other hand, correlates with involvement of the superior longitudinal fascicle and the arcuate fascicle [11, 47]. The dissociation of white matter tract involvement between speech apraxia and agrammatism is not absolute: motor speech scores also show some correlation with integrity of SLF and arcuate [48].
In NFV, 50–70 % of patients are neuropathologically diagnosed as FTLD-tau, corresponding to corticobasal degeneration, progressive supranuclear palsy or Pick’s disease [9, 26, 39]. Exclusive or predominant apraxia of speech predicts a tauopathy rather than a TDP43 proteinopathy [27] and may be more frequently associated with PSP than with CBD [39]. Approximately 20 % of NFV cases are due to FTLD-TDP, usually of type A [27], and 12–25 % to AD [9, 26].
