Histopathology and genetics

One of the first hints of underlying AD pathology in lvPPA came from measurements of frequency of the APOE4 haplotype. In the group originally described by Gorno-Tempini and colleagues, 67% were in the logopenic group, but 0% in the semantic group and only 20% in nfvPPA. Whereas nfvPPA and svPPA were respectively associated with frontal and anterior temporal atrophy patterns, lvPPA was connected with gray matter loss in the angular gyrus, the posterior third of the middle temporal gyrus, and the superior temporal sulcus, with smaller clusters of significant atrophy in the left anterior hippocampus, the right angular gyrus, and the precuneus. These patterns of atrophy, especially in combination with the increased prevalence of the APOE4 haplotype in lvPPA patients, were all suggestive of an underlying Alzheimer’s disease histopathology. Although the APOE4 finding has not been confirmed in other cohorts, postmortem examination and biomarkers in vivo show that amyloid plaques and neurofibrillary tangles of Alzheimer’s disease are the most common pathology to be associated with the logopenic variant of primary progressive aphasia. The association between Alzheimer’s pathology and lvPPA was subsequently demonstrated by Dr. Mesulam and colleagues by pathological examination [8]. The temporoparietal atrophy in lvPPA correlates with increased neurofibrillary tangles in that region [35]. Other supporting evidence includes cortical amyloid binding in nuclear imaging studies with Pittsburg Compound B PET scans [36], and cerebrospinal fluid studies consistent with a diagnosis of Alzheimer’s in logopenic patients [3, 37, 38]. Looking back before the diagnosis of lvPPA was established in the scientific community, patients with PPA who were subsequently found to have AD pathology also had significant logopenic symptoms in retrospective studies [39].

However, as in all complex neurodegenerative syndromes, the relationship between lvPPA and pathology is not absolute. Examples exist in which other disease processes can lead to lvPPA [8]. Tau or TDP-43 pathologies that would more commonly lead to nfvPPA, svPPA, or behavioral variant frontotemporal dementia have sometimes instead caused lvPPA. Other single cases have been described with Creutzfeldt–Jakob disease and Lewy body dementia [40, 41].

It is also important to note that in some individuals with lvPPA, atrophy extends into areas commonly associated with other variants of PPA. This may be especially true in the rare cases of lvPPA associated with a genetic mutation such as progranulin (PRGN). This gene has been associated with frontotemporal dementia as well, and may predispose toward asymmetric cortical atrophy. Rohrer and colleagues found that two out of nine patients with lvPPA had a mutation in the progranulin gene [42]. While this group fit most closely with lvPPA symptomatically, they had more severe deficits of naming, single word comprehension, and vocabulary-based (irregular word) reading, all of which are more in common with svPPA. Voxel-based morphometry demonstrated slightly different patterns of cortical involvement than those forms of lvPPA due to AD, with more anterior temporal involvement [27].

In conclusion the current view of lvPPA is that it is usually a variant of early-onset Alzheimer’s disease, presenting with early focal damage to the left temporoparietal cortex and symptoms of a phonological disorder. Recent data suggest that reduced “cognitive reserve” in this network might be related to neurodevelopmental factors. When AD biomarkers and imaging findings are not found, the possibility of a PGRN mutation should be considered.

Neuropsychological and language testing

There is no single standardized neuropsychological battery used to diagnose lvPPA. Most aphasia batteries were constructed to test patients with aphasia caused by stroke, and are not sensitive to the early, mild symptoms typical of the early stages of PPA. The Western Aphasia Battery (WAB) has good inter-rater and test–retest reliability and is especially useful to track progression [28, 43]. Examination should include measures that differentiate other PPA variants, but should also assess other parietal functions such as mathematical calculation and praxis. A thorough examination would also include tests of depression and anxiety. The classification paper in 2011 offers some suggestions on how to evaluate each relevant language domain, including orthography and semantics. An expert clinician should interpret results of specific language tests, since an impaired score might result from different cognitive mechanisms. Similarly, general neuropsychological tests should be interpreted with caution as impaired performance might be related to language deficits rather than true memory or executive difficulties.

As has been mentioned, the fluency of patients with lvPPA was somewhere between that of svPPA and nfvPPA [11, 17]. This has been confirmed with formal analyses of short speech samples, which can be elicited by means of a picture description. False starts, filled pauses, and repaired sequences are also typical features of lvPPA speech production [17]. One must make sure not to confound word-finding pauses and slow speech rate with “non-fluency” as this has caused much confusion.

A word-finding deficit is one of the key features in lvPPA. This is usually evident in spontaneous or elicited speech samples such as a picture description task. Confrontation naming is classically assessed with the Boston Naming Test (BNT), in which subjects are shown and asked to name pictures of items encountered in decreasing frequency in everyday language [44]. Scores in this test are usually mildly or moderately impaired depending on the stage of the disease. Patients can also usually recognize the word on multiple choice, and seem to know what the shown object is despite not knowing the name. Attempts to name the word may be characterized by circumlocutions or phonological paraphasias. Recent data indicate that lvPPA patients with a history of neurodevelopmental language disorder might be especially prone to phonological errors in spontaneous speech and naming.

Testing for sentence repetition deficits may require a highly sensitive tool in early stages [3, 28]. For instance, in the repetition section of the WAB patients might be able to correctly repeat such easy, highly probable phrases as “the telephone is ringing,” but show difficulties in improbable phrases such as “the pastry cook was elated.” The WAB has few such improbable stimuli, however, and so might not be sufficient to elicit repetition difficulties in early disease stages. Thus specific tests that contain longer and improbable sentences [45], as well as multisyllabic words and pseudo-words should be included in evaluations of repetition in lvPPA in order to sufficiently challenge the short-term phonological memory (or phonological loop). Basic phonological processing should also be assessed with batteries such as the Arizona Phonological Battery [46]. Also, reading and writing difficulties in lvPPA reflect the phonological impairment, with errors most consistent with phonological dyslexia and dysgraphia [47]. Individuals with both lvPPA and neurodevelopmental phonological difficulties such as dyslexia might show greater phonological deficits than lvPPA patients without such a developmental history.

Frank grammatical errors and motor speech deficits are not typical features of early lvPPA and are useful in the differential diagnosis from nfvPPA. Later in the course of the disease this distinction might become more difficult as speech becomes more effortful. Phonological errors can result in sound distortions, and phonological short-term memory deficits, which prevent the holding and rehearsal of sentences, cause lvPPA patients to lose track of what they are saying, resulting in word order errors and segmented sentences reminiscent of nfvPPA, though in nfvPPA sentence comprehension deficits instead result from true grammatical difficulties. Consistently, comprehension deficits in lvPPA are not influenced by morphosyntactic complexity but by the length of sentences [26]. Tests that elicit complex grammatical structures might be useful to better distinguish between nfvPPA and lvPPA. Examples of such tasks are the Northwestern Anagram Test (NAT) [48] and/or the Goodglass Production Test [49].

Semantic variant PPA is usually easy to distinguish from lvPPA, as non-verbal semantic association and single-word comprehension abilities are generally relatively preserved in lvPPA at time of diagnosis. The Peabody Picture Vocabulary Test [50] and the Pyramids and Palm Trees Test [51] are tasks commonly used for this purpose. When single-word comprehension is impaired early, it usually indicates involvement of the anterior temporal lobes, possibly indicating a PGRN mutation. It remains to be clarified whether these genetic cases really presented as lvPPA or more as a “mild” global aphasia. Sentence comprehension should be tested in lvPPA but results can be difficult to interpret if tests are not designed ad hoc. Sentence-to-picture matching tasks are the most utilized, such as those of the Curtiss–Yamada Comprehensive Language Evaluation (CYCLE) [52].

Tests of mental calculation are likely to be below expectations in lvPPA, and mild signs of limb apraxia might be found. Visuospatial tasks and spatial span might be more compromised in lvPPA than in the other PPA variants, despite the fact that patients do not report such difficulties in everyday life. Tests of verbal memory such as the California Verbal Learning Test (CVLT) are not really valid as memory tests of long-term memory in lvPPA as they rely too much on phonological short-term memory. Verbal working memory is also impaired for the same reason as sentence comprehension, as the patients are not able to retain phonological information enough to be able to manipulate it. The MMSE relies very much on verbal comprehension, working memory, and repetition, and is therefore likely to overestimate the severity of dementia. Functional measures such as the clinical dementia rating (CDR) are best suited to evaluate severity. Onset or aggravation of depression, irritability, and anxiety disorders is also common and requires assessment by any of a number of available measures [53].

Treatment

Like other forms of neurodegenerative illness, there is no cure for lvPPA, and any slowing of symptomatic progression is uncertain. Although formal studies have not been conducted, acetylcholinesterase inhibitors are likely to be useful in lvPPA, as in typical early-onset AD, and should be prescribed. Because of the overestimation of severity of the MMSE, lvPPA cases have been traditionally excluded by AD trials even if their disease is actually mild. Hopefully new recruitment strategies will correct this inequity. One pilot trial found possible benefit of memantine in undifferentiated PPA, and as this was not found to be the case in a larger trial dedicated to frontotemporal dementias, it is possible that Alzheimer’s disease pathology drove the pilot trial’s results [54, 55].

There is some evidence for benefit of speech therapy in patients with logopenic variant PPA, especially in early stages. Studies are necessarily small. Focusing on personally relevant words may provide significant enough relief to the individual to merit the time and effort of therapy [56]. One individual was reported to respond to training in written naming, reading, and repetition with significant improvement for not only trained items but generalization to untrained words [57]. Other studies have examined a brief but intensive treatment for lexical retrieval in patients with lvPPA, which were felt to result in significant and generalized improvements. In one study results were still evident 6 months after the intervention. Longer follow-up, however, is not available [56, 58].