Primary progressive aphasia (PPA) is a neurodegenerative syndrome that is known to be associated with both Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), which is characterized by progressive language impairment as the most salient clinical feature and is commonly associated with a selective lesion in the perisylvian region of the left hemisphere (1, 2). Logopenic variant (lv-)PPA is a syndrome characterized by fluent speech and impaired sentence repetition and sentence comprehension, resembling vascular conduction aphasia (3); the most frequent cause is AD (4–6), while less than 20% of cases are found to have FTLD-tau (6, 7).

The clinical characteristics of AD-related proteinopathies are often similar, but they are concurrently heterogeneous in every patient, complicating diagnosis (8, 9). From this viewpoint, genetic and molecular biomarkers could provide better clues to the underlying pathology. Among the known genetic markers, presenilin 1 (PSEN1)/PSEN2 and amyloid precursor protein (APP) variants can be observed in cases with lv-PPA, while chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and some progranulin (GRN) mutations have been reported in non-fluent/agrammatic variant (nfv-)PPA cases, and GRN/TAR DNA-binding protein of 43 kDa (TDP-43) has been reported in semantic variant (sv-)PPA cases (2). The plasma levels of phosphorylated tau (p-tau) 181 are elevated in AD (10), whereas the plasma levels of neurofilament light chain protein (NFL) are elevated in both AD and FTLD (11), although the levels are higher in FTLD (12). Positron emission tomography (PET), particularly tau PET, enables visual observation of the deposited causative proteins in a region-specific manner (13).

While the clinicopathological relationships in lv-PPA have remained somewhat unclear, recent studies have described the clinical characteristics of cases with atypical heterogeneous lv-PPA, as well as those of autopsy-confirmed cases of AD with lv-PPA, which have promoted a better understanding of the syndrome (5–7, 14–18). For example, approximately one-third of patients with lv-PPA may have cerebral microbleeds and superficial siderosis (16, 17); in rare instances, patients with lv-PPA may have GRN mutations (18).

Herein, we report a patient with lv-PPA who, despite an initial clinical diagnosis of AD, was suspected of having non-AD tauopathy. To the best of our knowledge, this patient represents an exceptional example of lv-PPA (19) in whom the pathological basis was difficult to predict even after multiple examinations including genome sequencing, plasma p-tau181 and NFL examinations, ¹¹C-Pittsburgh Compound-B (PiB) and ¹⁸F-florbetaben (FBB) amyloid PET (20, 21), and ¹⁸F-florzolotau, i.e., ¹⁸F-PM-PBB3 (propanol modification of pyridinyl-butandienyl-benzothiazole 3) tau PET (22). We hope that this report provides further insight into the correlations among clinical symptoms, biomarkers, and brain imaging findings in proteinopathies, paving the way for early diagnosis and novel therapies for this disease entity.

A woman in her late 60s was referred to our hospital for a detailed examination of her language impairment. She was right-handed and had more than 16 years of education. Two years previous to her visit to our hospital, she had been referred to a dementia specialist after the Mini-Mental State Examination (MMSE) performed while she was hospitalized for hypertension revealed mild dementia-level scores. She was diagnosed as having AD, taking into consideration that fluorodeoxyglucose (FDG) PET demonstrated hypometabolism in her left medial temporal lobe, posterior cingulate gyrus, and precuneus; ¹¹C-Pittsburgh Compound-B (PiB) amyloid PET yielded a positive plausible result with marginal tracer accumulation in the white matter and partial accumulation in the parietal and lateral temporal lobes; the mean standard uptake value ratio (MSUVR) on PiB amyloid PET was 1.36, which was slightly lower than a previously reported cutoff value of 1.50 (23). She was unaware of any cognitive decline, including memory impairment, at the time of the diagnosis, but she subsequently became gradually aware of a language impairment. Another doctor was asked for a second opinion, and she was referred to our hospital based on a suspicion of primary progressive aphasia with a pathological basis of FTLD (or atypical AD).

Her chief complaint was stagnation of speech, especially when she was nervous. Her husband also told us that she sometimes mispronounced words while reading aloud. She had a professional career and had no remarkable problems at work. She was aware of an age-appropriate memory decline but had no obvious subjective memory complaints. Her past medical history included hypertension and coxarthrosis. She had no family history of dementia, stroke, or other neurodegenerative diseases.

Based on the clinical findings, particularly the negative results of amyloid PET and the positive results of tau PET, and the contradictory results of the plasma measurements, the present patient was considered to be a rare case of non-AD tauopathy with lv-PPA, with an underlying pathology that was difficult to predict.

Her language symptoms were considered typical of lv-PPA (4, 6), meeting all the features described in the widely accepted current criteria for the clinical diagnosis of lv-PPA (33): “impaired single-word retrieval in spontaneous speech and naming” and “impaired repetition of sentences and phrases” as the core features, and “speech (phonologic) errors in spontaneous speech and naming,” “spared single-word comprehension and object knowledge,” “spared motor speech,” and “absence of frank agrammatism defined as the omission and/or substitution of grammatical morphemes with associated grammatical errors (36)” as non-core features.

The conspicuous tau PET tracer accumulations, which were predominantly in the left supramarginal/angular gyrus (Figure 1C), seemed to be consistent with the regional brain function and the manifested symptoms in the present case. In particular, tau PET tracer accumulations in the posterior temporal lobe and inferior parietal lobe (supramarginal/angular gyrus) may be the underlying neural basis for the “logopenic” status, which is explained by the dysfunction of the “phonological loop,” a component of short-term memory that includes a store in which phonological memory traces are held over a period of a few seconds, and an articulatory rehearsal process that refreshes them (3). The impairment of the “phonological loop,” which is generally well correlated with AD pathology (6, 14), seemed to have manifested in our patient as syllabic errors in naming and reading aloud, incomplete sentence repetition, and impaired auditory comprehension of sentences. For example, as also described in the Results section, she was able to repeat the first two or three words/morphemes in the sentence repetition task of the MMSE correctly, but she failed to complete subsequent parts because of simplifications or substitutions; in the SLTA, errors were observed in sentence-level auditory comprehension, despite spared word-level auditory comprehension and sentence-level reading comprehension; in the JART, she answered with gestures or a roundabout explanation for some kanji words with highly irregular readings, suggesting that she knew the meaning of the words, but could not find the proper words and/or phonological representation (i.e., how to read the words aloud). The same processes were assumed to account for most of the remaining unscored words. For these reasons, her predicted IQ of 81 (5/50 correct answers) was likely an underestimation caused by her verbal-predominant cognitive decline arising from disease-caused language impairment. Accordingly, the elements for a clinical diagnosis of lv-PPA based on the current diagnostic criteria (33) were applicable in this single case, even though the elements for an imaging-supported diagnosis or a diagnosis with a definite pathology were not present.

A decisive diagnosis based on the positive tau PET findings would be speculative, since ¹⁸F-florzolotau does not discriminate among the subtypes of tau isoforms [i.e., 3-repeat (3R), 4-repeat (4R), and a mixture of 3- and 4-repeat (3R + 4R) isoforms]. Nevertheless, the diagnostic likelihood could be considered as follows. The most common and important differential diagnosis would be other 3R + 4R tauopathies, such as primary age-related tauopathy (PART), including senile dementia of the neurofibrillary tangle type (SD–NFT) without amyloid plaques; however, the clinical findings lacked the distinctive features of PART, namely, an obvious memory decline, a late onset (i.e., late-80s), and the characteristic limitation of tau lesions to the medial temporal lobe (37). In addition, the findings of tau PET imaging in the present case may not necessarily be PART-like, since the radio signals of ¹⁸F-florzolotau were seen in the left superior and middle temporal gyrus, left supramarginal gyrus, and left frontal operculum, whereas those in the preclinical stage of AD or PART may expand from the medial temporal cortex, involving less-mature tau fibrils, to the other neocortical and limbic areas, along with the progression of the NFT stage (22). Four-repeat tauopathies such as corticobasal degeneration might be plausible, based on the asymmetric distribution patterns on tau PET imaging, despite not presenting with a typical corticobasal degeneration or progressive supranuclear palsy pattern (22), since pyramidal/extrapyramidal symptoms can appear after cognitive decline (38). The absence of behavioral deficits due to frontal lobe dysfunction and characteristic brain atrophy on MRI such as knife-blade atrophy, suggests that Pick's disease is unlikely. Furthermore, ¹⁸F-florzolotau distribution predominantly in the left supramarginal/angular gyrus is not consistent with three-repeat tauopathies (22).

In short, most of the biophysical and biological examinations (i.e., MRI, SPECT, FDG PET, and plasma p-tau and NFL measurements) showed an AD-like pattern consistent with the initial clinical diagnosis of AD. In contrast, amyloid PET using both ¹¹C-PiB and ¹⁸F-FBB showed marginal-to-negative results. An ¹⁸F-florzolotau tau PET and genome sequencing were informative, but the results were inconclusive. No known dominantly inherited mutations of AD or FTLD genes were identified. Notably, AD associated with the APP Osaka mutation E693Δ (39, 40) and the Arctic mutation E693G (41), which result in a markedly low amyloid PET retention, was ruled out because no known APP mutations were identified.

The above interpretations need to be understood in the context of the following issues. First, although ¹⁸F-florzolotau shows improved selectivity for tau proteins, including autopsy-confirmed binding to tau proteins in FTLD-tau (22), and does not bind to monoamine oxidase (MAO)-A or MAO-B nor does it cross-react with amyloid-β (22), the possibility of nonspecific/off-target binding should still be considered. Since ¹⁸F-florzolotau accumulates in the choroid plexus in healthy subjects, some type of off-target binding may exist in this region. Furthermore, in a recent report, the increased retention of ¹⁸F-florzolotau was found in the basal ganglia of patients with multiple system atrophy, suggesting that cross-reaction with α-synuclein cannot be completely ruled out (42). Second, some potential assessments were not performed: although PET with ¹⁸F-florzolotau can discriminate a wide range of tauopathies by the pattern of retention, a head-to-head comparison of ¹⁸F-florzolotau with another tau PET tracer that hardly binds to 4R tau, such as ¹⁸F-MK-6240 (43), or the dopamine transporter (DAT) imaging and/or ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy (44, 45), might be helpful for a differential diagnosis; it might be desirable to perform a forward digit span, as this task can be sensitive to impairments of the “phonological loop” (6). Third, positivity/negativity on the ¹⁸F-FBB amyloid PET was determined based only on visual interpretations by certified radiologists. Although our judgmental standards agree with the established guidelines, a quantitative analysis would aid the interpretation and comparison of results. This issue should be pressed forward for future work, while quantitative measures such as the Centiloid (CL) scale, which may allow a direct comparison of results even across different PET tracers, scanning facilities, or analytical methods, are being standardized (46, 47). For the above reasons, long-term follow-up and pathological evaluations might lead to a more precise diagnosis and a better understanding of the clinicopathological basis.

To conclude, we have reported a patient with suspected non-AD tauopathy who presented with lv-PPA and had impairments in naming and sentence repetition as well as verbal short-term memory. Clinical examinations, including MRI, SPECT, FDG-PET, and plasma measurements, showed results compatible with a diagnosis of AD, whereas the amyloid PET yielded mainly negative results and the results of both tau PET and genome sequencing were inconclusive. Since an antemortem diagnosis of proteinopathies is often difficult, we consider the present case to be important from the viewpoint of obtaining a better understanding of proteinopathies, particularly for the collation of clinical symptoms and biological/biophysical findings.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Certified Review Board of Keio, Keio University School of Medicine. The patients/participants provided their written informed consent to participate in this study.

YM: conceptualization, resources, investigation, and writing—original draft preparation. MK, KT, TT, and SB: resources and writing—review and editing. TK: writing—review and editing. HT and DI: resources, project administration, and writing—review and editing. MM: resources, writing—review and editing, project administration, funding acquisition, and supervision. All authors contributed to the article and approved the submitted version.

This work was supported by the Japan Agency for Medical Research and Development under Grant Number JP17pc0101006 to MM.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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