Primary progressive aphasia (PPA) is a dementia syndrome characterized early in its course by gradual dissolution of language and is associated with asymmetric atrophy in the language-dominant hemisphere (usually left). In contrast, behavioral variant frontotemporal dementia (bvFTD) is a dementia syndrome characterized by a progressive early decline in personality and comportment and is associated with relatively symmetric or rightward predominant bifrontal atrophy. This study analyzed the regional and hemispheric distributions of neuronal tau inclusions of the corticobasal degeneration variant of FTLD-tau pathology (FTLD-CBD) in individuals with PPA or bvFTD. The goal was to establish clinicopathologic concordance between FTLD-CBD and behavioral/comportmental vs aphasic dementia syndromes.

Seven participants were clinically diagnosed with PPA and 6 were diagnosed with bvFTD. All had FTLD-CBD as the principal neuropathologic diagnosis at postmortem study. Sections from the following cortical regions were stained immunohistochemically with AT-8 to visualize neuronal tau inclusions: bilateral middle frontal gyrus (MFG), inferior parietal lobule (IPL), superior temporal gyrus (STG); and unilateral occipital cortex (OCC). Bilateral anterior temporal lobes (ATL) were analyzed in PPA cases only. Unbiased stereological analysis was performed to compare regional and hemispheric distributions between and within PPA vs. bvFTD groups.

Overall neocortical (MFG+STG+IPL) tau densities were significantly greater in the PPA group compared to the bvFTD group (p<0.05). Within the bvFTD group, the highest densities of tau inclusions were observed in the right MFG (mean=6,871.17; SD=3,220). In the PPA group, highest densities were observed in the left ATL (mean=9,901.81; SD=6,871). There was leftward hemispheric asymmetry of tau inclusions in IPL, STG and ATL which trended towards significance in the latter (p=0.083). Cortical distributions were symmetric or rightward predominant within the bvFTD group. Occipital cortex was devoid of inclusions.

Preliminary stereological findings of FTLD-CBD tau inclusions suggest that the distributions of pathologic tau are different across two distinct clinical dementia phenotypes. The presence of left-sided neuronal tau inclusions in PPA is concordant with the aphasic phenotype whereas symmetric and frontal-predominant densities in bvFTD are consistent with comportmental dysfunction.

Semantic variant primary progressive aphasia (svPPA) is a progressive neurodegenerative syndrome characterized by prominent impairments in naming, conceptual knowledge, and comprehension, in the setting of preserved fluency, memory, and visuospatial perception. Generally, svPPA is caused by underlying TDP-43 neuropathology. In contrast, the clinical syndrome of Lewy Body Disease (LBD) is characterized by the presence of parkinsonism and prominent attentional and visuo-spatial deficits, with relative preservation of language skills and visual hallucinations. The underlying neuropathology is Lewy bodies. Here, we describe three unique cases from the UT Health San Antonio Brain Bank of patients with clinical diagnoses of svPPA, but primary neuropathological diagnoses of LBD.

We present three cases who had clinical presentations of svPPA but were found to have LB pathology as opposed to the expected TDP-43 or FTLD pathology. We studied demographic variables in these three patients, along with neuroimaging, clinical symptoms, and patterns of neuropathology, in order to demonstrate and further understand the similarities and connections between LBD and semantic deficits.

In Case 1, the patient exhibited fluent but empty speech with profound anomia. Symptoms started in his late 50s and progressed until he lost all purposeful capacity for language before his death at age 66. DaT scan was normal and brain MRI was unremarkable. Underlying neuropathology revealed diffuse LBD throughout the neocortex with intermediate Alzheimer’s disease neuropathic change (ADNC), and moderate cerebrovascular disease. In Case 2, the patient exhibited language comprehension difficulties with symptom onset in his early 70s before passing away at age 76. The patient also developed changes in judgment and trouble with activities of daily living. MRI revealed left more than right mesial temporal atrophy, left more than right mild to moderate frontal and insular atrophy, and moderate small vessel disease. FDG-PET was significant for hypometabolism in the left mid-frontal region and in the bilateral anterior cingulate and medial prefrontal cortices. Neuropathology revealed diffuse LBD throughout the neocortex with a high level of ADNC, along with limbic-predominant age-related TDP-43 encephalopathy (LATE) stage 1 and moderate cerebrovascular disease. In Case 3, the patient displayed dysgraphia and anomia, starting in his mid-50s, as well as REM behavior sleep disorder. The patient’s neuropathology revealed a high level of ADNC with diffuse LBD throughout the neocortex, and moderate, non-occlusive cerebrovascular disease. None of the patients exhibited the typical Parkinsonism symptoms associated with LBD, but all had prominent visual hallucinations.

This small case series illustrates that a small portion of subjects with underlying LBD pathology may exhibit profound language disturbance suggestive of svPPA. Additional study is warranted, and future endeavors will explore larger pathologically-confirmed samples of subjects with clinical svPPA and high degree of underlying LBD pathology.

Primary progressive aphasia (PPA) is a dementia syndrome characterized by initial development of progressive language deficits in the absence of impairment in other cognitive domains. It has historically been difficult to assess the presence or nature of true memory deficits in this population due to interference from language disturbance on task performance. The Three Words Three Shapes test (3W3S) is a relatively easy memory task that evaluates both verbal and nonverbal memory within the same modality and assesses different aspects of memory, including incidental encoding, effortful encoding, delayed recall, and recognition. Persons with PPA show a material-specific dissociation in performance on 3W3S; specifically, deficits in incidental encoding and recall are limited to verbal, not nonverbal material, in PPA, with preserved recognition of both types of information. However, it is unknown whether this pattern persists over time as the disease progresses.

Participants were 73 participants enrolled in an observational PPA research study at the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease (Mage = 66.75 years, SD = 6.77; Meducation = 16.11 years, SD = 2.38; 51% female). Participants were subtyped as semantic (n = 15), logopenic (n = 27), or agrammatic PPA (n = 31) based on Gorno-Tempini et al., 2011, using 3W3S and other neuropsychological measures as described previously. Participants were followed at 2-year intervals and tests were administered longitudinally. All participants in the current study had 3W3S scores from at least two research visits collected between September 2012 and September 2022.

There were no significant baseline group differences on 3W3S performance, except for better incidental encoding in the logopenic than the semantic group for shapes (p = .040) and words (p = .043). We then conducted a mixed measures ANOVAs to determine baseline within-person comparisons between words vs shapes. Within individuals, performance on incidental encoding, effortful encoding, and recognition was worse for words than shapes (ps < .01). There was an interaction between material and group for delayed recall (p < .001) such that there was a significantly larger discrepancy between word and shape recall in the semantic (Mdiff = -9.14) compared to logopenic (Mdiff = -3.07) and agrammatic groups (Mdiff = -2.13). Repeated measures ANOVAs determined changes in scores over time collapsed across PPA subtypes. Incidental encoding (ps = <.01), effortful encoding (ps < .05), and delayed recall (ps < .01) declined for both words and shapes over time. Copy and recognition of words (ps < .05), but not shapes declined over time.

The current results are consistent with prior findings of relative preservation of memory for nonverbal compared to verbal material in PPA as measured by 3W3S, especially in the semantic subtype. Learning and recall of words and shapes declined over time in all groups, whereas there was selective decline in copy and recognition of words compared to shapes. These results provide evidence of differential patterns of decline in certain aspects of memory over time in PPA and highlight the relative preservation of memory in this language-focused dementia even over time.