Case Report: Semantic Variant of Primary Progressive Aphasia Associated With Anti-Glial Fibrillary Acid Protein Autoantibodies

BackgroundFrontotemporal lobar degeneration is a heterogeneous disorder entailing a semantic variant of primary progressive aphasia (svPPA). A subtype of frontotemporal dementia associated with glutamate receptor subunit 3 (GluA3) antibody of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was recently identified. Here, we describe the novelty of a svPPA associated with anti-glial fibrillary acid protein (GFAP) antibodies.MethodsTo diagnose this 68-year-old woman we conducted a clinical examination, neuropsychological testing, CSF analysis, MRI and 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET)/computed tomography (CT) imaging.ResultsThe clinical phenotype corresponds to a svPPA based on impaired confrontation naming and single-word comprehension. In addition, we observed spared speech production, impaired object knowledge, and surface dyslexia - further supporting the diagnosis of svPPA. Additional characteristic imaging features such as anterior temporal hypometabolism in 18F-FDG PET/CT confirmed patient’s svPPA diagnosis. CSF analysis revealed signs of axonal degeneration, as both tau and phosphorylated tau proteins exceeded normal levels. Her serum showed anti-GFAP autoantibodies.ConclusionWe diagnosed a svPPA in this patient and report an association between serum anti-GFAP antibodies and svPPA never reported in the literature so far, thereby expanding the clinical spectrum of svPPA and anti-GFAP-antibody related disease. Further research is needed to elucidate the underlying immunopathology of this disease entity to ultimately improve treatment.

Semantic Variant Primary Progressive Aphasia: Practical Recommendations for Treatment from 20 Years of Behavioural Research

People with semantic variant primary progressive aphasia (svPPA) present with a characteristic progressive breakdown of semantic knowledge. There are currently no pharmacological interventions to cure or slow svPPA, but promising behavioural approaches are increasingly reported. This article offers an overview of the last two decades of research into interventions to support language in people with svPPA including recommendations for clinical practice and future research based on the best available evidence. We offer a lay summary in English, Spanish and French for education and dissemination purposes. This paper discusses the implications of right- versus left-predominant atrophy in svPPA, which naming therapies offer the best outcomes and how to capitalise on preserved long-term memory systems. Current knowledge regarding the maintenance and generalisation of language therapy gains is described in detail along with the development of compensatory approaches and educational and support group programmes. It is concluded that there is evidence to support an integrative framework of treatment and care as best practice for svPPA. Such an approach should combine rehabilitation interventions addressing the language impairment, compensatory approaches to support activities of daily living and provision of education and support within the context of dementia.

The Importance of Being Familiar: The Role of Semantic Knowledge in the Activation of Emotions and Factual Knowledge from Music in the Semantic Variant of Primary Progressive Aphasia

Background: The role of semantic knowledge in emotion recognition remains poorly understood. The semantic variant of primary progressive aphasia (svPPA) is a degenerative disorder characterized by progressive loss of semantic knowledge, while other cognitive abilities remain spared, at least in the early stages of the disease. The syndrome is therefore a reliable clinical model of semantic impairment allowing for testing the propositions made in theoretical models of emotion recognition. Objective: The main goal of this study was to investigate the role of semantic memory in the recognition of basic emotions conveyed by music in individuals with svPPA. Methods: The performance of 9 individuals with svPPA was compared to that of 32 control participants in tasks designed to investigate the ability: a) to differentiate between familiar and non-familiar musical excerpts, b) to associate semantic concepts to musical excerpts, and c) to recognize basic emotions conveyed by music. Results: Results revealed that individuals with svPPA showed preserved abilities to recognize familiar musical excerpts but impaired performance on the two other tasks. Moreover, recognition of basic emotions and association of musical excerpts with semantic concepts was significantly better for familiar than non-familiar musical excerpts in participants with svPPA. Conclusion: Results of this study have important implications for theoretical models of emotion recognition and music processing. They suggest that impairment of semantic memory in svPPA affects both the activation of emotions and factual knowledge from music and that this impairment is modulated by familiarity with musical tunes.

Differences in Sex Distribution Between Genetic and Sporadic Frontotemporal Dementia

Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n = 654), non-fluent variant primary progressive aphasia (nfvPPA; n = 99), semantic variant primary progressive aphasia (svPPA; n = 117), and right temporal variant frontotemporal dementia (rtvFTD; n = 40). We compared sex distribution between genetic and sporadic FTD using χ2-tests. Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases sex distribution was somewhat equal. Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research.

Differential chemokine alteration in the variants of primary progressive aphasia—a role for neuroinflammation

Background The primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer’s disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF) Methods Thirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11. Results In CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13). Conclusion Differential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.

MNI-FTD templates, unbiased average templates of frontotemporal dementia variants

Standard templates are widely used in human neuroimaging processing pipelines to facilitate group-level analyses and comparisons across subjects/populations. MNI-ICBM152 template is the most commonly used standard template, representing an average of 152 healthy young adult brains. However, in patients with neurodegenerative diseases such as frontotemporal dementia (FTD), high atrophy levels lead to significant differences between individuals’ brain shapes and MNI-ICBM152 template. Such differences might inevitably lead to registration errors or subtle biases in downstream analyses and results. Disease-specific templates are therefore desirable to reflect the anatomical characteristics of the populations of interest and reduce potential registration errors. Here, we present MNI-FTD136, MNI-bvFTD70, MNI-svFTD36, and MNI-pnfaFTD30, four unbiased average templates of 136 FTD patients, 70 behavioural variant (bv), 36 semantic variant (sv), and 30 progressive nonfluent aphasia (pnfa) variant FTD patients and a corresponding age-matched template of 133 controls (MNI-CN133), along with probabilistic tissue maps for each template. Public availability of these templates will facilitate analyses of FTD cohorts and enable comparisons between different studies in an appropriate common standardized space.

Neural dynamics of semantic categorization in semantic variant of Primary Progressive Aphasia

Semantic representations are processed along a posterior-to-anterior gradient reflecting a shift from perceptual (e.g., it has eight legs) to conceptual (e.g., venomous spiders are rare) information. One critical region is the anterior temporal lobe (ATL): patients with semantic variant primary progressive aphasia (svPPA), a clinical syndrome associated with ATL neurodegeneration, manifest a deep loss of semantic knowledge. We test the hypothesis that svPPA patients perform semantic tasks by over-recruiting areas implicated in perceptual processing. We compared MEG recordings of svPPA patients and healthy controls during a categorization task. While behavioral performance did not differ, svPPA patients showed indications of greater activation over bilateral occipital cortices and superior temporal gyrus, and inconsistent engagement of frontal regions. These findings suggest a pervasive reorganization of brain networks in response to ATL neurodegeneration: the loss of this critical hub leads to a dysregulated (semantic) control system, and defective semantic representations are seemingly compensated via enhanced perceptual processing.