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

Abstract 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.

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Differential Chemokine Alteration in the Variants of Primary Progressive Aphasia – A Role for Neuroinflammation

10.21203/rs.3.rs-386614/v1 ◽

2021 ◽

Author(s):

Aitana Sogorb Esteve ◽

Imogen J. Swift ◽

Ione O.C. Woollacott ◽

Jason D. Warren ◽

Henrik Zetterberg ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Primary Progressive Aphasia ◽

The Other ◽

Primary Progressive ◽

Total Tau ◽

Semantic Variant ◽

Primary Focus ◽

Underlying Pathology ◽

Proximity Extension Assay

Abstract 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 36 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.

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The role of the hippocampus in the semantic variant of primary progressive aphasia: A resting‐state fcMRI study

Hippocampus ◽

10.1002/hipo.23156 ◽

2019 ◽

Vol 29 (11) ◽

pp. 1127-1132

Author(s):

Marianne Chapleau ◽

Maxime Montembeault ◽

Mariem Boukadi ◽

Christophe Bedetti ◽

Robert Laforce ◽

...

Keyword(s):

Resting State ◽

Primary Progressive Aphasia ◽

Progressive Aphasia ◽

Primary Progressive ◽

Semantic Variant

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Differences in Sex Distribution Between Genetic and Sporadic Frontotemporal Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-210688 ◽

2021 ◽

pp. 1-9

Author(s):

Sterre C.M. de Boer ◽

Lina Riedl ◽

Sven J. van der Lee ◽

Markus Otto ◽

Sarah Anderl-Straub ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Primary Progressive Aphasia ◽

The Other ◽

Genetic Mutations ◽

Sex Distribution ◽

Progressive Aphasia ◽

Clinical Criteria ◽

Primary Progressive ◽

Sporadic Cases ◽

Semantic Variant

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.

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Supplemental Material for The Concept of Regularization: Resolving the Problem of Surface Dyslexia in Semantic Variant Primary Progressive Aphasia Across Different Languages

Neuropsychology ◽

10.1037/neu0000611.supp ◽

2019 ◽

Keyword(s):

Primary Progressive Aphasia ◽

Progressive Aphasia ◽

Primary Progressive ◽

Semantic Variant ◽

Surface Dyslexia

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Primary Progressive Aphasia: Toward a Pathophysiological Synthesis

Current Neurology and Neuroscience Reports ◽

10.1007/s11910-021-01097-z ◽

2021 ◽

Vol 21 (3) ◽

Author(s):

Justina Ruksenaite ◽

Anna Volkmer ◽

Jessica Jiang ◽

Jeremy CS Johnson ◽

Charles R Marshall ◽

...

Keyword(s):

Care Management ◽

Primary Progressive Aphasia ◽

Disease Stage ◽

Major Step ◽

Progressive Aphasia ◽

Primary Progressive ◽

New Findings ◽

Critical Issues ◽

Semantic Variant ◽

Auditory Impairments

Abstract Purpose of Review The term primary progressive aphasia (PPA) refers to a diverse group of dementias that present with prominent and early problems with speech and language. They present considerable challenges to clinicians and researchers. Recent Findings Here, we review critical issues around diagnosis of the three major PPA variants (semantic variant PPA, nonfluent/agrammatic variant PPA, logopenic variant PPA), as well as considering ‘fragmentary’ syndromes. We next consider issues around assessing disease stage, before discussing physiological phenotyping of proteinopathies across the PPA spectrum. We also review evidence for core central auditory impairments in PPA, outline critical challenges associated with treatment, discuss pathophysiological features of each major PPA variant, and conclude with thoughts on key challenges that remain to be addressed. Summary New findings elucidating the pathophysiology of PPA represent a major step forward in our understanding of these diseases, with implications for diagnosis, care, management, and therapies.

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Breakdowns in Informativeness of Naturalistic Speech Production in Primary Progressive Aphasia

Brain Sciences ◽

10.3390/brainsci11020130 ◽

2021 ◽

Vol 11 (2) ◽

pp. 130

Author(s):

Jeanne Gallée ◽

Claire Cordella ◽

Evelina Fedorenko ◽

Daisy Hochberg ◽

Alexandra Touroutoglou ◽

...

Keyword(s):

Primary Progressive Aphasia ◽

Speech Analysis ◽

Clinical Settings ◽

Functional Communication ◽

Or Efficiency ◽

Progressive Aphasia ◽

Primary Progressive ◽

Communication Impairment ◽

Semantic Variant ◽

Lower Production

“Functional communication” refers to an individual’s ability to communicate effectively in his or her everyday environment, and thus is a paramount skill to monitor and target therapeutically in people with aphasia. However, traditional controlled-paradigm assessments commonly used in both research and clinical settings often fail to adequately capture this ability. In the current study, facets of functional communication were measured from picture-elicited speech samples from 70 individuals with mild primary progressive aphasia (PPA), including the three variants, and 31 age-matched controls. Building upon methods recently used by Berube et al. (2019), we measured the informativeness of speech by quantifying the content of each patient’s description that was relevant to a picture relative to the total amount of speech they produced. Importantly, form-based errors, such as mispronunciations of words, unusual word choices, or grammatical mistakes are not penalized in this approach. We found that the relative informativeness, or efficiency, of speech was preserved in non-fluent variant PPA patients as compared with controls, whereas the logopenic and semantic variant PPA patients produced significantly less informative output. Furthermore, reduced informativeness in the semantic variant is attributable to a lower production of content units and a propensity for self-referential tangents, whereas for the logopenic variant, a lower production of content units and relatively ”empty” speech and false starts contribute to this reduction. These findings demonstrate that functional communication impairment does not uniformly affect all the PPA variants and highlight the utility of naturalistic speech analysis for measuring the breakdown of functional communication in PPA.

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