scholarly journals Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum

Brain ◽  
2020 ◽  
Vol 143 (3) ◽  
pp. 1010-1026 ◽  
Author(s):  
W Richard Bevan-Jones ◽  
Thomas E Cope ◽  
P Simon Jones ◽  
Sanne S Kaalund ◽  
Luca Passamonti ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Frontotemporal Dementia ◽  
Primary Progressive Aphasia ◽  
Amyloid Β Protein ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Activated Microglia ◽  
Clinical Syndromes ◽  
Semantic Variant

Abstract The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-β protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.

scholarly journals Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum

2019 ◽  
Author(s):  
W Richard Bevan-Jones ◽  
Thomas E Cope ◽  
P Simon Jones ◽  
Luca Passamonti ◽  
Young T Hong ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Frontotemporal Dementia ◽  
Close Association ◽  
Surrogate Marker ◽  
Primary Progressive Aphasia ◽  
Strong Positive Correlation ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Clinical Syndromes

AbstractThe clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the aggregation of Tau and TDP-43 in frontotemporal dementia, and to the heterogeneity of clinical disease. We used positron emission tomography in vivo with (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [18F]AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and diseases associated with TDP-43 protein aggregation, and which is used as a surrogate marker of non-β-amyloid protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant frontotemporal dementia, 11 with the semantic variant of primary progressive aphasia and 10 with the non-fluent variant of primary progressive aphasia), 28 of whom underwent both [18F]AV-1451 and [11C]PK-11195 PET, and matched controls (14 for [18F]AV-1451 and 15 for [11C]PK-11195). We used univariate region-of-interest analyses, and multivariate analysis of the distribution of binding that explicitly control for individual differences in ligand affinity for TDP-43 and different Tau isoforms. We found differences between patients and controls in frontotemporal regions for both neuroinflammation and protein aggregation, and a strong positive correlation between these two processes in all disease groups. Despite this regional co-localisation, the multivariate distribution of [11C]PK-11195 binding related better to clinical heterogeneity than did the distribution of [18F]AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate group classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.

scholarly journals Differences in Sex Distribution Between Genetic and Sporadic Frontotemporal Dementia

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.

scholarly journals Binding of [18F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients

2019 ◽  
Vol 47 (8) ◽  
pp. 1949-1960 ◽  
Author(s):  
Jolien Schaeverbeke ◽  
Sofie Celen ◽  
Julie Cornelis ◽  
Alicja Ronisz ◽  
Kim Serdons ◽  
...  
Keyword(s):  
Specific Binding ◽  
Brain Slices ◽  
Primary Progressive Aphasia ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Pet Tracer ◽  
Post Mortem Brain ◽  
Semantic Variant

Abstract Purpose In vivo tau-PET tracer retention in the anterior temporal lobe of patients with semantic variant primary progressive aphasia (SV PPA) has consistently been reported. This is unexpected as the majority of these patients have frontotemporal lobar degeneration TDP (FTLD-TDP). Methods We conducted an in vitro [18F]AV1451 autoradiography binding study in five cases with a clinical diagnosis of SV PPA constituting the range of pathologies (i.e., three FTLD-TDP, one Alzheimer’s disease (AD), and one Pick’s disease (PiD)). Binding was compared with two controls without neurodegeneration, two typical AD, one corticobasal syndrome with underlying AD, and one frontotemporal dementia behavioral variant with FTLD-TDP. The effect of blocking with the authentic reference material and with the MAO-B inhibitor deprenyl was assessed. Immunohistochemistry was performed on adjacent cryosections. Results Absence of specific [18F]AV1451 binding was observed for all three SV PPA FTLD-TDP cases. The absence of binding in controls as well as the successful blocking with authentic AV1451 in cases with tauopathy demonstrated specificity of the [18F]AV1451 signal for tau. The specific [18F]AV1451 binding was highest in AD, followed by PiD. This binding colocalized with the respective tau lesions and could not be blocked by deprenyl. Similar pilot findings were obtained with [18F]THK5351. Conclusion In vitro autoradiography showed no [18F]AV1451 binding in SV PPA due to FTLD-TDP, while specific binding was present in SV PPA due to AD and PiD. The discrepancy between in vitro and in vivo findings remains to be explained. The discordance is not related to [18F]AV1451 idiosyncrasies as [18F]THK5351 findings were similar.

scholarly journals [18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia

2017 ◽  
Vol 89 (10) ◽  
pp. 1032-1037 ◽  
Author(s):  
W R Bevan-Jones ◽  
Thomas E Cope ◽  
P Simon Jones ◽  
Luca Passamonti ◽  
Young T Hong ◽  
...  
Keyword(s):  
Frontotemporal Lobar Degeneration ◽  
Primary Progressive Aphasia ◽  
Hierarchical Cluster ◽  
Clinical Syndrome ◽  
Semantic Dementia ◽  
Binding Potential ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Semantic Variant

IntroductionSemantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which to test the specificity of in vivo binding of the putative tau ligand [18F]AV-1451, which is elevated in frontotemporal lobar degeneration tauopathies.Methods and resultsSeven patients (five with svPPA and two with ‘right’ semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with [18F]AV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BPND (non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BPND was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of [18F]AV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity.Conclusions[18F]AV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for [18F]AV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed ‘off target’ binding sites for [18F]AV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of [18F]AV-1451 to differentiate and track different types of frontotemporal lobar degeneration.

scholarly journals Laughter as a Paradigm of Socio-emotional Signal Processing in Dementia

2020 ◽  
Author(s):  
Harri Sivasathiaseelan ◽  
Charles R Marshall ◽  
Elia Benhamou ◽  
Janneke EP van Leeuwen ◽  
Rebecca L Bond ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signal Processing ◽  
Frontotemporal Dementia ◽  
Primary Progressive Aphasia ◽  
Identification Accuracy ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Emotional Dysfunction ◽  
Semantic Variant

Abstract Background: Laughter is a fundamental communicative signal in our relations with other people and is used to convey a diverse repertoire of social and emotional information. It is therefore potentially a useful probe of impaired socio-emotional signal processing in neurodegenerative diseases. Here we investigated the cognitive and affective processing of laughter systematically in patients representing all major syndromes of frontotemporal dementia, a disease spectrum characterised by severe socio-emotional dysfunction, as well as typical amnestic Alzheimer’s disease in relation to healthy age-matched individuals. Methods: We assessed cognitive labelling and valence rating of samples of spontaneous (mirthful and hostile) and volitional (posed) laughter versus two auditory control conditions (a synthetic laughter-like stimulus and spoken numbers) in 47 patients with frontotemporal dementia (22 with behavioural variant frontotemporal dementia, 12 with semantic variant primary progressive aphasia and 13 with nonfluent-agrammatic primary progressive aphasia), 15 patients with typical amnestic Alzheimer’s disease and 20 healthy age-matched individuals. Neuroanatomical associations of laughter processing were assessed using voxel-based morphometry of patients’ brain MR images. Results: While all dementia syndromes were associated with impaired identification of laughter subtypes relative to healthy controls, this was significantly more severe overall in frontotemporal dementia than in Alzheimer’s disease and particularly in the behavioural and semantic variants, which also showed abnormal affective evaluation of laughter. Certain striking syndromic signatures emerged, including enhanced liking for hostile laughter in behavioural variant frontotemporal dementia, impaired processing of synthetic laughter in the nonfluent-agrammatic variant (consistent with a generic complex auditory perceptual deficit) and ‘numerophilia’ in the semantic variant. Across the patient cohort, overall laughter identification accuracy correlated with regional grey matter in a core network encompassing inferior frontal and cingulo-insular cortices; and more specific correlates of laughter identification accuracy were delineated in cortical regions mediating affective disambiguation (identification of hostile and posed laughter in orbitofrontal cortex) and authenticity (social intent) decoding (identification of mirthful and posed laughter in anteromedial prefrontal cortex).Conclusions: These findings reveal a rich diversity of cognitive and affective laughter phenotypes in canonical dementia syndromes and suggest that laughter is an informative probe of neural mechanisms underpinning socio-emotional dysfunction in neurodegenerative disease.

Early-Onset Frontotemporal Dementia-Related Semantic Variant of Primary Progressive Aphasia

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Spyridon Tsiouris ◽  
Charalampos Bougias ◽  
Spyridon Konitsiotis ◽  
Athanasios Papadopoulos ◽  
Andreas Fotopoulos
Keyword(s):  
Frontotemporal Dementia ◽  
Early Onset ◽  
Primary Progressive Aphasia ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Semantic Variant

Frontotemporal Dementia

2019 ◽  
pp. 678-704
Author(s):  
Andrea G. Alioto ◽  
Christie C. Mead ◽  
Alicia B. Vanden Bussche Jantz ◽  
Adam M. Staffaroni ◽  
Joel H. Kramer
Keyword(s):  
Best Practices ◽  
Frontotemporal Dementia ◽  
Neuropsychiatric Symptoms ◽  
Primary Progressive Aphasia ◽  
Accurate Diagnosis ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Clinical Presentations ◽  
Language Difficulties

Frontotemporal dementia (FTD) is a progressive neurological syndrome with diverse clinical presentations and underlying pathologies. FTD is a common cause of dementia, particularly among individuals younger than age 65 years. The three core FTD syndromes are behavioral variant FTD, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia. Neuropsychiatric symptoms and language difficulties are common in FTD, but the heterogeneity of clinical presentations poses significant challenges that can impact accurate diagnosis and patient care. A comprehensive clinical assessment involving the evaluation of cognition, socioemotional functioning, neuroimaging, and other in vivo biomarkers assists with early diagnosis and treatment planning. As the understanding of genetic risk factors and the molecular basis for FTD improves, promising pharmacological therapies are being developed. This chapter summarizes the clinically relevant findings typically seen in each of the three FTD subtypes. It reviews the spectrum of underlying pathological and genetic substrates, addresses common diagnostic challenges, and summarize best practices associated with management of FTD.

scholarly journals Neuroimaging in Frontotemporal Dementia: Heterogeneity and Relationships with Underlying Neuropathology

2021 ◽  
Author(s):  
Bradley T. Peet ◽  
Salvatore Spina ◽  
Nidhi Mundada ◽  
Renaud La Joie
Keyword(s):  
Frontotemporal Dementia ◽  
Primary Progressive Aphasia ◽  
Resonance Imaging ◽  
Structural Magnetic Resonance Imaging ◽  
Progressive Aphasia ◽  
Temporal Lobes ◽  
Primary Progressive ◽  
Positron Emission ◽  
Clinical Syndromes ◽  
Pathologic Features

AbstractFrontotemporal dementia encompasses a group of clinical syndromes defined pathologically by degeneration of the frontal and temporal lobes. Historically, these syndromes have been challenging to diagnose, with an average of about three years between the time of symptom onset and the initial evaluation and diagnosis. Research in the field of neuroimaging has revealed numerous biomarkers of the various frontotemporal dementia syndromes, which has provided clinicians with a method of narrowing the differential diagnosis and improving diagnostic accuracy. As such, neuroimaging is considered a core investigative tool in the evaluation of neurodegenerative disorders. Furthermore, patterns of neurodegeneration correlate with the underlying neuropathological substrates of the frontotemporal dementia syndromes, which can aid clinicians in determining the underlying etiology and improve prognostication. This review explores the advancements in neuroimaging and discusses the phenotypic and pathologic features of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia, as seen on structural magnetic resonance imaging and positron emission tomography.

scholarly journals Primary Progressive Aphasia: Toward a Pathophysiological Synthesis

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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