Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer’s disease

Singleton, Ellen H.; Hansson, Oskar; Pijnenburg, Yolande A.L.; Joie, Renaud La; Mantyh, William G.; Tideman, Pontus; Stomrud, Erik; Leuzy, Antoine; Johansson, Maurits; Strandberg, Olof; Smith, Ruben; Berendrecht, Evi; Miller, Bruce L.; Iaccarino, Leonardo; Edwards, Lauren; Strom, Amelia; Wolters, E.Ch.; Coomans, Emma M.; Visser, Denise; Golla, Sandeep S.V.; Tuncel, Hayel; Bouwman, Femke H.; Swieten, John C. van; Papma, Janne M.; Berckel, Bart van; Scheltens, Philip; Dijkstra, Anke A.; Rabinovici, Gil D.; Ossenkoppele, Rik

doi:10.1136/jnnp-2020-325497

Cited by 22 publications

(21 citation statements)

References 43 publications

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“…In line with amyloid and tau PET findings, the meta-analyses on neuropathological data showed that bvAD and tAD did not differ in the neuropathological burden of amyloid-β (3 studies; 20 participants) across frontal regions (SMD, 0.23 [95% CI, −0.36 to 0.81]; P = .45), medial temporal lobe (SMD, −0.06 [95% CI, −0.65 to 0.53]; P = .84), or occipital cortex (SMD, −0.16 [95% CI, −1.05 to 0.73]; P = .73; eFigure 7 in the Supplement). Furthermore, there was no difference in tau burden (4 studies; 28 participants) across frontal regions (SMD, −0.05 [95% CI, −0.56 to 0.46]; P = .84), medial temporal lobe (SMD, 0.32 [95% CI, −0.19 to 0.83]; P = .22), or occipital cortex (SMD, −0.36 [95% CI, −0.95 to 0.23]; P = .24; eFigure 7 in the Supplement).…”

Section: Resultsmentioning

confidence: 54%

“…The systematic literature search yielded 1257 records, of which 116 studies were assessed at full-text level for eligibility and 83 studies met inclusion criteria (eFigure 5 in the Supplement for flowchart). Confirmation of AD pathology was present in 91.1% of cases with bvAD based on autopsy data (36 studies; n = 334), genetic data (9 studies; n = 21), or biomarker data (31 studies; n = 262), while no information was available in 9.9% of cases (11 studies including 68 cases of bvAD). Thirteen studies were eligible for meta-analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Amyloid-PET studies (2 studies; 28 participants) showed no differences in amyloid-β burden or distribution between patients with bvAD vs tAD. For tau-PET (2 studies; 22 participants), 1 study showed a temporoparietal pattern with higher uptake in anterior regions in bvAD compared with tAD, whereas another study showed heterogeneous patterns across patients with bvAD. Findings on functional connectivity (3 studies; 54 participants) and white matter hyperintensities (1 study; 29 participants) in bvAD are presented in eTable 6 in the Supplement.…”

Section: Resultsmentioning

confidence: 99%

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Research Criteria for the Behavioral Variant of Alzheimer Disease

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Section: Resultsmentioning

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Research Criteria for the Behavioral Variant of Alzheimer Disease

et al. 2022

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“…It is a better predictor of the severity of symptoms (especially cognition decline) and neuronal loss than amyloid beta peptide [3,98]. Intriguingly, patterns of brain atrophy implied by tau deposits can precede and be identical to later detection by MRI and FDG-PET [99,100]. Meanwhile, different AD phenotypes show higher NFT burden in specific brain regions.…”

Section: R and 4r Tauopathymentioning

confidence: 99%

Tauopathies: new perspectives and challenges

Zhang

Liu

et al. 2022

Mol Neurodegeneration

155

114

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Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics. Conclusions Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.

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“…Today, factors modulating the clinical course of pathology are still poorly understood. Several studies have outlined that tau pathology is associated with the heterogeneity of disease evolution [30], although this is not reported in all studies [31,32]. Modulation of Aβ structures is another potential culprit to explain different fate of AD evolution in particular to explain rapidly progressive forms of AD [33].…”

Section: Clinical Fate In Alzheimer'smentioning

confidence: 99%

Long term worsening of Alzheimer pathology and clinical outcome by a single inoculation of mutated beta-amyloid seeds

Célestine

Jacquier-Sarlin

Borel

et al. 2022

Preprint

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Background Alzheimer’s disease (AD) is characterized by intracerebral accumulation of abnormal proteinaceous assemblies made of amyloid-β (Aß) peptides or tau proteins. These lesions induce synaptic dysfunctions that are strongly correlated with cognitive decline. Intracerebral infusion of well-defined Aβ seeds from synthetic or recombinant non-mutated Aβ1−40 or Aβ1−42 peptides can increase Aβ plaque depositions several months after the infusion. Familial forms of AD are associated with mutations in the amyloid precursor protein (APP) that induce the production of Aβ peptides with different structures. The Aβosa mutation (E693Δ) is located within the Aβ sequence and thus the Aβosa peptides have different structures and properties as compared to non-mutated Aβ1−42 peptides (Aβwt). Here, we wondered if a single exposure to this mutated Aβ can worsen AD pathology as well as downstream events including cognition, cerebral connectivity and synaptic health several months after the inoculation compared to non-mutated Aβ. Method To answer this question we inoculated Aβ1−42-bearing Osaka mutation (Aβosa) in the dentate gyrus of APPswe/PS1dE9 mice at the age of two months. The inoculated mice were analyzed at 4 months post-inoculation by cognitive evaluation and functional MRI to assess cerebral connectivity. Aβ and tau lesions as well as synaptic density were evaluated by histology. The impact of Aβosa peptides on synaptic health was also measured on primary cortical neurons. Results Remarkably, compared to Aβwt, the intracerebral administration of Aβosa induced cognitive impairments, synaptic impairments and a reduction of the connectivity between different brain regions, 4 months post-inoculation. Aβ plaque depositions but not tau lesions were increased and Aβ oligomeric patterns were modified. Conclusion This is the first study showing long-term functional toxicity of Aβ seeds. It shows that a single, sporadic event as Aβosa inoculation can worsen the fate of the pathology and clinical outcome several months after the event. Extrapolation of this discovery suggests that any event that modulates focally Aβ aggregation process in the time-course of AD can be responsible for the heterogeneity of AD clinical outcome.

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Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer’s disease

Cited by 22 publications

References 43 publications

Research Criteria for the Behavioral Variant of Alzheimer Disease

Research Criteria for the Behavioral Variant of Alzheimer Disease

Tauopathies: new perspectives and challenges

Long term worsening of Alzheimer pathology and clinical outcome by a single inoculation of mutated beta-amyloid seeds

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