Four-repeat tauopathies

Rösler, Thomas W.; Marvian, Amir Tayaranian; Brendel, Matthias; Nykänen, Niko-Petteri; Höllerhage, Matthias; Schwarz, Sigrid C.; Hopfner, Franziska; Koeglsperger, Thomas; Respondek, Gesine; Schweyer, Kerstin; Xiong, Chengjie; Villemagne, Victor L.; Barthel, Henryk; Sabri, Osama; Müller, Ulrich; Meissner, Wassilios G.; Kovács, Gábor G.; Höglinger, Günter U.

doi:10.1016/j.pneurobio.2019.101644

Cited by 172 publications

(165 citation statements)

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“…Furthermore, other 4R-tauopathies, such as argyrophilic grain disease and globular glial tauopathy, are not represented by the MDS-PSP criteria, 2 and their detailed clinical characterization is still pending. 21 In conclusion, the concept of 4R-tauopathies imposes clear advantages for clinical diagnosis and research. In the light of potential tauopathy-specific interventions, the early clinical recognition of 4R-tauopathies is crucial and will require more research, especially into 4Rtauopathy-specific in vivo biomarkers, such as biofluid proteins and tauopathy positron emission tomography ligands.…”

Section: Discussionmentioning

confidence: 98%

“…Despite these shortcomings in our methodology, it is likely that clinical features alone will not be able to diagnose 4R‐tauopathies early on with good sensitivity. Furthermore, other 4R‐tauopathies, such as argyrophilic grain disease and globular glial tauopathy, are not represented by the MDS‐PSP criteria, and their detailed clinical characterization is still pending …”

Section: Discussionmentioning

confidence: 99%

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Validation of the Movement Disorder Society Criteria for the Diagnosis of 4‐Repeat Tauopathies

et al. 2019

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Background The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category “probable 4‐repeat (4R)‐tauopathy” for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration. Objectives To validate the accuracy of these clinical criteria for “probable 4R‐tauopathy” to predict underlying 4R‐tauopathy pathology. Methods Diagnostic accuracy for 4R‐tauopathies according to the established criteria was estimated retrospectively in autopsy‐confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R‐tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non‐4R‐tauopathies). Results We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non‐4R‐tauopathies (N = 161). Sensitivity and specificity of “probable 4R‐tauopathy” was 10% and 99% in the first year and 59% and 88% at final record. Conclusions The new diagnostic category “probable 4R‐tauopathy” showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R‐tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Validation of the Movement Disorder Society Criteria for the Diagnosis of 4‐Repeat Tauopathies

et al. 2019

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“…8,23 Pathologically, PSP is a tauopathy characterized by the presence of abnormally hyperphosphorylated tau-positive neurofibrillary tangles, neuropil threads, and inclusions in astrocytes and oligodendroglia in several cortical and subcortical structures. 1,6,7,23 Structures that are mostly affected in pathological studies include the globus pallidus, STN, SN, and LC, followed by the NBM, oculomotor complex, superior colliculus, periaqueductal gray matter, PPN, cuneiform nuclei, and DN. 1,6 The cortex, particularly the frontal lobes and the premotor cortex, was also found to be involved.…”

Section: Discussionmentioning

confidence: 99%

“…PSP is a tauopathy characterized by neurodegeneration in specific brain areas, 1,6,7 including the basal ganglia, the nucleus basalis of Meynert (NBM), nuclei in midbrain regions such as the SN, cuneiform nucleus, and pedunculopontine nucleus (PPN), and pons regions such as the locus coeruleus (LC) and, to a lesser degree, the medulla oblongata. 1,8 Neuroimaging is useful to detect brain changes in PSP and facilitate disease diagnosis.…”

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confidence: 99%

Multimodal Magnetic Resonance Imaging Quantification of Brain Changes in Progressive Supranuclear Palsy

et al. 2019

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Background Progressive supranuclear palsy (PSP) is a neurodegenerative clinically heterogeneous disorder, formal diagnosis being based on postmortem histological brain examination. Objective We aimed to perform a precise in vivo staging of neurodegeneration in PSP using quantitative multimodal MRI. The ability of MRI biomarkers to differentiate PSP from PD was also evaluated. Methods Eleven PSP patients were compared to 26 age‐matched healthy controls and 51 PD patients. Images were acquired at 3 Tesla (three‐dimensional T1‐weighted, diffusion tensor, and neuromelanin‐sensitive images) and 7 Tesla (three‐dimensional‐T2* images). Regions of interest included the cortical areas, hippocampus, amygdala, basal ganglia, basal forebrain, brainstem nuclei, dentate nucleus, and cerebellum. Volumes, mean diffusivity, and fractional anisotropy were measured. In each region, a threshold value for group categorization was calculated, and four grades of change (0–3) were determined. Results PSP patients showed extensive volume decreases and diffusion changes in the midbrain, SN, STN, globus pallidus, basal forebrain, locus coeruleus, pedunculopontine nucleus, and dentate nucleus, in close agreement with the degrees of impairment in histological analyses. The predictive factors for the separation of PSP and healthy controls were, in descending order, the neuromelanin‐based SN volume; midbrain fractional anisotropy; volumes of the midbrain, globus pallidus, and putamen; and fractional anisotropy in the locus coeruleus. The best predictors for separating PSP from PD were the neuromelanin‐based volume in the SN, fractional anisotropy in the pons, volumes of the midbrain and globus pallidus, and fractional anisotropy in the basal forebrain. Conclusions These results suggest that it is possible to evaluate brain neurodegeneration in PSP noninvasively, even in small brainstem nuclei, in close agreement with previously published histological data. © 2019 International Parkinson and Movement Disorder Society

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“…The discovery of tau mutations has facilitated the generation of several mouse models of human tauopathy e.g. P301S and P301L lines (transgenic for a human 4 repeat tau isoform) [6,[52][53][54], which have become important tools to study the mechanisms of abnormal tau aggregation and deposition in FTD (4 repeat tau) [61] and AD (3 and 4 repeat tau) [25, 33,41]. In the P301L 4 (Thy 1.2, pR5 line) [11,18], P301L (CaMKIIa) [23,43,62] and P301L (tetO) [14] mouse models, tau deposits begin forming before 3 months-of-age in neurons in the entorhinal cortex, hippocampus and later in the cortex, and amygdala; with neuroinflammation and impaired memory functions in hippocampus-and amygdala-dependent tasks manifesting at a later stage [49,50,67].…”

Section: Introductionmentioning

confidence: 99%

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

Zarb

Kuhn

et al. 2019

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Brain calcification is associated with several neurodegenerative proteinopathies. Here, we report a new phenotype of intracranial calcification in transgenic P301L mice overexpressing 4 repeat tau. P301L mice (Thy1.2) of 3, 5, 9 and 18-25 months-of-age and age-matched non-transgenic littermates were assessed using in vivo/ex vivo magnetic resonance imaging (MRI) with a gradient recalled echo sequence and micro computed tomography (μCT). Susceptibility weighted images computed from the gradient recalled echo data revealed regional hypointensities in the hippocampus, cortex, caudate nucleus and thalamus of P301L mice, which in corresponding phase images indicated diamagnetic lesions. Concomitantly, µCT detected hyperdense lesions.Occurrence of diamagnetic susceptibility lesions in the hippocampus, increased with age.Immunochemical staining of brain sections revealed bone protein-positive deposits. Furthermore, intra-neuronal and vessel-associated protein-containing nodules co-localized with phosphorylated-tau (AT8 and AT100) in the hippocampus. Protein-containing nodules were detected also in the thalamus in the absence of phosphorylated-tau deposition. In contrast, osteocalcin-containing nodules were vessel-associated, indicating ossified vessels, in the thalamus in absence of phosphorylated-tau. In summary, MRI and µCT demonstrated imaging pattern of intracranial calcification, concomitant with immunohistochemical evidence of formation of protein deposits containing bone proteins along with phosphorylated-tau in the P301L mouse model of human tauopathy. The P301L mouse model may thus serve as a future model to study the pathogenesis of brain calcifications in tauopathies.3

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Four-repeat tauopathies

Cited by 172 publications

References 500 publications

Validation of the Movement Disorder Society Criteria for the Diagnosis of 4‐Repeat Tauopathies

Validation of the Movement Disorder Society Criteria for the Diagnosis of 4‐Repeat Tauopathies

Multimodal Magnetic Resonance Imaging Quantification of Brain Changes in Progressive Supranuclear Palsy

Tau deposition is associated with imaging patterns of tissue calcification in the P301L mouse model of human tauopathy

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