7 research outputs found
Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [18F]PI-2620
Objectives: Autoradiography on brain tissue is used to validate binding targets of
newly discovered radiotracers. The purpose of this study was to correlate quantification
of autoradiography signal using the novel next-generation tau positron emission
tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined
tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue
samples of patients with Alzheimer’s disease (AD) and Progressive Supranuclear
Palsy (PSP).
Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain
samples of six patients with AD, five patients with PSP and five healthy controls,
respectively. Binding intensity was compared between both tissue types and different
disease entities. Autoradiography signal quantification (CWMR = cortex to white matter
ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining,
%-area) for FFPE and frozen tissue samples in the different disease entities.
Results: In AD tissue, relative cortical tracer binding was higher in frozen samples
when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001),
whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE:
0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding
and immunohistochemical tau load correlated significantly for both PSP (R = 0.641,
p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement
of relative tracer binding with underlying pathology. In frozen tissue, the correlation
between autoradiography and immunohistochemistry was only present in AD (R = 0.417,
p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.).
Conclusion: Our head-to-head comparison indicates that FFPE samples show
superiority over frozen samples for autoradiography assessment of PSP tau pathology
by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8
positive tau in samples of both PSP and AD patients
High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types
OBJECTIVE: To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia. METHODS: Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients. RESULTS: Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson’s disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline. INTERPRETATION: Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy
Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [18F]PI-2620
Objectives: Autoradiography on brain tissue is used to validate binding targets of
newly discovered radiotracers. The purpose of this study was to correlate quantification
of autoradiography signal using the novel next-generation tau positron emission
tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined
tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue
samples of patients with Alzheimer’s disease (AD) and Progressive Supranuclear
Palsy (PSP).
Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain
samples of six patients with AD, five patients with PSP and five healthy controls,
respectively. Binding intensity was compared between both tissue types and different
disease entities. Autoradiography signal quantification (CWMR = cortex to white matter
ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining,
%-area) for FFPE and frozen tissue samples in the different disease entities.
Results: In AD tissue, relative cortical tracer binding was higher in frozen samples
when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001),
whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE:
0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding
and immunohistochemical tau load correlated significantly for both PSP (R = 0.641,
p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement
of relative tracer binding with underlying pathology. In frozen tissue, the correlation
between autoradiography and immunohistochemistry was only present in AD (R = 0.417,
p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.).
Conclusion: Our head-to-head comparison indicates that FFPE samples show
superiority over frozen samples for autoradiography assessment of PSP tau pathology
by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8
positive tau in samples of both PSP and AD patients
Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [18F]PI-2620
Objectives: Autoradiography on brain tissue is used to validate binding targets of
newly discovered radiotracers. The purpose of this study was to correlate quantification
of autoradiography signal using the novel next-generation tau positron emission
tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined
tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue
samples of patients with Alzheimer’s disease (AD) and Progressive Supranuclear
Palsy (PSP).
Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain
samples of six patients with AD, five patients with PSP and five healthy controls,
respectively. Binding intensity was compared between both tissue types and different
disease entities. Autoradiography signal quantification (CWMR = cortex to white matter
ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining,
%-area) for FFPE and frozen tissue samples in the different disease entities.
Results: In AD tissue, relative cortical tracer binding was higher in frozen samples
when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p < 0.001),
whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE:
0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding
and immunohistochemical tau load correlated significantly for both PSP (R = 0.641,
p < 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement
of relative tracer binding with underlying pathology. In frozen tissue, the correlation
between autoradiography and immunohistochemistry was only present in AD (R = 0.417,
p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.).
Conclusion: Our head-to-head comparison indicates that FFPE samples show
superiority over frozen samples for autoradiography assessment of PSP tau pathology
by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8
positive tau in samples of both PSP and AD patients
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A genome-wide association study in multiple system atrophy.
ObjectiveTo identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS).MethodsWe performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed.ResultsWe found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA.ConclusionsWe present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps