Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer's disease patients: effect of polymorphisms in the ABCB1 gene

Background: P-glycoprotein is a blood-brain barrier efflux transporter involved in the clearance of amyloid-beta from the brain and, as such, might be involved in the pathogenesis of Alzheimer's disease. P-glycoprotein is encoded by the highly polymorphic ABCB1 gene. Single-nucleotide polymorphisms in the ABCB1 gene have been associated with altered P-glycoprotein expression and function. P-glycoprotein function at the blood-brain barrier can be quantified in vivo using the P-glycoprotein substrate tracer (R)-[11C]verapamil and positron emission tomography (PET). The purpose of this study was to assess the effects of C1236T, G2677T/A and C3435T single-nucleotide polymorphisms in ABCB1 on blood-brain barrier P-glycoprotein function in healthy subjects and patients with Alzheimer's disease. Methods: Thirty-two healthy subjects and seventeen patients with Alzheimer's disease underwent 60-min dynamic (R)-[11C]verapamil PET scans. The binding potential of (R)-[11C]verapamil was assessed using a previously validated constrained two-tissue plasma input compartment model and used as outcome measure. DNA was isolated from frozen blood samples and C1236T, G2677T/A and C3435T single-nucleotide polymorphisms were amplified by polymerase chain reaction. Results: In healthy controls, binding potential did not differ between subjects without and with one or more T present in C1236T, G2677T and C3435T. In contrast, patients with Alzheimer's disease with one or more T in C1236T, G2677T and C3435T had significantly higher binding potential values than patients without a T. In addition, there was a relationship between binding potential and T dose in C1236T and G2677T. Conclusions: In Alzheimer's disease patients, C1236T, G2677T/A and C3435T single-nucleotide polymorphisms may be related to changes in P-glycoprotein function at the blood-brain barrier. As such, genetic variations in ABCB1 might contribute to the progression of amyloid-beta deposition in the brain

Impact of Noise and Background on Measurement Uncertainties in Luminescence Thermometry

Materials with temperature-dependent luminescence can be used as local thermometers when incorporated in, for example, a biological environment or chemical reactor. Researchers have continuously developed new materials aiming for the highest sensitivity of luminescence to temperature. Although the comparison of luminescent materials based on their temperature sensitivity is convenient, this parameter gives an incomplete description of the potential performance of the materials in applications. Here, we demonstrate how the precision of a temperature measurement with luminescent nanocrystals depends not only on the temperature sensitivity of the nanocrystals but also on their luminescence strength compared to measurement noise and background signal. After first determining the noise characteristics of our instrumentation, we show how the uncertainty of a temperature measurement can be predicted quantitatively. Our predictions match the temperature uncertainties that we extract from repeated measurements, over a wide temperature range (303-473 K), for different CCD readout settings, and for different background levels. The work presented here is the first study that incorporates all of these practical issues to accurately calculate the uncertainty of luminescent nanothermometers. This method will be important for the optimization and development of luminescent nanothermometers

A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds

Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE-ϵ4; one heterozygous. The cognitive complaints, reduced amyloid-beta-42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity

BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD. METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family

A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds

Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE-ε4; one heterozygous. The cognitive complaints, reduced amyloid-beta-42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status

High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands

Mutations in microtubule-associated protein tau recently have been identified in familial cases of frontotemporal dementia (FTD). We report the frequency of tau mutations in a large population-based study of FTD carried out in the Netherlands from January 1994 to June 1998. Thirty-seven patients had >/=1 first-degree relative with dementia. A mutation in the tau gene was found in 17.8% of the group of patie

Beyond the energy gap law : the influence of selection rules and host compound effects on nonradiative transition rates in boltzmann thermometers

P.N. and M.H. contributed equally to this work. H.A.H., P.N., M.H., and E.T. thank the Deutsche Forschungsgemeinschaft (DFG) for generous support (Project HO 4503/5-1). Open access funding enabled and organized by Projekt DEAL.Apart from the energy gap law, control parameters over nonradiative transitions are so far only scarcely regarded. In this work, the impact of both covalence of the lanthanoid–ligand bond and varying bond distance on the magnitude of the intrinsic nonradiative decay rate between the excited 6P5/2 and 6P7/2 spin–orbit levels of Gd3+ is investigated in the chemically related compounds Y2[B2(SO4)6] and LaBO3. Analysis of the temperature-dependent luminescence spectra reveals that the intrinsic nonradiative transition rates between the excited 6PJ (  J = 5/2, 7/2) levels are of the order of only 10 ms−1 (Y2[B2(SO4)6]:Gd3+: 8.9 ms−1; LaBO3:Gd3+: 10.5 ms−1) and differ due to the different degree of covalence of the Gd—O bonds in the two compounds. Comparison to the established luminescent Boltzmann thermometer Er3+ reveals, however, that the nonradiative transition rates between the excited levels of Gd3+ are over three orders of magnitude slower despite a similar energy gap and the presence of a single resonant phonon mode. This hints to a fundamental magnetic dipolar character of the nonradiative coupling in Gd3+. These findings can pave a way to control nonradiative transition rates and how to tune the dynamic range of luminescent Boltzmann thermometers.Publisher PDFPeer reviewe