| 1. |
- Hampel, Harald, et al.
(författare)
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Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives.
- 2010
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Ingår i: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1784 .- 1474-1776. ; 9:7, s. 560-74
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Forskningsöversikt (refereegranskat)abstract
- Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease. To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates. Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments. Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies.
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| 2. |
- Sehlin, Dag, 1976-, et al.
(författare)
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Engineered antibodies : new possibilities for brain PET?
- 2019
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : SPRINGER. - 1619-7070 .- 1619-7089. ; 46:13, s. 2848-2858
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Forskningsöversikt (refereegranskat)abstract
- Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.
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| 3. |
- Nordberg, Agneta, et al.
(författare)
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A European multicentre PET study of fibrillar amyloid in Alzheimer's disease
- 2013
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 40:1, s. 104-114
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer's disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies. In this study 238 [C-11]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [C-11]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69 +/- 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 +/- 8 years) and 51 healthy controls (mean age 67.4 +/- 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 +/- 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype. [C-11]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [C-11]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [C-11]PIB retention was observed in MCI ApoE epsilon 4 carriers compared to non-ApoE epsilon 4 carriers (p < 0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted. This study demonstrated the robustness of [C-11]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.
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