Advances in the development of new biomarkers for Alzheimer’s disease

Alzheimer’s disease(AD)is a complex,heterogeneous,progressive disease and is the most common type of neurodegenerative dementia.The prevalence of AD is expected to increase as the population ages,placing an additional burden on national healthcare systems.There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost.The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity,including pathogenic proteins,markers of synaptic dysfunction,and markers of inflammation in the blood.There is a considerable potential in using microRNA(miRNA)as markers of AD,and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients.Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease.This review focuses on the recent developments of blood,plasma,and ocular biomarkers for the diagnosis of AD.

SPECT imaging of distribution and retention of a brain-penetrating bispecific amyloid-β antibody in a mouse model of Alzheimer's disease

Background:Alzheimer's disease(AD)immunotherapy with antibodies targeting amyloid-B(AB)has been extensively explored in clinical trials.The aim of this study was to study the long-term brain distribution of two radiolabeled monoclonal Aβ antibody variants-RmAb158,the recombinant murine version of BAN2401,which has recently demonstrated amyloid removal and reduced cognitive decline in AD patients,and the bispecific RmAb158-scFv8D3,which has been engineered for enhanced brain uptake via transferrin receptor-mediated transcytosis.Methods:A single intravenous injection of iodine-125(251)-labeled RmAb158-scFv8D3 or RmAb158 was administered to AD transgenic mice(tg-ArcSwe).In vivo single photon emission computed tomography was used to investigate brain retention and intrabrain distribution of the antibodies over a period of 4 weeks.Activity in blood and brain tissue was measured ex vivo and autoradiography was performed in combination with Aβand CD31 immunostaining to investigate the intrabrain distribution of the antibodies and their interactions with AB.Results:Despite faster blood clearance,[125]RmAb158-scFv8D3 displayed higher brain exposure than[25]RmAb158 throughout the study.The brain distribution of[l25]RmAb158-scFv8D3 was more uniform and coincided with parenchymal Aβ pathology,while[2 I]RmAb158 displayed a more scattered distribution pattern and accumulated in central parts of the brain at later times.Ex vivo autoradiography indicated greater vascular escape and parenchymal Aβ interactions for[25]RmAb158-scFv8D3,whereas[25]RmAb158 displayed retention and Aβ interactions in lateral ventricles.Conclusions:The high brain uptake and uniform intrabrain distribution of RmAb158-scFv8D3 highlight the benefits of receptor-mediated transcytosis for antibody-based brain imaging.Moreover,it suggests that the alternative transport route of the bispecific antibody contributes to improved efficacy of brain-directed immunotherapy.

ImmunoPET imaging of amyloid-beta in a rat model of Alzheimer’s disease with a bispecific,brain-penetrating fusion protein

Background:Hijacking the transferrin receptor(TfR)is an effective strategy to transport amyloid-beta(Aβ)immuno-positron emission tomography(immunoPET)ligands across the blood-brain barrier(BBB).Such ligands are more sensitive and specific than small-molecule ligands at detecting Aβpathology in mouse models of Alzheimer’s disease(AD).This study aimed to determine if this strategy would be as sensitive in rats and to assess how TfR affinity affects BBB transport of bispecific immunoPET radioligands.Methods:Two affinity variants of the rat TfR antibody,OX26,were chemically conjugated to a F(ab′)2 fragment of the anti-Aβantibody,bapineuzumab(Bapi),to generate two bispecific fusion proteins:OX265-F(ab′)2-Bapi and OX2676-F(ab′)2-Bapi.Pharmacokinetic analyses were performed 4 h and 70 h post-injection of radioiodinated fusion proteins in wild-type(WT)rats.[124I]I-OX265-F(ab′)2-Bapi was administered to TgF344-AD and WT rats for in vivo PET imaging.Ex vivo distribution of injected[124I]I-OX265-F(ab′)2-Bapi and Aβpathology were assessed.Results:More[125I]I-OX265-F(ab′)2-Bapi was taken up into the brain 4 h post-administration than[124I]I-OX2676-F(ab′)2-Bapi.[124I]I-OX265-F(ab′)2-Bapi PET visualized Aβpathology with significantly higher signals in the TgF344-AD rats than in the WT littermates without Aβpathology.The PET signals significantly correlated with Aβlevels in AD animals.Conclusion:Affinity to TfR affects how efficiently a TfR-targeting bispecific fusion protein will cross the BBB,such that the higher-affinity bispecific fusion protein crossed the BBB more efficiently.Furthermore,bispecific immunoPET imaging of brain Aβpathology using TfR-mediated transport provides good imaging contrast between TgF344-AD and WT rats,suggesting that this immunoPET strategy has the potential to be translated to higher species.