There are many promising compounds in development for Alzheimer's disease, based on substantial preclinical evidence supporting efficacy in model systems and acceptable safety data to allow chronic human exposure. Guidance for developing a clinical trial program is often held back by the absence of pharmacokinetic/pharmacodynamic (pK/pD) data to support target engagement within the central nervous system (CNS) and to aid in dose selection. For small molecules that target secretases or other key biochemical pathways in AD, studies involving CSF and plasma sampling in humans are the best way to demonstrate that a drug crosses the blood-brain barrier and engages the relevant target, and to help establish the relationship between blood levels and CNS effects. Repeated sampling through a lumbar CSF catheter over 24-36 hours, and the technique of stable metabolic labeling to measure parameters such as fractional synthesis rate of amyloid beta protein (ABeta), have helped to guide the development of gamma-secretase inhibitors developed by Pharma, but have not been available to biotechnology companies and academic laboratories. To fill this need to increase the efficacy and speed of drug development, continued CSF and plasma sampling and SILK will be established at 6 academic sites with initial proposed studies evaluating 4 candidate drugs for future ADCS Phase II/III trials.
These methods can enable the ADCS in collaboration with Biotechnology Companies and academic laboratories to obtain critical data to guide and prioritize further clinical development of novel compounds.
|Besser, Lilah; Kukull, Walter; Knopman, David S et al. (2018) Version 3 of the National Alzheimer's Coordinating Center's Uniform Data Set. Alzheimer Dis Assoc Disord 32:351-358|
|Jacobs, Heidi I L; Hedden, Trey; Schultz, Aaron P et al. (2018) Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals. Nat Neurosci 21:424-431|
|Buckley, Rachel F; Mormino, Elizabeth C; Amariglio, Rebecca E et al. (2018) Sex, amyloid, and APOE ?4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts. Alzheimers Dement 14:1193-1203|
|Jacobs, Diane M; Ard, M Colin; Salmon, David P et al. (2017) Potential implications of practice effects in Alzheimer's disease prevention trials. Alzheimers Dement (N Y) 3:531-535|
|Marquié, Marta; Verwer, Eline E; Meltzer, Avery C et al. (2017) Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case. Acta Neuropathol Commun 5:75|
|Dekhtyar, Maria; Papp, Kathryn V; Buckley, Rachel et al. (2017) Neuroimaging markers associated with maintenance of optimal memory performance in late-life. Neuropsychologia 100:164-170|
|Schultz, Aaron P; Chhatwal, Jasmeer P; Hedden, Trey et al. (2017) Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals. J Neurosci 37:4323-4331|
|Vannini, Patrizia; Hanseeuw, Bernard; Munro, Catherine E et al. (2017) Anosognosia for memory deficits in mild cognitive impairment: Insight into the neural mechanism using functional and molecular imaging. Neuroimage Clin 15:408-414|
|Donohue, Michael C; Sperling, Reisa A; Petersen, Ronald et al. (2017) Association Between Elevated Brain Amyloid and Subsequent Cognitive Decline Among Cognitively Normal Persons. JAMA 317:2305-2316|
|LaPoint, Molly R; Chhatwal, Jasmeer P; Sepulcre, Jorge et al. (2017) The association between tau PET and retrospective cortical thinning in clinically normal elderly. Neuroimage 157:612-622|
Showing the most recent 10 out of 490 publications