Jesse M. Cedarbaum, MD, FAAN (Neurology), FANA

The early focus of my work was on using neuroanatomical and neurophysiological tools to understand the pharmacology of drugs acting on the noradrenergic system of the brain, and the contribution of the locus coeruleus (LC) noradrenergic system to brain function. These efforts helped lay the groundwork for a theory of locus coeruleus function that is still widely supported – that the LC is involved in novelty detection and selective attention. Subsequent understanding of pathological changes in the LC and the correlation of loss of noradrenergic function in dementia are in keeping with this hypothesis.

My interest in the pharmacology of catecholaminergic systems in the brain led to a clinical interest in Parkinson’s disease. Significant novel clinical observations from work carried out at Cornell and the Burke Rehabilitation Center included the (at that time) novel understanding that the timing emergence of MRF and dyskinesia in the treatment of PD was related to age of onset and severity of disease, not the duration of levodopa administration. In addition, our group was among the first to report on the near-universal prevalence of dementia in advanced PD. Our group also was among the early pioneers in the utilization of enteral levodopa infusions to attempt to control MRFs, and we established the basis for the use of peripheral COMT inhibitors in PD through a combination of clinical observations and studies using novel COMT inhibitors in nonhuman primates. And finally, we described the relationship between plasma and brain pharmacokinetics levodopa and dopamine by sampling CSF from PD patients who had Ommaya reservoirs left in place following neurosurgical procedures.

Prior to initiation of clinical trials for ALS at Regeneron Pharmaceuticals, it became apparent to us that there was a need for a comprehensive clinical rating scale to be used as a clinical trial outcome measure. This work resulted in the development and validation of the ALS Functional Rating Scale (ALSFRS) and its revised, expanded version, the ALSFRS-R. Unfortunately, none of our ALS clinical trials were successful, but the ALSFRS-R continues to be the most-used outcome measure for ALS trials, and is endorsed by FDA for this use.

The neurotrophic factor trail led us to studies for treatment of retinal disorders, since the eye, after all, is a part of, and a window into, the brain. Subsequent to the completion of the ALS program, I led a series of clinical trials of an anti-VEGF agent, aflibercept, for treatment of neovascular Age Related Macular Degeneration (“wet”) AMD. This program resulted in the eventual approval of the drug, known commercially as Eyelea, for wet AMD and a variety of other retinal vascular diseases.

After leaving Regeneron, I joined Elan Pharmaceuticals. There my focus shifted back to neurodegenerative disease, in particular Alzheimer’s disease. Three publications from this period helped lay the groundwork for acceptance by both FDA and EMA of the Clinical Dementia Rating Sum of Boxes (CDR-SB), developed at Washington University in St. Louis, as a sole clinical outcome measure for trials in the MCI-early AD space, and its adoption as the outcome measure for most contemporary MCI-mild AD clinical trials.

Most recently, as we prepared for the development of novel therapeutic agents for the treatment of PD at Biogen, I established a number of external collaborative projects that resulted in the identification and preliminary validation of novel or pre-existing biomarkers for PD clinical trials, and helped lead pre-competitive collaborative efforts to secure regulatory support for the use of dopamine transporter (DaT) imaging as an enrichment biomarker for PD clinical trials.