Profile. Howard Feldman: master of dementia.

Profi le Howard Feldman: master of dementia Throughout his career, Howard Feldman has contributed to the characterisation of the natural history of the dementias, but he has also been involved in clinical trials and research on biomarkers, including his work on melanotransferrin and within the Alzheimer's Disease Neuroimaging Initiative. More recently, he was part of a research team that showed that patients with frontotemporal dementia (FTD) who have ubiquitin-immunoreactive neuronal cytoplasmic inclusions (FTDU-17) had mutations in the progranulin gene, a fi nding that caused great excitement among molecular geneticists working on dementia. " A seminal contribution to that paper began with the recognition that there was a condition that causes FTD that was associated with a particular pathology—the intranuclear inclusions " , recalls Feldman. " When we went back to our clinical material we discovered that it most often had an autosomal-dominant pattern of inheritance. " At that point, Feldman and his group did not have a research grant to pursue this discovery further. Together with his co-principal investigator Ian Mackenzie, resources were pooled from existing research accounts to hire a research coordinator to begin the onerous work of developing the pedigree and establishing the DNA samples for linkage and molecular analysis. " For 12 to 18 months I would see Caroline Lindholm our coordinator at a distance down a corridor. To be honest I wasn't sure what kind of progress we were making until she came to a research meeting and rolled out this 18 page pedigree that is ultimately the family that we found the gene on. " It was around that time that Feldman's group started to collaborate with Mike Hutton's team at the Mayo Clinic in Jacksonville, which did the molecular genetics. " You can't underestimate how involved these things are—there was an enormous amount of fi eldwork to be done to gather all the information on all the relatives before we could even start sequencing genes " , he says. Virginia Lee, who works at the University of Pennsylvania, then contacted Mackenzie and Feldman to ask for access to the bank of tissue samples from patients with FTD that the University of British Columbia had built up over the years. Lee was able to identify the protein within the intranuclear inclusions as TDP-43. " That fi nding had even broader implications—identifying a proteinopathy that is behind FTD and amyotrophic lateral sclerosis " , says Feldman, …