With or without FUS, it is the anatomy that dictates the dementia phenotype

Not so long ago, Alois Alzheimer's dominance over Arnold Pick appeared total and irreversible. Alzheimer's disease was placed at the helm of a global pandemic whilst Pick's disease was declared a rare curiosity and other non-Alzheimer dementias faced the embarrassment of lacking distinctive histopathology. How rapidly things change! We now know that the family of frontotemporal lobar degenerations (FTLDs), which includes Pick's disease, is arguably the most important cause of pre-senescent dementia; that its hereditary forms can be transmitted through mutations in the tau or progranulin ( PGRN ) genes; and that the abnormal protein accumulations include hyperphosphorylated tau and the TAR DNA binding protein TDP-43 (Arai et al. , 2006; Bigio, 2008; Boeve and Hutton, 2008; Josephs, 2008; Neumann et al. , 2006).Despite this relatively rapid progress over the past 15 years, there still remain FTLD cases either having non-specific ubiquitin deposits or lacking distinctive inclusions. One of these lingering pockets of resistance now appears to have yielded to the work of Mackenzie and colleagues (Mackenzie et al. , 2009). In this issue of Brain , these investigators report that 100% of their FTLD cases with heretofore uncharacterized ubiquitin inclusions harbour abnormal accumulations of the ‘fused in sarcoma’ (FUS) product, a protein also recently linked to amyotrophic lateral sclerosis (Kwiatkowski et al. , 2009; Vance et al. , 2009).The addition of FUS to the FTLD landscape gives neuropathologists and geneticists additional cause for celebration. But what about clinicians who see patients rather than stained brain slices? Can they use this new knowledge to infer the nature of the pathology at the bedside? Conversely, is there a straight path from molecular pathology to cognition, so that a disease-specific blood or cerebrospinal fluid biomarker may in time prove as informative for clinical deficits as …