Professor Glenda Halliday
Senior Principal Research Fellow, NHMRC, Professor of Neuroscience, School of Medical Sciences, UNSW and Team Leader, Neuroscience Research Australia, Barker Street, Randwick, NSW
All pharmacological treatments for dementia have failed over the last 20 years due to three main clinical phenotyping factors; 1) significant gaps in knowledge of the nosology and complexity of the different biological forms of dementia, 2) lack of validated biomarkers at entry and end-points, and 3) recruitment and retention of asymptomatic early disease stages .
Differentiating pure proteinopathies in dementia of late life has proven most difficult, due to many elderly having sufficient pathology for more than one type of dementia syndrome. In contrast, dementia in individuals under the age of 65 appears to be more pathologically homogeneous, with the majority of earlier onset cases due to either Alzheimer’s disease (AD) or frontotemporal dementia (FTD). FTD syndromes are an underappreciated cause of dementia and are commonly misdiagnosed as AD even by specialist centres. Pathologically, FTD patients deposit one of three main protein aggregates in their brain, the microtubule associated protein tau (that also forms neurofibrillary tangles in AD), or one of two the DNA/RNA binding proteins, tar DNA-binding protein-43 (TDP43) or, less frequently, fused in sarcoma (FUS).
Compared with AD, few studies have been able to identify a preclinical or early clinical phenotype, a finding which may relate to their more rapid disease course and shorter survival. Our research on FTD patients has identified different clinical and genetic phenotypes that can predict the underlying protein abnormality in the majority of patients.
Comparisons with predicting the underlying proteins in patients with AD will be made. Biomarkers that target the proteins depositing in AD have been developed, but protein targeting biomarkers remain elusive for FTD. Surrogate markers of neurodegeneration seem to hold more promise for the evaluation of biological progression in FTD. Overall, we are now in a position to identify FTD patients with different underlying protein abnormalities and can therefore start appropriate clinical trials.
. Gauthier S, Albert M, Fox N, et al. Why has therapy development for dementia failed in the last two decades? Alzheimers Dement 2016;12:60-4.