New treatments that target the protein tau, a neuronal scaffolding protein that accumulates in neurodegenerative diseases including Alzheimer's (AD), are rapidly entering human clinical trials. Increasingly, clinical trials of such tau therapies are focusing on pure tauopathies, or disorders in which tau is causally- or strongly-linked to the underlying pathology in the absence of other toxic proteins such as beta amyloid. Pure tauopathies include corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and some variants of frontotemporal lobar degeneration (FTLD). Because CBD and PSP are clinically similar and share a common 4 microtubule binding repeat (4R) tau molecular pathology, clinical trials focused on these disorders may have better potential to demonstrate efficacy of tau-directed therapies than studies of more pathologically heterogeneous disorders such as AD and FTLD. However, new biomarkers are needed to assess the biological effects of tau-directed therapies in such 4R tauopathy human clinical trials. The most advanced biomarkers have been developed for AD clinical trials as part of the AD Neuroimaging Initiative (ADNI), and recently, a new project to develop similar measurements for FTLD (the FTLDNI) was funded. The overall goal of the project is to determine the most precise clinical, neuroimaging and biomarker methods for quantification of disease progression in 4R tauopathies for planning future phase II and III clinical trials. Taking advantage of the FTLDNI infrastructure already in place at UCSF, the proposed project will recruit 40 CBD subjects and 40 PSP subjects, and study each subject for one year using a combination of clinical measurements, fluid biomarkers and 3T MRI scans. Data from 120 normal control subjects acquired in parallel as part of the FTLDNI will be used for comparison. Individuals will undergo longitudinal clinical, oculomotor and MRI measurements at baseline, 6 and 12 months, as well as blood and CSF biomarker measurements at baseline and 12 months.
The specific aims of the study are to 1) determine the most precise clinical rating scales for quantification of disease progression in 4R tauopathies;2) identify which regions show the greatest longitudinal change in brain volume and cerebral perfusion;3) identify the brain networks in which structural connectivity changes with disease progression;4) quantify the longitudinal changes in saccade function in 4R tauopathies, 5) identify the neuroimaging correlates of longitudinal changes in motor and cognitive function, and activities of daily living in 4R tauopathies, and 6) quantify the longitudinal changes in Abeta42, CSF tau, phospho-tau and tau isoform ratios with disease progression. Should these aims be achieved, the proposed study would provide firm data about the best clinical, imaging and fluid biomarkers for following the course of disease in CBD and PSP, whether trials that combine CBD and PSP are feasible, and provide estimates from which power could be estimated for future clinical trials. All the data will eventually be available in a publicly accessible database for use by other researchers.
TO PUBLIC HEALTH New drugs that target tau, a neuronal protein that is dysfunctional and accumulates in Alzheimer's disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), are entering human clinical trials, however the best methods for assessing whether these drugs are effective have not yet been established. This project will study the 4R Tauopathies, CBD and PSP, because there are no effective treatments for these disorders and they are more likely to respond to tau-directed therapies than AD. The data generated from this project will allow researchers to design better clinical trials to test the efficacy of new tau- directed drugs in humans.
|Wagshal, Dana; Sankaranarayanan, Sethu; Guss, Valerie et al. (2015) Divergent CSF ? alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 86:244-50|
|Li, Yun; Chen, Jason A; Sears, Renee L et al. (2014) An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy. PLoS Genet 10:e1004211|
|Scherling, Carole S; Hall, Tracey; Berisha, Flora et al. (2014) Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration. Ann Neurol 75:116-26|
|Woolley, Josh D; Khan, Baber K; Natesan, Alamelu et al. (2014) Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia. Neurology 82:512-20|
|Mohlenhoff, Brian S; Chao, Linda L; Buckley, Shannon T et al. (2014) Are hippocampal size differences in posttraumatic stress disorder mediated by sleep pathology? Alzheimers Dement 10:S146-54|
|Boxer, Adam L; Lang, Anthony E; Grossman, Murray et al. (2014) Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol 13:676-85|
|Pa, Judy; Dutt, Shubir; Mirsky, Jacob B et al. (2014) The functional oculomotor network and saccadic cognitive control in healthy elders. Neuroimage 95:61-8|
|Sanchez-Juan, Pascual; Ghosh, Pia M; Hagen, Jayne et al. (2014) Practical utility of amyloid and FDG-PET in an academic dementia center. Neurology 82:230-8|
|Lee, Suzee E; Khazenzon, Anna M; Trujillo, Andrew J et al. (2014) Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain 137:3047-60|
|Tsai, Richard M; Boxer, Adam L (2014) Clinical trials: past, current, and future for atypical Parkinsonian syndromes. Semin Neurol 34:225-34|
Showing the most recent 10 out of 26 publications