Frontotemporal dementia refers to a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The effects of these proteins in the brain are complex, and each can present with several different clinical syndromes. Clinical efficacy trials of drugs targeting these proteins must use endpoints that are meaningful to all participants despite the variability in symptoms across patients. There are many candidate clinical measures, including neuropsychological scores and functional measures. Brain imaging is another potentially attractive outcome that can be precisely quantified and provides evidence of disease modification. Most imaging studies in frontotemporal dementia have been cross-sectional, and few have compared longitudinal changes in cortical volume with changes in other measures such as perfusion and white matter integrity. The current study characterized longitudinal changes in 161 patients with three frontotemporal dementia syndromes: behavioural variant frontotemporal dementia (n = 77) and the semantic (n = 45) and non-fluent (n = 39) variants of primary progressive aphasia. Visits included comprehensive neuropsychological and functional assessment, structural MRI (3 T), diffusion tensor imaging, and arterial spin labelled perfusion imaging. The goal was to identify measures that are appropriate as clinical trial outcomes for each group, as well as those that might be appropriate for trials that would include more than one of these groups. Linear mixed effects models were used to estimate changes in each measure, and to examine the correlation between imaging and clinical changes. Sample sizes were estimated based on the observed effects for theoretical clinical trials using bootstrapping techniques to provide 95% confidence intervals for these estimates. Declines in functional and neuropsychological measures, as well as frontal and temporal cortical volumes and white matter microstructure were detected in all groups. Imaging changes were statistically significantly correlated with, and explained a substantial portion of variance in, the change in most clinical measures. Perfusion and diffusion tensor imaging accounted for variation in clinical decline beyond volume alone. Sample size estimates for atrophy and diffusion imaging were comparable to clinical measures. Corpus callosal fractional anisotropy led to the lowest sample size estimates for all three syndromes. These findings provide further guidance on selection of trial endpoints for studies in frontotemporal dementia and support the use of neuroimaging, particularly structural and diffusion weighted imaging, as biomarkers. Diffusion and perfusion imaging appear to offer additional utility for explaining clinical change beyond the variance explained by volume alone, arguing for considering multimodal imaging in treatment trials.

IntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial‐frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non–mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self‐monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial‐frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

IntroductionSome models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset.MethodsWe created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate‐adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor.ResultsCross‐validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]).DiscussionIndividualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

According to the cognitive reserve theory, intellectual stimuli acquired during life can prevent against developing cognitive impairment. The underlying cognitive reserve mechanisms were underexplored in low-educated individuals. Because episodic memory impairment due to hippocampal dysfunction is a key feature of Alzheimer’s dementia (AD), we sought to look at a possible cognitive reserve mechanism by determining whether few years of education moderated the relationship between the hippocampal volumes and the episodic-memory scores. The sample was composed by 183 older adults, 40.1% male, with the median age of 78[76,82] years and the median years of education of 4[2,10] who had undergone an episodic-memory test and a 3-Tesla MRI scan to access the hippocampal volumes. Overall, 112 were cognitively healthy, 26 had cognitive impairment-no dementia (CIND) and 45 had dementia. We used multiple linear regression to assess whether the interaction between years of education and each hippocampal volume significantly predicted the episodic-memory scores’ variance, controlling for cognitive diagnosis and nuisance variables. The interaction term with the left hippocampus (ß = 0.2, p = 0.043, CI = 1.0, 1.4), but not with the right (ß = 0.1, p = 0.218, CI = 0.9, 1.2) significantly predicted the variation on memory scores. The mechanism by which the left hippocampus seems to play a more important role on memory processing in more educated individuals needs to be further investigated and might be associated with a better use of mnemonic strategies or higher hippocampal connectivity. Because the sample’s median years of education was four, which corresponds to primary school, we may infer that this level might be sufficient to contribute for building cognitive reserve.