The power of neuroimaging biomarkers for screening frontotemporal dementia

Abstract

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative disease that can result from either frontotemporal lobar degeneration (FTLD) or Alzheimer’s disease (AD) pathology. It is critical to establish statistically powerful biomarkers that can achieve substantial cost-savings and increase feasibility of clinical trials. We assessed three broad categories of neuroimaging methods to screen underlying FTLD and AD pathology in a clinical FTD series: global measures (e.g., ventricular volume), anatomical volumes of interest (VOIs) (e.g., hippocampus) using a standard atlas, and data-driven VOIs using Eigenanatomy. We evaluated clinical FTD patients (N=93) with cerebrospinal fluid, gray matter (GM) MRI, and diffusion tensor imaging (DTI) to assess whether they had underlying FTLD or AD pathology. Linear regression was performed to identify the optimal VOIs for each method in a training dataset and then we evaluated classification sensitivity and specificity in an independent test cohort. Power was evaluated by calculating minimum sample sizes (mSS) required in the test classification analyses for each model. The data-driven VOI analysis using a multimodal combination of GM MRI and DTI achieved the greatest classification accuracy (89% SENSITIVE; 89% SPECIFIC) and required a lower minimum sample size (N=26) relative to anatomical VOI and global measures. We conclude that a data-driven VOI approach employing Eigenanatomy provides more accurate classification, benefits from increased statistical power in unseen datasets, and therefore provides a robust method for screening underlying pathology in FTD patients for entry into clinical trials.

The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI

“…In general, clinical applicability of task-based fMRI still remains an unresolved issue. Here, machine learning approaches were previously demonstrated to yield higher accuracies with a low minimum sample size [52]. Moreover, resting state analyses outperformed task-based fMRI in a metaanalysis comparing diagnostic classification by machine learning algorithms [21].…”

Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome

“…These studies suggested that on average there is reduced FA in the anterior corpus callosum of FTLD and reduced GM in the precuneus and posterior cingulate of AD. 7,8 While the neuroanatomic distribution of disease that contributed to classification in prior studies could be confounded by the clinical heterogeneity of the samples, the current study observed similar regions contributing to pathologic heterogeneity in a single clinical syndrome. Specifically, anterior corpus callosum WM and precuneus and posterior cingulate GM appear also to differentiate CBS-non-AD and CBS-AD.…”

“…Our findings also converge with 2 studies suggesting that reduced WM integrity in the corpus callosum is associated with CBS 21 and is sensitive and specific for detecting FTLD relative to AD pathology. 7,8 In one prior neuroimaging report of autopsy-confirmed corticobasal degeneration, GM disease was seen in posterior and superior frontal, insula, and supplementary motor regions, and WM disease was seen in the corpus callosum and external capsule. 22 While this study used both GM and WM imaging, this work differs from ours by assessing volumetric measures of WM rather than DTI.…”

“…2,5,6 Multimodal neuroimaging studies suggest that AD and FTLD can be dissociated on the basis of gray matter (GM) and white matter (WM) neuroimaging. 7,8 Specifically, GM atrophy was evident in both AD and FTLD in T1-weighted MRI studies, but diffusion tensor imaging (DTI) revealed more WM disease in FTLD than in AD. Additional neuroimaging evidence suggests that tau pathology, the most common form of underlying pathology in CBS, is associated with substantial WM imaging changes 9 and that these findings converge with neuropathologic evidence of WM disease burden in 4-repeat tauopathy.…”

P1‐196: Frontotemporal Dementia and Psychiatric Illness: Emerging Clinical and Biological Links in Gene Carriers

“…For the patients whose atrophy is too subtle to be identified by eye, quantitative assessment may ultimately be fruitful as quantification of brain structure and function is becoming increasingly fast and reliable. 34,35 Cases 4 and 5 suggest the possibility that neurodegenerative diseases may be associated with an earlier period of destabilized synaptic and neurotransmitter function that presents as a psychiatric disorder (figure 6). 36 The diagnostic considerations in atypical psychiatric syndromes could/should be extended to psychiatric syndromes that respond to treatment.…”