Efficacy of future treatments depends on biomarkers identifying patients with mild cognitive impairment at highest risk for transitioning to Alzheimer's disease. Here, we applied recently developed analysis techniques to investigate cross-sectional differences in subcortical shape and volume alterations in patients with stable mild cognitive impairment (MCI) (n = 23, age range 59–82, 47.8% female), future converters at baseline (n = 10, age range 66–84, 90% female) and at time of conversion (age range 68–87) compared to group-wise age and gender matched healthy control subjects (n = 23, age range 61–81, 47.8% female; n = 10, age range 66–82, 80% female; n = 10, age range 68–82, 70% female). Additionally, we studied cortical thinning and global and local measures of hippocampal atrophy as known key imaging markers for Alzheimer's disease. Apart from bilateral striatal volume reductions, no morphometric alterations were found in cognitively stable patients. In contrast, we identified shape alterations in striatal and thalamic regions in future converters at baseline and at time of conversion. These shape alterations were paralleled by Alzheimer's disease like patterns of left hemispheric morphometric changes (cortical thinning in medial temporal regions, hippocampal total and subfield atrophy) in future converters at baseline with progression to similar right hemispheric alterations at time of conversion. Additionally, receiver operating characteristic curve analysis indicated that subcortical shape alterations may outperform hippocampal volume in identifying future converters at baseline. These results further confirm the key role of early cortical thinning and hippocampal atrophy in the early detection of Alzheimer's disease. But first and foremost, and by distinguishing future converters but not patients with stable cognitive abilities from cognitively normal subjects, our results support the value of early subcortical shape alterations and reduced hippocampal subfield volumes as potential markers for the early detection of Alzheimer's disease.

Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer's disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n = 16) to healthy subjects (CS, n = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate "classical" cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD.

Aβ deposition is a driving force of Alzheimer's disease pathology and can be detected early by amyloid positron emission tomography. Identifying presymptomatic structural brain changes associated with Aβ deposition might lead to a better understanding of its consequences and provide early diagnostic information. In this respect we analyzed measures of cortical thickness and subcortical volumes along with hippocampal, thalamic and striatal shape and surface area by applying novel analysis strategies for structural magnetic resonance imaging. We included 69 cognitively normal elderly subjects after careful clinical and neuropsychological workup. Standardized uptake value ratios (cerebellar reference) for uptake of 11-C-Pittsburgh Compound B (PiB) were calculated from positron emission tomographic data for a cortical measurement and for bilateral hippocampus, thalamus and striatum. Associations to shape, surface area, volume and cortical thickness were tested using regression models that included significant predictors as covariates. Left anterior hippocampal shape was associated with regional PiB uptake (P < 0.05, FDR corrected), whereas volumes of the hippocampi and their subregions were not associated with cortical or regional PiB uptake (all P > 0.05, FDR corrected). Within the entorhinal cortical region of both hemispheres, thickness was negatively associated with cortical PiB uptake (P < 0.05, FDR corrected). Hence, localized shape measures and cortical thickness may be potential biomarkers of presymptomatic Alzheimer's disease.

Mild traumatic brain injury (mTBI) affects a large number of individuals and diffusion tensor imaging can be used to investigate microstructural integrity of brain tissue after mTBI. However, results have varied considerably between studies and gray matter (GM) integrity has been largely neglected in these investigations. Given impaired working memory processing after mTBI and its possible association with Alzheimer's disease, we investigated hippocampal integrity and parcellated this structure into five subregions: subiculum, cornu ammonis (CA) 1, CA 2/3, CA 4/dentate gyrus, and stratum radiatum/lacunosum-moleculare. We also employed shape analysis of bilateral hippocampi to explore whether morphological changes had occurred due to the traumatic injury and conducted neuropsychological memory tests. The sample comprised 15 subjects with mTBI (18-55 years, nine female) and 13 age- and sex-matched healthy control subjects (19-57 years, nine female). Voxelwise analyses showed significantly increased mean diffusivity in patients, compared with controls, in the right hippocampus and three of its five subregions (family-wise error corrected p < 0.05). Additionally, results from probabilistic tractography indicated impaired CA 1 connectivity after mTBI (Benjamini-Hochberg false discovery rate [FDR] corrected p < 0.05). Shape of bilateral hippocampi did not significantly differ between groups (Benjamini-Hochberg FDR corrected p > 0.05). Subjects with mTBI reported more symptoms and performed worse in a non-standard verbal working memory task. Based on these preliminary findings, we were able to demonstrate altered diffusivity of hippocampal subregions following mTBI, indicating impaired GM microstructural integrity. These differences highlight the potential of diffusion imaging for investigation of subtle yet relevant changes in GM microstructure not detected otherwise following mTBI.