Susanne G. Mueller

Ways toward an early diagnosis in Alzheimer's disease: The Alzheimer's Disease Neuroimaging Initiative (ADNI)

With the increasing life expectancy in developed countries, the incidence of Alzheimers disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non‐AD dementias would not benefit from an AD‐specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored. Although there currently is no ideal biomarker that would fulfill all these requirements, there is increasing evidence that a combination of currently existing neuroimaging and cerebrospinal fluid (CSF) and blood biomarkers can provide important complementary information and thus contribute to a more accurate and earlier diagnosis of AD. The Alzheimers Disease Neuroimaging Initiative (ADNI) is exploring which combinations of these biomarkers are the most powerful for diagnosis of AD and monitoring of treatment effects.

Measurement of hippocampal subfields and age-related changes with high resolution MRI at 4T.

Histological studies suggest that hippocampal subfields are differently affected by aging and Alzheimer’s disease (AD). The aims of this study were: (1) To test if hippocampal subfields can be identified and marked using anatomical landmarks on high resolution MR images obtained on a 4T magnet. (2) To test if age-specific volume changes of subfields can be detected. Forty-two healthy controls (21–85 years) and three AD subjects (76–86 years) were studied with a high resolution T2 weighted fast spin echo sequence. The entorhinal cortex (ERC), subiculum, CA1, CA2 and CA3/4 and dentate were marked. A significant correlation between age and CA1 (r = −0.51, p = 0.0002) which was most pronounced in the seventh decade of life was found in healthy controls. In AD subjects, CA1 and subiculum were smaller than in age-matched controls. These preliminary findings suggest that measurement of hippocampal subfields may be helpful to distinguish between normal aging and AD.

Hippocampal atrophy patterns in mild cognitive impairment and Alzheimer's disease

Histopathological studies and animal models suggest that hippocampal subfields may be differently affected by aging, Alzheimers disease (AD), and other diseases. High‐resolution images at 4 Tesla depict details of the internal structure of the hippocampus allowing for in vivo volumetry of different subfields. The aims of this study were as follows: (1) to determine patterns of volume loss in hippocampal subfields in normal aging, AD, and amnestic mild cognitive impairment (MCI). (2) To determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for differentiation between groups.

Magnetic Resonance Imaging of Hippocampal Subfields in Posttraumatic Stress Disorder

CONTEXT Most neuroimaging studies of posttraumatic stress disorder (PTSD) have focused on potential abnormalities in the whole hippocampus, but the subfields of this structure, which have distinctive histological characteristics and specialized functions, have not been investigated. Studies of individual subfields may clarify the role of the hippocampus in PTSD. OBJECTIVE To determine if PTSD is associated with structural alterations in specific subfields of the hippocampus. DESIGN Case-control study. PARTICIPANTS A total of 17 male veterans with combat trauma and PTSD (mean [SD] age, 41 [12] years) and 19 age-matched male veterans without PTSD who were recruited from the outpatient mental health clinic of the San Francisco Veterans Affairs Medical Center and by advertising in the community. INTERVENTIONS High-resolution magnetic resonance imaging at 4 T. MAIN OUTCOME MEASURE Volumes of hippocampal subfields. RESULTS Posttraumatic stress disorder was associated with 11.4% (1.5%) (P = .02) smaller mean (SD) cornu ammonis 3 (CA3)/dentate gyrus subfield volumes, irrespective of age-related alterations, whereas other subfields were spared. Age was associated with reduced volume of the CA1 subfield (P = .03). Total hippocampal volume was also reduced in PTSD by a mean (SD) of 6.5% (0.6%) but, related to both PTSD (P = .05) and age (P = .01), was consistent with the measurements in the subfields. CONCLUSIONS The findings indicate for the first time in humans that PTSD is associated with selective volume loss of the CA3/dentate gyrus subfields, consistent with animal studies, implying that chronic stress suppresses neurogenesis and dendritic branching in these structures.

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: Towards a harmonized segmentation protocol

OBJECTIVE An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Patterns of altered cortical perfusion and diminished subcortical integrity in posttraumatic stress disorder: an MRI study.

Posttraumatic stress disorder (PTSD) accounts for a substantial proportion of casualties among surviving soldiers of the Iraq and Afghanistan wars. Currently, the assessment of PTSD is based exclusively on symptoms, making it difficult to obtain an accurate diagnosis. This study aimed to find potential imaging markers for PTSD using structural, perfusion, and diffusion magnetic resonance imaging (MRI) together. Seventeen male veterans with PTSD (45 ± 14 years old) and 15 age-matched male veterans without PTSD had measurements of regional cerebral blood flow (rCBF) using arterial spin labeling (ASL) perfusion MRI. A slightly larger group had also measurements of white matter integrity using diffusion tensor imaging (DTI) with computations of regional fractional anisotropy (FA). The same subjects also had structural MRI of the hippocampal subfields as reported recently (W. Zhen et al. Arch Gen Psych 2010;67(3):296-303). On ASL-MRI, subjects with PTSD had increased rCBF in primarily right parietal and superior temporal cortices. On DTI, subjects with PTSD had FA reduction in white matter regions of the prefrontal lobe, including areas near the anterior cingulate cortex and prefrontal cortex as well as in the posterior angular gyrus. In conclusion, PTSD is associated with a systematic pattern of physiological and structural abnormalities in predominantly frontal lobe and limbic brain regions. Structural, perfusion, and diffusion MRI together may provide a signature for a PTSD marker.

Widespread Neocortical Abnormalities in Temporal Lobe Epilepsy With And Without Mesial Sclerosis

PURPOSE Extrafocal structural abnormalities have been consistently described in temporal lobe epilepsy (TLE) with mesial temporal lobe sclerosis (TLE-MTS). In TLE without MTS (TLE-no) extrafocal abnormalities are more subtle and often require region of interest analyses for their detection. Cortical thickness measurements might be better suited to detect such subtle abnormalities than conventional whole brain volumetric techniques which are often negative in TLE-no. The aim of this study was to seek and characterize patterns of cortical thinning in TLE-MTS and TLE-no. METHODS T1 weighted whole brain images were acquired on a 4 T magnet in 66 subjects (35 controls, 15 TLE-MTS, 16 TLE-no). Cortical thickness measurements were obtained using the FreeSurfer software routine. Group comparisons and correlation analyses were done using the statistical routine of FreeSurfer (FDR, p=0.05). RESULTS TLE-MTS and TLE-no showed both widespread temporal and extratemporal cortical thinning. In TLE-MTS, the inferior medial and posterior temporal regions were most prominently affected while lateral temporal and opercular regions were more affected in TLE-no. The correlation analysis showed a significant correlation between the ipsilateral hippocampal volume and regions of thinning in TLE-MTS and between inferior temporal cortical thickness and thinning in extratemporal cortical regions in TLE-no. CONCLUSION The pattern of thinning in TLE-no was different from the pattern in TLE-MTS. This finding suggests that different epileptogenic networks could be involved in TLE-MTS and TLE and further supports the hypothesis that TLE-MTS and TLE-no might represent two distinct TLE syndromes.

Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T

BACKGROUND Details of the internal hippocampal structure visible at 4 T allow for in vivo volumetry of subfields. The aims of this study were: 1. To determine if Apo e4 has subfield specific effects in controls. 2. To study the influence of Apo e4 on hippocampal subfields in AD. METHODS 81 subjects (66 controls, mean age 60.8+/-13.6, range: 28-85 years), and 15 AD (mean age 67.5+/-9.3) were studied. Entorhinal cortex, subiculum, CA1, CA1-CA2 transition zone, CA3-4 and dentate gyrus (CA3&DG) and total hippocampal volume were determined using a manual marking strategy. RESULTS Significant effects for Apo e4 on the CA3&DG were found in the total control population (p=0.042) and in older controls (61-85 years) (p=0.036) but not in younger (28-60 years) controls. Significant effects for Apo e4 (p=0.0035) on CA3&DG were also found in a subgroup of older subjects and AD subjects. AD with Apo e4 had smaller CA3&DG than AD without Apo e4 (p=0.027). CONCLUSIONS These findings suggest that Apo e4 exerts a regionally selective effect on CA3&DG in normal aging and AD.

Brain glutathione levels in patients with epilepsy measured by in vivo 1H-MRS

Objective: Glutathione in its reduced form (GSH) is the most important free radical scavenging compound in the mammalian nervous system that prevents membrane lipid peroxidation. It is suspected that epileptic seizures are accompanied by a massive production of reactive oxygen species, i.e., oxidative stress. Methods: Using an 1H MRS technique developed at the authors’ site, the authors measured glutathione levels in a volume of interest (VOI) of 25 × 25 × 25 mm placed in structurally normal-appearing tissue in the parietooccipital region of each hemispheres in patients with and without active epilepsy, and in a age-matched control group. Results: The GSH/water ratio in patients with epilepsy was significantly reduced in the parietooccipital region of both hemispheres (1.6 ± 1.0 × 10−5) compared to the GSH/water ratio in healthy controls (2.4 ± 1.1 × 10−5). There was no significant difference between the hemisphere with epileptogenic focus and the hemisphere without epileptogenic focus. The GSH/water ratios of the patients without active epilepsy were not different from the GSH/water ratios of patients with active epilepsy. Conclusion: The authors found evidence for a widespread impairment of the glutathione system in patients with epilepsy independent from seizure activity.

Advances in neuroimaging of traumatic brain injury and posttraumatic stress disorder

Improved diagnosis and treatment of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are needed for our military and veterans, their families, and society at large. Advances in brain imaging offer important biomarkers of structural, functional, and metabolic information concerning the brain. This article reviews the application of various imaging techniques to the clinical problems of TBI and PTSD. For TBI, we focus on findings and advances in neuroimaging that hold promise for better detection, characterization, and monitoring of objective brain changes in symptomatic patients with combat-related, closed-head brain injuries not readily apparent by standard computed tomography or conventional magnetic resonance imaging techniques.