Brainstem Dysfunction in Healthy Aging.

The brainstem controls sub-cortical and cortical activity and influences the processing of incoming information. The goal of this study was to characterize age related alterations of brainstem-brain interactions during different brain states detected by dynamic analysis of task-free fMRI. 79 young (20-40 years) and 51 older adults (55-80 years) were studied. Internal brainstem structures were segmented using a new multi-contrast segmentation approach. Brain and brainstem gray matter segmentations were warped onto a population template. The ICV-corrected Jacobian determinants were converted into z-score maps and the means from 420 cortical/subcortical/brainstem rois extracted. The fMRI was preprocessed in SPM12/Conn18 and the BOLD signal from 420 cortical/subcortical/brainstem rois extracted. A dynamic task-free analysis approach based on hierarchical cluster analysis was used to identify 15 brain states that were characterized using graph analysis (strength, diversity, modularity). Kruskal-Wallis tests and Spearman correlations were used for statistical analysis. One brain state (cluster 21) occurred more often in older adults (p=0.008). It was characterized by a lower mean modular strength and brainstem-cortical strength in older adults compared to younger adults. Global age related gray matter differences were positively correlated with brain state 21's modular strength. Furthermore, brain state 21 duration was negatively correlated with working memory (r = -0.28, p=0.002). The findings suggest an age related weakening of the within and between network synchronization at the brainstem level during brain state 21 in older adults that negatively affects cortical and subcortical synchronization and working memory performance.

A (Sub)field Guide to Quality Control in Hippocampal Subfield Segmentation on Highresolution T2-weighted MRI.

Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health.

Evidence for functional specialization of hippocampal subfields detected by MR subfield volumetry on high resolution images at 4 T.

Animal studies suggest an involvement of CA3 and dentate gyrus (CA3&DG) in memory encoding and early retrieval and an involvement of CA1 in late retrieval, consolidation and recognition. The aim of this study was to test if similar associations could be found between hippocampal subfield volumes measured in vivo using a manual parcellation scheme and selected scores of the California Verbal Learning Test II (CVLTII): total immediate free recall discriminability (IFRD), short free recall discriminability (SFRD), and delayed recall discriminability (DRD). 50 elderly subjects (25 controls and 25 cognitively impaired subjects) had CVLTII and high resolution hippocampal MRI at 4T. Entorhinal cortex, subiculum, CA1, CA1-CA2 transition zone, and CA3&DG were manually marked on five slices in the anterior hippocampal body on the MRI. Pearson correlations followed by stepwise regression analysis were used to test for associations between subfield volumes and CVLTII. IFRD and SFRD, which are measures of encoding/early retrieval, were associated with CA3&DG, and DRD, which measures consolidation/late retrieval, with CA1. These preliminary findings demonstrate that subfield volumetry has the potential to study non invasively subfield specific memory functions.

Network-level analysis of cortical thickness of the epileptic brain.

Temporal lobe epilepsy (TLE) characterized by an epileptogenic focus in the medial temporal lobe is the most common form of focal epilepsy. However, the seizures are not confined to the temporal lobe but can spread to other, anatomically connected brain regions where they can cause similar structural abnormalities as observed in the focus. The aim of this study was to derive whole-brain networks from volumetric data and obtain network-centric measures, which can capture cortical thinning characteristic of TLE and can be used for classifying a given MRI into TLE or normal, and to obtain additional summary statistics that relate to the extent and spread of the disease. T1-weighted whole-brain images were acquired on a 4-T magnet in 13 patients with TLE with mesial temporal lobe sclerosis (TLE-MTS), 14 patients with TLE with normal MRI (TLE-no), and 30 controls. Mean cortical thickness and curvature measurements were obtained using the FreeSurfer software. These values were used to derive a graph, or network, for each subject. The nodes of the graph are brain regions, and edges represent disease progression paths. We show how to obtain summary statistics like mean, median, and variance defined for these networks and to perform exploratory analyses like correlation and classification. Our results indicate that the proposed network approach can improve accuracy of classifying subjects into two groups (control and TLE) from 78% for non-network classifiers to 93% using the proposed approach. We also obtain network "peakiness" values using statistical measures like entropy and complexity-this appears to be a good characterizer of the disease and may have utility in surgical planning.

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.

Transforming growth factor alpha in arterioles: cell surface processing of its precursor by elastases.

Analysis of the transforming growth factor alpha (TGF alpha) cDNA predicts that the mature TGF alpha polypeptide is cleaved from the extracellular domain of its precursor, which is an integral membrane protein. Furthermore, the cleavage sites for the release of this mitogen are compatible with the participation of an elastaselike protease. We have immunohistochemically localized TGF alpha to the vascular smooth muscle cells in the arterioles. To investigate whether polymorphonuclear (PMN) leukocytic elastase, a blood-borne protease, could process the cell surface TGF alpha, NR6 cells were transfected with the rat TGF alpha cDNA. The cDNA encoded the entire open reading frame, and its expression was under the control of the mouse metallothionein I promoter. A cloned transfectant, termed 1B2, synthesized the TGF alpha precursor in a zinc-inducible manner, and the precursor was localized to the cell surface. Western blot (immunoblot) analysis indicated that treatment of the zinc-induced 1B2 cells with either PMN leukocytic or pancreatic elastase resulted in the release of the mature TGF alpha polypeptide. The released TGF alpha was bioactive, as it was capable of both competing with epidermal growth factor for binding to its receptor and stimulating [3H]thymidine incorporation in the mitogenic assay. Formaldehyde fixation of the 1B2 cells eliminated basal release of TGF alpha but allowed normal processing by both PMN leukocytic and pancreatic elastase to occur. However, human cathepsin G, bovine pancreatic alpha 1-chymotrypsin, collagenase, trypsin, subtilisin, and plasmin failed to release any detectable fragments of the TGF alpha precursor from the fixed cells. The location of TGF alpha in the arterioles and ability of PMN leukocytic elastase to process the membrane-bound TGF alpha precursor suggests a novel role for this elastase at the wound site.

Transient epileptic opercular syndrome.

Ictal transient opercular syndrome is rarely observed in benign epilepsy with centro-temporal spikes in children, and even more rarely in epilepsia partialis continua and symptomatic focal status epilepticus in adults. Here we report the ictal and interictal neuroimaging and electrophysiological findings in an adult female suffering from discontinuous focal status epilepticus presenting as a transient opercular syndrome. This patient was unusual insofar as the discharges were strictly unilateral, i.e., that even with extensive neuroimaging no structural abnormalities could be found.

Metabolic characteristics of cortical malformations causing epilepsy.

PURPOSE: Cortical malformations (CMs) are increasingly recognized as the epileptogenic substrate in patients with medically refractory neocortical epilepsy (NE). The aim of this study was to test the hypotheses that: 1. CMs are metabolically heterogeneous. 2. The structurally normal appearing perilesional zone is characterized by similar metabolic abnormalities as the CM. METHODS: Magnetic resonance spectroscopic imaging (MRSI) in combination with tissue segmentation was performed on eight patients with NE and CMs and 19 age matched controls. In controls, NAA, Cr, Cho,NAA/Cr and NAA/Cho of all voxels of a given lobe were expressed as a function of white matter content and thresholds for pathological values determined by calculating the 95% prediction intervals. These thresholds were used to identify metabolically abnormal voxels within the CM and in the perilesional zone. RESULTS: 30% of all voxels in the CMs were abnormal, most frequently because of decreases of NAA or increases of Cho. Abnormal voxels tended to form metabolically heterogeneous clusters interspersed in metabolically normal regions. Furthermore, 15% of all voxels in the perilesional zone were abnormal, the most frequent being decreases of NAA and Cr. CONCLUSION: In CMs metabolically normal regions are interspersed with metabolically heterogeneous abnormal regions. Metabolic abnormalities in the perilesional zone share several characteristics of CMs and might therefore represent areas with microscopic malformations and/or intrinsic epileptogenicity.

Transforming growth factor-beta (TGF beta) inhibits TGF alpha expression in bovine anterior pituitary-derived cells.

Transforming growth factor-beta 1 (TGF beta 1) is a multifunctional regulator of cell growth and differentiation. We report here that TGF beta 1 decreased the proliferation of nontransformed bovine anterior pituitary-derived cells grown in culture. We have previously demonstrated that these cells express both TGF alpha and its receptor [the epidermal growth factor (EGF) receptor] and that expression can be stimulated by phorbol ester (TPA) and EGF. TGF beta 1 treatment over a 2-day period decreased the proliferation of pituitary cells. This decreased growth rate was accompanied by a decrease in the TGF alpha mRNA level. The effect of TGF beta 1 on TGF alpha mRNA down-regulation was both dose dependent (maximal effect observed at 1.0 ng/ml TGF beta 1) and time dependent (minimum of 2-day treatment with TGF beta 1 was required before a decrease in TGF alpha mRNA was observed). Studies on TGF alpha mRNA stability indicated that TGF beta 1 did not alter the TGF alpha mRNA half-life. Treatment of the TGF beta 1 down-regulated cells with EGF resulted in the stimulation of TGF alpha mRNA levels; thus, the TGF beta 1-treated cells remained responsive to EGF. The decreased proliferation in response to TGF beta 1 could be only partially reversed by simultaneous treatment of the cells with EGF (10(-9)M) and TGF beta 1 (3.0 ng/ml). Qualitatively, the TGF beta 1-induced reduction of TGF alpha mRNA content was independent of cell density. TGF beta 1 treatment of the anterior pituitary-derived cells also reduced the levels of c-myc and EGF receptor mRNA. These results represent the first demonstration of the down-regulation of TGF alpha synthesis by a polypeptide growth factor and suggest that TGF beta 1 may be a physiological regulator of TGF alpha production in vivo.

Transforming growth factor-alpha expression in the anterior pituitary gland: regulation by epidermal growth factor and phorbol ester in dispersed cells.

We have previously reported the immunohistochemical localization of transforming growth factor-alpha (TGF alpha) in the intact bovine anterior pituitary gland. Furthermore, we have purified TGF alpha from the conditioned medium of cell cultures derived from the bovine anterior pituitary. We report her the identification of the TGF alpha mRNA from both the intact bovine anterior pituitary gland and the anterior pituitary derived cell cultures. The level of TGF-alpha mRNA in the cell cultures is greater than that present in the intact gland. The TGF-alpha mRNA level increased when the cell cultures were allowed to incubate in their conditioned medium for 3 days, suggesting that a secretory product from the cultured cells is capable of stimulating the accumulation of the TGF-alpha mRNA. 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation of these cells resulted in a 6-fold increase in the level of TGF-alpha secreted into the conditioned medium. TPA appears to stimulate TGF-alpha secretion at the level of gene transcription as TPA treatment also resulted in an increased accumulation of the TGF-alpha mRNA. The epidermal growth factor (EGF) receptor mRNA was examined in these cell cultures and it increased with TPA treatment in an analogous manner to the TGF-alpha mRNA. EGF treatment of the pituitary cells resulted in an increased level of TGF-alpha mRNA which followed the same time course as TPA, maximal stimulation occurred after 8 h of treatment. The magnitude of EGF stimulated TGF-alpha mRNA was not as great as that seen by TPA stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine receptor activation inhibits estrogen-stimulated transforming growth factor-alpha gene expression and growth in anterior pituitary, but not in uterus.

Transforming growth factor-alpha (TGF alpha) has been localized to the anterior pituitary, specifically to the lactotroph and somatotroph cell populations, by our previous studies. Since pituitary lactotrophs are known to undergo growth in response to estrogens, we have used an estradiol-induced pituitary hyperplasia/adenoma model. Estradiol treatment resulted in induction of TGF alpha mRNA in anterior pituitary, evident by 48 h, preceding actual macroscopic growth, which attained a maximum greater than 500% by 12 weeks. This rapid effect of estradiol also enhanced PRL mRNA, but did not affect other species of mRNA encoding for proenkephalin, D2 receptor mRNA, or hexosaminidase-A. TGF alpha mRNA remained elevated for the duration of rapid pituitary growth. D2 receptor activation by its agonist bromocriptine resulted in marked attenuation of TGF alpha mRNA preceding regression of growth. Coadministration of bromocriptine with estradiol resulted in an involution of pituitary size, indicating the overriding influence of dopamine in spite of a continued estrogenic stimulus. Epidermal growth factor receptor mRNA was not affected by any of these manipulations, suggesting that the receptor was not coregulated in this tissue similarly to TGF alpha. Estradiol also induced uterine TGF alpha mRNA and marked growth of the organ, but TGF alpha in this location was not regulated by dopamine. These results indicate that TGF alpha in the anterior pituitary is rapidly induced by estrogen in a time course preceding the growth of the gland. Estrogen-induced TGF alpha is rapidly attenuated by D2 dopamine receptor activation and is accompanied by a regression of pituitary growth. Interaction between these opposing hormonal/transmitter responses will determine the growth potential of the anterior pituitary.

Brain glutathione levels in patients with epilepsy measured by in vivo (1)H-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 (1)H MRS technique developed at the authors' site, the authors measured glutathione levels in a volume of interest (VOI) of 25 x 25 x 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 x 10(-5)) compared to the GSH/water ratio in healthy controls (2.4 +/- 1.1 x 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.

Influence of pyridoxal 5'-phosphate alone and in combination with vigabatrin on brain GABA measured by 1H-NMR-spectroscopy.

Both iso-forms of the gamma-aminobutyric acid (GABA) synthesising enzyme and also the GABA degrading enzyme need pyridoxal 5'-phosphate (PP) as co-enzyme. The aim of the study was to investigate the influence of PP alone and in combination with various doses of vigabatrin (VGB) on brain GABA levels. In eight healthy subjects 300 mg/d PP and various doses of VGB (range, 1000 mg/d to 4000 mg/d) were given alone or in combination. The GABA+/creatine (Cr) signals in both occipital lobes were measured before treatment, during monotherapy with PP or VGB, and during combination of both using 1H-NMR-spectroscopy (1H-NMRS). PP alone did not change the GABA+/Cr signals. VGB alone increased the GABA+/Cr signals in both hemispheres. The combination PP and low-medium dosed VGB (1000-2000 mg/d) did not increase the GABA+/Cr signals. The effects of the combination of PP and high dosed (3000-4000 mg/d) VGB on the GABA+/Cr signals varied depending on the sequence of the drugs and dose of VGB. PP alone has no effect on the GABA+/Cr signals in healthy volunteers. The combination of PP and low-high dosed VGB had inconsistent effects on the GABA+/Cr signals compared to a VGB monotherapy because PP activates also the GABA-degrading enzyme GABA-transaminase.

Proton magnetic resonance spectroscopy characteristics of a focal cortical dysgenesis during status epilepticus and in the interictal state.

We report the magnetic resonance imaging and proton magnetic resonance spectroscopic findings ((1)HMRS) in a patient with a focal cortical dysgenesis in the right superior frontal gyrus during intermittent frontal status epilepticus (IFSE) with simple partial seizures, and after she had become seizure free. During the status epilepticus, demonstrated by simultaneous behavioural and electroencephalographic telemetric long-term monitoring with scalp electrodes and ictal SPECT, we performed a single voxel spectroscopy of the dysgenic cortex. The(1)HMRS was repeated after 20 days when the patient's seizures were controlled. The N-acetyl-aspartate concentration in the focal dysgenic cortex was decreased in the interictal state but more during IFSE. The creatine/phosphocreatine concentration was normal in both instances. There was a clear lactate signal during IFSE, which was no longer visible in the interictal state. To our knowledge this is the first report of a(1)HMRS study of a focal cortical dysgenesis during an intermittent status epilepticus. We interpret the observed changes as signs of histopathological changes inherent to a cortical malformation and of an impaired energy metabolism due to the partial status epilepticus.

Impact of methodologic choice for automatic detection of different aspects of brain atrophy by using temporal lobe epilepsy as a model.

BACKGROUND AND PURPOSE: VBM, DBM, and cortical thickness measurement techniques are commonly used automated methods to detect structural brain changes based on MR imaging. The goal of this study was to demonstrate the pathology detected by the 3 methods and to provide guidance as to which method to choose for specific research questions. This goal was accomplished by 1) identifying structural abnormalities associated with TLE with (TLE-mts) and without (TLE-no) hippocampal sclerosis, which are known to be associated with different types of brain atrophy, by using these 3 methods; and 2) determining the aspect of the disease pathology identified by each method. MATERIALS AND METHODS: T1-weighted MR images were acquired for 15 TLE-mts patients, 14 TLE-no patients, and 33 controls on a high-field 4T scanner. Optimized VBM was carried out by using SPM software, DBM was performed by using a fluid-flow registration algorithm, and cortical thickness was analyzed by using FS-CT. RESULTS: In TLE-mts, the most pronounced volume losses were identified in the ipsilateral hippocampus and mesial temporal region, bilateral thalamus, and cerebellum, by using SPM-VBM and DBM. In TLE-no, the most widespread changes were cortical and identified by using FS-CT, affecting the bilateral temporal lobes, insula, and frontal and occipital lobes. DBM revealed 2 clusters of reduced volume complementing FS-CT analysis. SPM-VBM did not show any significant volume losses in TLE-no. CONCLUSIONS: These results demonstrate that the 3 methods detect different aspects of brain atrophy and that the choice of the method should be guided by the suspected pathology of the disease.

Evidence of neurodegeneration in brains of older adults who do not yet fulfill MCI criteria.

We sought to determine whether there are structural and metabolic changes in the brains of older adults with cognitive complaints yet who do not meet MCI criteria (i.e., preMCI). We compared the volumes of regional lobar gray matter (GM) and medial temporal lobe structures, including the hippocampus, entorhinal cortex (ERC), fusiform and parahippocampal gyri, and metabolite ratios from the posterior cingulate in individuals who had a Clinical Demetia Rating (CDR) of 0.5, but who did not meet MCI criteria (preMCI, N=17), patients with mild cognitive impairment (MCI, N=13), and cognitively normal controls (N=18). Controls had more ERC, fusiform, and frontal gray matter volume than preMCI and MCI subjects and greater parahippocampal volume and more posterior cingulate N-acetylaspartate (NAA)/myoinosotil (mI) than MCI. There were no significant differences between MCI and preMCI subjects on any of these measures. These findings suggest there are neurodegenerative changes in the brains of older adults who have cognitive complaints severe enough to qualify for CDR=0.5 yet show no deficits on formal neuropsychological testing. The results further support the hypothesis that detection of individuals with very mild forms of Alzheimer's disease (AD) may be facilitated by use of the CDR, which emphasizes changes in cognition over time within individuals rather than comparison with group norms.

A detailed analysis of localized J-difference GABA editing: theoretical and experimental study at 4 T.

The problem of low signal-to-noise ratio for gamma-aminobutyric acid (GABA) in vivo is exacerbated by inefficient detection schemes and non-optimal experimental parameters. To analyze the mechanisms for GABA signal loss of a MEGA-PRESS J-difference sequence at 4 T, numerical simulations were performed ranging from ideal to realistic experimental implementation, including volume selection and experimental radio frequency (RF) pulse shapes with a macromolecular minimization scheme. The simulations were found to be in good agreement with phantom and in vivo data from human brain. The overall GABA signal intensity for the simulations with realistic conditions for the MEGA-PRESS difference spectrum was calculated to be almost half of the signal simulated under ideal conditions (~43% signal loss). In contrast, creatine was reduced significantly less then GABA (~19% signal loss). The 'four-compartment' distribution due to J-coupling in the PRESS-based localization was one of the most significant sources of GABA signal loss, in addition to imperfect RF profiles for volume selection and editing. An alternative strategy that reduces signal loss due to the four-compartment distribution is suggested. In summary, a detailed analysis of J-difference editing is provided with estimates of the relative amounts of GABA signal losses due to various mechanisms. The numerical simulations presented in this study should facilitate both implementation of the more efficient acquisition and quantification process of J-coupled systems.

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.

Evaluation of treatment effects in Alzheimer's and other neurodegenerative diseases by MRI and MRS.

Neurodegeneration refers to a large clinically and pathologically heterogeneous disease entity associated with slowly progressive neuronal loss in different anatomical and functional systems of the brain. Neurodegenerative diseases often affect cognition, e.g. Alzheimer's disease (AD), dementia with Lewy bodies and vascular dementia, or different aspects of the motor system, e.g., amyotrophic lateral sclerosis, Parkinson's disease and ataxic disorders. Owing to increasing knowledge about the mechanisms leading to neurodegeneration, the development of treatments able to modify the neurodegenerative process becomes possible for the first time. Currently, clinical outcome measures are used to assess the efficacy of such treatments. However, most clinical outcome measures have a low test-retest reliability and thus considerable measurement variance. Therefore, large patient populations and long observation times are needed to detect treatment effects. Furthermore, clinical outcome measures cannot distinguish between symptomatic and disease-modifying treatment effects. Therefore, alternative biomarkers including neuroimaging may take on a more important role in this process. Because MR scanners are widely available and allow for non-invasive detection and quantification of changes in brain structure and metabolism, there is increasing interest in the use of MRI/MRS to monitor objectively treatment effects in clinical trials of neurodegenerative diseases. Particularly volumetric MRI has been used to measure atrophy rates in treatment trials of AD because the relationship between atrophic changes and neuron loss is well established and correlates well with clinical measures. More research is needed to determine the value of other MR modalities, i.e. diffusion, perfusion and functional MRI and MR spectroscopy, for clinical trials with neuroprotective drugs.