Jacob Penner

Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease

Galantamine is a cholinesterase inhibitor and allosteric potentiating ligand modulating presynaptic nicotinic acetylcholine receptors that is used in the treatment of Alzheimer disease (AD). The purpose of this study was to determine if galantamine treatment would result in detectable hippocampal metabolite changes that correlated with changes in cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Short echo-time proton magnetic resonance (MR) spectra were acquired from within the right hippocampus of ten patients using a 4 Tesla magnetic resonance imaging (MRI) scanner. Spectra were used to quantify absolute metabolite levels for N-acetylaspartate (NAA), glutamate (Glu), choline (Cho), creatine (Cr), and myo-inositol (mI). Patient scans and cognitive tests were performed before and 4 months after beginning galantamine treatment, which consisted of an 8 mg daily dose for the first month and a 16 mg daily dose for the remaining three months. The levels of Glu, Glu/Cr, and Glu/NAA increased after four months of treatment, while there were no changes in MMSE or ADAS-cog scores. Additionally, changes (Delta) in Glu over the four months (DeltaGlu) correlated with DeltaNAA, and Delta(Glu/Cr) correlated with DeltaMMSE scores. Increased Glu and the ratio of Glu to Cr measured by MR spectroscopy after galantamine treatment were associated with increased cognitive performance. The increase in Glu may be related to the action of galantamine as an allosteric potentiating ligand for presynaptic nicotinic acetylcholine receptors, which increases glutamatergic neurotransmission.

Semi‐LASER 1H MR spectroscopy at 7 Tesla in human brain: Metabolite quantification incorporating subject‐specific macromolecule removal

To develop an in vivo 1H short‐echo‐time semi‐LASER spectroscopy protocol at 7 Tesla (T) incorporating subject‐specific macromolecule removal.

Medial Prefrontal and Anterior Insular Connectivity in Early Schizophrenia and Major Depressive Disorder: A Resting Functional MRI Evaluation of Large-Scale Brain Network Models

Anomalies in the medial prefrontal cortex, anterior insulae, and large-scale brain networks associated with them have been proposed to underlie the pathophysiology of schizophrenia and major depressive disorder (MDD). In this study, we examined the connectivity of the medial prefrontal cortices and anterior insulae in 24 healthy controls, 24 patients with schizophrenia, and 24 patients with MDD early in illness with seed-based resting state functional magnetic resonance imaging analysis using Statistical Probability Mapping. As hypothesized, reduced connectivity was found between the medial prefrontal cortex and the dorsal anterior cingulate cortex and other nodes associated with directed effort in patients with schizophrenia compared to controls while patients with MDD had reduced connectivity between the medial prefrontal cortex and ventral prefrontal emotional encoding regions compared to controls. Reduced connectivity was found between the anterior insulae and the medial prefrontal cortex in schizophrenia compared to controls, but contrary to some models emotion processing regions failed to demonstrate increased connectivity with the medial prefrontal cortex in MDD compared to controls. Although, not statistically significant after correction for multiple comparisons, patients with schizophrenia tended to demonstrate decreased connectivity between basal ganglia-thalamocortical regions and the medial prefrontal cortex compared to patients with MDD, which might be expected as these regions effect action. Results were interpreted to support anomalies in nodes associated with directed effort in schizophrenia and nodes associated with emotional encoding network in MDD compared to healthy controls.

Higher order thalamic nuclei resting network connectivity in early schizophrenia and major depressive disorder

The pulvinar and the mediodorsal (MDN) nuclei of the thalamus are higher order nuclei which have been implicated in directed effort and corollary discharge systems. We used seed-based resting fMRI to examine functional connectivity to bilateral pulvinar and MDN in 24 schizophrenic patients (SZ), 24 major depressive disorder patients (MDD), and 24 age-matched healthy controls. SZ had less connectivity than controls between the left pulvinar and precuneus, left ventral-lateral prefrontal cortex (vlPFC), and superior and medial-frontal regions, between the right pulvinar and right frontal pole, and greater connectivity between the right MDN and left dorsolateral prefrontal cortex (dlPFC). SZ had less connectivity than MDD between the left pulvinar and ventral anterior cingulate (vACC), left vlPFC, anterior insula, posterior cingulate cortex (PCC), and right hippocampus, between the right pulvinar and right PCC, and between the right MDN and right dorsal anterior cingulate (dACC). This is the first study to measure the functional connectivity to the higher order nuclei of the thalamus in both SZ and MDD. We observed less connectivity in SZ than MDD between pulvinar and emotional encoding regions, a directed effort region, and a region involved in representation and salience, and between MDN and a directed effort region.

Reduced N-Acetylaspartate to Creatine Ratio in the Posterior Cingulate Correlates with Cognition in Alzheimer's Disease following Four Months of Rivastigmine Treatment

Aim: To determine whether 4 months of rivastigmine treatment would result in metabolic changes and whether metabolic changes correlate with changes in cognition in people with Alzheimers disease (AD). Methods: Magnetic resonance spectra were acquired from the posterior cingulate cortex of subjects with AD at 3 T. Magnetic resonance imaging scans and cognitive tests were performed before and 4 months after the beginning of the treatment. Metabolite concentrations were quantified and used to calculate the metabolite ratios. Results: On average, the N-acetylaspartate/creatine (NAA/Cr) ratio decreased by 12.7% following 4 months of rivastigmine treatment, but changes in the NAA/Cr ratio correlated positively with changes in Mini-Mental State Examination scores. Conclusion: This positive correlation between changes in NAA/Cr and changes in cognitive performance suggests that the NAA/Cr ratio could be an objective indicator of a response to rivastigmine treatment.

7T magnetic resonance spectroscopy of the hippocampus in mild cognitive impairment

Background: Mild cognitive impairment (MCI) is a state of cognitive decline that is often found before the criteria for Alzheimer disease (AD) are met. ProtonMagnetic Resonance Spectroscopy (1 HMRS) has been previously used to monitor metabolite level changes in brain tissue in subjects with MCI. The use of high fields increases signal to noise ratio and spectral dispersion leading to improved metabolite quantification. The purpose of this study was to quantify metabolic changes in the hippocampus over time in subjects with mild cognitive impairment. Methods: A 7T Agilent/ Siemens head-only MRI system was used to acquire images and singlevoxel short-echo-time 1 H MR from the hippocampus of five subjects with MCI (3 males, age 686 11 years) at baseline. Cognition was measured with the MMSE and the MoCA. T 2 -weighted images (1x1x1.5 mm 3 resolution, TR 1⁄4 1s, TE 1⁄4 5.3 ms) were acquired for MRS voxel placement. Single-voxel 1 H MRS data were acquired from an average 2.7 6 0.7 cm 3 volume of interest (localization by adiabatic selective refocusing, TR 1⁄4 3.7s, TE 1⁄4 38 ms) in the hippocampus. The metabolite spectra were fit to determine the contribution of each metabolite to the spectrum. N -acetylaspartate (NAA), choline (Cho), myo-inositol (Myo), and glutamate (Glu) were measured and normalized to creatine (Cr) (which typically remains constant even in neuropathological conditions) for evaluation of changes over time. Results: The average baseline ratios were NAA/Cr 1⁄4 2.07 6 0.68, Glu/Cr 1⁄4 1.25 6 0.25, Myo/Cr 1⁄4 1.60 6 0.64, and Cho/Cr 1⁄4 1.30 6 0.55. Furthermore, the average signal/noise ratio (SNR) per volume for this study was 3.56 1.5. The average MMSE and MoCA scores at baseline were 26.8 6 1.8 and 25.4 6 0.9, respectively. Conclusions: In a previous study at 4T the average SNR/volume was 2.0 6 0.7. The 75% increase in SNR/volume reported in the current study is in agreement with the theoretically expected linear increase in SNR as a function of field strength. Follow-up scans will be performed to measure the change in metabolite ratios over time and to correlate with cognitive scores. Additional subjects will be recruited to provide greater statistical power.

Enhanced amyloid plaque detection by magnetic resonance balanced steady state free precession imaging combined with susceptibility weighted imaging post-processing

Dementia (DEM; n 1⁄430). 3-D MRI scans using MP-RAGE (Siemens) or SPGR (General Electric) sequences were for: (1) volumetric measurements of the HPC, using IBASPM [Alemán-Gómez, Melie-Garcı́a, Valdés-Hernandez, 2006]; (2) VRS, using a 1.5 mm thick coronal slice intersecting the mammillary bodies to measure the mean atrophy score of the HPC, ERC and the PRC on each side. Results: The area under the receiver operating curve (aROC) for DEM versus NCI for the left hemisphere was .80 for volumetry and 0.83 for VRS (p1⁄4NS). Similar results were obtained for the right hemisphere. For aMCI versus NCI, the aROC for the left hemisphere were similar for volumetry and VRS, but on the right hemisphere aROC was 0.73 for VRS .61 for volumetry (p 1⁄4.05). The correlations of right and left VRS measures with scores on an episodic memory test (r1⁄4.55 and r1⁄4.55) were slightly higher than with volumetric measures (r1⁄4.51 and r1⁄4.44). Conclusions: The use of a semiquantitative method (VRS) to measure medial temporal structures to distinguish aMCI and DEM from NCI is at least as effective as validated volumetric methods. VRS should be considered as a method for measuring medial temporal atrophy in the diagnosis of prodromal and probable Alzheimer’s disease.

IC-P2-123: Increased glutamate/N-acetylaspartate in the hippocampus after galantamine treatment in Alzheimer's disease

activation in Cs at z 2.26, whereas AD-Rs were comparable at z 1.82 and AD-NRs at z 0.92. Voxel-by-voxel Mann-Whitney tests (p .05) revealed Cs had significantly more activation than AD and AD-NRs in task-specific frontal and parietal areas with frontal areas being most prominently different. Cs and AD-Rs were not significantly different but AD-Rs showed significantly more activation than AD-NRs (similar to Cs). Region-of -interest Mann-Whitney tests revealed the right and left ventrolateral and medial prefrontal cortex to be more active in Cs and AD-Rs than AD-NRs, with no difference between Cs and AD-Rs. Conclusions: Differences in the fMRI activation patterns between AD-Rs and AD-NRs may predict response to cholinesterase-inhibitor treatment. Relative preservation of activation in the frontal regions of AD patients may be a biomarker reflecting the likelihood of improvement with treatment. This stratification approach could be used in future trials to define subpopulations of AD that may be amenable to treatment.