Faculty Bibliography

Research indicates that female risk of developing Alzheimer's disease (AD) is greater than that of males. Moderate reduction of calorie intake, known as calorie restriction (CR), reduces pathology in AD mouse models and is a potentially translatable prevention measure for individuals at-risk for AD, as well as an important tool for understanding how the brain endogenously attenuates age-related pathology. Whether sex influences the response to CR remains unknown. In this study, we assessed the effect of CR on beta-amyloid peptide (Abeta) pathology and hippocampal CA1 neuron specific gene expression in the Tg2576 mouse model of cerebral amyloidosis. Relative to ad libitum (AL) feeding, CR feeding significantly reduced hippocampal Abeta burden in 15-month-old female, but not age-matched male, Tg2576 mice. Sustained CR also significantly reduced expression of presenilin enhancer 2 (Psenen) and presenilin 1, components of the gamma-secretase complex, in Tg2576 females. These results indicate that long-term CR significantly reduces age-dependent female Tg2576 Abeta pathology, which is likely to involve CR-mediated reductions in gamma-secretase-dependent amyloid precursor protein (APP) metabolism.

BACKGROUND: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. METHODS: Cognitively intact elderly individuals (n=37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25 - 3.00mg) or placebo on different days, approximately 1week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. RESULTS: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. CONCLUSIONS: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population.

Down syndrome (DS) is the most prevalent cause of intellectual disability (ID). Individuals with DS show a variety of cognitive deficits, most notably in hippocampal learning and memory, and display pathological hallmarks of Alzheimer's disease (AD), with neurodegeneration of cholinergic basal forebrain (CBF) neurons. Elucidation of the molecular and cellular underpinnings of neuropathology has been assessed via gene expression analysis in a relevant animal model, termed the Ts65Dn mouse. The Ts65Dn mouse is a segmental trisomy model of DS which mimics DS/AD pathology, notably age-related cognitive dysfunction and degeneration of basal forebrain cholinergic neurons (BFCNs). To determine expression level changes, molecular fingerprinting of Cornu Ammonis 1 (CA1) pyramidal neurons was performed in adult (4-9 month old) Ts65Dn mice, at the initiation of BFCN degeneration. To quantitate transcriptomic changes during this early time period, laser capture microdissection (LCM), terminal continuation (TC) RNA amplification, custom-designed microarray analysis, and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting was performed. Results indicate significant alterations within CA1 pyramidal neurons of Ts65Dn mice compared to normal disomic (2N) littermates, notably in the downregulation of neurotrophins and their cognate neurotrophin receptors among other classes of transcripts relevant to neurodegeneration. These results of this single population gene expression analysis at the time of septohippocampal deficits in a trisomic mouse model shed light on a vulnerable circuit that may cause the AD-like pathology invariably seen in DS that could help to identify mechanisms of degeneration, and provide novel gene targets for therapeutic interventions. J. Comp. Neurol., 2014. (c) 2014 Wiley Periodicals, Inc.

Background: Corpus callosum (CC) size and shape have been previously studied in Alzheimer's disease (AD) with the majority of studies having been cross-sectional. Due to the large variance in normal CC morphology, cross-sectional studies are limited in statistical power. Determining individual rates of change requires longitudinal data. Physiological changes are particularly relevant in mild cognitive impairment (MCI), in which CC morphology has not been previously studied longitudinally. Objective: To study temporal rates of change in CC morphology in MCI patients over a one-year period, and to determine whether these rates differ between MCI subjects who converted to AD (MCI-C) and those who did not (MCI-NC) over an average (+/-SD) observation period of 5.4 (+/-1.6) years. Methods: We used a novel multi-atlas based algorithm to segment the mid-sagittal cross-sectional area of the CC in longitudinal MRI scans. Rates of change of CC circularity, total area, and five sub-areas were compared between 57 MCI-NC and 81 MCI-C subjects. Results: The CC became less circular (-0.89% per year in MCI-NC, -1.85% per year in MCI-C) with time, with faster decline in MCI-C (p = 0.0002). In females, atrophy rates were higher in MCI-C relative to MCI-NC in total CC area (p = 0.0006), genu/rostrum (p = 0.005), and splenium (0.002). In males, these rates did not differ between groups. Conclusion: A greater than normal decline in CC circularity was shown to be an indicator of prodromal AD in MCI subjects. This measure is potentially useful as an imaging biomarker of disease and a therapeutic target in clinical trials.

BACKGROUND:It has been well documented that, along with tonsillar herniation, Chiari Malformation Type I (CMI) is associated with smaller posterior cranial fossa (PCF) and altered cerebrospinal fluid (CSF) flow and tissue motion in the craniocervical junction. OBJECTIVE:This study assesses the relationship between PCF volumetry and CSF and tissue dynamics toward a combined imaging-based morphological-physiological characterization of CMI. Multivariate analysis is used to identify the subset of parameters that best discriminates CMI from a healthy cohort. METHODS:Eleven length and volumetric measures of PCF, including crowdedness and 4th ventricle volume, 4 measures of CSF and cord motion in the craniocervical junction, and 5 global intracranial measures, including intracranial compliance and pressure, were measured by magnetic resonance imaging (MRI) in 36 symptomatic CMI subjects (28 female, 37 ± 11 years) and 37 control subjects (24 female, 36 ± 12 years). The CMI group was further divided based on symptomatology into "typical" and "atypical" subgroups. RESULTS:Ten of the 20 morphologic and physiologic measures were significantly different between the CMI and the control cohorts. These parameters also had less variability and stronger significance in the typical CMI compared with the atypical. The measures with the most significance were clival and supraocciput lengths, PCF crowdedness, normalized PCF volume, 4th ventricle volume, maximal cord displacement (P < .001), and MR measure of intracranial pressure (P = .007). Multivariate testing identified cord displacement, PCF crowdedness, and normalized PCF as the strongest discriminator subset between CMI and controls. MR measure of intracranial pressure was higher in the typical CMI cohort compared with the atypical. CONCLUSION/CONCLUSIONS:The identified 10 complementing morphological and physiological measures provide a more complete and symptomatology-relevant characterization of CMI than tonsillar herniation alone.

We propose a fused lasso logistic regression to analyze callosal thickness profiles. The fused lasso regression imposes penalties on both the l1-norm of the model coefficients and their successive differences, and finds only a small number of non-zero coefficients which are locally constant. An iterative method of solving logistic regression with fused lasso regularization is proposed to make this a practical procedure. In this study we analyzed callosal thickness profiles sampled at 100 equal intervals between the rostrum and the splenium. The method was applied to corpora callosa of elderly normal controls (NCs) and patients with very mild or mild Alzheimer's disease (AD) from the Open Access Series of Imaging Studies (OASIS) database. We found specific locations in the genu and splenium of AD patients that are proportionally thinner than those of NCs. Callosal thickness in these regions combined with the Mini Mental State Examination scores differentiated AD from NC with 84% accuracy.

Background: Alzheimer's disease (AD) has been shown to be associated with shrinkage of the corpus callosum mid-sagittal cross-sectional area (CCA). Objective: To study temporal rates of corpus callosum atrophy not previously reported for early AD. Methods: We used longitudinal MRI scans to study the rates of change of CCA and circularity (CIR), a measure of its shape, in normal controls (NC, n = 75), patients with very mild AD (AD-VM, n = 51), and mild AD (AD-M, n = 21). Results: There were significant reduction rates in CCA and CIR in all three groups. While CCA reduction rates were not statistically different between groups, the CIR declined faster in AD-VM (p < 0.03) and AD-M (p < 0.0001) relative to NC, and in AD-M relative to AD-VM (p < 0.0004). Conclusion: CIR declines at an accelerated rate with AD severity. Its rate of change is more closely associated with AD progression than CCA or any of its sub-regions. CIR may be a useful group biomarker for objective assessment of treatments that aim to slow AD progression.

Correctly identifying voxels or regions of interest (ROI) that actively respond to a given stimulus is often an important objective/step in many functional magnetic resonance imaging (fMRI) studies. In this article, we study a nonparametric method to detect active voxels, which makes minimal assumption about the distribution of blood oxygen level-dependent (BOLD) signals. Our proposal has several interesting features. It uses time lagged correlation to take into account the delay in response to the stimulus, due to hemodynamic variations. We introduce an input permutation method (IPM), a type of block permutation method, to approximate the null distribution of the test statistic. Also, we propose to pool the permutation-derived statistics of preselected voxels for a better approximation to the null distribution. Finally, we control multiple testing error rate using the local false discovery rate (FDR) by Efron [Correlation and large-scale simultaneous hypothesis testing. J Am Stat Assoc 102 (2007) 93-103] and Park et al. [Estimation of empirical null using a mixture of normals and its use in local false discovery rate. Comput Stat Data Anal 55 (2011) 2421-2432] to select the active voxels.