John D. West

Older adults with cognitive complaints show brain atrophy similar to that of amnestic MCI

Objective: To examine the neural basis of cognitive complaints in healthy older adults in the absence of memory impairment and to determine whether there are medial temporal lobe (MTL) gray matter (GM) changes as reported in Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI). Methods: Participants were 40 euthymic individuals with cognitive complaints (CCs) who had normal neuropsychological test performance. The authors compared their structural brain MRI scans to those of 40 patients with amnestic MCI and 40 healthy controls (HCs) using voxel-based morphometry and hippocampal volume analysis. Results: The CC and MCI groups showed similar patterns of decreased GM relative to the HC group on whole brain analysis, with differences evident in the MTL, frontotemporal, and other neocortical regions. The degree of GM loss was associated with extent of both memory complaints and performance deficits. Manually segmented hippocampal volumes, adjusted for age and intracranial volume, were significantly reduced only in the MCI group, with the CC group showing an intermediate level. Conclusions: Cognitive complaints in older adults may indicate underlying neurodegenerative changes even when unaccompanied by deficits on formal testing. The cognitive complaint group may represent a pre–mild cognitive impairment stage and may provide an earlier therapeutic opportunity than mild cognitive impairment. MRI analysis approaches incorporating signal intensity may have greater sensitivity in early preclinical stages than volumetric methods.

Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort

A genome-wide, whole brain approach to investigate genetic effects on neuroimaging phenotypes for identifying quantitative trait loci is described. The Alzheimers Disease Neuroimaging Initiative 1.5 T MRI and genetic dataset was investigated using voxel-based morphometry (VBM) and FreeSurfer parcellation followed by genome-wide association studies (GWAS). One hundred forty-two measures of grey matter (GM) density, volume, and cortical thickness were extracted from baseline scans. GWAS, using PLINK, were performed on each phenotype using quality-controlled genotype and scan data including 530,992 of 620,903 single nucleotide polymorphisms (SNPs) and 733 of 818 participants (175 AD, 354 amnestic mild cognitive impairment, MCI, and 204 healthy controls, HC). Hierarchical clustering and heat maps were used to analyze the GWAS results and associations are reported at two significance thresholds (p<10(-7) and p<10(-6)). As expected, SNPs in the APOE and TOMM40 genes were confirmed as markers strongly associated with multiple brain regions. Other top SNPs were proximal to the EPHA4, TP63 and NXPH1 genes. Detailed image analyses of rs6463843 (flanking NXPH1) revealed reduced global and regional GM density across diagnostic groups in TT relative to GG homozygotes. Interaction analysis indicated that AD patients homozygous for the T allele showed differential vulnerability to right hippocampal GM density loss. NXPH1 codes for a protein implicated in promotion of adhesion between dendrites and axons, a key factor in synaptic integrity, the loss of which is a hallmark of AD. A genome-wide, whole brain search strategy has the potential to reveal novel candidate genes and loci warranting further investigation and replication.

Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort.

Atrophic changes in early Alzheimers disease (AD) and amnestic mild cognitive impairment (MCI) have been proposed as biomarkers for detection and monitoring. We analyzed magnetic resonance imaging (MRI) atrophy rate from baseline to 1 year in 4 groups of participants from the Alzheimers Disease Neuroimaging Initiative (ADNI): AD (n = 152), converters from MCI to probable AD (MCI-C, n = 60), stable MCI (MCI-S, n = 261), and healthy controls (HC, n = 200). Scans were analyzed using multiple methods, including voxel-based morphometry (VBM), regions of interest (ROIs), and automated parcellation, permitting comparison of annual percent change (APC) in neurodegeneration markers. Effect sizes and the sample required to detect 25% reduction in atrophy rates were calculated. The influence of APOE genotype on APC was also evaluated. AD patients and converters from MCI to probable AD demonstrated high atrophy APCs across regions compared with minimal change in healthy controls. Stable MCI subjects showed intermediate atrophy rates. APOE genotype was associated with APC in key regions. In sum, APC rates are influenced by APOE genotype, imminent MCI to AD conversion, and AD-related neurodegeneration.

Alterations in Brain Activation During Working Memory Processing Associated With Breast Cancer and Treatment: A Prospective Functional Magnetic Resonance Imaging Study

PURPOSE To prospectively examine alterations in working memory (WM) -associated brain activation related to breast cancer and treatment by using functional magnetic resonance imaging. PATIENTS AND METHODS Patients treated with chemotherapy (CTx+; n = 16) or without chemotherapy (CTx-; n = 12) and healthy controls (n = 15) were scanned during an n-back task at baseline (after surgery but before radiation, chemotherapy, and/or antiestrogen treatment), 1 month after completion of chemotherapy (M1), and 1 year later (Y1), or at yoked intervals for CTx- and controls. SPM5 was used for all image analyses, which included cross-sectional between-group and group-by-time interaction and longitudinal within-group analyses, all using a statistical threshold of 0.001. RESULTS At baseline, patients with cancer showed increased bifrontal and decreased left parietal activation compared with controls. At M1, both cancer groups showed decreased frontal hyperactivation compared with controls, with increased hyperactivation at Y1. These cross-sectional findings were confirmed by group-by-time interaction analyses, which showed frontal activation decreases from baseline to M1 in patients compared with controls. Within-group analyses showed different patterns of longitudinal activation change by treatment group (CTx+ or CTx-), with prominent alterations in the frontal lobes bilaterally. CONCLUSION Significant frontal lobe hyperactivation to support WM was found in patients with breast cancer. Superimposed on this background, patients showed decreased frontal activation at M1, with partial return to the previously abnormal baseline at Y1. These functional changes correspond to frontal lobe regions where we previously reported structural changes in this cohort and provide prospective, longitudinal data that further elucidate mechanisms underlying cognitive effects related to breast cancer and its treatment.

Event-related functional magnetic resonance imaging of response inhibition in obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) has been hypothesized to involve inhibitory control dysfunction related to abnormal frontal-striatal-thalamic-cortical (FSTC) circuitry. METHODS We examined the neural substrates of response inhibition in adults with OCD using functional magnetic resonance imaging (fMRI) and a go/no-go task. Participants consisted of 12 adults with OCD and 14 healthy comparison subjects. RESULTS During response inhibition, healthy adults showed predominantly right-hemisphere activation including the right inferior frontal gyrus, whereas the patient group showed a more diffuse, bilateral pattern of activation. Furthermore, the OCD group demonstrated less activation than the comparison group in several right-hemisphere regions during response inhibition, including inferior and medial frontal gyri. Symptom severity was inversely correlated with activation in right orbitofrontal and anterior cingulate gyri and positively correlated with thalamic and posterior cortical activations. Neither depressed mood nor medication status could account for the results. CONCLUSIONS These findings indicate that adults with OCD demonstrate underactivation of FSTC circuitry during response inhibition. Results suggest that the thalamus and related circuitry may play a role in the expression or intensity of OCD symptoms, whereas right frontal subregions may be involved in the suppression of symptoms.

Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: A replication and extension study

Cognitive changes related to cancer and its treatment have been intensely studied, and neuroimaging has begun to demonstrate brain correlates. In the first prospective longitudinal neuroimaging study of breast cancer (BC) patients we recently reported decreased gray matter density one month after chemotherapy completion, particularly in frontal regions. These findings helped confirm a neural basis for previously reported cognitive symptoms, which most commonly involve executive and memory processes in which the frontal lobes are a critical component of underlying neural circuitry. Here we present data from an independent, larger, more demographically diverse cohort that is more generalizable to the BC population. BC patients treated with (N=27) and without (N=28) chemotherapy and matched healthy controls (N=24) were scanned at baseline (prior to systemic treatment) and one month following chemotherapy completion (or yoked intervals for non-chemotherapy and control groups) and APOE-genotyped. Voxel-based morphometry (VBM) showed decreased frontal gray matter density after chemotherapy, as observed in the prior cohort, which was accompanied by self-reported difficulties in executive functioning. Gray matter and executive symptom changes were not related to APOE ε4 status, though a somewhat greater percentage of BC patients who received chemotherapy were ε4 allele carriers than patients not treated with chemotherapy or healthy controls. These findings provide confirmatory evidence of frontal morphometric changes that may be a pathophysiological basis for cancer and treatment-related cognitive dysfunction. Further research into individual risk factors for such changes will be critical for development of treatment and prevention strategies.

Altered Default Mode Network Connectivity in Older Adults with Cognitive Complaints and Amnestic Mild Cognitive Impairment

Default mode network (DMN) disruption has been reported in Alzheimers disease (AD), yet the specific pattern of altered connectivity over the course of prodromal AD remains to be characterized. The aim of this study was to assess DMN connectivity in older adults with informant-verified cognitive complaints (CC) but normal neuropsychological performance compared to individuals with mild cognitive impairment (MCI) and healthy controls (HC). DMN maps were derived from resting-state fMRI using independent component analysis. Group comparisons of DMN connectivity were performed between older adults with MCI (n = 18), CC (n = 23), and HC (n = 16). Both CC and MCI showed decreased DMN connectivity in the right hippocampus compared to HC, with the CC group showing greater connectivity than MCI. These differences survived atrophy correction and correlated with cognitive performance. DMN connectivity appears sensitive to early prodromal neurodegenerative changes associated with AD, notably including pre-MCI individuals with cognitive complaints.

Selective Changes in White Matter Integrity in MCI and Older Adults with Cognitive Complaints

BACKGROUND White matter changes measured using diffusion tensor imaging have been reported in Alzheimers disease and amnestic mild cognitive impairment, but changes in earlier pre-mild cognitive impairment stages have not been fully investigated. METHODS In a cross-sectional analysis, older adults with mild cognitive impairment (n=28), older adults with cognitive complaints but without psychometric impairment (n=29) and healthy controls (n=35) were compared. Measures included whole-brain diffusion tensor imaging, T1-weighted structural magnetic resonance imaging, and neuropsychological assessment. Diffusion images were analyzed using Tract-Based Spatial Statistics. Voxel-wise fractional anisotropy and mean, axial, and radial diffusivities were assessed and compared between groups. Significant tract clusters were extracted in order to perform further region of interest comparisons. Brain volume was estimated using FreeSurfer based on T1 structural images. RESULTS The mild cognitive impairment group showed lower fractional anisotropy and higher radial diffusivity than controls in bilateral parahippocampal white matter. When comparing extracted diffusivity measurements from bilateral parahippocampal white matter clusters, the cognitive complaint group had values that were intermediate to the mild cognitive impairment and healthy control groups. Group difference in diffusion tensor imaging measures remained significant after controlling for hippocampal atrophy. Across the entire sample, diffusion tensor imaging indices in parahippocampal white matter were correlated with memory function. CONCLUSIONS These findings are consistent with previous results showing changes in parahippocampal white matter in Alzheimers disease and mild cognitive impairment compared to controls. The intermediate pattern found in the cognitive complaint group suggests the potential of diffusion tensor imaging to contribute to earlier detection of neurodegenerative changes during prodromal stages. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Comparison of Manual and Automated Determination of Hippocampal Volumes in MCI and Early AD

MRI-based hippocampal volume analysis has been extensively employed given its potential as a biomarker for brain disorders such as Alzheimer’s disease (AD), and accurate and efficient determination of hippocampal volumes from brain images is still a challenging issue. We compared an automated method, FreeSurfer (V4), with a published manual protocol for the determination of hippocampal volumes from T1-weighted MRI scans. Our study included MRI data from 125 older adult subjects: healthy controls with no significant cognitive complaints or deficits (HC, n = 38), euthymic individuals with cognitive complaints (CC, n = 39) but intact neuropsychological performance, and patients with amnestic mild cognitive impairment (MCI, n = 37) or a clinical diagnosis of probable AD (AD, n = 11). Pearson correlations and intraclass correlation coefficients (ICCs) were calculated to evaluate the relationship between results of the manual tracing and FreeSurfer methods and to estimate their agreement. Results indicated that these two methods derived highly correlated results with strong agreement. After controlling for the age, sex and intracranial volume in statistical group analysis, both the manual tracing and FreeSurfer methods yield similar patterns: both the MCI group and the AD group showed hippocampal volume reduction compared to both the HC group and the CC group, and the HC and CC groups did not differ. These comparisons suggest that FreeSurfer has the potential to be used in automated determination of hippocampal volumes for large-scale MCI/AD-related MRI studies, where manual methods are inefficient or not feasible.

Visual contrast sensitivity in Alzheimer’s disease, mild cognitive impairment, and older adults with cognitive complaints

Deficits in contrast sensitivity (CS) have been reported in Alzheimers disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker.