Diana Truran-Sacrey

Relations between brain tissue loss, CSF biomarkers, and the ApoE genetic profile: a longitudinal MRI study

Previously it was reported that Alzheimers disease (AD) patients have reduced beta amyloid (Abeta(1-42)) and elevated total tau (t-tau) and phosphorylated tau (p-tau(181p)) in the cerebrospinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly individuals and those with mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Abeta(1-42), t-tau, and p-tau(181p) and apolipoprotein E (ApoE) epsilon4 status, and that the pattern of this association would be diagnosis-specific. Our findings primarily showed that lower CSF Abeta(1-42) and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in healthy elderly and mild cognitive impairment subjects that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Abeta(1-42) levels and higher tau levels supports the hypothesis that CSF Abeta(1-42) and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE epsilon4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to beta amyloid and tau mediated pathology is regional and disease stage specific.

Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects

Objective: To determine whether elderly normal APOE E2 (APOE2) carriers exhibit slower rates of hippocampal atrophy and memory decline compared to APOE3/3 carriers. We also determined whether APOE2 carriers have less Alzheimer pathology as reflected by CSF biomarkers. Methods: We included longitudinal data from 134 cognitively normal individuals (27 APOE2/2 or E2/3, 107 APOE3/3) from the Alzheimers Disease Neuroimaging Initiative, a prospective cohort study. A linear mixed-effects model was used to determine how APOE2 affected rates of hippocampal atrophy and cognitive change over time. In a subsample of 72 individuals who also underwent CSF analysis, an ordinary least-squares regression was used to determine whether CSF β-amyloid (Aβ), total tau, and phosphorylated tau-181 (p-tau) differed by APOE2 status. Results: APOE2 carriers demonstrated slower rates of hippocampal atrophy (p = 0.004). The mean rate of hippocampal atrophy among APOE2 carriers was −33 mm3/year (95% confidence interval −65 to +0.4), or −0.5%/year, compared to −86 mm3/year (95% confidence interval −102 to −71), or −1.3%/year, in the APOE3/3 group. No differences in the rates of episodic memory (p = 0.23) or overall cognitive change (p = 0.90) were detected. In the CSF subsample, APOE2 carriers had higher levels of CSF Aβ (p = 0.01), lower p-tau (p = 0.02), and marginally lower tau (p = 0.12). Conclusion: A slower rate of hippocampal atrophy in normal APOE2 carriers is consistent with the lower risk of Alzheimer disease in these individuals. We hypothesize that the slower atrophy rate is related to decreased preclinical Alzheimer pathology.

Identifying Cognitively Healthy Elderly Individuals with Subsequent Memory Decline by Using Automated MR Temporoparietal Volumes

PURPOSE To determine whether automated temporoparietal brain volumes can be used to accurately predict future memory decline among a multicenter cohort of cognitively healthy elderly individuals. MATERIALS AND METHODS The study was approved by the institutional review board at each site and was HIPAA compliant, with written consent obtained from all participants. One hundred forty-nine cognitively healthy study participants were recruited through the Alzheimers Disease Neuroimaging Initiative and underwent a standardized baseline 1.5-T magnetic resonance (MR) imaging examination, as well as neuropsychological assessment at baseline and after 2 years of follow-up. A composite memory score for the 2-year change in the results of two delayed-recall tests was calculated, and memory decline was defined as a composite score that was at least 1 standard deviation below the group mean score. The predictive accuracy of the brain volumes was estimated by using areas under receiver operating characteristic curves and was further assessed by using leave-one-out cross validation. RESULTS Use of the most accurate region model, which included the hippocampus; parahippocampal gyrus; amygdala; superior, middle, and inferior temporal gyri; superior parietal lobe; and posterior cingulate gyrus, resulted in a fitted accuracy of 94% and a cross-validated accuracy of 81%. CONCLUSION Study results indicate that automated temporal and parietal volumes can be used to identify with high accuracy cognitively healthy individuals who are at risk for future memory decline. Further validation of this predictive model in a new cohort is required.

Patterns of Reduced Cortical Thickness in Late-Life Depression and Relationship to Psychotherapeutic Response

OBJECTIVE Cortical atrophy has been associated with late-life depression (LLD) and recent findings suggest that reduced right hemisphere cortical thickness is associated with familial risk for major depressive disorder, but cortical thickness abnormalities in LLD have not been explored. Furthermore, cortical atrophy has been posited as a contributor to poor antidepressant treatment response in LLD, but the impact of cortical thickness on psychotherapy response is unknown. This study was conducted to evaluate patterns of cortical thickness in LLD and in relation to psychotherapy treatment outcomes. METHODS Participants included 22 individuals with LLD and 12 age-matched comparison subjects. LLD participants completed 12 weeks of psychotherapy and treatment response was defined as a 50% reduction in depressive symptoms. All participants underwent magnetic resonance imaging of the brain, and cortical mapping of gray matter tissue thickness was calculated. RESULTS LLD individuals demonstrated thinner cortex than controls prominently in the right frontal, parietal, and temporal brain regions. Eleven participants (50%) exhibited positive psychotherapy response after 12 weeks of treatment. Psychotherapy nonresponders demonstrated thinner cortex in bilateral posterior cingulate and parahippocampal cortices, left paracentral, precuneus, cuneus, and insular cortices, and the right medial orbitofrontal and lateral occipital cortices relative to treatment responders. CONCLUSIONS Our findings suggest more distributed right hemisphere cortical abnormalities in LLD than have been previously reported. In addition, our findings suggest that reduced bilateral cortical thickness may be an important phenotypic marker of individuals at higher risk for poor response to psychotherapy.

Bayesian segmentation of brainstem structures in MRI

In this paper we present a method to segment four brainstem structures (midbrain, pons, medulla oblongata and superior cerebellar peduncle) from 3D brain MRI scans. The segmentation method relies on a probabilistic atlas of the brainstem and its neighboring brain structures. To build the atlas, we combined a dataset of 39 scans with already existing manual delineations of the whole brainstem and a dataset of 10 scans in which the brainstem structures were manually labeled with a protocol that was specifically designed for this study. The resulting atlas can be used in a Bayesian framework to segment the brainstem structures in novel scans. Thanks to the generative nature of the scheme, the segmentation method is robust to changes in MRI contrast or acquisition hardware. Using cross validation, we show that the algorithm can segment the structures in previously unseen T1 and FLAIR scans with great accuracy (mean error under 1mm) and robustness (no failures in 383 scans including 168 AD cases). We also indirectly evaluate the algorithm with a experiment in which we study the atrophy of the brainstem in aging. The results show that, when used simultaneously, the volumes of the midbrain, pons and medulla are significantly more predictive of age than the volume of the entire brainstem, estimated as their sum. The results also demonstrate that the method can detect atrophy patterns in the brainstem structures that have been previously described in the literature. Finally, we demonstrate that the proposed algorithm is able to detect differential effects of AD on the brainstem structures. The method will be implemented as part of the popular neuroimaging package FreeSurfer.

Impact of apolipoprotein ɛ4–cerebrospinal fluid beta-amyloid interaction on hippocampal volume loss over 1 year in mild cognitive impairment

The majority of studies relating amyloid pathology with brain volumes have been cross‐sectional. Apolipoprotein ɛ4 (APOE ɛ4), a genetic risk factor for Alzheimers disease, is also known to be associated with hippocampal volume loss. No studies have considered the effects of amyloid pathology and APOE ɛ4 together on longitudinal volume loss.

The effect of subsyndromal symptoms of depression and white matter lesions on disability for individuals with mild cognitive impairment

OBJECTIVE To assess the effect of subsyndromal symptoms of depression (SSD) on ratings of disability for individuals with mild cognitive impairment (MCI). METHODS Data from 405 MCI participants from the Alzheimers Disease Neuroimaging Initiative (ADNI) study were analyzed. Participants were evaluated at baseline and at 6-month intervals over 2 years. Severity of depressive symptoms was rated utilizing the Geriatric Depression Scale. Disability was assessed utilizing the Functional Assessment Questionnaire (FAQ). Other clinical variables included white matter lesion (WML) and intracranial brain (ICV) volumes derived from magnetic resonance imaging, ratings of overall cognitive function (Alzheimers Disease Assessment Scale, ADAS), and apolipoprotein E (ApoE) status. Demographic variables included age, education, and gender. RESULTS SSD individuals had a lower volume of WML and higher frequency of ApoE ε4 alleles than nondepressed participants but the two groups did not differ with respect to other clinical or demographic variables. At baseline, SSD individuals were 1.77 times more likely to have poorer FAQ scores than individuals with no symptoms of depression after controlling for the effect of cognitive functioning, ICV, WML, and ApoE status. The presence of SSD at baseline was not associated with a poorer course of disability outcomes, cognitive functioning, or conversion to dementia over 24 months. CONCLUSIONS SSD demonstrated a significant impact on disability for MCI individuals, who are also at high risk for functional limitations related to neurodegenerative disease. Therefore, the treatment of SSD may represent a significant avenue to reduce the burden of disability in this vulnerable patient population.

An MRI substudy of a donepezil clinical trial in mild cognitive impairment

A magnetic resonance imaging (MRI) study was conducted as part of an intervention study in subjects with amnestic mild cognitive impairment (aMCI) to assess donepezils treatment effect on brain atrophy. Adults with aMCI were randomly assigned to double-blind treatment with 10 mg/day donepezil hydrochloride or placebo for 48 weeks. Brain MRI scans were acquired at baseline and endpoint. The primary outcome measure was annualized percentage change (APC) in hippocampal volume; the main secondary outcome measure was APC in whole brain volumes. An analysis of variance (ANOVA) model including terms for treatment, site, and age was used to compare the treatment groups. APCs for hippocampal volumes were not significantly different between treatment groups. There were significant differences favoring the donepezil group for total (p = 0.001), ventricular region (p = 0.0002), and cortical region (p = 0.003) whole brain volumes. Although the primary MRI outcome measure was negative, the main secondary MRI outcome measure showed a positive result. These findings suggest a treatment effect of donepezil on brain atrophy in aMCI.

VALIDATION OF ONLINE DATA FROM IDEAS PARTICIPANTS WITH MCI AND AD USING THE BRAIN HEALTH REGISTRY

amyloid PET were better with in-clinic memory measures (0.360.61) than ARC Prices (0.31), a composite of ARC measures showed stronger correlations with both CSF tau (ARC 1⁄4 0.64 vs. in-clinic 1⁄4 0.25; Figure 2) and tau PET (ARC 1⁄4 0.41 vs. in-clinic 1⁄4 0.16). Conclusions: Extremely brief and frequent smartphone cognitive assessments demonstrate excellent reliability and are valid measures of cognition that are sensitive to AD biomarkers. These measures may be particularly sensitive to neurodegeneration in preclinical AD populations. Correlations between cerebrospinal fluid total-tau and ARC smartphone assessments and standard in-clinic assessments (n 1⁄4 30).

The Brain Health Registry: An internet-based platform for recruitment, assessment, and longitudinal monitoring of participants for neuroscience studies

Recruitment, assessment, and longitudinal monitoring of participants for neuroscience studies and clinical trials limit the development of new treatments. Widespread Internet use allows data capture from participants in an unsupervised setting. The Brain Health Registry, a website and online registry, collects data from participants and their study partners.