Gloria C. Chiang

Nonlinear time course of brain volume loss in cognitively normal and impaired elders

The goal was to elucidate the time course of regional brain atrophy rates relative to age in cognitively normal (CN) aging, mild cognitively impairment (MCI), and Alzheimers disease (AD), without a priori models for atrophy progression. Regional brain volumes from 147 cognitively normal subjects, 164 stable MCI, 93 MCI-to-AD converters and 111 ad patients, between 51 and 91 years old and who had repeated 1.5 T magnetic resonance imaging (MRI) scans over 30 months, were analyzed. Relations between regional brain volume change and age were determined using generalized additive models, an established nonparametric concept for approximating nonlinear relations. Brain atrophy rates varied nonlinearly with age, predominantly in regions of the temporal lobe. Moreover, the atrophy rates of some regions leveled off with increasing age in control and stable MCI subjects whereas those rates progressed further in MCI-to-AD converters and AD patients. The approach has potential uses for early detection of AD and differentiation between stable and progressing MCI.

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.

MRI Signatures of Brain Macrostructural Atrophy and Microstructural Degradation in Frontotemporal Lobar Degeneration Subtypes

Brain magnetic resonance imaging (MRI) studies have demonstrated regional patterns of brain macrostructural atrophy and white matter microstructural alterations separately in the three major subtypes of frontotemporal lobar degeneration (FTLD), which includes behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). This study was to investigate to what extent the pattern of white matter microstructural alterations in FTLD subtypes mirrors the pattern of brain atrophy, and to compare the ability of various diffusion tensor imaging (DTI) indices in characterizing FTLD patients, as well as to determine whether DTI measures provide greater classification power for FTLD than measuring brain atrophy. Twenty-five patients with FTLD (13 with bvFTD, 6 with SD, and 6 with PNFA) and 19 healthy age-matched control subjects underwent both structural MRI and DTI scans. Measurements of regional brain atrophy were based on T1-weighted MRI data and voxel-based morphometry. Measurements of regional white matter degradation were based on voxelwise as well as regions-of-interest tests of DTI variations, expressed as fractional anisotropy, axial diffusivity, and radial diffusivity. Compared to controls, bvFTD, SD, and PNFA patients each exhibited characteristic regional patterns of brain atrophy and white matter damage. DTI overall provided significantly greater accuracy for FTLD classification than brain atrophy. Moreover, radial diffusivity was more sensitive in assessing white matter damage in FTLD than other DTI indices. The findings suggest that DTI in general and radial diffusivity in particular are more powerful measures for the classification of FTLD patients from controls than brain atrophy.

Progression of white matter degeneration in amyotrophic lateral sclerosis: A diffusion tensor imaging study

Abstract Whether longitudinal diffusion tensor MRI imaging (DTI) can capture disease progression in patients with amyotrophic lateral sclerosis (ALS) is unclear. The primary goal of this study was to determine if DTI detects progression of the corticospinal tracts (CST) degeneration in ALS. Seventeen ALS patients and 19 age- and gender-matched healthy controls were scanned with DTI at baseline for cross-sectional analyses. For longitudinal analyses, the ALS patients had repeat DTI scans after eight months. Tractography of the CST was used to guide regions-of-interest (ROI) analysis and complemented by a voxelwise analysis. Cross-sectional study found that baseline FA of the right superior CST was markedly reduced in ALS patients compared to controls. The FA reductions in this region correlated with the disease severity in ALS patients. Longitudinal study found that FA change rate of the right superior CST significantly declined over time. In conclusion, longitudinal DTI study captures progression of upper motor fiber degeneration in ALS. DTI can be useful for monitoring ALS progression and efficacy of treatment interventions.

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.

MR volumetry of brain and CSF in fetuses referred for ventriculomegaly.

OBJECTIVE The purpose of this study was to validate the method of performing fetal brain volumetry. In particular, our objectives were to assess which imaging plane is most reproducible for the performance of brain volumetry measurements and to ascertain inter- and intraobserver variability in determining brain volume in fetuses referred for ventriculomegaly (VM). SUBJECTS AND METHODS In this prospective study, 50 consecutive fetuses at 17-37 weeks of gestational age referred for MRI for VM underwent fast spin-echo T2-weighted imaging. Supratentorial brain parenchyma, lateral ventricles, and extraaxial and cerebellar volumetric measurements were manually obtained in three planes by three radiologists. Inter- and intraobserver variability were assessed. The relationship between volumes and gestational age, and lateral ventricular diameter were assessed. RESULTS Volumes increased with gestational age. The presence of VM correlated with increased lateral ventricle diameter. The effect of imaging plane was negligible. Inter- and intraobserver variability were low. CONCLUSION Supratentorial parenchyma and lateral ventricular volumes can be reliably measured on fetal MRI, and imaging plane was not an important factor in measurement. Further studies are needed to correlate these indexes with long-term postnatal outcomes.

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

The apolipoprotein APOE4 allele confers greater risk of Alzheimers disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.

Cerebral Microbleeds, CSF p-Tau, and Cognitive Decline: Significance of Anatomic Distribution

BACKGROUND AND PURPOSE: Cerebral microbleeds are associated with aging, hypertension, and Alzheimer disease. Microbleeds in a lobar distribution are believed to reflect underlying amyloid angiopathy, whereas microbleeds in the deep gray matter and infratentorial brain are commonly seen with hypertension. However, it is unknown how microbleeds in either distribution are related to Alzheimer pathogenesis. The purpose of this analysis was to test whether lobar and deep gray/infratentorial microbleeds demonstrate differential associations with CSF amyloid-β and phosphorylated tau 181 protein levels and longitudinal cognitive decline. MATERIALS AND METHODS: A total of 626 subjects (151 cognitively normal, 389 with mild cognitive impairment, and 86 with Alzheimer disease) from the Alzheimers Disease Neuroimaging Initiative who had undergone 3T MR imaging and lumbar puncture were included in the analysis. The number and location of microbleeds were assessed visually. Associations between lobar or deep gray/infratentorial microbleeds with CSF amyloid-β levels, abnormal CSF phosphorylated tau 181 protein levels, and longitudinal cognitive decline were assessed by using ordinary least-squares, logistic, and mixed-effects regression models while adjusting for covariates. RESULTS: Having ≥3 lobar microbleeds was associated with lower levels of CSF amyloid-β (P = .001). After adjusting for CSF amyloid-β level, lobar microbleeds were independently associated with a higher likelihood of having an abnormal CSF phosphorylated tau 181 protein level (P = .004). Lobar microbleeds were associated with accelerated longitudinal cognitive decline (P = .007). Deep gray/infratentorial microbleeds revealed no significant associations. CONCLUSIONS: The distribution of microbleeds revealed different associations with amyloid-β and phosphorylated tau 181 protein levels and cognition. Lobar and deep gray/infratentorial microbleeds should be considered separately with regard to Alzheimer disease pathogenesis.

Longitudinal change in magnetic susceptibility of new enhanced multiple sclerosis (MS) lesions measured on serial quantitative susceptibility mapping (QSM).

To measure the longitudinal change in multiple sclerosis (MS) lesion susceptibility using quantitative susceptibility mapping (QSM).

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.