Po-Haong Lu

Dysregulated brain development in adult men with schizophrenia: A magnetic resonance imaging study

BACKGROUND Recent imaging evidence suggests that normal brain development/maturation of the frontal lobes and association areas is a well-regulated process consisting of continued myelination and expansion of white matter volumes into the late 40s accompanied by complementary reductions in gray matter volumes. The possibility that a dysregulation of this process may contribute to the syndrome of schizophrenia was investigated using magnetic resonance imaging. METHODS Fifty-two normal adult males and 35 males with schizophrenia underwent magnetic resonance imaging. Coronal images were acquired using pulse sequences that maximized myelin signal. The age-related change in the gray to white matter ratio was used as a measure of developmental dysregulation in the schizophrenic subjects and contrasted to the age-related changes of the normal control group. RESULTS Regression analyses on frontal and temporal gray to white matter ratio yielded highly significant interactions of diagnosis and age for both regions (p =.0003 and p =.01, respectively). In the normal group, both frontal and temporal gray to white matter ratios decreased significantly and linearly across the age range. In contrast, neither ratio showed meaningful age-related change in the schizophrenia group. Thus, differences in gray to white matter ratio between the groups increased markedly with age, driven primarily by the absence of a white matter volume expansion in the patient group. CONCLUSIONS The absence of the normal complementary volume changes in the gray and white matter with age in the schizophrenic sample suggests that this dynamic developmental process is dysregulated in adult schizophrenic subjects. The importance of myelination to the continued maturation and normal functioning of the brain has implications for the diagnosis, treatment, and prognosis of schizophrenia.

Donepezil delays progression to AD in MCI subjects with depressive symptoms

Objective: To determine whether the presence of depression predicts higher rate of progression to Alzheimer disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and whether donepezil treatment beneficially affect this relationship. Methods: The study sample was composed of 756 participants with aMCI from the 3-year, double-blind, placebo-controlled Alzheimers Disease Cooperative Study drug trial of donepezil and vitamin E. Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and participants were followed either to the end of study or to the primary endpoint of progression to probable or possible AD. Results: Cox proportional hazards regression, adjusted for age at baseline, gender, apolipoprotein genotype, and NYU paragraph delayed recall score, showed that higher BDI scores were associated with progression to AD (p = 0.03). The sample was stratified into depressed (BDI score ≥10; n = 208) and nondepressed (BDI <10; n = 548) groups. Kaplan-Meier analysis showed that among the depressed subjects, the proportion progressing to AD was lower for the donepezil group than the combined vitamin E and placebo groups at 1.7 years (p = 0.023), at 2.2 years (p = 0.025), and remained marginally lower at 2.7 years (p = 0.070). The survival curves among the three treatment groups did not differ within the nondepressed participants. Conclusions: Results suggest that depression is predictive of progression from amnestic mild cognitive impairment (aMCI) to Alzheimer disease (AD) and treatment with donepezil delayed progression to AD among depressed subjects with aMCI. Donepezil appears to modulate the increased risk of AD conferred by the presence of depressive symptoms.

A tensor-based morphometry study of brain volume changes in symptomatic and pre-symptomatic patients with familial Alzheimer's disease

Background: Resting state fMRI shows differences in default mode network (DMN) connectivity in cognitively normal (CN) APOE4 non-carriers (-) vs. carriers (+) and CN elderly vs. Alzheimer’s disease (AD). The posterior cingulate cortex (PCC) plays a central role in the DMN and is a brain region in which amyloid-b deposition occurs in early AD. This study examined disruption of PCC connectivity as a function of APOE4 status and AD in a group of age and education matched older adults. Methods: We scanned 56 CN-, 56 CN+, 9 AD-, 19 AD+ at 3T. Functional connectivity, although attractive conceptually, is actually measured as the strength of correlation between a reference time course and the time course of other voxels in the brain. Hence the terms connectivity and correlation are used interchangeably throughout. A seed was placed in the PCC (-2, -45, 34; radius1⁄4 6.00 mm) for connectivity analyses. We used a 2 x 2 factorial design to examine the effects of APOE4 status and clinical diagnostic category (CN vs. AD) at a threshold of FDR p< .05. Results: The main effect of APOE4 was 1) decreased direct PCC connectivity to the precuneus, and right supramarginal and right superior temporal gyri and 2) decreased inverse PCC connectivity to the anterior cingulate, left SMA, left superior medial, and left superior frontal gyri. The main effect of AD (vs. CN) was 1) decreased direct PCC connectivity to the middle cingulate cortex, precuneus, cuneus, and right calcarine and right superior occipital gyri, and 2) decreased inverse PCC connectivity to the right posterior temporal lobe, left SMA, left middle and superior frontal gyri, and right inferior and middle frontal gyri. The interaction showed decreased direct PCC connectivity to the left inferior frontal, precentral, and postcentral gyri and the left insular lobe; and, decreased inverse PCC connectivity to the left rectus gyrus and left middle and superior orbital gyri. Conclusions: Our results indicate there are similarities in the patterns of altered PCC connectivity according to APOE4 status and AD, with more extensive alterations in AD. Furthermore, alterations in PCC connectivity in AD vary as a function of APOE4 status.

Age-related memory decline is mediated by processing speed and myelin integrity

ated with slowing in CPS, reduced white matter integrity, and higher risk of conversion toMCI. These findings suggest that depressionmay reflect underlying pathological changes in white matter that may also be associated with prodromal AD. Thus, assessment of depressive symptomsmay be a potentially useful clinical marker in identifying at-risk individuals who are most likely to progress to AD.

Age-associated memory impairment increases risk of conversion to MCI and dementia

Background: Age-associated memory impairment (AAMI) was initially conceptualized to describe a feature of cognitive aging. It is defined as memory performance consistent with normal age-matched peers but significantly lower than younger adults. However, mounting evidence suggests that AAMI may represent a harbinger of future cognitive decline and dementia rather than simply normal cognitive aging. The objective of this study was to investigate whether a diagnosis of AAMI increases risk of cognitive decline and conversion to Mild Cognitive Impairment (MCI) or dementia. Methods: 1549 subjects (551males) from the National Alzheimer’s Coordinating Center (NACC) who were initially diagnosed with normal cognition at baseline and had at least 3 follow-up visits were included in the present study. Subjects ranged in age from 51 to 97 years (mean1⁄474.39, sd1⁄48.4). Baseline performance on the delayed recall of Logical Memory Story A was examined, and individuals scoring more than 1 standard deviation below themean of younger adults (mean age1⁄431.1 years, sd1⁄411.2) were classified as having AAMI. Survival analysis was performed using Cox regression to determine whether a diagnosis of AAMI predicted progression to MCI or dementia. Results: In the current sample, 486 subjects (31.4%) met criteria for AAMI while 1063 were considered normal (NC) compared to younger adults. The proportion of subjects who converted to MCI or dementia was significantly higher (x 2 1⁄428.65, P<.001) in the AAMI group (n1⁄4117, 24.1%) compared to the NC group (n1⁄4140, 13.2%). The average time to conversion in these subjects was 2.5 years (sd1⁄41.2). After adjusting for baseline age, gender, years of education, and APOE genotype, Cox regression analysis revealed that a classification of AAMI at baseline was significantly (P<.001) associated with increased risk of converting to MCI or dementia (HR1⁄41.93, 95% CI 1⁄4 1.44 2.58). Conclusions: Among individuals with normal cognition, those meeting criteria for AAMI had a higher risk of conversion to MCI or dementia. Thus, AAMI may represent an early stage of cognitive decline, even preceding MCI, and may be diagnostically useful in identifying individuals at risk for eventual development of dementia.

Myelin integrity mediates age-related slowing in cognitive processing speed in a sample of healthy elderly men

concerned the subiculum (r1⁄4 0.64; p< 10-5), a slighter effectwas found for CA1 (r 1⁄4 0.36; p 1⁄4 0.004), whereas the other subfields were spared (r 1⁄4 0.02; p 1⁄4 0.90). Subicular volume positively correlated to WM density in the posterior CC, the cingulum bundle and the fornix (Figure b). This association was still significant when controlling for age. No significant correlation was found for CA1 nor the Other subfields. Conclusions: We showed that with aging, WM undergoes extensive changes encompassing frontal but also limbic areas. Besides, WM density in limbic areas is correlated to the shrinkage of the subiculum, the major hippocampal output sending fibres through the fornix and to the retrosplenial cortex. It is thus likely that age-related alterations in the subiculum and in these WM tracts are related, and together participate to the impairment of a common brain network.

Age-associated memory impairment is associated with greater rate of longitudinal brain atrophy

N 105 203 159 98 63 116 85 Age in years 75.7 (5.2) 75.4 (7.3) 74.5 (7.0) 71.1 (7.3) 76.8 (5.7) 75.1 (6.6) 78.0 (7.1) <0.0001 Gender % male 51% 66% 60% 58% 83% 54% 69% <0.0001 Converters % 38% 48% 36% 59% 0.01 ApoE4 carrier % 20% 45% 69% 59% 46% 53% 61% 0.2 MMSE 29.1 (1.0) 27.2 (1.8) 26.7 (1.7) 27.2 (1.8) 26.9 (1.8) 27.1 (1.9) 26.6 (1.6) 0.2 CSF biomarkers Tau (baseline) y 69 (28) 93 (54) 114 (53) 92 (46) 80 (38) 110 (57) 119 (63) 0.01 P-tau (baseline) y 24 (13) 31 (17) 41 (17) 34 (18) 29 (13) 39 (18) 38 (18) 0.02 Abeta1-42 (baseline) y 209 (54) 175 (59) 145 (40) 166 (61) 156 (49) 166 (53) 154 (50) 0.6

IC-P3-197: Apolipoprotein genotype predicts rate of brain atrophy in healthy elderly adults: A tensor-based morphometry study

delineated regions. Results: Absolute volumes from FreeSurfer differed from manual volumes to different extents depending on region and subject group but were largely due to differences in protocols with more temporal stem white matter included in FreeSurfer regions. Volume differences (FreeSurfer-manual) were different between controls and SD (p 0.05), but not between control-AD or between AD-SD groups. Importantly however, expressed as fraction of control volume the FreeSurfer results showed a very similar pattern of loss to that found with manual measures (Table). In the SD group the most severely atrophied regions were the left entorhinal cortex, left amygdala and left parahippocampal gyrus. Furthermore, greatest atrophy in the AD group was shown bilaterally in the entorhinal cortex and hippocampus. There was no evidence for left-right asymmetry in the control or AD groups. In the SD group the left temporal volumes were significantly smaller than the equivalent right-sided structures (p 0.0001) (Figure). Conclusions: Despite absolute volumes differing for FreeSurfer and manual segmentations, between-group comparisons revealed remarkably similar patterns of loss with the two methods: in AD symmetrical losses were most marked in the entorhinal cortex and hippocampus whereas SD showed profound asymmetrical, predominantly left-sided, atrophy affecting in particular the anterior and medial temporal lobe structures. IC-P3-196 CLINICAL EVALUATION OF F-LABELED AV138 FOR PET AMYLOID IMAGING IN ALZHEIMER’S DISEASE