Michele E. Fitzgerald

White Matter in Aging and Cognition: A Cross-sectional Study of Microstructure in Adults Aged Eighteen to Eighty-Three

Structural brain change and concomitant cognitive decline are the seemingly unavoidable escorts of aging. Despite accumulating studies detailing the effects of age on the brain and cognition, the relationship between white matter features and cognitive function in aging have only recently received attention and remain incompletely understood. White matter microstructure can be measured with diffusion tensor imaging (DTI), but whether DTI can provide unique information on brain aging that is not explained by white matter volume is not known. In the current study, the relationship between white matter microstructure, age, and neuropsychological function was assessed using DTI in a statistical framework that employed white matter volume as a voxel-wise covariate in a sample of 120 healthy adults across a broad age range (18–83). Memory function and executive function were modestly correlated with the DTI measures while processing speed showed the greatest extent of correlation. The results suggest that age-related white matter alterations underlie age-related declines in cognitive function. Mean diffusivity and fractional anisotropy in several white matter brain regions exhibited a nonlinear relationship with age, while white matter volume showed a primarily linear relationship with age. The complex relationships between cognition, white matter microstructure, and white matter volume still require further investigation.

The influence of parental history of Alzheimer's disease and apolipoprotein E ε4 on the BOLD signal during recognition memory

First-degree family history (FH) of sporadic Alzheimers disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimers disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimers disease.

Microstructural diffusion changes are independent of macrostructural volume loss in moderate to severe Alzheimer's disease.

Although it is established that Alzheimers disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging.

fMRI activation during episodic encoding and metacognitive appraisal across the lifespan: risk factors for Alzheimer's disease.

In the present study, we used fMRI to examine the influence of age on two other known risk factors for Alzheimers disease (AD), APOE genotype and parental history of AD (FH status), during episodic encoding (ENC) and metacognitive self-appraisal (SA) paradigms. These paradigms have previously been shown to evoke activity from brain regions that are implicated in AD. First we examined the effect of age across the adult lifespan (age 18-84 years) on cerebral activity in a large sample (n=231) of cognitively healthy individuals. Next we examined a subset (n=155) on whom APOE status and FH status were known. For ENC, we found that increasing age was associated with reduced activity in the ventral temporal lobes and hippocampus. Our analysis of risk factors suggested that FH and age exerted independent effects, but APOE interacted with age such that APOE e4 carriers exhibit age-related increases in activity in the hippocampus. For the metacognitive SA task, increasing age was found to be associated with reduced activity in the medial prefrontal cortex, and increased activity in the mesial temporal lobe, posterior orbital cortex and striatum. Neither AD risk factor significantly modified age-related changes in brain activity during SA. These results suggest that FH and aging are exerting independent effects in both tasks while APOE affected the relationship with age in the hippocampus in one of the two tasks given.

Mapping the Structural Brain Changes in Alzheimer's Disease: The Independent Contribution of Two Imaging Modalities

The macrostructural atrophy of Alzheimers disease (AD) has been fully described. Current literature reports that also microstructural alterations occur in AD since the early stages. However, whether the microstructural changes offer unique information independent from macrostructural atrophy is unclear. Aim of this study is to define the independent contribution of macrostructural atrophy and microstructural alterations on AD pathology. The study involved 17 moderate to severe AD patients and 13 healthy controls. All participants underwent conventional and non conventional MRI (respectively, T1-weighted and diffusion-weighted MR scanning). We processed the images in order to obtain gray and white matter volumes to assess macrostructural atrophy, and fractional anisotropy and mean diffusivity to assess the microstructural damage. Analyses of covariance between patients and controls were performed to investigate microstructural tissue damage independent of macrostructural tissue loss, and vice versa, voxel by voxel. We observed microstructural differences, independent of macrostructural atrophy, between patients and controls in temporal and retrosplenial regions, as well as in thalamus, corticopontine tracts, striatum and precentral gyrus. Volumetric differences, independent of microstructural alterations, were observed mainly in the entorhinal cortex, posterior cingulum, and splenium. Measures of microstructural damage provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD as well as in others thought to be spared. This work expands the understanding of the topography of pathological changes in AD that can be captured with imaging techniques.

P2-028: Rate of whole brain volume decline in a cohort of cognitively normal participants with family history of Alzheimer's disease: A longitudinal study

ments were obtained. An ANCOVA was performed for each of the NP tests and SNI variables, using group membership as fixed factors, and age, sex and years of education as covariates. Only variables with a significant group effect in the ANCOVA (13 NP tests and 33 SNI variables) were used. A canonical correlation analysis was then performed between those NP and SNI variables. Results: We found that the first five of the canonical-variate-pairs (CVP) were statistically significant. The contribution of each of the NP and SNI variables to the canonical correlation depended on the canonical-dimension of each CVP, as follows. The first CVP related to language and attention with bilateral involvement of SNI; the second CVP had a stronger relation to language with elements of memory and attention, and involved mostly left hemispheric SNI; the third CVP related to more global deficits and bilateral SNI contribution; the fourth CVP related mostly to memory with bilateral SNI involvement; finally, the fifth CVP related mostly to attention with left hemispheric SNI involvement. Conclusions: These results reveal how information in the SNI relates to specific aspects of cognitive deficit.

P2-008: Regional gray matter brain volume differences in individuals with a maternal versus paternal family history of Alzheimer's disease

longitudinal MRI. The initial stage of BSI calculation typically involves time-consuming semi-automated delineation of brain on baseline and repeat scans. Automated propagation of the baseline brain region onto the repeat scan has been suggested as a method to reduce operator time. This study compares the performance, in terms of BSI values, of a novel automated propagation method with semi-automatic segmentation based on BSI values. Methods: Twenty-five AD, 74 MCI and 54 control subjects were selected from the Alzheimer’s Disease Neuroimaging Initiative cohort, each with a volumetric, T1-weighted 1.5T scan at baseline and 12 months. Scans from both time points were first semi-automatically segmented, with a threshold-based technique. The baseline scan was then registered to the repeat using both affine and freeform registration and the derived registration parameters were used to transform the baseline region to the repeat image. Morphological operations (1 erosion, 2 conditional dilations) were applied to improve boundary location. Finally, whole-brain BSIs were calculated for each subject by registering the semi-automatically segmented repeat and the automatically segmented (propagated) repeat separately to the baseline. Agreement between the resulting semi-automatic and propagated BSIs was calculated by plotting the 95% levels (1.96 std). Results: Limits of agreement were found to be narrow: for 95% of cases, propagated BSIs were between 0.108% greater and 0.128% lower than the semi-automated method (figure). There was a slight but significant bias (p 0.05) with semi-automated BSIs being 0.01% of brain volume higher; this is much lower than the BSI scan-rescan reproducibility (0.2%) and very much lower than typical annual brain atrophy in AD ( 2%). For low/negative rates of atrophy the semi-automated BSI tends to be slightly smaller than propagated, and for larger rates the semi-automated BSI tends to be larger. Conclusions: Although there is a small degree of bias the propagation method is comparable to the conventional semi-automated methods in terms of the BSI result and saves operator time.

IC-P2-157: fMRI activation in medial temporal lobe correlates with monthly decline rate of memory function in mild cognitive impairment patients

Background: This study is aimed to assess the relationship between BOLD fMRI memory task activation and cognition decline rate in nondemented older adults as well as in mild cognitive impairment amnestic (MCI) patients who are at greater risk for developing Alzheimer disease (AD). Methods: Twenty-nine cognitively normal middleage controls (55-60y), 14 MCI patients (65-75y) and 9 cognitively normal elder controls (65-75y) participated this longitudinal study. All subjects had their first neuropsychological assessment with a full set of cognitive battery test when they also performed a memory-encoding fMRI scan. The MCI and elderly control subjects had a two-year follow-up while the middle-aged controls had a 4-year follow-up. The same set of cognitive battery test was given during the follow-up visit. The monthly decline rates of Rey Auditory Verbal Learning Test (RAVLT) score were calculated for each subject after adjusting for their first-visit age, gender, year of education. A voxel-based multiple linear regression model was used to exam the relationship between first-time visit fMRI activation and decline rate of RAVLT scores. Results: During their first visit, the MCI patients exhibited less activity in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. The monthly decline rate of RAVLT trial7 score was found significantly correlated with the right insular cortex BOLD activation signal during the first-visit. Such a correlation is not significant among the elderly and middle-age controls. Conclusions: Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. The close correlation between MTL BOLD signal and the longitudinal cognitive decline rate in MCI subjects suggests the predicative value of fMRI signal in AD.

IC-P3-198: Memory formation in middle-aged adults: Dynamics of the bold signal across repetitions

Background: Memory formation and retrieval is a dynamic process that employs a network of brain regions. Here we aim to investigate the neural correlates of memory formation in healthy middle-aged individuals using an event-related fMRI paradigm. Methods: Participants were asked to remember forty simple line drawings of objects that were presented and repeated three times in a pseudo-random order while collecting fMRI data. Two conceptual approaches were used to analyze the fMRI images. First, we used a traditional approach with parametric modulation based on repetition to investigate which regions showed attenuation in the BOLD response over repetitions. In the second approach, we examined how the hippocampus interacts with other brain regions across repetitions. Using an in-house variant of psychophysiological interactions (PPI) to investigate context-dependent connectivity, we were able to identify regions where connectivity with the left and right hippocampus did not change over repetition (repetition-invariant connectivity [RI]) and regions that changed with repetition (repetitiondependent connectivity [RD]). Results: The first approach revealed numerous regions exhibiting an adaptation response including the fusiform gyrus, parahippocampal gyrus, hippocampus, amygdala, ventral occipital lobes, and lateral frontal lobes. The second approach provides a dynamic picture of memory representation in the network over time. Early memory representation, at least for visual stimuli, appears dependent upon synchronous activation of the hippocampus, occipital lobes, and frontal regions; whereas representation during later encoding requires less connectivity between hippocampus and visual processing areas [RD], but continues to evoke similar connectivity with frontal regions [RI]. Conclusions: Importantly, these findings demonstrate a need to consider the effects of repetition on the BOLD signal in any memory paradigm. In addition to informing our understanding of normal memory function in terms of functional brain networks, we believe these methods will be critical to investigating memory change in aging and disease. Specifically, our in-house variant of PPI allows investigators to identify which connections, involved in a cognitive process, might be altered between groups. In the future, we aim at investigating the impact of risk-factors for Alzheimer’s disease on the alteration of these memory systems.

P-054: Decreased posterior cingulate bold response in healthy middle-aged adults with a parental history of Alzheimer’s disease

ment of amyloid deposits (1.5mo), A 42 can readily be drawn into the plasma, but not after the transition to amyloid deposition, demonstrating that amyloid deposition efficiently sequesters A 42 disallowing access to the blood. The experimental approach described in the present study could provide a method to determine when a given individual has begun to deposit amyloid in the brain and is thus at higher risk for developing AD.