Duygu Tosun | University of California, San Francisco (original) (raw)

Papers by Duygu Tosun

The American Journal of Geriatric Psychiatry, 2015

Investigate the association of chronic depressive symptomatology (chrDS) with cortical atrophy ra... more Investigate the association of chronic depressive symptomatology (chrDS) with cortical atrophy rates and conversion to Alzheimer dementia (AD) over 3 years in mild cognitive impairment (MCI). In a multicenter, clinic-based study, MCI elderly participants were selected from the Alzheimer's Disease Neuroimaging Initiative repository, based on availability of both serial structural magnetic resonance imaging and chrDS endorsed on three depression-related items from the Neuropsychiatric Inventory Questionnaire (chrDS N = 32 or no depressive symptoms N = 62) throughout follow-up. Clinical and laboratory investigations were performed every 6 months during the first 2 years and yearly thereafter (median follow-up: 3 years; interquartile range: 1.5-4.0 years). Cortical atrophy rates in 16 predefined frontotemporoparietal regions affected in major depression and AD and the rate of incident AD at follow-up. ChrDS in a single domain amnestic MCI sample were associated with accelerated cortical atrophy in the frontal lobe and anterior cingulate but not with atrophy rates in temporomedial or other AD-affected regions. During follow-up, 38 participants (42.7%) developed AD. Participants with chrDS had 60% shorter conversion time to AD than those without depressive symptoms. This association remained significant in survival models adjusted for temporomedial atrophy rates and showed the same trend in models adjusted for frontal cortical atrophy rate, which all increased the risk of AD. Our results suggest that chrDS associated with progressive atrophy of frontal regions may represent an additional risk factor for conversion to dementia in MCI as opposite to representing typical prodromal AD symptomatology.

Alzheimer's & Dementia, 2014

Background: The reproducibility of algorithms for longitudinal hippocampal percentage volume chan... more Background: The reproducibility of algorithms for longitudinal hippocampal percentage volume change (PVC) measurement has direct repercussions on clinical trial design in diseases such as Alzheimer's (AD). The ADNI1 study provides an excellent data set on which to assess the back to back (BTB) reproducibility of hippocampal PVC as it acquired two identical MPRAGEs at each patient visit (Cover et al. Psychiatry Res. 2011;193:182-190). Methods: The BTB PVC for the baseline and 1 year MPRAGEs for 75 subjects (19 healthy controls, 38 MCI and 18 AD) was calculated using multiple algorithms. Algorithms included FreeSurfer/ ReconAll/longitudinal v5.3.0, FSL/FIRST v5.0.4, AdaBoost, manual, multiple-atlas propagation and segmentation (MAPS) and MAPS with the hippocampal boundary shift integral option (MAPS-HBSI) (Leung et al. NeuroImage 2010;51:1345-1359). The difference between the PVC's (non annualized) was calculated (BTBD). To compare the performance of any two algorithms, the absolute values of the BTBD for each subject were compared and the algorithm with the smallest absolute BTBDs was considered superior. Results: MAPS-HBSI had substantially better reproducibilities than all other algorithms. MAPS-HBSI had smaller absolute BTBD for the left hippocampus in 0.69 (FreeSurfer), 0.71 (FIRST), 0.72 (Ada-Boost), 0.68 (manual), 0.81 (MAPS) fraction of subjects, all which had a p-value smaller than 0.002. The median absolute value of the BTBD (MAVBTBD) were 2.36 (FreeSurfer), 2.19 (FIRST), 2.61 (AdaBoost), 2.75 (manual), 3.41 (MAPS) and 1.29 (MAPS-HBSI)

Journal of behavioral and brain science, 2012

The degree to which one identifies as male or female has a profound impact on one's life. Yet... more The degree to which one identifies as male or female has a profound impact on one's life. Yet, there is a limited understanding of what contributes to this important characteristic termed gender identity. In order to reveal factors influencing gender identity, studies have focused on people who report strong feelings of being the opposite sex, such as male-to-female (MTF) transsexuals. To investigate potential neuroanatomical variations associated with transsexualism, we compared the regional thickness of the cerebral cortex between 24 MTF transsexuals who had not yet been treated with cross-sex hormones and 24 age-matched control males. Results revealed thicker cortices in MTF transsexuals, both within regions of the left hemisphere (i.e., frontal and orbito-frontal cortex, central sulcus, perisylvian regions, paracentral gyrus) and right hemisphere (i.e., pre-/post-central gyrus, parietal cortex, temporal cortex, precuneus, fusiform, lingual, and orbito-frontal gyrus). These f...

Alzheimer's & Dementia, 2014

T1 image,allowing assessment of volume, mean diffusivity (MD) and fractional anisotropy (FA) in t... more T1 image,allowing assessment of volume, mean diffusivity (MD) and fractional anisotropy (FA) in these regions. Longitudinal DT images were coregistered using tensor-based registration to examine FA, MD, axial and radial diffusivity (AD and RD) in the cingulum and fornix (ICBM-DTI-81 atlas). Whole brain and ventricular volumes were segmented using semi-automated techniques and atrophy/expansion rates calculated using the boundary shift integral. Linear regression, adjusting for age and gender, was used to assess differences in the imaging measures and their mean rates of change between MC and non-carrier groups. Results: The cohort comprised 12 mutation-negative participants and 17 MCs, six of whom reported symptoms at follow-up. MCs were on average 6.7 years younger than their parental age at symptom onset. MCs had smaller thalamic volumes bilaterally at baseline and follow-up, but there was little evidence for a difference in the rate of change over this interval. There was weak evidence for higher FA in bilateral thalamus and decreased AD in right cingulum at baseline and follow-up and lower right thalamic MD at baseline in MCs. When examined separately, MCs who became symptomatic had higher thalamic FA at follow-up than MCs who remained asymptomatic but both MC groups had smaller thalamic volumes than non-carriers. No significant group differences were evident for other imaging measures. Conclusions: Lower thalamic volumes and altered diffusivity were evident in FAD MCs compared to non-carriers at a stage when whole brain volumes and atrophy rates were similar. Thalamic FA in particular merits further investigation as a marker of early disease progression in larger FAD cohorts.

NeuroImage, 2005

With the improvements in techniques for generating surface models from magnetic resonance (MR) im... more With the improvements in techniques for generating surface models from magnetic resonance (MR) images, it has recently become feasible to study the morphological characteristics of the human brain cortex in vivo. Studies of the entire surface are important for measuring global features, but analysis of specific cortical regions of interest provides a more detailed understanding of structure. We have previously developed a method for automatically segmenting regions of interest from the cortical surface using a watershed transform. Each segmented region corresponds to a cortical sulcus and is thus termed a bsulcal region.Q In this work, we describe two important augmentations of this methodology. First, we describe a user interface that allows for the efficient labeling of the segmented sulcal regions called the Program for Assisted Labeling of Sulcal Regions (PALS). An additional augmentation allows for even finer divisions on the cortex with a methodology that employs the fast marching technique to track a curve on the cortical surface that is then used to separate segmented regions. After regions of interest have been identified, we compute both the cortical surface area and gray matter volume. Reliability experiments are performed to assess both the long-term stability and short-term repeatability of the proposed techniques. These experiments indicate the proposed methodology gives both highly stable and repeatable results.

Journal of Neuroimaging, 2013

To determine if a voxel-wise &amp... more To determine if a voxel-wise "co-analysis" of structural and diffusion tensor magnetic resonance imaging (MRI) together reveals additional brain regions affected in mild cognitive impairment (MCI) and Alzheimer's disease (AD) than voxel-wise analysis of the individual MRI modalities alone. Twenty-one patients with MCI, 21 patients with AD, and 21 cognitively normal healthy elderly were studied with MRI. Maps of deformation and fractional anisotropy (FA) were computed and used as dependent variables in univariate and multivariate statistical models. Univariate voxel-wise analysis of macrostructural changes in MCI showed atrophy in the right anterior temporal lobe, left posterior parietal/precuneus region, WM adjacent to the cingulate gyrus, and dorsolateral prefrontal regions, consistent with prior research. Univariate voxel-wise analysis of microstructural changes in MCI showed reduced FA in the left posterior parietal region extending into the corpus callosum, consistent with previous work. The multivariate analysis, which provides more information than univariate tests when structural and FA measures are correlated, revealed additional MCI-related changes in corpus callosum and temporal lobe. These results suggest that in corpus callosum and temporal regions macro- and microstructural variations in MCI can be congruent, providing potentially new insight into the mechanisms of brain tissue degeneration.

Human Brain Mapping, 2014

Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modal... more Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remain a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer's disease, in which data from three MRI modalities are available.

Brain, 2011

Epilepsy is a prevalent childhood neurological disorder, but there are few prospective quantitati... more Epilepsy is a prevalent childhood neurological disorder, but there are few prospective quantitative magnetic resonance imaging studies examining patterns of brain development compared to healthy controls. Controlled prospective investigations initiated at or near epilepsy onset would best characterize the nature, timing and course of neuroimaging abnormalities in paediatric epilepsy. In this study, we report the results of a deformation-based morphometry technique to examine baseline and 2-year prospective neurodevelopmental brain changes in children with new and recent onset localization-related epilepsies (n = 24) and idiopathic generalized epilepsies (n = 20) compared to healthy controls (n = 36). Children with epilepsy demonstrated differences from controls in baseline grey and white matter volumes suggesting antecedent anomalies in brain development, as well as abnormal patterns of prospective brain development that involved not only slowed white matter expansion, but also abnormalities of cortical grey matter development involving both greater and lesser volume changes compared to controls. Furthermore, abnormal neurodevelopmental changes extended outside the cortex affecting several subcortical structures including thalamus, cerebellum, brainstem and pons. Finally, there were significant differences between the epilepsy syndromes (localization-related epilepsies and idiopathic generalized epilepsies) with the idiopathic generalized epilepsies group showing a more disrupted pattern of brain structure both at baseline and over the 2-year interval.

Understanding the function of the human brain cortex is a primary goal in human brain mapping. Me... more Understanding the function of the human brain cortex is a primary goal in human brain mapping. Methods to unfold and flatten the cortical surface for visualization and measurement have been described in previous literature; but comparison across multiple subjects is still ...

Alzheimer's & Dementia, 2013

Alzheimer's & Dementia, 2013

Alzheimer's & Dementia, 2013

Background: Impairment in instrumental activities of daily living (IADL) begins as individuals wi... more Background: Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). The objective of this study was to investigate the relationship between regional FDG metabolism and IADL cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods: Four hundred and two subjects (104 CN, 203 MCI, 95 AD dementia at baseline) participating in the Alzheimer's Disease Neuroimaging Initiative study underwent clinical assessments every 6 to 12 months for up to 3 years and FDG-PET at baseline. The subjective informant-based Functional Activities Questionnaire (FAQ) was used to assess IADL. We first performed data reduction analyses to reduce 35 FDG regions to 6 regions that appeared best associated with total FAQ score and were significant after adjusting for multiple tests. These 6 FDG regions were entered into a general linear model with backward elimination (p<0.05) assessing their cross-sectional relation to baseline FAQ and a mixed random and fixed coefficient linear longitudinal regression model assessing their relation to FAQ over time. Analyses included the following covariates: diagnosis, demographics, Apolipoprotein E4 (APOE4) carrier status, memory and executive function, and behavioral factors. Results: The cross-sectional analysis showed that middle frontal (p¼0.003) and orbitofrontal hypometabolism (p¼0.009) were significantly associated with greater IADL impairment, and the interaction of diagnosis with posterior cingulate (p<0.0001) and with parahippocampal hypometabolism (p¼0.0008) showed a steeper decline in IADL performance as FDG metabolism decreasedfor the AD dementia group relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal (p¼0.0005) and posterior cingulate hypometabolism (p¼0.004) were significantly associated with greater rate of increase in IADL impairment over time. Conclusions: These results suggest that frontal and medial parietal synaptic dysfunction relates to functional decline at baseline and over time across the AD spectrum independent of demographics, APOE4 carrier status, memory and executive function performance, and behavioral factors.

Alzheimer's & Dementia, 2013

Background: Alzheimer's disease (AD) causes widespread disruptions of large-scale neural communic... more Background: Alzheimer's disease (AD) causes widespread disruptions of large-scale neural communication as measured by resting-state functional connectivity magnetic resonance imaging (rs-fcMRI). However, healthy aging is also associated with altered rs-fcMRI, particularly in the default-mode network (DMN), but the extent of these reductions is unknown. Previous studies of healthy aging have primarily focused on a limited number of brain regions and have been cross-sectional in design Therefore it often remains difficult to differentiate early AD-related rs-fcMRI changes from healthy aging. Methods: This study investigates changes in functional connectivity in cognitively normal participants both cross-sectionally (N¼356) and longitudinally (mean follow up time ¼ 3 years, N¼95). Each participant was clinically evaluated using the clinical dementia rating scale (CDR) and determined to be cognitively normal at baseline and follow-up. rs-fcMRI was acquired and standard pre-processing procedures were used. Functional connectivity was calculated by measuring the temporal correlation between the blood oxygen level dependent time-series in two regions. We then calculated mean correlation strength within 5 networks (DMN, Dorsal Attention, Control, Salience, and Sensorimotor) and between pairs of networks. Results: Increasing age lead to decreased correlations within the DMN and salience network, as well as reduced anti-correlations between the DMN and dorsal attention network. We also noted a significant interaction of age and the presence of an APOE e4 allele in the connection between posterior cingulate cortex and medial prefrontal regions where there was a more dramatic effect of age in those with an e4 allele. Notably, the effects described in the cross-sectional cohort were replicated in the longitudinal cohort. Finally, the rate of change with respect to age was found to be comparable in both samples. Conclusions: These results demonstrate that cognitively normal aging is associated with decreases in functional connectivity in specific networks compared to a more general loss in AD. These results also demonstrate that APOE has a focal effect on changes in connectivity with age. The results are critical to the interpretation of AD studies because they will allow for the discrimination of changes due to AD compared to those simply due to advancing age.

Alzheimer's & Dementia, 2011

Alzheimer's & Dementia, 2011

Alzheimer's & Dementia, 2010

Background: It is now well established -based on longitudinal brain MRIthat MCI and AD are associ... more Background: It is now well established -based on longitudinal brain MRIthat MCI and AD are associated with higher rates of brain tissue loss than normal aging. Yet little is known about which parts of the brain loose tissue faster than others and how the losses relate to cognitive decline. A major difficulty in solving this puzzle has been lack of an accurate model for progression of brain tissue loss. To address this difficulty, we aimed to elucidate the dependence of regional brain tissue loss on age and on cognitive impairment. Methods: We measured regional brain volumes from ADNI MRI data of 274 MCI subjects, 101 AD patients and 146 controls, all between 55 to 90 years old. All subjects had between 3 and 6 serial 1.5T MRI scans over 2 1 / 2 years. To determine the dependence of volume loss on age and cognitive impair-ment, we treated variations in volume as well as in age and cognition across subjects as random variables and used a generalized additive model statistic to impose smooth variations on the variables while simultaneously accounting for fixed and random variations. This approach relaxed the need for explicitly parameterizing progression of volume loss while providing more data driven solutions. Results: Hippocampal volume loss as a function of age is shown in the figure top panel (estimated mean and residual values are shown), separately for control, MCI, and AD subjects. Hippocampal volume loss as a function of cognitive impairment (ADAScog) is shown in the bottom panel. Linear progression would be a straight line. This shows that progression of hippocampal loss is neither linear with age nor cognitive impairment. With advancing age, hippocampal loss ''bottoms-out'' in controls and MCI while loss continues in AD. With increasing impairment hippocampal loss accelerates in controls while it slightly declines in MCI and AD. In some parts of the brain, e.g. frontal cortex, losses start slower with age than in the hippocampus before they accelerate.

Alzheimer's & Dementia, 2010

latency parameters between controls and patients, whether in the 'on or the 'off' state; or betwe... more latency parameters between controls and patients, whether in the 'on or the 'off' state; or between the patients in the 'on' and the 'off' state. However, there was a negative correlation between letter fluency and the variability of saccade latency, whereas no correlation was found between overall motor function and any of the latency parameters. Voxel-wise grey matter volume estimates correlated with the latency parameters in several brain areas in patients and controls (p < 0.05 FWE corrected for multiple comparisons). Shorter saccade latency positively correlated with grey matter volume in regions of the prefrontal cortex, the cerebellar vermis, and the fusiform gyrus. The variability of saccade latency negatively correlated with grey matter volume in the frontal eye fields in patients; in controls, there was a negative correlation between the variability of latency and grey matter volume of the frontal and parietal eye fields, the premotor cortex, and the lateral prefrontal cortex. Conclusions: The behavioural and imaging findings point to an association between saccade latency, executive function and the prefrontal cortex. Our findings also suggest that saccadic latency and variability are associated with atrophy within a known oculomotor network. Therefore, saccadometry may provide important information on the severity of executive dysfunction and at the same time offer a rapid and non-invasive correlate of focal brain atrophy in healthy ageing and neurodegeneration.

Alzheimer's & Dementia, 2011

40 yrs, p ¼ 0.0009). There was no evidence of difference in ARWMC score between controls and the ... more 40 yrs, p ¼ 0.0009). There was no evidence of difference in ARWMC score between controls and the PSEN1Pre200 or APP cohort. Only one APP subject had a mutation within the amyloid-ß coding domain (A692G, Flemish). His total ARWMC score (14) was disproportionately higher than the median score for the APP group (0), the remainder of which had mutations at positions 717 and 719. Conclusions: The PSEN1Post200 mutation group in this study had a later age at onset and more severe white matter "burden" on MRI than the PSEN1Pre200 group. These increased, predominantly parieto-occipital, white matter changes probably reflect vascular pathology, most likely amyloid angiopathy given the subjects' young age and lack of comorbidities. Study of the differential influence of FAD mutations can inform our understanding of the pathophysiology of AD with potentially important implications for therapeutic trials.

Alzheimer's & Dementia, 2010

age¼69 6 6.1; MMSE¼27.8 6 1.9) and AD patients (n ¼ 7; age¼63 6 6.5; MMSE¼26.5 6 1.9). A modified... more age¼69 6 6.1; MMSE¼27.8 6 1.9) and AD patients (n ¼ 7; age¼63 6 6.5; MMSE¼26.5 6 1.9). A modified reference-Patlak model, with cerebellar grey matter as reference, was chosen for kinetic analysis of the DED data according to Johansson et al. (2007). Each participant's imaging data was analysed in native DED-PET space using a digital brain atlas; Hammers et al. (2003), DED data from 20-60 minutes was analysed. Mean regional glucose metabolism and PIB uptake ratios were calculated for each patient with cerebellum grey matter as reference. Results: A slope (DED-binding) and intercept (initial tracer distribution) ratio was calculated for each region from the DED data. ANOVA on the regional DED ratios revealed a significant group effect in the left temporal, left posterior cingulate, bilateral frontal, left occipital, bilateral parietal and right putamen (F2,19¼3.8-9.2 p ¼ 0.05). A trend for an increased DED ratio in MCI existed in cortical regions. All patients, except one MCI, were PIB+ (cortical uptake ratios >1.41). There were no correlations between significant regional DED ratios, FDG and PIB. There was no significant difference between FDG and PIB between MCI and AD patients. Conclusions: A significant effect of DED ratios in several brain regions existed between controls and patients. DED-PET did not correlate with FDG or PIB in the brain regions investigated. These findings contrary to post-mortem data support previous studies using PK11195 demonstrating a limited relationship between PIB uptake and neuroinflammation (e.g. Wiley et al 2009). The trend for increased DED ratios in the cortex of MCI patients might indicate neuroinflammation is an early phenomenon in AD evolution. This suggestion requires further investigation involving reliable in-vivo neuroinflammation markers.

The American Journal of Geriatric Psychiatry, 2015

Investigate the association of chronic depressive symptomatology (chrDS) with cortical atrophy ra... more Investigate the association of chronic depressive symptomatology (chrDS) with cortical atrophy rates and conversion to Alzheimer dementia (AD) over 3 years in mild cognitive impairment (MCI). In a multicenter, clinic-based study, MCI elderly participants were selected from the Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Disease Neuroimaging Initiative repository, based on availability of both serial structural magnetic resonance imaging and chrDS endorsed on three depression-related items from the Neuropsychiatric Inventory Questionnaire (chrDS N = 32 or no depressive symptoms N = 62) throughout follow-up. Clinical and laboratory investigations were performed every 6 months during the first 2 years and yearly thereafter (median follow-up: 3 years; interquartile range: 1.5-4.0 years). Cortical atrophy rates in 16 predefined frontotemporoparietal regions affected in major depression and AD and the rate of incident AD at follow-up. ChrDS in a single domain amnestic MCI sample were associated with accelerated cortical atrophy in the frontal lobe and anterior cingulate but not with atrophy rates in temporomedial or other AD-affected regions. During follow-up, 38 participants (42.7%) developed AD. Participants with chrDS had 60% shorter conversion time to AD than those without depressive symptoms. This association remained significant in survival models adjusted for temporomedial atrophy rates and showed the same trend in models adjusted for frontal cortical atrophy rate, which all increased the risk of AD. Our results suggest that chrDS associated with progressive atrophy of frontal regions may represent an additional risk factor for conversion to dementia in MCI as opposite to representing typical prodromal AD symptomatology.

Alzheimer's & Dementia, 2014

Background: The reproducibility of algorithms for longitudinal hippocampal percentage volume chan... more Background: The reproducibility of algorithms for longitudinal hippocampal percentage volume change (PVC) measurement has direct repercussions on clinical trial design in diseases such as Alzheimer's (AD). The ADNI1 study provides an excellent data set on which to assess the back to back (BTB) reproducibility of hippocampal PVC as it acquired two identical MPRAGEs at each patient visit (Cover et al. Psychiatry Res. 2011;193:182-190). Methods: The BTB PVC for the baseline and 1 year MPRAGEs for 75 subjects (19 healthy controls, 38 MCI and 18 AD) was calculated using multiple algorithms. Algorithms included FreeSurfer/ ReconAll/longitudinal v5.3.0, FSL/FIRST v5.0.4, AdaBoost, manual, multiple-atlas propagation and segmentation (MAPS) and MAPS with the hippocampal boundary shift integral option (MAPS-HBSI) (Leung et al. NeuroImage 2010;51:1345-1359). The difference between the PVC's (non annualized) was calculated (BTBD). To compare the performance of any two algorithms, the absolute values of the BTBD for each subject were compared and the algorithm with the smallest absolute BTBDs was considered superior. Results: MAPS-HBSI had substantially better reproducibilities than all other algorithms. MAPS-HBSI had smaller absolute BTBD for the left hippocampus in 0.69 (FreeSurfer), 0.71 (FIRST), 0.72 (Ada-Boost), 0.68 (manual), 0.81 (MAPS) fraction of subjects, all which had a p-value smaller than 0.002. The median absolute value of the BTBD (MAVBTBD) were 2.36 (FreeSurfer), 2.19 (FIRST), 2.61 (AdaBoost), 2.75 (manual), 3.41 (MAPS) and 1.29 (MAPS-HBSI)

Journal of behavioral and brain science, 2012

The degree to which one identifies as male or female has a profound impact on one's life. Yet... more The degree to which one identifies as male or female has a profound impact on one's life. Yet, there is a limited understanding of what contributes to this important characteristic termed gender identity. In order to reveal factors influencing gender identity, studies have focused on people who report strong feelings of being the opposite sex, such as male-to-female (MTF) transsexuals. To investigate potential neuroanatomical variations associated with transsexualism, we compared the regional thickness of the cerebral cortex between 24 MTF transsexuals who had not yet been treated with cross-sex hormones and 24 age-matched control males. Results revealed thicker cortices in MTF transsexuals, both within regions of the left hemisphere (i.e., frontal and orbito-frontal cortex, central sulcus, perisylvian regions, paracentral gyrus) and right hemisphere (i.e., pre-/post-central gyrus, parietal cortex, temporal cortex, precuneus, fusiform, lingual, and orbito-frontal gyrus). These f...

Alzheimer's & Dementia, 2014

T1 image,allowing assessment of volume, mean diffusivity (MD) and fractional anisotropy (FA) in t... more T1 image,allowing assessment of volume, mean diffusivity (MD) and fractional anisotropy (FA) in these regions. Longitudinal DT images were coregistered using tensor-based registration to examine FA, MD, axial and radial diffusivity (AD and RD) in the cingulum and fornix (ICBM-DTI-81 atlas). Whole brain and ventricular volumes were segmented using semi-automated techniques and atrophy/expansion rates calculated using the boundary shift integral. Linear regression, adjusting for age and gender, was used to assess differences in the imaging measures and their mean rates of change between MC and non-carrier groups. Results: The cohort comprised 12 mutation-negative participants and 17 MCs, six of whom reported symptoms at follow-up. MCs were on average 6.7 years younger than their parental age at symptom onset. MCs had smaller thalamic volumes bilaterally at baseline and follow-up, but there was little evidence for a difference in the rate of change over this interval. There was weak evidence for higher FA in bilateral thalamus and decreased AD in right cingulum at baseline and follow-up and lower right thalamic MD at baseline in MCs. When examined separately, MCs who became symptomatic had higher thalamic FA at follow-up than MCs who remained asymptomatic but both MC groups had smaller thalamic volumes than non-carriers. No significant group differences were evident for other imaging measures. Conclusions: Lower thalamic volumes and altered diffusivity were evident in FAD MCs compared to non-carriers at a stage when whole brain volumes and atrophy rates were similar. Thalamic FA in particular merits further investigation as a marker of early disease progression in larger FAD cohorts.

NeuroImage, 2005

With the improvements in techniques for generating surface models from magnetic resonance (MR) im... more With the improvements in techniques for generating surface models from magnetic resonance (MR) images, it has recently become feasible to study the morphological characteristics of the human brain cortex in vivo. Studies of the entire surface are important for measuring global features, but analysis of specific cortical regions of interest provides a more detailed understanding of structure. We have previously developed a method for automatically segmenting regions of interest from the cortical surface using a watershed transform. Each segmented region corresponds to a cortical sulcus and is thus termed a bsulcal region.Q In this work, we describe two important augmentations of this methodology. First, we describe a user interface that allows for the efficient labeling of the segmented sulcal regions called the Program for Assisted Labeling of Sulcal Regions (PALS). An additional augmentation allows for even finer divisions on the cortex with a methodology that employs the fast marching technique to track a curve on the cortical surface that is then used to separate segmented regions. After regions of interest have been identified, we compute both the cortical surface area and gray matter volume. Reliability experiments are performed to assess both the long-term stability and short-term repeatability of the proposed techniques. These experiments indicate the proposed methodology gives both highly stable and repeatable results.

Journal of Neuroimaging, 2013

To determine if a voxel-wise &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more To determine if a voxel-wise &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;co-analysis&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; of structural and diffusion tensor magnetic resonance imaging (MRI) together reveals additional brain regions affected in mild cognitive impairment (MCI) and Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) than voxel-wise analysis of the individual MRI modalities alone. Twenty-one patients with MCI, 21 patients with AD, and 21 cognitively normal healthy elderly were studied with MRI. Maps of deformation and fractional anisotropy (FA) were computed and used as dependent variables in univariate and multivariate statistical models. Univariate voxel-wise analysis of macrostructural changes in MCI showed atrophy in the right anterior temporal lobe, left posterior parietal/precuneus region, WM adjacent to the cingulate gyrus, and dorsolateral prefrontal regions, consistent with prior research. Univariate voxel-wise analysis of microstructural changes in MCI showed reduced FA in the left posterior parietal region extending into the corpus callosum, consistent with previous work. The multivariate analysis, which provides more information than univariate tests when structural and FA measures are correlated, revealed additional MCI-related changes in corpus callosum and temporal lobe. These results suggest that in corpus callosum and temporal regions macro- and microstructural variations in MCI can be congruent, providing potentially new insight into the mechanisms of brain tissue degeneration.

Human Brain Mapping, 2014

Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modal... more Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remain a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease, in which data from three MRI modalities are available.

Brain, 2011

Epilepsy is a prevalent childhood neurological disorder, but there are few prospective quantitati... more Epilepsy is a prevalent childhood neurological disorder, but there are few prospective quantitative magnetic resonance imaging studies examining patterns of brain development compared to healthy controls. Controlled prospective investigations initiated at or near epilepsy onset would best characterize the nature, timing and course of neuroimaging abnormalities in paediatric epilepsy. In this study, we report the results of a deformation-based morphometry technique to examine baseline and 2-year prospective neurodevelopmental brain changes in children with new and recent onset localization-related epilepsies (n = 24) and idiopathic generalized epilepsies (n = 20) compared to healthy controls (n = 36). Children with epilepsy demonstrated differences from controls in baseline grey and white matter volumes suggesting antecedent anomalies in brain development, as well as abnormal patterns of prospective brain development that involved not only slowed white matter expansion, but also abnormalities of cortical grey matter development involving both greater and lesser volume changes compared to controls. Furthermore, abnormal neurodevelopmental changes extended outside the cortex affecting several subcortical structures including thalamus, cerebellum, brainstem and pons. Finally, there were significant differences between the epilepsy syndromes (localization-related epilepsies and idiopathic generalized epilepsies) with the idiopathic generalized epilepsies group showing a more disrupted pattern of brain structure both at baseline and over the 2-year interval.

Understanding the function of the human brain cortex is a primary goal in human brain mapping. Me... more Understanding the function of the human brain cortex is a primary goal in human brain mapping. Methods to unfold and flatten the cortical surface for visualization and measurement have been described in previous literature; but comparison across multiple subjects is still ...

Alzheimer's & Dementia, 2013

Alzheimer's & Dementia, 2013

Alzheimer's & Dementia, 2013

Background: Impairment in instrumental activities of daily living (IADL) begins as individuals wi... more Background: Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). The objective of this study was to investigate the relationship between regional FDG metabolism and IADL cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods: Four hundred and two subjects (104 CN, 203 MCI, 95 AD dementia at baseline) participating in the Alzheimer's Disease Neuroimaging Initiative study underwent clinical assessments every 6 to 12 months for up to 3 years and FDG-PET at baseline. The subjective informant-based Functional Activities Questionnaire (FAQ) was used to assess IADL. We first performed data reduction analyses to reduce 35 FDG regions to 6 regions that appeared best associated with total FAQ score and were significant after adjusting for multiple tests. These 6 FDG regions were entered into a general linear model with backward elimination (p<0.05) assessing their cross-sectional relation to baseline FAQ and a mixed random and fixed coefficient linear longitudinal regression model assessing their relation to FAQ over time. Analyses included the following covariates: diagnosis, demographics, Apolipoprotein E4 (APOE4) carrier status, memory and executive function, and behavioral factors. Results: The cross-sectional analysis showed that middle frontal (p¼0.003) and orbitofrontal hypometabolism (p¼0.009) were significantly associated with greater IADL impairment, and the interaction of diagnosis with posterior cingulate (p<0.0001) and with parahippocampal hypometabolism (p¼0.0008) showed a steeper decline in IADL performance as FDG metabolism decreasedfor the AD dementia group relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal (p¼0.0005) and posterior cingulate hypometabolism (p¼0.004) were significantly associated with greater rate of increase in IADL impairment over time. Conclusions: These results suggest that frontal and medial parietal synaptic dysfunction relates to functional decline at baseline and over time across the AD spectrum independent of demographics, APOE4 carrier status, memory and executive function performance, and behavioral factors.

Alzheimer's & Dementia, 2013

Background: Alzheimer's disease (AD) causes widespread disruptions of large-scale neural communic... more Background: Alzheimer's disease (AD) causes widespread disruptions of large-scale neural communication as measured by resting-state functional connectivity magnetic resonance imaging (rs-fcMRI). However, healthy aging is also associated with altered rs-fcMRI, particularly in the default-mode network (DMN), but the extent of these reductions is unknown. Previous studies of healthy aging have primarily focused on a limited number of brain regions and have been cross-sectional in design Therefore it often remains difficult to differentiate early AD-related rs-fcMRI changes from healthy aging. Methods: This study investigates changes in functional connectivity in cognitively normal participants both cross-sectionally (N¼356) and longitudinally (mean follow up time ¼ 3 years, N¼95). Each participant was clinically evaluated using the clinical dementia rating scale (CDR) and determined to be cognitively normal at baseline and follow-up. rs-fcMRI was acquired and standard pre-processing procedures were used. Functional connectivity was calculated by measuring the temporal correlation between the blood oxygen level dependent time-series in two regions. We then calculated mean correlation strength within 5 networks (DMN, Dorsal Attention, Control, Salience, and Sensorimotor) and between pairs of networks. Results: Increasing age lead to decreased correlations within the DMN and salience network, as well as reduced anti-correlations between the DMN and dorsal attention network. We also noted a significant interaction of age and the presence of an APOE e4 allele in the connection between posterior cingulate cortex and medial prefrontal regions where there was a more dramatic effect of age in those with an e4 allele. Notably, the effects described in the cross-sectional cohort were replicated in the longitudinal cohort. Finally, the rate of change with respect to age was found to be comparable in both samples. Conclusions: These results demonstrate that cognitively normal aging is associated with decreases in functional connectivity in specific networks compared to a more general loss in AD. These results also demonstrate that APOE has a focal effect on changes in connectivity with age. The results are critical to the interpretation of AD studies because they will allow for the discrimination of changes due to AD compared to those simply due to advancing age.

Alzheimer's & Dementia, 2011

Alzheimer's & Dementia, 2011

Alzheimer's & Dementia, 2010

Background: It is now well established -based on longitudinal brain MRIthat MCI and AD are associ... more Background: It is now well established -based on longitudinal brain MRIthat MCI and AD are associated with higher rates of brain tissue loss than normal aging. Yet little is known about which parts of the brain loose tissue faster than others and how the losses relate to cognitive decline. A major difficulty in solving this puzzle has been lack of an accurate model for progression of brain tissue loss. To address this difficulty, we aimed to elucidate the dependence of regional brain tissue loss on age and on cognitive impairment. Methods: We measured regional brain volumes from ADNI MRI data of 274 MCI subjects, 101 AD patients and 146 controls, all between 55 to 90 years old. All subjects had between 3 and 6 serial 1.5T MRI scans over 2 1 / 2 years. To determine the dependence of volume loss on age and cognitive impair-ment, we treated variations in volume as well as in age and cognition across subjects as random variables and used a generalized additive model statistic to impose smooth variations on the variables while simultaneously accounting for fixed and random variations. This approach relaxed the need for explicitly parameterizing progression of volume loss while providing more data driven solutions. Results: Hippocampal volume loss as a function of age is shown in the figure top panel (estimated mean and residual values are shown), separately for control, MCI, and AD subjects. Hippocampal volume loss as a function of cognitive impairment (ADAScog) is shown in the bottom panel. Linear progression would be a straight line. This shows that progression of hippocampal loss is neither linear with age nor cognitive impairment. With advancing age, hippocampal loss ''bottoms-out'' in controls and MCI while loss continues in AD. With increasing impairment hippocampal loss accelerates in controls while it slightly declines in MCI and AD. In some parts of the brain, e.g. frontal cortex, losses start slower with age than in the hippocampus before they accelerate.

Alzheimer's & Dementia, 2010

latency parameters between controls and patients, whether in the 'on or the 'off' state; or betwe... more latency parameters between controls and patients, whether in the 'on or the 'off' state; or between the patients in the 'on' and the 'off' state. However, there was a negative correlation between letter fluency and the variability of saccade latency, whereas no correlation was found between overall motor function and any of the latency parameters. Voxel-wise grey matter volume estimates correlated with the latency parameters in several brain areas in patients and controls (p < 0.05 FWE corrected for multiple comparisons). Shorter saccade latency positively correlated with grey matter volume in regions of the prefrontal cortex, the cerebellar vermis, and the fusiform gyrus. The variability of saccade latency negatively correlated with grey matter volume in the frontal eye fields in patients; in controls, there was a negative correlation between the variability of latency and grey matter volume of the frontal and parietal eye fields, the premotor cortex, and the lateral prefrontal cortex. Conclusions: The behavioural and imaging findings point to an association between saccade latency, executive function and the prefrontal cortex. Our findings also suggest that saccadic latency and variability are associated with atrophy within a known oculomotor network. Therefore, saccadometry may provide important information on the severity of executive dysfunction and at the same time offer a rapid and non-invasive correlate of focal brain atrophy in healthy ageing and neurodegeneration.

Alzheimer's & Dementia, 2011

40 yrs, p ¼ 0.0009). There was no evidence of difference in ARWMC score between controls and the ... more 40 yrs, p ¼ 0.0009). There was no evidence of difference in ARWMC score between controls and the PSEN1Pre200 or APP cohort. Only one APP subject had a mutation within the amyloid-ß coding domain (A692G, Flemish). His total ARWMC score (14) was disproportionately higher than the median score for the APP group (0), the remainder of which had mutations at positions 717 and 719. Conclusions: The PSEN1Post200 mutation group in this study had a later age at onset and more severe white matter "burden" on MRI than the PSEN1Pre200 group. These increased, predominantly parieto-occipital, white matter changes probably reflect vascular pathology, most likely amyloid angiopathy given the subjects' young age and lack of comorbidities. Study of the differential influence of FAD mutations can inform our understanding of the pathophysiology of AD with potentially important implications for therapeutic trials.

Alzheimer's & Dementia, 2010

age¼69 6 6.1; MMSE¼27.8 6 1.9) and AD patients (n ¼ 7; age¼63 6 6.5; MMSE¼26.5 6 1.9). A modified... more age¼69 6 6.1; MMSE¼27.8 6 1.9) and AD patients (n ¼ 7; age¼63 6 6.5; MMSE¼26.5 6 1.9). A modified reference-Patlak model, with cerebellar grey matter as reference, was chosen for kinetic analysis of the DED data according to Johansson et al. (2007). Each participant's imaging data was analysed in native DED-PET space using a digital brain atlas; Hammers et al. (2003), DED data from 20-60 minutes was analysed. Mean regional glucose metabolism and PIB uptake ratios were calculated for each patient with cerebellum grey matter as reference. Results: A slope (DED-binding) and intercept (initial tracer distribution) ratio was calculated for each region from the DED data. ANOVA on the regional DED ratios revealed a significant group effect in the left temporal, left posterior cingulate, bilateral frontal, left occipital, bilateral parietal and right putamen (F2,19¼3.8-9.2 p ¼ 0.05). A trend for an increased DED ratio in MCI existed in cortical regions. All patients, except one MCI, were PIB+ (cortical uptake ratios >1.41). There were no correlations between significant regional DED ratios, FDG and PIB. There was no significant difference between FDG and PIB between MCI and AD patients. Conclusions: A significant effect of DED ratios in several brain regions existed between controls and patients. DED-PET did not correlate with FDG or PIB in the brain regions investigated. These findings contrary to post-mortem data support previous studies using PK11195 demonstrating a limited relationship between PIB uptake and neuroinflammation (e.g. Wiley et al 2009). The trend for increased DED ratios in the cortex of MCI patients might indicate neuroinflammation is an early phenomenon in AD evolution. This suggestion requires further investigation involving reliable in-vivo neuroinflammation markers.