Publications by authors named "Christine Fennema-Notestine"

114 Publications

Periventricular and deep abnormal white matter differ in associations with cognitive performance at midlife.

Neuropsychology 2021 Mar;35(3):252-264

Center for Behavior Genetics of Aging, University of California.

Abnormal white matter (AWM) on magnetic resonance imaging is associated with cognitive performance in older adults. We explored cognitive associations with AWM during late-midlife. Participants were community-dwelling men ( = 242; = 61.90 years; range = 56-66). Linear-mixed effects regression models examined associations of total, periventricular, and deep AWM with cognitive performance, controlling for multiple comparisons. Models considering specific cognitive domains controlled for current general cognitive ability (GCA). We hypothesized that total AWM would be associated with worse processing speed, executive function, and current GCA; deep AWM would correlate with GCA and periventricular AWM would relate to specific cognitive abilities. We also assessed the potential influence of cognitive reserve by examining a moderation effect of early life (mean age of 20) cognition. Greater total and deep AWM were associated with poorer current GCA. Periventricular AWM was associated with worse executive function, working memory, and episodic memory. When periventricular and deep AWM were modeled simultaneously, both retained their respective significant associations with cognitive performance. Cognitive reserve did not moderate associations. Our findings suggest that AWM contributes to poorer cognitive function in late-midlife. Examining only total AWM may obscure the potential differential impact of regional AWM. Separating total AWM into subtypes while controlling for current GCA revealed a dissociation in relationships with cognitive performance; deep AWM was associated with nonspecific cognitive ability whereas periventricular AWM was associated with specific frontal-related abilities and memory. Management of vascular or other risk factors that may increase the risk of AWM should begin during or before early late-midlife. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000718DOI Listing
March 2021

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.

Alzheimers Dement 2021 06 13;17(6):1017-1025. Epub 2021 Feb 13.

Department of Psychiatry, University of California San Diego, La Jolla, California, USA.

Introduction: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.

Methods: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LC ). We examined LC , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.

Results: Heritability of LC was .48. Participants with aMCI showed greater daytime dysfunction. Lower LC was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.

Discussion: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.
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http://dx.doi.org/10.1002/alz.12261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248066PMC
June 2021

Paresthesia Predicts Increased Risk of Distal Neuropathic Pain in Older People with HIV-Associated Sensory Polyneuropathy.

Pain Med 2021 Feb 10. Epub 2021 Feb 10.

Department of Neurosciences, University of California, San Diego.

Objective: Distal sensory polyneuropathy (DSP) is a disabling consequence of HIV, leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms, however there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized.

Methods: This was a prospective longitudinal study of 265 PWH enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates.

Results: Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART) and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (OR 1.56; 95% CI 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [1.51, 2.58]).

Conclusions: Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.
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http://dx.doi.org/10.1093/pm/pnab056DOI Listing
February 2021

Associations between depression and cardiometabolic health: A 27-year longitudinal study.

Psychol Med 2021 Jan 12:1-11. Epub 2021 Jan 12.

Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA.

Background: Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems.

Methods: The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)].

Results: Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60).

Conclusions: A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.
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http://dx.doi.org/10.1017/S003329172000505XDOI Listing
January 2021

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

Stroke 2020 07 10;51(7):2111-2121. Epub 2020 Jun 10.

Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

Background And Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.

Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.

Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (), 10q23.1 (), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 () and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.

Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
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http://dx.doi.org/10.1161/STROKEAHA.119.027544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365038PMC
July 2020

Use of Neuroimaging to Inform Optimal Neurocognitive Criteria for Detecting HIV-Associated Brain Abnormalities.

J Int Neuropsychol Soc 2020 02 2;26(2):147-162. Epub 2019 Oct 2.

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.

Objective: Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.

Method: Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.

Results: When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.

Conclusions: The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.
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http://dx.doi.org/10.1017/S1355617719000985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015796PMC
February 2020

Iron-regulatory genes are associated with Neuroimaging measures in HIV infection.

Brain Imaging Behav 2020 Oct;14(5):2037-2049

Department of Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

The pathogenesis of HIV-associated neurocognitive impairment (NCI) may involve iron dysregulation. In 243 HIV-seropositive adults without severe comorbidities, we therefore genotyped 250 variants in 20 iron-related genes and evaluated their associations with magnetic resonance imaging measures of brain structure and metabolites, including measures previously linked to NCI. Multivariable regression analyses examined associations between genetic variants and neuroimaging measures, adjusting for relevant covariates and multiple testing. Exploratory analyses stratified by NCI (Global Deficit Score ≥ 0.5 vs. <0.5), virus detectability in plasma, and comorbidity levels were also performed. Of 27 variants (in 12 iron-regulatory genes) associated with neuroimaging measures after correction for the 37 haplotype blocks represented, 3 variants survived additional correction for the 21 neuroimaging measures evaluated and demonstrated biologically plausible associations. SLC11A1 rs7576974_T was significantly associated with higher frontal gray matter N-acetylaspartate (p = 3.62e). Among individuals with detectable plasma virus, TFRC rs17091382_A was associated with smaller subcortical gray matter volume (p = 3.23e), and CP rs4974389_A (p = 3.52e) was associated with higher basal ganglia Choline in persons with mild comorbidities. Two other strong associations were observed for variants in SLC40A1 and ACO2 but were not robust due to low minor-allele frequencies in the study sample. Variants in iron metabolism and transport genes are associated with structural and metabolite neuroimaging measures in HIV-seropositive adults, regardless of virus suppression on antiretroviral therapy. These variants may confer susceptibility to HIV-related brain injury and NCI. Further studies are needed to determine the specificity of these findings to HIV infection and explore potential underlying mechanisms.
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http://dx.doi.org/10.1007/s11682-019-00153-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940558PMC
October 2020

Resting State Abnormalities of the Default Mode Network in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

J Alzheimers Dis 2019 ;70(1):107-120

Department of Psychiatry, University of California San Diego, San Diego, CA, USA.

Background: Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer's disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairment (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach.

Objective: We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups.

Methods: PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no group difference or hyper- versus hypo-connnectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences.

Results: Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI > HC and 22 showed HC > MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p < 0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies.

Conclusions: The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.
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http://dx.doi.org/10.3233/JAD-180847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697380PMC
September 2020

Data-Driven Exploration of Brain Structure Using Statistical Machine Learning: Validity of Derived Diagnostic Patterns in Alcohol Use Disorder and Human Immunodeficiency Virus Infection.

Biol Psychiatry Cogn Neurosci Neuroimaging 2019 06;4(6):508-509

Departments of Psychiatry and Radiology, University of California, San Diego, La Jolla, California. Electronic address:

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http://dx.doi.org/10.1016/j.bpsc.2019.04.008DOI Listing
June 2019

Body mass trajectories and cortical thickness in middle-aged men: a 42-year longitudinal study starting in young adulthood.

Neurobiol Aging 2019 07 12;79:11-21. Epub 2019 Mar 12.

Department of Psychiatry & Center for Behavior Genetics of Aging, University of California San Diego, La Jolla, CA, USA; Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, USA.

Evidence strongly suggests that being overweight or obese at midlife confers significantly higher risk for Alzheimer's disease and greater brain atrophy later in life. Few studies, however, examine associations between longitudinal changes in adiposity during early adulthood and later brain morphometry. Measures of body mass index (BMI) were collected in 373 men from the Vietnam Era Twin Study of Aging at average ages 20, 40, 56, and 62 years, yielding 2 BMI trajectories. We then examined associations between BMI phenotypes (trajectories, continuous BMI, obese/nonobese), cortical thickness, and white matter measures from structural magnetic resonance imaging at mean age 62 (time 4, range 56-66 years). Those on the obesity trajectory (N = 171) had a thinner cortex compared with the normal/lean trajectory (N = 202) in multiple frontal and temporal lobe bilateral regions of interest: superior, inferior, middle temporal gyri, temporal pole, fusiform gyrus, banks of the superior temporal sulcus, frontal pole, pars triangularis, caudal and rostral middle frontal gyri (all p < 0.05, false discovery rate corrected). Frontal lobe thinness tended to occur mainly in the right hemisphere. Results were similar for obese versus nonobese adults at age 62. There were no significant differences for white matter volume or abnormalities. Taken in the context of other research, these associations between brain structures and excess BMI at midlife suggest potential for increased risk for cognitive decline in later life.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591047PMC
July 2019

Effects of comorbidity burden and age on brain integrity in HIV.

AIDS 2019 06;33(7):1175-1185

Department of Psychiatry, University of California San Diego, La Jolla.

Objective: The influence of confounding neurocognitive comorbidities in people living with HIV (PLWH) on neuroimaging has not been systematically evaluated. We determined associations between comorbidity burden and brain integrity and examined the moderating effect of age on these relationships.

Design: Observational, cross-sectional substudy of the CNS HIV Antiretroviral Therapy Effects Research cohort.

Methods: A total of 288 PLWH (mean age = 44.2) underwent structural MRI and magnetic resonance spectroscopy as well as neurocognitive and neuromedical assessments. Consistent with Frascati criteria for HIV-associated neurocognitive disorders (HAND), neuromedical and neuropsychiatric comorbidity burden was classified as incidental (mild), contributing (moderate), or confounding (severe-exclusionary) to a diagnosis of HAND. Multiple regression modeling predicted neuroimaging outcomes as a function of comorbidity classification, age, and their interaction.

Results: Comorbidity classifications were 176 incidental, 77 contributing, and 35 confounded; groups did not differ in HIV disease characteristics. Relative to incidental and contributing participants, confounded participants had less cortical gray matter and more abnormal white matter and ventricular cerebrospinal fluid, alongside more neuroinflammation (choline, myo-inositol) and less neuronal integrity (N-acetylaspartate). Older age exacerbated the impact of comorbidity burden: to a greater extent in the confounded group, older age was associated with more abnormal white matter (P = 0.017), less total white matter (P = 0.015), and less subcortical gray matter (P = 0.014).

Conclusion: Neuroimaging in PLWH reveals signatures associated with confounding neurocognitive conditions, emphasizing the importance of evaluating these among individuals with suspected HAND. Older age amplifies subcortical and white matter tissue injury, especially in PLWH with severe comorbidity burden, warranting increased attention to this population as it ages.
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http://dx.doi.org/10.1097/QAD.0000000000002192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613389PMC
June 2019

Posttraumatic stress symptom persistence across 24 years: association with brain structures.

Brain Imaging Behav 2020 Aug;14(4):1208-1220

Department of Psychiatry MC 0738, University of California San Diego, La Jolla, CA, 92093, USA.

Posttraumatic stress disorder (PTSD) is known to persist, eliciting early medical co-morbidity, and accelerated aging. Although PTSD diagnosis has been found to be associated with smaller volume in multiple brain regions, posttraumatic stress (PTS) symptoms and their associations with brain morphometry are rarely assessed over long periods of time. We predicted that persistent PTS symptoms across ~24 years would be inversely associated with hippocampal, amygdala, anterior cingulate volumes, and hippocampal occupancy (HOC = hippocampal volume/[hippocampal volume + inferior lateral ventricle volume]) in late middle age. Exploratory analyses examined prefrontal regions. We assessed PTS symptoms in 247 men at average ages 38 (time 1) and 62 (time 2). All were trauma-exposed prior to time 1. Brain volumes were assessed at time 2 using 3 T structural magnetic resonance imaging. Symptoms were correlated over time (r = 0.46 p < .0001). Higher PTS symptoms averaged over time and symptoms at time 1 were both associated with lower hippocampal, amygdala, rostral middle frontal gyrus (MFG), and medial orbitofrontal cortex (OFC) volumes, and a lower HOC ratio at time 2. Increased PTS symptomatology from time 1 to time 2 was associated with smaller hippocampal volume. Results for hippocampal, rostral MFG and medial OFC remained significant after omitting individuals above the threshold for PTSD diagnosis. Even at sub-diagnostic threshold levels, PTS symptoms were present decades after trauma exposure in parallel with highly correlated structural deficits in brain regions regulating stress responsivity and adaptation.
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http://dx.doi.org/10.1007/s11682-019-00059-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722032PMC
August 2020

Influence of young adult cognitive ability and additional education on later-life cognition.

Proc Natl Acad Sci U S A 2019 02 22;116(6):2021-2026. Epub 2019 Jan 22.

Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093;

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56-66 ( = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for <1% of the variance in cognitive outcomes. The impact of these other factors likely reflects reverse causation-namely, downstream effects of early adult GCA. Supporting that idea, age 20 GCA, but not education, was associated with late midlife cortical surface area ( = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.
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http://dx.doi.org/10.1073/pnas.1811537116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369818PMC
February 2019

Genetic architecture of hippocampal subfields on standard resolution MRI: How the parts relate to the whole.

Hum Brain Mapp 2019 04 15;40(5):1528-1540. Epub 2018 Nov 15.

Department of Psychiatry, University of California San Diego, San Diego, California.

The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T -weighted images.
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http://dx.doi.org/10.1002/hbm.24464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397064PMC
April 2019

Effects of HIV Infection, methamphetamine dependence and age on cortical thickness, area and volume.

Neuroimage Clin 2018 7;20:1044-1052. Epub 2018 Oct 7.

Department of Psychiatry, University of California San Diego, United States.

Objective: This study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age.

Method: T1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels.

Results: Following correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers.

Conclusions: Methamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment.
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http://dx.doi.org/10.1016/j.nicl.2018.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197439PMC
February 2019

Predominantly global genetic influences on individual white matter tract microstructure.

Neuroimage 2019 01 5;184:871-880. Epub 2018 Oct 5.

Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA; Center of Excellence for Stress and Mental Health, Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA.

Individual differences in white matter tract microstructure, measured with diffusion tensor imaging (DTI), demonstrate substantial heritability. However, it is unclear to what extent this heritability reflects global genetic influences or tract-specific genetic influences. The goal of the current study was to quantify the proportion of genetic and environmental variance in white matter tracts attributable to global versus tract-specific influences. We assessed fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) across 11 tracts and 22 subdivisions of these tracts in 392 middle-aged male twins from the Vietnam Era Twin Study of Aging (VETSA). In principal component analyses of the 11 white matter tracts, the first component, which represents the global signal, explained 50.1% and 62.5% of the variance in FA and MD, respectively. Similarly, the first principal component of the 22 tract subdivisions explained 38.4% and 47.0% of the variance in FA and MD, respectively. Twin modeling revealed that DTI measures of all tracts and subdivisions were heritable, and that genetic influences on global FA and MD accounted for approximately half of the heritability in the tracts or tract subdivisions. Similar results were observed for the AD and RD diffusion metrics. These findings underscore the importance of controlling for DTI global signals when measuring associations between specific tracts and outcomes such as cognitive ability, neurological and psychiatric disorders, and brain aging.
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http://dx.doi.org/10.1016/j.neuroimage.2018.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289256PMC
January 2019

White matter damage, neuroinflammation, and neuronal integrity in HAND.

J Neurovirol 2019 02 5;25(1):32-41. Epub 2018 Oct 5.

University of California at San Diego, La Jolla, CA, USA.

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.
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http://dx.doi.org/10.1007/s13365-018-0682-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416232PMC
February 2019

Brain structure mediates the association between height and cognitive ability.

Brain Struct Funct 2018 Sep 11;223(7):3487-3494. Epub 2018 May 11.

Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.

Height and general cognitive ability are positively associated, but the underlying mechanisms of this relationship are not well understood. Both height and general cognitive ability are positively associated with brain size. Still, the neural substrate of the height-cognitive ability association is unclear. We used a sample of 515 middle-aged male twins with structural magnetic resonance imaging data to investigate whether the association between height and cognitive ability is mediated by cortical size. In addition to cortical volume, we used genetically, ontogenetically and phylogenetically distinct cortical metrics of total cortical surface area and mean cortical thickness. Height was positively associated with general cognitive ability and total cortical volume and cortical surface area, but not with mean cortical thickness. Mediation models indicated that the well-replicated height-general cognitive ability association is accounted for by individual differences in total cortical volume and cortical surface area (highly heritable metrics related to global brain size), and that the genetic association between cortical surface area and general cognitive ability underlies the phenotypic height-general cognitive ability relationship.
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http://dx.doi.org/10.1007/s00429-018-1675-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425087PMC
September 2018

Testing associations between cannabis use and subcortical volumes in two large population-based samples.

Addiction 2018 Apr 24. Epub 2018 Apr 24.

QIMR Berghofer Medical Research Institute, QLD, Australia.

Background And Aims: Disentangling the putative impact of cannabis on brain morphology from other comorbid substance use is critical. After controlling for the effects of nicotine, alcohol and multi-substance use, this study aimed to determine whether frequent cannabis use is associated with significantly smaller subcortical grey matter volumes.

Design: Exploratory analyses using mixed linear models, one per region of interest (ROI), were performed whereby individual differences in volume (outcome) at seven subcortical ROIs were regressed onto cannabis and comorbid substance use (predictors).

Setting: Two large population-based twin samples from the United States and Australia.

Participants: A total of 622 young Australian adults [66% female; μ  = 25.9, standard deviation SD) = 3.6] and 474 middle-aged US males (μ  = 56.1 ) of predominately Anglo-Saxon ancestry with complete substance use and imaging data. Subjects with a history of stroke or traumatic brain injury were excluded.

Measurements: Magnetic resonance imaging (MRI) and volumetric segmentation methods were used to estimate volume in seven subcortical ROIs: thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala and nucleus accumbens. Substance use measurements included maximum nicotine and alcohol use, total life-time multi-substance use, maximum cannabis use in the young adults and regular cannabis use in the middle-aged males.

Findings: After correcting for multiple testing (P = 0.007), cannabis use was unrelated to any subcortical ROI. However, maximum nicotine use was associated with significantly smaller thalamus volumes in middle-aged males.

Conclusions: In exploratory analyses based on young adult and middle-aged samples, normal variation in cannabis use is unrelated statistically to individual differences in brain morphology as measured by subcortical volume.
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http://dx.doi.org/10.1111/add.14252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200645PMC
April 2018

Negative fateful life events in midlife and advanced predicted brain aging.

Neurobiol Aging 2018 07 8;67:1-9. Epub 2018 Mar 8.

Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Center for Behavior Genetics of Aging, University of California, San Diego, La Jolla, CA, USA; Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, La Jolla, CA, USA.

Negative fateful life events (FLEs) such as interpersonal conflict, death in the family, financial hardship, and serious medical emergencies can act as allostatic stressors that accelerate biological aging. However, the relationship between FLEs and neuroanatomical aging is not well understood. We examined 359 men (mean age 62 years) participating in the Vietnam Era twin study of aging (VETSA) to determine whether negative midlife FLEs are associated with advanced brain aging after controlling for physical, psychological, and lifestyle factors. At two different time points, participants were assessed for negative FLEs, health and well-being, general cognitive ability, socioeconomic status, depression, and ethnicity. Participants underwent a magnetic resonance imaging examination, and T1-weighted images were processed with FreeSurfer. Subsequent neuroanatomical measurements were entered into the Brain-Age Regression Analysis and Computation Utility software (BARACUS) to predict brain age. Having more midlife FLEs, particularly relating to interpersonal relationships, was associated with advanced predicted brain aging (i.e., higher predicted brain age relative to chronological age). This association remained after controlling for the significant covariates of alcohol consumption, cardiovascular risk, adult socioeconomic status, and ethnicity.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955847PMC
July 2018

Alcohol intake and brain white matter in middle aged men: Microscopic and macroscopic differences.

Neuroimage Clin 2018 7;18:390-398. Epub 2018 Feb 7.

Department of Psychiatry, UCSD, 9500 Gilman Dr, La Jolla, CA, 92093, United States; Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, 3350 La Jolla Village Dr, San Diego, CA 92161.

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56-66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9-28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage.
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http://dx.doi.org/10.1016/j.nicl.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816025PMC
February 2019

Genetic relatedness of axial and radial diffusivity indices of cerebral white matter microstructure in late middle age.

Hum Brain Mapp 2018 05 9;39(5):2235-2245. Epub 2018 Feb 9.

Department of Psychiatry, University of California, San Diego, La Jolla, California.

Two basic neuroimaging-based characterizations of white matter tracts are the magnitude of water diffusion along the principal tract orientation (axial diffusivity, AD) and water diffusion perpendicular to the principal orientation (radial diffusivity, RD). It is generally accepted that decreases in AD reflect disorganization, damage, or loss of axons, whereas increases in RD are indicative of disruptions to the myelin sheath. Previous reports have detailed the heritability of individual AD and RD measures, but have not examined the extent to which the same or different genetic or environmental factors influence these two phenotypes (except for corpus callosum). We implemented bivariate twin analyses to examine the shared and independent genetic influences on AD and RD. In the Vietnam Era Twin Study of Aging, 393 men (mean age = 61.8 years, SD = 2.6) underwent diffusion-weighted magnetic resonance imaging. We derived fractional anisotropy (FA), mean diffusivity (MD), AD, and RD estimates for 11 major bilateral white matter tracts and the mid-hemispheric corpus callosum, forceps major, and forceps minor. Separately, AD and RD were each highly heritable. In about three-quarters of the tracts, genetic correlations between AD and RD were >.50 (median = .67) and showed both unique and common variance. Genetic variance of FA and MD were predominately explained by RD over AD. These findings are important for informing genetic association studies of axonal coherence/damage and myelination/demyelination. Thus, genetic studies would benefit from examining the shared and unique contributions of AD and RD.
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http://dx.doi.org/10.1002/hbm.24002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895525PMC
May 2018

Psychotic-spectrum symptoms, cumulative adversity exposure and substance use among high-risk girls.

Early Interv Psychiatry 2018 02 28;12(1):74-86. Epub 2017 Dec 28.

Department of Sociology, San Diego State University, San Diego, California.

Aim: Psychotic-spectrum symptoms are linked to trauma, substance/alcohol use (SAU), criminality/violence and poor functional outcomes, supporting the need for early detection in vulnerable populations. To better understand high-risk girls' mental health, we assessed: (1) psychotic-spectrum symptoms; (2) cumulative trauma, adversity and loss exposures (C-TALE) and adversity-indicators (symptoms, maladaptive coping, stressor-reactivity); and SAU risk-factors; and (3) relationships among psychotic-spectrum symptoms, adversity-indicators and SAU risk-factors.

Methods: We administered the Structured Clinical Interviews for Psychotic Spectrum, and Trauma and Loss Spectrum to 158 adolescent delinquent girls.

Results: Girls' psychotic-spectrum profiles were similar to previously reported adult psychotic patients and characterized by typical symptoms (hallucinations/delusions, reported largely SAU-independent), interpersonal sensitivity, schizoid traits and paranoia (over-interpretation, anger over-reactivity, hypervigilance). Auditory/visual hallucinations (55.7%), delusions (92.4%), ideas of reference (96.8%) and adversity (90.0% ≥10/24 C-TALE-types) were common. Mean loss (4) and trauma (8) onset-age occurred before SAU-onset (12). Significant positive correlations were found among psychotic-spectrum symptoms, stressor-reactivity, C-TALE, adversity-indicators; and number of SAU-types; and a negative correlation occurred between psychotic-spectrum symptoms and earlier alcohol use onset. After controlling for number of SAU-types, stressor-reactivity and adversity-related numbing individually had the largest associations with total psychotic-spectrum symptoms (b = 2.6-4.3). Girls averaged more than 4 maladaptive coping strategies (e.g., 24.8% attempted suicide) in response to adversity, amplifying potential health-disparities. No racial/ethnic differences emerged on psychotic-spectrum symptoms.

Conclusions: This symptom constellation during adolescence likely interferes with social and academic functioning. Whether representing a prodromal phase, trauma-response or cross-diagnostic psychopathology, accurate early detection and appropriate treatment of psychotic-spectrum symptoms are warranted to improve functional outcomes in vulnerable populations.
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http://dx.doi.org/10.1111/eip.12533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788710PMC
February 2018

Task-evoked pupil dilation and BOLD variance as indicators of locus coeruleus dysfunction.

Cortex 2017 12 7;97:60-69. Epub 2017 Oct 7.

Department of Psychiatry, University of California, San Diego, CA, USA; Center for Behavior Genetics of Aging, University of California, San Diego, CA, USA; VA San Diego Health Care System, San Diego, CA 92161, USA.

Pupillary responses during cognitive tasks are linked to functioning of the locus coeruleus (LC). The LC is an early site of abnormal tau deposition, which may contribute to key aspects of Alzheimer's disease (AD) pathophysiology. We previously found attenuation of pupillary responses to increases in cognitive load in individuals with mild cognitive impairment (MCI), suggesting pupillary responses may provide a biomarker of early risk for AD associated with LC dysfunction. The LC modulates cortical activity through two modes of operation: tonic and phasic. Early LC damage has been predicted to result in a state of persistent high tonic LC activity that may disrupt task-related phasic activity. To further examine whether pupillary responses are associated with early LC dysfunction, we measured pupil dilation during a digit span task as a measure of phasic activity, and low frequency BOLD variance (LFBV) during resting-state fMRI in key nodes of the ventral attention network (VAN) as a measure of cortical reactivity related to LC tonic activity in 358 middle-aged men. Individuals with greater LFBV in VAN nodes, i.e., higher tonic brain activity at rest, showed a smaller increase in pupil dilation from low to moderate cognitive loads. Thus, higher tonic LFBV activity at rest was related to reduced task-appropriate phasic dilation increases. The results support predictions from prominent models of LC functioning in which early LC dysfunction leads to persistent high tonic rates of activity during rest and lower signal-to-noise of phasic responses during task performance. Taken together with previous findings of early AD pathophysiology in LC and reduced phasic dilation responses to increased cognitive load in individuals with MCI, the present results suggest that pupillary responses may index early LC dysfunction and should receive further study as a potential biomarker of risk for AD.
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http://dx.doi.org/10.1016/j.cortex.2017.09.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716879PMC
December 2017

Genetic and environmental influences on mean diffusivity and volume in subcortical brain regions.

Hum Brain Mapp 2017 05 27;38(5):2589-2598. Epub 2017 Feb 27.

Department of Psychiatry, University of California, San Diego, California.

Increased mean diffusivity (MD) is hypothesized to reflect tissue degeneration and may provide subtle indicators of neuropathology as well as age-related brain changes in the absence of volumetric differences. Our aim was to determine the degree to which genetic and environmental variation in subcortical MD is distinct from variation in subcortical volume. Data were derived from a sample of 387 male twins (83 MZ twin pairs, 55 DZ twin pairs, and 111 incomplete twin pairs) who were MRI scanned as part of the Vietnam Era Twin Study of Aging. Quantitative estimates of MD and volume for 7 subcortical regions were obtained: thalamus, caudate nucleus, putamen, pallidum, hippocampus, amygdala, and nucleus accumbens. After adjusting for covariates, bivariate twin models were fitted to estimate the size and significance of phenotypic, genotypic, and environmental correlations between MD and volume at each subcortical region. With the exception of the amygdala, familial aggregation in MD was entirely explained by additive genetic factors across all subcortical regions with estimates ranging from 46 to 84%. Based on bivariate twin modeling, variation in subcortical MD appears to be both genetically and environmentally unrelated to individual differences in subcortical volume. Therefore, subcortical MD may be an alternative biomarker of brain morphology for complex traits worthy of future investigation. Hum Brain Mapp 38:2589-2598, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810123PMC
May 2017

Heritability of white matter microstructure in late middle age: A twin study of tract-based fractional anisotropy and absolute diffusivity indices.

Hum Brain Mapp 2017 04 29;38(4):2026-2036. Epub 2016 Dec 29.

Department of Psychiatry, University of California, San Diego, La Jolla, California.

There is evidence that differences among individuals in white matter microstructure, as measured with diffusion tensor imaging (DTI), are under genetic control. However, little is known about the relative contribution of genetic and environmental effects on different diffusivity indices among late middle-aged adults. Here, we examined the magnitude of genetic influences for fractional anisotropy (FA), and mean (MD), axial (AD), and radial (RD) diffusivities in male twins aged 56-66 years old. Using an atlas-based registration approach to delineate individual white matter tracts, we investigated mean DTI-based indices within the corpus callosum, 12 bilateral tracts and all these regions of interest combined. All four diffusivity indices had high heritability at the global level (72%-80%). The magnitude of genetic effects in individual tracts varied from 0% to 82% for FA, 0% to 81% for MD, 8% to 77% for AD, and 0% to 80% for RD with most of the tracts showing significant heritability estimates. Despite the narrow age range of this community-based sample, age was correlated with all four diffusivity indices at the global level. In sum, all diffusion indices proved to have substantial heritability for most of the tracts and the heritability estimates were similar in magnitude for different diffusivity measures. Future studies could aim to discover the particular set of genes that underlie the significant heritability of white matter microstructure. Hum Brain Mapp 38:2026-2036, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342936PMC
April 2017

Genetic and environmental influences on cortical mean diffusivity.

Neuroimage 2017 Feb 15;146:90-99. Epub 2016 Nov 15.

Department of Psychiatry, University of California San Diego, CA, USA; Center for Behavior Genetics of Aging, University of California San Diego, CA, USA; San Diego VA Health Care System, San Diego, CA 92161, USA.

Magnetic resonance imaging (MRI) has become an important tool in the early detection of age-related and neuropathological brain changes. Recent studies suggest that changes in mean diffusivity (MD) of cortical gray matter derived from diffusion MRI scans may be useful in detecting early effects of Alzheimer's disease (AD), and that these changes may be detected earlier than alterations associated with standard structural MRI measures such as cortical thickness. Thus, due to its potential clinical relevance, we examined the genetic and environmental influences on cortical MD in middle-aged men to provide support for the biological relevance of this measure and to guide future gene association studies. It is not clear whether individual differences in cortical MD reflect neuroanatomical variability similarly detected by other MRI measures, or whether unique features are captured. For instance, variability in cortical MD may reflect morphological variability more commonly measured by cortical thickness. Differences among individuals in cortical MD may also arise from breakdowns in myelinated fibers running through the cortical mantle. Thus, we investigated whether genetic influences on variation in cortical MD are the same or different from those influencing cortical thickness and MD of white matter (WM) subjacent to the cortical ribbon. Univariate twin analyses indicated that cortical MD is heritable in the majority of brain regions; the average of regional heritability estimates ranged from 0.38 in the cingulate cortex to 0.66 in the occipital cortex, consistent with the heritability of other MRI measures of the brain. Trivariate analyses found that, while there was some shared genetic variance between cortical MD and each of the other two measures, this overlap was not complete (i.e., the correlation was statistically different from 1). A significant amount of distinct genetic variance influences inter-individual variability in cortical MD; therefore, this measure could be useful for further investigation in studies of neurodegenerative diseases and gene association studies.
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http://dx.doi.org/10.1016/j.neuroimage.2016.11.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322245PMC
February 2017

White matter disease in midlife is heritable, related to hypertension, and shares some genetic influence with systolic blood pressure.

Neuroimage Clin 2016 6;12:737-745. Epub 2016 Oct 6.

Department of Psychiatry at the University of California, San Diego, La Jolla, CA, USA; Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, USA.

White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61.9 ± 2.6 years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age ( = 1.9,  = 0.05) and hypertension ( = 2.9,  = 0.004), but not ε4 status; and was greater in those with uncontrolled hypertension relative to controlled ( = 3.0,  = 0.003) and normotensive ( = 4.0,  = 0.0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a = 0.81) and shared some genetic influences with systolic blood pressure (r = 0.26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery.
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http://dx.doi.org/10.1016/j.nicl.2016.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071546PMC
November 2017

Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining "symptomatic" versus "asymptomatic" HAND.

J Neurovirol 2017 02 24;23(1):67-78. Epub 2016 Aug 24.

Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093, USA.

The criteria for differentiating symptomatic from asymptomatic HIV-associated neurocognitive disorder require evaluation of (1) cognitive impairment, (2) daily functioning declines, and (3) whether the functional declines are attributable to cognitive versus physical problems. Many providers rely only on self-report to evaluate these latter criteria. However, the accuracy of patient-provided information may be limited. This study evaluated the validity of self-assessment for HIV-associated neurocognitive disorder (HAND) diagnoses by comparing objective findings with self-report of criteria 2 and 3 above. Self-reports were used to stratify 277 cognitively impaired HIV+ individuals into functionally dependent (n = 159) and independent (n = 118) groups, followed by group comparisons of objective functional problems. The dependent group was then divided into those who self-attributed their functional dependence to only cognitive (n = 80) versus only physical (n = 79) causes, for further comparisons on objective findings. The functionally dependent group was significantly worse than the independent group on all objective disability characteristics except severity of cognitive impairment, while those who attributed their dependence to physical (versus cognitive) factors were similar on all objective physical, cognitive, and functioning variables. Of note, 28 % of physical attributors showed no physical abnormalities on neuromedical examinations. Results suggest that patient report is consistently associated with objective measures of functional loss; in contrast, patient identification of physical versus cognitive causes is poorly associated with objective criteria. These findings caution against relying solely on patient self-report to determine whether functional disability in cognitively impaired HIV+ individuals can be attributed to strictly physical causes.
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http://dx.doi.org/10.1007/s13365-016-0474-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325815PMC
February 2017

HIV Distal Neuropathic Pain Is Associated with Smaller Ventral Posterior Cingulate Cortex.

Pain Med 2017 03;18(3):428-440

Neurosciences, University of California San Diego, San Diego, California, USA.

Objective: . Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller.

Methods: . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images.

Results: . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P  = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain.

Conclusions: . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain.
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http://dx.doi.org/10.1093/pm/pnw180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074843PMC
March 2017