Beth A. Jerskey

Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping.

The elaboration of the myelinated white matter is essential for normal neurodevelopment, establishing and mediating rapid communication pathways throughout the brain. These pathways facilitate the synchronized communication required for higher order behavioral and cognitive functioning. Altered neural messaging (or ‘disconnectivity’) arising from abnormal white matter and myelin development may underlie a number of neurodevelopmental psychiatric disorders. Despite the vital role myelin plays, few imaging studies have specifically examined its maturation throughout early infancy and childhood. Thus, direct investigations of the relationship(s) between evolving behavioral and cognitive functions and the myelination of the supporting neural systems have been sparse. Further, without knowledge of the ‘normative’ developmental time-course, identification of early abnormalities associated with developmental disorders remains challenging. In this work, we examined the use of longitudinal (T1) and transverse (T2) relaxation time mapping, and myelin water fraction (MWF) imaging to investigate white matter and myelin development in 153 healthy male and female children, 3 months through 60 months in age. Optimized age-specific acquisition protocols were developed using the DESPOT and mcDESPOT imaging techniques; and mean T1, T2 and MWF trajectories were determined for frontal, temporal, occipital, parietal and cerebellar white matter, and genu, body and splenium of the corpus callosum. MWF results provided a spatio-temporal pattern in-line with prior histological studies of myelination. Comparison of T1, T2 and MWF measurements demonstrates dissimilar sensitivity to tissue changes associated with neurodevelopment, with each providing differential but complementary information.

Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease: A Cross-sectional Imaging Study

IMPORTANCE Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. OBJECTIVE To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. DESIGN, SETTING, AND PARTICIPANTS Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. MAIN OUTCOMES AND MEASURES Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. RESULTS Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions. CONCLUSIONS AND RELEVANCE While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

Vascular and cognitive functions associated with cardiovascular disease in the elderly.

This study examines the relationship between systemic vascular function, neurocognitive performance, and structural brain abnormalities on magnetic resonance imaging (MRI) among geriatric outpatients with treated, stable cardiovascular disease and no history of neurological illness (n = 88, ages 56–85 years). Vascular function was assessed by cardiac ejection fraction and output, sequential systolic and diastolic blood pressures, flow mediated brachial artery reactivity (BAR), and carotid intima media thickness (IMT). White matter hyperintensities (WMH) on MRI were quantified and examined relative to cognitive and vascular function. Principal component analysis revealed two primary vascular components: one associated with cardiac function, the other with atherosclerotic burden/endothelial dysfunction. Both factors were significantly associated with cognitive function and WMH volume. Reduced systolic variability and increased IMT were most strongly related to reduced attention, executive function, and information-processing speed. These findings suggest the possibility that systemic vascular indices may provide proxy measures of cerebrovascular dysfunction and reinforce the importance of achieving greater understanding of interaction between systemic vascular disease and brain dysfunction among elderly people with cardiovascular disease.

A Twin Study of Smoking, Nicotine Dependence, and Major Depression in Men

This study examined the nature of the relationship among lifetime major depression, smoking, and nicotine dependence. Subjects were 8,169 male twins from the Vietnam Era Twin Registry. Biometrical modeling demonstrated a genetic influence on daily smoking, nicotine dependence, and major depression, and a family environmental influence on daily smoking. Genetic factors influencing nicotine dependence also strongly influenced major depression. We also compared probands with a history of major depression (n = 398) from pairs discordant for major depression, their nondepressed cotwins (n = 364), and controls (n = 1,863) on a number of secondary smoking outcomes. Major depression was associated with current daily smoking and certain nicotine withdrawal symptoms. Individuals with a familial vulnerability for major depression, even without a personal history of major depression, were more likely to smoke despite a serious illness and to report nervousness, restlessness, difficulty concentrating, and depressed mood during past quit attempts. Among the 237 monozygotic pairs discordant for major depression, depressed probands were more likely to have a lifetime history of nicotine dependence than were cotwins. Findings extend Kendler and colleagues (1993) study of female twins by demonstrating in men that shared genetic factors predispose not only to major depression and daily smoking but also to major depression and nicotine dependence.

Subjective cognitive complaints relate to white matter hyperintensities and future cognitive decline in patients with cardiovascular disease.

OBJECTIVE Elderly patients with cardiovascular disease (CVD) often report cognitive difficulties including reduced cognitive processing speed and attention. On cross-sectional examination, such reports relate more closely to mood than to objective measures of cognitive performance, thus questioning the validity of subjective cognitive complaints as a marker of neurodegenerative processes. This study examined the longitudinal relationship among self-reported cognitive difficulties, depression, and performance on objective tests of global cognition in patients with CVD. PARTICIPANTS AND METHODS Forty-seven patients with CVD (aged 55-85 years) completed a measure of perceived cognitive dysfunction (Cognitive Difficulties Scale [CDS]), a medical history questionnaire, the Dementia Rating Scale (DRS), and the Beck Depression Inventory (BDI) at baseline and 12 months later. Baseline brain imaging was available on a small subsample (N = 17). RESULTS Hierarchical linear regression revealed that increased report of cognitive difficulties at baseline was significantly associated with poorer DRS performance at follow-up (F[3, 43] = 4.45, p = 0.008, CDS partial r = -0.30, p = 0.048), independent of age, education, baseline DRS, and BDI scores. Greater perceived cognitive dysfunction at baseline also related to higher level of white matter lesions (r = 0.53, df = 15, p = 0.028). CONCLUSIONS Self-reported cognitive difficulties may reflect early changes in cognitive aging that are difficult to detect using global cognitive screening measures at a single time point. However, these perceived difficulties relate to objectively measured cognitive decline over time. Thus, they may provide important clinical information about early neurodegenerative processes that should be carefully monitored.

Elevated C-Reactive Protein Is Related to Cognitive Decline in Older Adults with Cardiovascular Disease

OBJECTIVES: To prospectively relate C‐reactive protein (CRP), a systemic marker of inflammation, to cognitive change over a 1‐year follow‐up period.

The adverse effects of reduced cerebral perfusion on cognition and brain structure in older adults with cardiovascular disease

It is well established that aging and vascular processes interact to disrupt cerebral hemodynamics in older adults. However, the independent effects of cerebral perfusion on neurocognitive function among older adults remain poorly understood. We examined the associations among cerebral perfusion, cognitive function, and brain structure in older adults with varying degrees of vascular disease using perfusion magnetic resonance imaging (MRI) arterial spin labeling (ASL).

Effects of nicotine withdrawal on verbal working memory and associated brain response

Previous literature has reported effects of nicotine withdrawal on brain function during cognitive tasks such as verbal working memory (VWM). Mechanisms of these withdrawal effects have not been clearly identified. Functional neuroimaging offers an objective method to examine brain mechanisms associated with observable behavior and subjective reports. To investigate these mechanisms, 12 smokers were administered a 2-Back VWM challenge during two functional magnetic resonance imaging sessions. Participants abstained from smoking prior to both sessions; however, they applied a nicotine patch before one session and a placebo patch prior to the other. Among regions that exhibited a significant response to the 2-Back during either session, withdrawal was associated with significantly greater deactivation in left and right temporal poles and left medial frontal gyrus. The magnitude of task-related activation showed a significant inverse relationship to craving in the majority of regions during placebo administration. Also, individual brain responses varied more during placebo, suggesting inefficient neural processing. Results suggest that differences in brain response to a VWM challenge during abstinence may be attributed to increased craving. Further deactivation of regions associated with the default network (medial frontal and anterior temporal clusters) during the placebo condition suggests further suspension of default activity, possibly to compensate for inefficient neural processing.

Interactions between white matter asymmetry and language during neurodevelopment.

The human brain is asymmetric in gross structure as well as functional organization. However, the developmental basis and trajectory of this asymmetry is unclear, and its relationship(s) to functional and cognitive development, especially language, remain to be fully elucidated. During infancy and early childhood, in concert with cortical gray matter growth, underlying axonal bundles become progressively myelinated. This myelination is critical for efficient and coherent interneuronal communication and, as revealed in animal studies, the degree of myelination changes in response to environment and neuronal activity. Using a novel quantitative magnetic resonance imaging method to investigate myelin content in vivo in human infants and young children, we investigated gross asymmetry of myelin in a large cohort of 108 typically developing children between 1 and 6 years of age, hypothesizing that asymmetry would predict language abilities in this cohort. While asymmetry of myelin content was evident in multiple cortical and subcortical regions, language ability was predicted only by leftward asymmetry of caudate and frontal cortex myelin content and rightward asymmetry in the extreme capsule. Importantly, the influence of this asymmetry was found to change with age, suggesting an age-specific influence of structure and myelin on language function. The relationship between language ability and asymmetry of myelin stabilized at ∼4 years, indicating anatomical evidence for a critical time during development before which environmental influence on cognition may be greatest.

Cerebral atrophy, apolipoprotein E ɛ4, and rate of decline in everyday function among patients with amnestic mild cognitive impairment

Patients with amnestic mild cognitive impairment (MCI) demonstrate decline in everyday function. In this study, we investigated whether whole brain atrophy and apolipoprotein E (APOE) genotype are associated with the rate of functional decline in MCI.