Biomedical subjects

James R MacFall

Publications and source records attributed to James R MacFall.

At least 19 recordsLinked to original sources

PubMed2006

Differences in brain volumes among males and female hormone-therapy users and nonusers.

Numerous studies have shown gender differences in the brain volumes of elderly adults. Some evidence shows that higher estrogen levels may be neuroprotective, suggesting that hormone therapy (HT) may in part be responsible for these gender differences; however, few studies have examined the relation between HT and brain volumes. Brain volumes of caudate, putamen, hippocampus, gray matter, white matter, white-matter lesions, and cerebrospinal fluid were measured on magnetic resonance imaging scans. A comprehensive neuropsychological battery was administered. Women were separated into two groups based on HT use, and we used multiple regression analyses to compare these groups with one another and with men. Results of brain-volume measurements showed that HT users had significantly less gray matter and more cerebrospinal fluid than nonusers. Results of the neuropsychological testing showed that HT users performed better on the Shipley Vocabulary Test than males did.

Aged↗

PubMed2006

Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve.

Major predictors of Alzheimer's disease (AD) include apolipoprotein E (APOE)-epsilon4, hippocampal atrophy on magnetic resonance imaging (MRI), and memory dysfunction prior to diagnosis. We examined 159 normal elderly subjects with MRI and the California Verbal Learning Test (CVLT); 84 returned for longitudinal follow-up 5 years later. Analyses at baseline revealed significant variance in hippocampal volume accounted for by cerebral volume and age but not by APOE isoform. However, interactions involving APOE isoform and laterality were observed. As hypothesized, an APOE x time interaction was revealed for CVLT long-delay free recall: APOE-epsilon3/4 subjects had significantly poorer performance than APOE-epsilon3/3 subjects at follow-up. Forward stepwise multiple regression analysis predicting follow-up long-delay free recall selected baseline recall, followed by number of APOE-epsilon4 alleles, followed by left-hippocampal volume. Age and sex did not enter into the model. We conclude that APOE-epsilon4 predicts longitudinal memory decline in healthy controls and that MRI morphometry of hippocampus adds slightly to predictive value.

Aged↗

PubMed2006

Dorsolateral prefrontal cortex and anterior cingulate cortex white matter alterations in late-life depression.

BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) are critical for mood regulation. Alterations in the white matter connections of these regions may impair their role in mood regulation and increase the risk of developing depression. This study used diffusion tensor imaging to examine for white matter microstructural abnormalities of these regions and of central white matter structures in late-life depression. METHODS: One hundred six elderly depressed subjects and eighty-four elderly nondepressed subjects underwent clinical assessment and diffusion tensor imaging. The apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in regions of interest placed in the white matter of the DLPFC, ACC, corpus callosum, and internal capsule. Differences between groups were assessed, controlling for age, sex, and total cerebral volume. RESULTS: After controlling for covariates, depressed subjects had significantly lower FA values in white matter of the right ACC, bilateral superior frontal gyri, and left middle frontal gyrus. There were no significant differences in ADC values. CONCLUSIONS: Lower FA, representing lower tissue organization, is observed in depressed elders in the DLPFC and right ACC. These findings support the hypothesis that altered connectivity between brain regions contributes to the risk of depression.

Aged↗

PubMed2006

Chemodosimetry of in vivo tumor liposomal drug concentration using MRI.

Effective cancer chemotherapy depends on the delivery of therapeutic drugs to cancer cells at cytotoxic concentrations. However, physiologic barriers, such as variable vessel permeability, high interstitial fluid pressure, and heterogeneous perfusion, make it difficult to achieve that goal. Efforts to improve drug delivery have been limited by the lack of noninvasive tools to evaluate intratumoral drug concentration and distribution. Here we demonstrate that tumor drug concentration can be measured in vivo using T(1)-weighted MRI, following systemic administration of liposomes containing both drug (doxorubicin (DOX)) and contrast agent (manganese (Mn)). Mn and DOX concentrations were calculated using T(1) relaxation times and Mn:DOX loading ratios, as previously described. Two independent validations by high-performance liquid chromatography (HPLC) and histologic fluorescence in a rat fibrosarcoma (FSA) model indicate a concordant linear relationship between DOX concentrations determined using T(1) and those measured invasively. This method of imaging exhibits potential for real-time evaluation of chemotherapeutic protocols and prediction of tumor response on an individual patient basis.

Animals↗

PubMed2005

Lobar distribution of lesion volumes in late-life depression: the Biomedical Informatics Research Network (BIRN).

White matter hyperintense lesions on T2-weighted images are associated with late-life depression. Little work has been carried out examining differences in lesion location between elderly individuals with and without depression. In contrast to previous studies examining total brain white matter lesion volume, this study examined lobar differences in white matter lesion volumes derived from brain magnetic resonance imaging. This study examined 49 subjects with a DSM-IV diagnosis of major depression and 50 comparison subjects without depression. All participants were age 60 years or older. White matter lesion volumes were measured in each hemisphere using a semiautomated segmentation process and localized to lobar regions using a lobar atlas created for this sample using the imaging tools provided by the Biomedical Informatics Research Network (BIRN). The lobar lesion volumes were compared against depression status. After controlling for age and hypertension, subjects with depression exhibited significantly greater total white matter lesion volume in both hemispheres and in both frontal lobes than did control subjects. Although a similar trend was observed in the parietal lobes, the difference did not reach a level of statistical significance. Models of the temporal and occipital lobes were not statistically significant. Older individuals with depression have greater white matter disease than healthy controls, predominantly in the frontal lobes. These changes are thought to disrupt neural circuits involved in mood regulation, thus increasing the risk of developing depression.

Aged↗

PubMed2005

Greater MRI lesion volumes in elderly depressed subjects than in control subjects.

Hyperintense lesions in both white matter and gray matter on T2-weighted magnetic resonance imaging (MRI) are associated with late-life depression. This large study examined differences in gray and white matter lesion volumes on brain MRI between 253 elderly depressed and 146 control subjects. White matter and gray matter lesion volumes were measured in each hemisphere using a semi-automated segmentation process and compared against depression status. Depressed subjects exhibited significantly greater total white matter (mean 7.22 ml) and gray matter (mean 0.30 ml) lesion volumes in both hemispheres than did control subjects (mean 4.87 ml in white matter and 0.18 ml in gray matter). This difference remained statistically significant even after controlling for confounders such as age, sex, race and reports of hypertension, diabetes and heart disease. Patients with late-life depression have larger white matter lesion and gray matter lesion volumes than do control subjects. Future research should combine similar volumetric techniques with methods of identifying the location of lesions specific to late-life depression.

Aged↗

PubMed2005

Brain morphometry, T2-weighted hyperintensities, and IQ in children with neurofibromatosis type 1.

BACKGROUND: Larger gray matter (GM) volume in healthy children is correlated with higher IQ. Children with neurofibromatosis type 1 (NF1) have larger brains, their magnetic resonance images frequently show T2-weighted hyperintensities, and their IQs are lower. OBJECTIVES: To confirm the hypotheses that (1) children with NF1 have larger GM and white matter volumes, (2) the greatest volume differences are in the frontal and parietal regions and in children with NF1 with hyperintensities, and (3) GM volume is inversely related to IQ in children with NF1. DESIGN: Wechsler Intelligence Scale for Children-Third Edition IQ testing and measurement of cerebral volumes and hyperintensities in brain magnetic resonance images were performed on 36 children with NF1 and on 36 matched relatives who served as control subjects. RESULTS: Gray matter and white matter volumes were significantly larger in children with NF1. The greatest difference was observed in cerebral white matter volume, predominantly in the frontal lobes, whereas the greatest difference in GM volume was in the temporal, parietal, and occipital regions. In controls, IQ was significantly related to GM volume, but in children with NF1, IQ was not inversely associated with GM volume, although IQs of children with NF1 were significantly lower. CONCLUSIONS: Children with NF1 do not have the normal relationship between GM volume and IQ. Larger GM volume in the posterior brain regions and larger white matter volumes in the frontal brain regions contribute to the larger brain volume in children with NF1.

Brain↗

PubMed2005

Influence of serotonin transporter promoter region polymorphisms on hippocampal volumes in late-life depression.

CONTEXT: Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) influence transcription and may play a role in the pathogenesis and course of depression. Recent research demonstrates that specific polymorphisms may be associated with differences in hippocampal volumes in subjects with depression. OBJECTIVE: To examine associations between 5-HTTLPR genotype and hippocampal volumes in elderly control subjects and elderly subjects classified as having early or late onset of depression. DESIGN: Cohort study examining baseline characteristics. PARTICIPANTS: Subjects were community dwelling and 60 years or older. Using a definition of early-onset depression as depression first occurring at 50 years or younger, we examined 72 subjects with early-onset depression, 63 subjects with late-onset depression, and 83 healthy control subjects. MAIN OUTCOME MEASURES: All subjects underwent genotyping for the 5-HTTLPR and underwent brain magnetic resonance imaging. Analyses of hippocampal volumes were controlled for total cerebral volume, age, and sex. RESULTS: The interaction between diagnosis and 5-HTTLPR genotype was statistically significant for the right hippocampus (P = .04). Subjects with late-onset depression who were homozygous for the long (L) allele (L /L genotype) had significantly smaller right hippocampal volumes than did L /L subjects with early-onset depression (P = .046) or L /L control subjects (P = .01). Post hoc analyses showed that later age of depression onset was associated with smaller hippocampal volumes in subjects with the L /L genotype, but earlier age of onset was associated with smaller hippocampal volumes in subjects who were homozygous for the short (S) allele (S/S genotype). CONCLUSIONS: Subjects with late-onset depression who were homozygous for the L allele exhibited smaller hippocampal volumes than other groups. Genotype also mediated the effect of age of onset on hippocampal volumes. Our findings differ from previous work; however, we examined an older and larger cohort of subjects than previous studies. Possible explanations for these findings include interactions between the serotonergic system and neurotrophic factors or cortisol response to stresses, each of which may affect hippocampal volumes.

Age Factors↗

PubMed2005

Biological and social predictors of long-term geriatric depression outcome.

OBJECTIVE: In this study, we examined 204 older depressed individuals for up to 64 months to determine factors related to depression outcome. We hypothesized that both presence of vascular brain lesions seen on baseline magnetic resonance imaging (MRI) scans and lower baseline social support measures would be related to worse depression outcome. METHOD: At study entry, all subjects were at least 59 years old, had a diagnosis of major depression, and were free of other major psychiatric illness and primary neurological illness, including dementia and stroke. Depression was diagnosed via structured interview and clinical assessment by a geriatric psychiatrist who completed a Montgomery Asberg Depression Rating Scale (MADRS) to determine severity of depression. Subjects provided self-report data on social support variables and ability to perform basic and instrumental activities of daily living (ADL, IADL). All subjects agreed to have a baseline standardized MRI brain scan. Ratings of severity of hyperintensities were determined for the periventricular white matter, deep white matter, and subcortical gray matter by two readers who decided by consensus. Treatment was provided by geropsychiatrists following clinical guidelines. Using mixed models to analyze the data, we determined the effect of a variety of demographic, social and imaging variables on the trajectory of MADRS score, the outcome variable of interest. RESULTS: MADRS scores decreased steadily over time. In a final HLM model, in which time since entry, a baseline time indicator, age, gender, education and Mini-mental State Examination score were controlled, subjective social support, instrumental ADL impairment, subcortical gray matter severity, and the interactions of time with social network and with subcortical gray matter lesions remained significantly associated with MADRS score. CONCLUSIONS: Both social and biological factors at baseline are associated with longitudinal depression severity in geriatric depression.

Aged↗

PubMed2005

Cortical white matter microstructural abnormalities in bipolar disorder.

This article reports on preliminary findings describing microstructural abnormalities in the white matter of cortical areas thought to be associated with bipolar disorder. In all, 14 patients with bipolar disorder and 21 nonpsychiatrically ill control subjects underwent MR imaging including a diffusion tensor imaging (DTI) pulse sequence (six directions, b=1000 mm(2)/s). DTI data were analyzed on a workstation using a program that allowed calculation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within the following three white matter fiber tracts bilaterally: the orbital frontal cortex, and the superior and middle frontal gyri. These values were compared across patient groups. The left and right orbital frontal white matter exhibited significantly higher ADC values in bipolar subjects than control subjects on both the left (p=0.028) and right (p=0.011). Microstructural changes in the white matter of the orbital frontal areas as reflected by increased ADC values appear to be associated with bipolar disorder. Further research is needed to better understand the interaction of microstructural changes and bipolar symptoms and whether these changes are specific to bipolar disorder.

Adult↗

PubMed2004

Clinical characteristics of magnetic resonance imaging-defined subcortical ischemic depression.

BACKGROUND: There is a substantial body of research supporting the vascular depression hypothesis of late-life depression. To update this hypothesis so it incorporates recent research, we propose that the term subcortical ischemic vascular depression may be a more accurate representation of the disease process. We sought to investigate this diagnosis as a construct by examining differences between depressed subjects with and without magnetic resonance imaging defined subcortical ischemic vascular depression. METHODS: This case-control study examined 139 depressed elderly subjects. Demographic data, psychiatric, medical, and family history, depressive symptomatology, and functional impairment were compared between groups dichotomized based on neuroimaging findings. RESULTS: Seventy-five (54%) of the subjects met neuroimaging criteria for subcortical ischemic vascular depression. Age was most strongly associated with increased prevalence of subcortical ischemic vascular depression. Lassitude and a history of hypertension were also positively associated with the diagnosis; a family history of mental illness and loss of libido were negatively associated with the diagnosis. CONCLUSIONS: These data support that subcortical ischemic vascular depression may be a specific syndrome from other types of late-life depression. Further research is needed to further characterize this disorder, particularly in regards to cognitive function and treatment implications.

Age Factors↗

PubMed2004

Diffusion tensor imaging: background, potential, and utility in psychiatric research.

Diffusion tensor imaging is a variation of magnetic resonance imaging that measures the diffusion of water in tissues. This can help measure and quantify a tissue's orientation and structure, making it an ideal tool for examining cerebral white matter and neural fiber tracts. It is only beginning to be utilized in psychiatric research. This article reviews the theory behind diffusion tensor imaging, its potential to map fiber tracts in the brain, and its recent use in psychiatric research.

Body Water↗

PubMed2004

In vivo monitoring of tissue pharmacokinetics of liposome/drug using MRI: illustration of targeted delivery.

The purpose of this study was to determine if MnSO(4)/doxorubicin (DOX) loaded liposomes could be used for in vivo monitoring of liposome concentration distribution and drug release using MRI. In vitro results show that T(1) shortening correlates with MnSO(4) concentration. Using a temperature-sensitive liposome formulation, it was found that MnSO(4) release significantly shortened T(1). This feature, therefore, suggests that content release can also be measured with these MnSO(4)-loaded liposomes. The feasibility of monitoring this drug delivery and release-imaging agent was shown in a murine tumor model. Upon tumor heating, nonthermally sensitive liposomes selectively but heterogeneously accumulated in the tumor region. The thermally sensitive liposomes showed a clear pattern of accumulation at the periphery of the tumor, concordant with the release temperature of this formulation (39-40 degrees C). This liposome contrast agent has potential for use with hyperthermia by providing individualized monitoring of tissue drug concentration distribution during or after treatment. This would allow for: 1) modification of treatment variables to improve the uniformity of drug delivery, and 2) provide a means to select patients most likely to benefit from this liposomal drug treatment. Additionally, the drug-loading method used for this liposome is applicable to a wide range of drugs, thereby broadening its applicability. The method is also applicable to other liposomal formulations with triggered release mechanisms.

Animals↗

PubMed2004

Diffusion tensor imaging of adult age differences in cerebral white matter: relation to response time.

Diffusion tensor imaging (DTI) measures the displacement of water molecules across tissue components, thus providing information regarding the microstructure of cerebral white matter. Fractional anisotropy (FA), the degree to which diffusion is directionally dependent, is typically higher for compact, homogeneous fiber bundles such as the corpus callosum. Previous DTI studies in adults have demonstrated an age-related decline in white matter FA, but whether the relation between FA and behavioral performance varies as a function of age has not been determined. We investigated adult age differences in FA, and age-related changes in the relation between FA and response time (RT), in a visual target-detection task. The results confirmed that, independently of age, FA is higher in the corpus callosum than in other brain regions. We also observed an age-related decline in FA that did not vary significantly across the brain regions. For both age groups, a lower level of integrity of the cerebral white matter (as indexed by FA), in specific brain regions, was associated with slower responses in the visual task. An age-related change in this relation was evident, however, in that the best predictor of RT for younger adults was FA in the splenium of the corpus callosum, whereas for older adults the best predictor was FA in the anterior limb of the internal capsule. This pattern is consistent with measures of the task-related cortical activation obtained from these same individuals and suggests an age-related increase in the attentional control of responses mediated by corticostriatal or corticothalamic circuits.

Adult↗

PubMed2004

Late-life depression and microstructural abnormalities in dorsolateral prefrontal cortex white matter.

OBJECTIVE: The purpose of this study was to determine whether microstructural abnormalities in the white matter of the dorsolateral prefrontal cortex are associated with late-life depression. METHOD: Seventeen elderly depressed subjects were compared with 16 elderly subjects who were not depressed. Diffusion tensor imaging was used to measure the fractional anisotropy of the white matter in the dorsolateral prefrontal cortex's superior and middle frontal gyri bilaterally and in the left occipital lobe as a control region. The authors compared results between groups while controlling for age, sex, and comorbid medical disorders. RESULTS: Even after controlling for age, sex, hypertension, and heart disease, the authors found significantly lower fractional anisotropy values in the right superior frontal gyrus white matter of depressed patients than comparison subjects. CONCLUSIONS: Microstructural changes in the white matter of the right superior frontal gyrus are associated with late-life depression. Further work is needed to determine how these changes contribute to depression outcomes.

Aged↗

PubMed2003

Apolipoprotein E genotype and subcortical vascular lesions in older depressed patients and control subjects.

BACKGROUND: Several studies have linked geriatric depression with cerebrovascular disease. The apolipoprotein E gene (APOE) epsilon 4 allele has been associated with a variety of late-life neuropsychiatric disorders, including Alzheimer's disease, vascular dementia, and depression. METHODS: The sample consisted of 145 elderly depressive individuals and 100 nondepressed elderly control subjects. After a standardized clinical assessment, all subjects underwent a magnetic resonance imaging brain scan. Volumes of subcortical white and gray matter lesions were determined using a semi-automated method. Apolipoprotein E genotype was determined on blood sample using a standard protocol. A series of linear regression models were developed to assess the relationships between APOE genotype and white and gray matter lesion volumes. RESULTS: Older age, lower Mini-Mental State Examination score, and having any APOE epsilon 4 allele were each correlated with gray-matter lesion volume in depressed patients. Apolipoprotein E genotype was not associated with any lesion volume among control subjects. In a subsequent linear regression model, gray matter lesion volume was associated with older age, having at least one APOE epsilon 4 allele, and white matter lesion volume among depressed patients. CONCLUSIONS: These results are consistent with previous reports linking cerebrovascular disease and APOE genotype. Further studies are needed to replicate this finding in elderly depressive individuals and to explain the relationship between the APOE locus and development of central nervous system vascular pathology.

Aged↗

PubMed2003

White matter hyperintensity progression and late-life depression outcomes.

CONTEXT: White matter hyperintensities (WMHs) are bright foci seen in the parenchyma of the brain on T2-weighted cranial magnetic resonance imaging (MRI) scans and are associated with geriatric depression. Because they are associated with age, they should increase in number and size over time. To our knowledge, this is the first longitudinal, volumetric MRI study of WMHs in depression. OBJECTIVE: To determine if WMH progression over 2 years influences depression outcomes. DESIGN: Over 2 years, depressed subjects received antidepressant treatment according to a naturalistic somatic treatment algorithm designed to offer the best possible treatment to the individual. After the treatment period, depressed subjects were dichotomized based on whether they had reached and sustained remission during this period. PARTICIPANTS: One hundred thirty-three subjects aged 60 years or older meeting DSM-IV criteria for major depressive disorder. MEASURES: Cranial MRI was obtained at baseline and approximately 2 years later. White matter hyperintensity volume was measured in each hemisphere using a semiautomated segmentation process. OUTCOMES: Subjects were dichotomized based on achieving or not achieving remission of depressive symptoms, defined as a Montgomery-Asberg Depression Rating Scale score of 8 or less. RESULTS: The depressed subgroup that achieved and sustained remission had significantly less increases in WMH volume (11.5%) than did the group that did not achieve or sustain remission (31.6%) (P =.01). In a regression model, greater change in WMH volume was significantly associated with failure to sustain remission (P =.004) even when controlling for baseline depression severity, medical illness severity, age, sex, and race. Education was associated with achieving and sustaining remission (P =.02). CONCLUSIONS: Greater progression of WMH volume is associated with poor outcomes in geriatric depression. Future work is needed to develop means of slowing the rate of WMH progression and to determine whether this will lead to improved depression outcomes in elderly persons.

Aged↗

PubMed2003

Localization of age-associated white matter hyperintensities in late-life depression.

OBJECTIVE: Deep white matter hyperintense lesions are associated with advanced age and late-life depression. The authors examined where age-related cerebral lesions occurred in elderly depressed and healthy control subjects. METHODS: Eighty-seven depressed subjects and 47 control subjects underwent 1.5 T cranial magnetic resonance imaging (MRI). Utilizing a semiautomated method, a segmented image was created containing only white matter lesions. We created a statistical parametric map (SPM) separately for each subject group that displayed the association between lesions in any voxel and advanced age. RESULTS: The SPM analysis in depressed subjects demonstrates a significant association between age and lesions found in bilateral, frontal, and left parietal regions. The analysis in control subjects found significant associations only in bilateral parieto-temporal regions, not frontal regions. CONCLUSIONS: This study demonstrates a different pattern of age-related lesion location between depressed and control subjects. It further supports the theory that frontostriatal disconnection contributes to late-life depression.

Age Factors↗