George Bartzokis

The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods

The Alzheimers Disease Neuroimaging Initiative (ADNI) is a longitudinal multisite observational study of healthy elders, mild cognitive impairment (MCI), and Alzheimers disease. Magnetic resonance imaging (MRI), (18F)‐fluorodeoxyglucose positron emission tomography (FDG PET), urine serum, and cerebrospinal fluid (CSF) biomarkers, as well as clinical/psychometric assessments are acquiredat multiple time points. All data will be cross‐linked and made available to the general scientific community. The purpose of this report is to describe the MRI methods employed in ADNI. The ADNI MRI core established specifications thatguided protocol development. A major effort was devoted toevaluating 3D T1‐weighted sequences for morphometric analyses. Several options for this sequence were optimized for the relevant manufacturer platforms and then compared in a reduced‐scale clinical trial. The protocol selected for the ADNI study includes: back‐to‐back 3D magnetization prepared rapid gradient echo (MP‐RAGE) scans; B1‐calibration scans when applicable; and an axial proton density‐T2 dual contrast (i.e., echo) fast spin echo/turbo spin echo (FSE/TSE) for pathology detection. ADNI MRI methods seek to maximize scientific utility while minimizing the burden placed on participants. The approach taken in ADNI to standardization across sites and platforms of the MRI protocol, postacquisition corrections, and phantom‐based monitoring of all scanners could be used as a model for other multisite trials. J. Magn. Reson. Imaging 2008.

An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia

BACKGROUND Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. METHODS Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. RESULTS Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. CONCLUSIONS The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders.

Differences between smokers and nonsmokers in regional gray matter volumes and densities

BACKGROUND Magnetic resonance imaging (MRI) studies have demonstrated large-scale brain abnormalities in cigarette smokers, such as ventricular enlargement and atrophy. Converging lines of evidence point to functional differences between smokers and nonsmokers in specific brain regions, namely the lateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and thalamus. Using MRI, we examined these regions for differences in gray matter between smokers and nonsmokers. METHODS Thirty-six otherwise healthy adults (19 smokers and 17 nonsmoking control subjects) underwent three-dimensional Fourier-transform spoiled-gradient-recalled acquisition MRI of the brain. Both hand-drawn regions of interest and the computer program voxel-based morphometry were used to assess group differences in regional gray matter volumes and densities, respectively. RESULTS Smokers had smaller gray matter volumes and lower gray matter densities than nonsmokers in the PFC bilaterally, along with smaller volumes in the left dorsal ACC and lower gray matter densities in the right cerebellum. Smokers also had negative associations between pack-year smoking history and PFC gray matter densities. CONCLUSIONS Smokers and nonsmokers differed in regional gray matter in brain areas previously linked with nicotine dependence. These findings might reflect effects of chronic smoking, predisposing traits that lead to smoking, or some combination of these factors.

Brain ferritin iron may influence age- and gender-related risks of neurodegeneration

BACKGROUND Brain iron promotes oxidative damage and protein oligomerization that result in highly prevalent age-related proteinopathies such as Alzheimers disease (AD), Parkinsons disease (PD), and Dementia with Lewy Bodies (DLB). Men are more likely to develop such diseases at earlier ages than women but brain iron levels increase with age in both genders. We hypothesized that brain iron may influence both the age- and gender-related risks of developing these diseases. METHODS The amount of iron in ferritin molecules (ferritin iron) was measured in vivo with MRI by utilizing the field dependent relaxation rate increase (FDRI) method. Ferritin iron was measured in four subcortical nuclei [caudate (C), putamen (P), globus pallidus (G), thalamus (T)], three white matter regions [frontal lobe (Fwm), genu and splenium of the corpus callosum (Gwm, Swm)] and hippocampus (Hipp) in 165 healthy adults aged 19-82. RESULTS There was a high correlation (r>0.99) between published post-mortem brain iron levels and FDRI. There were significant age-related changes in ferritin iron (increases in Hipp, C, P, G, and decreases in Fwm). Women had significantly lower ferritin iron than men in five regions (C, T, Fwm, Gwm, Swm). CONCLUSIONS This is the first demonstration of gender differences in brain ferritin iron levels. It is possible that brain iron accumulation is a risk factor that can be modified. MRI provides the opportunity to assess brain iron levels in vivo and may be useful in targeting individuals or groups for preventive therapeutic interventions.

MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects.

Tissue iron levels in the extrapyramidal system of earlier- and later-onset Parkinsons disease (PD) subjects were evaluated in vivo using a magnetic resonance imaging (MRI) method. The method involves scanning subjects in both high- and low-field MRI instruments, measuring tissue relaxation rate (R2), and calculating the field-dependent R2 increase (FDRI) which is the difference between the R2 measured with the two MRI instruments. In tissue, only ferritin iron is known to increase R2 in a field-dependent manner and the FDRI measure is a specific measure of this tissue iron pool. Two groups of male subjects with PD and two age-matched groups of normal control males were studied. The two groups of six subjects with PD consisted of subjects with earlier- or later-onset (before or after age 60) PD. FDRI was measured in five subcortical structures: the substantia nigra reticulata (SNR), substantia nigra compacta (SNC), globus pallidus, putamen, and caudate nucleus, and in one comparison region; the frontal white matter. Earlier-onset PD subjects had significant (p < 0.05) increases in FDRI in the SNR, SNC, putamen, and globus pallidus, while later-onset PD subjects had significantly decreased FDRI in the SNR when compared to their respective age-matched controls. Controlling for illness duration or structure size did not meaningfully alter the results. Published post-mortem studies on SN iron levels indicate decreased ferritin levels and increased free iron levels in the SN of older PD subjects, consistent with the decreased FDRI observed in our later-onset PD sample, which was closely matched in age to the post-mortem PD samples. The FDRI results suggest that disregulation of iron metabolism occurs in PD and that this disregulation may differ in earlier- versus later-onset PD.

The vulnerability/stress model of schizophrenic relapse: a longitudinal study

A tentative model for conceptualizing the interplay of vulnerability factors, stressors, and protective factors in the course of schizophrenia is discussed. A study of the initial years after a first schizophrenic episode is testing the predictive role of key factors. During an initial 1‐year period of depot antipsychotic medication, independent life events and expressed emotion were found to predict the likelihood of psychotic relapse. Initial analyses indicate that independent life events play less of a role in relapse prediction during a medication‐free period. These results suggest that maintenance antipsychotic medication raises the threshold for return of psychotic symptoms, such that relapses are less likely unless major environmental stressors occur. A low expressed emotion environment may be a protective factor.

Schizophrenia: Breakdown in the Well-regulated Lifelong Process of Brain Development and Maturation

Recent evidence suggests that the temporal extent of brain development/maturation can be expanded into middle age when maximal white matter volume and myelination are reached in frontal lobes and association areas. This temporally expanded view of brain development underlies a more comprehensive conceptual model of schizophrenia that incorporates both the reduction of gray matter volume and the complementary expansion of white matter volume occurring from adolescence until middle age. The model posits that the brain is in a constant state of well-regulated structural and functional change roughly defined as periods of development continuing into middle age followed by degeneration. Multiple genetic and environmental factors can interfere with the developmental processes resulting in a dysregulation of the complementary changes occurring in gray and white matter. This dysregulation in development results in an insufficient capacity to maintain temporal synchrony of widely distributed neural networks and is manifested in the heterogeneity of symptoms and cognitive impairments of schizophrenia. The model highlights the contributory role of myelination to synchronous brain function, provides explanations for inconsistencies in the existing literature, and suggests testable hypotheses and novel approaches for intervention efforts.

Abuse of amphetamines and structural abnormalities in the brain.

We review evidence that structural brain abnormalities are associated with abuse of amphetamines. A brief history of amphetamine use/abuse and evidence for toxicity is followed by a summary of findings from structural magnetic resonance imaging (MRI) studies of human subjects who had abused amphetamines and children who were exposed to amphetamines in utero. Evidence comes from studies that used a variety of techniques including manual tracing, pattern matching, voxel‐based, tensor‐based, or cortical thickness mapping, quantification of white matter signal hyperintensities, and diffusion tensor imaging. Ten studies compared controls to individuals who were exposed to methamphetamine. Three studies assessed individuals exposed to 3–4‐methylenedioxymethamphetamine (MDMA). Brain structural abnormalities were consistently reported in amphetamine abusers, as compared to control subjects. These included lower cortical gray matter volume and higher striatal volume than control subjects. These differences might reflect brain features that could predispose to substance dependence. High striatal volumes might also reflect compensation for toxicity in the dopamine‐rich basal ganglia. Prenatal exposure was associated with striatal volume that was below control values, suggesting that such compensation might not occur in utero. Several forms of white matter abnormality are also common and may involve gliosis. Many of the limitations and inconsistencies in the literature relate to techniques and cross‐sectional designs, which cannot infer causality. Potential confounding influences include effects of pre existing risk/protective factors, development, gender, severity of amphetamine abuse, abuse of other drugs, abstinence, and differences in lifestyle. Longitudinal designs in which multimodal datasets are acquired and are subjected to multivariate analyses would enhance our ability to provide general conclusions regarding the associations between amphetamine abuse and brain structure.

Brain Ferritin Iron as a Risk Factor for Age at Onset in Neurodegenerative Diseases

Abstract: Tissue iron can promote oxidative damage. Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders, including Alzheimers disease (AD) and Parkinsons disease (PD). Higher iron levels in males may contribute to higher risk for younger‐onset PD and recent studies have linked the presence of the hemochromatosis gene with a younger age at onset of AD. We examined whether age at onset of PD and AD was associated with increased brain ferritin iron. Ferritin iron can be measured with specificity in vivo with MRI utilizing the field‐dependent relaxation rate increase (FDRI) method. FDRI was assessed in three basal ganglia regions (caudate, putamen, and globus pallidus) and frontal lobe white matter for younger‐ and older‐onset male PD and AD patients and healthy controls. Significant increases in basal ganglia FDRI levels were observed in the younger‐onset groups of both diseases compared to their respective control groups, but were absent in the older‐onset patients. The results support the suggestion that elevated ferritin iron and its associated toxicity is a risk factor for age at onset of neurodegenerative diseases such as AD and PD. Clinical phenomena such as gender‐associated risk of developing neurodegenerative diseases and the age at onset of such diseases may be associated with brain iron levels. In vivo MRI can measure and track brain ferritin iron levels and provides an opportunity to design therapeutic interventions that target high‐risk populations early in the course of illness, possibly even before symptoms appear.

Myelin Breakdown and Iron Changes in Huntington’s Disease: Pathogenesis and Treatment Implications

BackgroundPostmortem and in vivo imaging data support the hypothesis that premature myelin breakdown and subsequent homeostatic remyelination attempts with increased oligodendrocyte and iron levels may contribute to Huntington’s Disease (HD) pathogenesis and the symmetrical progress of neuronal loss from earlier-myelinating striatum to later-myelinating regions. A unique combination of in vivo tissue integrity and iron level assessments was used to examine the hypothesis.MethodsA method that uses two Magnetic resonance imaging (MRI) instruments operating at different field-strengths was used to quantify the iron content of ferritin molecules (ferritin iron) as well as tissue integrity in eight regions in 11 HD and a matched group of 27 healthy control subjects. Three white matter regions were selected based on their myelination pattern (early to later-myelinating) and fiber composition. These were frontal lobe white matter (Fwm) and splenium and genu of the corpus callosum (Swm and Gwm). In addition, gray matter structures were also chosen based on their myelination pattern and fiber composition. Three striatum structures were assessed [caudate, putamen, and globus pallidus (C, P, and G)] as well as two comparison gray matter regions that myelinate later in development and are relatively spared in HD [Hippocampus (Hipp) and Thalamus (Th)].ResultsCompared to healthy controls, HD ferritin iron levels were significantly increased in striatum C, P, and G, decreased in Fwm and Gwm, and were unchanged in Hipp, Th, and Swm. Loss of tissue integrity was observed in C, P, Fwm, and especially Swm but not Hipp, Th, G, or Gwm. This pattern of findings was largely preserved when a small subset of HD subjects early in the disease process was examined.ConclusionsThe data suggest early in the HD process, myelin breakdown and changes in ferritin iron distribution underlie the pattern of regional toxicity observed in HD. Prospective studies are needed to verify myelin breakdown and increased iron levels are causal factors in HD pathogenesis. Tracking the effects of novel interventions that reduce myelin breakdown and iron accumulation in preclinical stages of HD could hasten the development of preventive treatments.