Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.

BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical biopsy. METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain. RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-ß levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003). CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-ß in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-ß pathology, both in patients with possible NPH and among the wider population.

Safety, tolerability and pharmacokinetics after single and multiple doses of preladenant (SCH420814) administered in healthy subjects.

WHAT IS KNOWN AND OBJECTIVE: Preladenant (SCH420814, MK-3814) is a highly selective orally bioavailable non-methylxanthine adenosine 2A (A(2A) ) receptor antagonist under investigation for the treatment for Parkinson's disease. This study evaluated the safety, tolerability and pharmacokinetics of preladenant at single and multiple doses for the first time in humans. METHODS: These were two randomized, double-blind, placebo-controlled, ascending-dose studies, one evaluating single rising preladenant doses (5-200 mg) compared with placebo and the other evaluating multiple rising preladenant doses (10-200 mg once daily over 10 days) compared with placebo. Safety was the primary end point of both studies. Safety evaluations, physical examinations, electrocardiograms, vital signs determinations and routine laboratory tests were performed before and at intervals throughout the studies. Blood samples were collected immediately before study drug administration and at various time points after dosing. Pharmacokinetic assessments of plasma preladenant and metabolites SCH434748 and SCH446637 were performed. RESULTS AND DISCUSSION: One hundred and eight healthy adult men were randomly assigned in a 3 : 1 ratio to receive oral preladenant or matching placebo capsules under fasting conditions. Preladenant reached peak plasma concentrations in ∼1 h and then declined rapidly. Dose-related increases in exposure were observed up to 100 mg/day; accumulation was negligible at all doses. Transient mild increases in blood pressure occurred within a few hours after preladenant administration; blood pressure changes were neither cumulative nor dose-related nor associated with clinical sequelae. WHAT IS NEW AND CONCLUSION: Preladenant was generally well tolerated up to the maximum dose tested (200 mg/day).

Association between dorsolateral prefrontal N-acetyl aspartate and depression in chronic back pain: an in vivo proton magnetic resonance spectroscopy study.

Most studies of pain, including chronic pain, agree that depression and pain are interrelated, although the neurobiology of this relationship remains unknown. Neuroimaging studies suggest a specific role of the prefrontal brain regions in the mechanisms of mood disorders and chronic pain. The present study examines the interrelationships between regional brain N-Acetyl aspartate (NAA) levels (as identified by in vivo proton magnetic resonance spectroscopy in the right and left dorsolateral prefrontal cortex [DLPFC], orbitofrontal cortex, cingulate and thalamus), depression (as measured by the Beck Depression Inventory), and pain (as measured by short form of the McGill Pain Questionnaire) in 10 chronic back pain (CBP) patients with depression, and compared to the relationship between regional brain NAA levels and depression in 10 normal subjects (sex and age-matched). Reduction of NAA levels was demonstrated in the right DLPFC of CBP patients with depression, as compared to the normal controls (p < 0.02, two-tailed t-test). The depression levels in CBP patients were highly correlated with NAA levels in the right DLPFC (r = -0.99, p < 0.0001), and were unrelated to the other studied regional NAA in both groups, including the right DLPFC in normal subjects (p < 10(-6); comparing the difference between r values in the right DLPFC between the two groups). The pain levels in CBP patients were also associated with the right DLPFC (r = -0.62, p < 0.05), although these relationships were much weaker as compared to depression-NAA correlations (p < 0.0001; comparing the difference between r values). The interrelationships between NAA across brain regions were examined using correlation analysis, which detected different connectivity patterns between CBP patients with depression and normal subjects. These findings provide evidence for a stronger association of prefrontal NAA to depression than to pain in CBP, which may reflect the common neurobiological substrate underlying these conditions in CBP patients. Spectroscopic brain mapping of NAA, the marker of neuronal density and function, to the depression and pain measures might be used for segregation of their circuitries in the chronic pain brain.

Brain chemistry reflects dual states of pain and anxiety in chronic low back pain.

The neurobiology of the interaction between pain and anxiety is unknown. The present study examined interrelationships between: regional brain chemistry (as identified by in vivo proton magnetic resonance spectroscopy [(1)H-MRS] in dorsolateral prefrontal cortex [DLPFC], orbitofrontal cortex [OFC], cingulate and thalamus), pain (as measured by short form of the McGill Pain Questionnaire [SF-MPQ]), and anxiety (measured by the State-Trait Anxiety Inventory) in chronic low back pain (CLBP) patients, and contrasted to the relationship between brain chemistry and anxiety in sex and age-matched normal subjects. The results show that brain chemistry depends on a 3-way interaction of brain regions examined, subject groups (normal vs. CLBP), and anxiety levels (high vs. low). The concentration of N-Acetyl aspartate (the largest peak in (1)H-MRS) in OFC could distinguish between anxiety levels and between subject groups. Chemical-perceptual relationships were analyzed by calculating correlations between regional chemicals and perceptual measures of pain and anxiety. To isolate pain from anxiety, these maps were subdivided based on anxiety and, in the CLBP patients along anxiety-more-related vs. anxiety-less-related pain descriptors and along sensory vs. affective pain descriptors. There was a precise relationship between perception and brain chemistry. The chemical-perceptual network best related to pain in CLBP patients was comprised of the DLPFC and OFC; the chemical-anxiety network was best related to the OFC chemistry in normals and to all four regions studied in CLBP patients; and the cingulate was best related to the affective component of pain. We conclude that the chemical-perceptual mapping differentiates between closely related perceptual states of pain and anxiety in chronic pain and provides a brain regional-chemical-perceptual description of the long-term reorganization that occurs with chronic pain.

Multi-chemical networking profile of the living human brain: potential relevance to molecular studies of cognition and behavior in normal and diseased brain.

Anatomical, electrophysiological and functional neuroimaging studies show that the human brain is a complex network, where cortico-cortical and thalamo-cortical connections are organized in a specific pattern giving rise to brain function. In our recent studies we found that chemical connectivity between brain regions might be changed in different conditions (e.g. aging, chronic pain, cognitive interference). The elucidation of properties of the human brain multi-chemical networking profile is the subject of this study. In vivo proton magnetic resonance spectroscopy was used to determine relative concentrations of multiple chemicals (N-Acetyl aspartate, choline, glutamate, glutamine, GABA, inositol, glucose, and lactate in relation to creatine/phosphocreatine complex) in 6 brain regions: thalamus, and cingulate, insula, sensorimotor, orbital frontal, and dorsolateral prefrontal cortices. The properties of the brain multi-chemical networking profile within and across the studied regions were examined using correlation analysis. Strong positive correlations were seen between chemicals within brain regions. Negative correlations were primarily seen across brain regions. The cortical connectivity for both neurotransmitters (GABA and glutamate) was stronger than for the other chemicals, and was stronger than for the same neurotransmitters in the thalamus. Factor analysis indicated that the natural clustering of regional chemical concentrations is by brain region and not by chemicals. These findings support the idea for the existence of a specific pattern of multi-chemical networking profile in the brain where the major excitatory and inhibitory neurotransmitters in neocortex perform a regulatory function.

Cognitive interference is associated with neuronal marker N-acetyl aspartate in the anterior cingulate cortex: an in vivo (1)H-MRS study of the Stroop Color-Word task.

The neurobiology of cognitive interference is unknown. Previous brain imaging studies using the Stroop Color-Word (SCW) task indicate involvement of the cingulate cortex cognitive division. The present study examines interrelationships between regional brain N-Acetyl aspartate (NAA) levels (as identified by in vivo proton magnetic resonance spectroscopy in the right and left anterior cingulate cortex (ACC), dorsolateral prefrontal cortex, orbitofrontal cortex and thalamus) and cognitive interference (as measured by the SCW task) in 15 normal subjects. The results show that brain chemistry depends on cognitive interference levels (high vs low). Reduction of NAA levels was demonstrated in the right ACC (ie, cognitive midsupracallosal division) of high interference subjects, as compared to the low interference group (P < 0.01, two-tailed t-test). Chemical-cognitive relationships were analyzed by calculating correlations between regional NAA levels and the SCW task scores. Cognitive interference was highly correlated with the right anterior cingulate NAA (r = 0.76, P < 0.001), and was unrelated to other studied regional NAA, including the left ACC (P < 0.025; comparing the difference between r values in the right and left ACC). The interrelationships between NAA across brain regions were examined using correlation analysis (square matrix correlation maps), which detected different connectivity patterns between the two groups. These findings provide evidence of ACC involvement in cognitive interference suggesting a possibility of neuronal reorganization in the physiological mechanism of interference (most likely due to genetically predetermined control of the number of neurons, dendrites and receptors, and their function). We conclude that spectroscopic brain mapping of NAA, the marker of neuronal density and function, to the SCW task measures differentiates between high and low interference in normal subjects. This neuroimaging/cognitive tool may be useful for documentation of interference in studying cognitive control mechanisms, and in diagnosis of neuropsychiatric disorders where dysfunction of cingulate cortex is expected.

Chemical network of the living human brain. Evidence of reorganization with aging.

We recently described the chemical network properties of the human brain using in vivo proton magnetic resonance spectroscopy ((1)H MRS). In a separate study of aging we found increased concentration of chemicals in the prefrontal and sensorimotor cortices up to the third decade of life, and subsequent decrease of chemical concentrations in the same brain regions after the third decade between young and middle age. We anticipated that these age-dependent differences in chemical concentrations might be a reflection of the chemical network reorganization of the brain during aging. The pattern of chemical connectivity within and across brain regions for all regional chemicals, and specific patterns of chemical connectivity for each chemical type were examined for young and middle age groups using (1)H MRS and correlation analysis. For all studied ages, the dominant positive correlations occurred within brain regions and negative correlations were seen across brain regions. However, the pattern of negative chemical connectivity across brain regions was weaker in middle-aged group (F = 40.4, P < 10(-7) comparing r-values between the two age groups, ANOVA). Within brain regions, the age effects on chemical correlations were seen in the cingulate cortex (46% decrease in the middle-aged group, F = 7.2, P < 0.007) and sensorimotor cortex (SMC) (27% decrease, F = 8.9, P<0.003). Between brain regions, the age effects on chemical correlations were seen in the chemical interactions between the thalamus (433.3% increase in the middle-aged group, F = 11.7, P < 0.003), SMC (280% increase, F=20.1, P < 10(-5)), cingulate cortex (100.7% increase, F = 21.3, P < 10(-7)), and other brain regions. We found also age-differential patterns of chemical connectivity across the studied brain regions for most chemical types. The results provide evidence that normal aging is associated with reorganization of chemical network of the human brain.

Aging alters the multichemical networking profile of the human brain: an in vivo (1)H-MRS study of young versus middle-aged subjects.

In our most recent study of normal aging, we found decreased concentration of multiple chemicals in the brain of middle-aged subjects, as compared with younger subjects using in vivo proton magnetic resonance spectroscopy ((1)H-MRS). We hypothesized that these age-dependent differences in brain chemistry changes might be a reflection of the multichemical-networking-profile (MCNP) changes during aging. Using (1)H-MRS and correlation analysis, we examined the patterns of regional chemical levels and MCNP within and across multiple brain regions for all nine chemicals of (1)H-MR spectra. The brain chemistry changes and MCNP patterns were compared between 21 young (19--31-year-old) and 31 middle-aged (40--52-year-old) normal volunteers. Middle-aged subjects demonstrated a significant decrease of chemical levels in the prefrontal cortex and sensorimotor cortex (SMC), as compared with the young age group. Of these, neurotransmitters GABA and glutamate in the dorsolateral prefrontal cortex (DLPFC) were altered the most. We also found a significant increase of overall chemical correlation strength in MCNP within and across all studied brain regions with increased age. These changes were caused by alterations in the pattern of negative chemical connectivity across brain regions, which become weaker (less negative) in middle-aged subjects. The interregional chemical connectivity for the cingulate cortex, SMC and the thalamus was changed the most with increased age. Increased levels of chemical correlation strength across brain regions in aging were found for most chemicals studied (including neurotransmitters GABA and glutamate), and not for N-acetyl aspartate. These age-related differences in the connectivity of neurotransmitters were not region dependent. The results suggest that aging is associated with changes of the regional brain chemistry and the brain MCNP. The latter process may reflect an adaptive or compensatory response (possibly related to the elongation of dendrites with aging) to reduced levels of regional brain chemicals. The (1)H-MRS approach proposed here can be used as a valuable tool in the study of the brain chemistry, MCNP and their relationships in normal and abnormal aging.

Aging alters regional multichemical profile of the human brain: an in vivo 1H-MRS study of young versus middle-aged subjects.

Age-related differences in the multichemical proton magnetic resonance spectroscopy (1H-MRS) profile of the human brain have been reported for several age groups, and most consistently for ages from neonates to 16-year-olds. Our recent 1H-MRS study demonstrated a significant age-related increase of total chemical concentration (relative to creatine) in the prefrontal and sensorimotor cortices within young adulthood (19-31-year-olds). In the present study we test the hypothesis that the level of brain chemicals in the same cortices, which show increased chemical levels during normal development, are reduced with normal aging after young adulthood. The multichemical 1H-MRS profile of the brain was compared between 19 young and 16 middle-aged normal subjects across multiple brain regions for all chemicals of 1H-MRS spectra. Chemical concentrations were measured relative to creatine. Over all age groups the total relative chemical concentration was highest in the prefrontal cortex. Middle-aged subjects demonstrated a significant decrease of total relative chemical concentration in the dorsolateral prefrontal (F = 54.8, p < 10(-7), ANOVA), orbital frontal (F = 3.7, p < 0.05) and sensorimotor (F = 15.1, p < 0.0001) cortices, as compared with younger age. Other brain regions showed no age-dependent differences. The results indicate that normal aging alters multichemical 1H-MRS profile of the human brain and that these changes are region-specific, with the largest changes occuring in the dorsolateral prefrontal cortex. These findings provide evidence that the processes of neuronal maturation of the human brain, and neurotransmitters and other chemical changes as the marker of these neuronal changes are almost finished by young adulthood and then reduced during normal aging toward middle age period of life. The present data also support the notion of heterochronic regressive changes of the aging human brain, where the multichemical brain regional profile seems to inversely recapitulate cortical chemical maturation within normal development.

Anxiety in healthy humans is associated with orbital frontal chemistry.

The present study examines relationships between regional brain chemistry (as identified by localized in vivo three-dimensional single-voxel proton magnetic resonance spectroscopy (1H-MRS) and anxiety (as measured by the State-Trait Anxiety Inventory) in 16 healthy subjects. The relative concentrations of N-Acetyl aspartate, choline, glutamate, glutamine, gamma-aminobutyric acid, inositol, glucose and lactate were measured relative to creatine within six 8-cm3 brain voxels localized to: thalamus, cingulate, insula, sensorimotor, dorsolateral prefrontal, and orbital frontal cortices (OFC) in the left hemisphere. Analysis of variance, across brain regions, chemicals, and high and low anxiety groups, showed a relationship between anxiety and chemical composition of OFC, with high anxiety subjects demonstrating 32% increase in overall chemical concentrations within OFC, as compared to the lower anxiety group (F= 60.8, P < 10(-7)). Other brain regions, including cingulate, showed no detectable anxiety dependence. The combination of the state and trait anxiety was highly correlated with the concentration of OFC chemicals (r2 = 0.98), and N-Acetyl aspartate in OFC was identified as the strongest chemical marker for anxiety (changed by 43.2% between the two anxiety groups, F = 21.5, P = 0.000005). The results provide direct evidence that the OFC chemistry is associated with anxiety in healthy humans. The method can be used as a neuroimaging/behavioral tool for documentation of OFC chemistry changes in relation to anxiety per se and anxiety disorders. The presented relationship between regional brain chemistry and anxiety reflects the functional/behavioral state of the brain, pointing to possible mechanisms of the neurobiology of anxiety.

Chemical heterogeneity of the living human brain: a proton MR spectroscopy study on the effects of sex, age, and brain region.

Brain chemistry was compared between 19 male and female normal volunteers in the age group 19-31 years, across six brain regions and nine metabolites using in vivo proton magnetic resonance spectroscopy. The relative concentrations of N-acetyl aspartate, choline, glutamate, glutamine, GABA, inositol, glucose, and lactate were measured relative to creatine within 8-cm(3) brain voxels. These measurements were performed in six brain regions: thalamus and cingulate, insula, sensorimotor, dorsolateral prefrontal, and orbital frontal cortices in the left hemisphere. Total metabolite concentration was highest in prefrontal regions (28% higher in orbital frontal cortex and 18.7% higher in dorsolateral prefrontal cortex compared with insula and thalamus, P < 10(-7)). Subjects 25-31 years of age demonstrated a significant increase in total metabolite concentration in the orbital frontal cortex (35%, P < 10(-7)) and sensorimotor cortex (16.7%, P < 10(-5)) compared to those 19-20 years of age. These two brain regions also showed gender dependence, with women demonstrating increased metabolite concentrations compared to men (9% increase in sensorimotor cortex, P < 0.002, and 2.1% in orbital frontal cortex). Most other brain regions showed no gender- or age-dependent differences. The results indicate that the living human brain is chemically heterogeneous. The chemical heterogeneity is sex and age dependent and specific for brain region.

Chemical mapping of anxiety in the brain of healthy humans: an in vivo 1H-MRS study on the effects of sex, age, and brain region.

We recently presented results in an in vivo study of human brain chemistry in 'physiologic' anxiety, i.e., the anxiety of normal everyday life. Normal subjects with high anxiety demonstrated increased concentration of chemicals in orbital frontal cortex (OFC) as compared to lower anxiety. In a separate study of aging we demonstrated a decrease of total chemical concentration in OFC of middle-aged subjects, as compared with younger age. This brain region also showed gender dependence; men demonstrating decreased chemical concentration compared to women. We hypothesized that these sex- and age-dependent differences in OFC chemistry changes are a result of anxiety effects on this brain region. In the present study we examined these sex- and age-differential regional brain chemistry changes (as identified by localized in vivo proton magnetic resonance spectroscopy [1H-MRS]) in relation to the state-trait-anxiety (as measured by the State-Trait Anxiety Inventory) in 35 healthy subjects. The concentrations for all nine chemicals of 1H-MRS spectra were measured relative to creatine across multiple brain regions, including OFC in the left hemisphere. Analysis of variance showed anxiety-specific effects on chemical concentration changes in OFC, which were different for both sexes and age groups. Male subjects showed larger effect of anxiety on OFC chemistry as compared to females when the same sex high-anxiety subjects were compared to lower anxiety. Similarly, middle-aged subjects showed larger effect of anxiety on OFC chemistry as compared to younger age when the same age subjects with high anxiety were compared to lower anxiety. Largest effect of anxiety on OFC chemistry was due to changes of N-Acetyl aspartate. The results indicate that the state-trait anxiety has sex- and age-differential patterns on OFC chemistry in healthy humans, providing new information about the neurobiological roots of anxiety.

A method for assessing the accuracy of intersubject registration of the human brain using anatomic landmarks.

Several groups have developed methods for registering an individual's 3D MRI by deforming a standard template. This achievement leads to many possibilities for segmentation and morphology that will impact nuclear medical research in areas such as activation and receptor studies. Accordingly, there is a need for methods that can assess the accuracy of intersubject registration. We have developed a method based on a set of 128 anatomic landmarks per hemisphere, both cortical and subcortical, that allows assessment of both global and local transformation accuracy. We applied our method to compare the accuracy of two standard methods of intersubject registration, AIR 3.0 with fifth-order polynomial warping and the Talairach stereotaxic transformation (Talairach and Tournoux, 1988). SPGR MRI's (256 x 256 x 160) of six normal subjects (age 18-24 years) were derformed to match a standard template volume. To assess registration accuracy the landmarks were located on both the template volume and the transformed volumes by an experienced neuroanatomist. The resulting list of coordinates was analyzed graphically and by ANOVA to compare the accuracy of the two methods and the results of the manual analysis. ANOVA performed over all 128 landmarks showed that the Woods method was more accurate than Talairach (left hemisphere F = 2.8, P < 0.001 and right hemisphere F =2.4, P < 0.006). The Woods method provided a better brain surface transformation than did Talairach (F = 18.0, P < 0.0001), but as expected there was a smaller difference for subcortical structures and both had an accuracy <1 mm for the majority of subcortical landmarks. Overall, both the Woods and Talairach method located about 70% of landmarks with an error of 3 mm or less. More striking differences were noted for landmark accuracy

MRI-based morphometric topographic parcellation of human neocortex in trichotillomania.

The purpose of the present study was to test specific hypotheses regarding volumetric changes of the neocortex between 10 female trichotillomania (TTM) subjects and 10 female normal controls. A standard three-dimensional (3-D) brain coordinate system was imposed over each newly acquired native magnetic resonance imaging (MRI) scan for positional normalization and 3-D shape/geometric localization analyses were based on the midpoints of anterior and posterior commissures, and the longitudinal fissure. The brain segmentation method, using well-characterized semiautomated intensity and differential contour algorithms by signal intensity-frequency histograms, was used blind to segment the principal gray and white matter structures. The segmented neocortical ribbon was subdivided into 48 regions (i.e. parcellation units) per hemisphere via a new method of morphometric topographic parcellation. There were no significant volumetric changes of the precentral gyrus, postcentral gyrus, supplementary motor cortex or opercular cortex in TTM patients compared with control subjects. A broader analysis as a hypothesis-generating post-hoc effort showed that TTM subjects exhibited significantly reduced left inferior frontal gyrus volume of 27% (t = 2.21, d.f. = 18, P = 0.04) and enlarged right cuneal cortex volume of 40% (t = -2.30, d.f. = 18, P = 0.03) compared to normal controls. This is the first report of a structural neocortex abnormality in TTM. Results are discussed in terms of the behavioral specialization of these two brain neocortical regions and the complex interractions between visual and sensorimotor cortices. The results also showed the feasibility of the MRI-based morphometric topographic parcellation for investigation of the human neocortex in neuroscience research.

Reduced basal ganglia volumes in trichotillomania measured via morphometric magnetic resonance imaging.

A morphometric magnetic resonance imaging (MRI) study compared volumes of brain structures in 10 female subjects with trichotillomania (repetitive hair-pulling) versus 10 normal controls matched for sex, age, handedness, and education. Three-dimensional MRI scans were blindly normalized and segmented using well-characterized semiautomated intensity and differential contour algorithms by signal intensity-frequency histograms. Consistent with one a priori hypothesis, left putamen volume was found to be significantly smaller in trichotillomania subjects as compared with normal matched controls. This is the first report of a structural brain abnormality in trichotillomania. Results are discussed in terms of putative relationships between trichotillomania, Tourette's syndrome, and obsessive-compulsive disorder.