Jeffrey A. Stanley

In vivo magnetic resonance spectroscopy and its application to neuropsychiatric disorders.

In vivo magnetic resonance spectroscopy (MRS) is the only noninvasive imaging technique that can directly assess the living biochemistry in localized brain regions. In the past decade, spectroscopy studies have shown biochemical alterations in various neuropsychiatric disorders. These first-generation studies have, in most cases, been exploratory but have provided insightful biochemical information that has furthered our understanding of different brain disorders. This review provides a brief description of spectroscopy, followed by a literature review of key spectroscopy findings in schizophrenia, affective disorders, and autism. In schizophrenia, phosphorus spectroscopy studies have shown altered metabolism of membrane phospholipids (MPL) during the early course of the illness, which is consistent with a neurodevelopmental abnormality around the critical period of adolescence when the illness typically begins. Children and adolescents who are at increased genetic risk for schizophrenia show similar MPL alterations, suggesting that schizophrenia subjects with a genetic predisposition may have a premorbid neurodevelopmental abnormality. Independent of medication status, bipolar subjects in the depressive state tended to have higher MPL precursor levels and a deficit of high-energy phosphate metabolites, which also is consistent with major depression, though these results varied. Further bipolar studies are needed to investigate alterations at the early stage. Lastly, associations between prefrontal metabolism of high-energy phosphate and MPL and neuropsychological performance and reduced N-acetylaspartate in the temporal and cerebellum regions have been reported in individuals with autism. These findings are consistent with developmental alterations in the temporal lobe and in the cerebellum of persons with autism. This paper discusses recent findings of new functions of N-acetylaspartate.

Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites

BACKGROUND There is evidence for membrane abnormalities in schizophrenia. It is unclear whether the observed membrane deficits in peripheral cells parallel central membrane phospholipid metabolism. To address this question we examined the relations between red blood cell polyunsaturated fatty acids and brain phospholipid metabolites from different regions of interest in schizophrenia and healthy subjects. METHODS Red blood cell membrane fatty acids were measured by capillary gas chromatography and in vivo brain phospholipid metabolite levels were measured using a multi-voxel (31)P Magnetic Resonance Spectroscopy technique on 11 first-episode, neuroleptic-naïve schizophrenic subjects and 11 normal control subjects. RESULTS Both the total polyunsaturated fatty acids and the individual 20:4(n-6) contents were significantly correlated with the freely-mobile phosphomonoester [PME(s-tau(c))] levels (r =.5643, p =.0062 and r =.6729, p =.0006, respectively). The 18:2(n-6) polyunsaturated fatty acids content correlated positively with freely-mobile phosphodiester [PDE(s-tau(c))] levels (r =.5573, p =.0071). The above correlations were present in the combined right and left prefrontal region of the brain, while other regions including the basal ganglia, occipital, inferior parietal, superior temporal and centrum semiovale yielded no significant correlations. CONCLUSIONS Our preliminary data support the association between the decreased red blood cell membrane phospholipid polyunsaturated fatty acids content and the decreased building blocks [PME(s-tau(c))] and breakdown products [PDE(s-tau(c))] of membrane phospholipids in the prefrontal region of first-episode, neuroleptic-naïve schizophrenic subjects.

Processing speed is correlated with cerebral health markers in the frontal lobes as quantified by neuroimaging.

We explored relationships between decline in cognitive processing speed (CPS) and change in frontal lobe MRI/MRS-based indices of cerebral integrity in 38 healthy adults (age 57-90 years). CPS was assessed using a battery of four timed neuropsychological tests: Grooved Pegboard, Coding, Symbol Digit Modalities Test and Category Fluency (Fruits and Furniture). The neuropsychological tests were factor analyzed to extract two components of CPS: psychomotor (PM) and psychophysical (PP). MRI-based indices of cerebral integrity included three cortical measurements per hemisphere (GM thickness, intergyral and sulcal spans) and two subcortical indices (fractional anisotropy (FA), measured using track-based spatial statistics (TBSS), and the volume of hyperintense WM (HWM)). MRS indices included levels of choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), and N-acetylaspartate (NAA), measured bilaterally in the frontal WM bundles. A substantial fraction of the variance in the PM-CPS (58%) was attributed to atrophic changes in frontal WM, observed as increases in sulcal span, declines in FA values and reductions in concentrations of NAA and choline-containing compounds. A smaller proportion (20%) of variance in the PP-CPS could be explained by bilateral increases in frontal sulcal span and increases in HWM volumes.

An MRI and proton spectroscopy study of the thalamus in children with autism

Thalamic alterations have been reported in autism, but the relationships between these abnormalities and clinical symptoms, specifically sensory features, have not been elucidated. The goal of this investigation is to combine two neuroimaging methods to examine further the pathophysiology of thalamic anomalies in autism and to identify any association with sensory deficits. Structural MRI and multi-voxel, short echo-time proton magnetic resonance spectroscopy ((1)H MRS) measurements were collected from 18 male children with autism and 16 healthy children. Anatomical measurements of thalamic nuclei and absolute concentration levels of key (1)H MRS metabolites were obtained. Sensory abnormalities were assessed using a sensory profile questionnaire. Lower levels of N-acetylaspartate (NAA), phosphocreatine and creatine, and choline-containing metabolites were observed on the left side in the autism group compared with controls. No differences in thalamic volumes were observed between the two groups. Relationships, although limited, were observed between measures of sensory abnormalities and (1)H MRS metabolites. Findings from this study support the role of the thalamus in the pathophysiology of autism and more specifically in the sensory abnormalities observed in this disorder. Further investigations of this structure are warranted, since it plays an important role in information processing as part of the cortico-thalamo-cortical pathways.

Proton spectroscopy study of the left dorsolateral prefrontal cortex in pediatric depressed patients

The dorsolateral prefrontal cortex (DLPFC) plays an essential role in mood regulation and integration of cognitive functions that are abnormal in major depressive disorder (MDD). Few neuroimaging studies have evaluated the still maturing DLPFC in depressed children and adolescents. We conducted single voxel proton magnetic resonance spectroscopy ((1)H MRS) of the left DLPFC in 14 depressed children and adolescents (13.3 +/- 2.3 years old, 10 males) and 22 matched healthy controls (13.6 +/- 2.8 years old, 13 males). Depressed subjects had significantly lower levels of glycerophosphocholine plus phosphocholine (GPC + PC; or choline-containing compounds) and higher myo-inositol levels in the left DLPFC compared to healthy controls. In the depressed subjects, we found significant inverse correlations between glutamate levels and both duration of illness and number of episodes. In healthy controls there was a significant direct correlation between age and glutamine levels, which was not present in the patient group. Lower GPC + PC levels in pediatric MDD may reflect lower cell membrane content per volume in the DLPFC. Increased myo-inositol levels in MDD may represent a disturbed secondary messenger system. GPC + PC and myo-inositol abnormalities further demonstrate the involvement of DLPFC in pediatric MDD.

1H MRS study of dorsolateral prefrontal cortex in healthy individuals before and after lithium administration

The mechanism of action of lithium is still largely unknown. However, recent animal and human studies suggested the possible neuroprotective effects of this medication. In particular, a recent magnetic resonance spectroscopy (MRS) study showed the increase of cortical brain levels of N-acetyl-aspartate (NAA), a putative marker of neuronal integrity/functioning, in both bipolar patients and normal controls after 4 weeks of lithium administration. We investigated the effects of lithium on NAA levels in a sample of healthy individuals using in vivo 1H MRS in dorsolateral prefrontal cortex (DLPFC), a region likely implicated in the pathophysiology of bipolar disorder. In vivo short echo-time 1H-MRS measurements of 8 cm3 single voxels placed bilaterally in the DLPFC were conducted at baseline and after 4 weeks of lithium administration on 12 healthy individuals (mean age±SD=25.0±9.8 years; six males). After lithium administration, no significant differences in NAA, phosphocreatine plus creatine, glycerophosphocholine plus phosphocholine (or choline-containing molecules), and myo-inositol absolute levels or ratios were found in DLPFC (paired t-tests, p>0.05). Contrary to prior MRS reports in bipolar patients, we found that lithium administration did not significantly increase NAA levels in the DLPFC of healthy individuals. Future longitudinal studies will be needed to further investigate whether chronic lithium treatment increases NAA levels in other brain regions in healthy individuals, and whether it promotes changes in these levels in specific brain regions in bipolar patients.

Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study

In vivo 31P magnetic resonance spectroscopy (31P MRS) studies have shown abnormal membrane phospholipid metabolism in the prefrontal cortex (PF) in the early course of schizophrenia. It is unclear, however, whether these alterations also represent premorbid risk indicators in schizophrenia. In this paper, we report in vivo 31P MRS data on children and adolescents at high risk (HR) for schizophrenia. In vivo 31P MRS studies of the PF were conducted on 16 nonpsychotic HR offspring of parents with schizophrenia or schizoaffective disorder, and 37 age-matched healthy comparison (HC) subjects. While 11 of the HR subjects had evidence of Axis I psychopathology (HR-P), five HR subjects had none (HR-NP). We quantified the freely mobile phosphomonoester (PME) and phosphodiester (PDE) levels reflecting membrane phospholipid precursors and breakdown products, respectively, and the relatively broad signal underlying PDE and PME peaks, comprised of less mobile molecules with PDE and PME moieties (eg, synaptic vesicles and phosphorylated proteins). Compared to HC subjects, HR subjects had reductions in freely mobile PME; the differences were accounted for mainly by the HR-P subjects. Additionally, HR-P subjects showed increases in the broad signal underlying the PME and PDE peaks in the PF. To conclude, these data demonstrate new evidence for decreased synthesis of membrane phospholipids and possibly altered content or the molecular environment of synaptic vesicles and/or phosphoproteins in the PF of young offspring at risk for schizophrenia. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.

Metabolic alterations in postmortem Alzheimer's disease brain are exaggerated by Apo-E4

Alterations in phospholipid metabolites are a characteristic abnormality of Alzheimers disease (AD). Many of these alterations have been demonstrated by magnetic resonance spectroscopy (MRS) studies of postmortem tissue. Phosphodiesters appear to be elevated late in the disease and phosphomonoesters appear to be elevated early in the disease and then decrease. Second to aging, the most robust risk factor for AD identified to date is the presence of the E4 allele of apolipoprotein-E (Apo-E). Because apolipoproteins are intimately involved in lipid metabolism, this study was performed to determine if the presence of the Apo-E4 allele affects the abnormalities in phospholipid metabolites in AD brain. Perchloric acid extracts from 12 Apo-E 3/3, 31 3/4, 6 4/4 AD brains and 5 Apo-E 3/3 control brains were studied by both proton magnetic resonance spectroscopy and phosphorus-31 magnetic resonance spectroscopy. When the E4-positive AD samples were compared with the 3/3 AD samples, an exaggeration in both phosphomonoester and phosphodiester abnormalities was observed. The decrease in N-acetyl-L-aspartate (NAA) was also exaggerated. These results suggest membrane phospholipid metabolite alterations observed in AD are more severe in the presence of the Apo-E4 allele.

Magnetic resonance spectroscopic changes in Alzheimer's disease

ABSTRACT: In vitro and in vivo31P magnetic resonance (MR) spectroscopy studies of Alzheimers disease (AD) brain have revealed alterations in membrane phospholipid metabolism and high‐energy phosphate metabolism. Mildly demented AD patients compared with control subjects have increased levels of phosphomonoesters, decreased levels of phosphocreatine and probably adenosine diphosphate and an increased oxidative metabolic rate. As the dementia worsens, levels of phosphomonoesters decrease and levels of phosphocreatine and adenosine diphosphate increase. The changes in oxidative metabolic rate suggest that the AD brain is under energetic stress. The phosphomonoester findings support our in vitro findings and implicate basic defects in membrane metabolism in AD brain. MR spectroscopy provides new diagnostic insights and a noninvasive method to follow the progression of the disease and the metabolic response to therapeutic interventions.

Striatal metabolic alterations in non-psychotic adolescent offspring at risk for schizophrenia: A 1H spectroscopy study

In vivo proton ((1)H) Magnetic Resonance spectroscopy ((1)H MRS) has shown abnormalities in young first-episode patients with schizophrenia. It is unclear whether these abnormalities reflect trait related vs. state related alterations in schizophrenia. We compared young first-degree relatives of schizophrenia patients and healthy controls using (1)H MRS. We hypothesized alterations in the (1)H MRS metabolites N-acetyl aspartate (NAA) and glutamate in corticostriatal and thalamic brain regions. We obtained multi-voxel, short-TE (1)H MRS measurements at 1.5 Tesla in 40 consenting adolescent offspring at risk for schizophrenia (HR), and 48 age matched healthy controls (HC). Absolute levels of NAA, phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol and glutamate plus glutamine (Glu+Gln) were obtained from the seven different anatomical brain areas (nominal voxel size of 4.5cm(3) each) and corrected for tissue voxel composition. HR subjects showed NAA (p=.0049), PCr+Cr (p=0.028) and GPC+PC (p=0.0086) reductions in the caudate compared with HC subjects. Male HR subjects had significant Glu+Gln reductions compared to male HC subjects (p=.0022). HR subjects had increased NAA in prefrontal white matter. NAA levels in the prefrontal white matter and Glu+Gln levels in the inferior parietal/occipital region were both increased in HR without psychopathology compared with HC subjects. Lower NAA, PCr+Cr and GPC+PC levels may reflect an overall reduction in cellular processes in the caudate of HC subjects, perhaps related to decreases in cell density, or synaptic overpruning. Further studies are needed to examine the pathophysiologic significance of these observations, and their potential predictive value for schizophrenia related psychopathology that may emerge in these at risk relatives during adolescence and early adulthood.