Developmental aspects and neurobiological correlates of working and associative memory.

OBJECTIVE: It has been shown that verbal working and associative memory have different developmental trajectories with working memory, taking a linear course from early childhood to adolescence, whereas associative memory takes a curvilinear course asymptoting at about age 12. This study made a determination of whether these trajectories tracked with 2 magnetic resonance spectroscopy imaging (MRSI) variables: phosphocreatine level (PCr) and gray matter percentage (GM%). METHOD: In a cross-sectional study, 94 children ranging in age from 6-14 years were administered tests of verbal working and associative memory and underwent an MRSI procedure evaluating 6 major brain regions. The study considered PCr levels and GM% in the 6 regions. Loess curves were constructed plotting the memory tests and MRSI variables across age, and trajectories were evaluated. RESULTS: PCr showed a linear increase with age, particularly in the left superior temporal lobe with this increase closely tracking improvement in working memory but not associative memory scores. GM% did not increase with age in any brain region, and there was no tracking with either of the memory tests. CONCLUSION: Verbal working memory and verbal associative memory have differing age trajectories, with working memory showing close tracking with PCr level, mainly in the left superior temporal lobe. No such tracking was found for the associative memory tests. GM% curves were flat across regions, showing no association with age.

Developmental aspects of working and associative memory.

Developmental differences between working and long-term associative memory were evaluated through a cross-sectional age difference study based on data from a memory battery's standardization sample. The scores of 856 children and adolescents ranging from 5 to 17 years of age were compared on memory subtests that assess verbal working and long-term memory. Data were examined using curve fitting and ANOVA procedures that evaluated age group and years of age differences. The major finding was that the developmental trajectories across age differed substantially between the two memory domains. The working memory trajectory was linear until age 11, whereas the long-term memory trajectory was curvilinear with an inflection point at age 8. Both trajectories plateaued after age 11. ANOVAs produced significant interactions between tests of working and associative memory with age, supporting the view that the age trajectories had differing courses. The results are discussed in terms of neurobiological implications for the two memory systems studied.

Molecular neurodevelopment: an in vivo 31P-1H MRSI study.

Synaptic development and elimination are normal neurodevelopmental processes, which if altered could contribute to various neuropsychiatric disorders. 31P-1H magnetic resonance spectroscopic imaging (MRSI) and structural magnetic resonance imaging (MRI) exams were conducted on 105 healthy children ages 6-18 years old to identify neuromolecular indices of synaptic development and elimination. Over the age range studied, age-related changes in high-energy phosphate (phosphocreatine), membrane phospholipid metabolism (precursors and breakdown products), and percent gray matter volume were found. These neuromolecular and structural indices of synaptic development and elimination are associated with development of several cognitive domains. Monitoring of these molecular markers is essential for devising treatment strategies for neurodevelopmental disorders.

Evidence of developmental alterations in cortical and subcortical regions of children with attention-deficit/hyperactivity disorder: a multivoxel in vivo phosphorus 31 spectroscopy study.

CONTEXT: There is mounting evidence of neurodevelopmental alterations implicating the prefrontal cortex (PFC) and basal ganglia in children with attention-deficit/hyperactivity disorder (ADHD). The brain undergoes substantive structural and functional changes with a differential timing between brain regions during development from childhood to adolescence. In vivo phosphorus 31 magnetic resonance spectroscopy ((31)P MRS) is a noninvasive neuroimaging approach that is sensitive in assessing developmental changes of overproducing/pruning of synapses. OBJECTIVE: To provide support for a developmental mechanism targeting a bottom-up dysfunction of the basal ganglia impairing the fine-tuning of prefrontal functions in ADHD. DESIGN: Cross-sectional study. SETTING: Pittsburgh, Pennsylvania, and the surrounding areas. PARTICIPANTS: Thirty-one psychostimulant-naive children with ADHD (mean [SD] age, 8.1 [1.2] years; range, 6.1-10.0 years) and 36 healthy control subjects (mean [SD] age, 8.1 [1.3] years; range, 6.1-10.4 years). MAIN OUTCOME MEASURE: Membrane phospholipid (MPL) precursor levels (ie, phosphomonoesters that are anabolic metabolites of MPL) were assessed in the PFC and basal ganglia as well as in 4 other brain regions using in vivo (31)P MRS. RESULTS: Lower bilateral MPL precursor levels in the basal ganglia and higher MPL precursor levels in the inferior parietal region (primarily right side) were noted in the children with ADHD as compared with healthy control children. There was a group x age interaction in the PFC and inferior parietal region, with relatively older psychostimulant-naive children with ADHD showing significantly lower PFC and higher inferior parietal MPL precursor levels. No differences between groups were noted in the superior temporal, posterior white matter, or occipital regions. CONCLUSION: Though based on cross-sectional data, these results are suggestive of possible progressive, nonlinear, and sequential alterations implicating a bottom-up developmental dysfunction in parts of the cortico-striato-thalamo-cortical network in ADHD.

Clinically relevant concentration determination of inhaled anesthetics (halothane, isoflurane, sevoflurane, and desflurane) by 19F NMR.

Biophysical studies of protein-anesthetic interactions using nuclear magnetic resonance (NMR) spectroscopy are often conducted by the addition of micro amounts of neat inhaled anesthetic which yields much higher than clinically relevant (0.2-0.5 mM) anesthetic concentrations. We report a 19F NMR technique to measure clinically relevant inhaled anesthetic concentrations from saturated aqueous solutions of these anesthetics (halothane, isoflurane, sevoflurane, and desflurane). We use a setup with a 3-mm NMR tube (containing trifluoroacetic acid as standard), coaxially inserted in a 5-mm NMR tube containing anesthetic solution under investigation. All experiments are conducted in a 5-mm NMR probe. We also have provided standard curves for four inhaled anesthetics using NMR technique. The standard curve for each of these anesthetics is helpful in determining the prerequisite amount of aqueous anesthetic solution required to prepare clinically relevant concentrations for protein-anesthetic interaction studies.

Abeta peptide interactions with isoflurane, propofol, thiopental and combined thiopental with halothane: a NMR study.

Abeta peptide is the major component of senile plaques (SP) which accumulates in AD (Alzheimer's disease) brain. Reports from different laboratories indicate that anesthetics interact with Abeta peptide and induce Abeta oligomerization. The molecular mechanism of Abeta peptide interactions with these anesthetics was not determined. We report molecular details for the interactions of uniformly (15)N labeled Abeta40 with different anesthetics using 2D nuclear magnetic resonance (NMR) experiments. At high concentrations both isoflurane and propofol perturb critical amino acid residues (G29, A30 and I31) of Abeta peptide located in the hinge region leading to Abeta oligomerization. In contrast, these three specific residues do not interact with thiopental and subsequently no Abeta oligomerization was observed. However, studies with combined anesthetics (thiopental and halothane), showed perturbation of these residues (G29, A30 and I31) and subsequently Abeta oligomerization was found. Perturbation of these specific Abeta residues (G29, A30 and I31) by different anesthetics could play an important role to induce Abeta oligomerization.

Reduced N-acetyl-aspartate levels in schizophrenia patients with a younger onset age: a single-voxel 1H spectroscopy study.

Schizophrenia is widely considered a neurodevelopmental disorder. The timing of psychosis onset may determine the degree of functional and biological deficits. In this study, the association between age of onset of psychosis and in vivo biochemical levels was assessed in first-episode, antipsychotic-naive (FEAN) schizophrenia subjects. We hypothesized greater biochemical deficits in the younger-onset FEAN subjects. In vivo, (1)H spectroscopy measurements of the left dorsolateral prefrontal cortex (DLPFC) were conducted on FEAN subjects (15 schizophrenia and 3 schizoaffective subjects) and healthy comparison subjects of comparable age and gender distribution (N=61). N-acetyl-aspartate was significantly lower in the left DLPFC of FEAN subjects as compared to healthy comparison subjects. However, there was a significant subject group-by-age interaction for N-acetyl-aspartate. Early-onset FEAN subjects showed lower N-acetyl-aspartate levels compared to the younger healthy comparison subjects, while adult-onset FEAN and older healthy comparison subjects did not differ. The lower N-acetyl-aspartate levels in the DLPFC of early-onset subjects suggest a reduction in functioning neurons or specifically a reduction in the proliferation of dendrites and synaptic connections, which is not apparent in the adult-onset schizophrenia subjects.

Regionally specific alterations in membrane phospholipids in children with ADHD: An in vivo 31P spectroscopy study.

This multi-voxel, phosphorus magnetic resonance spectroscopy ((31)P MRS) study examined the prefrontal cortex (PFC), basal ganglia (BG) and superior temporal (ST) region in 10 children with attention-deficit/hyperactivity disorder (ADHD) and 15 healthy controls. ADHD patients had lower PFC and BG phosphomonoester (PME) levels compared to healthy children. No differences were noted in the ST. These deficits in membrane phospholipid (MPL) precursor levels suggest reduced mass of cellular MPLs due to a possible underdevelopment of neuronal processes and synapses in ADHD.

Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease.

Amyloidogenic proteins (Abeta peptide) in Alzheimer's disease (AD) and alpha-synuclein (alpha-Syn) in Parkinson's disease (PD) are typically soluble monomeric precursors, which undergo remarkable conformational changes and culminate in the form of aggregates in diseased condition. Overlap of clinical and neuropathological features of both AD and PD are observed in dementia with Lewy body (DLB) disease, the second most common form of dementia after AD. The identification of a 35-amino acid fragment of alpha-Syn in the amyloid plaques in DLB brain have raised the possibility that Abeta and alpha-Syn interact with each other. In this report, the molecular interaction of alpha-Syn with Abeta40 and/or Abeta42 are investigated using multidimensional NMR spectroscopy. NMR data in the membrane mimic environment indicate specific sites of interaction between membrane-bound alpha-Syn with Abeta peptide and vice versa. These Abeta-alpha-Syn interactions are demonstrated by reduced amide peak intensity or change in chemical shift of amide proton of the interacting proteins. Based on NMR results, the plausible molecular mechanism of overlapping pathocascade of AD and PD in DLB due to interactions between alpha-Syn and Abeta is described. To the best of our knowledge, it is the first report using multidimensional NMR spectroscopy that elucidates molecular interactions between Abeta and alpha-Syn which may lead to onset of DLB.

Alzheimer's disease: halothane induces Abeta peptide to oligomeric form--solution NMR studies.

Alzheimer's disease (AD) is a significant contributor to cognitive decline and is responsible for about half of the cases of dementia in later life. Although exact etiology of AD is not known, however, many risk factors for AD are identified. Anesthesia for elderly patients is considered as a risk factor in AD as they frequently experience deterioration in cognitive function with long exposure to anesthetics during surgery. Inhaled anesthetic agents remain the mainstay for patients undergoing major surgical operations. This study using multidimensional NMR spectroscopy provides the first direct evidence in vitro that inhaled anesthetic, halothane specifically interacts with Abeta40 and Abeta42 peptide. Halothane induces structural alternation of Abeta peptide from soluble monomeric alpha-helical form to oligomeric beta-sheet conformation, which may hasten the onset of AD. Abeta42 is more prone to oligomerization compared to Abeta40 in the presence of halothane. The molecular mechanism of halothane induced structural alternation of Abeta peptide is discussed.

Effect of intraperitoneal acetyl-L-carnitine (ALCAR) on anxiety-like behaviours in rats.

Acetyl-L-carnitine (ALCAR) is an acetyl derivative of carnitine, an endogenous molecule synthesized in vivo and supplemented by diet (mainly via meat and dairy products). Several parallel, double-blind, placebo-controlled studies have demonstrated that ALCAR treatment produces beneficial effects in geriatric depression. Since most antidepressants also have anti-anxiety effects we examined whether ALCAR shows anti-anxiety effects in a rat model of anxiety. Compared to a saline-injected control group, chronic administration of ALCAR at doses of 10 and 100 mg/kg (tested 24 h after the last dose administration) showed no effects, whereas doses of 50 and 75 mg/kg significantly reduced anxiety-like behaviours in the elevated plus-maze. Acute ALCAR (100 mg/kg), on the other hand (tested 6 h after administration), demonstrated anxiogenic effects. Our data suggest that chronic ALCAR administration may produce an inverted U-shaped curve of dose-dependent changes in anxiety-like behaviour. The precise mechanism by which ALCAR decreases anxiety-like behaviour after peripheral administration remains to be determined.

Alzheimer's disease: NMR studies of asialo (GM1) and trisialo (GT1b) ganglioside interactions with Abeta(1-40) peptide in a membrane mimic environment.

Amyloid peptide (Abeta) is the major protein constituent of neuritic plaques in Alzheimer's disease (AD). This peptide is an amphipathic molecule that perturbs membranes and binds to raft-like membranes composed of gangliosides. Ganglioside GM1 binds tightly with Abeta and it is speculated that GM1 inhibits Abeta from undergoing alpha-helix to beta-sheet conformational changes. Although the role of gangliosides in conformational changes of Abeta have been studied, the specific nature of these interactions have not been reported. In the present report multidimensional NMR studies of ganglioside-Abeta interactions were conducted in sodium dodecyl sulphate (SDS) micelles, a membrane-mimicking environment. These studies reveal that asialoGM1 binds specifically with Abeta in a manner which could prevent beta-sheet formation. but that ganglioside GT1b does not bind Abeta. Plausible pathways for the involvement of gangliosides in amyloidogenesis are discussed.

Abnormalities in MRI-measured signal intensity in the corpus callosum in schizophrenia.

The microstructural integrity of the corpus callosum (CC) in first-episode schizophrenia patients was assessed by measuring the signal intensity (SI) in T1-weighted MRI images. Analyses revealed that compared to both healthy controls and non-schizophrenic patients, schizophrenia patients showed reductions in SI in all the callosal subregions, the genu, body, isthmus and splenium in first-episode schizophrenia. These results indicate that schizophrenia is characterized by pathology of this principal interhemispheric commissure; the abnormalities may reflect distributed (rather than localized) interhemispheric disconnectivity that extends beyond the heteromodal association cortices.

Premorbid characterization in schizophrenia: the Pittsburgh High Risk Study.

Prospective studies of young relatives at risk for schizophrenia can shed light on the possible premorbid precursors of the disease. Ongoing studies in Pittsburgh suggest that young non-psychotic high risk relatives have neurobehavioral, brain structural, physiological, and neurochemical deficits that may date back to childhood or earlier. We summarize these data, review the relevant literature in this emerging field, and provide some new data suggesting alterations in sleep architecture in young relatives at risk for schizophrenia. Collectively, such data are likely to help us to predict the eventual emergence of schizophrenia, schizophrenia spectrum or non-spectrum psychopathology.

Alzheimer's disease: soluble oligomeric Abeta(1-40) peptide in membrane mimic environment from solution NMR and circular dichroism studies.

Amyloid beta peptide (Abeta) is a small peptide present in normal cells and aggregated Abeta is the main constituent of the extracellular amyloid plaques found in Alzheimer's disease (AD) brain. Recent studies suggest that soluble Abeta oligomers are neurotoxic rather than amyloid fibrils found in amyloid plaques. This study using multidimensional NMR spectroscopy and circular dichroism (CD) provides the first direct evidence that alterations in membrane structure can trigger the conversion of soluble alpha-helical monomeric Abeta into oligomeric Abeta in a beta-sheet conformation.

Interactions of Abeta(1-40) with glycerophosphocholine and intact erythrocyte membranes: fluorescence and circular dichroism studies.

Deposition of amyloid beta peptide in human brain in the form of senile plaques is a neuropathological hallmark of Alzheimer's disease (AD). Levels of a phospholipid breakdown product, glycerophosphocholine (GPC), also increase in AD brain. The effect of GPC on amyloid beta(1-40) peptide (Abeta) aggregation in PBS buffer was investigated by circular dichroism and fluoresence spectroscopy; interactions of Abeta and GPC with the intact erythrocyte membrane was examined by fluoresence spectroscopy. Fluorescamine labeled Abeta studies indicate GPC enhances Abeta aggregation. CD spectroscopy reveals that Abeta in the presence of GPC adopts 14% more beta-sheet structure than does Abeta alone. Fluorescamine anisotropy measurements show that GPC and Abeta interact in the phospholipid head-group region of the erythrocyte membrane. In summary, both soluble Abeta and GPC insert into the phospholipid head-group region of the membrane where they interact leading to beta-sheet formation in soluble Abeta which enhances Abeta aggregation.

Diagnostic specificity and neuroanatomical validity of neurological abnormalities in first-episode psychoses.

OBJECTIVE: Neurological abnormalities are frequently seen in patients with first-episode psychotic disorders but are generally considered to be diagnostically nonspecific, neurologically nonlocalizing, and, hence, "soft." This study examined the neuroanatomical correlates and diagnostic specificity of abnormal findings on the neurological examination in first-episode schizophrenia and other psychotic disorders. METHOD: Neuroleptic-naive patients with schizophrenia (N=90) and with nonschizophrenia psychoses (N=39) and carefully matched healthy subjects (N=93) were compared on total and factor scores for a reliable subset of Neurological Evaluation Scale items. The relationship between neurological examination abnormalities and alterations in the relevant brain structures as assessed by magnetic resonance imaging was examined in a subset of subjects. RESULTS: Factor scores for repetitive motor task abnormalities were higher in both patient groups, relative to the healthy group, and did not distinguish between the patient groups. Factor scores for abnormalities in cognitively demanding and perceptual tasks were markedly higher in the schizophrenia group, relative to both comparison groups, and were not different between the nonschizophrenia psychoses group and the healthy comparison group. Higher scores for the cognitive/perceptual abnormalities factor were correlated with smaller volumes of the left heteromodal association cortex. CONCLUSIONS: Neurological signs may serve as expedient bedside measures that are potentially useful in the assessment of idiopathic psychoses, and cognitive/perceptual neurological signs may have a measure of diagnostic specificity. These findings provide neurobiological validation of abnormal findings on the neurological examination. These abnormalities may reflect discrete neuroanatomical alterations in schizophrenia and may have a localizing value.

Chrysamine G and its derivative reduce amyloid beta-induced neurotoxicity in mice.

The neurotoxicity of amyloid beta (Abeta) is widely believed to play a seminal role in neurodegeneration in Alzheimer's disease. We examined the effect of Chrysamine G (CG) on such neurotoxicity using the specific measurement of surviving neurons. CG was found to reduce the neurodegeneration induced by both the active short fragment of Abeta(25-35) and full-sized Abeta(1-40). In this study, we synthesized a new chemical compound from a monovalent structure of CG (hCG), with a lower affinity for Abeta, and compared its activity with that of CG. Both CG and hCG were found to be equally efficacious in reducing Abeta-induced neuronal death at a concentration of 0.1-1 microM, indicating that the mechanism of action for CG was not due to its chelating activity, but rather due to its anti-oxidant activity.