Molecular insights into neurodevelopmental and neurodegenerative diseases

doi:10.1016/S0361-9230(00)00376-2

Brain Research Bulletin

Volume 53, Issue 4, 1 November 2000, Pages 455-469

https://doi.org/10.1016/S0361-9230(00)00376-2 Get rights and content

Abstract

Magnetic resonance spectroscopy (MRS) is a non-invasive physical technique that is routinely used to determine the quantity and structure of organic molecules in solution. Technical advances that have expanded the usefulness of this technique include: (1) high resolution MRS to identify and quantify individual molecules present in complex mixtures of tissue extracts; (2) in vivo MRS techniques to non-invasively monitor metabolites in humans; (3) stucture determination of proteins of moderate size; and (4) improved structure characterization of solids and liquid crystals, such as the detection of phase changes in membranes. The focus of this review is on the first two technical advances mentioned above. The strengths of MRS as a research tool to investigate molecular alterations in disease states include ease of sample preparation, minimum sample manipulation, avoidance of the preparation of derivatives, and the ability to analyze an unfractionated sample. The strengths of MRS in the clinic are its ability to measure neuronal metabolite levels non-invasively in humans and its potential for disease diagnosis, monitoring disease progression, and assessing the efficacy of experimental therapies.

Introduction

Magnetic resonance spectroscopy (MRS) is a non-invasive physical technique that is routinely used to determine the quantity and structure of organic molecules in solution. High resolution in vitro MRS provides the identity and quantity of individual molecules present in complex mixtures of tissue extracts and in vivo MRS provides a non-invasive technique to monitor metabolite levels in humans. MRS detects atomic nuclei that have a magnetic moment, ¹H and ³¹P are the most common nuclei utilized for biological applications (MRS terms and theory have been previously described [62]). MRS provides a powerful technique to obtain molecular insights into membrane and high-energy metabolic changes in brain associated with neurodevelopmental and neurodegenerative diseases. In this review we will discuss the molecular information available from MRS and its relevance to neurodevelopmental and neurodegenerative diseases.

Section snippets

Sample preparation

In vitro MRS techniques are adaptable for studying extracts of brain tissues from a variety of sources, such as autopsy tissue and freeze-clamped tissue. MRS studies of extracts of human autopsy tissue provide brain metabolite levels of those metabolites found to be stable after death. High-energy metabolites such as 5′-adenosine triphosphate (ATP) and phosphocreatine (PCr) are not stable after death. Freeze clamping brain tissue of animals with liquid nitrogen at the time of harvesting results

In vitro ³¹P NMR studies of rat brain development

The Fischer 344 rat was chosen for these studies because this strain is extensively used in developmental and aging research and there is a wealth of behavioral, physiological, and pathological information with which to compare the metabolic information. Changes in high-energy phosphate and membrane phospholipid metabolism that take place during brain development and aging may have neurobiological implications for neuropsychiatric disorders. An in vitro ³¹P NMR study of Fischer 344 rat brain

Alzheimer’s disease

Alzheimer’s disease (AD) is a neuropsychiatric disorder without an effective treatment or prevention. AD is characterized, neuropathologically, by the presence of neuritic senile plaques (SP) and neurofibrillary tangles (NFT), and neuronal cell death [53]. Cerebrovascular amyloid deposits and neuritic plaques are extracellular deposits of amyloid-beta (Aβ) peptide 70, 92. In vitro studies demonstrated that the Aβ peptide aggregates to form fibrils [44] associated with significant neurotoxicity

Postmortem ³¹P MRS studies

In vitro ³¹P MRS studies of PCA extracts of postmortem AD brain demonstrate that PME and PDE levels are elevated compared to controls 5, 67, 83, 84, 85, 99. PME levels correlate inversely with SP counts and PDE levels correlate directly with SP counts [87]. Postmortem studies utilizing a combination of chromatographic techniques and enzymatic assays also find elevations in PDE levels in AD versus controls 7, 74, 75. The initial ³¹P MRS studies led to the suggestion that abnormal phospholipid

In vivo ³¹P MRS of phospholipid metabolites

The alterations in phospholipid metabolism detected in the ³¹P MRS examination of postmortem AD tissue also are detectable by in vivo ³¹P MRS 14, 27, 86. An in vivo ³¹P MRS investigation of the frontal and temporoparietal regions of AD subjects, multiple subcortical cerebral infarction (MSID) subjects, and age-matched controls found significant elevations of PME levels in the temporoparietal region of AD brain compared to either controls or MSID subjects [14]. The resonances of individual PMEs

Acknowledgements

This work was supported in part by National Institutes of Health Grants AG08371, AG08974, AG50133, AG9017, AG14290 and grants from Sigma Tau Pharmaceuticals.

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Existing data on altered membrane phospholipid metabolism in schizophrenia are diverse. We conducted a meta-analysis of studies of phosphorus magnetic resonance spectroscopy, a noninvasive imaging approach that can assess molecular biochemistry of cortex by measuring phosphomonoester (PME) and phosphodiester (PDE) levels, which can provide evidence of altered biochemical processes involved in neuropil membrane expansion and contraction in schizophrenia.
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Citation Excerpt :
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We conducted a short echo time, single-voxel, in vivo proton spectroscopy study involving children with 22q11DS (n = 26) and matched control subjects (n = 23).
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Although several different chemical compounds (e.g., choline, myo-inositol) have been examined in older individuals, decreased hippocampal N-acetylaspartate (NAA) and its ratio to creatine (Cr) has been a particularly robust age-associated finding (Angelie et al., 2001; Driscoll et al., 2003; Schuff et al., 1999). NAA is primarily located in neurons and is thought to be a marker of neuronal viability (Pettegrew et al., 2000), while Cr reflects biochemical energy reserves of glia and neurons and is presumed to be stable in the context of pathologic processes (Narayana, 2005). MRS was used in the current study to obtain measures of hippocampal NAA/Cr.
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ArticleMolecular insights into neurodevelopmental and neurodegenerative diseases

Abstract

Introduction

Section snippets

Sample preparation

In vitro 31P NMR studies of rat brain development

Alzheimer’s disease

Postmortem 31P MRS studies

In vivo 31P MRS of phospholipid metabolites

Acknowledgements

Neurochem. Int.

Brain Res.

Lancet

Brain Res.

Neuron

Biochim. Biophys. Acta

Prog. Brain Res.

Biochim. Biophys. Acta

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

Neurobiol. Aging

Neurosci. Lett.

Biochim. Biophys. Acta

Neurobiol. Aging

Neurobiol. Aging

Mech. Ageing Dev.

Neuron

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Biol. Psychiatry

J. Biol. Chem.

Neuron

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Magn. Reson. Imaging

Lancet

Biochim. Biophys. Acta

Brain Res.

Neurobiol. Aging

Characterization and possible role of growth factor and lymphokine receptors in the regulation of cholinergic function in the mammalian brain

Prog. Clin. Biol. Res.

Women, myocardial infraction, and dementia in the very old

Neurology

Solution structures of β peptide and its constituent fragmentsRelation to amyloid deposition

Science

Localization in clinical NMR spectroscopy

Alzheimer’s disease and cellular agingMembrane-related events as clues to primary mechanisms

Gerontology

Alzheimer dementiaQuantification of energy metabolism and mobile phosphoesters with P-31 NMR spectroscopy

Radiology

Changes of synaptic density in the primary visual cortex of the Macaque monkey from fetal to adult stage

J. Neurosci.

Confirmation of the epsilon 4 allele of the apolipoprotein E gene as a risk factor for late-onset Alzheimer’s disease

Neurology

In vivo 31P NMR profiles of Alzheimer’s disease and multiple subcortical infarct dementia

Neurology

Pathological alterations of the cerebral microvasculature in Alzheimer’s disease and related dementing disorders

Acta Neuropathol. (Berl.)

Rapid induction of Alzheimer A beta amyloid formation by zinc

Science

Release of excess amyloid β protein from a mutant amyloid β protein precursor

Science

Clues to the mechanism of action of acetyl-L-carnitine in the central nervous system

Dementia

Selegiline versus L-acetylcarnitine in the treatment of Alzheimer-type dementia

Clin. Ther.

Metabolic heterogeneities in rapidly metabolizing tissues

J. Appl. Cardiol.

High and low energy states of cytochromes

J. Biol. Chem.

Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production

Nature

Article
Molecular insights into neurodevelopmental and neurodegenerative diseases

In vitro ³¹P NMR studies of rat brain development

Postmortem ³¹P MRS studies

In vivo ³¹P MRS of phospholipid metabolites

In vivo ³¹P NMR profiles of Alzheimer’s disease and multiple subcortical infarct dementia