Edward Rubenstein

Alzheimer's disease, normal‐pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis

There is evidence that production and turnover of CSF help to clear toxic molecules such as amyloid-beta peptide (Abeta) from the interstitial-fluid space of the brain to the bloodstream. Two changes in CSF circulatory physiology have been noted as part of ageing: first, a trend towards lower CSF production, hence a decrease in CSF turnover; and second, greater resistance to CSF outflow. Our hypothesis is that, all else being equal, the initially dominant physiological change determines whether CSF circulatory failure manifests as Alzheimers disease (AD) or as normal-pressure hydrocephalus (NPH). If CSF production failure predominates, AD develops. However, if resistance to CSF outflow predominates, NPH results. Once either disease process takes hold, the risk of the other disorder may rise. In AD, increased deposition of Abeta in the meninges leads to greater resistance to CSF outflow. In NPH, raised CSF pressure causes lower CSF production and less clearance of Abeta. The disorders may ultimately converge in vulnerable individuals, resulting in a hybrid as has been observed in several clinical series. We postulate a new nosological entity of CSF circulatory failure, with features of AD and NPH. NPH-AD may cover an important subset of patients who carry the diagnosis of either AD or NPH.

The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type

Objective: To evaluate the production rate of CSF in patients with differing disease states. Methods: The authors measured the production rate of CSF in three groups of patients: five patients with PD below age 60 (aged 51 ± 4 years, mean ± SD), nine with PD over age 60 (aged 69 ± 6 years, mean ± SD), and seven with dementia of the Alzheimer’s type (AD) (aged 72 ± 9 years, mean ± SD). This method, based on the Masserman technique, employs ventricular rather than a lumbar access to the CSF space. Furthermore, the volume of CSF removed during the procedure is only 3 mL rather than 10 mL. Results: These measurements indicate that the mean rate of CSF production in patients with PD under age 60 was 0.47 ± 0.13 mL/minute, in patients with PD aged 60 or older the mean rate was 0.40 ± 0.12 mL/minute, and in patients with AD the mean rate was 0.20 ± 0.06 mL/minute. Conclusion: These results indicate that the rate of CSF production in patients with PD is normal, and that the rate of CSF production in patients with AD is markedly reduced.

Relationship of senescence of cerebrospinal fluid circulatory system to dementias of the aged

In common with other organ systems, the cerebrospinal fluid circulatory system is subject to senescence. Cerebrospinal fluid production and turnover rates decline. The choroid plexus calcifies and its blood supply falters. Microvascular disease violates the integrity of the blood-brain barrier. The arachnoid membranes thicken. Arachnoid villi occlude and degenerate. The consequent functional losses are exacerbated by the deterioration of other interacting organ systems. Eventually, the cerebrospinal fluid circulatory system may fail, resulting in stagnation, contamination, compositional deficiencies, and impaired clearance of noxious substances. The hypothesis is that senescence of the cerebrospinal fluid circulatory system plays a part in some dementias of the aged.

Supernovae, neutron stars and biomolecular chirality

Recent theoretical and experimental investigations of the origin of biomolecular chirality are reviewed briefly. Biotic and abiotic theories are evaluated critically with the conclusion that asymmetric photochemical processes with circulary polarized light (CPL), particularly asymmetric photolyses, constitute the most viable mechanisms. Solar CPL sources appear too weak and random to be effective. We suggest an alternative CPL source, namely, the synchrotron radiation from the neutron star remnants of supernova explosions. This could asymmetrically process racemic compounds in the organic mantles of the dust grains in interstellar clouds, and the resulting chiral molecules could be transferred to Earth by cold accretion as the solar system periodically traverses these interstellar clouds.

First operation of the medical research facility at the NSLS for coronary angiography

The Synchrotron Medical Research Facility (SMERF) at the National Synchrotron Light Source has been completed and is operational for human coronary angiography experiments. The imaging system and hardware have been brought to SMERF from the Stanford Synchrotron Radiation Laboratory where prior studies were carried out. SMERF consists of a suite of rooms at the end of the high‐field superconducting wiggler X17 beam line and is classified as an Ambulatory Health Care Facility. Since October of 1990 the coronary arteries of five patients have been imaged. Continuously improving image quality has shown that a large part of both the right coronary artery and the left anterior descending coronary artery can be imaged following a venous injection of contrast agent.

Proline: The Distribution, Frequency, Positioning, and Common Functional Roles of Proline and Polyproline Sequences in the Human Proteome

Proline is an anomalous amino acid. Its nitrogen atom is covalently locked within a ring, thus it is the only proteinogenic amino acid with a constrained phi angle. Sequences of three consecutive prolines can fold into polyproline helices, structures that join alpha helices and beta pleats as architectural motifs in protein configuration. Triproline helices are participants in protein-protein signaling interactions. Longer spans of repeat prolines also occur, containing as many as 27 consecutive proline residues. Little is known about the frequency, positioning, and functional significance of these proline sequences. Therefore we have undertaken a systematic bioinformatics study of proline residues in proteins. We analyzed the distribution and frequency of 687,434 proline residues among 18,666 human proteins, identifying single residues, dimers, trimers, and longer repeats. Proline accounts for 6.3% of the 10,882,808 protein amino acids. Of all proline residues, 4.4% are in trimers or longer spans. We detected patterns that influence function based on proline location, spacing, and concentration. We propose a classification based on proline-rich, polyproline-rich, and proline-poor status. Whereas singlet proline residues are often found in proteins that display recurring architectural patterns, trimers or longer proline sequences tend be associated with the absence of repetitive structural motifs. Spans of 6 or more are associated with DNA/RNA processing, actin, and developmental processes. We also suggest a role for proline in Kruppel-type zinc finger protein control of DNA expression, and in the nucleation and translocation of actin by the formin complex.

Biologic effects of and clinical disorders caused by nonprotein amino acids.

Despite the fact that nonprotein amino acids are present in many commonly eaten foods, the biologic and clinical significance of this class of molecules has been largely overlooked. This is owing in part to their relatively low concentrations and their negligible nutritive value. Many of these compounds have the ability to interfere with a wide range of fundamental biochemical processes and cause disease. It is likely that the clinical effects of the ingestion of some nonprotein amino acids are yet to be described. Serious disorders in humans have followed the ingestion of these compounds as the result of food faddism, prodded by the commercial promotion of inadequately tested products. In view of the current popularity of herbal remedies and alternative medicine, these facts serve as another reminder to health care providers and the public at large about the need for critical analysis of the alleged benefits and the risks of exotic remedies and nutritional supplements. Beyond the public health issues they raise, non-protein amino acids take on significance because their misincorporation into proteins can trigger vigorous autoimmune attacks. To what extent this mechanism is responsible for highly prevalent diseases of autoimmunity remains to be determined.

The application of synchrotron radiation to non-invasive angiography☆

Abstract Synchrotron radiation provides a new source of X-rays highly-suited to iodine K-edge Digital Subtraction Angiography (DSA). The use of such beams provides maximum sensitivity to intra-arterial iodine and virtually eliminates image contrast due to non-vascular body structures. The intensity of the beams permits short exposure times and allows images to be recorded, in line-scan fashion, in sharp focus despite arterial motions. The sensitivity of this method offers the prospect of visualizing arteries, and in particular the coronary arteries, by peripheral venous injection. The principles of DSA have been demonstrated using phantoms and excised animal hearts, and in vivo studies in animals have begun. The instrumentation developed for this purpose and the results obtained to date are summarized.

Misincorporation of the proline analog azetidine-2-carboxylic acid in the pathogenesis of multiple sclerosis: a hypothesis.

The misconstruction of proteins as a result of the displacement of one of more proline residues by their congener, azetidine-2-carboxylic acid (Aze), can result in various disorders. A number of lines of evidence suggest that multiple sclerosis may be among these. This concept adheres to the current view that multiple sclerosis lesions originate in the myelin sheath and that the underlying molecular abnormality involves the myelin basic protein. The Aze hypothesis posits that myelin basic protein and possibly other closely related molecules are misassembled in sites of lesion formation because of the substitution of Aze for one or more prolines within consensual epitopes. These include a highly conserved myelin basic protein hexapeptide sequence, PRTPPP, and an &agr; helix bounded by prolyls. Recent studies have focused on the immunopathogenetic effects of posttranslational modification of this region. This hypothesis proposes that the domain is structurally, functionally, and antigenically altered by the intrusion of Aze in place of proline and that such misassembly may involve other proteins and adversely affect interactions with neighboring molecules. This report reviews evidence supporting the hypothesis that ingestion of Aze in the diet, in conjunction with genetic susceptibility, may predispose or contribute to the pathogenesis of multiple sclerosis.

Bronchial imaging in humans using xenon K-edge dichromography

Abstract This report describes the initial use of K-edge xenon dichromography for imaging the bronchial tree in humans. The subjects inhale an anatomic dead-space volume of a mixture of 80% xenon and 20% oxygen, following which a dichromographic line-scan image is recorded using two monochromatic synchrotron radiation beams closely bracketing the k-edge of xenon (34.56 keV). Images of airways, from main-stem bronchi to fourth-order branches, are recorded with a pixel resolution of 0.5×0.5 mm. The scanning rate is 12 cm/s, the line exposure time is 4 ms, the skin dose to the exposed area (125 mm × 150 mm) is