The Bingo Card Sign as an Early Symptom of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized pathologically by irreversible protein misfolding-induced neuronal loss, and clinically by progressive impairments in memory, judgment, decision making, literacy and numeracy. We report a patient referred to Memory Clinic with a single complaint, "reduced capacity to play bingo." We suggest that the capacity to successfully play bingo may afford clinical clues indicating an early symptom of dementia and inquiries about bingo participation may be a useful when assessing individuals for dementia. Bingo requires the use of multiple cognitive skills which are impaired by AD, including number recognition, letter recognition, short term memory and concentration. With the game of bingo steadily gaining in popularity it may become an easily utilized line of questioning to detect indications of dementia prior to the development of currently recognized clinical symptoms.

The development of new therapeutics for Alzheimer's disease.

Existing treatments for Alzheimer's disease (AD) fail to address the underlying pathology of the disease; they merely provide short-lived symptomatic relief. Consequently, the progression of AD is unrelenting, leading to a continual decrease in cognitive abilities. Recent advances in understanding the genetic factors that predispose to AD, as well as in biomarker development, have brought with them the promise of earlier and more reliable diagnosis of this disease. As improvements continue to be made in these areas, the shortcomings of current AD treatments appear all the more acute because opportunities for early intervention are hindered by a lack of "curative" or even disease-modifying drugs. This State of the Art report reviews existing AD therapeutics and highlights recent progress made in the design and development of drugs that are aimed at disrupting AD disease progression by inhibition of the protein misfolding of ß-amyloid (Aß) into neurotoxic oligomeric aggregates.

Beta-alanine as a small molecule neurotransmitter.

This review discusses the role of beta-alanine as a neurotransmitter. Beta-alanine is structurally intermediate between alpha-amino acid (glycine, glutamate) and gamma-amino acid (GABA) neurotransmitters. In general, beta-alanine satisfies a number of the prerequisite classical criteria for being a neurotransmitter: beta-alanine occurs naturally in the CNS, is released by electrical stimulation through a Ca(2+) dependent process, has binding sites, and inhibits neuronal excitability. beta-Alanine has 5 recognized receptor sites: glycine co-agonist site on the NMDA complex (strychnine-insensitive); glycine receptor site (strychnine sensitive); GABA-A receptor; GABA-C receptor; and blockade of GAT protein-mediated glial GABA uptake. Although beta-alanine binding has been identified throughout the hippocampus, limbic structures, and neocortex, unique beta-alaninergic neurons with no GABAergic properties remain unidentified, and it is impossible to discriminate between beta-alaninergic and GABAergic properties in the CNS. Nevertheless, a variety of data suggest that beta-alanine should be considered as a small molecule neurotransmitter and should join the ranks of the other amino acid neurotransmitters. These realizations open the door for a more comprehensive evaluation of beta-alanine's neurochemistry and for its exploitation as a platform for drug design.

Epilepsy and antiepileptic drug use in elderly people as risk factors for dementia.

OBJECTIVE: To assess the role of epilepsy and antiepileptic drugs (AEDs) as risk factors for probable Alzheimer's disease (AD) and for all dementias in the Canadian Study of Health and Aging (CSHA). A secondary objective was to isolate the effect of the AED phenytoin on the development of dementia and AD. METHODS: The cohort consists of 5376 participants aged 65 years or older with no evidence of dementia, defined as Modified Mini-Mental State (3MS) score > or =78. Primary exposure was self-report or clinical diagnosis of epilepsy at baseline (n=39), or self-report of AED therapy (n=67). Primary outcomes were development of dementia, defined as 3MS<78, or AD, determined by clinical examination using standard criteria, during a 5-year follow-up period. People whose 3MS score remained > or =78 served as the comparison group. RESULTS: People reporting AED use at baseline had an age, sex and baseline 3MS adjusted odds ratio (OR) of 2.11 (95% CI 1.11 to 4.01) for developing dementia compared to those not taking AEDs at baseline. The association remained significant using only phenytoin as the exposure. No significant association was found between AED use and development of AD, nor between epilepsy and development of either AD or dementia. CONCLUSIONS: Older adults taking AEDs are at a significantly higher relative risk of developing dementia than those not taking AEDs. Further investigation of this finding is warranted.

N-, alpha-, and beta-Substituted 3-Aminopropionic acids: design, syntheses and antiseizure activities.

A treatment for epilepsy is proposed based on analogues of 3-aminopropionic acid (beta-alanine), a putative neurotransmitter in the central nervous system (CNS). A model three point pharmacophore was proposed based on modelling data obtained from the study of antagonists for both the glial gamma-aminobutyric acid (GABA)-uptake site and the glycine co-agonist site of N-methyl-D-aspartate (NMDA) receptor. Three series of 3-aminopropionic acids containing, N-, alpha-, and beta-substituents, were designed and synthesized to probe the position and the size of a lipophilic binding pocket within the proposed pharmacophore. These analogues were tested in vivo for both their antiseizure activities and their neurologic toxicities. Among the fourteen novel 3-aminopropionic acids synthesized, eight were found to have promising antiseizure activity. This study shows that substitution on the N-terminus confers the greatest antiseizure activity, particularly against pilocarpine-induced seizures.

Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-controlled trial of three dose levels (300, 600 and 800 mg/day) in a B.I.D. regimen.

Remacemide hydrochloride is a low-affinity, non-competitive NMDA receptor channel blocker under investigation for the treatment of epilepsy. This double-blind, placebo-controlled, multicentre study assessed the safety and efficacy of adjunctive remacemide hydrochloride or placebo, in adult patients with refractory epilepsy who were already taking up to three antiepileptic drugs (including an enzyme-inducer). Patients (n= 262) were randomized to one of three doses of remacemide hydrochloride (300, 600 or 800 mg/day) or placebo, in a B.I.D. regimen, for up to 14 weeks. Plasma concentrations of carbamazepine (CBZ) and phenytoin (PHT) were controlled throughout. Patients recorded their seizures on a diary card. There was an increase in the percentage of responders (defined as a reduction in seizure frequency from baseline > or = 50 %), from 15 % (9/60) with placebo, to 30 % (18/60) in the 800 mg/day group. A pairwise comparison between remacemide hydrochloride 800 mg/day and placebo was statistically significant (P = 0.049). Most reported adverse events (mainly CNS and gastrointestinal) were mild or moderate in severity and dose-dependent. Adjunctive remacemide hydrochloride treatment was associated with a higher, dose-related responder rate compared with placebo. The difference reached significance at the highest dose tested (800 mg/day). Remacemide hydrochloride was well tolerated.

Regional access to acute ischemic stroke intervention.

BACKGROUND AND PURPOSE: Benefit-risk ratios from recombinant tissue plasminogen activator (rtPA) therapy for acute ischemic stroke demonstrate lack of efficacy if intravenous administration is commenced beyond 3 hours of symptom onset. We undertook to enhance therapeutic effectiveness by ensuring equitable access to rtPA for patients affected by acute ischemic stroke within a 20 000 km(2) population referral base served by a tertiary facility. METHODS: Representatives of all provider groups involved in emergency medical services developed a Regional Acute Stroke Protocol (RASP), a coordinated regional system response by dispatch personnel, paramedics, physicians, community service providers, emergency and inpatient staff in community hospitals, and the tertiary facility acute stroke team. RESULTS: As of July 26, 1999, all ambulance services in Southeastern Ontario began bypassing the closest hospital to deliver patients meeting the criteria for the RASP to the Kingston General Hospital. At 12 months, approximately 403 ischemic strokes have occurred in the region, the RASP has been activated 191 times, and 42 patients have received rtPA. CONCLUSIONS: We conclude that (1) acute stroke patients in Southeastern Ontario have improved access to interventions for stroke care; (2) geography of the region is not a barrier to access to interventions for patients with acute stroke; and (3) acute ischemic stroke patients treated with rtPA account for 5% of all acute strokes and 10% of all ischemic strokes in this region.

Recent advances in research on radiofrequency fields and health.

Since the Royal Society of Canada report on potential health risks of radiofrequency (RF) fields from wireless telecommunications in the spring of 1999, there have been several newly published reports on risks associated with the use of mobile phones. This article provides a summary of scientific research on the potential health effects of radiofrequency fields that has been reported since the original Royal Society report was published. This update also discusses several earlier results not included in the original report.

The interaction of neurotrophins with the p75NTR common neurotrophin receptor: a comprehensive molecular modeling study.

Neurotrophins are a family of proteins with pleiotropic effects mediated by two distinct receptor types, namely the Trk family, and the common neurotrophin receptor p75NTR. Binding of four mammalian neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), to p75NTR is studied by molecular modeling based on X-ray structures of the neurotrophins and the extracellular domain of p55TNFR, a homologue of p75NTR. The model of neurotrophin/receptor interactions suggests that the receptor binding domains of neurotrophins (loops I and IV) are geometrically and electrostatically complementary to a putative binding site of p75NTR, formed by the second and part of the third cysteine-rich domains. Geometric match of neurotrophin/receptor binding domains in the complexes, as characterized by shape complementarity statistic Sc, is comparable to known protein/protein complexes. All charged residues within the loops I and IV of the neurotrophins, previously determined as being critical for p75NTR binding, directly participate in receptor binding in the framework of the model. Principal residues of the binding site of p75NTR include Asp47, Lys56, Asp75, Asp76, Asp88, and Glu89. The additional involvement of Arg80 and Glu53 is specific for NGF and BDNF, respectively, and Glu73 participates in binding with NT-3 and NT-4/5. Neurotrophins are likely to induce similar, but not identical, conformational changes within the p75NTR binding site.

A computational quantitative structure-activity relationship study of carbamate anticonvulsants using quantum pharmacological methods.

A pattern recognition quantitative structure-activity relationship (QSAR) study has been performed to determine the molecular features of carbamate anticonvulsants which influence biological activity. Although carbamates, such as felbamate, have been used to treat epilepsy, their mechanisms of efficacy and toxicity are not completely understood. Quantum and classical mechanics calculations have been exploited to describe 46 carbamate drugs. Employing a principal component analysis and multiple linear regression calculations, five crucial structural descriptors were identified which directly relate to the bioactivity of the carbamate family. With the resulting mathematical model, the biological activity of carbamate analogues can be predicted with 85-90% accuracy.

Reciprocal modulation of TrkA and p75NTR affinity states is mediated by direct receptor interactions.

Equilibrium binding of 125I-nerve growth factor (125I-NGF) to cells coexpressing the tyrosine kinase receptor A (TrkA) and common neurotrophin receptor (p75NTR), cells coexpressing both receptors where p75NTR is occupied, and cells expressing only p75NTR, revealed reciprocal modulation of receptor affinity states. Analysis of receptor affinity states in PC12 cells, PC12 cells in the presence of brain-derived neurotrophic factor (BDNF), and PC12nnr5 cells suggested that liganded and unliganded p75NTR induce a higher affinity state within TrkA, while TrkA induces a lower affinity state within p75NTR. These data are consistent with receptor allosterism, and prompted a search for TrkA/p75NTR complexes in the absence of NGF. Chemical crosslinking studies revealed high molecular weight receptor complexes that specifically bound 125I-NGF, and were immunoprecipitated by antibodies to both receptors. The heteroreceptor complex of TrkA and p75NTR alters conformation and/or dissociates in the presence of NGF, as indicated by the ability of low concentrations of NGF to prevent heteroreceptor crosslinking. These data suggest a new model of receptor interaction, whereby structural changes within a heteroreceptor complex are induced by ligand binding.

Molecular pathogenesis of alcohol withdrawal seizures: the modified lipid-protein interaction mechanism.

The phrase alcohol withdrawal seizures (AWS) refers to seizures that result from the withdrawal of alcohol after a period of chronic alcohol administration. A mechanism of AWS is postulated, namely the modified lipid-protein interaction (MLPI) mechanism. This hypothesis is based upon an evaluation of the mechanisms of membrane fluidity, calcium channels, gamma-aminobutyric acid (GABA) and glutamate in the molecular pathogenesis of AWS. The mechanism hypothesizes that acute ethanol treatment alters the neuronal membrane lipids which then perturbs protein events, such as affecting the GABAA receptors, NMDA receptors and voltage-dependent Ca2+ channels synergistically or in combination. Subsequent adaptations in these systems occur after prolonged administration of ethanol. A sudden withdrawal of ethanol then leads to hyperexcitability which results in AWS.

Zinc alters conformation and inhibits biological activities of nerve growth factor and related neurotrophins.

A role for Zn2+ in a variety of neurological conditions such as stroke, epilepsy and Alzheimer's disease has been postulated. In many instances, susceptible neurons are located in regions rich in Zn2+ where nerve growth factor (NGF) levels rise as a result of insult. Although the interaction of Zn2+ with this neurotrophin has previously been suggested, the direct actions of the ion on NGF function have not been explored. Molecular modeling studies predict that Zn2+ binding to NGF will induce structural changes within domains of this neurotrophin that participate in the recognition of TrkA and p75NTR. We demonstrate here that Zn2+ alters the conformation of NGF, rendering it unable to bind to p75NTR or TrkA receptors or to activate signal transduction pathways and biological outcomes normally induced by this protein. Similar actions of Zn2+ are also observed with other members of the NGF family, suggesting a modulatory role for this metal ion in neurotrophin function.

Characterization of a distinctive motif of the low molecular weight neurotrophin receptor that modulates NGF-mediated neurite growth.

The cytoplasmic region of the common neurotrophin receptor (p75(NGFR)) (rat, human, chick) contains a putative membrane-associating domain implicated in intracellular signalling. A peptide (R3) identical to this domain (p75(NGFR) 367-379) and various analogues of this peptide displayed circular dichroism spectra in aqueous and non-polar environments identical to the amphiphilic tetradecapeptide mastoparan (MP) and were internalized by PC12 rat pheochromocytoma cells. The R3 peptide enhanced neurite growth in PC12 cells, embryo chick primary sensory neurons and fetal rat primary sensory neurons in vitro in the presence of sub-saturating concentrations of NGF. Peptide analogues of R3 not faithful to the distance and angular relationships of ionic groups and the putative amphiphilic structure of p75(NGFR)367-379 displayed reduced potency to enhance p75(NGFR) (PC12(nnr5)), had no influence on neurite growth. The R3 peptide had no effects on cell survival, cell binding or uptake of [125]NGF, affinity cross-linking of [125]NGF to p75(NGFR) or trkA monomers and homodimers, of NGF-mediated trkA monomer tyrosine phosphorylation. The studies implicate a role for a highly conserved motif of p75(NGFR) in the downstream modulation of NGF-mediated neurite growth.

Dose-related potent brain stimulation by the neuropeptide endothelin-1 after intraventricular administration in conscious rats.

Injection of the neuropeptide, endothelin-1 (ET, range of 3-9 pmol), into a lateral ventricle (ICV) of rats produced barrel rolling and other convulsions including ataxia, forelimb and facial clonus, nystagmus, and tonic extension of the tail and hindlimbs. Using the quantitative autoradiographic [14C]deoxyglucose method, we resolved the focal hypermetabolic correlates of the convulsive activity in numerous brain regions. The present study tested whether the effects of ET were dose dependent by assessing 13 behavioral, 9 physiological, and brain metabolic responses in six individual structures of rats treated separately with ICV ET in doses between 1.5 and 18 pmol. Barrel-rolling convulsions, having a threshold for onset at 3 pmol, displayed increased incidence and severity, and a shorter latency to onset, with the higher ET doses. Within 10-20 min, ET evoked dose-dependent increases in mean arterial pressure and plasma glucose levels, and a significant reduction in arterial PCO2. Among brain structures, the periventricular caudate nucleus near the injection site had an elevated rate of glucose metabolism (+60%) at a 3 pmol threshold. The substantia nigra pars reticulata, medial terminal nucleus of the accessory optic tract, rostral lamella of the inferior olivary nucleus, cerebellar paramedian lobule, and cerebellar copula pyramis, all of which have moderate to dense populations of ET-1 receptors and are related by anatomical connections, displayed significant metabolic stimulation by 9 pmol ET (+47 to +122%). The behavioral, physiological, and focal hypermetabolic effects of the central ET appear to be time coordinated, interrelated, and dose dependent. Identification of the threshold dose for central actions of ET at 3 pmol ICV reveals this peptide as the most potent neuroactive substance yet described in vivo.

Rational design of anticonvulsants: a quantum pharmacologic study of the ion channel-modulating FMRFamide tetrapeptide as an endogenous anticonvulsant.

We applied the computational techniques of quantum pharmacology to examine molecular conformations (shapes and geometries) of the tetrapeptide FMR-Famide (L-Phe-L-Met-L-Arg-L-Phe-NH2), determining the geometric features necessary for anticonvulsant activity. The rigorous tiered hierarchical approach used molecular mechanics, molecular dynamics, and semiempirical quantum mechanics calculational methods. Low-energy conformations showed pertinent conformational information to be considered in the rational design of novel anticonvulsants. The FMRFamide peptide backbone assumes a bent but primary planar geometry. Distinct polar and nonpolar regions are created as the two Phe residues occupy one "face" of the bent conformation, while the Met and Arg residues occupy the opposite face. The aromatic rings point away from each other along the backbone, and this separation is consistent among the low-energy conformations at approximately 11-12 A. The Met side chain interacts with neither the peptide backbone nor the side chains of other residues. Molecular mechanics and semiempirical quantum mechanics calculations predict limited variation in the orientation of the Arg side chain.